Osteoporosis International

, Volume 27, Issue 4, pp 1281–1386

The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations

Authors

  • C. M. Weaver
    • Department of Nutritional Sciences, Women’s Global Health InstitutePurdue University
  • C. M. Gordon
    • Division of Adolescent and Transition MedicineCincinnati Children’s Hospital
    • Department of PediatricsUniversity of Cincinnati College of Medicine
  • K. F. Janz
    • Departments of Health and Human Physiology and EpidemiologyUniversity of Iowa
  • H. J. Kalkwarf
    • Division of Gastroenterology, Hepatology and NutritionCincinnati Children’s Hospital Medical Center
  • J. M. Lappe
    • Schools of Nursing and MedicineCreighton University
  • R. Lewis
    • Department of Foods and NutritionUniversity of Georgia
  • M. O’Karma
    • The Children’s Hospital of Philadelphia Research Institute
    • Department of Nutrition and Food StudiesGeorge Mason University
    • National Osteoporosis Foundation
    • National Osteoporosis Foundation
  • B. S. Zemel
    • University of Pennsylvania Perelman School of Medicine
    • Division of Gastroenterology, Hepatology, and NutritionThe Children’s Hospital of Philadelphia
Open AccessPosition Paper

DOI: 10.1007/s00198-015-3440-3

Cite this article as:
Weaver, C.M., Gordon, C.M., Janz, K.F. et al. Osteoporos Int (2016) 27: 1281. doi:10.1007/s00198-015-3440-3

Abstract

Lifestyle choices influence 20–40 % of adult peak bone mass. Therefore, optimization of lifestyle factors known to influence peak bone mass and strength is an important strategy aimed at reducing risk of osteoporosis or low bone mass later in life. The National Osteoporosis Foundation has issued this scientific statement to provide evidence-based guidance and a national implementation strategy for the purpose of helping individuals achieve maximal peak bone mass early in life. In this scientific statement, we (1) report the results of an evidence-based review of the literature since 2000 on factors that influence achieving the full genetic potential for skeletal mass; (2) recommend lifestyle choices that promote maximal bone health throughout the lifespan; (3) outline a research agenda to address current gaps; and (4) identify implementation strategies. We conducted a systematic review of the role of individual nutrients, food patterns, special issues, contraceptives, and physical activity on bone mass and strength development in youth. An evidence grading system was applied to describe the strength of available evidence on these individual modifiable lifestyle factors that may (or may not) influence the development of peak bone mass (Table 1). A summary of the grades for each of these factors is given below. We describe the underpinning biology of these relationships as well as other factors for which a systematic review approach was not possible. Articles published since 2000, all of which followed the report by Heaney et al. [1] published in that year, were considered for this scientific statement. This current review is a systematic update of the previous review conducted by the National Osteoporosis Foundation [1].

Lifestyle Factor

Grade

Macronutrients

 Fat

D

 Protein

C

Micronutrients

 Calcium

A

 Vitamin D

B

 Micronutrients other than calcium and vitamin D

D

Food Patterns

 Dairy

B

 Fiber

C

 Fruits and vegetables

C

 Detriment of cola and caffeinated beverages

C

Infant Nutrition

 Duration of breastfeeding

D

 Breastfeeding versus formula feeding

D

 Enriched formula feeding

D

Adolescent Special Issues

 Detriment of oral contraceptives

D

 Detriment of DMPA injections

B

 Detriment of alcohol

D

 Detriment of smoking

C

Physical Activity and Exercise

 Effect on bone mass and density

A

 Effect on bone structural outcomes

B

Considering the evidence-based literature review, we recommend lifestyle choices that promote maximal bone health from childhood through young to late adolescence and outline a research agenda to address current gaps in knowledge. The best evidence (grade A) is available for positive effects of calcium intake and physical activity, especially during the late childhood and peripubertal years—a critical period for bone accretion. Good evidence is also available for a role of vitamin D and dairy consumption and a detriment of DMPA injections. However, more rigorous trial data on many other lifestyle choices are needed and this need is outlined in our research agenda. Implementation strategies for lifestyle modifications to promote development of peak bone mass and strength within one’s genetic potential require a multisectored (i.e., family, schools, healthcare systems) approach.

Keywords

Bone mineral content Diet Nutrition Peak bone mass Physical activity

Abbreviations

%ucOC

Percentage of undercarboxylated osteocalcin

95 % CI

95 % Confidence interval

aBMD

Areal bone mineral density

BMC

Bone mineral content

CDC

US Centers for Disease Control and Prevention

CSA

Cross-sectional area

CSMI

Cross-sectional moment of inertia

CT

Computed tomography

DEQAS

Vitamin D External Quality Assessment Scheme

DMPA

Depot medroxyprogesterone acetate

DONALD

Dortmund Nutritional and Anthropometric Longitudinally Designed

DXA

Dual-energy x-ray absorptiometry

HHS

US Department of Health and Human Services

HRpQCT

High-resolution peripheral quantitative computed tomography

HSA

Hip structural analysis

IGF

Insulin-like growth factor

IOM

Institute of Medicine

NHANES

National Health and Nutrition Examination Survey

OC

Oral contraceptive

OR

Odds ratio

pQCT

Peripheral quantitative computed tomography

PRAL

Potential renal acid load

QCT

Quantitative computed tomography

RCT

Randomized controlled trial

RDA

Recommended dietary allowance

SSI

Stress–strain index

UHT

Ultra-heat-treated

uN

Urinary nitrogen

USDA

US Department of Agriculture

vBMD

Volumetric bone mineral density

Introduction

Bone accretion

During growth and development, skeletal growth proceeds through the coordinated action of bone deposition and resorption to allow bones to expand (periosteal apposition of cortical bone) and lengthen (endochondral ossification) into their adult form [2]. This process of bone modeling begins during fetal growth and continues until epiphyseal fusion, usually by the end of the second decade of life [1]. Bone modeling is sensitive to mechanical loading, emphasizing the importance of physical activity throughout growth [2]. Some skeletal characteristics, such as cortical density and structural strength, determined by bone dimensions and thickness, continue to increase after epiphyseal fusion and into the third decade of life. Quantitatively, the amount of bone mineral acquired from birth to adulthood follows distinct age- and sex-specific patterns (Fig. 1). Bone mass is acquired relatively slowly throughout childhood. With the onset of puberty and the adolescent growth spurt in height, bone mineral accretion is rapid, reaching a peak shortly after peak height gain (Fig. 2). For total body bone mineral, the peak bone mineral accretion rate occurs at 12.5 ± 0.90 years in girls and 14.1 ± 0.95 years in boys of European ancestry [3]. During the 4 years surrounding the peak in bone accretion, 39 % of total body bone mineral is acquired; by 4 years following the peak, 95 % of adult bone mass has been achieved [4]. Within a population, the distribution of bone mass becomes more variable, in part due to differences in height and other skeletal dimensions as adult size is attained, the timing and magnitude of peak bone mineral accrual, the cessation of bone accretion, and lifestyle factors. This period of rapid accretion may be a time of both opportunity and vulnerability for optimizing peak bone mass.
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Fig. 1

Bone mass across the lifespan with optimal and suboptimal lifestyle choices

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Fig. 2

Peak BMC gain and peak height velocity in boys and girls from longitudinal DXA analysis. Adapted from Bailey et al. [3]

Changes in the structure (size and shape) and composition (amount of cartilage, cortical, and trabecular bone) of bone also occur with progression through puberty and thereby influence bone strength (Fig. 3). Cortical bone is the compact bone that forms the outer shell protecting bone marrow and trabecular bone. Trabecular bone is composed of rods and plates in a sponge-like structure, adding to the structural strength of bone. Cortical and trabecular bone differ in their responsiveness to disease effects, medications, muscle-loading and impact-loading physical activity, and hormonal changes. The relative importance of cortical versus trabecular bone in optimizing peak bone mass and strength and in minimizing fracture risk has not been firmly established in either childhood or adulthood. Distinct increases in trabecular bone of the spine and long bones occur between sexual maturity stages 3 and 4 [57]. The density of cortical bone is lower among children and adolescents than among adults, and it may even go through a transient period of increased porosity, particularly for boys [7, 8]. The density of cortical bone increases more rapidly as epiphyseal fusion occurs and continues into the third decade of life [9]. Both the inner and outer dimensions of long bones increase as growth proceeds, providing greater structural strength. The accumulation of bone mineral and changes in density and structural strength of bone may also continue into the third decade of life, depending on the bone compartment and skeletal site under consideration (Fig. 1).
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Fig. 3

Changes in structural composition of bone throughout the lifespan

Definition of peak bone mass

Peak bone mass is generally thought of as the amount of bone gained by the time a stable skeletal state has been attained during young adulthood. The concept of peak bone mass more broadly captures peak bone strength, which is characterized by mass, density, microarchitecture, microrepair mechanisms, and the geometric properties that provide structural strength.

There are several nuances to this concept that deserve recognition. The concept of peak bone mass is different when applied to an individual as opposed to a population. For an individual, peak bone mass may refer to the maximum amount of bone accrued during young adulthood. Alternatively, the concept of peak bone mass may refer to an individual’s maximal or genetic potential for bone strength (i.e., bone mineral content (BMC), areal bone mineral density (aBMD), or other measures of bone strength). At the population level, peak bone mass is attained when age-related changes in a bone outcome are no longer positive and have attained a plateau or maximum value [10].

Importance of peak bone mass

Fracture

Optimizing bone accrual during growth may be of greatest significance in preventing current or future fractures, as measures of bone mass, density, and structural strength are associated with fracture in children and adults [1113]. The frequency of fractures is higher among children compared to young and middle-aged adults [14], reflecting the vulnerability of the growing skeleton prior to peak bone mass. Among healthy children, as many as one half of boys and one third of girls will sustain a fracture by age 18 years, with one fifth sustaining two or more fractures [15, 16]. Children who sustain a fracture before age 4 years are especially vulnerable to a subsequent fracture [17]. Thirty to 50 % of childhood fractures involve the forearm [14, 15, 1820] and result from falls to an outstretched arm. There is a positive relationship between fracture frequency and level of physical activity due to the increased risk of falls during physical activity [21]. Thus, although physical activity is critical for bone modeling, children with higher levels of physical activity are more likely to have fractures [3, 2228].

There is a developmental period during the rapid growth of late childhood and early adolescence when the skeleton is particularly vulnerable to fracture (Fig. 4) [29]. Recently, high-resolution peripheral quantitative computed tomography (HRpQCT) has been used to explain the microarchitectural basis for the observation of increased fracture frequency among young adolescents [7]. The combination of thinner cortical bone, lower total volumetric bone mineral density (vBMD), and increased cortical porosity, particularly in boys, suggests that linear bone growth outpaces bone mineralization, resulting in transient bone fragility.
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Fig. 4

Incidence of fractures of the distal forearm from birth through young adulthood. Adapted from Khosla et al. [29]

Understanding factors that affect bone strength early in life is important because low bone strength is associated with fracture risk in later life, independent of fall incidence and physical activity [30]. Childhood bone mass is predictive of fracture risk during childhood, with an 89 % increase in fracture risk per SD decrease in size-adjusted bone mass [31]. Moreover, among children who experience similar forearm injuries, those with greater bone density have been shown to be less likely to fracture [32]. Preterm children have low bone mass during late childhood [33], and birth weight is related to bone mass in later adult life (age ≥60 years) [34].

Recent work using HRpQCT suggests that microarchitectural changes underlie increased bone fragility in children who sustain a distal forearm fracture following mild trauma compared to nonfracture controls [35]. Differences such as cortical thinning are seen at both the distal radius and distal tibia in children presenting with a forearm fracture in which the degree of trauma is mild (e.g., fall from standing height), but not in those where the trauma is moderate (e.g., fall while riding a bicycle). Further analysis, including microfinite element analysis of HRpQCT data, showed that the mild trauma distal forearm fracture cases had reduced bone strength (i.e., failure load) compared to children without a fracture history. Moderate trauma is sufficient to break healthy bones that are not otherwise inherently at increased risk of fracture. Clark et al. [21] have shown that, irrespective of bone mass, fracture risk rises as the amount of vigorous activity increases. Additional studies have shown that a forearm fracture in a child is associated with lower areal and vBMD, cortical area, and bone strength using peripheral quantitative computed tomography (pQCT) and dual-energy x-ray absorptiometry (DXA) [11]. Cohort studies in the USA and South Africa show that boys and girls of European descent have a greater fracture risk than children of African descent [36, 37], a finding that parallels patterns of osteoporosis and hip fracture in elderly adults [38, 39].

In childhood and adolescence, stress fractures exhibit a different pattern from typical long bone fractures. The lifetime prevalence of stress fracture among the general population is below 4 % [40], and stress fractures are more common among women than among men [41]. In studies of military populations, where stress fractures are most common, the rate ratio may be 10:1 [4247], with up to 20 % of female recruits in basic training reported to have sustained a stress fracture [4448] (note: military studies include young adults aged ≥18 years). Risk factors for stress fractures among recruits include low quantitative ultrasound values, smoking, history of being sedentary [49], and volume of training [40, 44, 50]. White race and a reported family history of osteoporosis or osteopenia may also represent significant risk factors [51, 52].

Tracking

Tracking refers to the stability of a trait over time. The degree to which indicators of bone strength track from childhood to peak bone mass and beyond is of paramount importance to optimizing peak bone mass for lifelong skeletal health. If bone “status” (i.e., bone mass, density, or structural strength relative to one’s peers of the same age and sex) at any given time point were not associated with its future status, then concerns would only be relevant to prevention of childhood fractures, not osteoporosis later in life. In fact, numerous prospective studies have demonstrated that measures of bone density track quite strongly from childhood through adolescence, with tracking correlations ranging from 0.5 to 0.9 depending on the skeletal site, trait, and duration of follow-up, with most estimates falling in the range of 0.6 to 0.7 [32, 5357]. Tracking correlations decline during adolescence and then rebound, a phenomenon that is likely due to variability in the timing of puberty and peak bone accrual. Adjustment for height status largely eliminates this transient decline in tracking [32, 57]. One study of children aged 8–16 years (n = 183) examined the factors associated with tracking deviation. Positive deviation (i.e., improvement in spine and hip aBMD tertile) was associated with having been breast-fed, gains in lean mass, aerobic fitness, and sports participation. Gains in adiposity were associated with negative deviations in tracking [55]. These findings provide strong evidence that bone status during childhood, when peak bone mass is accumulated, is indicative of bone status in young adulthood. However, the fact that tracking correlations are far from unity suggests that lifestyle factors can alter bone status in both positive and negative directions.

Timing of peak bone mass

If the magnitude of peak bone mass attained in young adulthood is an important predictor of osteoporosis later in life, then the timing of peak bone mass is also important because it defines the lifecycle phase during which peak bone mass can be optimized. Regardless of whether one is referring to peak bone mass of an individual or a population, the timing of peak bone mass varies by skeletal site. Estimates based on longitudinal studies are preferred over cross-sectional population studies for identifying the timing of peak bone mass because they capture the process of bone accretion. For example, using longitudinal observations and the plateau method, the Canadian Multicentre Osteoporosis Study identified the ages of peak bone mass for women; for lumbar spine aBMD, it was between the ages of 33 and 40 years, whereas ages of peak bone mass for total hip BMD were between 16 and 19 years [10].

Estimates of the timing of peak bone mass further depend on the parameters of bone (i.e., mass, density, geometry, microarchitecture) under consideration. Using quantitative computed tomography (QCT), Riggs et al. [9] showed that women aged 20–29 years (n = 15) were losing trabecular bone at a rate of 1–1.75 % per year at the distal radius and lumbar spine, but they were gaining cortical bone at a rate of 0.25 % per year in the tibia. By contrast, men (n = 8) in this age range did not exhibit significant changes in these outcomes [9]. Cross-sectional data on >1000 men, aged 18.0–20.9 years, in the Gothenburg Osteoporosis and Obesity Determinants Study suggest that aBMD of the lumbar spine, femoral neck, and total body did not increase with age, but positive age-related associations were observed for aBMD of the radius, cortical, and trabecular vBMD, and cortical thickness of the radius and tibia as measured by DXA and pQCT [58]. The positive association with cortical thickness was attributed to a smaller medullary diameter, and not to periosteal expansion.

Because the timing of peak bone mass and strength varies by skeletal site and bone compartment, it is important to establish and retain behaviors that contribute to skeletal health, including region-specific changes (e.g., hip, spine). Moreover, until the lifelong importance of peak bone mass is fully understood [52], it is prudent to assume that these behaviors are needed to sustain skeletal health through the life cycle.

Methods for measuring peak bone mass

Insights into the development of peak bone mass are based on studies using DXA and QCT. These measurement techniques characterize different aspects of bone strength; DXA primarily measures bone mass (or bone mineral content [BMC]) and aBMD, which are integrated measures of cortical and trabecular bone.QCT can provide distinct measures of cortical and trabecular vBMD, bone geometry (e.g., periosteal and endosteal circumference and structural strength) and, in some cases, microarchitecture.

Dual-energy x-ray absorptiometry

The vast majority of studies on peak bone mass have utilized DXA, a low-dose x-ray technology that measures the attenuation of x-ray beams as they pass through tissues of varying density. DXA is a two-dimensional imaging technique that uses a planar image to estimate bone area. This technology is ideal for use in children because it is rapid, safe, widely available, and precise, with effective dose ranges from 0.03 to 15.2 μSV [59]. Because of the smaller bone size and lower density of bones in growing children, special software has been developed by the major DXA manufacturers to measure aBMD and BMC in children. DXA does not measure vBMD but instead provides what is referred to as aBMD. Since DXA does not capture the depth of bone, it systematically underestimates vBMD in children with poor growth. For this reason, adjusting DXA measures of BMC and aBMD for stature is recommended [60, 61]. This adjustment serves to distinguish between gains in BMC or aBMD that are independent of gains in stature. In addition, cortical and trabecular bone are superimposed in the DXA image, thus providing a composite estimate of the mass and density of these two bone compartments.

Lack of agreement exists regarding whether BMC or aBMD should be the outcome of interest in bone accretion studies in children. BMC is determined, in large part, by bone size because it reflects the mineral content of one region or the entire skeleton; aBMD only partly adjusts for bone size and a size-related artifact remains [61]. Using spine QCT measures as a reference method, Wren and colleagues have shown that DXA BMC was a better measure to use in children (ages 6–17 years), particularly in prepubertal children, than aBMD [62]. We agree with those who argue that, to account for size in studies of children, it is best to use BMC adjusted for bone area [63, 64], height-for-age Z-score [61], lean mass [65, 66], or other combinations of anthropometric variables [64, 67, 68] or to use calculated bone mineral apparent density [69], because these provide a more accurate reflection of a child’s bone health.

DXA measures have also been used to estimate structural strength of the proximal femur using the hip structural analysis (HSA) algorithm [70]. HSA estimates subperiosteal width, cross-sectional area (CSA), and section modulus in the narrow neck, intertrochanteric region, and shaft of the proximal femur. These outcomes are associated with treatment effects in adults as well as disease and exercise effects in children and adolescents [7173].

Peripheral quantitative computed tomography

DXA only partly describes bone strength, which is the broader concern for understanding peak bone mass. Other modalities are used to more directly measure vBMD, microarchitecture, and geometry. Many of these characteristics can easily be measured in children with relatively low radiation exposure (0.59–1.09 mSv) [74]. QCT and pQCT are three-dimensional techniques that also use attenuation of x-ray beams to construct bone images. Cortical and trabecular bone compartments vary in density, and the differential attenuation of x-ray beams in the three-dimensional reconstruction allows for separate determination of trabecular and cortical vBMD, as well as numerous other measures of bone geometry (e.g., total bone area, periosteal and endosteal circumference) and structural strength in compression, bending, and torsion (e.g., section modulus, strain–strength index). Full-sized computed tomography (CT) scanners are used to measure the spine and other sites, and dedicated pQCT scanners measure the radius, tibia, or distal femur. Newer HRpQCT scanners achieve sufficient resolution for building microstructural finite element models of whole bone failure load, a surrogate measure of bone’s resistance to fracture, as well as cortical porosity, and trabecular plate and rod microstructure [74].

Mechanical loading

Physical activity comprises any body movement produced by muscle contraction resulting in energy expenditure above a resting level [75]. Exercise is a more restrictive concept and is defined by planned, organized, and repetitive physical activity aimed at maintaining or enhancing one or more components of physical fitness or a specific health outcome, such as bone strength [68]. The randomized controlled trials (RCTs) reviewed in this scientific statement used targeted exercise as an intervention to improve bone strength, whereas most of the longitudinal studies measured physical activity, including active transportation and activities of everyday life [76]. Physical activity has long been regarded as behavior likely to influence bone health [77, 78]. Epidemiological and clinical trial research dating back more than two decades confirms the positive impact of regular physical activity on bone [3, 27, 7881]. However, we are only beginning to quantify the specific dimensions, dose, and timing of physical activity needed for maximal bone strength. What is known, primarily from animal studies, is that increased mechanical loads placed on bone through both impact and muscle forces cause deformation (strains) of whole bone [82, 83]. These strains activate mechanosensitive cells (i.e., osteocytes), embedded within the bone, which signal molecules to activate osteoblasts and osteoclasts. The signaling begins the process of bone adaptation to changes in physical activity, as well as other mechanical loads (e.g., an increase in body weight). To initiate an osteogenic response, bone must be subjected to a strain magnitude that surpasses a threshold determined by the habitual strain range in the predominant loading direction. The threshold varies between individuals (and also bone sites) according to physical activity habits and other factors (e.g., maturity status). Thus, children and adolescents may respond differently to similar mechanical loading conditions. Inactive children may respond to low-impact loading and improve bone mass or structure, while more active children will need a higher mechanical load to promote a skeletal response [84].

The skeleton needs to be strong for load bearing and light for mobility. A manner of minimizing the amount of bone mass needed in a cross-section without decreasing strength is to modify the distribution of bone mass and therefore changing bone structure. Throughout life, but mainly during growth, periosteal apposition increases the diameter of long bones and endocortical resorption enlarges the marrow cavity. Cortical thickness is determined by the net changes occurring at the periosteal and endosteal surface of bone. However, even without an increase in cortical thickness, the displacement of the cortex increases bending strength because resistance to bending is proportional to the fourth power of the distance from the neutral axis. In addition to the independent effect of physical activity on mass and density, increased mechanical loading via physical activity may influence structural changes in bone to increase strength in response to the new loading condition [25, 73, 85].

Bone is most responsive to physical activities that are dynamic, moderate to high in load magnitude, short in load duration, odd or nonrepetitive in load direction, and applied quickly [84]. The load magnitude is produced by impact with the ground (e.g., tumbling or jumping), impact with an object (racquet sports), or muscle power moves such as the lift phase in jumping and vaulting. On the other hand, due to desensitization of the osteocytes, static loads and repetitive low-magnitude loads are not osteogenic [8688]. Although physical activity is a modifiable factor that contributes to peak bone mass and strength, our understanding of how to quantify the dimensions of physical activity that are osteogenic (including frequency, intensity, time, and type) is incomplete.

Body composition

It is widely recognized that lean body mass is among the strongest correlates of bone mass, density, and structural strength during childhood [8992]. During adolescence, the peak in total body lean mass accretion occurs just prior to peak bone mineral accretion [2, 93], although at specific sites, peak increases in lean mass and bone strength may be coordinated [94]. In the latter phase of the adolescent growth spurt, following the peak, continued gains in lean mass are strong predictors of increases in BMC [95].

A major challenge in understanding the relationship between lean mass and bone is that both lean mass and bone mass have a strong heritable component. A study of young adult twins (aged 23–31 years) found that additive genetic factors accounted for 87 % of the variation in total body BMD, 81 % of the variation in lean mass, and 69–88 % of the covariance between lean mass and BMD depending on the skeletal site. Population differences also provide evidence of genetic determinants of lean and bone mass. Cardel et al. [96] compared groups of African or European ancestry (n = 301, aged 7–12 years) using ancestry informative DNA markers and found that a greater amount of African admixture was associated with greater lean mass and BMC after adjusting for socioeconomic status, sex, age, height, race/ethnicity, and pubertal status.

The effect of fat mass on bone mineral accretion and attainment of peak bone mass is far more controversial. Generally, greater body weight increases the effects of weight-bearing activity on bone. As children grow and increase in weight, both lean and fat mass increase. To reduce the likelihood of confounding from the bone loading effects of lean mass, it is important to first account for the effect of lean mass on bone in order to determine the effects of fat mass.

The source of adipose tissue may be important in considering the effects of body composition on bone outcomes. Visceral adipose tissue has different metabolic effects compared to subcutaneous fat, and it may be deleterious to bone by reducing bone quality. Adipose infiltrations of muscle and bone marrow associated with excess adiposity also have adverse effects on bone. Muscle density measured by pQCT is lower when the fat content within muscle is increased.

Nonmodifiable factors

Genetics

An estimated 60–80 % of the variability in bone mass and osteoporosis risk is explained by heritable factors. aBMD is lower among daughters of women with osteoporosis [97] and in men and women with first-degree relatives who have osteoporosis [98]. The familial resemblance of BMC is expressed prior to puberty [99, 100]. Genome-wide association studies have identified more than 70 loci associated with adult bone density or fractures [101, 102]. However, only a few such studies have been conducted in children [1, 103106]. Twin studies also suggest that genetic predisposition determines up to 80 % of peak bone mass; the remaining 20 % is modulated by environmental factors and sex hormone levels during puberty [107].

Population ancestry

In North America, ethnic differences in vBMD and aBMD have been reported in children [5, 108, 109]. Among individuals aged 9–25 years, aBMD was consistently greater at all sites for African Americans compared to other groups, whereas Caucasians had greater values than Asians and Hispanics. In studies comparing children of Asian, European, and Hispanic ancestry, group differences in BMC were attributable to differences in bone size [110112]. Ethnic differences in the rate of BMD gain have also been observed [109]. Differences between Caucasians, Asians, and Hispanics are smaller than between blacks and other groups; thus, pediatric reference ranges for BMC and aBMD are presented for African Americans and non-African Americans, and the International Society for Clinical Densitometry recommends using race-specific reference ranges in childhood because they reflect genetic potential for bone accretion [60, 111]. Studies using QCT provide insights into the population ancestry differences in DXA measures by describing cortical bone dimensions and trabecular density [5, 113115]. As noted earlier, trabecular density increases during puberty. The magnitude of the pubertal increase in trabecular density is greater in African-American individuals than in Caucasians, and African-American children have greater total femoral bone in cross-sectional analyses [5, 6, 115].

Sex

Among children and adolescents, males have greater BMC and aBMD than females. These differences become more pronounced with the onset and progression through puberty or at the ages that correspond to these maturational changes [108, 109, 116118]. The exact age at which these differences emerge is unclear. Earlier studies of infants (aged ≤12 months) did not find sex differences in total body BMD [119, 120] or spine BMC and aBMD [121, 122]; however, males (aged 1–18 months) had greater total body BMC than females [123]. A recent study of infants and toddlers aged 1–36 months confirmed the absence of sex differences in aBMD in very young children but found greater BMC in males than in females. Sex differences in the body size of infants and toddlers may account for BMC differences and the absence of aBMD differences. By about 5 years of age, girls have lower values for spine and hip aBMD than boys, a finding that persists when adjusted for age, height, and weight [124].

Studies of bone strength by pQCT reveal a more complex pattern of sex differences. In a study of 665 healthy individuals aged 5–35 years, cortical BMC, periosteal circumference, and section modulus were lower in the 38 % site of the tibia for females compared with males across all stages of puberty. However, cortical vBMD was greater and endosteal circumference was lower in peripubertal and postpubertal females compared to males. These differences were not attributable to differences in muscle mass or bone size [115]. In a 20-month longitudinal study of 128 children across puberty, boys exhibited a 10 % greater increase in total area and cortical area compared to girls, but the increase in the size of the marrow cavity was significantly less for girls than for boys [125]. Further evaluation showed that sex differences in bone strength are primarily due to the 4–6 % greater bone area in boys, which is evident in prepubertal children [126]. HRpQCT studies of the radius show that girls have higher cortical vBMD in midpuberty and postpuberty (9.4 and 7.4 %, respectively) and lower cortical porosity than boys (−118 and −56 %, respectively) [127].

Maturation

Advancement through puberty is associated with increases in BMC and aBMD, as well as cortical and trabecular vBMD. Moreover, several studies suggest that the timing of maturation may affect peak bone mass, particularly in girls. For example, Gilsanz et al. [128] showed that earlier age of pubertal onset was associated with greater DXA BMC and aBMD at skeletal maturity in both boys and girls, independent of prepubertal BMC and aBMD values and duration of puberty. Chevalley et al. [129] found that girls who attained menarche earlier had higher aBMD at multiple skeletal sites prior to, during, and after puberty. A Canadian longitudinal study (depicted in Fig. 2) found that girls who mature early had 3–4 % more total body BMC at age 20 years than girls who matured at an average age. However, maturational effects were only observed at the total body and not at other sites; no maturational timing effects were observed in males [130]. The absence of a maturation timing effect on aBMD and BMC of the lumbar spine, femoral neck, and total body was confirmed in a study of Swedish military recruits in which young men were followed until age 24 years. However, as with girls, later puberty in boys was associated with lower radius aBMD (−4.2 %, by DXA), as well as lower cortical (−0.7 %) and trabecular vBMD (−4.8 %, by pQCT) [131]. The long-term consequences of the effect of pubertal timing on peak bone mass remain to be determined.

Modifiable factors

Diet and physical activity are the primary modifiable factors associated with bone health, although other lifestyle and environmental factors may also be at play. Here, we review these factors and their contribution to peak bone mass.

Although we separately address the contribution of physical activity to peak bone mass and strength, we address nutrient interactions with physical activity and their effects on bone in the respective nutrient discussions. Several narrative and meta-analysis review articles were recently published that also address the strength of the evidence for physical activity and bone development [132137].

Scientific statement aims

In this scientific statement, we (1) report the results of an evidence-based review of the literature since 2000 on factors that influence achieving the full genetic potential for skeletal mass, (2) recommend lifestyle choices that promote maximal bone health throughout the lifespan, (3) outline a research agenda to address current gaps, and (4) identify implementation strategies.

Methods

We performed a comprehensive PubMed (http://www.ncbi.nlm.nih.gov/pubmed) search of the scientific literature for articles published from January 2000 through December 2014. For all search terms, the following search strategy was used: ((((search term[Title/Abstract]) AND bone[Title/Abstract]) AND child*[Title/Abstract]) AND adolescen*[Title/Abstract]) NOT review[Publication Type]. Language, date, and species filters were then applied to the list of search results to eliminate articles not in English, articles published outside the 2000–2014 window, and animal studies. Searches for some of the topics required less restrictive searching in order to yield viable results, such as removal of the terms “child*” and/or “adolescen*,” or by expanding searches to scan terms found in “All Fields” rather than just “Title/Abstract.” MeSH terms were also utilized in some instances. Studies that contained subjects aged ≤21 years were included, except in the alcohol and smoking literature, in which studies that contained subjects aged ≤22 years were accepted due to lack of data in younger populations. Figure 5 represents the flow diagram of the systematic review for peak bone mass that includes search topics and the number of search returns.
https://static-content.springer.com/image/art%3A10.1007%2Fs00198-015-3440-3/MediaObjects/198_2015_3440_Fig5_HTML.gif
Fig. 5

Flow diagram of the systematic review on peak bone mass

To further narrow the search results for the broader topics (e.g., calcium, vitamin D, physical activity), we assigned authors to subcommittees based on their expertise and these subcommittees then reviewed the resultant abstracts. We excluded any articles that were not describing RCTs or observational studies, any studies that did not examine bone outcomes, and any interventions that were <6 months in duration. Studies and drug trials addressing disease states, with the exceptions of eating disorders and obesity, were likewise excluded. The articles that remained after the applications of these criteria were then rated based on the extent of scientific evidence as outlined in Table 1. This evidence grading system has previously been utilized by prominent organizations such as American Society for Nutrition [138] and the American Diabetes Association [139] and is recommended by other experts [140]. The assigned grade reflects the strength of available evidence on individual modifiable lifestyle factors that may (or may not) influence the development of peak bone mass. We assigned evidence grades after we achieved consensus among the writing group.
Table 1

Evidence grading system

Level of evidencea

Description

A: Strong

Clear evidence from at least one large, well-conducted, generalizable RCT that is adequately powered with a large effect size and is free of bias or other concerns

OR

Clear evidence from multiple RCTs or many controlled trials that may have few limitations related to bias,measurement imprecision, inconsistent results, or other concerns

B: Moderate

Evidence obtained from multiple, well-designed, conducted, and controlled prospective cohort studies that have used adequate and relevant measurements and that gave similar results from different populations

OR

Evidence obtained from a well-conducted meta-analysis of prospective cohort studies from different populations

C: Limited

Evidence obtained from multiple prospective cohort studies from diverse populations that have limitations related to bias, measurement imprecision, or inconsistent results or have other concerns

OR

Evidence from only one well-designed prospective study with few limitations

OR

Evidence from multiple well-designed and conducted cross-sectional or case-controlled studies that have very few limitations that could invalidate the results from diverse populations

OR

Evidence from a meta-analysis that has design limitations

D: Inadequate

Evidence from studies that have one or more major methodological flaws or many minor methodological flaws that result in low confidence in the effect estimate

OR

Insufficient data to support a hypothesis

OR

Evidence derived from clinical experience, historical studies (before and after), or uncontrolled descriptive studies or case reports

RCT randomized controlled trial

aRefers to the body of evidence

Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13

Table 2

Fat and bone health in children and adolescents

Macronutrient

Reference

Study description

Population description

Number of subjects

End points

Results

Prospective studies

 Fat

Hogstrom et al. 2007 [141]

The objective of this study was to investigate the role of fatty acids in bone accumulation and the attainment of peak bone mass in young men

Sex: male

Age: 16.7 years at baseline

Race: white

Location: Sweden

Year(s): 1994 (baseline), first follow-up was at a mean of 6 years (age 22 years)

78

Data are shown for the overall group (N = 78)

Total body

Hip

Spine

     

r

P

r

P

r

P

    

Palmitic acid

−0.04

NS

01

NS

0.01

NS

    

Palmitoleic acid

0.04

NS

0.03

NS

0.02

NS

    

Stearic acid

0.07

NS

0.02

NS

0.04

NS

    

Oleic acid

−0.19

NS

−0.10

NS

−0.22

NS

    

Linoleic acid

0.00

NS

−0.06

NS

−0.15

NS

    

Eicosatrienoic acid

−0.09

NS

−0.04

NS

−0.08

NS

    

Arachidonic acid

0.12

NS

0.15

NS

0.25

<0.05

    

Eicosapentaenoic acid

0.04

NS

0.02

NS

0.16

NS

    

Docosapentaenoic acid

0.02

NS

−0.07

NS

0.05

NS

    

DHA

0.10

NS

0.07

NS

0.26

<0.05

    

PUFA

0.14

NS

0.07

NS

0.16

NS

    

MUFA

−0.18

NS

−0.09

NS

−0.21

NS

    

SFA

0.04

NS

0.03

NS

0.05

NS

    

n-6

0.04

NS

0.00

NS

0.07

NS

    

n-3

0.10

NS

0.07

NS

0.26

<0.05

    

n-6:n-3

−0.12

NS

−0.13

NS

−0.26

<0.05

    

Data presented above include Pearson’s correlations between fatty acids measured in the phospholipid fraction for changes in aBMD from 16 to 22 years

Cross-sectional studies

 Fat

Eriksson et al. 2009 [142]

Serum phospholipid fatty acid pattern was studied in relation to bone parameters in healthy children

Sex: male and female

Mean age: 8.2 years

Race: Caucasian

Location: Gothenburg, Sweden

Year(s): not specified

85

Data are shown for the overall group (N = 85)

Total body BMC (g)

     

Correlation (r)

P

    

Palmitic acid (16:0)

0.17

NS

    

Stearic acid (18:0)

−0.15

NS

    

Arachidic acid (20:0)

0.20

NS

    

Nervonic acid (24:1n-9)

0.27

<0.05

    

Linoleic acid (18:2n-6)

−0.17

NS

    

Arachidonic acid (20:4n-6)

0.23

<0.05

    

α-Linolenic acid (18:3n-3)

−0.22

<0.05

    

DHA (22:6n-3)

0.03

NS

    

∑ n-6

−0.07

NS

    

∑ n-3

0.03

NS

    

n-6:n-3

−0.06

NS

    

Data presented above are from Pearson’s correlations

25(OH)D 25-hydroxyvitamin D, aBMD areal bone mineral density, ANCOVA analysis of covariance, BMC bone mineral content, IGF insulin-like growth factor, NS not significant

Table 3

Protein and bone health in children and adolescents

Macronutrient

Reference

Study description

Population description

Number of subjects

End points

Results

RCTs

 Protein

Ballard et al. 2006 [143]

This study investigated whether 6 months of protein supplementation in conjunction with a strength and conditioning training program improves vBMD, bone geometry, and total body BMC.

Sex: male and female

Age: 18–25 years

Race: not specified

Location: South Dakota, USA

Year(s): not specified

68

Data are shown for the protein supplemented group (n = 36)

Mean change, protein group (n = 36)

P

    

4 % site

    

 Total vBMD (mg/cm3)

0.20

NS

    

 Trabecular vBMD (mg/cm3)

−0.50

NS

    

 Total area (cm2)

5.0

NS

    

20 % site

    

 Cortical vBMD (mg/cm3)

2.4

NS

    

 Cortical area (cm2)

1.7

NS

    

 Cortical thickness (mm)

0.05

NS

    

 Periosteal circumference (mm)

−0.20

NS

    

 Endosteal circumference (mm)

−0.50

NS

    

 Polar SSI (mm3)

57

NS

    

Total body

    

 BMC (g)

−3.5

NS

    

 Bone area (cm2)

−3.9

NS

    

Leg

    

 BMC (g)

1.3

NS

    

Arm

    

 BMC (g)

5.7

NS

    

Data presented above are least-squares means determined by ANCOVA while controlling for initial height and weight and baseline bone value.

Prospective studies

 Protein

Alexy et al. 2005 [144]

This study examined whether the long-term dietary protein intake and diet net acid load are associated with bone status in children. In a prospective study design, long-term dietary intakes were calculated from 3-day weighed dietary records that were collected yearly over the 4-year period before a one-time bone analysis using pQCT.

Sex: male and female

Age: 6–18 years

Race: white

Location: Dortmund, Germany

Year(s): 1998–1999 subcohort of the DONALD study

229

Data are shown for the overall group (N = 229)

Protein (g/day)

     

ß

ßstand

r 2

P

    

Forearm

    

 Periosteal circumference (mm2)

0.07

0.17

0.03

<0.01

    

 Cortical area (mm2)

0.42

0.27

0.04

<0.01

    

 BMC (mg/mm)

0.46

0.26

0.03

<0.01

    

 Polar SSI (mm3)

1.83

0.29

0.06

<0.01

    

• Data presented above are results from stepwise multiple regression and after adjustment for age, sex, and energy intake.

• ßstand is the standardized parameter estimate.

• Children with a higher dietary PRAL had significantly less cortical area (P < 0.05) and BMC (P < 0.01).

• Long-term calcium intake had no significant effect on any bone variable.

 Protein

Bounds et al. 2005 [146]

This study aimed to identify factors related to children’s bone mineral indexes at age 8 years, and to assess bone mineral indexes in the same children at ages 6 and 8 years. Children’s dietary intake and BMC were assessed as part of a longitudinal study from ages 2 months to 8 years.

Sex: male and female

Age: 6 years (baseline) and 8 years (follow-up)

Race: white

Location: Knoxville, TN

Year(s): not specified

52

Data are shown for the overall group (N = 229)

Protein intake (g) over ages 2–8 years

     

r

P

    

Total body

    

 BMC at age 8 years

0.37

≤0.05

     

ß

Partial R 2

P

    

 BMC model 1

(+) 2.40

0.08

<0.01

    

Data presented above show the Pearson’s correlation coefficient (r) relating protein intake over ages 2–8 years, representing 27 days of dietary data. BMC model 1 (R 2 = 0.69, F = 20.7, P < 0.01)

 Protein

Vatanparast et al. 2007 [147]

This mixed-longitudinal study investigated the influence of protein intake on bone mass measures in young adults, considering the influence of calcium intake through adolescence. Dietary intake was assessed via serial 24-h recalls carried out at least once yearly.

Sex: male and female

Age: 8–21 years during phase I of the study; 17–29 years for phase II

Race: majority Caucasian

Location: Saskatoon, Saskatchewan, Canada

Year(s): 1991–1997 (phase I); 2003–2006 (phase II); participating in the University of Saskatchewan Pediatric Bone Mineral Accrual Study

133

Data are shown for the overall group (N = 133) and a subgroup (n = 44)

Protein intake (g)

     

Regression coefficient

Partial R 2

P

    

Total body (N = 133)

    

 BMC

NS

NS

    

 BMC net gain

0.11

0.21

0.02

    

Total body (n = 44)

    

 BMC

0.21

0.33

0.04

    

 BMC net gain

0.21

0.37

0.02

    

The net gain of total body BMC and the net gains of height and weight from age of peak height velocity to early adulthood were entered into the model. Variables in the multiple regression model (stepwise) were sex, current height, weight, physical activity level, protein intake, vegetable and fruit intake, and periadolescence intakes of vegetables and fruit, protein, and physical activity.

Protein intake predicted total body BMC net gain in all subjects.

In females at periadolescence or early adulthood with adequate calcium intake(>1000 mg/day) (n = 44), protein intake positively predicted total body BMC and BMC net gain.

 Protein

Zhang et al. 2010 [148]

This study assessed the association between protein intakes and bone mass accrual in girls who participated in a 5-year study including 2 years of milk supplementation (intervention groups only) and 3 years of follow-up study.

Sex: female

Mean age: 10.1 years

Race: Chinese

Location: Beijing

Year(s): 1999–2004

757

Data are shown for the overall group (N = 757)

Average protein intake

     

ß

P value

    

Total body

    

 Bone area

NS

    

 BMC

−1.92

0.02

    

Proximal forearm

    

 Bone area

−9.11

<0.01

    

 BMC

−10.2

<0.01

    

Distal forearm

    

 Bone area

NS

    

 BMC

−4.82

<0.01

    

• Data presented above (ß) represent the percentage change in the dependent variable associated with intake of protein after controlling for baseline bone mass and pubertal development, age and physical activity, survey time, group, and clustering by schools. Protein, among other nutrients, was included in an initial model and flowed by backward elimination with P < 0.01 as the standard for retention, exclusion by the regression model.

• When protein intake was considered according to animal or plant food sources, protein from animal foods, particularly meat, had significant negative effects on BMC accrual at the proximal and distal forearm (P < 0.05).

 Protein

Remer et al. 2011 [145]

The aim of the study was to examine whether the association of long-term dietary acid load and protein intake with children’s bone status can be confirmed using approved urinary biomarkers and whether these diet influences may be independent of potential bone-anabolic sex steroids. Data were collected in 197 healthy children during the 4 years preceding proximal forearm bone analyses by pQCT.

Sex: male and female

Age: 6–18 years

Race: white

Location: Dortmund, Germany

Year(s): 1998–1999 subcohort of the DONALD study

197

Data are shown for the overall group (N = 197)

Urinary uN

Urinary PRAL

     

ß

P

ß

P

    

Forearm

    

 BMC (mg/mm) [log 10]

0.03

<0.01

−0.02

0.03

    

 Cortical area (mm2) [log 10]

0.02

<0.01

−0.02

0.03

    

 Polar SSI (mm3) [log 10]

0.02

<0.01

−0.01

NS

    

 Periosteal circumference (mm)

0.50

0.03

0.02

NS

    

 BMD (mg/cm3)

5.40

NS

−8.70

NS

    

• Data presented above are from multivariate regression models showing independent associations of both long-term protein intake (as uN) and PRAL as explanatory variables with forearm bone variables. Data are adjusted for age, sex, pubertal stage, forearm muscle area, forearm length, and urinary calcium.

• Data show that 1 Z-score variation in uN leads to an average 7.2 % increase in BMC and a 4.7 % increase in cortical area as well as SSI. A 1 Z-score uN corresponds to 0.28-g protein intake/kg body wt, implying that an additional 1-g protein intake/kg body wt may lead to an average increase of 26 % in BMC and 17 % in cortical area and SSI. A 1-g protein intake/kg body wt is associated with an average increase of 1.8-mm periosteal circumference.

Cross-sectional studies

 Protein

Hoppe et al. 2000 [149]

The objective of the study was to identify associations between dietary factors and total body bone measurements in a random sample of healthy Danish children.

Sex: male and female

Age: 10 years

Race: Danish, otherwise unspecified

Location: Hvidovre, Denmark

Year(s): 1997–1998, from the Copenhagen Cohort Study on Infant Nutrition and Growth

105

Data are shown for the overall group (N = 105)

Protein (g/day)

     

Pearson’s r

P

    

Total body

    

 Bone area (cm2)

0.31

<0.01

    

 BMC (g)

0.33

<0.01

    

• The data above are unadjusted.

• In the multiple linear regression analysis including height, weight, sex, energy intake, and bone-related nutrients in the model, dietary protein was not significantly associated with bone area or BMC.

After backward elimination, in which height, weight, and sex were forced to stay in the model, dietary protein was positively associated with bone area (P < 0.05).

• Inclusion of pubertal stages in the analyses did not alter the bone area or BMC outcomes.

 Protein

Iuliano-Burns et al. 2005 [150]

This cross-sectional study assessed monozygotic and dizygotic male twin pairs to test the following hypotheses: (1) associations between bone mass and dimensions and exercise are greater than between bone mass and dimensions and protein or calcium intakes; and (2) exercise or nutrient intake are associated with appendicular bone mass before puberty and axial bone mass during and after puberty.

Sex: male

Age: 7–20 years

Race: not specified

Location: Melbourne, Australia

Year(s): 1997–2001

112 (56 twin pairs)

Data are shown for the overall group (N = 112)

Differences in protein

     

Univariate

Size adjusted

All lifestyle and size adjusted

     

ß

P

ß

P

ß

P

    

Differences in BMC (g)

    

 Total body

3.5

NS

1.3

NS

1.3

NS

    

 Arms

0.8

<0.05

0.7

<0.05

0.8

<0.05

    

 Legs

1.6

NS

0.3

NS

0.3

NS

    

 Lumbar spine

0.0

NS

0.0

NS

0.0

NS

    

Differences in BMC (%)

    

 Total body

0.3

<0.05

0.2

<0.05

0.1

NS

    

 Arms

0.4

<0.05

0.4

<0.01

0.4

<0.05

    

 Legs

0.3

NS

0.1

NS

0.1

NS

    

 Lumbar spine

0.1

NS

0.1

NS

0.2

NS

    

Differences in bone dimensions (mm)

    

 Cortical thickness

0.0

NS

0.0

NS

0.0

NS

    

 Periosteal diameter

0.0

NS

0.0

NS

0.0

NS

    

 Endosteal diameter

0.0

NS

0.0

NS

−0.0

NS

    

Differences in bone dimensions (%)

    

 Cortical thickness

0.2

NS

0.1

NS

0.4

NS

    

 Periosteal diameter

0.1

NS

0.0

NS

0.0

NS

    

 Endosteal diameter

−0.0

NS

−0.1

NS

−0.3

NS

    

• Data presented above are ß coefficients for within-pair differences in protein versus (1) within-pair differences in BMC and bone dimensions, (2) within-pair differences in size-adjusted BMC and bone dimensions, and (3) when all within-pair differences in protein, calcium, exercise duration, and size are included in the regression equation.

• A 1-g difference in protein intake was associated with a 0.8-g (0.4 %) difference in arm BMC (P < 0.05). These relationships were present in peripubertal and postpubertal pairs but not in prepubertal pairs. Exercise during growth appears to have greater skeletal benefits than variations in protein or calcium intakes, with the site-specific effects evident in more mature twins.

 Protein

Chevalley et al. 2008 [151]

This study analyzed the relationship between physical activity levels and protein compared with calcium intake on BMC in healthy prepubertal boys.

Sex: male

Age: 6.5–8.5 years

Race: white

Location: Geneva, Switzerland

Year(s): recruitment period 1999–2000, otherwise unspecified

232

Data are shown for the overall group (N = 232)

Correlation with protein intake (g/day)

     

r

P

ßAdjusted

P

    

BMC (g)

    

 Radial metaphysis

0.26

<0.01

0.20

0.01

    

 Radial diaphysis

0.21

<0.01

0.12

NS

    

 Total radius

0.27

<0.01

0.20

0.01

    

 Femoral neck

0.20

<0.01

0.19

0.03

    

 Total hip

0.18

<0.01

0.12

NS

    

 Femoral diaphysis

0.23

<0.01

0.19

0.03

    

 Lumbar spine

0.24

<0.01

0.22

<0.01

    

Data presented above are from univariate (r) and multivariate (ßAdjusted) analyses; the latter takes into account the respective contribution of physical activity, protein, and calcium intakes.

 Protein

Esterle et al. 2009 [152]

This study explored dietary calcium sources and nutrients possibly associated with lumbar bone mineralization and calcium metabolism in adolescent girls and evaluated the possible influence of a genetic polymorphic trait associated with adult-type hypolactasia.

Sex: female

Age: 12–22 years

Race: Caucasian

Location: France

Year(s): not specified

192

Data are shown for the postmenarchal group only (n = 142)

Protein from milk

Protein from other foods

     

Adj R 2

ßstand

P

Adj R 2

ßstand

P

    

Lumbar spine BMC (g)

    

 Absolute

0.61

0.14

<0.01

0.61

<0.01

NS

    

 Adjusted

0.60

0.13

0.02

0.60

<0.01

NS

    

• Data presented above are from multivariate linear analyses.

• Absolute protein intake is expressed in g/days.

• Adjusted protein intake for weight, years after menarche, and vertebral area is expressed in g/kg/days.

• Girls with milk intakes <55 mL/day had significantly lower BMC compared to girls consuming >260 mL/day.

• Neither BMC nor milk consumption was associated with −13,910 LCT polymorphism.

 Protein

Ekbote et al. 2011 [153]

The aim of this study was to examine lifestyle factors as determinants of total body BMC and bone area in Indian preschool children.

Sex: male and female

Age: 2–3 years

Race: Indian

Location: Pune, India

Year(s): 2009

71

Data are shown for the overall group (N = 71)

Protein (g/days)

     

Normal

Malnourished

All

     

r

P

r

P

r

P

    

Total body

    

 Bone area

0.65

<0.01

0.57

<0.01

0.58

<0.05

    

 BMC

0.62

<0.01

0.44

<0.05

0.55

<0.01

    

Data presented above are from Pearson’s correlation coefficients correlating protein intake and bone among normal children, malnourished children, and all (normal and malnourished children combined).

Protein

Libuda et al. 2011 [154]

This study examined relevant nutrients that are supposed to have an impact on bone parameters and compared their effect sizes with those of known predictors of bone development.

Sex: male and female

Median age: 8.1 years

Race: white

Location: Dortmund, Germany

Year(s): 1998–1999 subcohort of the DONALD study

107

Data are shown for the overall group (N = 107)

Protein (g/MJ)

     

ß

ßstand

R 2

P

    

Forearm

    

 Polar SSI (mm3)

NS

    

 Periosteal circumference (mm)

NS

    

 BMC (mg/mm)

1.49

0.11

0.01

NS

    

 Cortical area (mm2)

1.37

0.11

0.01

NS

    

• Data presented above are from stepwise linear regression analyses, considering muscle area, BMI standard deviation scores, body fat %, age, sex, and rostenediol, as well as intakes of protein, calcium, vitamin D, and PRAL.

• Of all nutrients considered, only protein showed a trend for an association with BMC (P = 0.073) and cortical area (P = 0.056) in stepwise linear regression models.

• None of the other dietary variables were associated with bone parameters.

• The protein effect did not differ between sexes.

Adj adjusted, ANCOVA analysis of covariance, BMC bone mineral content, BMD bone mineral density, DONALD Dortmund Nutritional and Anthropometric Longitudinally Designed Study, NS not significant, pQCT peripheral quantitative computed tomography, PRAL potential renal acid load, RCT randomized controlled trial, SSI stress–strain index, uN urinary nitrogen, vBMD volumetric bone mineral density

Table 4

Calcium and bone health in children and adolescents

Nutrient

Reference

Study description

Population description

Number of subjects

End points

Results

RCTs

 Supplements

  Calcium carbonate, 1000 mg/day

Dibba et al. 2000 [160]

12-month randomized, double-blind, placebo-controlled study

Supplementation increased calcium intake from 342 to 1056 mg/day

By young adulthood, there was no difference in the amount of bone accrued (mineral or size) or the rate of bone growth between supplemented and placebo.

Sex: 80 boys, 80 girls

Age: 8.3–11.9 year

Race: Gambian, otherwise unspecified

Location: rural Gambia,

West Africa

160

 

Difference in % gain between groups

    

Midshaft arm BMC

4.6 ± 0.9a

    

Distal radius BMC

5.5 ± 2.7a

    

Adjusted for bone width, weight, and height

  Calcium carbonate, 800 mg + 400 IU vitamin 3/day

Moyer-Mileur et al. 2003 [163]

1-year double-blind RCT

Baseline calcium: not reported

Average intake during study: supplement, 1524 (353); placebo, 906 (345); 30 % dropout

Trabecular vBMD values were significantly greater in the supplemented group at baseline.

Sex: female

Age: 12 years; Tanner stage 2

Race: white

Location: USA

100

Tibial pQCT measurements

Calcium and D

Placebo

    

 Trabecular vBMD % increasea

1.0

−2.0

    

 Trabecular BMC % increasea

4.1

1.6

    

Adjusted for baseline values

  Elemental calcium, 1000 mg/day

Rozen et al. 2003 [330]; Dodiuk-Gad et al. 2005 [331]

12-month double-blind, placebo-controlled

Habitual calcium intakes <800 mg/day

Compliance dropped from 71 ± 26 % during the initial 6 months to 56 ± 34 % for the remaining study period (P = 0.0001)

In follow-up study by Dodiuk-Gad et al., girls who have had compliance of ≥75 % on supplementation had significantly higher total body BMD after 3.5 years after supplementation than controls.

Sex: female; >1 year postmenarchal

Age: 12–17 years

Race: 85 Jewish girls and 27 Arab girls

Location: Haifa, Israel

112

 

Calcium supplement

Placebo

    

Lumbar spine BMC

4.52 ± 0.48

3.95 ± 0.58

    

Total body BMC

4.63 ± 0.42

4.65 ± 0.54

    

Femoral neck BMC

4.30 ± 0.86

3.00 ± 0.81

    

Lumbar spine BMD

3.66 ± 0.35a

3.00 ± 0.43

    

Total body BMD

3.80 ± 0.30a

3.07 ± 0.29

    

Femoral neck BMD

2.00 ± 0.51

1.39 ± 0.42

    

Not adjusted

  Calcium carbonate (Caltrate) supplement, 1200 mg/day

Cameron et al. 2004 [161]

24-month RCT of twins

Baseline calcium intake: 786, trt; 772, control in those who completed 24 months

All were premenarchal at baseline

24 (38 %) of pairs completed 24 months

Compliance was 76 % for both groups

Sex: female

Age: 8–13 years

Race: not specified

Location: Australia

103

(50 twin pairs + 1 set of triplets)

End of 24-month intention to treat

Difference in % gain between groups

    

 Total body BMC

3.69a

    

 Hip BMD

−0.39a

    

 Spine BMD

1.40a

    

 Femoral neck BMD

−0.57

    

End of 12 months

    

 Total body BMC

2.47a

    

 Hip BMD

1.64a

    

 Spine BMD

1.64a

    

 Femoral neck BMD

1.13

    

Adjusted for age, height, and weight

  Calcium carbonate, 500 mg/day

Molgaard et al. 2004 [332]

12-month randomized, double-blind, placebo-controlled intervention

Subjects stratified at randomization according to baseline calcium intake

Group A (n = 60) habitually consumed 1000–1307 mg/day (40th–60th percentile), and group B (n = 53) habitually consumed <713 mg/day (<20th percentile)

Sex: female

Age: 12 years ± 6 months

Race: white

Location: Denmark

113

No significant interaction between habitual calcium intake (groups A and B) and the intervention (Calcium carbonate–Placebo) in the analyses of height, weight, BMC, size-adjusted BMC, bone area, or BMD (all P > 0.15).

When groups A and B were analyzed together, there was a significant effect of the intervention on BMD (0.8 %; 95 % CI, 0.01 %, 1.54 %; P = 0.049).

  Calcium citrate malate, 1000 mg/day

Matkovic et al. 2005 [333]

4-year randomized clinical trial and optionally extended for an additional 3 years

Baseline calcium: 830 ± 236 mg/day

51 % of the subjects completed the 7-year trial.

Sex: female

Age: 11 years; Tanner 2

Race: white

Location: USA

354

 

Calcium supplement

Placebo

    

End of 4-year gain

    

 Total body BMD (g/cm2)

0.215 ± 0.037a

0.204 ± 0.0353

    

 Proximal radius BMD (g/cm2)

0.167 ± 0.088

0.171 ± 0.079

    

 Distal radius BMD (g/cm2)

0.106 ± 0.047a

0.092 ± 0.046

    

 Cortical area/total area

0.079 ± 0.021

0.072 ± 0.0213

    

End of 7-year gain

    

 Total body BMD (g/cm2)

0.268 ± 0.049

0.263 ± 0.044

    

 Proximal radius BMD (g/cm2)

0.162 ± 0.038

0.156 ± 0.036

    

 Distal radius BMD (g/cm2)

0.171 ± 0.047

0.165 ± 0.040

    

 Cortical area/total area

0.095 ± 0.025a

0.085 ± 0.0242

    

By young adulthood, significant effects remained at metacarpals and at the forearm of tall persons.

  Calcichew, 1000 mg/day

Prentice et al. 2005 [162]

13-month randomized, double-blind, placebo-controlled study

Subjects were stratified by high or low exercise at baseline. Those in the low group were randomized to exercise intervention or none.

Compliance with exercise was poor and no statistically significant differences were found between groups. For final analysis, all exercise intervention groups were combined.

Subjects were told to not take the supplement with meals.

Baseline calcium: 1197, supplement; 1199, placebo

Total calcium intake during study: supplement, 1858 ± 629; placebo, 1283 ± 586

Latter factored in compliance

Sex: male

Age: 16–18 years

Race: 90 % white; 10 % from various ethnic groups

Location: Cambridge, UK

143

 

Difference in % gain between groups

    

Total body BMC

0.33 ± 0.34

    

Lumbar spine BMC

0.18 ± 0.54

    

Total hip BMC

1.09 ± 0.54a

    

Femoral neck BMC

1.21 ± 0.65

    

Intertrochanter BMC

0.99 ± 0.56

    

Trochanter BMC

0.29 ± 0.80

    

Ultradistal radius BMC

0.36 ± 0.86

    

Adjusted for bone area, weight, and height

  Calcium carbonate, 800 mg/day and vitamin D3 400 IU/day

Greene and Naughton 2011 [164]

6-month randomized placebo-controlled trial

Baseline calcium: 763–786 mg/day

Sex: female; identical twins

Age: 9–13 years

Race: not indicated

Location: Australia

40 (20 pairs)

pQCT

Tibial difference in % gain between groups

    

4 % location

    

 Trabecular vBMD (mg/mm3)

5.2 ± 1.96a

    

 Trabecular area (mm2)

5.4 ± 1.33a

    

 Subcort density (mg/mm3)

3.4 ± 0.82

    

 Subcortical area (mm2)

0.8 ± 0.07

    

 SSI (mm3)

6.6 ± 1.26a

    

14 %

    

 Cortical BMD (mg/mm3)

0.1 ± 0.04

    

 Cortical area (mm2)

1.3 ± 0.35

    

 Total bone area (mm2)

0.3 ± 0.02

    

 Medullary CSA (mm2)

−0.4 ± 0.02

    

 SSI (mm3)

1.7 ± 0.22

    

38 %

    

 Cortical BMD (mg/mm3)

0.8 ± 0.03

    

 Cortical area (mm2)

5.8 ± 0.8a

    

 Total bone area (mm2)

0.5 ± 0.03

    

 Medullary CSA (mm2)

−6.2 ± 1.6a

    

 SSI (mm3)

0.7 ± 0.06

    

66 %

    

 Cortical BMD (mg/mm3)

0.1 ± 0.02

    

 Cortical area (mm2)

5.7 ± 0.39a

    

 Total bone area (mm2)

−0.7 ± 0.03

    

 Medullary CSA (mm2)

−8.1 ± 1.82a

    

 Muscle CSA (mm2)

0.6 ± 0.02

     

Radial difference in % gain between groups

    

4 % location

    

 Trabecular vBMD (mg/mm3)

3.3 ± 0.28a

    

 Trabecular area (mm2)

2.8 ± 0.36a

    

 Subcortical density (mg/mm3)

0.1 ± 0.03

    

 Subcortical area (mm2)

0.3 ± 0.01

    

 SSI (mm3)

5.7 ± 0.51a

  Calcium carbonate pills

Khadilkar et al. 2012 [334]

1-year double-blind RCT of calcium, multivitamin with zinc, and vitamin D3

Sex: female

Age: 8–12 years

Race: Indian

Location: Pune, India

214

Total body BMC increase

Percent gain by group

     

Calcium + multivitamin

Calcium

Control

     

21.5 ± 5.7a

23.1 ± 6.1a

19.4 ± 4.2

    

Adjusted for Tanner stage and lean body mass

  Calcium, 1000 mg/day by pill or cheese

Vitamin D, 800 IU/day

Cheng et al. 2005 [159]

2-year RCT; randomized to 1 of 4 groups: calcium 1000 mg/day + vitamin D 200 IU/day; calcium 1000 mg/day; cheese (1000 mg/day); placebo

Baseline calcium 664–680 mg/day

Sex: female

Age: 10–12 years

Race: not indicated

Location: Finland

195

 

Calcium + vitamin D

Calcium

Placebo

    

DXA

    

 Total body BMC (%)

34.7

35.0

35.0

    

 Femoral neck BMC (%)

24.0

23.3

22.4

    

 Total femur BMC (%)

33.6

36.4

33.6

    

pQCT

    

 Radius CSA

23.0

26.0

21.3

    

 Radius BMC

22.6

24.4

22.2

    

 Tibial CSA

15.6

15.8

14.8

    

 Tibial BMC

23.0

24.3

22.7

    

No significant differences

 Fortified foods

  Calcium citrate-malate, 792 mg/day dissolved in a fruit drink

Lambert et al. 2008 [165]

18-month randomized trial with follow-up 2 years after supplement withdrawal

Low calcium intake at baseline (mean 636 mg/day)

Differences in gain no longer apparent 2 years after supplement withdrawal

Sex: 96 girls

Age: 11–12 years

Race: white

Location: Sheffield, UK

96

 

Calcium supplement

Placebo

    

Total body BMC (g)

1698 ± 14a

1667 ± 14

    

Lumbar spine BMC

43.0 ± 0.6a

41.1 ± 0.6

    

Total hip BMC

27.7 ± 0.3

27.2 ± 0.4

    

Adjusted for baseline values, age at menarche, and age at menarche × visit interaction

  Calcium-enriched beverage, 1200 mg/day

Gibbons et al. 2004 [166]

18-month placebo-controlled, double-blind RCT of a high-calcium beverage. Controls received 400 mg/day

Baseline calcium intake: 934, supplement; 985, placebo

12-month additional follow-up after end of intervention

Sex: male and female

Age: 8–10 years

Race: NZ European or Pakeha

Location: New Zealand

154

 

Treatment

Control

    

Total body BMD

4.4 %

3.3 % (NS)

    

Hip BMD

4.8 %

3.9 % (NS)

    

Spine BMD

5.9 %

5.8 % (NS)

    

Trochanter BMD

6.2 %

5.1 % (NS)

    

Femoral neck BMD

6.7 %

7.0 % (NS)

  Calcium-fortified foods, 850 mg/day

Chevalley et al. 2005 [168]

1-year double-blind RCT of calcium-fortified foods (850 mg/day) compared to an isocaloric control

Sex: male

Age: 6.5–8.5 years

Race: white

Location: Switzerland

235

Spine BMD (L2–4)

Femoral diaphysis BMD

Femoral neck BMD

Trochanter BMD

Radius BMD

No difference in gain

19 % greater increase in trt (P < 0.006)

3 % lesser increase (NS)

22 % greater (NS)

15 % greater (NS)

  600 mg calcium in 375 mL soymilk

Ho et al. 2005 [167]

1-year follow-up study between 104 adolescent girls receiving the fortified food and 95 girls in the control group

Sex: female

Age: 14–16 years

Race: Chinese

Location: Hong Kong, China

210

 

Mean % change treatment ± SD

Mean % change, control

    

Neck of the femur BMD

2.7 ± 2.94

1.8 ± 3.49

    

Trochanter BMD

3.3 ± 3.27a

1.6 ± 2.94

    

Intertrochanter BMD

3.6 ± 3.05a

2.32 ± 2.95

    

Total hip BMD

3.1 ± 2.39a

2.05 ± 2.22

    

Total hip BMC

3.8 ± 3.05a

2.6 ± 2.96

 Dairy foods

  Dairy foods, 1000 mg/day

Merrilees et al. 2000 [169]

2-year RCT of dairy foods

Baseline calcium: 744, supplement; 765, control

1 year after end of supplementation, differences no longer seen

Sex: female

Age: 15–17 years

Race: unspecified NZ

Location: New Zealand

91

Spine BMD

Trochanter BMD

Femoral neck BMD

1.5 % greater increase in trt (P < 0.05)

4.6 % greater increase in trt

4.8 % greater increase in trt

 330 mL UHT milk (560 mg calcium), 330 mL UHT milk + 200 or 320 IU vitamin D3, or control

Du et al. 2004 [170]

2-year school-based randomized trial

Sex: female

Age: 10–12 years

Race: Chinese

Location: Beijing, China

757

Total body BMC

Bone area

35.9 % (P = 0.03)

31.3 % greater increase in trt (P = 0.2)

95 % CI 95 % confidence interval, BMC bone mineral content, BMD bone mineral density, CSA cross-sectional area, NS not significant, pQCT peripheral quantitative computed tomography, RCT randomized controlled trial, SSI stress–strain index, trt treatment, UHT ultra-heat-treated, vBMD volumetric bone mineral density

aSignificantly greater than the control

Table 5

Calcium and exercise and bone health in children and adolescents

Reference

Study description

Population description

Number of subjects

End points

Results

Molgaard et al. 2001 [245]

1-year prospective observational study to determine effects of dietary calcium and physical activity on bone changes.

Sex: 140 boys, 192 girls

Age: 5–19 years at baseline

Race: Caucasian

Location: Copenhagen, Denmark

332

 

Correlation with calcium intake, r

Correlation with physical activity, r

   

Whole bone area gain adjusted for height and weight

0.03, girls

0.28

    

−0.34, boys

0.28

   

Total body BMC gain adjusted for bone area, height, and weight

0.21, girls

−0.06

    

0.34, boys

−0.04

Carter et al. 2001 [171]

Cross-sectional study to investigate the relationship between calcium intake and BMC.

Sex: 108 boys and 119 girls

Mean age: 13 years

Race: Primarily Caucasian

Location: Saskatoon Canada

227

Total body BMC

No association

   

Lumbar spine BMC

No association

Lloyd et al. 2000 [174]

6-year prospective study to determine effects of dietary calcium and physical activity on bone changes

Sex: girls

Age: 12–18 years at baseline

Race: Caucasian

Location: Pennsylvania

81

Total body BMC gain

NS

   

Total body BMD gain

NS

   

Femoral neck BMDa

r = 0.42 with exercise

Lappe et al. 2014 [172]

6-year prospective study of calcium intake and physical activity on bone accrual

Sex: boys and girls

Age: 5–16 years at baseline

Race: white, black, Asian, Hispanic, and non-Hispanic

Location: 5 sites in the USA

1743

 

Mixed-model analyses

   

Total body BMC gaina

Associated with physical activity in nonblacks

   

Spine BMC gaina

Associated with physical activity in blacks and nonblack males

   

Total hip BMC gaina

Associated with calcium in nonblack females

   

Adjusted for changes in height, age, and baseline BMC

Associated with physical activity in nonblacks and black males

BMC bone mineral content, BMD bone mineral density, NS not significant

aSignificantly greater than the control

Table 6

Vitamin D and bone health in children and adolescents

Reference

Study description

Population description

Number of subjects

Primary end points

Results

RCTs

 Du et al. 2004 [170]

This study was a 2-year milk intervention trial in girls from nine primary schools in Beijing. Schools were randomized into three groups: (1) a carton of 330-mL milk fortified with calcium per school day, (2) a carton of 330-mL milk fortified with 200 or 320 IU 8 mg vitamin D3, and (3) control

Sex: female

Age: 10–12 years

Race: Asian (Chinese)

Location: Beijing, China

Year(s): 1999–2001

Baseline 25(OH)D as mean (SD) in nmol/L:

Control: 19.1 (7.4)

Calcium only: 17.7 (8.7)

Calcium + vitamin D: 20.6 (8.8)

757

Data are shown for a subsample with bone measures (N = 346)

Percent change

P

    

Milk with calcium (n = 111)

Milk with calcium + vitamin D (n = 113)

Control (n = 122)

   

Total body

   

 Bone area

29.5

28.5

31.3

NS

   

 BMC

38.4

39.7

35.9

<0.01

    

Percent change, calcium + vitamin D, minus calcium

P

Percent change, calcium + vitamin D, minus control

P

   

Total body

   

 Bone area

0.8

NS

−1.8

0.04

   

 BMC

−0.8

NS

2.6

<0.01

   

 Size-adjusted BMC

1.3

<0.01

2.4

<0.01

   

• Mean percent change values in the calcium + vitamin D group were significantly different from controls.

• Adjusted percentage difference in change values are adjusted for baseline.

• Size-adjusted BMC is adjusted for baseline BMC, bone area, height, weight, and menstrual status.

 Cheng et al. 2005 [159]

The purpose of this study was to examine the effects of both food-based and pill supplements of calcium and vitamin D3 on bone mass and body composition. Children were randomized into four groups: (1) 1000 mg calcium + 200 IU vitamin D3, (2) 1000 mg calcium + vitamin D3 placebo, (3) 1000 mg calcium from dairy products,and (4) calcium + vitamin D3 placebo for 2 years

Sex: female

Age: 10–12 years

Race: Finnish, otherwise unspecified

Location: Jyvaskyla and surrounding cities in Central Finland

Year(s): Unspecified

Baseline 25(OH)D as mean (95 % CI):

45.9 (43.8, 48.0) nmol/L

195

Data are shown for the overall group who started the intervention (N = 181)

Percent change

P

    

Calcium (n = 41)

Calcium + vitamin D3 (n = 46)

Cheese (n = 39)

Placebo (n = 39)

   

Lumbar spine

   

 Bone area

28.4

23.0

25.3

23.4

NS

   

 BMC

24.0

46.9

52.4

47.0

NS

   

Total hip

   

 Bone area

24.1

17.0

18.1

17.3

NS

   

 BMC

20.3

33.6

36.9

33.6

NS

   

Femoral neck

   

 Bone area

3.8

12.6

13.1

15.0

NS

   

 BMC

3.3

24.0

26.5

22.4

NS

   

Radius

   

 CSA

26.0

23.0

26.2

21.3

NS

   

 BMC

24.4

22.6

25.9

22.2

NS

   

 vBMD

2.6

3.4

3.1

2.0

NS

   

Polar moment of inertia

62.0

53.3

61.8

51.8

NS

   

Tibia

   

 CSA

15.8

15.6

15.9

14.8

NS

   

 BMC

24.3

23.0

25.2

22.7

NS

   

 vBMD

7.5

6.9

8.3

7.8

NS

   

 Cortical bone thickness

29.8

31.7

37.1

31.1

NS

   

 Polar moment of inertia

41.5

41.3

42.6

39.7

NS

   

• Data presented above show no interaction between the groups with the intent-to-treat analysis.

• There was a significant interaction with cortical thickness of the tibia between the groups (P < 0.05) where this measure increased more in the cheese group with a compliance >50 % versus placebo (P = 0.01), calcium + vitamin D (P < 0.01), or calcium (P = 0.04).

• Bonferroni correction for multiple comparisons was applied to these analyses.

 El-Hajj Fuleihan et al. 2006 [175]

Musculoskeletal responses were determined in response to weekly doses of vitamin D3 (1400 and 14,000 IU) over 1 year

Sex: female

Age: 10–17 years

Race: Lebanese, otherwise unspecified

Location: greater Beirut, Lebanon area

Year(s): 2001–2003

Baseline 25(OH)D as mean (SD): 14 (8) ng/ml

179

Data are shown for the overall group (N = 168)

Percent change

P

    

High-dose treatment, 14,000 IU/week (n = 55)

Low-dose treatment, 1400 IU/week (n = 58)

Placebo (n = 55)

   

Lumbar spine

   

 Bone area

4.3

5.0

4.0

NS

   

 BMC

12.9

14.5

10.8

NS

   

Total hip

    
   

 Bone area

5.7

4.0

2.4

<0.01

   

 BMC

12.8

11.2

7.8

0.02

   

Femoral neck

   

 Bone area

0.8

0.0

0.7

NS

   

 BMC

5.2

4.4

3.9

NS

   

Trochanter

   

 Bone area

7.8

6.8

4.7

NS

   

 BMC

14.2

13.6

9.4

NS

   

Total body

   

 Bone area

6.2

6.1

5.0

NS

   

 BMC

12.0

11.3

8.7

NS

   

 Lean mass

9.0

8.7

5.7

0.05

   

• In premenarchal girls, trochanter BMC and lean mass reached significance.

• Postmenarchal girls did not exhibit significant changes in any parameters of interest.

 Viljakainen et al. 2006 [177]

This study sought to determine the effect of vitamin D3 supplementation (200 or 400 IU/day) for 1 year on bone mineral augmentation in adolescent girls with adequate dietary calcium intake.

Sex: female

Age: 11.4 ± 0.4 years

Race: white

Location: Helsinki, Finland

Year(s): 2001–2003

Baseline 25(OH)D as mean (SD) in nM:

Placebo: 47.8 (18.2)

5 μg/day: 46.3 (17.4)

10 μg/day: 46.7 (16.2)

228

Data are shown for the overall group (N = 212)

Mean change

P

    

High-dose treatment, 400 IU/day (n = 74)

Low-dose treatment, 200 IU/day (n = 65)

Placebo (n = 73)

   

Lumbar spine

   

 Bone area (cm2)

3.8

4.1

3.5

NS

   

 BMC (g)

6.2

5.9

5.1

NS

   

Femur

   

 Bone area (cm2)

2.0

2.2

2.4

NS

   

 BMC (g)

3.3

3.4

3.2

NS

   

• Data presented above are for the intent-to-treat analysis.

• In the compliance-based analysis only in the entire sample, vitamin D supplementation vs placebo increased femoral BMC augmentation by 14.3 % with 200-IU doses and by 17.2 % with 400-IU doses (P = 0.012)

• In the compliance-based analysis only in the entire sample, a dose–response effect was observed at the lumbar spine with the 400-IU (P = 0.039), but not the 200-IU dose.

• In a subanalysis based on puberty (n = 111) and using a compliance-based analysis only, adjusted for Tanner stage, increase in bone area, and weight gain, there was a dose-dependent and significant difference in the lumbar spine BMC augmentation at midpuberty (P = 0.01), but not at early puberty.

 Andersen et al. 2008 [180]

The aim of this study was to assess the effect of supplemental vitamin D on bone status in Pakistani immigrants. This 1-year intervention with vitamin D3 (10 and 20 μg /day) included girls (10.1–14.7 years), women (18.1–52.7 years), and men (17.9–63.5 years) of Pakistani origin living in Denmark

Sex: male and female

Age: 10–63 years

Race: of Pakistani origin

Location: Copenhagen area, Denmark

Year(s): 2002–2003

Baseline 25(OH)D as median (25th, 75th percentiles) in nmol/L:

Placebo: 7.3 (5.3, 23.6)

10 μg/day: 16.9 (12.1, 21.1)

20 μg/day: 8.8 (5.2, 17.1)

247

Data are shown for the girls group only (n = 26)

Median value

P

    

20 μg/day (n = 9)

10 μg/day (n = 9)

Placebo (n = 8)

   

Baseline

   

 Total body

   

  Bone area (cm2)

1633

1497

1760

NS

   

  BMC (g)

1473

1308

1666

NS

   

 Lumbar spine

   

  Bone area (cm2)

39.9

41.2

43.2

NS

   

  BMC (g)

30.0

28.3

33.9

NS

   

1 year

   

 Total body

   

  Bone area (cm2)

1784

1669

1906

NS

   

  BMC (g)

1625

1595

1923

NS

   

 Lumbar spine

   

  Bone area (cm2)

42.7

42.7

46.5

NS

   

  BMC (g)

39.5

35.6

41.9

NS

   

Data presented above indicate no significant differences between groups at baseline (nonparametric ANOVA) and no effect of the intervention on bone indices.

 Khadilkar et al. 2010 [178]

This study investigated the effect of quarterly doses of vitamin D2 supplementation (300,000 IU or 7.5 mg) on BMC in underprivileged adolescent girls over 1 year

Sex: female

Age: 14–15 years

Race: Indian

Location: Pune, India

Year(s): 2006–2007

Baseline 25(OH)D as median (25th percentile–75th percentile):

Vitamin D + calcium group: 24.5 (12.7–33.2) nmol/L

Placebo + calcium group: 20.8 (12.7–30.4) nmol/L

50

Data are shown for the overall group (N = 50)

Percent change

P

    

Vitamin D + calcium (n = 25)

Placebo + calcium (n = 25)

   

Total body

   

 Bone area

5.1

3.6

NS

   

 BMC

10.1

8.2

NS

   

Lumbar spine

   

 Bone area

3.3

3.9

NS

   

 BMC

10.5

11.3

NS

   

• Data presented above are unadjusted median percent change values.

• After adjusting for age (current), height, weight, lean body mass, initial dietary calcium, and calcium compliance, there was a significant increase in the size and compliance adjusted total BMC and bone area change in subjects who were within 2 years of menarche versus those less than 2 years since menarche (both P ≤ 0.04).

 Molgaard et al. 2010 [173]

This study investigated the effect of vitamin D3 supplementation (5 or 10 μg/day) for 1 year on bone mass and bone turnover, as well as the possible influence of VDR and ER genotype on the effect of the supplementation

Sex: female

Age: 10–11 years

Race: Danish-born citizens, otherwise unspecified

Location: Copenhagen and Frederiksberg, Denmark

Year(s): 2001–2003

Baseline 25(OH)D as mean (SD) in nmol/L:

Placebo: 43.4 (17.1)

5 μg/day: 41.9 (17.6)

10 μg/day: 44.4 (16.6)

225

Data are shown for the overall group (N = 225)

Mean change

P

    

High-dose treatment, 400 IU/day (n = 75)

Low-dose treatment, 200 IU/day (n = 75)

Placebo (n = 75)

   

Total body

   

 Bone area (cm2)

195

189

188

NS

   

 BMC (g)

249

245

241

NS

   

Lumbar spine

   

 Bone area (cm2)

4.9

5.5

5.6

0.04

   

 BMC (g)

7.4

8.1

8.2

NS

   

• Lumbar spine bone area in the high-dose group differed significantly from placebo.

• Vitamin D supplementation increased total body BMC (P = 0.048) in the FF VDR genotype but not in the Ff or ff VDR genotypes.

 Ward et al. 2010 [179]

This study aimed to determine the effect of vitamin D2 supplementation (4 doses of 150,000 IU given over 1 year) on the adolescent musculoskeletal system determined by DXA and peripheral quantitative computed tomography.

Sex: female

Age: 12–14 years

Race: multiethnic, primarily South Asian

Location: Manchester, UK

Year(s): 2006–2007

Baseline 25(OH)D as mean (SD) in nmol/L:

Placebo: 17.9 (7.4)

Vitamin D: 18.1 (8.0)

73

Data are shown for the overall group (N = 72)

Mean change

P

    

Vitamin D

Placebo

   

Lumbar spine

   

 Bone area (cm2)

0.20

0.15

NS

   

 BMC (g)

0.52

0.57

NS

   

Radius 4 %

   

 Total BMD (mg/cm3)

21.3

13.01

NS

   

 Trab BMD (mg/cm3)

3.07

3.23

NS

   

 CSA_4 (mm2)

6.19

9.27

NS

   

Radius 50 %

   

 CSMA (mm2)

−29.4

47.1

NS

   

 CSA_50 (mm2)

−0.67

−1.91

NS

   

 Ct BMC (mg/mm)

2.73

3.12

NS

   

 Ct BMD (mg/cm3)

17.4

23.9

NS

   

 Ct area (mm2)

1.26

1.28

NS

   

 Cort thk (mm)

0.10

0.12

NS

   

 SSI (mm3)

3.02

6.91

NS

   

Tibia 4 %

   

 Total BMD (mg/cm3)

10.5

9.79

NS

   

 Trab BMD (mg/cm3)

9.31

7.00

NS

   

 CSA_4 (mm2)

−1.19

−3.28

NS

   

Tibia 66 %

   

 CSMA (mm2)

161.2

197.6

NS

   

 CSA_66 (mm2)

17.09

7.70

NS

   

 Ct BMC (mg/mm)

7.68

9.66

NS

   

 Ct BMD (mg/cm3)

14.26

13.98

NS

   

 Ct area (mm2)

3.98

5.85

 
   

 Cort thk (mm)

−0.02

0.09

 
   

 SSI (mm3)

116.3

85.15

 
   

• P values presented above are adjusted for baseline and follow-up weight, follow-up height, and baseline bone measurement.

• There were no effects of vitamin D supplementation on bone.

 Al-Shaar et al. 2013 [176]

This study investigated the impact of weekly vitamin D3 (1400 and 14,000 IU) on hip geometric dimensions over 1 year. The images were acquired from DXA-derived hip structural analyses

Sex: male and female

Age: 10–17 years

Race: Lebanese, otherwise unspecified

Location: greater Beirut, Lebanon area

Year(s): 2001–2003

Baseline 25(OH)D as medians [interquartile range]:

Overall, girls: 11.9 [9.1–16.6] ng/ml

Overall, boys: 15.5 [6.0–44.9] ng/ml

338

Data are shown for females only (n = 167)

Percent change

P

    

High-dose treatment, 14,000 IU/week (n = 54)

Low-dose treatment, 1400 IU/week (n = 58)

Placebo (n = 55)

   

Narrow neck

   

 CSA

8.1

8.3

8.2

NS

   

 Outer diameter

2.0

0.8

2.8

0.02

   

 Section modulus

11.4

11.3

11.7

NS

   

 Buckling ratio

−4.2

−6.5

−2.0

0.05

   

Shaft

   

 CSA

10.4

11.6

9.9

NS

   

 Outer diameter

2.1

2.3

1.4

NS

   

 Section modulus

12.5

13.5

11.0

NS

   

 Buckling ratio

−7.2

−8.4

−8.9

NS

   

Intertrochanter

   

 CSA

8.5

9.5

7.1

NS

   

 Outer diameter

2.5

1.3

1.9

NS

   

 Section modulus

12.7

13.1

10.1

NS

   

 Buckling ratio

−3.0

−5.6

−3.6

NS

   

• Data presented above were adjusted for baseline height, change in lean mass and height, sun exposure, physical activity, calcium intake, and menarchal status.

• Boys did not exhibit significant changes in any parameters of interest.

• A dose effect was not detected and no beneficial effect of vitamin D was observed by pubertal stage.

Prospective studies

 Breen et al. 2011 [181]

This study sought to determine relationships among 25(OH)D, IGF-I, and bone in prepubertal females over a period of up to 9 years (median of 5 years)

Sex: female

Age: 4–8 years

Race: white and black

Location: Georgia, USA

Year(s): 1997–2008

76

Data are shown for the overall group (N = 76)

Combined 25(OH)D + IGF-I

25(OH)D

IGF-I

   

BMC

   

 Total body

0.84

0.81

0.87

   

 Lumbar spine

0.72

0.70

0.76

   

 Proximal femur

0.81

0.77

0.85

   

 Forearm

0.78

0.76

0.81

   

• Data are presented above as R 2 and the linear mixed models regressed BMC on age, IGF-I, 25(OH)D, season, and race, and interactions among these variables and show that IGF-I was more strongly associated with BMC accrual than 25(OH)D at all sites

• The rate of BMC accrual was negatively associated with 25(OH)D. When IGF-I and 25(OH)D were included in the same regression equation, 25(OH)D did not have a significant predictive effect on BMC accrual above and beyond that of IGF-I.

Cross-sectional studies

 Cheng et al. 2003 [182]

Associations of serum 25(OH)D with BMC at different bone sites were measured by DXA and pQCT.

Sex: female

Age: 10–12 years

Race: Finnish, otherwise unspecified

Location: Jyvaskyla, Finland

Year(s): 1999–2000

193

Data are shown for the overall group (N = 193)

Deficient, ≤25 nmol/L (n = 61)

Insufficient, 26–40 nmol/L (n = 89)

Sufficient, >40 nmol/L (n = 43)

P

 
   

Total body

   

 Bone area (cm2)

1468

1475

1436

NS

   

 BMC (g)

1380

1414

1347

NS

   

Femur

   

 Bone area (cm2)

23.9

23.7

23.1

NS

   

 BMC (g)

19.7

20.4

18.9

0.05

   

Femoral neck

   

 Bone area (cm2)

3.837

3.84

3.67

NS

   

 BMC (g)

3.21

3.30

3.13

NS

   

Lumbar spine

   

 Bone area (cm2)

27.5

28.1

27.3

NS

   

 BMC (g)

22.6

23.9

21.9

NS

   

Distal radius

   

 Whole bone CSA (mm2)

241

226

209

<0.01

   

 Whole bone vBMD (mg/cm3)

273

292

298

<0.01

   

 Trabecular vBMD (mg/cm3)

221

229

231

NS

   

Tibia shaft

   

 Whole bone CSA (mm2)

368

372

363

NS

   

 Whole bone vBMD (mg/cm3)

848

865

853

0.02

   

 Trabecular vBMD (mg/cm3)

525

534

524

NS

   

• Data are adjusted for Tanner stage and BMI.

P value is shown with Bonferroni adjustment in the ANOVA for multiple comparisons.

• Sufficient is different from the insufficient group in BMC of the femur (P = 0.04).

• Sufficient is different from the deficient group in whole bone CSA and vBMD of the radius (P < 0.01).

• Insufficient is different from the deficient group in whole bone CSA (P = 0.05) and vBMD (P < 0.01) of the radius and whole bone vBMD (P < 0.02) of the tibia.

 Foo et al. 2009 [183]

This cross-sectional study investigated the influence of low vitamin D status on bone mass, bone turnover, and muscle strength.

Sex: female

Age: 15 years

Race: Chinese, otherwise unspecified

Location: Beijing, China

Year(s): 2004

301

Data are shown for the overall group (N = 301)

Severe deficiency, <25 nmol/L (n = 94)

Deficiency, ≤50 nmol/L (n = 174)

Sufficient, >50 nmol/L (n = 33)

P trend

   

Size-adjusted BMC (g)

   

 Total body

2230

2291

2417

<0.01

   

 Proximal forearm

1.44

1.47

1.53

<0.01

   

 Distal forearm

1.10

1.52

1.86

<0.01

   

Data are presented as means adjusted for pubertal breast stage, handgrip muscle strength, organized sports participation, physical activity level, dietary vitamin D, and calcium.

 Lee et al. 2013 [184]

Risk factors were evaluated for low 25(OH)D status and its relationships with bone health

Sex: male and female

Age: 9.3 ± 1.9 years

Race: Korean, otherwise unspecified

Location: Seoul and Gyeonggi-do, South Korea

Year(s): unspecified

100

Data are shown for the overall group (N = 100)

Total body BMC

P

   

Unadjusted

0.028

0.08

   

Adjusted model 1

0.02

0.07

   

Adjusted model 2

0.02

0.04

   

• Data presented above are β scores correlating 25(OH)D with BMC and corresponding P values using multiple linear regression analyses

• Model 1 is adjusted for sex, puberty, fat mass, and lean mass

• Model 2 is adjusted for model 1 variables + physical activity and calcium intake

25(OH)D 25-hydroxyvitamin D, 95 % CI 95 % confidence interval, ANOVA analysis of variance, BMC bone mineral content, Cort thk cortical thickness, CSA cross-sectional area, CSMA cross-sectional moment of inertia, Ct cortical, DXA dual-energy x-ray absorptiometry, IGF insulin-like growth factor, NS not significant, RCT randomized controlled trial, SSI stress–strain index, Trab trabecular, vBMD volumetric bone mineral density, VDR vitamin D receptor

Table 7

Other micronutrients and bone health in children and adolescents

Micronutrient

Reference

Study description

Population description

Number of subjects

End points

Results

RCTs

 Magnesium

Carpenter et al. 2006 [185]

1-year placebo-controlled, double-blind RCT of 300 mg/day supplementation of MgO

Sex: female

Age: 8–14 years

Race: white

Location: New Haven, CT

44

BMC of total hip, femoral neck, Ward’s area, and lumbar spine

Combined overall hip

     

Treatment

Placebo

     

1.05 %

0.97 %, P = 0.0534

Prospective studies

 Fluoride

Levy et al. 2009 [187]

Lifetime associations of average daily fluoride intake and DXA bone outcomes at age 11 years

Sex: male and female

Age: birth to 11 years for fluoride assessments; mean age 11.2 years for DXA assessment

Race: 97 % white

Location: Iowa

Year(s): recruitment took place from 1992 to 1995 (fluoride study) and from 1998 to 2000 (bone development study)

481

BMC

Hip

Spine

Total body less head

    

Girls

    

 0–11 years

0.07, NS

0.17, NS

0.10, NS

    

 0–8.5 years

0.04, NS

0.13, NS

0.08, NS

    

 0–3 years

0.03, NS

0.06, NS

0.05, NS

    

 3–6 years

−0.01, NS

0.05, NS

0.02, NS

    

 6–8.5 years

0.11, NS

0.19, 0.01

0.16, NS

    

 85.5–11 years

0.18, 0.01

0.24, <0.01

0.19, NS

    

Boys

    

 0–11 years

0.21, 0.01

0.23, 0.01

0.23, 0.01

    

 0–8.5 years

0.21, 0.01

0.23, 0.01

0.24, 0.01

    

 0–3 years

0.22, 0.01

0.22, 0.01

0.23, 0.01

    

 3–6 years

0.14, NS

0.18, NS

0.19, 0.01

    

 6–8.5 years

0.09, NS

0.12, NS

0.10, NS

    

 85.5–11 years

0.14, NS

0.14, NS

0.15, NS

    

• Data are from unadjusted bivariate associations (r) with fluoride intake and bone outcomes and corresponding P value.

• No statistically significant relationships between daily fluoride intake and bone measures were found in adjusted models (for age, height, weight, and Tanner stage).

 Fluoride

Levy et al. 2014 [188]

Lifetime associations of average daily fluoride intake and DXA bone outcomes at age 15 years

Sex: male and female

Age: birth to 15 years for fluoride assessments; mean age 15.3 years for DXA assessments

Race: 98 % white

Location: Iowa

Year(s): recruitment took place from 1992 to 1995 (fluoride study) and from 1998 to 2000 (bone development study)

358

BMC

Females

Males

     

ß

R 2

Partial R 2

ß

R 2

Partial R 2

    

Total body less head

234, 0.02

0.03

0.03

182, NS

0.02

0.02

    

Spine

7.32, 0.04

0.03

0.03

5.24, NS

0.02

0.02

    

Hip

2.92, NS

0.01

0.01

1.79, NS

<0.01

<0.01

    

• Data are from unadjusted bivariate associations (β) with fluoride intake and bone outcomes and corresponding P value.

• With adjustment for height, weight, time since PHV, Tanner stage, calcium intake, and physical activity, none of the associations remained statistically significant.

• No significant differences were observed between fluoride intake and bone measures across tertiles of fluoride intake from birth to 15 years.

Observational studies

 Vitamin K

O’Connor et al. 2007 [191]

Cross-sectional associations of undercarboxylated osteocalcin (%ucOC) as an index of vitamin K status and BMC

Sex: female

Age: 11–12 years

Race: presumed white

Location: Denmark

223

Serum %ucOC and total body BMC

β = −0.045, P = 0.016

    

Lumbar BMC

β = −0.055, P = 0.037

 Sodium

Hoppe et al. 2000 [149]

Cross-sectional analysis of nutrient intakes determined by 7-day diet records and bone

Sex: half were female, half were male

Age: 10 years

Race: presumed white

Location: Denmark

Year(s): 1997–1998

105

Total body BMC

r = −0.206, P < 0.05

    

Anterior–posterior projected bone area (cm2)

r = −0.215, P < 0.05

 Phosphorous

Hoppe et al. 2000 [149]

Cross-sectional analysis of nutrient intakes determined by 7-day diet records and bone

Sex: half were female and half were male

Age: 10 years

Race: presumed white

Location: Denmark

Year(s): 1997–1998

105

Total body BMC

r = −0.297, P < 0.01

    

Anterior–posterior projected bone area (cm2)

r = −0.284, P < 0.01

 Vitamin C

Prynne et al. 2006 [189]

Cross-sectional Cambridge Bone Studies to relate fruit and vegetable and nutrient intake from 7-day food diaries in 5 age and sex cohorts

Sex: female and male, nearly half of each

Age: 16–19 years

Race: presumed white

Location: UK

257

 

Percent change with doubling in vitamin C intake from univariate analysis, in 4th-grade girls only

     

Boys

Girls

    

Total body BMC

5.5, P < 0.01

1.4, NS

    

Spine BMC

5.6, P < 0.05

2.1, NS

    

Total hip BMC

5.7, P < 0.05

−0.05, NS

    

Femoral neck BMC

5.4, P < 0.01

5.2, NS

    

Trochanter BMC

5.8, P < 0.05

2.5, NS

 Vitamin C, zinc, and iron

Laudermilk et al. 2012 [190]

Cross-sectional analysis of nutrient intakes determined by the Harvard Youth/Adolescent Food frequency Questionnaire

Sex: female

Age: 8–12 years, 4th- and 6th-grade students

Race: ~87 % white, 7 % Asian, 3 % black, 2 % Latino and 1 % Native Hawaiian

Location: Tucson, Arizona

453

(n = 184 4th graders, n = 179 6th graders)

pQCT

Vitamin C

Zinc

    

Femur 20 % site

    

 Cortical density

NS

0.16, P < 0.05

    

 Periosteal circumference

0.17, P < 0.05

NS

    

 Endosteal circumference

0.17, P < 0.05

NS

    

 SSI

0.18, P < 0.05

NS

    

Tibia 4 % site

    

 Trabecular area

0.18, P < 0.05

NS

    

 Periosteal circumference

0.19, P < 0.01

NS

    

Tibia 66 % site

    

 Cortical density

NS

0.15, P < 0.05

    

 Cortical area

0.15, P < 0.05

NS

    

 SSI

0.18, P < 0.05

NS

    

In regression modeling, iron was negatively associated with femoral cortical area and tibia SSI.

 Fluoride

Grobler 2009 [186]

This field study included the whole population of children aged 10–15 years living in areas of high and low fluoride in the drinking water.

Sex: male and female

Age: 10–15 years

Race: not specified, but of mixed ethnicity (i.e., from Khoi, Caucasian, and Negroid roots that developed into a homogenous ethnic group over many years)

Location: South Africa

Year(s): not specified

166

(n = 77 from a 0.19 mg/L F area; n = 89 from a 3.00 mg/L F area)

 

High fluoride

Low fluoride

P

     

Girls

Boys

Girls

Boys

    

Radius BMC (g)

    

 10–11 years

1.29

1.29

1.26

1.32

NS

    

 12–13 years

1.56

1.41

1.33

1.29

<0.05a

    

 14–15 years

1.80

1.80

1.18

1.52

<0.05a

    

Radius bone width (cm)

    

 10–11 years

0.97

0.98

0.98

1.01

NS

    

 12–13 years

1.09

1.08

1.04

1.15

NS

    

 14–15 years

1.10

1.14

1.18

1.21

NS

%ucOC percentage of undercarboxylated osteocalcin, BMC bone mineral content, DXA dual-energy x-ray absorptiometry, NS not significant, PHV peak height velocity, pQCT peripheral quantitative computed tomography, RCT randomized controlled trial, SSI stress–strain index

aSignificant differences in BMC in the 12- to 13-year-olds and the 14- to 15-year-olds were found among boys from the high fluoride area and girls from the low fluoride area

Table 8

Food patterns and bone health in children and adolescents

Food

Source

Study description

Population description

Number of subjects

End points

Results

RCTs

 Dairy

Du et al. 2004 [170]

2-year school-based randomized trial of 330 mL milk, 330 mL milk + 5 or 8 μg vitamin D3, or control

Sex: female

Age: 10–12 years

Race: Chinese

Location: Beijing, China

757

 

Group mean increase

P

      

Treatment

Placebo/control

    

Height

0.95 %

0.087 %

<0.0005

    

Total body BMC

38.4 %

35.9 %

0.03

    

Bone area

29.5 %

31.3 %

0.2

 Dairy

Courteix et al. 2005 [158]

12-month randomized, double-blind, placebo-controlled study

Baseline calcium: supplement = 1008 (398); placebo = 988 (345)

Was combined with an exercise intervention that found a combined effect not reported here. After randomization, fewer subjects were in the dairy group than in the placebo group (34 vs 79, respectively, at the baseline). It was expected that 240 subjects would be recruited, but because of the publicity surrounding Mad Cow disease, many parents were afraid of dairy products.

Sex: premenarchal female

Age: 8–13 years

Race: Caucasian

Location: France

113

 

Calcium supplement

Placebo

    

Total body

BMC

155 ± 79

166 ± 66

    

Lumbar spine

BMC

3.429 ± 2.388

3.228 ± 2.642

    

Femoral neck

BMC

0.248 ± 0.187

0.185 ± 0.103

    

Trochanter

BMC

0.941 ± 0.525

0.796 ± 0.582

    

Wards

BMC

0.001 ± 0.054

0.047 ± 0.086

    

Ultradistal radius

BMC

0.104 ± 0.091

0.111 ± 0.107

    

Mid radius

BMC

0.305 ± 0.230

0.355 ± 0.322

    

1/3 distal

BMC

0.072 ± 0.078

0.093 ± 0.077

    

Adjusted for lean tissue mass. All NS

 Dairy

Cheng et al. 2005 [159]

2 year double-blind, placebo-controlled RCT of calcium (1000 mg) + vitamin D3 (200 IU), calcium (1000 mg), cheese (1000 mg calcium), and placebo

Sex: female

Age: 10–12 years

Race: presumed white

Location: Finland

195

 

Cheese

P

    

Total body

BMD (%)

10.4

8.9 (compliance >50)

0.044

    

Femoral neck

BMC (%)

26.5

22.4

NS

    

Total femur

BMC (%)

36.9

33.6

NS

    

Spine

BMC (%)

52.4

47.0

NS

    

Tibia cortical thickness

pQCT (%)

37.1

31.1 (compliance 50)

0.01

 Dairy

Merrilees et al. 2000 [169]

2-year RCT of dairy food supplementation and 1-year follow-up after cessation of intervention

Sex: female

Age: 15–17 years

Race: presumed white

Location: New Zealand

Stratified by forearm BMD at baseline

91

Total body

BMC (g)

168.9

167.4

NS

    

Lumbar spine

BMC (g)

3.83

2.58

NS

    

Femoral neck

BMC (g)

0.12

0.06

NS

    

Trochanter

BMC (g)

0.75

0.25

<0.05

    

Difference disappeared 1 year after cessation

 Fiber

Abrams et al. 2005 [193]

1-year placebo-controlled RCT of 8 g/day mixed short and long inulin-type fructans

Sex: half were male and half were female

Age: 9–13 years Tanner stage 2 or 3

Race: 53 % white, 14 % black, 22 % Hispanic, 10 % Asian

Location: Houston, TX

Between 5th and 95th percentile BMI

100

Total body

BMC, %

18.3

16.7

0.03

Observational studies

 Total diet

Wosje et al. 2010 [335]

Prospective study with cross-sectional analysis by age to relate 3-day diet records to fat and bone mass in children during the age period of 3.8–7.8 years, using reduced-rank regression

Sex: male and female (167/158)

Age: 3.8–7.8 years

Race: 75 % white, 25 % black

Location: Cincinnati, OH

Year(s): 2000–2004

325

Fat mass (kg)

Bone mass (g)

Diets high in dark-green and deep-yellow vegetables and processed meats and low in fried foods were associated with lower fat mass (P < 0.001) and higher bone mass (P = 0.03 for year 1, P = 0.2 for year 2, and P < 0.01 for years 3 and 4)

 Fruits and Vegetables

Prynne et al. 2006 [189]

Cross-sectional Cambridge Bone Studies to relate fruit and vegetable and nutrient intake from 7-day food diaries in 5 age and sex cohorts

Sex: female and male, nearly half of each

Age: 16–19 years

Race: presumed white

Location: UK

257

 

Percent change with doubling in fruit and vegetable intake from univariate analysis

     

Boys

P

Girls

P

    

Total body BMC

9.2

<0.001

5.2

0.02

    

Spine BMC

7.8

0.002

8.8

0.001

    

Total hip BMC

6.6

0.008

5.0

0.04

    

Femoral neck BMC

10.3

<0.001

6.5

0.07

    

Trochanter BMC

7.9

0.01

5.2

NS

 Fruits and vegetables

McGartland et al. 2004 [195]

Cross-sectional study on effect of fruit and vegetable intake on BMD

Sex: male and female

Age: 12 and 15 years

Race: presumed white

Location: Northern Ireland

1345

Forearm BMD

Heel BMD

12-year-old girls consuming high amounts of fruit had significantly higher heel BMD (β = 0.037; 95 % CI, 0.017, 0.056). No other associations were observed.

 Fruits and vegetables

Tylavsky et al. 2004 [196]

Cross-sectional study on the effect of low (<3 servings) versus high (≥3 servings) fruit and vegetable intake on urinary calcium excretion and bone mass

Sex: female

Age: 8–13 years

Race: white

Location: Tennessee, USA

56

Total body bone area

Wrist bone area

Compared with the low-consumption group, the high fruit and vegetable consumption group had 6 and 8.3 % larger total body (P < 0.03) and wrist bone area (P < 0.03).

    

Total body BMC

Wrist BMC

Whole body and wrist BMC was 7.4 (P = 0.07) and 7.0 % (P = 0.09) larger in the high-consumption group (P > 0.05).

    

Total body BMD

Wrist BMD

Whole body and wrist BMD did not differ significantly between the low- and high-consumption groups (P > 0.05).

    

Urinary calcium

Those reporting high fruit and vegetable intake had lower concentrations of urinary calcium/kg body weight (P < 0.02).

 Fruits and vegetables

Whiting et al. 2004 [197]

Cross-sectional study of bone growth in children

Sex: male and female

Age: 8–14 years

Race: presumed white

Location: Saskatoon, Canada

Year(s): 1991–1997

131

BMC

Fruit and vegetable intake appears to influence BMC in adolescent girls but not boys.

 Fruits and vegetables

Vatanparast et al. 2005 [198]

Cross-sectional study on the effect of milk products, vegetables, and fruit on total body BMC

Sex: male and female

Age: 8–20 years

Race: presumed white

Location: Saskatoon, Canada

Year(s): 1991–1997

150

Total body BMC

Fruit and vegetable intake was a significant independent predictor of total body BMC in boys but not girls.

 Caffeine

Conlisk and Galuska 2000 [204]

Cross-sectional study on effect of caffeine on BMD in healthy women

Sex: 177 women

Age: 19–26 years

Race: presumed white

Location: Midwestern USA

Year(s): 1991

177

Caffeine consumption for past 12 weeks by self-report

BMD at the lumbar spine and femoral neck by DXA

Caffeine was not significantly associated with BMD.

 Carbonated beverages

Wyshak 2000 [200]

Cross-sectional study of carbonated beverage consumption and bone fractures

Sex: girls

Age: 9th and 10th graders (mean age 15.8 years)

Race: unspecified, American high school students

Location: “urban high school,” USA

460

Self-reported physical activity, carbonated beverage consumption, and bone fractures

Carbonated beverage consumption and bone fractures were associated (OR, 3.14; 95 % confidence limit, 1.45, 6.78; P = 0.004).

 Carbonated beverages

McGartland et al. 2003 [194]

Cross-sectional observational study of the association between CSDs and BMD in postprimary schools in Northern Ireland

Sex: 744 girls, 591 boys

Age: 12 years (323 boys, 376 girls); 15 years (268 boys, 368 girls)

Race: presumed white

Location: Belfast, Northern Ireland

Year(s): 2000

1335

CSD consumption via RD-administered dietary history method

BMD of the nondominant forearm (distal radius) and dominant heel (os calcis) by DXA

A significant inverse relationship between total CSD intake and BMD was observed in girls at the dominant heel (β, −0.099; 95 % CI, −0.173 to −0.025). Non-cola consumption was inversely associated with dominant heel BMD in girls (β, −0.121; 95 % CI, −0.194 to −0.048), and diet drinks were also inversely associated with heel BMD in girls (β, −0.087; 95 % CI, −0.158 to −0.016). No consistent relationships were observed between CSD intake and BMD in boys.

 Carbonated beverages

Ma and Jones 2004 [199]

Population-based case–control study to investigate the association between soft drink and milk consumption, physical activity, bone mass, and upper limb fractures in children aged 9–16 years

Sex: half male and half female

Age: 9–16 years

Race: presumed white

Location: Tasmania, Australia

Year(s): 1998–2002

206 fractures

206 controls

Bone mass using DXA at the total body, lumbar spine, right femoral neck:

BMC

aBMD

BMAD

Soft drink and dairy drink consumption (in-person interview)

None of the drink types (milk, cola, and carbonated drinks) was significantly different between cases and controls for total fracture. For wrist and forearm fractures, there was a positive association between cola drink consumption and fracture risk (OR, 1.39/unit; 95 % CI, 1.01, 1.91).

 Carbonated beverages

Manias et al. 2006 [201]

Cross-sectional study of recurrent fracture, diet, and physical activity

Sex: 78 girls, 72 boys

Age: 4–16 years

Race: presumed white

Location: Sheffield, UK

150

Bone area, BMC, BMD of spine, lower body, and upper body by DXA

Fracture history and trauma severity

Diet (including beverage consumption), physical activity, and other lifestyle factors via questionnaires

Children with recurrent fractures had a significantly lower milk intake, lower levels of physical activity, a higher BMI, and a higher consumption of carbonated beverages than controls.

 Carbonated beverages

Libuda et al. 2008 [202]

Prospective (DONALD) study of diet from 3-day diet records for 4 years prior to a single forearm pQCT measure

Sex: 113 girls, 115 boys

Age: 6–18 years

Race: presumed white

Location: Germany

228

Forearm pQCT

Carbonated beverage consumption was inversely associated with BMC (P < 0.05), cortical area (P < 0.05), and polar strength strain index (P < 0.05), polar strength strain index (P < 0.01), and periosteal circumference (P < 0.05) of the radius assessed by pQCT, after adjustment for age, sex, total energy intake, muscle area, BMI SD scores, and growth velocity.

95 % CI 95 % confidence interval, aBMD areal bone mineral density, BMAD bone mineral apparent density, BMC bone mineral content, BMD bone mineral density, CSD carbonated soft drink, DONALD Dortmund Nutritional and Anthropometric Longitudinally Designed, DXA dual-energy x-ray absorptiometry, NS not significant, OR odds ratio, pQCT peripheral quantitative computed tomography, RCT randomized controlled trial, RD registered dietician, SSI stress–strain index

Table 9

Infant nutrition and bone health in children and adolescents

Source

Study description

Population description

Number of subjects

End points

Results

 Koo et al. 2003 [211]

6-month randomized, double-blind, parallel study assessing changes in bone mineral accretion by DXA in healthy infants fed a milk-based formula with or without palm olein

Sex: 57 males, 71 females

Age: Infants >2 weeks at baseline

Race:72 African American, 48 Caucasian, 8 Hispanic/Asian/other

Location: USA and Canada

128

Total body BMC (%)

Group mean increase

     

Breast-fed

Control formula (milk-based formula)

Treatment (milk-based formula with palm olein)

    

3 months

 

62.1

76.2*

    

6 months

 

134.3

149.6*

Observational studies

 Butte et al. 2000 [216]

Prospective cohort study of breast-fed and formula-fed infants over 24 months

Sex: 33 males, 43 females

Age: >2 weeks at baseline

Race: 55 Caucasian, 7 African American, 11 Hispanic, 3 Asian

Location: USA

76

Total body BMC (g)

Breast-fed (<12 months)

Breast-fed (>12 months)

Formula-fed

    

12 months

Data not reported

Lowera

Highera,**

    

24 months

310 (P = 0.05)

289 (P = 0.05)

Data not reported

 Jones et al. 2000 [217]

Prospective cohort study to determine whether breastfeeding in early life is associated with bone mass in prepubertal children

Sex: 215 males, 115 females

Age: 8 years at follow-up

Race: predominantly Caucasian

Location: Tasmania

330

 

Breast-fed

Bottle fed

    

Total body BMD at 8 years (g/cm2)

0.642 ± 0.082

0.627 ± 0.073*

    

Femoral neck BMD at 8 years (g/cm2)

0.608 ± 0.072

0.590 ± 0.068

    

Lumbar spine BMD at 8 years, g/cm2

0.781 ± 0.047

0.766 ± 0.047**

 Ma and Jones 2003 [219]

Population-based case-controlled study to examine the association between bone mass and upper limb fractures in children

Sex: 206 males, 124 females

Age: 8 years at follow-up

Race: predominantly Caucasian

Location: Tasmania

324

 

Breast-fed

    

Multivariate OR (95 % CI)

0.43 (0.19–0.94)a

 Young et al. 2005 [221]

BMD was assessed in healthy 4-year-old children after confirming the type of infant feeding by history. All children had exclusively consumed human milk, infant formula without palm olein oil, or an infant formula with palm olein oil.

Sex: 58 % male

Mean age: 4.5 years

Race: 85 % Caucasian

Location: USA

178

 

Human milk

Formula without palm olein oil

Formula with palm olein oil

    

Total body BMC at 4 years (g)

566 ± 12

583 ± 10c

570 ± 7

 Harvey et al. 2009 [213]

Prospective cohort study examining associations between duration of breastfeeding and compliance with infant dietary guidelines and later bone size and density at age 4 years

Sex: 158 males, 149 females

Age: 6 months at baseline

Race: not reported

Location: UK

599

 

Breast milk (<1 month)

Breast milk (2–6 months)

     

No differencea

No differencea

 Molgaard et al. 2011 [212]

Random sample of infants from the Copenhagen Cohort Study of Infant Growth and Nutrition were investigated to determine if early nutrition and early growth are associated with later bone mass in adolescence.

Sex: 44 males, 65 females

Age: birth to 12 weeks. Examination at 17 years

Race: Danish origin; otherwise not reported

Location: Denmark

Years: 1987–2005

109

Lumbar spine BMC

The duration of exclusive breastfeeding was positively correlated with the sex-adjusted lumbar spine BMCa,**.

 Pirila et al. 2011 [214]

Prospective study of infants divided into three equal-sized groups according to the total duration of breastfeeding (short = 3 months, intermediate = >3 to <7 months, and prolonged = >7 months) followed-up after 32 years

Sex: 76 males, 82 females

Age: 2 weeks to 12 months in original cohort; 31.7–34.0 years at follow-up

Race: not reported

Location: Finland

Year(s): 2007–2009

158

Total body BMC

In males, short breastfeeding was associated with higher bone area, BMC, and BMD compared to longer breastfeeding. Males in the short breastfeeding group had on average 4.7 % higher total body BMD than males in the prolonged breastfeeding groupa,**.

 Fewtrell et al. 2013 [220]

To compare total body and lumbar spine bone in children aged 10 years that as infants participated in a randomized trial and either were breast-fed or randomly received a control formula or an sn-2 palmitate-enriched formula using a double-blind permuted block allocation. The study was completed at 12 weeks and follow-up measurements were taken at 10 years.

Sex: 52 % male, 48 % female

Age: birth to 12 weeks; follow-up at 10 years

Race: not reported

Location: Cambridge, UK

91

 

Breast-fed

Formula with standard fat blend

Formula with high sn-2 fat blend

    

Lumbar spine BMC (g)

23.12 ± 4.46

22.54 ± 4.52

24.38 ± 5.15

    

Total body BMC (g)

1062 ± 213

1049 ± 264

1097 ± 231

 Jones et al. 2013 [218]

Birth cohort study to determine if early life factors (e.g., breastfeeding) were associated with bone mass and fractures in 16-year-old adolescents

Sex: 265 males, 150 females

Age: 16 years at follow-up

Race: predominantly Caucasian

Location: Tasmania

415

OR (95 % CI)

Any fracture

Upper limb fracture

Lower limb fracture

    

Intention to breastfeed

0.71 (0.55–0.94)c

0.80 (0.55–1.66)

0.63 (0.36–1.13)

    

Breastfeeding at 1 month

0.65 (0.48–0.87)c

0.84 (0.54–1.73)

0.49 (0.26–0.93)c

    

Breastfeeding at 3 months

0.80 (0.60–1.09)

0.87 (0.58–1.31)

0.82 (0.45–1.48)

    

Maternal recall of breastfeeding

0.69 (0.54–0.89)c

0.73 (0.51–1.39)

0.75 (0.42–1.34)

 Kalkwarf et al. 2013 [215]

A cross-sectional study to describe age, sex, race, growth, and human milk feeding effects on bone

Sex: 158 males, 149 females

Age: 1–36 months

Race: 225 Caucasian, 63 African American, 15 mixed Caucasian and African American, and 4 Asian

Location: USA

307

 

Human milk

No human milk

    

Overall BMD Z-score

−0.05

0.21**

95 % CI confidence interval, BMC bone mineral content, BMD bone mineral density, DXA dual-energy x-ray absorptiometry, OR odds ratio, RCT randomized controlled trial

aValues were reported in a figure and via text

*P < 0.01; **P < 0.05

Table 10

DMPA injections and oral contraceptive use on bone health in adolescents

Source

Study description

Population description

Number of subjects

End points

Results

Observational studies

 Lloyd et al. 2000 [223]

An 8-year longitudinal study of white females in the Penn State Young Women’s Health Study. OC users were those individuals who had used low-dose monophasic OCs for a minimum of 6 months at age ~12 and were still using them at age 20 years.

Sex: 62 females

Age: 11.9 ± 0.5 years at baseline

Race: Caucasian

Location: USA

62

Total body BMC (g) at 12 years

OC users

Nonusers

     

1463.0 ± 64.0

1402.5 ± 45.5

    

Total body BMC (g) at 20 years

2272.2 ± 55.9

2214.2 ± 45.1

    

Total body BMD (g/cm2) at 12 years

0.92 ± 0.01

0.91 ± 0.01

    

Total body BMD (g/cm2) at 20 years

1.13 ± 0.01

1.12 ± 0.01

    

Hip BMD (g/cm2) at 20 years

1.01 ± 0.02

0.99 ± 0.02

    

The OC users did not differ in anthropometric, body, or total bone measurements at baseline or at age 20 years (no differences in age at menarche or exercise at age 20 years).

OC pill use by healthy white teenage females did not affect acquisition of peak bone mass.

 Lara-Torre et al. 2004 [225]

Nonrandomized prospective study to examine BMD in control adolescent subjects vs those receiving DMPA injections or OCs over a 2-year period

Sex: 71 females

Age: 11–19 years

Race: Caucasian and black

Location: USA

148

 

OC usersb

DMPA injectionb

Nonuserb

    

% change in lumbar BMD at 6 months

1.170 (−0.14, 2.48)

−0.249 (−1.25, −0.75)*

2.768 (0.48, 5.05)

    

% change in lumbar BMD at 12 months

2.35 (0.16, 3.78)

−1.59 (−2.53, 0.59)*

2.45 (−2.01, 5.99)

    

% change in lumbar BMD at 18 months

3.82 (−0.62, 6.41)

−2.91 (−3.64, −2.23)*

0.73 (−1.01, 1.54)

    

% change in lumbar BMD at 24 months

−1.01 (−1.23, 5.33)

−1.85 (−4.15, −0.23)*

5.89 (5.37, 6.85)

    

There was a statistically significant difference in BMD between DMPA users and the control at 6, 12, 18, and 24 months. There was no statistical difference between OC pill users and the control at any time point.

 Lloyd et al. 2004 [224]

A 10-year longitudinal study of white females in the Penn State Young Women’s Health Study. OC users were those individuals who had used low-dose monophasic OCs for a minimum of 6 months at age ~12 years and were still using them at age 22 years.

Sex: 80 females

Age: 21.7 ± 0.1 years

Race: Caucasian

Location: USA

80

 

OC users

Nonusers

    

Total body BMC (g) at 22 years

2260 ± 55

2316 ± 66

    

Total body BMD (g/cm2) at 22 years

1.14 ± 0.01

1.15 ± 0.02

    

Hip BMD (g/cm2) at 22 years

1.0 ± 0.02

1.0 ± 0.02

    

Femoral neck section modulus (cm3) at 22 years

1.29 ± 0.05

1.32 ± 0.05

    

Femoral neck section modulus (cm3) at 22 years

1.70 ± 0.06

1.74 ± 0.07

    

OC pill use among adolescents was not correlated with bone or body composition measurements.

 Rome et al. 2004 [227]

Prospective, observational design study to examine the effects of DMPA injections or OC (20 μg ethinyl estradiol/100 μg levonorgestrel) use on bone biochemical markers over 12 months

Sex: 165 females

Age: 11–18 years

Race: Caucasian and black

Location: USA

370

Spine and femoral neck BMD

No significant differences reported between spine and femoral neck BMD for each group at each time point. Spine BMD was lower in the DMPA injection group vs the OC group. Exact values not reported

 Cromer et al. 2008 [226]

Observational prospective cohort study to examine the effects of DMPA injections or OC (20 μg ethinyl estradiol/100 μg levonorgestrel) use on BMD over 24 months

Sex: 375 females

Age: 12–18 years

Race: Caucasian and black

Location: USA

433

 

OC users

DMPA injection

Nonuser

    

Spine BMD (g/cm2)

1.03 ± 0.11

0.98 ± 0.09*

0.98 ± 0.11

    

Femoral neck BMD (g/cm3)

0.97 ± 0.14

0.92 ± 0.14*

0.92 ± 0.15

    

Over 24 months, mean percent change in spine BMD was −1.5 % (DMPA injection), 4.2 % (OC use), and 6.3 % (control).

Over 24 months, mean percent change in femoral neck BMD was −5.2 % (DMPA injection), 3.0 % (OC use), and 3.8 % (control).

Adolescent girls receiving DMPA injections had significant loss of BMD. Clinical significance of this loss may be mitigated by the slowed loss after the first year of DMPA use.

 Pikkarainen et al. 2008 [228]

4-year follow-up study examining the effects of estrogen-progestin OC use

Sex: 122 females

Age: 12–19 years

Race: Assumed predominantly Caucasian

Location: Finland

122

 

OC user (1–2 years)

OC user (>2 years)

Nonuser

    

Lumbar spine area (cm2) at baseline

56.1 ± 6.1

56.7 ± 5.9

55.1 ± 5.9

    

Lumbar spine area (cm2) at 4 years

58.6 ± 6.1

58.7 ± 0.7

59.5 ± 6.3

    

Femoral neck area (cm2) at baseline

4.79 ± 4.33

4.64 ± 0.37

4.66 ± 0.40

    

Femoral neck area (cm2) at 4 years

4.80 ± 0.3

4.7 ± 0.4

4.7 ± 0.40

    

Lumbar spine BMC (g) at baseline

54.3 ± 11.8

57.5 ± 11.9

51.2 ± 10.2

    

Lumbar spine BMC (g) at 4 years

59.10 ± 11.7

60.2 ± 12.3

59.2 ± 10.0

    

Femoral neck BMC (g) at baseline

4.3 ± 0.8

4.4 ± 0.8

4.1 ± 0.6

    

Femoral neck BMC (g) at 4 years

4.5 ± 0.8

4.4 ± 0.7

4.3 ± 0.6

    

There was a significant trend of a lesser increase of BMC in lumbar spine in the OC users (>2 years) than in the other two groups (P < 0.0046).

The development of the femoral neck was significantly different between the OC users (1–2 years) and OC users (>2 years). The longer duration of OC use seemed to suppress normal BMC development (P for linearity = 0.038)

 Walsh et al. 2008 [230]

A case-controlled matched study aiming to examine whether the effects of DMPA injections are age-specific and to determine the effects of DMPA on hormones and bone turnover

Sex: 100 females (50 pairs)

Age: 12–18 years

Race: Caucasian and black

Location: USA

100

 

DMPA injectiona

Nonusersa

    

Lumbar spine BMD (g/cm2)

1.003 (0.972–1.035)*

0.947 (0.950–0.977)

    

Total hip BMD (g/cm2)

0.983 (0.950–1.016)*

0.931 (0.897–0.966)

    

Distal forearm BMD (g/cm2)

0.465 (0.446–0.483)

0.474 (0.457–0.491)

    

DMPA injections are associated with a bone density deficit at the spine and hip when used before peak bone mass.

 Bonny et al. 2011 [222]

Prospective longitudinal study examining the relationship between weight and BMD and the correlation between weight change and BMD in premenarcheal girls reporting DMPA use or OC (20 μg ethinyl estradiol/100 μg levonorgestrel) use

Sex: 433 females

Age: 12–18 years

Race: Caucasian and black

Location: USA

433

 

User

DMPA injection

Nonuser

    

Correlation between absolute change in weight (kg) and absolute change in femoral neck BMD at 12 months

1.000

1.000

1.000

    

Correlation between absolute change in weight (kg) and absolute change in femoral neck BMD at 24 months

1.000

1.000

1.000

    

Correlation between absolute change in weight (kg) and absolute change in spine BMD at 12 months

−0.82

−0.101

0.10

    

Correlation between absolute change in weight (kg) and absolute change in spine BMD at 24 months

−0.12

0.098

0.48

    

Body weight was significantly positively associated with femoral neck BMD and spine BMD regardless of the contraceptive method (P < 0.05).

Change in body weight at 12 and 24 months was highly correlated with change in femoral neck BMD (P < 0.0001) for all treatment groups.

No statistically significant correlation between change in weight and change in spine BMD was seen in the DMPA, OC, or control subjects at 12 or 24 months.

 Biason et al. 2015 [229]

Nonrandomized parallel-control study with 1-year follow-up assessing the effect of OC (20 μg ethinyl estradiol/150 μg desogestrel) users on bone density

Sex: 67 females

Age: 12–19 years

Race: Assumed Brazilian

Location: Brazil

67

 

OC user

Nonuser

    

% variation lumbar BMD (g/cm2)

2.07

12.16

    

% variation lumbar BMC (g)

1.57*

16.84

    

% variation subtotal BMD (g/cm2)

0.56*

5.28

    

% variation subtotal BMC (g)

1.18*

16.04

    

% variation whole body BMD (g/cm2)

0.84

5.28

    

% variation whole body BMC (g)

1.22*

11.34

    

Use of low-dose OCs was associated with lower bone mass acquisition in adolescents over a 1-year period.

OC users showed low bone mass acquisition in the lumbar spine and had BMD and BMC median variations of 2.07 and 1.57 %, respectively, between the measurements at baseline and 12 months.

Nonusers showed median variations of 12.16 and 16.84 % for BMD and BMC, respectively, over the same period.

95 % CI confidence interval, BMC, bone mineral content, BMD bone mineral density, RCT randomized controlled trial

aMean (95 % CI)

bMedian (25 %, 75 %)

*P < 0.05 compared with control

Table 11

Alcohol consumption and bone health in children and adolescents

Reference

Study description

Population description

Number of subjects

End points

Results

Prospective studies

 Korkor et al. 2009 [231]

This 4-year prospective study assessed the relationship between smoking and alcohol intake and bone mass. Students in 9th grade were recruited. Number of alcoholic beverages in the last week was reported in the 9th through 12th grades. Subjects classified as any alcohol over 4 years vs not

Sex: 37 males, 72 females

Age: 14–19 years at enrollment

Race: white 83 %, Asian 1 %, Hispanic 4 %, unknown 12 %

Location: Wisconsin, USA

Year(s): 2000–2003

109

Peripheral DXA

Simple model, any alcohol intake

Adjusted model, any alcohol, or smoking

    

Heel aBMD in 12th grade (g/cm2)

−0.042, P = 0.047 (7.2 %)

−0.028, P = 0.05 (4.8 %)

  
    

The simple model includes any alcohol over the 4-year study (yes, n = 13; no, n = 96). The adjusted model was adjusted for sex baseline aBMD dairy intake. Large overlap in smoking and alcohol use. Any smoking or alcohol combined (N = 14) was associated with a −0.028-g/cm2 lower aBMD.

 Lucas et al. 2012 [235]

This prospective study quantified the association between early initiation of smoking and alcohol intake and forearm BMD in early and late adolescence. Alcohol intake reported at age 13 and 17 years and classified as never, tried but not currently drinking, <1 drink/week, or ≥1 drink/week

Sex: female

Age: 13 and 17 years

Race: not specified

Location: Portugal

Year(s): 2003–2007

716

Peripheral DXA

Drinking at age 13 years vs never (n = 298)

    

Distal radius aBMD

Tried, not currently drinking (n = 380)

Drinks < 1/week (n = 26)

Drinks ≥ 1/week (n = 8)

P value

    

At age 13 years

0.3 %

−2.0 %

−1.1 %

0.826

    

At age 17 years

−1.1 %

2.3 %

−4.8 %

0.282

     

Drinking at age 17 years vs never (n = 120)

     

Tried, not currently(n = 273)

Drinks, not daily (n = 266)

Drinks, daily (n = 54)

P value

    

At age 17 years

1.1 %

0.0 %

−2.3 %

0.471

     

Ever drank in adolescence vs never (n = 84)

     

Tried 13 years but before 17 years (n = 213)

Tried before 13 years (n = 419)

P value

     

−0.9 %

−2.0 %

0.216

     

Means are adjusted for menarche age, alcohol intake, sports, and BMI.

 Dorn et al. 2013 [233]

This 3-year prospective study of girls examined bone accrual according to smoking, alcohol intake, depression, and anxiety. Alcohol use was coded as 0–5 drinks or ≥6 drinks in lifetime.

Sex: female

Age: 11–17 years

Race: 62 % white, 33 % black, 5 % other

Location: Ohio, USA

Year(s): 2003–2010

262

DXA

Total body BMC (g)

Spine aBMD (g/cm2)

Hip aBMD (g/cm2)

There was no significant association between alcohol use and any bone outcome measure. Regression models were adjusted for race, puberty stage, weight, height, age at menarche, contraceptive use, calcium intake, vitamin D status, and physical activity.

Cross-sectional studies

 Elgan et al. 2002 [237]

This cross-sectional study conducted in nursing students measured lifestyle and physiologic factors. Alcohol intake was measured by questionnaire.

Sex: female

Age: 16–24 years

Race: not reported

Location: Lund, Sweden

Year(s): 1999

218

Peripheral DXA

Heel aBMD (g/cm2)

Correlation with alcohol intake, r = −0.05 (P = NS)

Alcohol intake not significant (P = 0.84) in regression models adjusting for age, weight, physical activity, and hormonal age

Average alcohol intake 16.6 g/month; 79 % reported some alcohol intake

 Kyriazopoulos et al. 2006 [236]

This cross-sectional study evaluated the influence of current dietary factors (calcium, proteins, alcohol, coffee, and tea intake), exercise, smoking, and sunlight on forearm bone mass in young Greek men. Alcohol intake reported as consumption per week

Sex: male

Age: 18–30 years, mean 22 years

Race: not reported

Location: Greece

Year(s): not reported

300

Peripheral DXA

Distal radius BMC (g)

Distal radius aBMD (g/cm2)

Ultradistal radius aBMD (g/cm2)

Mean alcohol intake 3.78 ± 1.35 times/week. No association between alcohol intake (times/week) and bone measures with and without adjustment for height, weight, calcium intake, sunlight exposure, exercise, and work

 Dorn et al. 2011 [232]

This cross-sectional analysis of baseline data examined how bone mass and density varied according to smoking, alcohol intake, depression, and anxiety. Alcohol intake reported as no drinks (n = 135), 1–5 drinks (n = 59), ≥6 drinks (n = 67) in the past year

Sex: female

Age: 11–17 years

Race: 62 % white, 33 % black, 5 % other

Location: Ohio, USA

Year(s): 2003–2007

261

DXA

Total body BMC (g)

Spine aBMD (g/cm2)

Total hip aBMD (g/cm2)

Femoral neck aBMD (g/cm2)

No significant main effect of alcohol group and any outcome measure (P > 0.10). Analyses were adjusted for age, weight, height, race, and maturational stage.

    

Significant interactions between alcohol, smoking, and depression symptoms on bone outcomes. Stronger negative association between depressive symptoms and total body BMC among individuals who smoked and used alcohol

 Eleftheriou et al. 2013 [238]

A cross-sectional study evaluating the association of smoking, alcohol consumption, and prior exercise with lower limb bone volume, composition, and structure by MRI and DXA in a large cohort of healthy Caucasian males. Alcohol intake was coded as none, low (1–9 U/week), moderate (12–21 U/week), or high (>21 U/week)

Sex: male

Age: mean 19.9 years

Race: Caucasian

Location: UK

Year(s): not reported

651

DXA

Difference between Alcohol intake group vs none

     

Low 1–9 U/week

Moderate 12–24 U/week

High > 24 U/week

P value

    

Total hip aBMD

1.5 %

2.3 %

−0.6 %

0.017

    

Femoral neck aBMD

−1.1 %

2.8 %

−0.7 %

0.015

    

Proximal femur geometry by MRI

    

 Periosteal volume

NS, data not shown

    

 Endosteal volume

NS, data not shown

    

 Cortical volume

NS, data not shown

    

Adjusted for height, weight, smoking, and weight-bearing activity

 Winther et al. 2014 [234]

This cross-sectional, population-based study compared BMD levels of Norwegian adolescents with lifestyle factors. Alcohol intake reported as never, ≤1 per month, or ≥2 per month. Alcohol use recoded for analysis as yes vs no

Sex: male and female

Age: 15–17 years

Race: not reported

Location: Norway

Year(s): 2010–2011

835

 

Difference between alcohol users vs not

     

Age adjusted

Multivariable adjusted

    

DXA

β

P value

β

P value

    

Males (n = 492)

    

 Total hip aBMD (g/cm2)

0.027

0.057

0.035

0.006

    

 Femoral neck aBMD (g/cm2)

0.030

0.037

0.028

0.021

    

Females (n = 469)

    

 Total hip aBMD (g/cm2)

−0.014

0.297

    

 Femoral neck aBMD (g/cm2)

−0.013

0.330

    

Alcohol uses include intakes of up to 1/month (44.7 % of girls, 36.4 % of boys) and ≥2 times/month (30.3 % of girls, 30.9 % of boys) vs never (23.4 % of girls, 30.4 % of boys).

Multivariable analyses were adjusted for age, BMI, height, sexual maturation, physical activity, smoking, diseases, and medications known to affect bone hormonal contraceptives.

aBMD areal bone mineral density, BMC bone mineral content, BMD bone mineral density, DXA dual-energy x-ray absorptiometry, NS not significant

Table 12

Smoking and bone health in children and adolescents

Reference

Study description

Population description

Number of subjects

End points

Results

Prospective studies

 Lappe et al. 2001 [42]

This prospective study of female army recruits examined risk factors for developing stress fractures during 8 weeks of basic training.

Sex: female

Age: 21.1 ± 3.7 years

Race: 31 % black, 53 % white, 16 % other

Location: USA

Years: 1995–1996

3758

Stress fracture

Odds ratios (95 % CI)

    

History of smoking 1.34 (1.05–1.71)

Years smoked 1.05 (1.02–1.08)

    

•Adjusted for age, race and bone speed of sound

 Elgan et al. 2003 [240]

This prospective study is a 2-year follow-up of the cohort reported in 2002 and investigated the joint effects of OC use and smoking. Smoking reported as monthly average. Twenty-eight subjects smoked as follows: n = 1, >25 cig/day; n = 6, 15–24 cig/day; n = 16, 5–14 cig/day;, n = 4, ≤4 cig/day.

Sex: female

Age: 18–26

Race: not reported

Location: Lund, Sweden

Year(s): 2001

118

Peripheral DXA

Difference from reference group, nonsmoker/no OC use (n = 35)

   

Heel aBMD

Smoker/no OC use (n = 9)

Nonsmoker/OC use (n = 57)

Smoker/OC use (n = 17)

   

T2 aBMD (g/cm2)

   

 Unadjusted

0.0013

0.014

−0.012

   

 Adjusteda

−0.032*

−0.014

−0.017*

   

2-year change in aBMD (g/cm2)

   

 Unadjusted

−0.035*

−0.013

−0.016

   

 Adjusteda

−0.06

−0.010

−0.021

   

aAdjusted for age, physical activity baseline BMD, body weight

*P < 0.05

 Lappe et al. 2008 [241]

Secondary analyses of this randomized calcium and vitamin D supplementation trial examined other risk factors for developing stress fractures during basic training.

Sex: female

Age: 19 years (17–35 years)

Race: not specified

Location: USA

Years 2001–2006

5201

Stress fracture

Risk of fracture was 41 % higher in women with history of smoking when adjusted for treatment group, P = 0.0075

Odds ratio for fracture was 1.32 (0.99–1.75) in women with history of smoking when adjusted for treatment, amenorrhea, high exercise, Depo Provera use, age, and running speed.

 Korkor et al. 2009 [231]

This 4-year prospective study assessed the relationship between smoking and alcohol intake and bone mass. Students in 9th grade were recruited. Number of cig smoked per day reported in the 9th, 10th, 11th, and 12th grades. Subjects classified as any smoking over 4 years vs not

Sex: 37 males, 72 females

Age: 14–19 years at enrollment

Race: white 83 %, Asian 1 %, Hispanic 4 %, unknown 12 %

Location: Wisconsin, USA

Year(s): 2000–2003

109

Peripheral DXA

Simple model, any smokinga

Adjusted model, any alcohol or smokingb

   

Heel aBMD in 12th grade (g/cm2)

−0.0249, P = 0.29

−0.0281, P = 0.05

    

−4.3 %

−4.8 %

   

aAny smoking over the 4-year study (yes, n = 8; no, n = 101)

bAdjusted for sex baseline aBMD dairy intake

Large overlap in smoking and alcohol use. Any smoking or alcohol combined (N = 14) was associated with a −0.028-g/cm2 lower aBMD.

 Lucas et al. 2012 [235]

This prospective study quantified the association between early initiation of smoking and alcohol intake and forearm BMD in early and late adolescence. Smoking reported at age 13 and 17 years and classified as: tried but not currently smoking, smokes but not daily or smokes daily

Sex: female

Age: 13 years and 17 years

Race: not specified

Location: Portugal

Year(s): 2003–2007

713

Peripheral DXA

Smoking at age 13 years vs never smoked (n = 523)

   

Distal radius aBMD

Tried, not currently smoking (n = 165)

Smokes (n = 24)

P value

   

At age 13 years

1.1 %

−0.6 %

0.410

   

At age 17 years

−2.3 %

−0.7 %

0.068

    

Smoking at age 17 years vs never (n = 390)

    

Tried, not currently (n = 224)

Smokes, not daily (n = 33)

Smokes, daily (n = 72)

P value

   

At age 17 years

−2.3 %

−3.2 %

−0.7 %

0.438

    

Ever smoked in adolescence vs never smoked (n = 353)

   

At age 17 years

Tried 13 years but before 17 years (n = 167)

Tried before 13 years (n = 192)

P value

    

0.4 %

−1.8 %

0.103

   

Adjusted for menarche age, alcohol intake, sports, and BMI

 Dorn et al. 2013 [233]

This 3-year prospective study of girls examined bone accrual according to smoking, alcohol intake, depression, and anxiety. Smoking measured every 3 months and coded as cigarettes smoked in last 30 days: 0, 1–2 days, 3–5 days, 6–9, 10–19 days, 20–29 days, or 30 day

Sex: female

Age: 11–17 years

Race: 62 % white, 33 % black, 5 % other

Location: Ohio, USA

Year(s): 2003–2010

262

DXA

Total body BMC (g)

Spine aBMD (g/cm2)

Hip aBMD (g/cm2)

No significant main effect or age × smoking interaction on total body

Significant age × smoking interaction for spine and hip aBMD. As smoking increased, the rate of bone accrual decreased as girls got older.

Regression models adjusted for race, puberty stage, weight, height, and contraceptive use

Cross-sectional studies

 Elgan et al. 2002 [237]

This cross-sectional study conducted in nursing students measured lifestyle and physiologic factors. Smoking was measured by questionnaire and dichotomized as yes/no. 23 % smoked on a daily basis, 22 % were party smokers, and 55 % were nonsmokers.

Sex: female

Age: 16–24 years

Race: not reported

Location: Lund, Sweden

Year(s): 1999

218

Peripheral DXA

Heel aBMD (g/cm2)

Smoking status not significantly associated with aBMD in bivariate analyses. Data not shown

Smoking not significant (P = 0.48) in regression models adjusting for age, weight, physical activity, and hormonal age

 Afghani et al. 2003 [336]

A cross-sectional analysis of baseline data from a smoking cessation trial. Analyses investigated the role of body composition, physical activity, menarche, smoking, and second-hand smoke on regional bone mass among Asian adolescents living in Wuhan, China. Smoking questions assessed if subjects “smoked at least 100 cigarettes in their life?” and “have smoked in last 30 day.” Smoking was reclassified for analyses as smoking yes/no.

Sex: male and female

Age: 12–16 years, 14.5 ± 0.5

Race: Asian

Location: Wuhan, China

Year(s): not reported

466

Peripheral DXA

Correlation with smoking (yes/no)a

P value

Multivariable modelsb

   

Boys (n = 300)

   

 Forearm BMC

0.05

NS

NS

   

 Forearm aBMD

0.04

NS

   

 Heel BMC

0.05

NS

NS

   

 Heel aBMD

0.00

NS

   

Girls (n = 166)

   

 Forearm BMC

0.15

<0.05

NS

   

 Forearm aBMD

0.04

NS

   

 Heel BMC

0.08

NS

NS

   

 Heel aBMD

0.09

NS

   

aUnclear how correlation derived given that smoking was a dichotomous variable

bAdjusting for age, height, lean mass, fat mass, team sports participation, menarche, and passive smoking

Low level of smoking and inconsistent report of smoking in the sample limits conclusions. 38 % of girls and 14 % of boys inconsistently answered smoking questions. Among smokers, 58 % of girls and 51 % of boys smoked ≤1 cigarette in last 30 days.

 Kyriazopoulos et al. 2006 [236]

This cross-sectional study evaluated the influence of current dietary factors (calcium, proteins, alcohol, coffee, and tea intake), exercise, smoking, and sunlight on forearm bone mass in young Greek men. Smoking coded as daily smoking (58.6 %) or no

Sex: male

Age: 18–30 years, mean 22 years

Race: not reported

Location: Greece

Year(s): not reported

300

Peripheral DXA

Distal Radius BMC

Distal radius aBMD

Ultradistal radius aBMD

There was no association between daily smoking (58.6 % of sample) and bone measures with and without adjustment for height, weight, calcium intake, sunlight exposure, exercise, and work. Data not shown

 Lorentzon et al. 2007 [239]

The GOOD study is a cross-sectional study involving a random selection of males in Gothenburg. Bone mass, density, and geometry measured by DXA and pQCT. Smoking quantified as cigarettes/day and duration. For analyses, subjects were classified as smokers ≥1 cig/day vs not.

Sex: male

Age: 18–20 years

Race: not reported

Location: Gothenburg, Sweden

Year(s): not reported

1063

 

Difference between smoked ≥1 cigarette/daya vs not

    

Unadjusted

P value

Adjustedb

P value

   

DXA

   

 Total body aBMD

−2.1 %

<0.01

−1.8 %

0.01

   

 Spine aBMD

−4.3 %

<0.001

−3.3 %

<0.01

   

 Femoral neck aBMD

−5.3 %

<0.001

−3.9 %

<0.01

   

 Trochanter aBMD

−6.6 %

<0.001

−5.0 %

<0.01

   

pQCT

   

 Tibia

   

  Cortical vBMD

0.0 %

0.91

NS

   

  Cortical thickness

−4.5 %

<0.001

−4.0 %

<0.001

   

  Periosteal circumference

0.0 %

0.97

NS

   

  Endosteal circumference

2.5 %

<0.05

2.7 %

0.01

   

  Trabecular vBMD

−4.2 %

<0.01

−3.8 %

<0.01

   

Radius

   

 Cortical vBMD

−0.1 %

0.55

NS

   

 Cortical thickness

−2.8 %

<0.01

−2.9 %

<0.01

   

 Periosteal circumference

0.7 %

0.32

NS

   

 Endosteal circumference

3.3 %

0.02

4.5 %

<0.01

   

 Trabecular vBMD

−2.7 %

0.16

NS

   

aSmokers consumed 9.3 ± 6.3 cig/day. Mean duration of smoking 4.1 ± 2.1 years. Smokers less active than nonsmokers

bAdjusted for calcium intake, physical activity, age, height, and weight. Smokers had reduced BMD due to smaller cortical thickness greater endosteal circumference

 Dorn et al. 2011 [232]

This cross-sectional analysis of data examined how bone mass and density varied according to smoking, alcohol intake, depression, and anxiety. Smoking ever in their life coded as never (n = 104), 1 puff to 2 cig (n = 54), and 3–99 cig (n = 51), >100 cig/day (n = 52)

Sex: female

Age: 11–17 years

Race: 62 % white

33 % black, 5 % other

Location: Ohio, USA

Year(s): 2003–2007

261

DXA

   

 Total body BMC (g)

No significant differences among smoking groups

   

 Spine aBMD (g/cm2)

No significant differences among smoking groups

   

 Total hip aBMD (g/cm2)

1 puff to 2 cig group 6.5 % greater than >100 cig group, P < 0.05

   

 Femoral neck aBMD (g/cm2)

1 puff to 2 cig group 6.0 % greater than >100 cig group, P < 0.05

   

Analyses adjusted for age, weight, height, race, and maturational stage.

Significant interactions between alcohol and tobacco use, and depression symptoms on bone outcomes. Stronger negative association between depressive symptoms and total body BMC among individuals who smoked and used alcohol.

 Eleftheriou et al. 2013 [238]

A cross-sectional study evaluating the association of smoking, alcohol consumption, and prior exercise with lower limb bone volume, composition, and structure by MRI and DXA in a large cohort of healthy Caucasian males. Smoking status coded as nonsmoker, ex-smoker (>6 months), recent ex-smoker (≤6 months), or current smoker

Sex: male

Age: mean 19.9 years

Race: Caucasian

Location: UK

Year(s): not reported

651

 

Differencea between smoking status vs nonsmoker (n = 329)

    

Ex-smoker >6 months (n = 41)

Recent ex-smoker ≤ 6 months (n = 35)

Current smoker (n = 244)

P value

   

DXA

   

 Total hip aBMD

−5.0 %

−6.0 %

−4.7 %

0.0001

   

 Femoral neck aBMD

−5.9 %

−5.3 %

−4.0 %

0.001

   

MRI

   

 Periosteal volume

−5.0 %

−4.3 %

−0.4 %

0.004

   

 Endosteal volume

NS, data not shown

   

 Cortical volume

NS, data not shown

   

aAdjusted for height weight, alcohol intake, and weight-bearing activity

 Winther et al. 2014 [234]

This cross-sectional population-based study compared BMD levels of Norwegian adolescents with lifestyle factors. Smoking was classified as daily smoking, sometimes smokes, or never smokes.

Sex: male and female

Age: 15–17 years

Race:

Location: Norway

Year(s): 2010–2011

835

 

Difference between smokinga vs not

    

Age adjusted

Multivariable adjusteda

   

DXA

Beta

P value

Beta

P value

   

Males (n = 492)

   

 Total hip aBMD (g/cm2)

−0.039

0.012

0.029

0.037

   

 Femoral neck aBMD (g/cm2)

−0.025

0.116

   

Females: (n = 469)

   

 Total hip aBMD (g/cm2)

−0.026

0.074

   

 Femoral neck aBMD (g/cm2)

−0.031

0.031

   

aIncludes daily smoking (5.5 % of girls and 3.8 % of boys) and sometimes smokes (15.9 % girls, 20.2 % of boys) vs never smokes (76.6 % of girls and 74.2 % of boys)

bAdjusted for age, BMI, height, sexual maturation, physical activity, alcohol intake, diseases, and medications known to affect bone and hormonal contraceptives

aBMD areal bone mineral density, BMC bone mineral content, BMD bone mineral density, cig cigarette, DXA dual-energy x-ray absorptiometry, GOOD Gothenburg osteoporosis and obesity determinants, OC oral contraceptive, pQCT peripheral quantitative computed tomography

Table 13

Physical activity and exercise on bone mass and density in children and adolescents

Reference

Study description

Population description

Number of subjects

Intervention

End points

Results

RCTs

 Witzke and Snow 2000 [337]

9-month jumping intervention

Recruited for exercise group

No randomization

Sex: female

Age: 13–15 years

Race: not listed

Location: Corvallis, OR

53

Frequency: 3×/week

Intensity: varied

Time: 30–45 min/session

Type: resistance training: squats, lunges, toe/heel raises, bench stepping, and jumping. Plyometric training: two-footed, in-place jumps to stair jumping, bounding, depth jumps

Control: regular PE

DXA

Percent change, mean ± SD

    

Significant

EX

CON

    

 TR BMC

3.13 ± 6.44*

1.96 ± 6.69

    

NS

Both groups experienced a significant increase in percent change in bone mass compared to zero for TB, FN, LS, and FS, but only EX improved BMC of the TR (3.1 vs 1.9 %).

    

 TB, FN, LS, FS BMC

 McKay et al. 2000 [338]

8-month loading intervention

Randomized by school

Sex: male and female

Age: 6.9–10.2 years

Race: 34 % Asian, 66 % white

Location: Richmond, British Columbia

144

Frequency: 3×/week (2× PE, 1× classroom)

Intensity: progressive

Time: 10–30 min (minimum 10 min loading)

Type: variety: games, circuit training, dances. Ten tuck jumps required at beginning of each session

Control: regular PE

DXA

Percent change, mean ± SEM

    

Significant

EX

CON

    

 TR aBMD

4.4 ± 0.5*

3.2 ± 0.3

    

NS

EX group showed significantly greater change in TR aBMD than CON group (4.4 vs 3.2 %). No group differences at other sites.

    

 TB, LS, PF, FN aBMD

 Heinonen et al. 2000 [244]

9-month step aerobics/jumping intervention

Randomized by school

Sex: female

Age: 10–15 years

Race: not specified

Location: Tampere, Finland

126

Frequency: 2×/week

Intensity: progressive

Time: 50 min (10-min warm-up, 15-min nonimpact aerobic exercises, 20-min high-impact/jump training, 5-min cool down)

Type: both-leg jumps at floor level, both-leg box jumps, one-leg box jumps

Control: normal PA

DXA

Difference (g), mean (95 % CI)

    

Significant

Premenarchal

EX vs CON

Postmenarchal

EX vs CON

P value

Effect of EX (pre vs post)

    

 LS BMC

1.01 (0.23, 1.78)*

  
    

 FN BMC

0.09 (0.02, 0.15)*

 

*

    

 TR BMC

  

*

     

In the premenarchal girls, BMC increased significantly more in the EX than in CON at LS (8.6 vs 5.3 %) and FN (9.3 vs 5.3 %). The postmenarchal girls showed no significant posttraining intergroup differences at any site.

 Fuchs et al. 2001 [306]

7-month jumping intervention

Randomized by gender

Sex: male and female

Age: 7.5 years ± 0.17

Race: 87 white, 1 Asian, 1 white-Hispanic

Location: Corvallis, OR

89

Frequency: 3×/week, opposite PE

Intensity: progressed from 50 to 80 jumps/day over 12 sessions; 100 jumps/day were performed for the remaining sessions

Time: 20 min/session (5-min warm-up, 10-min jumping or stretching, 5-min cool down)

Type: jumps off 61-cm box

Control: nonimpact stretching

DXA

Postintervention values

    

Significant

EX

CON

    

 FN BMC

2.00 ± 0.07***

1.89 ± 0.06

    

 FN BA

3.13 ± 0.08***

2.96 ± 0.07

    

 LS BMC

22.06 ± 0.57*

21.64 ± 0.58

    

 LS aBMD

0.571 ± 0.008**

0.553 ± 0.008

    

NS

EX group had significantly greater changes in FN and LS BMC than CON group (4.5 and 3.1 %, respectively). EX group also had significantly greater changes in FN BA (2.9 %) and LS aBMD (2.0 %) than CON group.

    

 FN aBMD, LS BA

 Nichols et al. 2001 [243]

15-month resistance training intervention

Randomized

Sex: female

Age: 14–17 years

Race: not specified

Location: Texas Woman’s University, TX

16

Frequency: 3×/week

Intensity: progressive

Time: not specified

Type: 15 exercises all major muscle groups, combination free weights and machines

Control: not specified

DXA

Percent change, mean

    

Significant

EX

CON

    

 FN aBMD

3.67**

1.35

    

NS

 TB, LS, WA, TR aBMD

 TB, LS, FN, WA, TR BMC

 LS, FN BMAD

FN aBMD increased significantly in EX group (40 %), but not in CON group. No significant changes seen at other sites

 Mackelvie et al. 2001 [26]

9-month jumping intervention

Randomized by school

Sex: female

Age: 9–12 years

Race: multiethnic population of city (45 % white, 34 % Asian, and 21 % mixed ethnicities) reflected in cohort

Location: Richmond, British Columbia

177

Frequency: 3×/week (2x PE, 1 classroom)

Intensity: progressed over school year by increasing number of jumps per station (from 10 to 20) and height (from 10 to 50 cm)

Time: 10–12 min (5 circuits, ~1.5–2 min each)

Type: jumping exercises—jumping jacks, lunge jumps, hopping, jumping over various obstacles, drop jumps from platform

Control: stretching

DXA

Change, mean (95 % CI)

    

Significant

Prepubertal EX

Prepubertal CON

Early Pubertal EX

Early Pubertal CON

    

 LS BMC

  

4.70 (4.38, 5.02)*

4.18 (3.92, 4.44)

    

 LS aBMD

  

0.057 (0.050, 0.064)**

0.044 (0.038, 0.049)

    

 FN BMC

  

0.31 (0.28, 0.34)*

0.26 (0.24, 0.29)

    

 FN aBMD

  

0.043 (0.036, 0.050)*

0.034 (0.028, 0.039)

    

 FN vBMD

  

0.010 (0.004, 0.015)*

0.002(−0.003, 0.006)

    

NS

There were no significant differences between prepubertal EX and CON groups. Early pubertal girls in EX group gained 1.5 to 3.1 % more bone at FN and LS than CON girls; gain at other sites did not differ

    

 TB, PF, TR BMC

    

 TB, PF, TR aBMD

 Mackelvie et al. 2002 [339]

7-month jumping intervention

Randomized by school

Sex: male

Age: 8.8–11.7 years

Race: multiethnic population of city (45 % white, 34 % Asian, and 21 % mixed ethnicities) reflected in cohort

Location: Richmond, British Columbia

121

Frequency: 3×/week (2× PE, 1 classroom)

Intensity: progressed over school year by increasing number of jumps per station (from 10 to 20) and height (from 10 to 50 cm)

Time: 10–12 min (5 circuits, ~1.5–2 min each)

Type: jumping exercises—jumping jacks, lunge jumps, hopping, jumping over various obstacles, drop jumps from platform

Control: stretching

DXA

Change, mean (95 % CI)

    

Significant

EX

CON

    

 TB BMC

105.8 (97.7, 113.9)**

90.0 (81.9, 98.2)

    

 PF aBMD

0.025 (0.020, 0.030)*

0.017 (0.013, 0.022)

    

NS

The EX group gained more TB BMC (1.6 %) and PF aBMD (1 %) than CON group did after adjusting for age, baseline weight, change in height, and loaded PA.

    

 LS, PF, FN, TR BMC

    

 LS, FN, TR aBMD

 Kontulainen et al. 2005 [125]

20-month follow-up to 9-month step aerobics/jumping intervention

Randomized by school

Sex: female

Age: 10–15 years

Race: not specified

Location: Tampere, Finland

99

Frequency: 2×/week

Intensity: 100 both-leg jumps at floor level, increased to 200 box jumps (30 cm) using both legs and one leg

Time: 50 min (10-min warm-up, 15-min nonimpact aerobic exercises, 20-min high-impact/jump training, 5-min cool down)

Type: both-leg jumps at floor level, both-leg box jumps, one-leg box jumps

Control: normal PA

DXA

Percent difference, mean (95 % CI)

    

Significant

 
    

  LS BMC

4.9 (0.9, 8.8)*

    

NS

EX group had 4.9 % greater BMC accrual at the LS than the CON group during the 20-month follow-up. No other sites showed significant differences.

    

  FN, TR BMC

 Petit et al. 2002 [73]

7-month jumping intervention

Randomized by school

Sex: female

Baseline age: 9–12 years

Race: multiethnic population of city (~34 % Hong Kong Chinese and 57 % white) reflected in cohort

Location: Richmond, British Columbia

177

Frequency: 3×/week (2× PE, 1 classroom)

Intensity: progressed over school year by increasing number of jumps per station (from 10 to 20) and height (from 10 to 50 cm)

Time: 10–12 min (5 circuits, ~1.5–2 min each)

Type: jumping exercises—jumping jacks, lung jumps, hopping, jumping over various obstacles, drop jumps from platform

Control: stretching

DXA

No significant differences seen between EX and CON groups

    

Significant

    
    

  None

    
    

NS

    
    

  NN, IT, FS aBMD

    

 Laing et al. 2002 [340]

36-month gymnastics participation

Recruited due to enrollment in gymnastics

Sex: female

Age: 8–13 years at baseline

Race: all Caucasian (except one Hispanic control)

Location: Athens, Georgia

17

Frequency: not specified

Intensity: not specified

Time: 9–24 h/week

Type: regionally competitive gymnastics: vault, uneven bars, balance beam, floor routine

Control: no gymnastics

DXA

At year 3, significant differences between EX and CON were noted at TB, LS, and PF for aBMD. Significant differences were noted for TB and LS for BMC. Both the EX group and CON groups had significant increases in BA at the TB, LS, FN, and PF.

    

Significant

    

  TB aBMD

    

  LS aBMD

    

  PF aBMD

    

  TB BMC

    

  LS BMC

    

  TB BA

    

  LS BA

    

  FN BA

    

  PF BA

    

NS

    

  FN, TR, Rad aBMD

    

  PF, FN, TR, Rad BMC

    

  FN, Rad BA

 MacKelvie et al. 2003 [341]

20-month jumping intervention

Randomized by school

Sex: female

Age: 8.8–11.7 years at baseline

Race: multiethnic population of city (57 % white, 34 % Hong Kong Chinese, 5 % East Indian, 4 % other ethnic origin or mixed ethnicity) reflected in the cohort

Location: Richmond, British Columbia

75

Frequency: 3×/week (2× PE, 1 classroom)

Intensity: year 1: progressed over school year by increasing number of jumps per station (from 10 to 20) and height (from 10 to 50 cm); year 2: higher proportion of high-impact jumps. Height increased every 8–10 weeks

Time: 10–12 min (5 circuits, ~1.5–2 min each)

Type: year 1: jumping exercises such as jumping jacks, lung jumps, hopping, jumping over various obstacles, and drop jumps from platform; year 2: plyometric jumps, alternating-foot jumps, and 2-ft obstacle jumps

Control: stretching

DXA

Change, mean (95 % CI)

    

Significant

EX

CON

    

  LS BMC

10.9 (9.9, 11.9)*

9.3 (8.4, 10.1)

    

  FN BMC

0.66 (0.58, 0.73)*

0.55 (0.48, 0.61)

    

NS

There were substantially greater gains in LS (41.7 vs 38.0 %) and FN (24.8 vs 20.2 %) BMC in EX group than in CON group. No significant differences between groups at other sites.

    

  TB, PF, TR BMC

    

  LS, PF, FN, TR BA

 Van Langendonck et al. 2003 [342]

9-month impact intervention on twins

Twins randomized to exercise or control, keeping birth order equal between groups

Sex: female (21 twin pairs)

Age: 8.7 years (SD = 0.7)

Race: not specified

Location: Belgium

42

Frequency: 3×/week

Intensity: after the first trimester, participants went barefoot or wore very thin gym shoes to enhance mechanical loading

Time: 10 min/session

Type: 3 impact exercises- rope skipping 50 times; hopping 20 times as far as possible with the left and right leg; jumping from a wooden box of 40 cm high landing on both feet 30 times. 2 nonimpact exercises- moving 3.5 m sideways in a push-up position six times and six times moving 3.5 m backward on hands and feet like a crab

Control: asked not to perform the exercises at school or home

DXA

None of the bone indices differed significantly between the EX and CON groups after the 9-month intervention.

    

Significant

    

  None

    

NS

    

  LS, FN, PF, RA, TB BMC

    

  LS, FN, PF, RA, TB aBMD

    

  LS, FN, PF, RA, TB BA

 Iuliano-Burns et al. 2003 [155]

8.5-month randomized intervention trials with two factors (exercise and calcium) that each had two levels

Sex: female

Age: 7–11 years

Race: 15 % Asian descent

Location: Melbourne, Australia

66

Frequency: 3×/week (PE)

Intensity: moderate (2–4× body wt GRF)

Time: 20 min/session

Type: hopping-, jumping-, and skipping-based activities

Control: stretching and low-impact dance routines (1× body wt)

DXA

Change, mean ± SEM

     

EX

CON

    

   Significant

Calcium

Placebo

Calcium

Placebo

    

 Leg BMC

58.9 ± 7.1b

 

50.1 ± 3.3b

 
    

 Femur BMC

29.9 ± 4.1b

 

24.1 ± 2.0b

 
    

 T-F BMC

 

21.1 ± 1.8d,f

17.1 ± 1.3d

18.3 ± 2.2f

    

 Arm BMC

15.5 ± 1.9a,c

10.3 ± 1.3c,d

13.1 ± 0.91d

10.8 ± 1.3a

    

 Hum BMC

7.3 ± 0.9c

5.2 ± 0.5c

  
    

 U-R BMC

4.4 ± 0.5a,c

3.1 ± 0.4c,d

4.7 ± 0.4d,e

3.3 ± 0.4a,c

    

NS

Like letters denote significant difference between groups (P < 0.05).

An exercise-calcium interaction was detected at the femur (7.1 %). By contrast, there was no exercise–calcium interaction detected at the T-F; however, there was a main effect of exercise: BMC increased 2–4 % more in the calcium-supplemented groups than in the nonsupplemented groups at the humerus (12.0 vs 9.8 %) and R-U (12.6 vs 8.6 %).

    

  TB, LS BMC

 Specker and Binkley 2003 [81]

1-year randomized, placebo-controlled, partially blinded trial of PA and calcium supplementation

Sex: male and female

Age: 3–5 years

Race: 94 % white, 6 % other

Location: South Dakota

178

Frequency: 5×/wk

Intensity: not specified

Time: 30 min/day (5-min warm-up, 20-min activity, 5-min cool down)

Type: hopping, jumping, skipping activities (17 different weekly programs)

Control: 30 min/day of activities to keep them sitting quietly

DXA

Change, mean ± SEM

    

 Significant

EX

 

CON

 
     

Calcium

Placebo

Calcium

Placebo

    

  Leg BMC

40.9 ± 1.3

38.2 ± 1.2

37.3 ± 1.4

38.5 ± 1.3

    

NS

There was a significant interaction (P < 0.05) between the activity and supplement groups in leg BMC gain; the difference in BMC gain between EX and CON groups was more pronounced in children receiving calcium vs placebo. Among children receiving the placebo, leg BMC gain was similar in the EX and CON groups. However, among children receiving calcium, those in EX group has 9.7 % greater increase in leg BMC than those in CON group.

    

  TB, arm BMC

    

  TB, arm, leg BA

 Stear et al. 2003 [156]

15.5-month randomized, double-blind trial of PA and calcium supplementation

Sex: female

Age: 17.3 ± 0.4 years

Race: not listed

Location: UK

131

Frequency: 3×/wk

Intensity: moderate-to-vigorous intensity, moderate-to-high impact

Time: 45 min/session (7- to 10-min warm-up, 30-min workout, 5- to 8-min warm-down and stretch)

Type: exercise-to-music aerobics class

Control: not invited to exercise sessions

DXA

No significant differences seen between EX and CON groups

    

Significant

    

  None

    

NS

    

  TB, LS, Rad, R-Ul, R-Dis BMC

    

  TB, LS, Rad, R-Ul, R-Dis SA-BMC

 MacKelvie et al. 2004 [295]

20-month jumping intervention

Randomized by school

Sex: male

Age: 8.8–12.1 years

Race: multiethnic population of city (~34 % Hong Kong Chinese and 57 % North American/Western European Caucasian, 5 % Southeast Asian, and 4 % other or mixed ethnicity) reflected in cohort

Location: Richmond, British Columbia

64

Frequency: 3×/wk (2× PE, 1 classroom)

Intensity: progressed over 2 years by increasing number of jumps per station (from 10 to 20) and height (from 10 to 50 cm

Time: 10–12 min (5 circuits, ~1.5–2 min each)

Type: jumping exercises such as jumping jacks, lung jumps, hopping, jumping over various obstacles, drop jumps from platform

Control: stretching

DXA

Change, mean (95 % CI)

    

Significant

EX

CON

    

  FN BMC

0.50 (0.45, 0.55)**

0.39 (0.34, 0.43)

    

  TB, LS, PF, FN, TR BA

  
    

NS

FN BMC changes were significantly greater in EX boys (4.3 %); changes in bone area and BMC for other regions were not significantly different between groups.

    

  TB, LS, PF, TR BMC

 McKay et al. 2005 [297]

8-month jumping intervention

Control group used from previous study

Sex: male and female

Age: 8.9 to 11.0 years

Race: 38 % Caucasian, 48 % Asian, 15 % other (including mixed ethnic, black, and South Asian)

Location: Richmond, British Columbia

124

Frequency: 3×/days

Intensity: 5× body wt, maximum rate of force was >400 body wt/s (independent sample of 70 boys and girls)

Time: 3 min/day

Type: 10 counter movement jumps (two-foot take off, clutch knees, two-foot landing)

Control: not specified, from previous study

DXA

Change, mean (95 % CI)

    

Significant

EX

CON

    

  TB BMC

92.7 (83, 102)*

106 (98, 114)

    

  TB BA

76.7 (66.9, 86.5)*

95.6 (87.6, 103.6)

    

  PF BMC

2.3 (2.1, 2.6)*

1.9 (1.7, 2.1)

    

  IT BMC

1.5 (1.3, 1.7)*

1.2 (1.0, 1.3)

    

NS

CON group had greater increase in adjusted TB BMC (1.4 %). EX group gained significantly more BMC at the PF (2 %) and at the IT region (27 %).

    

 LS, PF, IT, GT, FN BA

    

 LS, GT, FN BMC

 Laing et al. 2005 [343]

24-month quasi-experimental prospective gymnastics study

Recruited due to enrollment in gymnastics

Sex: female

Age: 4–8 years

Race: 64 % white, 27 % black, 3 % Asian, 2 % Hispanic, 1 % Indian, and 3 % other

Location: Athens, Georgia

143

Frequency: 1×/week

Intensity: not specified

Time: 1 h/session

Type: recreational gymnastics class

Control: participating in nongymnastic activities or no activities

DXA

Postintervention values, mean ± SD

    

Significant

EX

CON

    

  TB BA

1392 ± 247*

1545 ± 314

    

  TB BMC

997 ± 255*

1151 ± 323

    

  TB aBMD

0.708 ± 0.06*

0.736 ± 0.07

    

  LS BA

34.1 ± 50.5*

36.6 ± 6.17

    

  LS BMC

20.5 ± 5.47*

22.6 ± 6.24

    

  PF BA

18.8 ± 4.04*

20.4 ± 4.53

    

  PF BMC

12.5 ± 4.07*

14.1 ± 4.56

    

  FA BA

7.39 ± 1.58*

8.05 ± 1.80

    

  FA BMC

2.85 ± 0.85*

3.19 ± 0.97

    

NS

Values suggest that EX remained lower in bone mineral measures after 2 years; however, after adjusting for initial differences, it was determined that EX had greater BA, BMC, and aBMD responses compared with CON at some skeletal sites.

    

  LS, PF, FA aBMD

 Yu et al. 2005 [242]

36-week strength training intervention

Randomized

Sex: male and female

Age: 9–11 years

Race: not specified

Location: Hong Kong

63

Frequency: phase 1: 3×/week; phase 2: 1×/week

Intensity: phase 1: 75 % 10 RM, increased to 100 % over time. 1 set, 20 reps; phase 2: weight adjusted according to ability. 2–3 sets of 10–20 reps

Time: phase 1: 75 min/session (10-min warm-up, 30-min strength training, 10-min agility training, 5-min cool down); phase 2: 60 min/session (5-min warm-up, 10-min stretching, 40-min strength training, 5-min cool down)

Type: phase 1: circuits (9 stations for strength training, 1 station for agility, 1 aerobic station); phase 2: similar to phase 1

Control: hypocaloric diet, no strength training

DXA

No significant differences in BMC were observed between the EX and CON groups at 36 weeks.

    

Significant

    

  None

    

 NS:

    

  TB, TH, LS BMC

 Valdimarsson et al. 2006 [344]

1-year expanded PE intervention

Randomized by school

Sex: female

Age: 6.5–8.9 years

Race: Caucasian

Location: Malmö, Sweden

103

Frequency: 5 days/week

Intensity: varied

Time: 40 min/day

Type: normal PE curriculum (running, jumping, climbing ropes, variety of ball games). Activities varied to reduce boredom. No specific osteogenic training program was added.

Control: normal PE curriculum, duration within normal limits (1–2 sessions/week, in total 60 min/week)

DXA

Change, mean (SD)

     

Significant

EX

CON

     

  L2-L4 BMC

2.4 (1.1)**

1.8 (0.7)

     

  L3 BMC

0.94 (0.63)***

0.53 (0.30)

     

  L2-L4 aBMD

0.044 (0.03)***

0.026 (0.01)

     

  L3 aBMD

0.047 (0.03)***

0.025 (0.02)

     

  L3 width

0.17 (0.12)***

0.09 (0.06)

     

NS

The annual gain in BMC was 4.7 % higher in the LS and 9.5 % higher in L3 in the EX group than in the CON group. The annual gain in aBMD was 2.8 % higher in the LS and 3.1 % higher in L3 in the EX group than in the CON group. The annual gain in L3 width was 2.9 % higher in the EX group than in the CON group.

     

  TB, FN, leg BMC

     

  TB, FN, leg aBMD

     

  L3, FN vBMD

     

  FN width

 Linden et al. 2006 [345]

2-year expanded PE intervention

Randomized by school

Sex: female

Age: 6.5–8.9 years

Race: white

Location: Malmö, Sweden

99

Frequency: 5 days/week

Intensity: varied

Time: 40 min/day

Type: normal PE curriculum (running, jumping, climbing ropes, variety of ball games). Activities varied to reduce boredom. No specific osteogenic training program was added.

Control: normal PE curriculum, duration within normal limits (1–2 sessions/week, in total 60 min/week)

DXA

Change, mean

     

Significant

EX

CONZ

     

  L2-L4 BMC

2.2*

1.8

     

  L3 BMC

0.8***

0.6

     

  L2-L4 aBMD

0.034*

0.026

     

  FN vBMD

−0.004**

0.006

     

  L3 width

0.136**

0.092

     

NS

The annual gain in BMC was greater in the EX group than in the CON group: L2-L4 3.8 %, L3 7.2 %. The EX group had greater annual gain in aBMD at L2-L4 (1.2 %). There was also a greater mean annual gain in bone size in the L3 vertebra (1.8 %).

     

  TB, FN, leg BMC

     

  TB, L3, FN, leg aBMD

     

  L3 vBMD

     

  FN width

 Bass et al. 2007 [157]

8.5-month randomized intervention trials with two factors (exercise and calcium) that each had two levels

Sex: male

Age: 7–11 years

Race: 22 % Asian descent

Location: Melbourne, Australia

88

Frequency: 3×/week (PE)

Intensity: moderate (2–8× body wt GRF)

Time: 20 min/session

Type: hopping-, jumping-, and skipping-based activities

Control: stretching and low-impact dance routines (1× body wt)

DXA

Change, mean (SD)

      

EX

 

CON

 
     

Significant

Calcium

Placebo

Calcium

Placebo

     

  Leg BMC

64.4 (4.2)abc

54.0 (4.7)a

47.7 (4.2)b

43.3 (3.2)c

     

  Femur BMC

30.1 (1.8)abc

24.9 (1.9)a

24.8 (1.4)b

23.1 (1.3)c

     

  T-F

23.4 (2.1)a

  

16.8 (1.5)a

     

NS

Like letters denote significant difference between groups (P < 0.05).

The increase in femur BMC in the EX + calcium group was ~2 % greater than the increase in the EX + placebo, no-EX + calcium, or no-EX + placebo groups. At the T-F, the increase in BMC in the EX + calcium group was ~3 % greater than in the no-EX + placebo group

     

  TB, LS, arm, Hum, U-R BMC

 Linden et al. 2007 [298]

1-year expanded PE intervention

Randomized by school

Sex: male

Age: 6.7–9.0 years

Race: Caucasian (except 1 boy adopted from Colombia)

Location: Malmö, Sweden

138

Frequency: 5 days/week

Intensity: varied

Time: 40 min/day

Type: normal PE curriculum (running, jumping, climbing ropes, variety of ball games). Activities varied to reduce boredom. No specific osteogenic training program was added.

Control: normal PE curriculum, duration within normal limits (1–2 sessions/week, in total 60 min/week)

DXA

Change, mean (SD)

     

Significant

EX

CON

     

  L3 BMC

0.87 (0.55)***

0.58 (0.26)

     

  L3 aBMD

0.041 (0.04)**

0.027 (0.02)

     

  L3 width

0.14 (0.14)***

0.07 (0.07)

     

NS

The mean annual gain in L3 BMC was 5.9 % higher, L3 aBMD a mean 2.1 % higher, and L3 width a mean 2.3 % higher in the EX group than in the CON group.

     

  TB, FN BMC

     

  TB FN aBMD

     

  L3, FN vBMD

     

  FN width

 Barbeau et al. 2007 [346]

10-month MVPA intervention

Randomized

Sex: female

Age: 8–12 years

Race: black

Location: Georgia

201

Frequency: every day school in session during school year; during summer

Intensity: HR > 150 bpm during MVPA activity (HR monitor)

Time: 110-min after-school program (80 min of PA)

Type: 25-min skills development (dribbling basketball), 35-min MVPA, 20-min toning and stretching

Control: no intervention

DXA

Difference, mean (95 % CI)

   
     

Significant

    
     

  BMC

0.044 (0.024, 0.064)***

     

  aBMD

0.020 (0.012, 0.027)***

      

Compared to the CON group, the EX group had a greater increase in BMC and aBMD.

 Schneider et al. 2007 [347]

1-year MVPA intervention

Randomized by school

Sex: female

Age: 15.04 years (SD = 0.79)

Race: 57 % non-Hispanic white, 20 % Hispanic, 17 % Asian, 6 % other

Location: 2 public high schools, location not specified

122

Frequency: 5 days/week

Intensity: varied

Time: 60 min/day

Type: supervised activities included variety of aerobic (3×/week, including aerobic dance, kickboxing, and brisk walking) and strength-building (1×/week, including weightlifting and yoga) activities

Control: no intervention

DXA

Percent change, mean

     

Significant

EX

CON

     

 TS BMC

6.3**

1.4

     

NS

The effect of EX on BMC for the TS was significant and increased 6.3 % as opposed to 1.4 % in the CON group. None of the other sites for BMC or any aBMD measures were significant.

     

  TB, LS, FN, TH, TR BMC

     

  TB, LS, FN, TH, TS, TR aBMD

 Gunter et al. 2008 [24]

7-month jumping intervention

Randomized by school

Sex: male and female

Age: 7–10 years

Race: not specified

Location: Corvallis, OR

56

Frequency: 3×/week, during PE

Intensity: Progressed to reach 90–100 jumps per session

Time: 30 min/session (warm-up, fitness development (jumping), lesson focus, closing activity)

Type: jumping

Control: similar class structure, no jumping during fitness development

DXA

Postintervention values, mean (SD)

      

Male

Female

     

Significant

EX

CON

EX

CON

     

  TH BMC

28.5 (9.2)a

25.7 (7.56)a

24.6 (6.2)a

24.3 (6.1)a

     

  FN BMC

3.8 (0.96)b

3.6 (0.77)b

3.3 (0.74)b

3.3 (0.71)b

     

Other variables

aMales greater than females (P < 0.05); bmales greater than females (P < 0.01)

Three years after the intervention had concluded, the EX group had 2.3, 3.2, 4.4, and 2.9 % greater BMC than controls at the LS, TH, FN, and TB, respectively.

     

  TB, LS, TR BMC

 Gunter et al. 2008 [24]

7-month jumping intervention

Randomized by school

Sex: male and female

Age: 7–10 years

Race: 47 white, 2 Asian

Location: Corvallis, OR

49

Frequency: 3×/week, opposite PE

Intensity: progressed to reach 100 jumps/session by the 5th wk of the program

Time: 20 min/session (5-min warm-up, 10-min jumping or stretching, 5-min cool down)

Type: jumps off 24 in box

Control: nonimpact stretching

DXA

Postintervention values, mean (SD)

     

Significant

Males

Females

      

EX

CON

EX

CON

     

  TH BMC

39.93 (9.56)a

39.31 (9.93)

31.26 (5.40)a

30.15 (3.38)

     

  FN BMC

4.92 (0.88)a

4.73 (0.93)

4.18 (0.53)a

4.21 (0.69)

     

  TR BMC

11.11 (2.62)a

10.91 (2.54)

8.31 (1.42)a

7.49 (1.05)

      

aMales significantly greater than females for all values (P < 0.01).

Participants in the EX group had 1.4 % more TH BMC than those in the CON group after 8 years

 Weeks et al. 2008 [296]

8-month jumping intervention

Randomized

Sex: male and female

Age: boys 13.8 years (0.4); girls 13.7 years (0.5)

Race: not specified

Location: Gold Coast, Australia

81

Frequency: 2×/week

Intensity: 1–3 Hz at a height of 0.2–0.4 m

Time: 10 min (~300 jumps)

Type: varied, but included jumps, hops, tuck jumps, jump squats, stride jumps, star jumps, lunges, side lunges, and skipping. Occasionally supplemented with upper body strengthening activities, including push-ups and exercises with resistive latex bands

Control: usual PE warm-up and stretching

DXA

Girls in the EX group improved FN BMC (13.9 %) more than those in the CON group. Between-group comparisons of change showed EX group effects only for TB BMC (10.6 %) for boys. Boys in the EX group gained more TR BMC, LS BMC, and TB BMC than girls in the EX group.

     

Significant

     

  FN BMC

     

  TR BMC

     

  TB BMC

     

NS

     

  FN, LS BA

     

  LS BMC

 Macdonald et al. 2008 [299]

11-month PA and jumping intervention

Randomized by school

Sex: male and female

Age: 9–11 years

Race: 53 % Asian (both parents or all four grandparents born in Hong Kong or China, India, Philippines, Vietnam, Korea, or Taiwan. 35 % Caucasian (parents born in North America or Europe). 12 % children mixed ethnicity or other ethnic origins

Location: Vancouver and Richmond, British Columbia

410

Frequency: Classroom Action: 5 days/week; Bounce at the Bell: 5 days/week PA + 3×/day, 4 days/week jumping

Intensity: not specified

Time: Classroom Action: 15 min PA; Bounce at the Bell: 15 min PA + short bouts high-impact jumping

Type: Classroom Action: skipping, dancing, playground circuits, simple resistance exercises with bands; Bounce at the Bell: Classroom Action + short bouts high-impact jumping. Phase I included 5 two-foot landing jumps (or 10 one-foot landing jumps) at each session. Phase II jumps were increased each month of the school year until a maximum of 36 jumps/day was reached.

Control: usual PE

DXA

Percent difference, mean (95 % CI)

     

Significant

Males

Females

     

 FN BMC

0.96 (−0.003, 1.93)*

0.09 (0.005, 0.172)**

     

 LS BMC

30.8 (7.2, 54.4)**

  
     

 TB BMC

    
     

NS

Boys in EX group had greater gains in BMC at the LS (2.7 %) and TB (1.7 %) than the controls did. Girls in the EX group had greater gains in FN BMC (3.5 %) than in controls.

     

  PF BMC

 Alwis et al. 2008 [300]

1-year expanded PE intervention

Randomized by school

Sex: female

Age: 6.5–8.9 years

Race: Caucasian

Location: Malmö, Sweden

103

Frequency: 5 days/week

Intensity: varied

Time: 40 min/day

Type: normal PE curriculum (running, jumping, climbing ropes, variety of ball games). Activities varied to reduce boredom. No specific osteogenic training program was added.

Control: normal PE curriculum, duration within normal limits (1–2 sessions/week, in total 60 min/week)

DXA

No between-group differences were found during the 12-month study period for changes in FN variables.

     

Significant

     

  None

     

NS

     

  FN BMC, aBMD, vBMD

 Alwis et al. 2008 [300]

2-year expanded PE intervention

Randomized by school

Sex: male

Age: 6.7–9.0 years

Race: Caucasian

Location: Malmö, Sweden

137

Frequency: 5 days/week

Intensity: varied

Time: 40 min/day

Type: normal PE curriculum (running, jumping, climbing ropes, variety of ball games). Activities varied to reduce boredom. No specific osteogenic training program was added.

Control: normal PE curriculum, duration within normal limits (1–2 sessions/week, in total 60 min/week)

DXA

Change, mean (SD)

     

Significant

EX

CON

     

  L3 BMC

0.72 (0.30)**

0.58 (0.26)

     

  L3 width

0.11 (0.07)**

0.07 (0.07)

     

NS

The mean annual gain in L3 BMC (3 %) and L3 width (1.3 %) were greater in the EX group than in the CON group .

     

  TB, FN BMC

     

  FN width

 Alwis et al. 2008 [300]

2-year expanded PE intervention

Randomized by school

Sex: female

Age: 6.8–8.9 years

Race: Caucasian

Location: Malmö, Sweden

83

Frequency: 5 days/week

Intensity: varied

Time: 40 min/day

Type: normal PE curriculum (running, jumping, climbing ropes, variety of ball games). Activities varied to reduce boredom. No specific osteogenic training program was added.

Control: normal PE curriculum, duration within normal limits (1–2 sessions/week, in total 60 min/week)

DXA

No between-group differences were observed for annual changes in the FN variables.

     

Significant

     

  None

     

NS

     

  FN BMC, aBMD

 Meyer et al. 2011 [348]

9-month additional PE session intervention

Randomized by class

Sex: male and female

Age: prepubertal = 6–7 years; early pubertal = 11–12 years

Race: not specified

Location: Aargau and Baselland, Switzerland

291

Frequency: 2×/week (PE); 3×/day (activity breaks); 1×/day (home activity)

Intensity: not specified

Time: 45 min/session (PE); 2–5 min/session (activity breaks); 10 min/day (home activity)

Type: Two PE lessons (plus 3 regular PE classes) taught mostly outdoors by PE teachers. All five sessions included jumping activities like hopping, jumping up and down stairs, rope skipping, etc. During academic lessons, 3–5 activity breaks comprised motor skill tasks such as jumping around on one leg, balancing on one leg, power games, or coordinative tasks were introduced every day. Daily home activity included aerobic, strength, or motor skill tasks like tooth brushing while standing on one leg, jumping up and down the stairs, and rope jumping.

Control: participated in regular PE classes 3×/week

DXA

Difference, Z-score (95 % CI)

     

Significant

EX

     

  TB BMC

0.138 (0.06, 0.216)***

     

  FN BMC

0.136 (0.008, 0.264)*

     

  LS BMC

0.118 (0.028, 0.2017)**

     

  TB aBMD

0.212 (0.088, 0.337)***

     

  LS aBMD

0.184 (0.083, 0.285)***

     

NS

Compared to CON group, children in EX group showed statistically significant increases in BMC of TB (5.5 %), FN (5.4 %), and LS (4.7 %) and aBMD of TB (8.4 %) and LS (7.3 %)

     

  FN aBMD

 Silva et al. 2011 [349]

Sports study

Recruited based on sport participation

Sex: male

Age: 10–18 years

Race: not specified

Location: Brazil

46

Inclusion criteria: 3 year experience in sport, training at least 10 h/week in previous 6 months, only PA associated with sport, high competitive level

Control: normal PE

DXA

aBMD, mean (SD)

     

Significant

Tennis

Soccer

Swimming

Controls

     

  PF aBMD

1.02 (0.18)*

1.08 (0.16)*

  
     

NS

Results showed higher mean values in the PF region of tennis and soccer players than of swimmers and controls. In relation to the impact of sporting activities based on bone age determination, a significant difference in aBMD was observed at all evaluated sites at the end of puberty (16–18 years) compared with 10–12 years, with increases of 78 % at the LS, 37 % at the PF, and 38 % TB.

     

  LS, TB aBMD

 Lofgren et al. 2012 [28]

4-year expanded PE intervention

Randomized by school

Sex: male and female

Age: 6.5–8.7 years

Race: Caucasian

Location: Malmö, Sweden

221

Frequency: 5 days/week

Intensity: varied

Time: 40 min/day

Type: normal PE curriculum (running, jumping, climbing ropes, variety of ball games). Activities varied to reduce boredom. No specific osteogenic training program was added

Control: normal PE curriculum, duration within normal limits (1–2 sessions/week, in total 60 min/week)

DXA

Change, mean (95 % CI)

     

Significant

Male

Female

      

EX

CON

EX

CON

     

  TB BMC

  

179.6 (160.5, 198.7)*

166.4 (149.4, 183.4)

     

  LS BMC

7.0 (6.5, 7.6)*

6.2 (5.8, 6.6)

9.1 (7.9, 10.3)**

7.1 (6.1, 8.0)

     

  FN BMC

0.29 (0.26, 0.31)

0.27 (0.24, 0.31)

0.39 (0.33, 0.45)**

0.28 (0.23, 0.33)

     

  TR BMC

  

0.92 (0.82, 1.02)**

0.72 (0.62, 0.83)

     

 L3 width

  

0.13 (0.11, 0.14)**

0.11 (0.09, 0.12)

     

 FN width

0.12 (0.11, 0.13)*

0.11 (0.09, 0.12)

0.15 (0.12, 0.17)**

0.10 (0.08, 0.13)

      

The mean annual gain in LS BMC was 7.0 % higher in girls and 3.3 % higher in boys, and in FN width 1.7 % higher in girls and 0.6 % higher in boys in the EX group than in the CON group.

 Detter et al. 2014 [303]

6-year expanded PE intervention

Randomized by school

Sex: male and female

Age: 6–8 years

Race: Caucasian

Location: Malmö, Sweden

295

Frequency: 5 days/week

Intensity: varied

Time: 40 min/day

Type: normal PE curriculum (running, jumping, climbing ropes, variety of ball games). Activities varied to reduce boredom. No specific osteogenic training program was added,

Control: normal PE curriculum, duration within normal limits (1–2 sessions/week, in total 60 min/week)

DXA

Difference, mean (95 % CI)

     

Significant

Male

Female

     

  LS aBMD

0.006 (0.002, 0.01)**

0.01 (0.003, 0.02)*

     

  FN BMC

  

0.07 (0.01, 0.12)*

     

NS

Girls in the EX group, compared with girls in the CON group, had 0.009 g/cm2 larger gain annually in LS aBMD and 0.07 g larger gain in FN BMC. Boys in the EX group has 0.006 g/cm2 larger gain annually in LS aBMD than CON boys,

     

  TB, FN aBMD

     

  TB, LS BMC

     

  FN, LS BA

Observational studies

Reference

Study description

Population description

N

Exposure

End points

Results

Lehtonen-Veromaa et al. 2000 [350]

1-year prospective case comparison

Sex: 155 females

Baseline age: 9–15 years

Race: white

Location: Turku, Finland

51 gymnasts, 50 runners, 54 controls

Method: self-report questionnaire (2×)

Variable: leisure-time PA met (h/week)

Follow-up TH (and subregions), LS aBMD, and BA

The 1-year increase in adjusted aBMD at the FN of the gymnasts was 115 % larger than that of the controls and 125 % larger than that of the runners. The 1-year increase in adjusted aBMD at the TR of the gymnasts was 49 % larger than that of controls.

Molgaard et al. 2001 [245]

1-year prospective follow-up

Sex: 140 males, 192 females

Baseline age: 5–19 years

Race: white

Location: Copenhagen, Denmark

332

Method: 24-h recall questionnaire (3×)

(I, supine; II, sitting; III, walking; IV, breathless PA)

Variable: breathless PA (h/day)

Follow-up TB BMC, BA

Breathless PA not associated with BMC or BA

Gustavsson et al. 2003 [351]

2.5-year and 6-year prospective case comparison

Sex: 68 males

Baseline age: 16 years

Race: white

Location: Umea, Sweden

22 hockey, 21 retired hockey, 25 controls

Method: reported participation in ice hockey

Variable: group membership: hockey, retired hockey, no hockey

Follow-up at 30 months (~2.5 years) and follow-up at 70 months (~6 years) TB, FN, LS aBMD

At 30 months, hockey players had greater gains in aBMD FN than controls (0.07 vs 0.03 g/cm2). Hockey players had significantly higher aBMD at FN and TB than controls. At 70 months, hockey players had greater aBMD at the FN, TB, and LS compared to nonplayers. Retired hockey players still had 4 % higher aBMD of FN than nonplayers after 70 months

Nurmi-Lawton et al. 2004 [352]

3-year prospective case comparison

Sex: 97 females

Baseline age: 7.9–17.2 years

Race: primarily white

Location: England

45 gymnasts, 52 controls

Method: reported participation in gymnastics

Variable: group membership gymnastics, no gymnastics

Multilevel model comparing differences in TB, LS, arm, and leg BMC, as well as aBMD each year

Gymnasts had 24–51 % greater BMC and 13–28 % greater aBMD than controls.

Laing et al. 2005 [343]

2-year quasi-experimental

Sex: 143 females

Baseline age: 4–8 years

Race: 64 % white, 27 % Black, 3 % Asian, 2 % Hispanic, 4 % other

Location: Athens, Georgia

65 gymnasts, 78 controls

Method: reported participation in gymnastics

Variables: group membership gymnastics, no gymnastics, and h gymnastics participation per week

Follow-up TB, LS, PF, forearm BMC, aBMD, and BA

LS aBMD and forearm BA increased at a greater rate in gymnasts than in controls. Forearm BA increased at a greater rate in high-hours-per-week gymnastics over low-hours-per-week gymnastics

Janz et al. 2006 [353]

3-year prospective follow-up

Sex: 171 males, 199 females

Baseline age: 5 years

Race: primarily white

Location: Iowa, USA

370

Method: ActiGraph accelerometer

Variables: total PA ct/min, active min/day

(≥3000 ct/min)

Follow-up TB, TH, TR, and LS BMC

PA was significantly associated with TB, TH, TR, and LS BMC in males. In females, PA was associated with TB and TR BMC. PA explained 1–2 % of variance in BMC.

Nordstrom et al. 2006 [354]

~8-year prospective case comparison

Sex: 90 males

Baseline age: 15–19 years

Race: Caucasian

Location: Umea, Sweden

63 athletes,

27 controls

Method: reported participation in ice hockey or badminton

Variables: weight-bearing PA (h/week)

Follow-up and sustained effects TB, FN, TH, and Hum BMD; FN BA, TH BA

Active athletes had significantly higher BMD at all measured sites vs controls (P < 0.05). Former athletes still had higher BMD of the FN, TH, and Hum than did controls (P < 0.05).

Baxter-Jones et al. 2008 [22]

~15-year prospective follow-up

Sex: 72 males, 82 females

Baseline age: 8–15 years

Race: not specified

Location: Saskatoon, Saskatchewan, Canada

154

Method: self-report questionnaire (3×/year for 3 years, 2×/year after)

Variable: general level of PA for year (1–5)

Follow-up (age 23–30 years) TB, LS, TH, and FN BMC

In young adulthood, males who were physically active as adolescents had 8–9 % greater BMC at TB, TH, and FN compared to inactive adolescent males. In young adulthood, females who were active adolescents had 9 % greater TH and 10 % greater FN compared to inactive adolescent females

Cheng et al. 2009 [54]

7-year prospective follow-up

Sex: 396 females

Baseline age: 10–13 years

Race: not specified

Location: Jyvaskyla, Finland

396

Method: self-report leisure-time PA questionnaire with parent help

Variables: leisure-time PA score

Follow-up TB BMC

PA did not contribute to variability in BMC.

Janz et al. 2010 [355]

3-year and 6-year prospective follow-up

Sex: 148 males, 185 females

Baseline age: 5 years

Race: primarily white

Location: Iowa, USA

333

Method: ActiGraph accelerometer

Variables: MVPA min/day (>3000 ct/min)

Follow-up at age 8 and age 11 TB, TH, and LS BMC

After adjustment for concurrent (age 8 or 11) age, height, weight, somatic maturity, and MVPA, age 5 MVPA was significant predictor of ages 8 and 11 BMC in boys and girls at TB, TH, and LS.

Tervo et al. 2010 [356]

~12-year case comparison

Sex: 85 males

Baseline age: 15–19 years

Race: not specified

Location: Umea, Sweden

18 badminton, 44 ice hockey, 23 controls

Method: reported participation in badminton or ice hockey

Variables: weight-bearing PA (h/week)

Follow-up and sustained effects of TB, Hum, LS, FN, and leg aBMD

After adjusting for confounders, badminton players gained significantly more aBMD at all sites compared to both ice hockey players and controls. Ice hockey players gained significantly more aBMD at FN and Hum than at controls. After the end of the active career, ice hockey players and badminton players lost aBMD at a similar rate resulting in still significantly higher aBMD at all sites in badminton players compared to both ice hockey players and controls

Erlandson et al. 2011 [357]

4 year prospective case comparison

Sex: 163 males and females

Baseline age: 4–7 years

Race: 95 % white, 2 % Asian, 3 % other (biracial)

Location: Saskatoon, Saskatchewan, Canada

163 gymnasts, ex-gymnasts, nongymnasts

Method: parental-report questionnaire

Variables: current PA score

Multilevel model comparing TB, FN, and LS BMC

By year 4, recreational and precompetitive gymnasts had 3 % more TB and 7 % more FN BMC than those in other sports when body size, PA, and diet were considered

Scerpella et al. 2011 [358]

~12-year prospective case comparison

Sex: 20 females

Baseline age: 8–12 years

Race: not specified

Location: Syracuse, New York, USA

6 ex-gymnasts, 14 nongymnasts

Method: self-report questionnaire

Variables: activity (h/week)

Follow-up and sustained effect of skull aBMD and BMC; R-UD and 1/3 radius BA, BMC, and aBMD

All R-UD parameters were higher in ex-gymnasts than in nongymnasts (P < 0.02). In contrast, skull aBMD was not associated with gymnastic status. Gymnastic cessation was associated with an abrupt, temporary decrease in 1/3 aBMD, R-UD BMC, and R-UD aBMD. No significant gymnast cessation effects were observed for 1/3 BMC, 1/3 BA, R-UD BA, or skull aBMD

Erlandson et al. 2012 [359]

14-year prospective case comparison

Sex: 47 females

Baseline age: 8–15 years

Race: not specified

Location: Saskatoon, Saskatchewan, Canada

25 gymnasts, 22 controls

Method: self-report questionnaire

Variables: past-week PA score

Follow-up TB, FN, LS BMC, and aBMD

Gymnasts had significantly greater size-adjusted BMC and aBMD compared to nongymnasts at all sites, with the exception of FN aBMD in adulthood. Retired gymnasts had greater size-adjusted TB (13 %), LS (19 %), and FN (13 %) BMC and TB (8 %) and LS (13 %) aBMD compared to nongymnasts.

Farr et al. 2013 [360]

2-year prospective follow-up

Sex: 248 females

Baseline age: 9–12 years

Race: 90 % white, 6 % Asian, 2 % black or African American, 1 % Native American or Alaska Native, 1 % Native Hawaiian or Pacific Islander, and 0.5 % other

Location: Tucson, Arizona, USA

248

Method: self-report questionnaire

Variables: past-year PA score

Follow-up tibia and femur cortical and trabecular vBMD

PA associated with increases in trabecular vBMD at metaphyseal femur

Francis et al. 2014 [361]

10-year prospective follow-up

Sex: 156 males, 170 females

Baseline age: 5 years

Race: primarily white

Location: Iowa, USA

326

Method: ActiGraph accelerometer

Variables: MVPA min/day (> 2296 ct/min)

VPA min/day (> 4011 ct/min)

Follow-up at ages 13 and 15 LS and TH BMC

Ages 13 and 15 male LS BMC adjusted for baseline LS BMC predicted by age 5 MVPA and VPA

Janz et al. 2014 [248]

10-year prospective follow-up

Sex: 217 males, 235 females

Baseline age: 5 years

Race: primarily white

Location: Iowa, USA

452

Method: ActiGraph accelerometer

Variables: MVPA min/day (>2296 ct/min)

VPA min/day (> 4011 ct/min)

TH and LS BMC at five measurement cycles (age 5, 8, 11, 13, and 15 years). Multilevel model included individual growth curves for each participant

MVPA and VPA added to prediction BMC at all assessed cycles except MVPA LS BMC in females age 5, and males in the 90th percentile for VPA had 8.5 % more hip BMC than males in the 10th percentile for VPA. At age 15, this difference was 2.0 %. Females at age 5 in the 90th percentile for VPA had 6.1 % more hip BMC than those in the 10th percentile for VPA. Age 15 difference was 1.8 %.

Janz et al. 2014 [248]

12-year prospective follow-up

Sex: 160 males, 189 females

Baseline age: 5 years

Race: primarily white

Location: Iowa, USA

349

Method: ActiGraph accelerometer

Variables: MVPA min/day (>2296 ct/min)

Follow-up (age 17) TB and TH BMC and aBMD

At age 17, girls in high trajectory for MVPA had greater TB BMC, TH BMC, and TH aBMD than in the other trajectories. Boys in the high trajectory for MVPA had greater TB BMC, TH BMC, and TH aBMD than in the other trajectories.

Cardadeiro et al. 2014 [362]

1-year prospective follow-up

Sex: 81 males, 96 females

Baseline age: 10–12 years

Race: primarily white

Location: Lisbon area, Portugal

177

Method: bone-specific administered questionnaire

ActiGraph accelerometer

Variables: PA score

Sedentary min/day (≤100 ct/min)

Light min/day (101–2295 ct/min)

Moderate min/day (2296–4011 ct/min)

Vigorous min/day (>4012 ct/min)

Follow-up aBMD PF and subregions

PA measured with questionnaire and accelerometer measured MVPA significant in TR aBMD males. Questionnaire significant in superolateral FN aBMD, inferomedial FN aBMD, and FN aBMD in females

Lappe et al. 2014 [172]

6-year prospective follow-up

Sex: 910 males, 833 females

Baseline age: 5–19 years

Race: nonblack, black

Location: Los Angeles, CA; Cincinnati, OH; Omaha, NE; Philadelphia, PA; New York, NY

1743

Method: self/parental-report questionnaire (1×/year)

Variable: weight-bearing PA (h/week)

Follow-up and mixed-model analysis %chgBMC for TB, LS, and TH at each TS of maturity

The greatest BMC accrual at all skeletal sites occurred at TS4, with the exception that the greatest % accrual in hip BMC in females was at TS3. Significant PA × TS interactions were only observed in nonblack males and only for TB BMC. All other PA × TS interaction effects were nonsignificant. PA was a significant predictor of chgBMC at all skeletal sites after adjustment for calcium in nonblack males, LS and TH in black males, TB and TH in nonblack females, and at LS in black females.

%chgBMC percent accrual of BMC, 95 % CI 95 % confidence interval, aBMD areal bone mineral density (g/cm2), BA bone area (cm2), BMAD bone mineral apparent density (g/cm2), BMC bone mineral content (g), CON control group, DXA dual-energy x-ray absorptiometry, EX exercise group, FA forearm, FN femoral neck, FS femoral shaft, GRF ground reaction force, GT greater trochanter, Hum humerus, IT intertrochanter, LS lumbar spine, MVPA moderate-through-vigorous-intensity physical activity, NN narrow neck, NS not significant, PA physical activity, PE physical education, PF proximal femur, RA right arm, Rad radius, RCT randomized controlled trial, R-Dis radius, distal, R-Ul radius, ultradistal, SA-BMC size-adjusted bone mineral content, TB total body, T-F tibia–fibula, TH total hip, TR trochanter, TS Tanner stage, U-R ulna-radius, vBMD volumetric bone mineral density (g/cm3), VPA vigorous physical activity, WA Ward’s area

*P < 0.05; **P < 0.01; ***P < 0.001

summarize the articles that were chosen for inclusion in the current review, and these include additional articles located via review articles, meta-analyses, and expert knowledge of the literature.

Results

Nutrition and peak bone mass

Macronutrients

Fat (Table 2)

The search for fat identified no RCTs, 1 prospective study, and 1 cross-sectional study published since 2000, encompassing 163 individuals (Table 2). Data from the prospective study demonstrated that changes in aBMD of the spine in males between ages 16 and 22 years were positively associated with serum levels of arachidonic acid and all omega-3 fatty acids, including DHA [141]. The cross-sectional study by Eriksson et al. [142] showed positive correlations between total body BMC and serum nervonic acid and arachidonic acid as well as negative associations with α-linolenic acid.

Our evidence grade for fat was based on findings from one prospective study with methodological limitations and one cross-sectional study.
  • Grade: Level of evidence D was assigned for evidence for the benefit of fat on bone.

Protein (Table 3)

The search for protein identified 1 RCT, 5 prospective studies, and 6 cross-sectional studies published since 2000, encompassing 2255 individuals (Table 3). In the one RCT, there was no effect of supplementing 42 g protein over 6 months on changes in tibia trabecular or cortical bone measures at the 4 or 20 % sites, respectively, measured from the distal tibia metaphysis, or on changes in total body BMC [143]. Alexy et al. [144] demonstrated in a cohort of German children that protein intakes over 4 years were positively associated with, and were predictors of, forearm periosteal circumference, cortical area, BMC, and stress–strain index (SSI). The investigators also showed that long-term dietary potential renal acid load (PRAL) was negatively associated with forearm BMC and cortical area. PRAL is increased by sulfur amino acid content of the diet and is decreased by alkaline salts as occurs in plant foods. In the same cohort studied over 4 years, Remer et al. [145] reported that urinary nitrogen (uN) was positively associated with forearm periosteal circumference, cortical area, BMC, and SSI, and urinary PRAL was negatively associated with forearm BMC and cortical area. Protein intakes in males and females between the ages of 2 months and 8 years were positively associated with total body BMC [146]. Using a mixed-longitudinal design, protein intakes were shown to positively predict total body BMC net gain in males and females between ages 8 and 21 years [147]. Moreover, protein intakes in periadolescent females were positively associated with total body BMC and total body BMC net gains, but only in those with calcium intakes >1000 mg/day. Over a period of 5 years, protein intakes in children with low calcium intakes were negatively associated with distal and proximal forearm BMC and total body BMC [148].

Hoppe et al. [149] reported that protein intakes among Danish children were positively related to total body bone area, but not BMC, when adjusted for height, weight, and sex. Differences in arm BMC between twins were partially explained by protein intakes, such that a 1-g difference in protein intake resulted in a 0.4 % difference in arm BMC [150]. Chevalley et al. [151] reported that protein intakes in prepubertal males were positively related to BMC of the radial metaphysis, total radius, femoral neck, femoral diaphysis, and the lumbar spine when controlling for physical activity and calcium intakes. Absolute or adjusted (for body weight, years after menarche, and vertebral area) protein intake from milk, but not from other foods, was positively associated with lumbar spine BMC [152]. In a group of healthy and malnourished Indian children aged 2–3 years, protein intake was positively related to total body BMC and bone area [153]. However, energy-adjusted protein intakes were not significantly associated with forearm geometrical measures in another group of children [154].

Our evidence grade for protein was based on findings from four prospective studies indicating positive findings and one null RCT.
  • Grade: Level of evidence C was assigned for the benefit of protein on bone.

Micronutrients

Calcium (Tables 4 and 5)

The search for calcium identified 16 RCTs published since 2000, encompassing 3077 individuals (Table 4). In addition, five studies that used both calcium and physical activity interventions were evaluated for main and interaction effects [81, 155158]. Four observational studies published since 2000, encompassing 2383 individuals, looked at calcium and physical activity interactions on bone (Table 5). When categorized according to the type of calcium intervention, nine studies included supplementation with pills/chews, four used calcium-fortified foods, two used dairy foods, and one used a combination of dairy and pills. Most of the studies included primarily white subjects. A variety of skeletal variables were used as study outcomes. Most studies evaluated the effects of calcium intake on DXA outcomes, including BMC, aBMD, and bone area of the total body, lumbar spine, total hip, femoral neck, intertrochanteric and trochanteric areas of the hip, and distal and ultradistal areas of the forearm. Very few studies reported all possible DXA outcomes, and specific outcomes varied among studies. Three RCTs assessed bone mass and structure using pQCT.

All but one [159] of the nine RCTs using supplement pills found a small, but consistent, positive effect on aBMD and/or BMC accrual as measured by DXA. The benefit to the supplemented group compared to the placebo group ranged from 0.57 to 5.80 %. None of the studies found a significant effect at all (i.e., hip, spine, and radius) of the usual DXA skeletal sites, and the specific sites that benefited varied among the studies. Only three of the RCTs with DXA reported adjusting for body size [160162], which is important because longitudinal growth confounds interpretation of changes in aBMD and BMC. The difference in height-adjusted BMC accrual between supplemented and placebo groups in these four studies ranged from 0.80 to 4.60 %.

One of the best-designed studies was a single-blind co-twin study of girls aged 8–13 years given calcium carbonate 1200 mg/day or placebo for 24 months [161]. Baseline calcium intake was 786 mg/day (calcium) and 772 mg/day (control; not significant), values considerably lower than the recommended dietary allowance (RDA) (1000 mg/day for ages 4–8 years and 1300 mg/day for ages 9–18 years). Of 64 twin pairs enrolled, 24 pairs completed the study. Compliance with supplementation was 76 % for both groups (calcium and placebo). At the end of study, the calcium group had gained 3.69 % more total body BMC (adjusted for age, height, and weight) than the control group. There were no significant differences in change in BMD at the total hip, spine, or femoral neck. In post hoc analyses, significant differences in gain were seen in total body BMC (2.47 %), hip BMD (1.64 %), and spine BMD (1.64 %) in the calcium group after 12 months of supplementation. Confidence in the findings at 24 months is lessened due to the high rate of attrition (63 %). Another confounder is that the girls studied were peripubertal and thus varied in their estrogen status. At baseline, all subjects were premenarchal, whereas by the end of the study, 13 of the 48 subjects were postmenarchal (five concordant and three discordant pairs.)

Dibba et al. [160] tested the effects of calcium carbonate 1000 mg/day on radius BMC and BMD accrual in a 12-month RCT of prepubertal Gambian children who had low baseline calcium intake (342 mg/day). Supplementation resulted in a higher size-adjusted BMC in the midshaft radius (4.6 ± 0.9 %; P < 0.0001) and in the distal radius (5.5 ± 2.7 %; P = 0.042). This study showed a greater difference in gain between groups than the study by Cameron et al. [161], which supports the premise that children more deficient in a nutrient are likely to have greater benefit from supplementation. Prentice et al. [162] conducted a 13-month RCT of calcium carbonate 1000 mg/day in older adolescent males in Great Britain. Baseline and study calcium intakes were high, even in the placebo group, which was meeting the RDA. Nonetheless, calcium supplementation resulted in an approximately 1 % greater increase in total hip BMC after adjustment for bone area, weight, and height. The calcium intervention also resulted in greater height.

Three RCTs evaluated the effect of both calcium and vitamin D supplement pills on gain in tibial trabecular vBMD as measured by pQCT measurement on the distal tibia. Moyer-Mileur et al. [163] found a significant difference in gain at the 10 % skeletal measurement site on the distal tibia, whereas Greene and Naughton [164] found a significant 5.2 % difference in gain at the 4 % distal tibia site. Both the 10 and 4 % tibia sites represent primarily trabecular bone. Cheng et al. [159] found no effects. Only Greene and Naughton [164] reported adjusting for body size (limb length). However, the vitamin D doses (200 and 400 IU/day) were below the RDA of 600 IU/day, which raises doubt as to whether vitamin D status was optimized in these subjects.

Of the four RCTs using calcium fortification of food or beverages [165168], all but one [166] found a significant supplement effect on skeletal gain, which ranged from 3.2 to 19.0 %. In the study showing no effect [166], the average dietary calcium intake of the placebo group was 1395 mg/day, which was above the threshold and likely accounts for the lack of effect of a calcium supplement.

Two RCTs were identified that supplemented with dairy foods. One study [169] found that 1000 mg of dairy resulted in a 1.5 % greater gain in spine BMD compared to controls. In the study by Du et al. [170], 10-year-old girls were randomized to one of three groups: group 1 consumed 330 mL/day of ultra-heat-treated (UHT) milk fortified with a calcium salt containing 560-mg calcium, group 2 consumed 330 mL/day of UHT and 200–320 μg of vitamin D, and a control group followed their usual diet. The calcium salt also contained phosphorus and protein, both of which affect bone. Baseline calcium intake was about one third of the RDA among the three groups. After 24 months, groups 1 and 2 gained significantly greater size-adjusted total body BMC than the controls, and group 2 with vitamin D supplementation gained more than group 1 (P = 0.006). Cheng et al. [159] supplemented with both pills and cheese, and the authors found an effect with cheese only.

Three of the four RCTs of calcium and exercise combined [81, 155, 157] found that the combined intervention had a significantly greater effect on bone accrual as assessed by DXA than either exercise or calcium alone. Specker and Binkley [81] also found an interaction effect on cortical thickness and area as measured by pQCT.

Only four observational studies of calcium intake and bone accrual were found [171174]. Three found no association between calcium intake and accrual, whereas one prospective study [172] found a significant association between calcium intake and spine BMC adjusted for height change only in nonblack girls.

Our evidence grade for calcium was based on positive findings from 90 % of the RCTs using supplement pills, which found a small, biologically, and statistically significant positive effect on aBMD and/or BMC accrual. The bone accrual in the supplemented group compared to the placebo group was largest in children who had the lowest intakes at baseline. This supports the premise of a threshold nutrient such as calcium (i.e., if usual intake of calcium exceeds requirements, then it is unlikely that any benefit of the intervention will be detected). Thus, on the basis of this review, we conclude that dietary intake guidelines for calcium are not being met by all children and adolescents.
  • Grade: Level of evidence A was assigned for the benefit of calcium on bone.

Vitamin D (Table 6)

The search for vitamin D identified nine publications from 8 RCTs, 1 prospective study, and 3 cross-sectional studies published since 2000, encompassing 2962 individuals (Table 6). Four of the eight RCTs provide evidence for a beneficial effect of vitamin D supplementation on bone accrual. El-Hajj Fuleihan et al. [175] found that Lebanese children receiving weekly doses of 14,000 IU vitamin D3 over 1 year had improved hip BMC and bone area (using conventional DXA) and narrow neck outer diameter and buckling ratio (using the HSA program) [176]. Furthermore, trochanter BMC improved in premenarchal, but not postmenarchal, females [175]. There were no significant effects of supplementation observed in boys. Viljakainen et al. [177] showed that Finnish females assigned to placebo or 200 or 400 IU vitamin D3 over 1 year exhibited no differences in BMC gains at the lumbar spine or femur. A compliance-based analysis was conducted, which included only those subjects with >80 % compliance. After adjusting for bone area, weight gain, and changes in maturation, greater increases in lumbar spine BMC were observed with 400 IU vitamin D3 and in femur BMC with either 200 or 400 IU D3 [177]. The increase in lumbar spine BMC in this study was identified in perimenarchal, but not premenarchal, females. Du et al. [170] demonstrated that the addition of 200–320 IU of vitamin D3 to calcium-fortified milk significantly increased size-adjusted total body BMC over 2 years compared to controls. When analyzing the data by menarchal status, the significant increase in size-adjusted total body BMC was observed only in females that had experienced menarche versus premenarche. Khadilkar et al. [178] found that supplementing vitamin D-deficient girls (girls with mean baseline serum 25(OH)D concentrations 20–25 nmol/L) with quarterly doses of 300,000 IU vitamin D2 along with daily supplementation of 250 mg elemental calcium over 1 year improved adjusted total body BMC and bone area more compared with girls who were supplemented with calcium alone. These positive findings were observed in the compliance-based analyses only and in females within 2 years of starting their menstrual cycle, adjusting for multiple factors including fat-free mass.

Four of the eight RCTs showed no effect of vitamin D supplementation on bone. Ward et al. [179] reported that quarterly supplementation with 150,000 IU vitamin D2 versus placebo in vitamin D-deficient adolescent females did not improve DXA- and pQCT-derived bone outcomes over 1 year, including measures of tibia and radius trabecular or cortical bone. Molgaard et al. [173] reported that supplementation with 200 or 400 IU vitamin D in 10- to 11-year-old females over 1 year had no effect on changes in total body or lumbar spine BMC or in bone area. Similarly, supplementation with either 400 or 800 IU to vitamin D-deficient females over 1 year had no effect on unadjusted total body BMC gains compared to placebo [180]. Finally, supplements containing 200 IU with 1000-mg calcium had no effect on total body, lumbar spine, femoral neck, or total femur BMC gains over 2 years compared to placebo, calcium alone (1000 mg), or a cheese-supplemented group [159].

A prospective study in prepubertal girls conducted over a 5-year period found that as serum 25(OH)D concentrations declined with age, there were significant increases in BMC at multiple skeletal sites [181]. This study showed that serum 25(OH)D did not have a predictive effect on BMC accrual above and beyond that of insulin-like growth factor (IGF)-I [181]. In a cross-sectional study of females aged 10–12 years, those with deficient serum 25(OH)D ≤25 nmol/L had lower cortical vBMD at the distal radius than those with values ≥26 nmol/L, and they also had lower cortical vBMD at the tibial shaft compared to subjects with values between 26 and 40 nmol/L [182]. Moreover, Foo et al. [183] found that 15-year-old Chinese females with vitamin D deficiency (i.e., <25 nmol/L) had lower size-adjusted total body and forearm BMC than females with sufficient values (>50 nmol/L). In a study of 9-year-old Korean children, serum 25(OH)D was positively associated with total body BMC after adjusting for multiple variables, which included physical activity and calcium intake [184].

The evidence grade for vitamin D was based on the point that four of eight RCTs showed improvements in BMC accrual. Furthermore, one of the positive RCTs was well designed, used an intent-to-treat analysis, was adequately powered, and employed a wide range of supplement doses. The evidence grade B reflects the lack of generalizability across the RCTs, which included primarily female subjects with little diversity in population ancestry.
  • Grade: Level of evidence B was assigned for the benefit of vitamin D on bone.

Micronutrients other than calcium and vitamin D (Table 7)

The search for other micronutrients identified 1 RCT, 2 prospective studies, and 6 cross-sectional studies published since 2000, encompassing 2192 individuals (Table 7). Only one RCT was identified and that was for magnesium [185]. Magnesium supplementation at 300 mg/day for 1 year was significantly associated with a ~3 % increase in overall hip measures of BMC and a borderline significant increase in lumbar spine BMC among white girls. In prospective studies, fluoride was not related to BMC in adjusted models [186188]. Cross-sectional studies report that a positive association of vitamin C intake and BMC was observed only in boys [189], and positive associations of vitamin C and zinc intakes with bone size and strength were observed in fourth-grade, but not sixth-grade, girls [190]. By contrast, negative associations between high intakes of sodium and phosphorus and total body BMC and bone area in white boys and girls were observed [149]. Iron intake was negatively associated with femoral cortical area [190].

Cross-sectional studies also showed advantages of a biomarker of vitamin K status only in white females [191]. In their study of 245 healthy girls in the USA aged 3–16 years, Kalkwarf et al. [192] reported that better vitamin K status (assessed by plasma phylloquinone and serum percentage of undercarboxylated osteocalcin [%ucOC]) was associated with decreased bone turnover, but it was not associated with baseline BMC. Serum %ucOC was not associated with changes in BMC of the hip, total body, or total body minus the head, but it was surprisingly associated with positive changes in lumbar spine BMC [192]. In contrast with this study, a more recent association study of 223 healthy peripubertal Danish girls found that better vitamin K status was associated with increased total body and lumbar spine BMC, but not with bone turnover [191].

Our evidence grade for other micronutrients was based on one RCT of magnesium supplementation, two prospective studies of fluoride intake, two cross-sectional studies assessing vitamin C and vitamin K intake, and one cross-sectional study assessing intakes of zinc, iron sodium, and phosphorus.
  • Grade: Level of evidence D was assigned for the benefit of micronutrients other than calcium and vitamin D on bone.

Food patterns (Table 8)

The search for food patterns identified 5 RCTs and 12 observational studies published since 2000, encompassing 6282 individuals (Table 8).

Dairy

Three 2-year RCTs showed increased gains in some bone sites with dairy food consumption [159, 169, 170]. The study by Cheng et al. [159] found an increase with cheese consumption in bone quality assessed by tibia cortical thickness using pQCT in addition to total body BMD, but only in those participants who were at least 50 % compliant. The advantage of trochanter BMC in the study with dairy supplementation disappeared 1 year after cessation [169]. These RCTs were not generalizable because they were conducted only in presumably white girls, except for the study by Du et al. [170] conducted in Asians.

Fiber

One RCT was found and the authors reported a benefit of prebiotic fibers on total body BMC gains in boys and girls over 1 year [193]. One cross-sectional study [194] showed dietary patterns that favored higher bone mass and lower fat mass including higher amounts of dark-green and deep-yellow vegetables and lower amounts of fried foods.

Fruits and vegetables

The five cross-sectional studies identified consistently found some type of benefit to bone with increased and/or high intake of fruits and vegetables [189, 195198].

Detriment of cola and caffeinated beverages

We identified six studies that examined the effects of carbonated beverages or caffeine-containing beverages and bone accrual during childhood and peak bone mass. Several cross-sectional studies have shown inverse associations between cola or carbonated beverages and bone outcomes in children or young adults. In a population-based, case–control study of children who had experienced upper limb fractures, Ma and Jones [199] found that wrist and forearm fractures were significantly associated with cola drink consumption (odds ratio (OR), 1.39 per unit; 95 % confidence interval (95 % CI), 1.01, 1.91), but not after adjustment for sedentary activities (e.g., television, computer, and video watching). Wyshak [200] found that carbonated beverage consumption was associated with a history of fracture (OR, 3.14; 95 % CI, 1.45, 6.78). The association was strongest for girls reporting higher levels of physical activity (OR, 7.00; 95 % CI, 2.00, 24.45). Similarly, Manias et al. [201] evaluated children with a first-time fracture (n = 50), those who had recurrent fractures (n = 50), and a fracture-free group (n = 50). The recurrent fracture group had lower levels of milk intake and physical activity and higher BMI and carbonated beverage intake than controls; those with one or more fractures had significantly lower total body and lumbar spine BMC and aBMD. A 4-year prospective study of 228 children showed that carbonated beverage consumption increased as milk intake declined, and carbonated beverage intake was negatively associated with strength of the radius (polar SSI) even after adjusting for milk intake [202].

Lower aBMD has been found in children with higher carbonated beverage intakes [194, 201]. McGartland et al. [194] found a significant inverse relationship between total carbonated beverage intake and heel (but not forearm) BMD among girls after adjusting for age, height, weight, pubertal status, social status, alcohol intake, smoking habits, physical activity, liquid milk consumption, and calcium obtained from sources other than liquid milk. These findings suggest that aBMD in girls may be more sensitive to the effects of carbonated beverages compared with boys. McGartland et al. [194] also observed a significant inverse association between carbonated beverage intake and milk intake in both boys and girls.

Remarkably few studies have considered the potential effects of caffeinated beverages on peak bone mass. Caffeine consumption is of concern because it is associated with increased urinary excretion of calcium [203]. In a cross-sectional study of young white women, aged 19–26 years (n = 177), Conlisk and Galuska [204] examined the association of caffeine consumption and femoral neck BMD. Caffeine intake was estimated by self-reported consumption of coffee, decaffeinated coffee, tea, colas, chocolate products, and select medications. After adjustment for potential confounders (height, BMI, age at menarche, calcium intake, protein consumption, alcohol consumption, and tobacco use), caffeine consumption was not significantly associated with aBMD. These findings do not provide support for negative effects of caffeine intake in this age range.

Fruits and vegetables

To our knowledge, there are no long-term prospective studies of vegetarian children with bone outcomes. Few studies have examined the influences of vegetarian dietary patterns on bone, but there is some evidence in adults that adhering to vegan diets is associated with lower bone mass [205] and fractures [206]. It has been hypothesized that following a diet composed primarily of fruits and vegetables would provide a nutrient profile, specifically higher potassium and plant-based proteins, which would favorably influence acid–base balance and bone mass [207]. Alternatively, following a vegetarian diet may exclude certain food groups that contain essential bone-related nutrients such as calcium [208], although a recent large US study using National Health and Nutrition Examination Survey (NHANES) data found no differences in calcium intakes between strict vegetarians and nonvegetarians [209]. In an editorial, Lanham-New [210] takes the position that vegetarianism is not a serious risk factor for osteoporosis. She recognizes that the study of vegetarian dietary patterns and bone is complex because specific patterns of vegetarian diets include or exclude bone-related nutrients and lifestyle factors, serum hormone concentrations, and dietary assessment methods could confound the findings.

Our evidence grade for food patterns was based on 3 RCTs showing a positive benefit of dairy consumption to bone accrual, 1 RCT using mixed chain length fermentable fibers, and 12 observational studies, respectively.
  • Grade: Level of evidence B was assigned for the benefit of dairy consumption on bone. Level of evidence C was assigned for the benefit of certain types of fiber and fruit and vegetable intake on bone, as well as for a detrimental effect of cola and caffeinated beverages on bone.

Infant nutrition (Table 9)

The search for infant nutrition identified 1 RCT and 10 observational studies published since 2000, encompassing 2715 individuals (Table 9). In the identified RCT, Koo et al. [211] found a positive effect of infant formula enriched with palm olein on bone mineral accretion in healthy term infants compared to the control formula. Of the ten observational studies identified in the search, three compared the effects of duration of breastfeeding [212214], three assessed later bone outcomes in breast-fed versus formula-fed infants [215217], two assessed later bone outcomes of breast-fed infants only [218, 219], and two compared breast-fed versus formula-fed versus enriched formula-fed infants [220, 221].

Formula-fed infants had better BMC and BMD in the first 6 months of life compared to breast-fed infants in two of the observational studies [215, 216]; however, breastfeeding was shown to be advantageous in two observational studies assessing later bone outcomes in 8-year-old children [217, 219] and 16-year-old adolescents [218]. Mixed results were obtained for studies testing the duration of breastfeeding in infants who were exclusively breast-fed [212214]. The addition of palm olein and sn-2 palmitate to infant formula was not shown to be beneficial on later total body BMC outcomes in 4.5- and 10-year-old children [220, 221]. This is contrary to the RCT by Koo et al. [211].

Our evidence grade for infant nutrition was based on the lack of RCTs, inconsistent length of follow-up observational studies, and lack of consistent results across studies.
  • Grade: Level of evidence D was assigned for the benefit of duration of breastfeeding on bone. Level of evidence D was assigned for the benefit of breastfeeding versus formula feeding on bone. Level of evidence D was assigned for the benefit of enriched formula feeding on bone.

Adolescent special issues

Detriment of DMPA injections and oral contraceptives (Table 10)

The search for contraception identified no RCTs, 8 observational studies, and no cross-sectional studies since 2000, encompassing 1815 individuals (Table 10). Six studies reported null effects of oral contraceptives (OCs) versus a control on bone [222227] and two studies reported suppression of bone mineral accrual and bone mass acquisition in adolescents [228, 229]. Injections of depot medroxyprogesterone acetate (DMPA) showed a consistent detrimental effect to bone in three studies [225, 226, 230], while one study found null effects [227]. An additional study suggested that the change in body weight due to DMPA injection may override the potential detrimental effect to bone [222].
  • Grade: Level of evidence B was assigned for the detriment of DMPA injections on bone. Level of evidence D was assigned for the detriment of OCs on bone.

Detriment of alcohol (Table 11)

The search for alcohol identified no RCTs, 3 prospective studies, and 5 cross-sectional studies published since 2000, encompassing 3352 individuals (Table 11). Four studies used peripheral DXA measurements only. There was large variability among studies in the amount of alcohol consumed by study participants and the classification of alcohol intake from ever tried to number of drinks per day. Overall, the reported alcohol consumption by adolescents studied was relatively low. In some studies, adolescents who consumed alcohol were more likely to smoke [231235], necessitating statistical adjustment for smoking to investigate the independent effects of alcohol intake on bone. The majority of studies found no association between alcohol intake and bone outcomes [232, 233, 235237]. Among studies reporting a statistically significant association, the direction of the association was inconsistent. Some reported that alcohol intake was associated with lower bone density [231], whereas others reported that alcohol intake was associated with higher bone density [234, 238].

Our evidence grade for alcohol consumption was based on insufficient data to support a hypothesis, owing to no RCTs, low alcohol exposure, and multiple methodological differences among the few studies performed.
  • Grade: Level of evidence D was assigned for the detriment of alcohol on bone.

Detriment of smoking (Table 12)

The search for smoking identified no RCTs, 6 prospective studies, and 7 cross-sectional studies published since 2000, encompassing 13,955 individuals (Table 12). Six of the studies used peripheral DXA, and two studies examined stress fractures as the bone outcome. There was large variability among studies with respect to extent of smoking in the study participants, both in terms of the proportion who had ever smoked as well as frequency of smoking (e.g., cigarettes per day). Smoking exposure was lowest in young adolescents and increased with age up to young adulthood. Classification of smoking exposure for statistical analyses was also variable across studies (e.g., 1 puff in lifetime versus daily smoking). Some studies reported that adolescents who smoked were more likely than their nonsmoking peers to engage in behaviors that also could negatively impact bone health, namely lower physical activity levels [238, 239], lower dietary calcium intake [239], and greater alcohol use [231235], making statistical adjustment for these behaviors critical to enable the interpretation of study findings.

Results from studies examining the association between bone density and smoking during adolescence are mixed. Some find significant deficits in bone mass or aBMD at one or more skeletal sites, ranging from −1.8 (not available for all studies) to −6.5 % [232234, 239, 240], whereas others found no difference in bone according to smoking exposure [231, 235237]. In the prospective study of adolescent females (aged 13–19 years) by Dorn et al. [233], the effect of smoking on bone accrual became more pronounced as girls got older. Compelling data demonstrating the deleterious effects of smoking on bone come from studies of military recruits. Among male military recruits (aged 18–22 years), Lorentzon et al. [239] found that smoking ≥1 cigarette/day (average 9/day) for an average of 4 years was associated with lower aBMD ranging from −1.8 to 5.0 % depending on the skeletal site. Cortical thickness measured by pQCT was −2.9 to −4.0 % lower in smokers owing to greater endosteal circumference. Eleftheriou et al. [238] found that aBMD at the hip was −4.7 % lower among current smokers compared to never smokers. By contrast, the authors found that ex-smokers had a smaller (−4.3 to −5.0 %) periosteal circumference measured by MRI compared to never smokers, but there were no differences in bone dimensions between current smokers and never smokers. In a study of female military recruits, Lappe et al. [42] found that a history of smoking was associated with an increased risk (OR, 1.34; 95 % CI, 1.05, 1.71) of stress fracture during 8 weeks of basic training. However, years of exercise, which was associated with a reduced risk of stress fracture, was not accounted for in these analyses and effects of smoking may have been overestimated. In a second study of female military recruits, history of smoking was similarly associated (OR, 1.32; 95 % CI, 0.99, 1.75) with risk of stress fracture even when accounting for fitness (running speed) and years of prior exercise [241].

Our evidence grade for smoking was based on multiple well-designed cross-sectional studies.
  • Grade: Level of evidence C was assigned for the detriment of smoking on bone.

Physical activity and exercise

Effect on bone mass and density (Table 13)

The search for the effects of physical activity on BMC identified 36 RCTs and 20 observational studies published since 2000, encompassing 9942 individuals (Table 13). Eighty-three percent (n = 30) of the RCT studies reported statistically significant (P < 0.05), and many were likely clinically significant (~3 % difference), differences between exercise and control groups at the completion of the intervention. With one exception [242], interventions finding no statistically significant difference between exercise and control groups used similar exercise volume, type, and length as those studies reporting significant effects. Most of the exercise intervention studies of prepubertal, early pubertal, and midpubertal children found increases (~1–6 % difference over 6 months) in the bone mineral of the total body, hip, or lumbar spine. The type of interventions varied but typically ranged from 7 to 24 months in duration, 2–5 sessions per week, 10–60 min per session, and they included sports, games, dance, or high-impact exercises (jumping, hopping). Fewer studies existed for late-pubertal and postpubertal adolescents, and the effects were less dramatic (0.3–1.9 % difference over 6 months), despite a similar intervention dose compared to interventions that focused on younger participants [156, 243]. For example, within the same intervention, one study found skeletal effects in premenarchal but not in postmenarchal females [244].

We reviewed 20 prospective longitudinal studies, with 90 % of these studies (n = 18) reporting statistical differences in bone mass or density between the most physically active children and adolescents in their cohorts and those who were less active. The range in percent difference was wide, although studies that examined youth engaged in organized sports consistently reported greater differences than other study populations. Two studies [54, 245] reported no differences in mass or density between the most active and less active participants. However, these studies used specific self-report measures of physical activity known to have considerable measurement error [246, 247]. By contrast, when using an objective measure of physical activity, the Iowa Bone Development Study demonstrated 10–16 % greater hip BMC and 8 % greater hip aBMD in participants who accumulated the greatest amount of activity from childhood through adolescence (12-year follow-up) [248]. One of the most important of the prospective observational studies, the University of Saskatchewan Paediatric Bone Mineral Accrual Study [3], used a mixed-longitudinal design to evaluate relationships between self-reported general level of physical activity and BMC in a group of healthy Canadian adolescents. The investigators reported that children and adolescents who were physically active at ages 8–15 years had 8–10 % more hip BMC as young adults (aged 23–30 years) compared to less active peers (after controlling for their adult physical activity levels and baseline bone outcomes). This study suggested the possibility of long-term sustained benefits of childhood physical activity on adult BMC [22]. In conclusion, long-term prospective observational studies of heterogeneous cohorts of youth have examined self-selected, everyday physical activity levels and BMC, aBMD, or vBMD. These studies have convincingly and repeatedly shown that participation in high levels of physical activity is associated with greater bone mass accrual compared to less active peers.

Our evidence grade for physical activity and exercise on bone mass and density was based on consistent evidence from many RCTs and observational studies.
  • Grade: Level of evidence A was assigned for the benefit of physical activity and exercise on bone mass and density.

Effect on bone structural outcomes (Table 14)

Table 14

Physical activity and exercise on bone structure in children and adolescents

Reference

Study description

Population description

Number of subjects

Intervention

End points

Results

RCTs

Heinonen et al. 2000 [244]

9-month step aerobics/ jumping intervention

Randomized by school

Sex: female

Age: 10–15 years

Race: not specified

Location: Tampere, Finland

126

Frequency: 2×/week

Intensity: progressive

Time: 50 min (10-min warm-up, 15-min nonimpact aerobic exercises, 20-min high-impact/jump training, 5-min cool down)

Type: both-leg jumps at floor level, both-leg box jumps, one-leg box jumps

Control: normal PA

pQCT

Significant

None

NS

Tibia CoD, CoA, BSI

At the tibial midshaft, the intergroup differences (CoD, CoA, and BSI) were not significant

Petit et al. 2002 [73]

7-month jumping intervention

Randomized by school

Sex: female

Age: 9–12 years

Race: multiethnic population of city (~34 % Hong Kong Chinese and 57 % white) reflected in cohort

Location: Richmond, British Columbia

177

Frequency: 3×/week (2× PE, 1 classroom)

Intensity: progressed over school year by increasing number of jumps per station (from 10 to 20) and height (from 10 to 50 cm)

Time: 10–12 min (5 circuits, ~1.5–2 min each)

Type: jumping exercises—jumping jacks, lung jumps, hopping, jumping over various obstacles, drop jumps from platform

Control: stretching

pQCT

Change in early pubertal girls, mean (95 % CI)

    

Significant

EX

CON

    

  NN CSA

0.060 (0.043, 0.077)*

0.035 (0.021, 0.049)

    

  NN Z

0.145 (0.118, 0.0172)*

0.106 (0.084, 0.129)

    

  NN CT

0.012 (0.008, 0.016)*

0.007 (0.004, 0.010)

    

  IT ED

0.092 (0.064, 0.120)*

0.138 (0.114, 0.161)

    

NS

There was no difference in change for bone structure in the PRE girls. The more mature girls (EARLY) in the EX group showed significantly greater gains in CSA and reduced endosteal expansion. Changes in SPW did not differ. Structural changes improved Z at the NN (4.0 %), but not at the IT region. There were no differences at the primarily cortical FS.

    

  NN length, SPW, ED

    

  IT CSA, SPW, Z

    

  FS CSA, SPW, Z, ED, CT

Specker and Binkley 2003 [81]

1-year randomized, placebo-controlled, partially blinded trial of PA and calcium supplementation

Sex: male and female

Age: 3–5 years

Race: 94 % white, 6 % other

Location: South Dakota

178

Frequency: 5 days/week

Intensity: not specified

Time: 30 min/day (5-min warm-up, 20-min activity, 5-min cool down)

Type: hopping, jumping, skipping activities (17 different weekly programs)

Control: 30 min/day of activities to keep them sitting quietly

pQCT

Exercise group had greater PCirc and ECirc than control group (P < 0.05).

    

Significant

    

  PCirc

    

  ECirc

    

NS

    

  CA, CT

MacKelvie et al. 2004 [295]

20 month jumping intervention

Randomized by school

Sex: male

Age: 8.8–12.1 years

Race: multiethnic population of city (~34 % Hong Kong Chinese and 57 % North American/Western European Caucasian, 5 % Southeast Asian, and 4 % other or mixed ethnicity) reflected in cohort

Location: Richmond, British Columbia

64

Frequency: 3×/week (2× PE, 1 classroom)

Intensity: progressed over school year by increasing number of jumps per station (from 10 to 20) and height (from 10 to 50 cm

Time: 10–12 min (5 circuits, ~1.5–2 min each)

Type: jumping exercises- jumping jacks, lung jumps, hopping, jumping over various obstacles, drop jumps from platform

Control: stretching

HSA

Change, mean (95 % CI)

    

Significant

EX

CON

    

  NN CSMI

0.23 (0.20, 0.27)*

0.17 (0.14, 0.20)

    

  NN Z

0.13 (0.11, 0.15)*

0.09 (0.072, 0.11)

    

NS

At the NN region, EX boys had significantly greater changes in Z (7.5 %). Changes at the IT and FS regions were not significantly different between groups.

    

NN length, CSA, PW, EW, CT

    

IT CSMI, CSA, PW, Z, ED, CT

    

FS CSA, PW, CSMI, Z, EW, CT

McKay et al. 2005 [297]

8-month jumping intervention

Control group used from previous study

Sex: male and female

Age: 8.9 to 11.0 years

Race: 38 % Caucasian, 48 % Asian, 15 % other (including mixed ethnic, black, and South Asian)

Location: Richmond, British Columbia

124

Frequency: 3×/day

Intensity: 5× body wt, maximum rate of force was > 400 body wt/s (independent sample of 70 boys and girls)

Time: 3 min/day

Type: 10 counter movement jumps (two-foot take off, clutch knees, two-foot landing)

Control: not specified, from previous study

HSA

Change in bone structural parameters did not differ between groups.

    

Significant

    

  None

    

NS

    

  NN and FS BMD, CSA, SW, Z, ED, CT

Macdonald et al. 2007 [25]

16-month PA and jumping intervention

Randomized by school

Sex: male and female

Age: 10.2 ± 0.6 years

Race: 53 % Asian (Hong Kong or China, India Philippines, Vietnam, Korea, or Taiwan), 35 % Caucasian (North America or Europe), 12 % mixed or other ethnic origins

Location: Richmond and Vancouver, British Columbia

410

Frequency: Classroom Action: 5 days/week; Bounce at the Bell: 5 days/week PA + 3×/day, 4 days/week jumping

Intensity: not specified

Time: Classroom Action: 15 min of PA; Bounce at the Bell: 15 min of PA + short bouts of high-impact jumping

Type: Classroom Action: skipping, dancing, playground circuits and simple resistance exercises with bands; Bounce at the Bell: Classroom Action + short bouts high-impact jumping

Control: regular PE

pQCT

Change in bone structural parameters did not differ between groups.

    

Significant

    

  None

    

NS

    

  Distal and midshaft BSI, ToA, ToD

Linden et al. 2007 [298]

1 year expanded PE intervention