Current Osteoporosis Reports

, Volume 9, Issue 3, pp 129–140

A Review of Osteoporosis Diagnosis and Treatment Options in New and Recently Updated Guidelines on Case Finding Around the World

Authors

    • University of Manitoba
    • Department of Medicine (C5121)St. Boniface General Hospital
  • John T. Schousboe
    • University of Minnesota
Article

DOI: 10.1007/s11914-011-0060-5

Cite this article as:
Leslie, W.D. & Schousboe, J.T. Curr Osteoporos Rep (2011) 9: 129. doi:10.1007/s11914-011-0060-5

Abstract

Fracture rates are known to vary by more than an order of magnitude worldwide; therefore, a single approach cannot be universally applied to all countries. National considerations must reflect the burden of osteoporosis, available resources, the disease costs to the individual and society, and how these relate to competing health and other societal priorities. Recent developments in terms of diagnosis, fracture risk prediction, and therapeutic options have prompted many countries to review and update their clinical practice guidelines (CPGs) for the prevention and management of osteoporosis intended for use in primary care in the general adult population. This paper reviews recently updated CPGs from the following countries: Australia, Belgium, Canada, Germany, the United Kingdom, and the United States.

Keywords

OsteoporosisFractureClinical practice guidelinesBone mineral densityDiagnosisTreatment

Introduction

Osteoporosis is characterized by low bone mass and increased risk of fractures [1]. In the absence of a defining fracture, the diagnosis of osteoporosis is based on the measurement of bone mineral density (BMD) by dual x-ray absorptiometry (DXA). The World Health Organization (WHO) has provided an operational definition of osteoporosis given as a BMD that lies 2.5 standard deviations (SD) or more below the average mean value for young healthy women (T-score ≤−2.5 SD) based upon a standardized reference site (the femoral neck) and a standard reference range for both men and women (the NHANES III [third National Health and Nutrition Examination Survey] data for white women ages 20–29 years) [24].

Worldwide, the number of people who have suffered a prior osteoporotic fracture was estimated to be 56 million in 2000 with approximately 9 million new osteoporotic fractures each year [5]. As the prevalence of osteoporosis increases with age, the global burden of osteoporosis is projected to rise markedly over the next few decades as the number of elderly individuals increases [6]. The presence of osteoporosis is a major risk factor for the development of fractures of the hip, proximal humerus, vertebra, and forearm but all skeletal sites (other than craniofacial) are at increased risk of fracture [7]. The consequences of fracture include increased mortality, morbidity, institutionalization, and economic costs [8, 9]. An individual with a hip fracture has a markedly increased risk of death within the first 6 months that is partly attributable to the fracture itself. Both hip and vertebral fractures are associated with an excess risk of death beyond the first year [1012], and are largely attributed to underlying comorbidity [13, 14]. Moreover, all osteoporosis-related fractures can lead to significant long-term disability and decreased quality of life [15, 16].

Fracture rates are known to vary by more than an order of magnitude worldwide [17]; therefore, a single approach cannot be universally applied to all countries. National considerations must reflect the burden of osteoporosis, available resources, the disease costs to the individual and society, and how these relate to competing health and other societal priorities. As a result, different countries have evolved their own unique approaches to case finding and treatment that are responsive to their particular circumstances. Recent developments in terms of diagnosis, fracture risk prediction, and therapeutic options have prompted many countries to review and update their clinical practice guidelines (CPGs) for the prevention and management of osteoporosis.

Although reduced bone mass is an important and easily quantifiable measurement, studies have shown that most fractures occur in individuals with a BMD T-score above the operational threshold for osteoporosis [18]. Recently, the use of new fracture risk prediction systems that integrate multiple clinical risk factors (CRFs) has been shown to enhance the performance of BMD in the prediction of hip and other major osteoporotic fractures [19]. This has initiated a paradigm shift in the field of osteoporosis. One such example, the fracture risk assessment tool (FRAX®), was developed by the WHO Collaborating Centre for Metabolic Bone Diseases for estimation of individual 10-year osteoporotic and hip fracture probability [20••]. In addition to a prior fragility fracture, age, sex, body mass index, and additional risk factors for fractures were identified including the prior use of glucocorticoids, secondary osteoporosis, rheumatoid arthritis, a parental history of hip fracture, current cigarette smoking, and alcohol intake of 3 or more units/day. Population-specific FRAX tools can be customized to the fracture and mortality epidemiology in that specific region [20••]. At present more than 35 FRAX models are available, and others are being developed. The FRAX system been endorsed and integrated into CPGs by several national bodies [2129]. Adaptations of the FRAX algorithm and completely separate algorithms have also been developed for estimating fracture probability.

In light of the above, it is timely and instructive to review how different countries have approached the development of CPGs for the prevention and management of osteoporosis. This review focuses on recently updated CPGs from the following countries: Australia, Belgium, Canada, Germany, the United Kingdom (UK), and the United States (US). In two cases (UK and US), more than one national organization had produced a CPG and two from each of these countries are reviewed. We acknowledge that additional countries have or will soon be updating their national osteoporosis guidelines (eg, the Netherlands) and therefore our review should be considered illustrative rather than exhaustive.

Methods

We considered CPGs that were intended for use in primary care in the general adult population. Specifically, we did not consider CPGs that were intended for specialists or secondary osteoporosis (eg, glucocorticoid-induced osteoporosis). Furthermore, we selected guidelines that were developed by national organizations for countrywide application and that included diagnostic, risk assessment, and therapeutic components. In addition to a narrative review, we also identified seven specific criteria for categorizing guidelines as good, moderate, or poor quality based upon the Appraisal of Guidelines, Research, and Evaluation (AGREE) instrument [30••]. Scott et al. [31••] identified 7 of the 23 AGREE criteria as “essential” and provided a scoring system (maximum possible of 28 [7 × 4]). The quality assessments were performed independently by the two coauthors and then averaged, except in the case of the Canadian CPGs in which only a single individual performed the scoring due to the fact that one of the authors (WDL) was a coauthor on this CPG (Table 1). Individual elements that differed by more than a single point were resolved through discussion. Specific content elements from each CPG are summarized in Table 2.
Table 1

Quality assessment of clinical practice guidelines

 

Australia

Belgium

Canada

Germany

UK-NICE

UK-NOGG

US-AACE

US-PSTF

Systematic search conducted

3.5

2

4

4

4

2.5

2

4

Methods used to formulate recommendations described

2.5

2

4

4

3

2.5

2.5

4

Link between recommendations and evidence

3

2

4

4

3

2.5

3.5

3

External review by experts

3.5

1

3

4

4

3.5

3

4

Specific, unambiguous recommendations

4

2.5

3

4

4

3.5

3.5

3.5

Editorially independent from funder

4

1.5

3

2.5

4

3

1.5

4

Conflicts of interest reported

4

3.5

4

4

4

2

3.5

4

Total

24.5

14.5

25

26.5

26

19.5

19.5

26.5

Quality assessments scores were averaged for the two co-authors, except in the case of the Canadian clinical practice guidelines, which are based on a single scoring

US-AACE United States Association of Clinical Endocrinologists; UK-NICE United Kingdom National Institute for Health and Clinical Excellence; UK-NOGG United Kingdom National Osteoporosis Guideline Group; US-PSTF United States Preventive Services Task Force

Table 2

Summary of clinical practice guidelines

 

Australia [32•, 33]

Patient population

Postmenopausal women and older men

Scope

Screening, prevention, treatment (nonpharmacologic and pharmacologic)

BMD testing

Women and men age ≥70 y (younger with additional CRFs)

Risk assessment

Garvan fracture risk calculator

Calcium

1200 mg/d

Vitamin D

> 800–1000 IU/d (target serum 25(OH)D ≥60 nmol/L)

Drug treatment

•BMD T-score ≤−2.5

•Hip or spine fracture

•BMD −1.0 to −2.5 plus low trauma fracture

•Consider absolute fracture risk but no treatment thresholds recommended

BMD monitoring

•Consider at 1 y after change in osteoporosis Rx

•Consider at 1 y if on glucocorticoid Rx ≥7.5 mg/d of prednisone

•Consider if BMD T-score is likely to be approaching −2.5 (at intervals no more frequent than once every 2 y)

 

Belgium [34•]

Patient population

Postmenopausal women

Scope

Treatment (calcium, vitamin D, and pharmacologic therapies)

BMD testing

Beyond scope of guidelines

Risk assessment

BMD plus vertebral fracture history

Calcium

1000–1200 mg/d

Vitamin D

800–1000 IU/d (target serum 25(OH)D ≥50 nmol/L)

Drug treatment

BMD spine or hip T-score ≤−2.5 plus prevalent vertebral fracture

BMD monitoring

Beyond scope of guidelines

 

Canada [29•]

Patient population

Adult women and men age ≥50 y

Scope

Screening and treatment

BMD testing

Women and men age ≥65 y (younger with additional CRFs)

Risk assessment

FRAX or CAROC

Calcium

1200 mg/d

Vitamin D

800–1000 IU/d (target serum 25(OH)D ≥75 nmol/L)

Drug treatment

•10-y major fracture risk ≥20%

•Hip fracture

• Spine fracture

•Multiple (>1) fragility fractures

BMD monitoring

•High risk or on treatment: initial repeat BMD 1–3 y, less once treatment shown to be effective

•Moderate risk: initial repeat BMD 1–3 y

•Low risk: 5–10 y

 

Germany and the Dachverband Osteologie [38•]

Patient population

All adult women and men

Scope

Prevention, diagnosis, and therapy of primary osteoporosis; common forms of secondary osteoporosis

BMD testing

Women age ≥70 y and men age ≥80 y (younger with additional CRFs)

Risk assessment

10-y risk morphometric vertebral or hip fracture

Calcium

1000 mg/d

Vitamin D

800–2000 IU/d (target 25(OH)D ≥50 mol/L)

Drug treatment

•10-y risk clinical or radiologic vertebral or hip fracture ≥30% with T-score ≤−2.0

•Single grade 2+ or multiple grade 1+ vertebral fractures with minimum T-score −2.0

•Prednisolone, 7.5 mg/d, for >3 mo with ≤ T-score −1.5

BMD monitoring

•On treatment 2–5 y

•High-dosage glucocorticoids 1 y or less

 

UK National Institute for Health and Clinical Excellence [40•, 4143]

Patient population

Postmenopausal women

Scope

Treatment for primary and secondary fracture prevention

BMD testing

No specific recommendation

Risk assessment

T-score (spine and/or hip), age, number of independent CRFs for fracture, and indicators of low BMD

Calcium

No specific recommendations. Assumes that women who receive treatment have an adequate calcium intake and are vitamin D replete. Unless clinicians are confident that women who receive treatment meet these criteria, calcium and/or vitamin D supplementation should be considered

Vitamin D

No specific recommendations

Drug treatment

•Based upon incremental cost-effectiveness ratio

•T-score intervention criteria vary by agent (base case generic alendronate), age, fracture status, number of independent CRFs for fracture, and indicators of low BMD

BMD monitoring

No specific recommendations

 

UK National Osteoporosis Guideline Group [44•]

Patient population

Adult women and men age ≥50 y

Scope

Assessment, diagnosis, and treatment

BMD testing

Case-finding strategy based upon age-specific fracture probability thresholds

Risk assessment

FRAX

Calcium

500–1000 mg/d (1000–1200 mg/d for housebound elderly or nursing home residents)

Vitamin D

800 IU/d

Drug treatment

•Prior fragility fracture

•FRAX major fracture risk (without BMD) above the age-specific upper assessment threshold

•FRAX major fracture risk (with BMD) above the age-specific intervention threshold

BMD monitoring

No specific recommendations

 

US American Academy of Clinical Endocrinology [45•]

Patient population

Postmenopausal women

Scope

Prevention, diagnosis, and treatment (pharmacologic and nonpharmacologic)

BMD testing

Women age ≥65 y, men age ≥70 y, younger ages with CRFs

Risk assessment

FRAX plus DXA of hip, spine, and/or forearm

Calcium

1200 mg/d

Vitamin D

No amount specified; adjust dose to achieve 25(OH)D level 75–150 nmol/L

Drug treatment

•Hip or vertebral fracture

•BMD T-score ≤−2.5

•BMD T-score −1.0 to −2.5 plus 10-y hip fracture risk ≥3%

•BMD T-score −1.0 to −2.5 plus 10-y major osteoporotic fracture risk ≥20%

BMD monitoring

•Not on Rx, near treatment threshold: test every 1–2 y

•Not on Rx, BMD borderline low: test every 3–5 y

•Not on Rx, well above treatment threshold: test every 5–10 y or longer

•On Rx: baseline DXA plus DXA every 1–2 y until BMD is stable

 

US Preventive Services Task Force [47•]

Patient population

Postmenopausal women and older men

Scope

Screening for osteoporosis

BMD testing

Women age ≥65 y, postmenopausal women younger than age 65 y with absolute (by US FRAX) 10-y major osteoporotic fracture risk ≥9.3%

No recommendations for men: available data judged to be insufficient

Risk assessment

FRAX plus DXA of hip, spine, and/or forearm

Calcium

Beyond scope of guidelines

Vitamin D

Beyond scope of guidelines

Drug treatment

No criteria for drug therapy specified

BMD monitoring

Beyond scope of guidelines

BMD bone mineral density; CAROC Canadian Association of Radiologists and Osteoporosis Canada; CRFs clinical risk factors; DXA dual x-ray absorptiometry; Rx medication.

Guidelines Overviews

Australia

The CPG for Australia was commissioned by the Royal College of Australian General Practitioners and the Australian Government Department of Health and Aging, and approved by the Australian National Health and Medical Research Council (NHMRC) of the Australian Government in 2010 [32•, 33]. The target audience of this CPG is specifically primary care general practitioners in Australia, and its use is intended to assist general practitioners’ management of osteoporosis in clinical practice. The guideline focused on postmenopausal women and men over age 50 years at risk of developing osteoporosis, those diagnosed with osteoporosis by bone density criteria, and those age 60 years and older who had one or more fractures with minor trauma. The guideline is not intended to apply to those on prolonged glucocorticoid therapy, those with osteoporosis secondary to other morbid conditions, men with hypogonadism, or women with hypogonadism due to conditions other than natural menopause.

A multidisciplinary guideline working group (including physician specialists, general practitioners, patient/health care consumer advocates) selected the German guidelines as a basis after review of various recent guidelines using the Scottish Intercollegiate Guidelines Network (SIGN) methodology (http://www.sign.ac.uk/guidelines/fulltext/50/checklist1.html) Additional references were added from the time of those guidelines. In addition a comprehensive literature search was carried out using OVID Medline, Cochrane review databases, the Health Technology Assessment database, and the National Health Service (NHS) economic database. A total of 2500 articles were reviewed and graded by two or more working group members to ensure no relevant information was excluded from the guidelines. Twenty-eight consensus recommendations were formulated by the group based on unanimous agreement. These recommendations were graded A (excellent) to D (poor), and were sent to 14 outside experts (Australian and non-Australian) for review and released for public comment. The working group then revised the document based on stakeholder comments and sent it to NHMRC for review and approval.

Bone densitometry using DXA was recommended for those men and women age 70 years and older, and for women age ≥50 years and older and men age ≥60 years and older with additional risk factors. For postmenopausal women and men suffering a fragility fracture at any skeletal site, bone densitometry is recommended but not considered essential before starting pharmacologic fracture prevention therapy. Follow-up bone densitometry was judged to be appropriate 2 years after starting pharmacologic therapy. Recommendations were also made for additional investigations including lateral spine imaging for suspected vertebral fracture, indications for specialist referral, calcium, vitamin D, lifestyle interventions, exercise, and intervention to reduce of falls risk. Use of pharmacologic agents (bisphosphonates, hormone therapy, selective estrogen receptor modulator therapy, parathyroid hormone, and strontium ranelate) to reduce the risk of fragility fractures were recommended for consideration in light of a person’s absolute fracture risk (once bone densitometry and other BMD fracture risk factors are assessed). Nomograms for the Garvan fracture risk calculator are provided in the guideline to aid absolute fracture risk assessment. In line with current Australian pharmaceutical benefits treatment availability, no specific cutpoints of bone density or absolute fracture risk are offered as an indication for fracture prevention therapy.

Belgium

In 2010, the Belgian Bone Club updated their guidelines from 2005 regarding screening and treatment of osteoporosis [34•, 35]. The target audience was clinicians in Belgium, both generalist and specialist, involved in the care of those at risk of osteoporosis and fragility fractures. The scope of the guideline was limited to postmenopausal women; osteoporosis due to glucocorticoid therapy, to other secondary medical conditions, and osteoporosis in men were considered to be outside the scope of the guideline. The Belgian Bone Club has previously published a guideline regarding management of glucocorticoid-induced osteoporosis [36].

Systematic literature reviews from Medline and the Cochrane databases were done, and grading of the evidence was done by consensus of a committee of experts in the field. The precise criteria by which articles were selected from the literature search, were graded for quality of evidence, and the method by which consensus was achieved were not described. The evidence regarding the fracture prevention efficacy of calcium and vitamin D supplementation was extensively reviewed, and daily intakes of 1000 to 1200 mg of calcium and 800 IU of vitamin D recommended.

Oral and intravenous bisphosphonates, raloxifene, and strontium ranelate were recommended as first-line therapies for fracture prevention in those with either osteoporosis (lumbar spine or hip T-score ≤−2.5) or a prevalent vertebral fracture. Criteria for choosing among these agents were not explicitly offered, although the relative efficacy of the agents in prevention of hip and other nonvertebral fractures, and the underlying risk of breast cancer (because raloxifene has been shown to prevent invasive breast cancer) were stated to be reasonable considerations when choosing a specific therapeutic agent. Hormone therapy (estrogen) was recommended only for those with symptoms of estrogen deficiency for short periods of time. Teriparatide was recommended only for those with both very low bone density (T-score ≤−2.5) and a prevalent vertebral fracture. Combinations of antiresorptive medications and alendronate combined with teriparatide were specifically discouraged.

Fall prevention strategies were recommended, but the specific content of these strategies or their specific indications were not explicated. No recommendations were made regarding indications for bone densitometry, use of other screening tools such as fracture risk calculators, workup for secondary causes of bone loss, or regarding monitoring of individuals on pharmacologic fracture prevention therapy.

Canada

The CPGs for Canada was released in 2010 and updated the 2002 guidelines [29•, 37]. The CPG development followed the AGREE process. Systematic reviews were performed in two key areas, one related to absolute fracture risk assessment and the other related to the benefits and harms of osteoporosis therapies. A level of evidence was assigned to each abstracted paper, and graded recommendations were developed. An expert panel provided feedback on the CPG using a modified RAND/UCLA Delphi method, the considerable “care gap” that exists in patients at highest risk of fractures, namely those who have already sustained a fragility fracture.

BMD testing is recommended as part of the risk assessment process in all individuals over age 65 years, and in younger individuals with additional risk factors for fracture or rapid BMD loss. A FRAX tool for Canada was developed, based upon national hip fracture and mortality data, and the accuracy of the fracture predictions was validated in two large, independent cohorts. Therefore, the FRAX tool, and the Canadian Association of Radiologists and Osteoporosis Canada tool (a simplified, semiquantitative version of FRAX) are recommended for prediction of fracture risk. Major osteoporotic fracture probability is categorized as low (<10%), moderate (10–20%), or high (>20%). Individuals who have already sustained fragility fractures affecting the vertebra or hip, or those with more than one fragility fracture, are also designated at high risk, regardless of BMD value. Pharmacotherapy, in addition to regular weight-bearing exercise, appropriate calcium (1200 mg daily) and vitamin D supplementation (800–1000 IU daily to achieve a serum level of at least 75 nmol/L), and fall prevention strategies, are recommended for high-risk individuals. In those at low risk, there is little evidence for benefit from pharmacotherapy and basic bone health measures are recommended with periodic risk re-evaluation (5 years following the initial evaluation).

The Canadian CPGs recognize that the largest number of osteoporotic fractures occurs in those at moderate risk, just as the majority of osteoporotic fractures occurs in individuals with a T-score between −1 and −2.5. For those at moderate risk of fracture, patient preference and additional risk factors are outlined for identifying moderate-risk individuals who may benefit from pharmacotherapy. These include spinal imaging to look for clinically silent vertebral fractures, features that indicate greater fracture risk (eg, lumbar spine T-score much lower then femoral neck T-score, wrist fracture with T-score −2.5 or lower, recurrent falls in the last year), or risk factors for rapid BMD loss (eg, women undergoing aromatase inhibitor therapy for breast cancer, men undergoing androgen deprivation therapy for prostate cancer).

The CPGs appreciate that no randomized trials have directly established the value of BMD monitoring in terms of clinical outcomes, and that such recommendations are based upon expert opinion. For patients undergoing pharmacologic treatment, repeat BMD is initially recommended 1 to 3 years after starting treatment, with a longer testing interval once therapy is shown to be effective. Improved or stable BMD is considered to represent an appropriate response to therapy. For individuals with low fracture risk and without additional risk factors for rapid BMD loss, a testing interval of 5 to 10 years is considered sufficient. Combination therapy and “drug holidays” are not recommended, based upon currently available evidence. Criteria for referral to a specialist are provided. There is also a discussion of approaches that can be used to enhance the use of appropriate treatment, such as case managers and point-of-care tools.

Germany and the Dachverband Osteologie

The Dachverband Osteologie (DVO) is the osteology umbrella organization of the scientific societies for Germany, Austria, and Switzerland. The 2009 update of the (DVO) CPGs for the prevention, diagnosis, and therapy of osteoporosis in adults updated the earlier 2006 DVO CPGs, with the next regular update planned for 2012 [38•]. The guidelines, approved in Germany, target primary care and specialist physicians who are clinically involved in the care of persons with osteoporosis, and provide recommendations on both primary osteoporosis and common forms of secondary osteoporosis. A systematic literature search was performed until December 31, 2008, and followed a multidisciplinary internal and external consensus process.

The guideline highlights that diagnosis and treatment of patient’s at risk, especially the elderly and those who have already sustained an osteoporotic fracture, are insufficient. Prevention focuses on regular physical activity, an annual fall history after age 70 years, correction of vitamin D deficiency (<50 nmol/L), and a nutritional intake of 1000 mg of calcium. Daily sun exposure of at least 30 min, or vitamin D3 supplementation 800 to 2000 IU, is recommended to avoid vitamin D deficiency (defined as <50 nmol/L). Supplementation with vitamin B12 and folic acid, as well as avoidance of smoking, are recommended. A detailed list of CRFs and medications associated with osteoporotic fractures and/or falls is used in the risk assessment and treatment algorithm. Although FRAX tools exist for the DVO countries (Germany, Austria, and Switzerland), the CPGs recommend an alternative absolute 10-year fracture risk approach developed by the DVO in 2003. It was felt that changing to FRAX would not offer substantial advantages, and that the FRAX model was still in development and could change.

The DVO risk assessment system is based upon clinical or radiologic vertebral and/or hip fracture risk over the following 10 years, with 20% or higher considered to be the cutoff for diagnostic investigation. Specific drug treatment is recommended for an estimated 10-year risk of vertebral and hip fracture greater than 30% if accompanied by a minimum T-score (lumbar spine, total hip, or femoral neck) of −2.0 or lower. Pharmacotherapy for a T-score above −2.0 is not recommended. Age- and sex-specific T-score cutoffs for initiation of treatment are provided. In the absence of additional risk factors, a 65- to 70-year-old woman or 75- to 80-year-old man with minimum T-score of −3.0 or lower would be recommended for treatment; prior to age 60 years in women or age 70 years in men a T-score of −4.0 or lower is the threshold for treatment. The T-score intervention threshold is adjusted upward (0.5 T-score adjustment per risk factor up to a maximum T-score of −2.0) for additional CRFs (9 general risks, 9 diseases, 3 drugs). For example, if a women age 67 years without additional risks would qualify for treatment based upon a T-score of −3.0, in the presence of a peripheral fracture after age 50 years treatment would be initiated at a T-score of −2.5; if in addition she also had type 1 diabetes mellitus then treatment would be initiated below a T-sore of −2.0.

Drug therapy is also recommended for a single vertebral fracture (Genant grade 2 or 3, >25% height reduction) or multiple vertebral fractures (Genant grades 1–3, >20% height reduction) if at the same time the minimum T-score is −2.0 or lower. For individuals on oral glucocorticoids at daily doses ≥7.5 mg of prednisolone equivalent for 3 months or more then treatment is also recommended if there is a minimum T-score of −1.5 or lower. Lower doses of oral glucocorticoids are considered under the earlier DVO risk assessment system.

Combination treatment is not recommended. Continuation of drug therapy beyond 3 to 5 years is recommended in the case of persisting high 10-year fracture risk. In the event that a CRF is eliminated (eg, smoking cessation) then the fracture risk should be reassessed and if the newly calculated 10-year fracture risk is less than 30% the specific drug treatment can be stopped. BMD monitoring of drug therapy is generally not recommended before a treatment period of 2–5 years except in the case of high-dosage glucocorticoid treatment. A lack of increasing BMD when taking antiresorptive drugs does not mean decreased antifracture benefit. Conversely, the BMD measurement prior to treatment is recommended to determine long-term fracture risk. Therapy failure is defined as greater than 5% BMD decrease in the total hip, or two or more osteoporotic fractures within 3 years, despite appropriate treatment. Additional sections of the CPGs discuss treatment of acute vertebral fracture, kyphoplasty/vertebroplasty, and chronic pain.

UK National Institute for Health and Clinical Excellence

The National Institute for Health and Clinical Excellence (NICE) is an NHS organization in the UK set up on April 1, 1999 to provide guidance, set quality standards, and manage a national database to improve people’s health and prevent and treat ill health. NICE makes recommendations to the NHS on new and existing medicines, treatments, and procedures treating and caring for people with specific diseases and conditions. Topics covered by NICE guidance range from helping people to stop smoking and encouraging physical activity through to the treatment of specific conditions including osteoporosis. The framework for NICE recommendations follows a detailed review and analysis of effectiveness and cost-effectiveness based upon incremental cost-effectiveness ratio for cost per quality adjusted life year gained [39]. The Appraisal Committees, one of NICE’s standing advisory committees, contain members who are appointed for a 3-year term. Each Appraisal Committee considers its own list of technologies, and topics are not moved between the branches. Committee members are asked to declare any interests in the topic to be appraised. If a conflict of interest is considered, the member is excluded from participating further in that appraisal. Experts are invited to attend Appraisal Committee meetings to observe and to contribute as advisers to the Committee.

NICE has recently issued three guidance documents relevant to osteoporosis: 1) use of bisphosphonates, raloxifene, and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (issued October 2008, updated January 2011) [40•]; 2) use of bisphosphonates, raloxifene, strontium ranelate, and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (issued October 2008, updated January 2011) [41]; and 3) use of denosumab for the primary or secondary prevention of osteoporotic fragility fractures in postmenopausal women (issued October 2010) [42]. These reports do not consider primary prevention in those with non-osteoporotic BMD, glucocorticoid-induced osteoporosis, or other populations (men, premenopausal women, and children). Separate guidelines and care pathways have been created for assessment and prevention of falls in older people (issued 2004) [43]. Clinical guidelines on risk assessment of patients with osteoporosis and hip fractures are currently being developed. There are no guidelines on calcium and vitamin D, although it is stated that the guidance assumes that women who receive treatment have an adequate calcium intake and are vitamin D replete.

FRAX was not used as the basis for treatment initiation by NICE. Justifications included that the use of absolute fracture risk alone did not accurately predict cost effectiveness, and therefore would not provide a robust basis for decision making. Different fracture sites have different impacts on quality of life, costs, and mortality, and cost effectiveness is therefore dependent on the contribution from each fracture site to the total fracture risk. The NICE guidance recommends using a combination of T-score (spine and/or hip DXA), age, and number of independent CRFs for fracture. Independent CRFs for fracture (a subset of the FRAX risk factors) are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. Indicators of low BMD are low body mass index (<22 kg/m2), medical conditions such as ankylosing spondylitis, Crohn’s disease, rheumatoid arthritis, conditions that result in prolonged immobility, and untreated menopause.

Generic alendronate was considered as the base treatment option. Treatment is recommended for the primary prevention of osteoporotic fragility fractures for: 1) women ages 70 years or older who have an independent CRF for fracture or an indicator of low BMD (see preceding paragraph) and confirmed osteoporosis (T-score of −2.5 SD or below); 2) women ages 75 years or older who have two or more independent CRFs for fracture or indicators of low BMD (DXA scan not required); 3) women ages 65 to 69 years with an independent CRF for fracture and confirmed osteoporosis (T-score of −2.5 SD or below); and 4) younger postmenopausal women with an independent CRF for fracture and at least one additional indicator of low BMD and confirmed osteoporosis (T-score of −2.5 SD or below). More severe reductions in T-score are required for treatment with other bisphosphonates (eg, T-score of −3.5 SD or below plus one independent risk factor for fracture women ages 65–69 years), strontium ranelate, or denosumab (eg, T-score of −4.5 SD or below plus one independent risk factor for fracture women ages 65–69 years).

Alendronate is recommended for the secondary prevention of osteoporotic fragility fractures in postmenopausal women who have sustained a clinically apparent osteoporotic fragility fracture and have osteoporosis by DXA (in women ages 75 years or older, a DXA scan is not required). More severe reductions in T-score and/or independent risk factors for fracture are required for treatment with other bisphosphonates, strontium ranelate, or denosumab. Teriparatide is an alternative treatment option for secondary prevention in postmenopausal women with intolerance, contraindications, or unsatisfactory response to other agents (unsatisfactory response means another fragility fracture despite adhering fully to treatment for 1 year plus a decline in BMD below the pretreatment baseline). In addition, women ages 65 years or older must have a T-score of −4.0 SD or below, or a T-score of −3.5 SD or below plus more than two fractures; women ages 55–64 years must have a T-score of −4 SD or below plus more than two fractures.

UK National Osteoporosis Guideline Group

The UK National Osteoporosis Guideline Group (NOGG), representing several British organizations and societies, provided guidance on the prevention and treatment of osteoporosis in the UK subsequent to dissemination of the NICE guidelines [44•]. The target population is postmenopausal women and men ages over 50 years. The recommendations contained in the CPGs are intended to aid management decision making as a framework from which local management protocols could be developed.

The CPGs endorse the WHO definition of osteoporosis including its operational translation using T-scores. The CPGs explicitly note that the same diagnostic cutoff values for BMD be applied to men and women, with femoral neck DXA designated as the reference technology for the diagnosis of osteoporosis and a normal reference range in men and women based upon the NHANES survey for Caucasian women ages 20–29 years. The CPGs specifically state that use of additional BMD sites for diagnosis (eg, the lumbar spine) is not recommended except where hip measurement is not possible, or in younger postmenopausal women and men in whom the spine is differentially affected. Population screening is not recommended; the NOGG recommends use of BMD testing in the context of a case-finding strategy based upon age-specific fracture probability thresholds. In the context of high-risk strategies (selective case finding), no distinction is made between prevention and treatment. Recommendations are based on high levels of evidence (meta-analysis or randomized controlled trials [RCTs]), with the recommendations graded and summarized based on systematic literature reviews.

The guidelines review global strategies for the prevention of osteoporosis, but make no recommendations concerning population-based strategies due to uncertainty over their causal relationship with osteoporosis and the lack of data regarding uptake and compliance of such strategies for osteoporosis prevention in the population at large. Supportive measures based upon the selective case finding approach are identified. Positive recommendations are made for the use of dietary supplements in the housebound elderly and those in nursing homes (800 IU of vitamin D and 1.0–1.2 g of calcium daily) or as adjuncts to other treatments in patients with osteoporosis (800 IU of vitamin D and 500–1000 mg of calcium daily). Adequate protein intake for maintenance and function of the musculoskeletal system is also recommended.

A case-finding strategy is recommended in which patients are identified because of a fragility fracture or by the presence of CRFs. Under these CPGs, fracture risk should be assessed in postmenopausal women and men ages 50 years or more with specific risk factors that have been associated with increased fracture risk (many of which operate independently of BMD and are incorporated in the FRAX algorithm). The NOGG Guideline Group notes that treatment should not be undertaken without recourse to a BMD test except in those with prior fragility fractures. The CPGs acknowledge that the FRAX algorithm does not take into account prior treatment, dose responses for several risk factors, or additional risk factors for fracture (eg, recurrent falls and elevated bone turnover markers), and highlight the need for clinical judgment in the care of individual patients in clinical practice.

Fracture probability estimates in the NOGG guidelines are based upon the UK FRAX tool with major osteoporotic fracture probability estimated without BMD. In individuals in which the probability exceeds the age-specific upper assessment threshold then drug treatment without BMD testing is recommended. In individuals with the fracture probability below the lower assessment threshold, no further testing or treatment is required. For those with fracture probabilities falling between the lower and upper assessment thresholds, BMD testing with DXA is recommended to improve the accuracy of the FRAX-derived probability estimate. Treatment is then recommended for individuals in whom the fracture probability exceeds the intervention threshold (based upon the fracture probability for a woman of the same age with a prior fragility fracture, without knowledge of BMD). This approach is underpinned by cost-effective analysis for one specific intervention (generic alendronate) with the assumption that second-line intervention (other bisphosphonates, denosumab, raloxifene, or strontium ranelate) would be used in approximately 20% of patients. The proportion of women potentially eligible for treatment rises with age, from 20% at age 50 years to 40% after age 80 years.

General practitioners are encouraged to follow up patients to monitor their use of medications, to ensure co-prescription of calcium and vitamin D with bone-protective interventions, and to encourage adherence to therapy. There is no recommendation regarding BMD monitoring by the NOGG guidelines. There is a general statement that BMD measurements may be used to monitor the effects of treatment.

Unique features of the CPGs are recommendations for training of physicians in osteoporosis and metabolic bone diseases given the diverse specialties that are implicated, as well as training in the management of osteoporosis for nursing and other allied professions. Specific recommendations are made to health authorities and other commissioners of health care regarding prevention, diagnosis/investigation, and treatment of osteoporosis, as well as to the Department of Health.

US American Association of Clinical Endocrinologists

The American Academy of Clinical Endocrinology updated and released guidelines for prevention of and treatment of osteoporosis and related fractures in 2010 [45•]. A task force of American Association of Clinical Endocrinologists (AACE) members was assembled to perform literature searches and update the previous guidelines of 2004, and a team of three external reviewers (two of whom are recognized experts within the field of metabolic bone disease but are not endocrinologists) independently evaluated the guidelines. The exact processes of how medical literature was extracted and evaluated, and the precise roles and interactions of the task force and external review panel were not explicated. The target audience of the guidelines was not only endocrinologists but also generalists and other specialty physicians who care for patients at risk of osteoporosis and fragility fracture. The scope of the guidelines was limited to postmenopausal women; specifically, these guidelines were not intended to apply to men.

Bone densitometry is recommended in the guidelines for all women ages 65 years and older, and for postmenopausal women younger than age 65 years with one or more additional risk factors for fracture. The diagnosis of osteoporosis by BMD criteria is recommended to be limited to BMD at the lumbar spine, total hip, femoral neck, and one-third radius site. Recommendations are also given for workup of individuals with osteoporosis by bone density criteria or fragility fractures for causes of secondary osteoporosis, indications for lateral spine imaging to detect prevalent vertebral fractures, for calcium and vitamin D intakes, and for lifestyle interventions to reduce risk of fractures.

With respect to indications for pharmacologic treatment, AACE endorsed the US National Osteoporosis Foundation 2008 guidelines, and on these aspects the two guidelines are identical. Pharmacotherapy (with an oral or intravenous bisphosphonate, calcitonin, denosumab, raloxifene, or teriparatide) is recommended for those who have had a hip or vertebral fracture (radiographic or clinical), T-score ≤−2.5 at femoral neck, total hip, or lumbar spine, or T-score −1.0 to −2.5 with hip or major osteoporotic 10-year fracture risks, respectively, of ≥3% or ≥20%. These guidelines recommend pharmacologic therapy for a substantially wider proportion of the population than other guidelines (eg, 91% of non-Hispanic white women ages 80 years and older with T-scores between −1.0 and −2.5 would be offered drug therapy using these guidelines) [46].

Because of their proven hip fracture reduction efficacy, alendronate, risedronate, zoledronic acid, and denosumab are recommended as the first-line agents. Simultaneous use of two or more agents is not recommended. However, sequential therapy is stated to be appropriate at times, especially use of antiresorptive agents after a treatment course of teriparatide. The duration of drug therapy considered to be safe is explicated in the guidelines. Drug holidays after many years of bisphosphonate therapy are thought to be possibly reasonable so long as BMD is followed and treatment re-initiated if bone loss occurs.

US Preventive Services Task Force

The US Preventive Services Task Force (USPSTF) in 2011 released updated guidelines for public comment regarding screening and treatment for osteoporosis [47•], in part to address screening men and postmenopausal women younger than age 65 years, and to also address the effect of treatment of those without any known prior fractures who after screening are judged to be candidates for osteoporosis. The target audience is all physicians who care for those who have or are at risk of osteoporosis. The scope was limited to postmenopausal women and men who have not had a fragility fracture, a secondary cause of bone loss, and who are not already known to have osteoporosis.

The committee based their recommendations on an updated systematic review of medical literature regarding: 1) risk calculators to predict low bone density or fractures; 2) bone densitometry with DXA and other technologies such as quantitative ultrasound; 3) and pharmacologic therapy to prevent fractures [48]. No RCTs were found directly evaluating the effects of screening on fracture incidence or fracture-related mortality. With respect to clinical evidence of pharmacologic therapies, the committee identified only seven high-quality RCTs of postmenopausal women that either excluded those with prior clinical fractures or prevalent radiographic vertebral fractures, or else limited enrollment of those with prior fractures to no more than 20% of their study populations. No primary prevention RCTs of any pharmacologic agent to prevent fractures have been reported in men. The task force found “convincing evidence” for significant benefit from treatment (with bisphosphonates, estrogen, raloxifene, or teriparatide) of women age 65 years and older without prior fracture but with osteoporosis and for women younger than age 65 years of comparable fracture risk, with small to modest risk of harm. They concluded with moderate certainty, therefore, that screening for osteoporosis with DXA yields moderate net benefit for women age 65 years with no additional risk factors, and for postmenopausal women younger than age 65 years of comparable risk. Because according to the US FRAX calculator a 65-year-old Caucasian woman with no additional risk factors (and presumably average femoral neck bone density) and body mass index for her age is 9.3%, they recommend bone densitometry for postmenopausal women younger than age 65 years if their calculated 10-year risk of major osteoporotic fracture is 9.3% or higher according to the US FRAX calculator (without BMD). Evidence regarding screening in men was judged to be insufficient to issue any recommendations regarding screening of men without prior fracture or secondary causes of bone loss, or regarding use of pharmacologic agents for primary prevention of fractures in men.

These guidelines did not address choice among available pharmacologic agents, duration of therapy, the issues of drug holidays, combination or sequential therapy, calcium or vitamin D intakes, or nonpharmacologic therapy such as exercise.

Conclusions

International differences also reflect the burden of osteoporosis, available resources, the disease costs to the individual and society, and how these relate to competing health and other societal priorities. Not surprisingly, we found significant differences between the updated CPGs from Australia, Belgium, Canada, Germany, the UK, and the US. Although each CPG claims to be based upon scientific evidence, the methods for identifying this evidence, assessing data quality, and translating this information into specific recommendations varied considerably. Fundamental differences in “philosophy” were also evident, such that some guidelines will not issue specific recommendations in which the evidence is considered very weak. In contrast, as an aide to physicians responsible for clinical decision making, other guidelines issue recommendations in areas in which the evidence base is limited while acknowledging these limitations. Different approaches to risk assessment and variable incorporation of absolute fracture risk prediction systems contribute to the very wide indications for drug therapy.

Disclosures

Conflicts of interest: W.D. Leslie: Advisory boards for Novartis, Amgen, Genzyme; unrestricted research grants from Merck Frosst, Genzyme, Amgen, Sanofi-Aventis, Warner Chilcott (formerly Procter & Gamble); speaker fees from Merck Frosst and Amgen; and conference expenses from Genzyme; J.T. Schousboe: has received grant support from Eli Lilly and Co.

Copyright information

© Springer Science+Business Media, LLC 2011