Does osteoporosis therapy invalidate FRAX for fracture prediction?

Abstract

Ten-year fracture risk assessment with the fracture risk assessment system (FRAX) is increasingly used to guide treatment decisions. Osteoporosis pharmacotherapy reduces fracture risk, but the effect is greater than can be explained from the increase in bone mineral density (BMD). Whether this invalidates fracture predictions with FRAX is uncertain. A total of 35,764 women (age !50 years) and baseline BMD testing (1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007) had FRAX probabilities retroactively calculated. A provincial pharmacy database was used to identify osteoporosis medication use. Women were categorized as untreated, current high adherence users [medication possession ratio (MPR) !0.80 in the year after BMD testing], current low adherence users (MPR <0.80), and past users. Fractures outcomes to 10 years were established form a population-based health data repository. FRAX and femoral neck BMD alone stratified major osteoporotic and hip fracture risk within untreated and each treated subgroup (all p-values <0.001) with similar area under the receiver operating characteristic curve. In untreated and each treated subgroup, a stepwise gradient in observed 10-year major osteoporotic and hip fracture incidence was found as a function of the predicted probability tertile (all p-values <0.001 for linear trend). Concordance (calibration) plots for major osteoporotic fractures and hip fractures showed good agreement between the predicted and observed 10-year fracture incidence in untreated women and each treated subgroup. Only in the highest risk tertile of women highly adherent to at least 5 years of bisphosphonate use was observed hip fracture risk significantly less than predicted, though major osteoporotic fracture risk was similar to predicted. In summary, this work suggests that the FRAX tool can be used to predict fracture probability in women currently or previously treated for osteoporosis. Although FRAX should not be used to assess the reduction in fracture risk in individuals on treatment, it may still have value for guiding the need for continued treatment or treatment withdrawal. ß

Interpretation and use of FRAX in clinical practice

“…In those receiving treatment for osteoporosis, FRAX is likely to overestimate fracture probability since treatment effects are not accommodated in the model. The empirical data suggest that FRAX remains a good predictive tool in women currently or previously on treatments for osteoporosis [88], possibly related to the contribution of treatment-induced changes in BMD.…”

Goal-Directed Treatment for Osteoporosis: A Progress Report From the ASBMR-NOF Working Group on Goal-Directed Treatment for Osteoporosis

“…(21) Observational studies have found that the FRAX is not sensitive enough to the changes in BMD and fracture risk with treatment, with fracture probabilities tending to increase because of increasing age during treatment. (22,23) In addition, FRAX fracture risk calculations do not take into account how recently a fracture occurred. Recent clinical trial and observational data in individuals treated for osteoporosis suggest that a history of recent fracture during treatment is associated with an increased risk of another fracture during treatment.…”

Goal-directed treatment of osteoporosis in Europe

“…Several treatments have had efficacy evaluated in terms of FRAX score at baseline [69][70][71][72][73], indicating either a greater anti-fracture efficacy at higher risk or no interaction between anti-fracture efficacy and baseline risk. In a single study, FRAX has been shown to perform similarly in treated and untreated patients, suggesting that the impact of treatment on fracture risk may be difficult to detect and that FRAX may have a low sensitivity for treatment-induced reductions in fracture risk [74]. A recent analysis of a subset of the same cohort, comprising more than 11,000 women undergoing baseline and follow-up DXA scans, not only confirmed that FRAX scores were strongly predictive of incident major fracture and hip fracture over 4 years of treatment but also reported that the change in FRAX score on treatment was not independently associated with the subsequent risk of a major fracture (P=0.8) or hip fracture (P=0.3) [75].…”