Progress in Osteoporosis and Fracture Prevention: Focus on Postmenopausal Women

Kenneth G Saag; Piet Geusens

Disclosures

Arthritis Res Ther. 2009;11(5):251 

In This Article

The Fracture Risk Assessment Tool for Calculating the Individual 10-year Fracture Risk

The clinical expression of osteoporosis is a fragility fracture, but bone loss in and of itself is asymptomatic, which has led to the description of osteoporosis as a 'silent thief'. The asymptomatic nature of bone loss suggests that osteoporosis cannot be detected before a fragility fracture occurs, unless BMD is measured. Indeed, BMD is related to bone strength and low BMD is a major risk factor for fractures. However, most patients presenting with a fracture do not have BMD-based osteoporosis, defined according to the World Health Organization (WHO) definition as a T score of −2.5 or below.[1] Many qualities of bone, other than low BMD, are involved in fracture risk such as structural and material components of bone and the cellular activities and molecular signals that regulate lifelong bone remodeling under control of mechanical load, hormones, growth factors, and cytokines. Some of these characteristics of bone are measurable in clinical practice (for example, BMD, bone size, vertebral deformities and fractures, and markers of bone turnover), but many are not (for example, material properties) or are just evolving (for example, microarchitecture by microcomputer tomography or magnetic resonance imaging). In addition, and independent of bone-related risks, extraskeletal risk factors such as fall risk contribute to fracture risk and are present in the majority of patients older than 50 years presenting with a clinical fracture.[1]

Large-scale prospective population studies have enabled the specification of clinical risk factors for fractures that are independent of low BMD and have allowed quantification of their relative risks (RRs) for predicting fractures. Thus, many aspects of osteoporosis and fracture risk are clinically recognizable (such as age, gender, and body weight), even before a first fracture has occurred. However, RRs are difficult to apply in daily clinical practice since their clinical significance depends on the prevalence of fractures in the general population. From this observation and for the purpose of clinical application, the concept of the absolute risk (AR) of fractures has emerged and refers to the individual's risk for fractures over a certain time period (for example, over the next 10 years).[2]

During the last decade, the development of the Fracture Risk Assessment Tool (FRAX) algorithm as a clinical tool for calculation of fracture risk in the individual patient is a major achievement in the field of case finding.[2,3] The FRAX is based on large-scale prospective population-based studies and includes age, gender, body weight and body mass index, a history of fracture, hip fracture in parents, current smoking, excessive alcohol intake, rheumatoid arthritis, glucocorticoid use, and other forms of secondary osteoporosis (Table 1). The WHO developed FRAX especially for primary care physicians for calculating the individual 10-year risk of hip and major fractures (defined as clinical spine, forearm, hip, or humerus fracture) in daily practice in women and men, based on the above-mentioned clinical risk factors, with and without results of BMD measurement in the femoral neck.

Strengths of the Fracture Risk Assessment Tool

FRAX is based on a large sample of primary data of prospective population studies and takes into account variability in fracture probability between geographic regions. FRAX should not be considered a gold standard but rather a platform technology and provides an aid to enhance patient assessment. FRAX can be integrated in clinical practice in many countries worldwide, both in women and men. FRAX is therefore likely to become, in many countries, the most popular instrument for identifying women and men at highest risk for fractures.

FRAX has been included in guidelines as a tool for case finding for identifying postmenopausal women at high risk for fractures, for selecting subjects to measure BMD, and for treatment decisions. The National Osteoporosis Foundation (NOF) in the US and the National Osteoporosis Society (NOS) in the UK have recently updated their guidelines on postmenopausal osteoporosis in this context (Figure 1).[4,5] These groups have integrated FRAX and BMD for case finding of individuals at high risk for fracture and for treatment decisions. Both sets of guidelines make a clear distinction between postmenopausal women with and without a fracture history. This is a major step forward in the clinical applicability for postfracture treatment in patients presenting with a fracture. Based on the fracture risk profile, the NOS, together with the National Osteoporosis Guideline Group (NOGG) and the Royal College of Physicians, determined treatment thresholds at which fracture prevention became cost-effective (Figure 2).[2,5]

Figure 1.

Algorithms for case finding and drug treatment decisions in postmenopausal women with and without a history of fractures according to the National Osteoporosis Foundation (NOF) in the US and the National Osteoporosis Society (NOS) in the UK. DXA, dual-energy x-ray absorptiometry; FRAX, Fracture Risk Assessment Tool. *Previous fragility fracture, particularly of the hip, wrist and spine including morphometric vertebral fracture. **Based on UK guidelines by NOGG.

Figure 2.

Assessment and intervention thresholds based on the 10-year risk of major fracture, as proposed in the UK.[2] BMD, bone mineral density. With kind permission from Springer Science+Business Media.[5]

Postmenopausal Women with a History of Fractures

The NOS advocates drug treatment in all postmenopausal women with a history of any fragility fracture (defined as distal radius, proximal humerus, spine [including morphometric vertebral fracture], pelvis [pubic rami], tibia, and ankle).[5] The NOF advocates drug treatment in postmenopausal women with a vertebral or hip fracture (without need of BMD or FRAX for decisions about pharmacotherapy), but after a nonvertebral nonhip fracture, the NOF advocates performing a dual-energy x-ray absorptiometry (DXA) measurement and starting drug treatment in patients having osteoporosis and in patients with osteopenia when FRAX indicates a 10-year fracture probability of at least 3% for hip or at least 20% for major fractures. Thus, in postmenopausal women with a history of vertebral or hip fracture, neither set of guidelines uses FRAX for decisions about drug treatment (and neither does the NOS for after any fragility fracture), and both sets consider such fracture history by itself as a starting point for case finding and treatment decisions.

Postmenopausal Women without a Fracture History

The NOS advocates applying FRAX (without BMD) in all postmenopausal women. Women at high risk according to FRAX without BMD are then considered candidates for drug treatment. Women with an intermediate risk according to FRAX without BMD are recommended to have a DXA measurement, and when FRAX with BMD is above the intervention threshold according to the NOGG, drug treatment should be considered.

The NOF advocates using DXA in all women older than 65 years and in postmenopausal women younger than 65 years in whom there is concern about their fracture risk based on the presence of clinical risk factors. This approach suggests that all postmenopausal women under 65 years of age should be clinically classified as having at least one of the risk factors of FRAX. Treatment is then recommended in patients with osteoporosis, in patients with osteopenia when the FRAX indicates a 10-year risk of greater than 3% for hip fractures or greater than 20% for major osteoporotic fractures, and in other patients considered at high risk (on glucocorticoids, total immobilization). These upgraded guidelines indicate that FRAX is an emerging tool in clinical decision making about case finding, selecting patients for DXA, and treatment decisions in postmenopausal women without a fracture history. Patients with a fracture are considered at high enough risk to make treatment decisions without additional need for using FRAX. It is expected that FRAX will also be helpful in designing fracture prevention studies and in reimbursement issues. In a study from Switzerland, profiles of patients at increased probability of fracture beyond currently accepted reimbursement thresholds for bone BMD measurement by DXA and osteoporosis treatment were identified and constitute an additional group of patients in whom treatment should be considered.[6]

Limitations of the Fracture Risk Assessment Tool

In spite of its solid scientific basis and clinical attractiveness, FRAX has several limitations, as acknowledged by the authors (Table 2).[2] Meanwhile, FRAX has been integrated in guidelines/guidance in the US, UK, Europe, Canada, Germany, and Japan,[2] but with different approaches for diagnostic and treatment thresholds, as shown above for the NOS and the NOF.[4,5] Fracture reduction has been demonstrated in randomized controlled clinical trials in patients selected on the basis of the presence of a morphometric vertebral fracture, hip fracture, or a low BMD, but not on the basis of FRAX. Therefore, of great interest is the finding that fracture reduction was greater at higher fracture probabilities based on FRAX, with or without BMD. Antifracture efficacy was evident when baseline fracture probabilities for major fractures were greater than 20% in the clodronate trial (in preventing major fractures)[7] and greater than 16% in the bazedoxifene trial (in preventing clinical fractures), irrespective of whether BMD was used in the fracture calculation.[2] Further studies will be needed on the ability of treatment to reduce fracture risk in subjects at high risk for fractures based on FRAX in the absence of a morphometric vertebral fracture, hip fracture, or a low BMD, which is the case in most patients presenting with a nonvertebral fracture. Decisions on treatment thresholds will furthermore depend on factors related to health care providers and patients and the willingness of society to reimburse treatment as health economic aspects are becoming increasingly important to determine the cost-effectiveness of treatment. Meanwhile, the NOGG of the UK has indicated FRAX-based thresholds for measuring BMD and for treatment decisions, with and without BMD (Figure 2). The management algorithms proposed by the NOGG are underpinned by a health economic analysis applied to the epidemiology of fracture in the UK.

Fall-related risks were explicitly excluded from the FRAX calculations but were recognized as risks for fractures independently of bone-related risks, especially for non-vertebral fractures such as hip fractures. More than 80% of women and men presenting with a clinical fracture to the emergency unit have, beside bone-related risks, one or more fall-related risks and have, independently from BMD, a fourfold increased risk of a fall history during the previous year.[1] In an integrated bone- and fall-related risk evaluation tool for the estimation of the 5- and 10-year ARs for fractures in patients using glucocorticoids, a history of falls had a greater impact on fracture risk than any other evaluated risk, and its contribution to fracture risk was similar to, and independent of, using a high dose of glucocorticoids (prednisone greater than 15 mg/day).[8] Thus, with FRAX, fracture risk calculation could be underestimated in patients with fall risks.

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