From the Journals

Analysis finds no mortality reductions with osteoporosis drugs



Despite earlier research suggesting that some drug treatments for osteoporosis reduce mortality, a meta-analysis has failed to find any clear mortality benefits in patients with osteoporosis.

A paper published in JAMA Internal Medicine analyzed data from 38 randomized, placebo-controlled clinical trials of osteoporosis drugs involving a total of 101,642 participants.

“Studies have estimated that less than 30% of the mortality following hip and vertebral fractures may be attributed to the fracture itself and, therefore, potentially avoidable by preventing the fracture,” wrote Steven R. Cummings, MD, of the San Francisco Coordinating Center at the University of California, San Francisco, and colleagues. “Some studies have suggested that treatments for osteoporosis may directly reduce overall mortality rates in addition to decreasing fracture risk.”

Despite including a diversity of drugs including bisphosphonates, denosumab (Prolia), selective estrogen receptor modulators, parathyroid hormone analogues, odanacatib, and romosozumab (Evenity), the analysis found no significant association between receiving a drug treatment for osteoporosis and overall mortality.

The researchers did a separate analysis of the 21 clinical trials of bisphosphonate treatments, again finding no impact of the treatment on overall mortality. Similarly, analysis of six zoledronate clinical trials found no statistically significant impact on mortality, although the authors noted that there was some heterogeneity in the results. For example, two large trials found 28% and 35% reductions in mortality, however these effects were not seen in another other zoledronate trials.

An analysis limited to nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) showed a nonsignificant trend toward lower overall mortality, although this became even less statistically significant when trials of zoledronate were excluded.

“More data from placebo-controlled clinical trials of zoledronate therapy and mortality rates are needed to resolve whether treatment with zoledronate is associated with reduced mortality in addition to decreased fracture risk,” the authors wrote.

They added that the 25%-60% mortality reductions seen in previous observational were too large to be attributable solely to reductions in the risk of fracture, but were perhaps the result of unmeasured confounders that could have contributed to lower mortality.

“The apparent reduction in mortality may be an example of the ‘healthy adherer effect,’ which has been documented in studies reporting that participants who adhered to placebo treatment in clinical trials had lower mortality,” they wrote, citing data from the Women’s Health Study that showed 36% lower mortality in those who were at least 80% adherent to placebo.

“This effect is particularly applicable to observational studies of treatments for osteoporosis because only an estimated half of women taking oral drugs for the treatment of osteoporosis continued the regimen for 1 year, and even fewer continued longer,” they added.

They did note one limitation of their analysis was that it did not include a large clinical trial of the antiresorptive drug odanacatib, which was only available in abstract form at the time.

One author reported receiving grants and personal fees from a pharmaceutical company during the conduct of the study, and another reported receiving grants and personal fees outside the submitted work. No other conflicts of interest were reported.

SOURCE: Cummings SR et al. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.2779.

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