Abstract
Osteoporosis is a major public health problem due to consequent fragility fractures; data from the UK suggest that up to 50% of women and 20% men aged 50 years will have an osteoporosis-related fracture in their remaining lifetime. Skeletal size and density increase from early embryogenesis through intrauterine, infant, childhood and adult life to reach a peak in the third to fourth decade. The peak bone mass achieved is a strong predictor of later osteoporosis risk. Epidemiological studies have demonstrated a positive relationship between early growth and later bone mass, both at peak and in later life, and also with reduced risk of hip fracture. Mother–offspring cohorts have allowed the elucidation of some of the specific factors in early life, such as maternal body build, lifestyle and 25(OH)-vitamin D status, which might be important. Most recently, the phenomenon of developmental plasticity, whereby a single genotype may give rise to different phenotypes depending on the prevailing environment, and the science of epigenetics have presented novel molecular mechanisms which may underlie previous observations. This review will give an overview of these latter developments in the context of the burden of osteoporosis and the wider data supporting the link between the early environment and bone health in later life.
Similar content being viewed by others
References
Harvey N, Dennison E, Cooper C (2008) Epidemiology of osteoporotic fracture. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism, 7th edn. ASMBR, Washington, pp 198–203
Department of Health (1994) Advisory group on osteoporosis. Department of Health, London
Cooper C, Westlake S, Harvey N et al (2006) Review: developmental origins of osteoporotic fracture. Osteoporosis Int 17:337–347
Hui SL, Slemenda CW, Johnston CC Jr (1990) The contribution of bone loss to postmenopausal osteoporosis. Osteoporosis Int 1(1):30–34
Hernandez CJ, Beaupre GS, Carter DR (2003) A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporosis Int 14(10):843–847
Cooper C, Eriksson JG, Forsen T et al (2001) Maternal height, childhood growth and risk of hip fracture later in life: a longitudinal study. Osteoporosis Int 12:623–629
Bateson P (2001) Fetal experience and good adult disease. Int J Epidemiol 30:928–934
Barker DJ (1990) The fetal and infant origins of adult disease. BMJ 301(6761):1111
Barker DJ (1995) The fetal and infant origins of disease. Eur J Clin Invest 25(7):457–463
Gluckman PD, Hanson MA, Cooper C et al (2008) Effect of in utero and early-life conditions on adult health and disease. N Eng J Med 359(1):61–73
Cooper C, Fall C, Egger P, Hobbs R, Eastell R, Barker D (1997) Growth in infancy and bone mass in later life. Ann Rheum Dis 56:17–21
Dennison EM, Syddall HE, Sayer AA, Gilbody HJ, Cooper C (2005) Birth weight and weight at 1 year are independent determinants of bone mass in the seventh decade: the Hertfordshire cohort study. Pediatr Res 57(4):582–586
Keen R, Egger P, Fall C, Major P, Lanchbury J, Spector TD, Cooper C (1997) Polymorphisms of the vitamin D receptor, infant growth and adult bone mass. Calcif Tiss Int 60:233–235
Cooper C, Harvey N, Javaid K, Hanson M, Dennison E (2008) Growth and bone development. Nestle Nutr Workshop Ser Pediatr Program 61:53–68
Javaid MK, Lekamwasam S, Clark J, Dennison EM, Syddall HE, Loveridge N, Reeve J, Beck TJ, Cooper C (2006) Infant growth influences proximal femoral geometry in adulthood. J Bone Miner Res 21:508–512
Oliver H, Jameson KA, Sayer AA, Cooper C, Dennison EM (2007) Growth in early life predicts bone strength in late adulthood: the Hertfordshire Cohort Study. Bone 41:400–405
Javaid MK, Godfrey KM, Taylor P, Robinson SM, Crozier SR, Dennison EM, Robinson JS, Breier BR, Arden NK, Cooper C (2005) Umbilical cord leptin predicts neonatal bone mass. Calcif Tissue Int 76:341–347
Harvey NC, Poole JR, Javaid MK, Dennison EM, Robinson S, Inskip HM, Godfrey KM, Cooper C, Sayer AA (2007) Parental determinants of neonatal body composition. J Clin Endocrinol Metab 92:523–526
Javaid MK, Crozier SR, Harvey NC (2006) Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 367(9504):36–43
Harvey NC, Javaid MK, Poole JR et al (2008) Paternal skeletal size predicts intrauterine bone mineral accrual. J Clin Endocr Metab 93(5):1676–1681
Ganpule A, Yajnik CS, Fall CH, Rao S, Fisher DJ, Kanade A, Cooper C, Naik S, Joshi N, Lubree H, Deshpande V, Joglekar C (2006) Bone mass in Indian children. Relationships to maternal nutritional status and diet during pregnancy: the Pune Maternal Nutrition Study. J Clin Endocrinol Metab 91:2994–3001
Cole ZA, Gale CR, Javaid MK, Robinson SM, Law CM, Boucher BJ, Crozier SR, Godfrey KM, Dennison EM, Cooper C (2009) Maternal dietary patterns during pregnancy and childhood bone mass: a longitudinal study. J Bone Min Res 24(4):663–668
Kanis JA, Johnell O, De Laet C et al (2002) International variations in hip fracture probabilities: implications for risk assessment. JBMR 17:1237–1244
Cooper C (1993) Epidemiology and public health impact of osteoporosis. Balliere’s Clin Rheumatol 7:459–477
Huncharek M, Muscat J, Kupelnick B (2008) Impact of dairy products and dietary calcium on bone-mineral content in children: results of a meta-analysis. Bone 43:312–321
Winzenberg T, Shaw K, Fryer J, Jones G (2006) Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomised controlled trials. BMJ 333:775
Du XQ et al (2002) Milk consumption and bone mineral content in Chinese adolescent girls. Bone 30:521–528, JID: 8504048
Rozen GS et al (2001) Calcium intake and bone mass development among Israeli adolescent girls. J Am Coll Nutr 20:219–224, JID: 8215879
Black RE, Williams SM, Jones IE, Goulding A (2002) Children who avoid drinking cow milk have low dietary calcium intakes and poor bone health. Am J Clin Nutr 76:675–680, JID: 0376027
Goulding A et al (2004) Children who avoid drinking cow's milk are at increased risk for prepubertal bone fractures. J Am Diet Assoc 104:250–253
Barr SI, Petit MA, Vigna YM, Prior JC (2001) Eating attitudes and habitual calcium intake in peripubertal girls are associated with initial bone mineral content and its change over 2 years. J Bone Miner Res 16:940–947, JID: 8610640
Bonjour JP et al (1997) Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial. J Clin Invest 99:1287–1294, JID: 7802877
Bonjour JP, Chevalley T, Ammann P, Slosman D, Rizzoli R (2001) Gain in bone mineral mass in prepubertal girls 3.5 years after discontinuation of calcium supplementation: a follow-up study. Lancet 358:1208–1212, JID: 2985213R
French SA, Fulkerson JA, Story M (2000) Increasing weight-bearing physical activity and calcium intake for bone mass growth in children and adolescents: a review of interventional trials. Preventive Med 31:722–731
Kalwarf HJ, Khoury JC, Lanpear BP (2003) Milk intake during childhood and adolescence, adult bone density, and osteoporotic fractures in US women. Am J Clin Nutr 77:257–265
Harvey NC, Cole ZA, Crozier SR, Kim M, Ntani G, Goodfellow L, Robinson SM, Inskip HM, Godfrey KM, Dennison EM, Wareham N, Ekelund U, Cooper C, The SWS Study Group (2011) Physical activity, calcium intake and childhood bone mineral: a population-based cross-sectional study. Osteoporos Int (in press)
Janz KF et al (2001) Physical activity and bone measures in young children: the Iowa bone development study. Pediatrics 107:1387–1393, JID: 0376422
Bass S, Pearce G, Bradney M, Hendrich E, Delmas PD, Harding A et al (1998) Exercise before puberty may confer residual benefits in bone density in adulthood: studies in active prepubertal and retired female gymnasts. J Bone Miner Res 13(3):500–507 (JID: 8610640)
Lanham SA, Roberts C, Perry MJ, Cooper C, Oreffo RO (2008) Intrauterine programming of bone. Part 2: alteration of skeletal structure. Osteoporos Int 19:157–167
Lanham SA, Roberts C, Cooper C, Oreffo RO (2008) Intrauterine programming of bone. Part 1: alteration of the osteogenic environment. Osteoporos Int 19:147–156
Oreffo RO, Lashbrooke B, Roach HI, Clarke NM, Cooper C (2003) Maternal protein deficiency affects mesenchymal stem cell activity in the developing offspring. Bone 33:100–107
Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic environmental signals. Nature Genetics 33(Suppl):245–254
Gicquel C, El-Osta A, Le Bouc Y (2008) Epigenetic regulation of fetal programming. Best Practise and Research Clinical Endocrinology & Metabolism 22(1):1–16
Gluckman PD, Hanson MA, Beedle AS (2007) Non-genomic transgenerational inheritance of disease risk. BioEssays 29:145–154
Tang W, Ho S (2007) Epigenetic reprogramming and imprinting in origins of disease. Rev Endocr Metab Disord 8:173–182
Bird A (2001) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21
Kwong WY, Wild AE, Roberts P et al (2000) Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 127:4195–4202
Levitt NS, Lindsay RS, Holmes MC et al (1996) Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat. Neuroendocrinology 64:412–418
Nyirenda MJ, Lindsay RS, Kenyon CJ et al (1998) Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest 101:2174–2181
Welberg LAM, Seckl JR, Holmes MC (2001) Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour. Neuroscience 04:71–79
Weaver ICG, Cervoni N, Champagne FA et al (2004) Epigenetic programming by maternal behaviour. Nat Neurosci 7:847–854
Lillycrop KA, Phillips ES, Jackson AA et al (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135:1382–1386
Burdge GC, Slater-Jefferies J, Torrens C, Phillips ES, Hanson MA, Lillycrop KA (2007) Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 97:437–439
Pham TD, MacLennan NK, Chiu CT et al (2003) Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. Am J Physiol Regul Integr Comp Physiol 285:R962–R970
Bogdarina I, Welham S, King PJ et al (2007) Epigenetic modification of the renin–angiotensin system in the fetal programming of hypertension. Circ Res 100:520–526
Grønbaek K, Hother C, Jones PA (2007) Epigenetic changes in cancer. APMIS 115(10):1039–1059
Heijmans BT, Elmar WT, Stein Ad (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. PNAS 105(44):17046–17049
Namgung R, Tsang RC (2003) Bone in the pregnant mother and newborn at birth. Clin Chim Acta 333:1–11
Kimball S, El-Hajj Fuleihan G, Vieth R (2008) Vitamin D: a growing perspective. Critical Reviews in Clinical Laboratory Sciences 45(4):339–414
Martin R, Harvey NC, Crozier SR et al (2007) Placental calcium transporter (PMCA3) gene expression predicts intrauterine bone mineral accrual. Bone; 40:1203–1208
Dennison E, Hindmarsh P, Fall C et al (1999) Profiles of endogenous circulating cortisol and bone mineral density in healthy elderly men. J Clin Endocrinol Metab 84(9):3058–3063
Lillycrop KA, Slater-Jefferies JL, Hanson MA et al (2007) Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr 97(6):1064–1073
Biniszkiewicz D, Gribnau J, Ramsahoye B et al (2002) Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mo Cell Biol 22:2124–2135
Conflicts of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Holroyd, C., Harvey, N., Dennison, E. et al. Epigenetic influences in the developmental origins of osteoporosis. Osteoporos Int 23, 401–410 (2012). https://doi.org/10.1007/s00198-011-1671-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-011-1671-5