A meta-analysis suggests that drug treatments for osteoporosis should be recommended only for the prevention of fracture and not for any additional reduction in mortality.

The purpose of treating patients with osteoporosis is primarily to reduce the risk of fracture and subsequent pain and disability. Some types of fractures, such as hip fractures, are accompanied by an increased risk of mortality that might be partly avoided by preventing the fracture. However, research has suggested that treatments for osteoporosis may directly improve overall mortality rates not by preventing fractures. “Several observational studies have reported that patients with osteoporosis who received drug treatments, most notably bisphosphonates, experienced 25% to 60% reductions in overall mortality rates,” says Steven R. Cummings, MD. “If this were true, then clinicians should be prescribing these therapies to all older patients, regardless of their fracture risk. These observed reductions in mortality are too large to be attributed to fewer fractures. It is unlikely that these treatments substantially reduce all-cause mortality in addition to reducing fracture risk.”

A Comprehensive Meta-Analysis

To examine this correlation more closely, Dr. Cummings and colleagues published a systematic review and meta-analysis in JAMA Internal Medicine. The study assessed 38 randomized placebo-controlled clinical trials of drug treatments for osteoporosis to evaluate if these treatments, particularly bisphosphonates and zoledronate, reduced overall mortality. Data were available on 101,642 unique participants from the 38 clinical trials in the meta-analysis, with 45,594 patients randomized to placebo and 56,048 to treatment. Of all the clinical trials in the meta-analysis, 21 compared bisphosphonates with placebo and 6 compared zoledronate with placebo.

“Our results showed that there was no significant association between all drug treatments for osteoporosis and overall mortality rate, most notably bisphosphonates,” says Dr. Cummings (Table). “There was less certainty regarding the association of intravenous zoledronate treatment with overall mortality. This is because two randomized trials found that treatment with zoledronate also reduced mortality, whereas four other trials found no such reduction. The heterogeneity of the meta-analysis of zoledronate and mortality highlights a need for more data from large placebo-controlled clinical trials to establish if zoledronate directly reduces mortality in addition to decreased fracture risk.”

Contextualizing the Data

According to the study, the reduced mortality rates seen with osteoporosis treatments in previous research may be due to reasons other than reducing fracture risk. Results of the metaanalysis suggest that studies reporting patients who received bisphosphonates had lower mortality rates may not have measured confounding factors that could have contributed to these findings. “Our data demonstrate that ‘real world’ observational studies on the effect of osteoporosis treatments and reductions in mortality can be misleading,” Dr. Cummings says. “This is similar to what has been seen with previous research in which observational studies produced misleading results, suggesting that estrogen therapy and vitamin D reduced mortality, while randomized clinical trials proved that they had no effect.”

The apparent reductions in mortality among patients taking osteoporosis treatments in observational studies may be an example of the “healthy adherer effect,” which has been seen in studies in which participants who adhered to placebo treatment in clinical trials had lower mortality than those with poor adherence. Other data suggest that decreased mortality in patients taking osteoporosis treatments may be because they receive more comprehensive care from some healthcare services rather than drug therapy itself. There is no clear biological mechanism that could lead to an association between osteoporosis treatments and overall mortality rates.

“It should be noted that preventing fractures, such as hip fractures, is likely to prevent some of the excess death due to the fracture,” says Dr. Cummings. “Our study did not exclude that possibility. To demonstrate that relatively small effect would require much more data. The result of our analysis supports that drug treatments for patients with osteoporosis be recommended solely for reducing fracture risk in accordance with clinical guidelines from respected groups like the National Osteoporosis Foundation and the Endocrine Society.” Contributor Steven R. Cummings, MD Director, San Francisco Coordinating Center Research Scientist California Pacific Medical Center Research Institute Professor of Medicine, Epidemiology and Biostatistics, Emeritus University of California San Francisco Table Summarizing Key Findings A meta-analysis of 38 clinical trials  demonstrated the following risk ratios and  95% confidence intervals for osteoporosis   and overall mortality rate: Domain Risk Ratio 95% Confidence Interval All drug  treatments  0.98 0.91-1.05 Bisphosphonate  treatment 0.95 0.86-1.04 Zoledronate  treatment 0.88 0.68-1.13 Source:  Adapted from: Cummings SR, et al.  JAMA Intern Med. 2019;179(11):1491-1500. Osteoporosis Treatments and Overall Mortality A