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You are seeing one of your patients, a vivacious and active 60-year-old woman who works full time. She underwent bone densitometry testing, and the results show a T score of -2.7 at the femoral neck. Further, a short sentence on the report confirms a diagnosis of osteoporosis. Knowing that osteoporosis can lead to both vertebral and nonvertebral fractures that can affect quality of life and increase mortality risk, you must decide what to recommend.
Treatment of osteoporosis prevents further deterioration of bone mineral density. Although effective options are available, patients and physicians are often concerned about the side effects of bisphosphonates, which are antiresorptive agents, and have been approved for treatment of osteoporosis for more than a decade. Another type of medication, denosumab, a monoclonal antibody that inhibits osteoclast activation, has been shown to reduce vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. Denosumab was the first biologic therapy approved for osteoporosis treatment, but reservations exist about its widespread use because, as with bisphosphonates, osteonecrosis of the jaw and atypical femoral fractures have been reported. Yet another type of agent is now available, a monoclonal antibody developed to target and inhibit sclerostin, a protein synthesized by osteoclasts that negatively affects bone formation.
In this week’s issue of NEJM, Cosman and colleagues report the results of a phase 3, international, randomized, placebo-controlled trial that examined the effect of romosozumab on fracture risk. The investigators randomized 7180 ambulatory post-menopausal women, aged 55–90 years with T-scores of -2.5 to -3.5 at the total hip or femoral neck, to receive subcutaneous injections of romosozumab or placebo once monthly for 12 months. Most participants were recruited from Central and Latin America. Patients, investigators, and sponsors were blinded during the initial 12-month phase of the trial; during a follow-on phase, all participants received open-label subcutaneous injections of denosumab every 6 months for an additional 12 months. Thoracic and lumbar spine radiographs were obtained every 6 months during both phases of the study. The coprimary endpoints were the incidences of new vertebral fracture at 12 and 24 months.
During the first 12 months, the incidence of new vertebral fractures among the 3589 romosozumab recipients was 0.5%, compared to 1.8% among the 3591 placebo recipients, representing a relative decrease of 73% with romosozumab (risk ratio, 0.27; 95% CI, 0.16 to 0.47; P<0.001). During the same period, the relative decrease in the number of clinical fractures in the romosozumab group compared to placebo was 36% (P=0.008); however, a 25% relative decrease in nonvertebral fractures between groups was not significant (P=0.096). At 24 months, after the two groups transitioned to denosumab, the relative decrease in vertebral fractures among those treated with romosozumab remained significant at 75% (risk ratio, 0.25; 95% CI 0.16 – 0.40; P<0.001).
Rates of adverse events, such as arthralgia and cardiovascular events, were similar in the two groups; however, in the romosozumab group, seven cases of hypersensitivity were reported in the first year, as well as one atypical femoral fracture and two cases of osteonecrosis of the jaw (one during the first year and the other after one dose of denosumab).
Although romosozumab was associated with a reported relative decrease in the incidence of vertebral fractures, it is unclear whether bone biologists and clinicians will be satisfied with these outcomes. The editorialists, Dr. Clifford Rosen and Dr. Julie Ingelfinger, noted the “relatively rapid progress from discovery of sclerostin (1999) to the completion of a phase 3 trial (2016) with a sclerostin antibody” but raised concerns about romosozumab’s potentially limiting adverse events. Other factors to consider when considering biologic therapy for osteoporosis and other conditions include cost, access, and efficacy.
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Ramya Ramaswami is a 2016-2017 NEJM editorial fellow. She is a medical oncologist within the National Health Services of the United Kingdom. Ramya received her medical degree, postgraduate medical and oncology training from Imperial College London, and a masters in public health from Columbia University, Mailman School of Public Health. Her clinical and research interests include cancer prevention, viral driven cancers, as well as disparities and access issues in global oncology.