To FRAX or not to FRAX

The WHO Fracture Risk Assessment Tool (FRAX) calculator is the most thoroughly studied and widely used tool of fracture risk assessment. FRAX is now available in 39 countries and is increasingly being used as a guide for clinical decision-making. The specific objective of developing FRAX was to aid clinicians in identifying the most appropriate patients to receive pharmacologic therapy to reduce fracture risk. Prior to FRAX, treatment decisions were based primarily on bone mineral density (BMD) values with the threshold at which treatment was recommended being modified crudely by the simple presence of absence of other clinical risk factors. For example, the 1998 National Osteoporosis Foundation (NOF) guidelines suggested treating all postmenopausal women with a BMD T-score of 2 or lower and all women with a T-score of 1.5 or lower who had one of several risk factors, including being thin, having a fragility fracture as an adult or a family history of fragility fracture. These guidelines identified for therapy almost all patients at high risk for fracture (sensitivity of the approach was good) but enfranchised therapy for many younger postmenopausal womenwith low bone density but whowere atmodest or even low fracture risk (poor specificity). Understanding this, clinicians asked themselves ‘‘Which patients who do not have osteoporosis should be treated? ’’ FRAX was specifically developed to answer that question. After the 1998 NOF guidelines were released, we recognized that individuals could be stratified into gradations of fracture risk more effectively if BMD was combined with other independent clinical risk factors for fracture than could be accomplished by using individual risk factors for such as age, BMD, or fracture history alone. The FRAX tool was derived by evaluating the relationships between BMD, clinical risk factors, and fracture risk using individual patient data comprising almost 250,000 patient-years of observation in nine large observational studies performed in different parts of the world. Subjects in those studies were generally healthy older adults who were not on osteoporosis treatment. In the United States and Europe, FRAX accurately predicts the 10-year probability of major osteoporotic fracture and hip fracture in patients with characteristics like the study subjects. Importantly, because FRAX was designed to identify patients for whom treatment would be beneficial, analyses of clinical trials with different classes of osteoporosis treatments have documented that this is true. Since its availability in 2008, FRAX estimates of fracture probability have been incorporated, albeit in various ways, into clinical guidelines of several national societies including the NOF. The fracture risk thresholds at which treatment is recommended in the NOF guidelines were based on clinical and health economic considerations. Despite the scientific basis of FRAX and its strengths, several limitations are recognized. FRAX treats all risk factors as categorical, not taking into account the dose or duration of glucocorticoid therapy or the number, type, severity, or recency of a fragility fracture, which are clinical variables known to affect fracture risk. In patients with risk factors for fracture that are not accounted for in the FRAX model, such as diabetes, FRAX estimates of fracture probability are less accurate. Clinicians often use additional information such as history of fall risk to make treatment decisions. Although these are well-recognized risk factors for fracture, they were intentionally not included in the FRAX calculator. Remember that FRAX was developed to identify patients who would benefit from pharmacologic therapy. While FRAX was being developed, evidence existed that elderly patients with fall-related risk factors but who did not have osteoporosis did not experience fracture risk reduction with bisphosphonate therapy. Other risk calculators, such as one based on an American cohort in the Study of Osteoporotic Fractures and the Garvan Fracture Risk Calculator, do take measures of frailty and fall risk into account. While these other risk calculators are effective tools to assess fracture risk, they have not been evaluated as a means to identify patients who are responsive to bone-strengthening drugs. When FRAX became available, clinicians were advised not to use the tool in patients receiving osteoporosis treatment. To avoid the use of FRAX in patients on treatment in the United States, the NOF and the International Society for Clinical Densitometry (ISCD) developed the ‘‘FRAX filter,’’ which COMMENTARY JBMR