Focus: FRAX® and treatment efficacy in osteoporosis




Eugene V. McCLOSKEY,
MRCP, MD, FRCPI
Academic Unit of Bone Metabolism
Metabolic Bone Centre
Northern General Hospital
Sheffield, UK

FRAX®and treatment efficacy in osteoporosis
by E. V. McCloskey,United Kingdom

Fracture risk prediction can be enhanced by the concurrent assessment of clinical risk factors in addition to measurements of bone mineral density (BMD). FRAX®, a combination of four algorithms, can calculate the 10-year probability of hip or major osteoporotic fracture, with or without the input of femoral neck BMD. A number of studies have now examined the efficacy of osteoporosis treatments across a range of fracture probabilities and are contributing to a body of evidence demonstrating that treatments can generally reduce fracture risk in women identified to be at high risk by FRAX®. A community-based study of oral clodronate clearly demonstrated a reduction in nonvertebral fractures, and the treatment was equally or more effective in women with higher FRAX® probabilities. The original studies of bazedoxifene and alendronate demonstrated significant reductions in vertebral fractures, but required post hoc subgroup analyses to demonstrate significant reductions in nonvertebral fractures. For bazedoxifene, while the interaction with treatment was not statistically significant, the efficacy was clearly more obvious in patients with higher baseline FRAX® probabilities. The interpretation of the alendronate study (Second Fracture Intervention Trial [FIT2]) is somewhat more problematic. One conclusion is that the drug is simply not effective in reducing nonvertebral fractures in this study population and that this is equally true across a wide range of baseline FRAX® probabilities. The evidence base will continue to expand as a number of other studies will shortly be examined to determine the interaction between treatment efficacy and baseline FRAX®.

Medicographia. 2010;32:422-428 (see French abstract on page 428)

Anumber of agents are available for the treatment of osteoporosis, all of which have been shown to significantly reduce fracture risk in at least one skeletal site.1-11 In the very near future, several new agents that have shown reductions in fracture risk will also be available for clinical use.12-14

Treatment efficacy, fracture probability, and FRAX®

The efficacy of osteoporosis therapies has usually been characterized in individuals with low bone mass, such that the bone mineral density (BMD) thresholds published by the World Health Organization (WHO) in 199415 are widely accepted as both a diagnostic and an intervention threshold. Indeed, to date most pivotal antifracture studies have reported on the use of these agents in individuals selected to be at high risk for fracture usually by the presence of low BMD and/or a prior fragility fracture, most commonly at the spine. A problem with the predominant use of BMD to direct interventions is that BMD alone is not optimal for the detection of individuals at high risk of fracture. Indeed, the majority of osteoporotic fractures will occur in individuals without osteoporosis.16,17

In the past decade, other factors have been identified that contribute to fracture risk, partially or wholly independent of BMD, which improve fracture prediction and the selection of individuals at high risk for treatment.18-22 A series of metaanalyses using individualized data from 12 global population cohorts23-30 has identified clinical risk factors for use in the assessment of fracture risk with or without the use of BMD. The adequacy of the risk factors has been validated in a further 12 independent population-based cohorts.31 The risk factors identified formed the basis for the development of the WHO algorithms that calculate fracture probability in an individual, expressed as the 10-year fracture probability (FRAX®).31 Unlike many previous algorithms, the FRAX® tool takes into account the relationship between individual risk factors and both fracture and death hazards.31 The risk factors in the FRAX® tool include age, sex, glucocorticoid use, secondary osteoporosis, parental history of hip fracture, prior fragility fracture, low body mass index (BMI), current smoking, excess alcohol consumption (3 or more units daily) and femoral neck BMD selected on the basis of their international validity.32

A critical question in proposing the use of clinical risk factors for patient risk assessment relates to the reversibility by pharmacological intervention of the risk so identified. The risk factors in FRAX® were also selected on the basis of having at least indirect evidence that the risk was likely to be modified by subsequent intervention (modifiable risk). This was validated from clinical trials (BMD, prior fracture, glucocorticoid use, secondary osteoporosis), or partially validated by excluding interactions of risk factors on therapeutic efficacy in large randomized intervention studies (eg, smoking, family history, BMI). It is important to note that risk factors for falling were not considered for inclusion in the FRAX® tool, since there is some concern that the risk identified would not be modified by a pharmaceutical intervention targeted at the skeleton.7 It is notable that in this latter study, the precise criteria for inclusion were not documented, and further work is required to determine whether risk factors for falls or a history of falls would identify a risk that was modifiable by pharmacological intervention.33 A number of studies have now addressed the interaction between treatment efficacy and fracture probabilities assessed by FRAX®.

Clodronate

Daily oral clodronate 800 mg has been shown to decrease vertebral fracture risk in women with postmenopausal or secondary osteoporosis.1 More recently, it has been demonstrated to reduce clinical and osteoporotic fracture risk in elderly women unselected for osteoporosis.34 The latter study was a double-blind, prospective, randomized, placebo-controlled, single center study in elderly community-dwelling women aged 75 years or more. Treatment was associated with a significant reduction in all clinical fractures (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.68-0.94)34 and clinical osteoporotic fractures (HR, 0.76, 95% CI, 0.63-0.93, P=0.006).35

The interaction between efficacy and FRAX® probabilities was conducted in a cohort comprising 76% of the women recruited to the main part of the study, in whom complete data on clinical risk factors required for the computation of 10-year fracture probability were available.35 The following clinical variables were used to compute the 10-year probability of a major osteoporotic fracture (hip, clinical vertebral, wrist or humerus) by FRAX®, age, BMI, history, of prior fragility fracture after the age of 50 years, maternal history of hip fracture (father’s history of hip fracture was not documented), rheumatoid arthritis (yes, if patient self-reported ever being told they probably had or did have rheumatoid arthritis), oral glucocorticoid use (yes, if ever used) and smoking (yes, if current). Information on alcohol intake was not captured in the study. The 10-year probability was calculated with and without input of femoral neck BMD.

The mean±SD 10-year probability of amajor osteoporotic fracture calculated by clinical risk factors alone was 20%±7%. When femoral neck BMD was added to the FRAX® calculation, the mean 10-year probability was slightly lower at 18% ±9%.35 This suggests that the mean femoral neck BMD in the study population was slightly higher than expected for age and a healthy selection bias had already been noted in the study.34

The effects of clodronate to reduce fracture incidence at various 10-year probabilities of fracture, calculated with and without femoral neck BMD, are shown in Figures 1 and 2 (page 424). In the absence of BMD, there was a borderline statistically significant interaction (P=0.043) with a better effect of clodronate at higher probabilities (Figure 1). For example, at a probability of 15% (25th percentile), the relative risk for fracture was reduced by 8%(NS) whereas at a probability of 24% (75th percentile) the reduction was 27% (95% CI 8% to 42%). The interaction between efficacy and probability of fracture was not statistically significant when BMD was used in the calculation of probability (P=0.10), but the pattern of efficacy was very similar with more evident fracture reductions at higher probabilities of fracture (Figure 2).

Figure 1
Figure 1. Clodronate and reduction of clinical osteoporotic risk (clinical risk factors without femoral neck BMD).

Relationship between 10-year probabilities of major osteoporotic fracture, calculated with clinical risk factors alone (ie, without femoral neck bone mineral
density [BMD]) and the efficacy of clodronate to reduce clinical osteoporotic
fracture risk (hazard ratio [HR] with 95% confidence intervals). The black horizontal
line represents the overall treatment efficacy and the dashed horizontal
line a hazard ratio of 1. The diamonds correspond to the 10th, 50th, and 90th
percentiles of probability in the population studied.

Figure 2
Figure 2. Clodronate and reduction of clinical osteoporotic risk
(clinical risk factors + femoral neck BMD).

Relationship between 10-year probabilities of major osteoporotic fracture, calculated with clinical risk factors combined with femoral bone mineral density [BMD],
and the efficacy of clodronate to reduce clinical osteoporotic fracture risk (hazard
ratio [HR] with 95% confidence intervals). The black horizontal line represents
the overall treatment efficacy and the dashed horizontal line a hazard ratio of 1.
The diamonds correspond to the 10th, 50th and 90th percentiles of probability
in the population studied.

In summary, this study suggests that those individuals identified at higher risk of fracture by the FRAX® tool are responsive to treatment with clodronate, even when the risk is calculated in the absence of information on BMD.

Bazedoxifene

Bazedoxifene acetate is a new agent within the class of drugs known as selective estrogen receptor modulators (SERMs). Its fracture efficacy has been examined in a phase 3 study designed to determine the primary effect of this agent on vertebral fracture risk in postmenopausal women with osteoporosis.14 In brief, the study was a double-blind, randomized, placebo- and raloxifene-controlled trial including 7492 postmenopausal women with osteoporosis. They were recruited either on the basis of low BMD (T-score ≤−2.5 SD at the lumbar spine or femoral neck) or a prior vertebral fracture, and were randomized to four treatment groups: two groups received bazedoxifene (20 or 40 mg daily; n=1886 and 1872, respectively), a third group received raloxifene (60 mg daily), and a placebo group (n=1885). All patients took calcium (1200 mg daily) and vitamin D (400–800 IU daily). At the two doses tested, bazedoxifene significantly decreased the risk of vertebral fractures by 37% to 42%. A secondary end point was the effect of treatment on the risk of nonvertebral fractures, but overall there was only a nonsignificant 11% reduction in such fractures. A post hoc analysis in a subgroup of patients at high risk (femoral neck T-score ≤−3 SD and or ≥_1 moderate or severe, or multiple mild vertebral fractures) reported that the combined doses of bazedoxifene reduced the incidence of nonvertebral fractures by 40% (5%-63%). Subsequently, as requested for new phase 3 studies by the Committee for Medicinal Products for Human Use (CHMP),36 an analysis was undertaken to test the hypothesis that the combined data for the two doses of bazedoxifene would demonstrate a reduced fracture risk in women with the higher fracture probabilities.13 Baseline data were used to calculate 10-year fracture probabilities with the FRAX® tool in placebo- and bazedoxifenetreated patients.13< The risk factors at baseline were further clarified in the following ways; for a prior fracture, data on selfreported peripheral fractures was combined with the finding of a grade 2 or greater morphometric vertebral fracture on baseline spine radiographs. No information was available on parental history of hip fracture, so that this variable was simulated resulting in a prevalence of 6%—in a sensitivity analysis, a more conservative position assumed that no patient had a family history of hip fracture. Three different types of dual-energy x-ray absorptiometry (DXA) equipment were used so that a machine specific Z-score was calculated by age to remove the systematic differences between machine manufacturers and permit the computation of 10-year probabilities with the FRAX® tool.13

The mean±SD 10-year probability of a major osteoporotic fracture calculated by clinical risk factors alone was 11%±8% and was similar when femoral neck BMD was added to the FRAX® calculation. The probability is somewhat lower than that observed in the population-based cohort recruited to the clodronate study above and reflects the younger age of the present study population (mean age 66 years vs 80 years in the clodronate study), despite the selection criteria based on BMD and prior fracture. The latter observation is supportive of the need to use of age-dependent intervention thresholds as adopted by the UK.37 Overall, bazedoxifene was associated with a significant 39% decrease in incident morphometric vertebral fractures (P=0.005) and a 16% decrease in the incidence of all clinical fractures (P=0.14). While there was no significant interaction between baseline FRAX® probability and treatment efficacy (P>0.3), the reduction in fracture risk increased progressively at higher baseline fracture probabilities (Figures 3 and 4). For morphometric vertebral fractures, treatment with bazedoxifene was associated with a significant decrease in the risk at probability values above 7%, corresponding to the 41st percentile of the study population. In patients with fracture probabilities above 16%, the 80th percentile, bazedoxifene was associated with a significant decrease in all clinical fractures. When BMD was not used in the FRAX® tools to compute fracture probabilities, similar results were observed, but with wider confidence estimates.

Figure 3
Figure 3. Bazedoxifene and reduction of morphometric fracture risk.

Relationship between 10-year probabilities of major osteoporotic fracture, calculated with clinical risk factors combined with femoral neck bone mineral density
[BMD], and the efficacy of bazedoxifene to reduce morphometric vertebral fracture
risk (hazard ratio with 95% confidence intervals). The black horizontal line
represents the overall treatment efficacy and the dashed horizontal line a hazard
ratio [HR] of 1. The diamonds correspond to the 10th, 50th, and 90th percentiles
of probability in the population studied.

Figure 4
Figure 4. Bazedoxifene and reduction of clinical osteoporotic
fracture risk.

Relationship between 10-year probabilities of major osteoporotic fracture, calculated with clinical risk factors combined with femoral neck bone mineral
density [BMD], and the efficacy of bazedoxifene to reduce clinical osteoporotic
fracture risk (hazard ratio [HR] with 95% confidence intervals). The black horizontal
line represents the overall treatment efficacy and the dashed horizontal
line a hazard ratio of 1. The diamonds correspond to the 10th, 50th, and 90th
percentiles of probability in the population studied.

Alendronate

The pivotal studies for the clinical use of alendronate in postmenopausal osteoporosis were the two arms of the Fracture Intervention Trial (FIT). The first (FIT1) examined the efficacy of alendronate over 36 months in approximately 2000 women aged 55 to 81 years with low femoral-neck BMD and at least one vertebral fracture at baseline.4 Under double-blind conditions, the initial dose of alendronate, 5 mg daily by mouth, was increased to 10 mg daily at the 24-month visit. New vertebral fractures, identified on lateral spine radiographs at 24 and 36 months, were reduced by 47% (95% CI, 32% to 59%) by alendronate. In contrast, non-spine clinical fractures were reduced by 20%, an effect that did not quite achieve statistical significance (P=0.06).4 The second placebo-controlled arm (FIT2) sought to determine the efficacy of alendronate over 4 years on the risk of clinical and vertebral fractures in over 4000 postmenopausal women with low BMD (defined as a femoral neck BMD of 0.68 g/cm2 or less on Hologic densitometers), but without prior vertebral fractures.5 As in FIT1, alendronate was administered at 5mg daily until the 24 month visit at which the dose was increased to 10mg daily. In the primary analysis, alendronate reduced all clinical fractures by 14%, but the reduction was again not of statistical significance (P=0.07). The reduction in non-spine clinical fractures was 12%(P=0.13). Alendronate did, however, significantly decrease the risk of radiographic vertebral fractures by 44% (95% CI, 20% to 61%).

In a post hoc analysis, an interaction was noted between baseline BMD and efficacy, so that a further analysis examined efficacy in tertiles of BMD.5 Alendronate apparently reduced clinical fractures (vertebral and non-spine) by 36% in women with BMDs in the lowest tertile (by chance corresponding to osteoporosis at the femoral neck as defined by a T-score <−2.5 SDs based on the young adult mean from the National Health And Nutrition Examination Survey [NHANES] study). There was no significant reduction in the remaining women with higher BMD, though all of these had BMD T-score values less than −1.6. A pre-planned analysis of the two arms of FIT combined was subsequently published, though this deviated from the original plan as it concentrated solely on women with BMD T-scores <−2.5 or at least one vertebral fracture.38 This further post hoc analysis suggested that alendronate treatment was associated with a significant 30% reduction in clinical fractures and a 27%reduction in nonvertebral fractures.38 It should be borne in mind though that the overall results from the two individual arms of FIT suggested an overall nonsignificant 12% to 20% decrease in nonvertebral fractures.

Figure 5
Figure 5. Alendronate and reduction of clinical osteoporotic fracture
risk (clinical risk factors + femoral neck BMD).

Relationship between 10-year probabilities of major osteoporotic fracture, calculated with clinical risk factors combined with femoral neck bone mineral density,
and the efficacy of alendronate to reduce clinical osteoporotic fracture risk
(hazard ratio with 95% confidence intervals).
Abbreviations: FN BMD, femoral neck bone mineral density; HR, hazard ratio;
LCL, lower confidence limit; UCL, upper confidence limit.
Modified from reference 39: Cummings et al. J Bone Miner Res. 2009;24(suppl
1):S10. © 2009, American Society for Bone and Mineral Research.

An analysis of the interaction between alendronate efficacy and baseline FRAX® probabilities in the clinical fracture arm of the FIT (FIT2) has also recently been presented, but full publication is still awaited.39 The analysis used Cox proportional hazards models with interaction terms to analyze whether the effect of alendronate on risk of nonvertebral and major osteoporotic fractures was greater in women with higher baseline FRAX® probabilities.While FRAX® predicted incident fractures in the study, there was no significant association between FRAX® probability, calculated with femoral neck BMD, and reduction in risk of clinical or nonvertebral fractures by alendronate (Figure 5). Results were similar for “major osteoporotic fractures” and whether or not FRAX® calculations included FN BMD. The authors concluded that there is no significant association between FRAX® score and efficacy of alendronate for nonvertebral or major clinical fractures.

Summary

Relatively little is known about the determinants of antifracture efficacy in patients using osteoporosis medications. The efficacy of inhibitors of bone resorption has been well characterized in individuals with low bone mass, such that the BMD thresholds published by the WHO in 1994,15 are widely accepted as both a diagnostic and an intervention threshold. BMD alone is not optimal for the detection of individuals at high risk of fracture and several recent studies indicate that pharmacological interventions have efficacy in patients with osteopenia or in whom BMD was not assessed.40-44 It is clear that the availability of the FRAX® tool for predicting fracture risk will lead to major changes in the management of patients. Indeed, recently developed European guidelines for the evaluation of drugs in osteoporosis recognize the importance of global risk assessments and it is likely that further data will become available from current and future clinical trials of antiosteoporotic agents.

The studies reviewed here are the first to contribute to the body of evidence demonstrating that treatments can generally reduce fracture risk in women identified to be at high risk by FRAX®. Certainly the analysis of clodronate is consistent with this hypothesis. The original studies of bazedoxifene and alendronate demonstrated significant reductions in vertebral fractures, but required post hoc subgroup analyses to demonstrate significant reductions in nonvertebral fractures. There are obvious difficulties with post hoc analyses that are particularly acute when undertaken on subgroups, especially subgroups that may be difficult to justify on clinical grounds. The post hoc nature, the change in the significance of the primary outcome, and the way of categorizing the high-risk group, all weaken the validity of these analyses. Against this background, examination of the interaction of treatment efficacy with baseline FRAX® probabilities, as a continuous variable, while not avoiding post hoc status, aims to avoid subgroup analysis and the associated loss of statistical power. For bazedoxifene, while the interaction with treatment was not statistically significant, the efficacy was clearly more obvious in patients with higher baseline FRAX® probabilities. The interpretation of the alendronate study (FIT2) is somewhat more problematic. One conclusion is that the drug is simply not effective at reducing nonvertebral fractures in this study population and that this is equally true across a wide range of baseline FRAX® probabilities. The Fracture intervention trial Long-term EXtension (FLEX) trial, a randomized extension to the FIT, may also be consistent with the lack of efficacy at nonvertebral sites.45 In this study, women randomized to continue alendronate 10 mg daily for a further 5 years after the original study showed no difference in nonvertebral fracture rates compared with those randomized to receive placebo during the extension. This “lack of offset” has been widely interpreted to suggest that 5 years of therapy with alendronate shows similar nonvertebral fracture efficacy as 10 years, so that patients may be able to get “treatment-free” windows. An alternative interpretation is that it is not possible to show an offset of effect if one has not demonstrated an onset of effect.

A number of other studies will shortly be examined to determine the interaction between treatment efficacy and baseline FRAX® probabilities. _

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Keywords: fracture; FRAX®; osteoporosis; bone mineral density; treatment; alendronate; clodronate; bazedoxifene