From the Journals

Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large



Long-term use of alendronate and zoledronic acid for more than 3 years reduces the rate of vertebral fracture in treatment-naive postmenopausal women with notable, yet rare, adverse events, but too little evidence exists to make determinations on the long-term benefit/risk profile of other bisphosphonates or other osteoporosis drugs besides raloxifene and oral hormone therapy, according to a report coming out of a recent National Institutes of Health workshop.

Dr. Albert Siu, Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York

Dr. Albert Siu

This situation leaves a large research gap that authors of an accompanying position paper hope to bridge with recommendations for studying therapy discontinuation and drug holidays during long-term osteoporosis drug treatment.

The NIH’s Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention outlined the findings of the systematic review of long-term osteoporosis drug treatment (ODT), which was commissioned by the NIH Office of Disease Prevention. The systematic review and a position paper summarizing the workshop were published April 23 in Annals of Internal Medicine.

“Clinicians and patients need increased information on benefits and risks to inform shared decision making about the use of these treatments, taking into account patients’ values and preferences,” Albert Siu, MD, of the Brookdale Department of Geriatrics and Palliative Medicine at the Icahn School of Medicine at Mount Sinai in New York, and his colleagues wrote in the position paper (Ann Intern Med. 2019 Apr 23. doi: 10.7326/M19-0961). “The research ... is urgently needed to advance prevention of osteoporosis-related mortality and morbidity.”

In the systematic review, by a group of researchers separate from the workshop, 48 studies were identified (35 trials, 13 observational studies) that compared men and postmenopausal women 50 years or older who used treatments such as alendronate, raloxifene, zoledronic acid, and hormone therapy. The researchers found that use of alendronate for 4 years reduced the rate of clinical fractures (hazard ratio, 0.64; 95% confidence interval, 0.50-0.82) and radiographic vertebral fractures (HR, 0.50; 95% CI, 0.31-0.82) in women with osteoporosis. Raloxifene use for 4 years reduced the rate of clinical vertebral fractures (relative risk, 0.58; 95% CI, 0.43-0.79) and radiographic vertebral fractures (RR, 0.64; 95% CI, 0.53-0.76) but not nonvertebral fractures. Zoledronic acid use for 6 years was associated with a lower rate of nonvertebral fractures (HR, 0.66; 95% CI, 0.51-0.85) and clinical vertebral fractures (HR, 0.41; 95% CI, 0.22-0.75) in women with both osteoporosis and osteopenia. Estrogen-progestin use for 5.6 years and unopposed estrogen for 7 years was associated with clinical fracture reduction in women with unspecified osteoporosis and osteopenia when compared with placebo (Ann Intern Med. 2019 April 23. doi: 10.7326/M19-0533).

Controlled observational studies collectively show that long-term use of alendronate and of bisphosphonates as a class increased risk for radiologically confirmed atypical femoral fracture but by a small absolute amount, with less evidence for risks of subtrochanteric or femoral shaft fractures without radiologically confirmed atypical femoral fracture features and osteonecrosis of the jaw. However, there were no eligible observational studies with long-term use of zoledronic acid that evaluated risk for these adverse events.

Long-term raloxifene therapy was associated with a threefold increased risk for deep venous thrombosis and a three- to fourfold increased risk for pulmonary embolism, although not all results were statistically significant, the researchers said. In two long-term trials, both estrogen and estrogen-progestin compared with placebo increased risk for cardiovascular disease and cognitive impairment. Estrogen-progestin also increased risk for invasive breast cancer.

The researchers also studied abaloparatide, denosumab, ibandronate, risedronate, and teriparatide, but noted there were insufficient data to show the long-term effects of their use on fractures and other harms.

Dr. Siu and coauthors on the position paper made the following recommendations with regard to future research on long-term ODT:

• Using “innovative designs and approaches” for new research such as modeling studies, clinical trials, and observational studies of existing and potential treatments.

• Evaluating new agents or multicomponent interventions, such as fracture liaison services and oral care, that do not carry the downsides of antiresorptive therapies.

• Researching and preventing atypical femoral fracture and osteonecrosis of the jaw, particularly when associated with long-term denosumab or bisphosphonate use.

• Determining which patients are indicated for drug holidays, sequential therapies, and strategies for avoiding serious adverse events.

• Studying barriers to ODT.

“When we have information on these outcomes, such as how medication use after a fragility fracture is linked to future fractures or survival rates, we need to understand how to convey that information to patients so they can make more informed decisions about their care,” noted Dr. Siu and colleagues.

In an editorial related to both the position paper and the systematic review, Carolyn J. Crandall, MD, of the University of California, Los Angeles, agreed that clinical trial data do not answer questions about shared decision making for women with multiple comorbid conditions, the long-term effects of ODT with regard to rare fracture risk, and which patients are well-suited for drug holidays.

Dr. Carolyn J. Crandall, professor of medicine at the University of California, Los Angeles

Dr. Carolyn J. Crandall

“The National Institutes of Health should support research to answer these high-impact clinical questions, in addition to encouraging approaches for clinicians to determine which individual patients are at greater risk for harms related to long-term bisphosphonate use,” she said. “The need to rigorously study patient preferences in the context of ODT is pressing because of the complex dosing instructions of oral bisphosphonates and the dramatic underutilization of ODT among persons who have already had a vertebral or hip fracture.”

The systematic review was funded by the National Institutes of Health and the Agency for Healthcare Research and Quality. The authors of the position paper and Dr. Crandall reported no conflicts of interest.

SOURCE: Siu A et al. Ann Intern Med. 2019 April 23. doi: 10.7326/M19-0961.

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