Bisphosphonates Lower Fracture Risk, but Not Mortality

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In patients with osteoporosis, bisphosphonate treatment reduces fracture risk but it may not reduce mortality rates, according to a meta-analysis published in JAMA Internal Medicine.

“Drug treatments, including treatment with bisphosphonates, for osteoporosis should be recommended only for the prevention of fracture and not for any additional reduction in mortality,” wrote Steven R. Cummings, M.D., of the San Francisco Coordinating Center in California, and colleagues.

Most fracture types are associated with increased mortality, and the purpose of treating osteoporosis patients with medication is to reduce the risk of fracture. Since the increased risk for both fracture and mortality may be due to the patients’ poor health or other factors, it is not clear whether preventing fractures can reduce fracture associated mortality. Research has suggested that drug therapies for patients with osteoporosis, particularly treatments with bisphosphonates or zoledronate, reduced mortality in addition to decreasing fractures. This finding would suggest that drug treatments should be recommended to reduce overall mortality, regardless of a patient’s risk of fracture.

In this meta-analysis of 38 randomized placebo-controlled trials, including a total of 101,642 participants, the researchers evaluated whether drug treatments for osteoporosis, particularly bisphosphonates or zoledronate, reduced the overall mortality rate.

All drug treatments for osteoporosis and overall mortality rate showed no significant association (risk ratio [RR], 0.98; 95% CI, 0.91-1.05), which was also the case for bisphosphonate treatment (RR, 0.95; 95% CI, 0.86-1.04). While, zoledronate treatment showed no association with overall mortality rate (RR, 0.88; 95% CI, 0.68-1.13), this finding was less certain because heterogeneity was noted between the results of the clinical trials. Two large clinical trials of zoledronate found 28 percent and 35 percent reductions in mortality that were not observed in other studies.

Bisphosphonates may not reduce all-cause mortality in addition to reducing fracture risk, because “these drugs bind almost exclusively to bone, are cleared from the blood to extremely low or undetectable levels within 24 hours of administration, and are only detectable in extremely low concentrations in tissues other than bone,” the authors wrote. “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.”

This meta-analysis was much larger than a 2010 meta-analysis reporting a 10 percent reduction in mortality, and it explored subgroups of drug therapies, along with clinical trials lasting at least three years. While a more recent meta-analysis of bisphosphonate treatment studies also reported a 10 percent overall reduction in mortality, the analysis included only 22 trials for osteoporosis.

Meanwhile, a meta-analysis of clinical trials of fracture liaison services also reported a reduction in mortality in patients with osteoporosis, a finding that that may have been explained by the increase in comprehensive health care provided rather than to drug therapy. While other studies have suggested that the association between drug treatments for osteoporosis and reduced mortality rates remains after adjusting for several potential confounders, these associations may be explained by other, unmeasured confounding factors. For example, study participants who took drug treatments for the prevention of fracture may have had better health and nutrition, and exercised more frequently than those who did not take such drug treatments.

Of note, this meta-analysis did not support the claim that drug treatments for osteoporosis may reduce overall mortality rates due to causes other than decreased fracture risk, but it did not exclude the possibility that decreasing the fracture risk may reduce the mortality caused by those fractures.

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REFERENCE

Steven R. Cummings, Li-Yung Lui, Richard Eastell, et al. “Association Between Drug Treatments for Patients With Osteoporosis and Overall Mortality Rates: A Meta-analysis.”JAMA Internal Medicine. Aug. 19, 2020. doi:10.1001/jamainternmed.2019.2779