Are Osteoporosis Drugs Linked With Survival? Debate Casts Doubt

Marlene Busko

October 11, 2018

MONTREAL, QUEBEC — In a poll taken prior to the debate here at the American Society for Bone and Mineral Research (ASBMR) 2018 Annual Meeting, almost three quarters (72%) of the bone doctors agreed with the motion that "osteoporosis treatments are associated with improved mortality [rates]."

But afterward, only 56% still agreed.

So Steven R. Cummings, MD, from the University of California, San Francisco, who argued against the motion was awarded the society's "Gold Humerus" award, since he convinced more people to change their minds.

Roland Chapurlat, MD, PhD, from Université de Lyon and Hôpital E. Herriot, in France, presented a slew of slides of studies to support his case that osteoporosis drugs are associated with lower mortality.

But Cummings, who followed, was very persuasive in raising doubts about the strength of the evidence. The decreased mortality rate during follow-up in two meta-analyses of randomized controlled trials was barely statistically significant, he noted. And in a more recent meta-analysis by his group, there was no significant mortality benefit from bisphosphonates.  

An audience member pointed out that treatment for osteoporosis also includes, for example, exercise — which neither debater had mentioned and is known to be associated with longer life.

Moreover, the debate topic was whether treatment is associated with a lower mortality rate, not whether it leads to improved survival, so people should vote "for" the motion, the delegate argued.

However, it was too late. Cummings had been too convincing.

"Ten Percent Mortality Benefit" vs "Evidence Is Just Not There"

In the end, more than half the audience still believed that treatment for osteoporosis is associated with improved mortality, cochair Jane A. Cauley, DrPH, University of Pittsburgh Graduate School of Public Health, Pennsylvania, pointed out to Medscape Medical News.

Although unmeasured confounders may be present, "I believe there is an association," said Cauley, who was also the principal investigator of several large cohort trials including the Study of Osteoporotic Fracture (SOF) and Osteoporotic Fracture Risk in Older Men (MrOS) study.

Meanwhile, Chapurlat told Medscape Medical News that although a number of observational studies show a high mortality benefit with bisphosphonates, "randomized controlled trials must be favored because they are less biased, and from those we found several trials showing a small benefit."

"We are prescribing these drugs to prevent fracture" which is their indication, he continued, "but they might have a small additional benefit in terms of mortality." The mortality benefit, according to Chapurlat, is "probably around 10%."

Looking at the bigger picture, Cummings told Medscape Medical News that he believes "our treatments for osteoporosis now can have substantive benefits in reducing [patients'] disability and pain. Given to people at high risk of fracture, they have really terrific benefits with very few and rare adverse effects."

However, "they're not yet ready to prescribe to everybody who's old, who's got disease," he emphasized.

Building a Case for Lower Mortality Rates

Chapurlat began by citing the strong association between osteoporosis drugs and lower mortality in the Dubbo Osteoporosis Epidemiology Study of men and women aged 60 years and older. The patients had better survival after a fracture if they received osteoporosis therapies (J Clin Endocrinol Metab.  2011;96:1006-1014).

In this epidemiologic study, "in men over 70, mortality decreased by 70%," Chapurlat noted, so "there must be something."

On the other hand, there could be a healthy user bias, he acknowledged, where the people who took the drug were healthier, or perhaps less likely to skip or stop taking their medication.

However, in the randomized placebo-controlled HORIZON Recurrent Fracture Trial, Lyles and colleagues showed that an annual infusion of zoledronic acid starting after repair of a hip fracture was associated with a reduced rate of new clinical fractures and 28% improved survival (N Engl J Med. 2007;357:1799-1809).

And in a meta-analysis, Bolland and coauthors reported that there was an 11% reduced mortality rate with osteoporosis therapies (J Clin Endocrinol Metab. 2010;95:1174-1181).

These were older, frailer individuals with osteoporosis who are at high risk of fracture and "would benefit the most," Chapurlat noted.

In another meta-analysis, Kranenburg and colleagues reported a 10% decrease in mortality in patients with osteoporosis treated with bisphosphonates (Atherosclerosis. 2016;252:106-115).

Moreover, Chapurlat added, Ian Reid presented a study of zoledronate given every 18 months at the ASMBR meeting that showed lower mortality in patients in the treatment group, as reported by Medscape Medical News.

"Evidence from randomized placebo-controlled trials with bisphosphonates [shows they] are associated with reduced all-cause mortality," Chapurlat summarized.

These drugs may act on the immune system or affect atherosclerosis, researchers hypothesize.

All in all, "bisphosphonates are highly likely to reduce mortality in postmenopausal men and women with osteoporosis," he concluded

Counter Argument: "No Solid Evidence"

Cummings began his counterargument somewhat facetiously: "If treatments for osteoporosis also reduce mortality, they should be prescribed to older adults to reduce mortality regardless of fracture risk" or added to the water supply, he said.

To determine whether treatments for osteoporosis are associated with improved mortality requires randomized controlled trials, he stressed, as observational studies might have unknown confounders. 

Cummings noted that the meta-analysis by Kranenburg and colleagues cited by Chapurlat looked at 61 trials of bisphosphonates — 32 for cancer, 22 for osteoporosis, and seven for other diseases — and 16 of the trials did not have placebo controls.

And in the study by Bolland and colleagues, Cummings noted, the findings from a secondary analysis of the 10 trials of bisphosphonates for osteoporosis were of "borderline significance" for mortality (relative risk, 0.90; 95% CI, 0.81 - 1.0; P = 0.044).

Cummings cited results that were also presented at the meeting (Abstract 905) from a more rigorous meta-analysis of 24 trials from his research group. That trial showed bisphosphonate treatment for osteoporosis did not reduce mortality (relative risk, 0.96; 95% CI, 0.88 - 1.05).

Thus, the evidence for prescribing these drugs to improve survival, for example, in older people without osteoporosis "is just not there," so "let's not do it," he concluded.

Cauley and Chapurlat have reported no relevant financial relationships. Cummings has reported being a consultant for and receiving grant research support from Amgen.

American Society of Bone and Mineral Research Annual Meeting. September 28 - October 01, 2018. Montreal, Quebec. Debate "Treatment for Osteoporosis is Associated with Improved Mortality." Posters FRI-905, SAT-905.

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