Research Needed on Long-Term Osteoporosis Drug Therapies

By Will Boggs MD

April 23, 2019

NEW YORK (Reuters Health) - A variety of drugs are effective for preventing osteoporotic fractures, but there are gaps in the evidence supporting their safety and effectiveness beyond three years, according to a National Institutes of Health Pathways to Prevention Workshop.

Clinical trials have demonstrated the safe and effective use of osteoporosis drug therapy in reducing the incidence of vertebral fractures and, possibly, hip fractures in postmenopausal white women. Evidence regarding rare and serious complications, including atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), is limited. There is little information regarding the safety and effectiveness of anabolic agents beyond two years.

For these and other reasons, Dr. Albert Siu from Icahn School of Medicine at Mount Sinai, New York and colleagues conducted an NIH-sponsored workshop in October 2018 to identify research opportunities to fill gaps in our understanding of long-term (>3 years) treatment of osteoporosis.

First, they recommend the use of innovative designs and approaches for assessing both existing and potential treatments and optimizing duration. These should include comparative effectiveness trials and observational studies with diverse populations.

Second, future clinical trials should evaluate new agents or multimodal interventions that might lack the side effects of current treatments and provide greater efficacy.

Third, more research using standard case definitions is needed to prevent and characterize AFF and ONJ, according to the report online April 22nd in Annals of Internal Medicine.

Fourth, more drug-and patient-specific studies are needed to determine which patients are optimal candidates for drug holidays and sequential therapies and to identify strategies for mitigating serious adverse events associated with long-term drug use.

Finally, more research is needed on barriers to osteoporotic drug therapy, specifically addressing the efficacy of different management approaches, factors that influence decisions about osteoporotic drug therapy use, patient and provider attitudes, and shared decision-making among patients, providers, family members, and other caregivers.

"The research outlined above is urgently needed to advance prevention of osteoporosis-related mortality and morbidity," the workshop panel concludes.

In a related article, Dr. Howard A. Fink from University of Minnesota and Minneapolis VA Health Care System, Minneapolis, Minnesota and colleagues reviewed long-term drug therapy and drug discontinuations and holidays for osteoporosis fracture prevention.

Dr. Fink told Reuters Health by email, "From the studies included in our review, we didn't find clear evidence to guide which patients are more likely to benefit with continued treatment versus discontinuation, or regarding the optimal timing, duration or monitoring of patients during drug holidays. Research on these questions is important to help inform future patient and clinician treatment decisions."

The review included 48 publications. All 35 clinical trials enrolled only postmenopausal women, most with osteoporosis defined by bone mineral density or vertebral fraction history, and the proportion of women in the 13 observational studies was 84% to 100%.

"In osteoporotic women who haven't previously been treated with bisphosphonate medications, when compared to placebo, the reduction in typical symptomatic fractures with alendronate for up to four years or zoledronic acid for up to six years appears to greatly outweigh the increase in risk of atypical femoral fractures," Dr. Fink said. "Reductions in symptomatic fractures with zoledronic acid compared with placebo also appear to apply to older women with osteopenia. However, in women who have been treated with bisphosphonates for several years, the balance of benefits to harms of continued bisphosphonate treatment versus discontinuation is less clear."

"Longer term bisphosphonate treatment appears to prevent less fracture morbidity than initial bisphosphonate treatment, and the risk of rare atypical femoral fractures becomes somewhat less rare," he concluded.

Dr. Sundeep Khosla from Mayo Clinic, Rochester, Minnesota, who recently reviewed developments and ongoing challenges in osteoporosis treatment, told Reuters Health, "The research recommendations do point to important gaps in knowledge regarding osteoporosis treatments, but these are certainly not easy to address. Although many investigators would be interested in pursuing these research directions, the critical barrier remains being able to fund these types of studies. As such, it may take a concerted effort by NIH and perhaps other federal agencies, as well as potentially foundations, to provide the resources to do the types of studies suggested in this perspective."

"There has, in fact, been enormous progress in the development of drugs available to treat osteoporosis over the past 30 years," he said. "We have gone from mainly using estrogen therapy in the late 1980s to now having a broad range of drugs that either inhibit bone resorption (e.g., bisphosphonates, denosumab) or stimulate bone formation (teriparatide, abaloparatide) or both (romosozumab). The problem now, as noted in the perspective, is implementation strategies - how do we get physicians to appropriately prescribe and patients who really need these drugs to appropriately take them."

Dr. Erik Fink Eriksen from Oslo University Hospital in Norway, who has extensively researched the treatment of osteoporosis, told Reuters Health by email, "I agree that some of the gaps identified (reasons for patients denying treatment, perception of risk benefit ratios among patients) are very important. However, unless trials are financed from public sources, there is very little incentive to take up these recommendations. Currently, the pharmaceutical industry is putting very little emphasis on developing new osteoporosis drugs. Only a few companies have ongoing development programs pertaining to osteoporosis treatments."

"Doctors should take more time to explain the excellent risk benefit ratio for and efficacy of osteoporosis drugs," he said. "It is amazing that very rare side effects (ONJ, AFF) play such a dominating role in the decision making for patients. They have to be put in perspective. This is very different from other therapeutic areas (e.g., cardiovascular disease)."

"The report does not mention at all the mortality benefits shown in now two randomized trials with bisphosphonates," Dr. Eriksen said. "Since then also the paper by Read et al. (NEJM 2019) showed significant reduction of cancer (30%) in women treated with zoledronic acid for six years. This data should be put in perspective to the AFF and ONJ data, as well as a total of five observational studies showing mortality benefit in bisphosphonate users."

Dr. Siu did not respond to a request for comments.

SOURCE:, and

Ann Intern Med 2019.