For patients with osteoporosis, drug treatments with bisphosphonates, particularly zoledronate, may not reduce overall mortality rates, according to a meta-analysis of 38 clinical trials of drug treatments for osteoporosis among 101,642 patients. Consequently, the authors of the analysis in JAMA Internal Medicine recommend that these medications be restricted to decreasing fracture risk.
The investigators searched Science Direct, MEDLINE, Embase and the Cochrane Library for randomized, placebo-controlled clinical trials published or in press between 2010 and April 2019; conference abstracts from annual osteoporosis society meetings were also included.
Of the 2,045 records screened, only 1.8% were included in the meta-analysis. The four inclusion criteria were clinical trials that were randomized, double-blind and placebo-controlled; drug treatments with proven antifracture efficacy; agents used at the approved dose for treatment of osteoporosis; and study duration of at least 1 year.
No significant connection was found between all drug treatments for osteoporosis and overall mortality rate: risk ratio (RR) = 0.98; 95% confidence interval (CI): 0.91 to 1.05 (I2 = 0%). Clinical trials of bisphosphonate treatment also showed no significant association with overall mortality: RR = 0.95; 95% CI: 0.86 to 1.04. The same relationship held true for zoledronate treatment as well: RR = 0.88; 95% CI: 0.68 to 1.13. However, there was evidence for heterogeneity of the overall results: I2 = 48.2%.
A prior review of a small number of clinical trials of drug treatments for osteoporosis in Osteoporosis International indicated there may be a link with increased mortality, reflecting the comorbidity and age of the participants.
But the current larger analysis found “no significant association between the mortality rates in the placebo groups of the clinical trials and the association of treatment with mortality for all drug treatments,” the authors wrote. There was less certainty, though, for the association between intravenous zoledronate treatment and mortality rates because of the heterogeneous results of the clinical trials. Specifically, two large studies of zoledronate treatment found 28% and 35% reductions in mortality, respectively, which were not observed in other clinical trials.
Similarly, observational studies reported 25% to 60% reductions in total mortality rates, which were too great of a reduction to attribute to a decrease in fracture risk. “Therefore, the reduced mortality rates would likely be owing to the direct biological effects of these treatments rather than the reduced fracture risk,” the authors wrote. In addition, observational studies of patients receiving bisphosphonate therapy who had lower mortality may not have measured confounding factors that could have contributed to this lower mortality.
The apparent reduction in mortality may be the power of the placebo effect, for which the authors cite a Women’s Health Initiative study which showed that women in the placebo group who had at least 80% adherence to placebo treatment attained a 36% lower overall mortality than those with less than 80% adherence, despite adjusting for multiple potential confounding factors. The placebo effect is especially apropos for treating osteoporosis because only roughly 50% of women who take oral medications for the condition continue their regimen for 1 year, with even fewer continuing longer.
The authors said additional studies are needed to elucidate whether treatment with zoledronate reduces mortality rates in patients with osteoporosis.