Fracture risk in the placebo group
The univariate analysis of the placebo group confirmed the impact of some potential clinical risk factors for vertebral fractures(19,20) in the MORE cohort, such as older age, a long time since menopause, impaired cognitive and musculoskeletal function, low BMD, and previous vertebral fractures. Other potential risk factors did not increase the vertebral fracture risk, such as a high level of circulating PTH, a low vitamin D level, smoking, alcohol intake, type 2 diabetes (p = 0.07), and a low endogenous estradiol level, possibly because of either no effect or a small effect and insufficient power of the current analysis. Interestingly, being shorter, but not low weight or BMI, increased the risk of vertebral fractures after adjusting for LS BMD. In the subset of placebo patients with biochemical bone marker measurements, none of the investigated markers (bone ALP, osteocalcin, or U-CTX) influenced fracture risk. This lack of influence is in conflict with the results of prospective cohort studies, where elevated levels of both formation and resorption markers were associated with increased vertebral and nonvertebral fracture risk, as independent risk factors.(21,22)
The association between cognitive or musculoskeletal impairment and an increased risk of vertebral fractures has not been described previously. These associations were independent of age, suggesting that these measurements may be of clinical importance. The strength of this analysis was that a variety of known and potential baseline risk factors for osteoporotic fractures were collected in a well-defined study population, and the influence of these risk factors on fracture efficacy of an antiresorptive agent was prospectively examined. A limitation of this analysis is that all potential clinical risk factors for fractures were not recorded at the study baseline, so the results are not comprehensive. Patients receiving glucocorticoid therapy or those with endocrine diseases (with the exception of type 2 diabetes), for example, were excluded from the study. Patients were selected either based on low BMD or prevalent fracture status.
Efficacy of raloxifene
Data from this analysis suggest that the efficacy of raloxifene in the reduction of vertebral fractures is largely independent of the existence of clinical risk factors for osteoporotic fractures. These are among the first data showing that the efficacy of an antiresorptive agent does not interact with a variety of known and potential risk factors of osteoporotic fractures. Using the same population (the MORE study database), some individual clinical risk factors have already been investigated. In those investigations, current smoking(23) and serum estradiol level(24) did not alter the efficacy of raloxifene to reduce vertebral fracture risk. The results obtained with the current multivariate model confirm these findings. Some other factors, such as younger age(25) and low LS BMD,(26) have been shown to increase the efficacy of raloxifene based on the results of univariate analyses of the MORE study. These findings are consistent with this analysis, but in the multivariate model, younger age was no longer a significant factor in affecting the efficacy of raloxifene.
In the univariate interaction analysis, a significantly greater vertebral fracture risk reduction was observed in patients with higher values of baseline bone formation markers (bone ALP and osteocalcin). Baseline levels of bone resorption marker U-CTX did not correlate with fracture reduction. These results are consistent with a previous report describing the relationship between the changes in bone turnover marker and vertebral fracture reduction in this subset of the MORE population. In this study,(27) a greater 12-month reduction of bone ALP and osteocalcin but not U-CTX was significantly correlated with a greater vertebral fracture reduction after 3 years on raloxifene therapy.
Numerous risk factors interact with each other, so it is not possible to determine from a univariate analysis which factors interact with treatment independently of any other factors. For this reason, a multivariate model was established and used to analyze all possible interactions between risk factors that affected the vertebral fracture risk reduction achieved on raloxifene therapy. A total of 13 of the 27 factors qualified for inclusion in the model. Based on the results of the systematic model, only serum triglyceride level and LS BMD could be considered as independent determinants of the efficacy of raloxifene in reducing vertebral fracture risk.
Raloxifene was more effective in patients with higher baseline triglyceride levels and/or lower baseline LS BMD values. Raloxifene, however, significantly reduced the risk of vertebral fractures across the spectrum of the triglyceride and LS BMD values measured in the MORE study. Thus, no pretreatment measurements of triglycerides and LS BMD are necessary to predict the drug efficacy. The fact that patients with low LS BMD, who if untreated have a higher risk of vertebral fracture, seem to benefit more from raloxifene would seem to be a desirable treatment effect.
Interestingly, the effect of both the triglyceride and LS BMD levels on the absolute fracture incidence was negligible in patients treated with raloxifene but was very pronounced in placebo-treated patients. Consequently, the influence of elevated triglyceride and lower LS BMD values on risk reduction was mainly because of the higher fracture incidence in the placebo group. The higher fracture incidence in placebo patients with the lower LS BMD values is plausible, but the relationship between higher fracture incidence and elevated serum triglycerides has not been previously described. It is possible that elevated triglyceride levels could reflect a metabolic state such as increased insulin resistance and type 2 diabetes mellitus associated with higher risk for fragility fractures. Indeed, in a meta-analysis, diabetes mellitus was associated with increased risk of peripheral fractures.(28) Additional results in this study also support this view. Patients with diabetes mellitus in the placebo group (N = 45) had an increased vertebral fracture risk, the OR being 2.17 (p = 0.07, see Table 3). In the univariate efficacy analysis, raloxifene was more effective in patients with type 2 diabetes mellitus. In addition, patients with diabetes in the MORE study had significantly elevated serum triglyceride levels. Thus, the increased efficacy of raloxifene in patients with elevated triglyceride levels may be because of greater efficacy of raloxifene in patients with increased insulin resistance and type 2 diabetes mellitus.
Among the different types of osteoporotic fractures, the clinical significance of vertebral fractures is increasingly acknowledged, because these are associated with significant pain, disability, and impairment of quality of life. Vertebral fractures have also been shown to be associated with increased mortality in postmenopausal women.(29–31) Some risk factors apply to all of the major types of osteoporotic fractures (i.e., femoral neck, forearm, vertebra), but their predictive value differs for each location.(31) Specifically, each SD decrease in LS BMD is associated with an ∼2-fold increase in vertebral fracture risk.(33) Prevalent fractures are one of the strongest predictors of subsequent vertebral fractures.(34) Other risk factors associated with vertebral fracture are age, late menarche, early menopause, a short duration of fertility, low consumption of cheese and yogurt, a history of osteoporosis, a reduction in height, and low levels of physical activity.(35–37) Interestingly, in elderly women, increased body weight and BMI were associated with a reduced risk of vertebral fractures in the European Prospective Osteoporosis Study (EPOS) study.(19)
Within this framework, these data suggest that the efficacy of raloxifene to reduce vertebral fracture risk is largely independent of the existence of clinical risk factors for osteoporotic fractures.