Wednesday, 13 Nov 2019

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Osteoporosis Tx: Good for Bones, but Not for Cutting Death Risk

Osteoporosis treatments were not linked with reduced overall mortality, according to a meta-analysis of placebo-controlled trial data.

Looking at data from 38 clinical trials, there was no significant association found between all drug-based osteoporosis treatments and overall mortality rate (risk ratio 0.98, 95% CI 0.91-1.05), reported Steven Cummings, MD, of the San Francisco Coordinating Center, and colleagues.

With no evidence of heterogeneity (I2=0%), this analysis included a wide variety of osteoporosis treatments, including bisphosphonates, denosumab (Xgeva, Prolia), selective estrogen receptor modulators, parathyroid hormone analogues, the investigational cathepsin K inhibitor odanacatib, and romosozumab (Evenity), they stated in JAMA Internal Medicine.

When the analysis was narrowed down to just 21 clinical trials on bisphosphonate treatment, there still was no relationship between treatment and mortality risk (RR 0.95, 95% CI 0.86-1.04), which led the authors to suggest that "bisphosphonate treatment ... should only be recommended to reduce fracture risk."

"It is not clear whether there are biological mechanisms that could lead to an association between bisphosphonate treatments and overall mortality rates, particularly because the concentration of bisphosphonates in blood and tissue other than bone is undetectable or very low within days after bisphosphonate administration," explained Cummings' group.

Similarly, the six clinical trials looking solely at treatment with the bisphosphonate derivative zoledronate (Zometa, Reclast) also did not show any link with mortality rate (RR 0.88, 95% CI 0.68-1.13). However, the authors pointed out there was a high level of heterogeneity across these trials (I2=48.2%), limiting this finding.

"In particular, two large clinical trials of zoledronate treatment observed 28% and 35% reductions in mortality that were not observed in other clinical trials," they wrote.

Notably, all but five studies included in the analysis lasted 3 years or less, thereby obscuring any mortality benefits developing only with longer follow-up. On the other hand, there was no suggestion of survival improvement in those five studies, which had follow-up of 4-6 years.

The researchers searched the Science Direct, MEDLINE, Embase, and the Cochrane Library database, yielding data on over 100,000 individuals. They additionally conducted seven subgroup exploratory analyses. One subgroup analysis in particular looked only at those treated with alendronate, which also didn't find any link with mortality risk (RR 1.00, 95% CI 0.71-1.40).

Several other subgroup analyses came to similar conclusions regarding mortality risk, including trials restricting to patients that received osteoporosis treatment for 3-plus years (RR 0.97, 95% C 0.88-1.08). There was also no link with morality risk when restricting the analysis to clinical trials lasting ≥3 years of bisphosphonate treatment with or without zoledronate (RR 0.94, 95% CI 0.83-1.06; RR 1.00, 95% CI 0.89-1.12, respectively).

When the researchers assessed trials that only looked at nitrogen-containing bisphosphonate treatments -- alendronate (Binosto, Fosamax), risedronate (Atelvia, Actonel), ibandronate (Boniva), and zoledronate -- there was a slight trend toward a reduced mortality risk with this class, though this didn't quite reach statistical significance (RR 0.90, 95% CI 0.81-1.00, P=0.06).

"Although this meta-analysis did not support the claim that drug treatments for osteoporosis have an association with reduced overall mortality rates owing to causes other than decreased risk, it did not exclude the possibility that decreasing the risk of fractures may be associated with reducing the mortality caused by those fractures," the researchers concluded. For instance, "if hip and vertebral fractures were associated with a preventable 20% mortality rate, and drug treatment reduced the absolute risk of these fractures by 10%, then this treatment would have reduced the mortality rate by only 2%, a small effect that would have been detectable only with more data than was available from current clinical trials," they added.

But "prevention of fracture would have remained the only rationale for prescribing drug treatments to patients with osteoporosis," they stated.

Cummings' group ultimately recommended that osteoporosis treatments "should only be recommended for reducing fracture risk in accordance with clinical guidelines," referencing the National Osteoporosis Foundation and Endocrine Society's practice guidelines.

Disclosures: 
The author has no conflicts of interest to disclose related to this subject
The author has an ownership interest in this subject

Rheumatologists' Comments

Why I love evidence based medicine. 8 days ago nitrogenated bisphosphonates improved mortality. Now they don't.

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