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Relationship between bone mineral density changes and risk of fractures among patients receiving calcium with or without vitamin D supplementation: a meta-regression - pdf attached
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Osteoporos Int (March 2011) 22:893-901
V. Rabenda1 Contact Information, O. Bruyere1 and J.-Y. Reginster1
(1) Department of Public Health, Epidemiology and Health Economics, University of Liege, CHU-Bat. B23, 4000 Liege, Belgium
"our results, as well as the results of other studies, suggest that BMD changes cannot be used as a surrogate of anti-fracture efficacy.... The magnitude of the changes in spine or hip BMD does not explain the reductions in risk for fractures. It is likely that calcium, alone or in combination with vitamin D, have anti-fracture efficacy through a mechanism independent of bone density.......During treatment, the bone quality may be increased, by changing the microstructure of bone in the absence of a change in BMD. Calcium and/or Vitamin D may have anti-fracture efficacy through a mechanism independent of bone density. In addition, increases in BMD could be accompanied by formation of bone of poor quality. The relationship between BMD and fractures and the ability of BMD to predict fracture risk is also complicated by a variety of nonskeletal factors for fractures. Among them, balance and propensity to falls are significant factors. Eventually, techniques for assessing changes in bone mass may lack the precision required to quantify this relationship accurately."
Abstract
Summary
Surrogate measures of fracture risk, such as effects on bone mineral density, may be of great interest to assess the efficacy of available osteoporosis treatments. Our results suggest that bone mineral density (BMD) changes cannot be used as a surrogate of anti-fracture efficacy, among patients receiving calcium, with or without vitamin D.
Introduction
The purpose of this study is to examine the association between changes in bone mineral density with reduction in the risk of fractures in patients receiving calcium with or without vitamin D.
Methods
We selected all randomized placebo-controlled clinical trials of calcium with or without vitamin D supplementation. To be included in this analysis, the studies were required to report both BMD (hip/proximal femur and/or lumbar spine) and the incidence of fractures. Meta-regression analyses were used to examine the associations of changes in BMD with reduction in risk of fracture over the duration of each study. The change in BMD was the difference between changes (from baseline) observed in the active treatment group and placebo group.
Results
A total of 15 randomized trials (n = 47,365) were identified, most of whom (77%) came from the Women's Health Initiative trial. Results show that larger increases in BMD at the lumbar spine were not associated with greater reduction in fracture risk. Concerning hip BMD changes, we found a statistically significant relationship between hip BMD changes and reduction in risk. However, results were not quite significant after excluding the both largest studies, in which BMD changes were measured in very small subset of patients. These points may have largely biased our results.
Conclusions
In conclusion, there was no evidence of a relationship between BMD changes and reduction in risk of fractures among patients receiving calcium with or without vitamin D supplementation. Calcium and/or Vitamin D may reduce fracture rates through a mechanism independent of bone density.
Introduction
Osteoporosis is a disease characterized by a decrease in bone mass and deterioration in skeletal microarchitecture, leading to increased fragility and susceptibility to fracture. Given the social and economic burden of osteoporotic fractures, the prevention of fractures is essential and has become a major public health priority. Moreover, the primary goal of treatment is to reduce the risk of fracture [1]. However, trials with fractures as the primary endpoint require a study design that is either very large or very long in order to demonstrate the anti-fracture efficacy. As a consequence, surrogate measures of fracture risk that may be more quickly and easily measured, such as effects on bone mineral density or biochemical markers of bone turnover, may be of great interest to assess the efficacy of available osteoporosis treatments.
A surrogate endpoint of a clinical trial, as defined by Temple [2], is "a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint". To be a validated surrogate endpoint, three requirements must be met [3, 4]. Firstly, a valid surrogate must be correlated with the clinical endpoint. Secondly, the effect of the treatment on the surrogate endpoint must predict the effect on the clinical outcome. Lastly, the surrogate endpoint must explain a substantial proportion of the treatment effect on the clinical endpoint.
Today, calcium and vitamin D are widely recognized as essential components in osteoporosis management [1, 5, 6]. Calcium and vitamin D deficiency are important factors for bone health, because reduced calcium absorption increases parathyroid hormone concentration and accelerates the rate of bone loss, which raises the number and activity of osteoclasts that release calcium from bone. Studies analyzing the effects of calcium, alone or in combination with vitamin D, on bone loss and fractures produced conflicting results, partly because of their low statistical power to assess fracture incidence (i.e., few subjects included, short period of follow-up). Moreover, some studies only report bone mineral density (BMD) data and do not assess the impact of these agents on the risk of fractures. The validation of a surrogate marker (e.g., BMD) for fracture would allow to assess the clinical interest of calcium, alone or in combination with vitamin D, in published manuscripts with BMD data only or in new clinical studies including fewer patients and with a reduced period of follow-up. Moreover, such surrogate measures may be useful to the clinician to monitor therapy with calcium and vitamin D.
The purpose of this study was to examine the associations between changes in BMD with reductions in the risk of fractures by conducting a meta-regression of randomized placebo-controlled clinical trials of calcium, alone or in combination with oral vitamin D, in patients aged 50 years and older. The objective was to test the validation of BMD change as a surrogate of fracture incidence, for calcium with or without vitamin D treatment.
Discussion
In this study, we investigated whether BMD change from baseline can be validated as a surrogate endpoint for fracture among patients receiving calcium, alone or in combination with vitamin D. Results of this meta-regression show no significant relationship between the reduction in risk of fractures and the magnitude of the increase in BMD at the lumbar spine at the study endpoint. Concerning hip BMD changes, we found a statistically significant relationship between hip BMD changes and reduction in risk. However, as already mentioned, caution should be used in interpreting the results of this analysis. In fact, results were not quite significant after excluding the both largest studies included in this analysis [20, 24]. Moreover, in these both studies [20, 24], BMD changes were only measured in very small subset of patients. This may also have largely biased our results and in consequence, our results not provide a strong evidence of a relationship between BMD changes and fracture risk reduction.
Estimation of fracture risk reduction based solely on BMD changes is not supported by the current body of data. In fact, over the last decade, in the treatment of osteoporosis there has been increasing interest in quantifying the relationship between fracture endpoints and surrogates such as bone mineral density. However, studies exploring the association between BMD changes and fracture reduction have yielded contradictory results. Sarkar et al. estimated that only 4-5% of the fracture reduction observed with raloxifene treatment could be attributed to an increase in BMD [27]. Combining data from three pivotal risedronate fracture endpoint trials, Watts et al. showed that the increases in lumbar spine and femoral neck BMD account for only 18% and 11%, respectively, of the effect of risedronate on vertebral fracture incidence [28]. However, patients whose BMD decreased were at significantly greater risk of sustaining a fracture than patients whose BMD increased. Another study found that lumbar spine BMD changes accounted for about 28% of the overall risedronate treatment effect [29]. Among women treated with alendronate, Hochberg et al. found that larger increases in hip and spine BMD were associated with lower risk of vertebral fractures [30]. Women with BMD increases of at least 3% during the first 12-24 months had approximately half the incidence of new vertebral fractures compared with the small proportion of women whose BMD did not measurably increase during the first year or two of treatment. Among women treated with strontium ranelate for 3 years, Bruyere et al. found that for each percentage point increase in femoral neck or total proximal femur BMD, the risk of sustaining a new vertebral fracture decreased by 3% and 2%, respectively [31]. The changes in total proximal femur and femoral neck BMD explained 74% and 76%, respectively, of the vertebral anti-fracture efficacy of strontium ranelate.
Moreover, meta-analysis, using a variety of statistical methods, performed by several groups in an attempt to resolve this issue, have produced conflicting results. Wasnich and colleagues analyzed the relationship between the increase in BMD and the reduction in vertebral fracture risk from 13 placebo-controlled trials of alendronate, etidronate, tiludronate, calcitonin, and raloxifene using Poisson regression [32]. They concluded that BMD increases explain up to half of the observed vertebral fracture risk reductions. In contrast, Cummings et al., using data from the Fracture Intervention Trial, showed that improvement in spine bone mineral density explained only 16% of the reduction in risk of vertebral fractures [33]. Moreover, using meta-analysis techniques, they demonstrated that the reductions in risk were greater than predicted from improvement in BMD. Their model estimated that antiresorptive treatments predicted to reduce fracture risk by 20%, based on improvement in BMD, actually reduce the risk of fracture by about 45%.
Hochberg et al. found a relationship between changes in BMD during the first year of antiresorptive treatment and reduction in the incidence of nonvertebral fractures occurring over the duration of studies using meta-analyses based on summary data at the trial level [34]. However, Delmas and Seeman, analyzing individual instead of group data, concluded that only a small proportion of the risk reduction in vertebral and nonvertebral fractures observed with antiresorptive treatment was explained by the increase in BMD [35]. Lastly, using individual patient data, Bauer et al. did not find a significant relationship between changes in hip or spine BMD during the first year of treatment with alendronate and subsequent reduction in nonvertebral fractures [36].
Thus, our results, as well as the results of other studies, suggest that BMD changes cannot be used as a surrogate of anti-fracture efficacy. Moreover, the poor ability of BMD changes to predict reduction of facture risk may limit its use in monitoring osteoporosis treatment, as it has been suggested by some authors [37]. In clinical practice, monitoring is particularly important during the first few years of treatment to establish therapeutic efficacy. Because not all patients who are prescribed medications for osteoporosis will maintain or have significant increases in BMD, monitoring with BMD testing can be used to identify patients who have significant decreases in BMD on therapy, decreases that can be the result of nonresponse to the treatment, poor compliance or persistence, incorrect dosing, malabsorption, or secondary causes of osteoporosis that were either unrecognized before starting treatment or developed after treatment was initiated. Therefore, in absence of other validated surrogate marker and as recommended by some guidelines [38, 39], a DXA spine and/or proximal femur study remains for most patients, the most appropriate tool for monitoring therapeutic effectiveness and identifying patients who are not adherent with treatment or who do not respond to therapy. Alternative approaches to monitoring using other surrogate markers of bone strength and fracture risk should be explored.
Our findings, as well as those from other studies assessing the relationship between changes in BMD and fracture risk reduction, raise important questions about the mechanisms underlying the improvement in bone strength associated with treatment. During treatment, the bone quality may be increased, by changing the microstructure of bone in the absence of a change in BMD. Calcium and/or Vitamin D may have anti-fracture efficacy through a mechanism independent of bone density. In addition, increases in BMD could be accompanied by formation of bone of poor quality. The relationship between BMD and fractures and the ability of BMD to predict fracture risk is also complicated by a variety of nonskeletal factors for fractures. Among them, balance and propensity to falls are significant factors. Eventually, techniques for assessing changes in bone mass may lack the precision required to quantify this relationship accurately.
Our study has some potential limitations. There is a possibility that publication bias may have influenced the results. Trials that observed positive or significant results may tend to be published more often than those that did not. Small trials that had little or no effect on BMD, but which found an apparent reduction in fracture risk simply by chance may have been published more often than similar trials that failed to find a significant effect on fractures. Another limitation is that some trials reported only fracture or BMD data, and were excluded from the analysis. In order to resolve this issue, we attempted to contact the authors but, this approach was not successful. Moreover, differences in clinical trials, such as patient's characteristics, may have influenced our findings.
We choose to perform analyses employing meta-regression based on summary statistics to quantify the underlying relationship between BMD and fracture risk reduction. As already mentioned, researchers have used a variety of statistical methods to evaluate the relationship between changes in BMD and fracture risk reduction and found varying levels of correlation between these two measurements. The proportion of fracture risk reduction explained by BMD according to these analyses varied widely. Analyses based on individual patient data have suggested that increases in BMD account for only 4-28% of reductions in fracture risk. Analyses using meta-regression based on summary statistics, however, indicated that most of the anti-fracture benefits were due to improvements in BMD.
The techniques of meta-regression based on summary statistics have several limitations [40]. Statistical power to detect useful associations using meta-regression is limited by the number of available studies [41]. Associations between aggregated values may not be representative of the true relationships in the data at the individual level. The results of meta-regression analyses may not be as robust as those of regression analyses using individual patient data. Analyses based on individual patient data make possible a more comprehensive analysis since all relevant data on a patient level are available. However, one limitation of the individual patient data approach is that researchers who wish to perform a meta-regression analysis often do not have access to the individual data. The usual unavailability and expense of collecting such data and the availability of summary data from published studies has led to the application of meta-regression for predicting summary treatment effects by summary patient statistics across studies. Regular use of this method would require a very high degree of collaboration.
We conclude from the present meta-regression that there is no evidence of relationship between BMD changes and reduction in risk of fracture among patients receiving calcium with or without vitamin D supplementation. The magnitude of the changes in spine or hip BMD does not explain the reductions in risk for fractures. It is likely that calcium, alone or in combination with vitamin D, have anti-fracture efficacy through a mechanism independent of bone density.
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