Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports that he is a consultant for and receives grant/research support from Bayer, Abbvie, ContraMed, and Merck; receives grant/research support from Medicines 360, Agile, and Teva; and is a consultant for MicroChips and Evofem.
SYNOPSIS: A randomized trial demonstrated a reduced risk of fragility fractures in high-risk women with osteoporosis treated monthly with the monoclonal antibody romosozumab compared with weekly alendronate.
SOURCE: Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 2017;377:1417-1427.
Fragility fractures that occur in women with osteoporosis lead to significant morbidity, and prevention of fractures represents the primary reason for treatment. This recent publication from the New England Journal of Medicine presents results from a multicenter, international, randomized, double-blind trial comparing standard therapy with weekly oral alendronate (70 mg) to monthly subcutaneous romosozumab (210 mg) for 12 months. After completion of this first year of study, all subjects entered an open-label observation period for an additional 12 months during which they received weekly oral alendronate (70 mg). Subjects also received oral vitamin D (600 to 800 IU) and calcium (500 to 1,000 mg) daily. The study enrolled postmenopausal women aged 55 to 90 years who were at high risk for fragility fracture defined as: 1) bone mineral density T score of -2.5 or less at the total hip or femoral neck and at least one moderate/severe vertebral fractures or two mild vertebral fractures; or 2) T score of -2.0 or less at the total hip or femoral neck and either two or more moderate or severe vertebral fractures or a fracture of the proximal femur sustained 3 to 24 months before randomization. Subjects underwent bone density screens and lateral X-rays of the spine every 12 months to assess incidence of new fractures. Women < 75 and ≥ 75 years of age were randomized in separate groups.
The primary trial endpoints were the cumulative incidence of new vertebral and other clinical fractures at 24 months. Key secondary endpoints included bone mineral density at the lumbar spine, total hip, and femoral neck at 12 and 24 months and the incidence of nonvertebral fractures (including hip). The sample size had sufficient power to detect a 30% lower risk of clinical fracture in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group at 24 months.
A total of 4,093 women underwent randomization, with 3,654 (89.3%) completing 12 months of the trial and 3,150 (77.0%) completing the 24-month primary analysis period. Dropout between the treatment groups was non-differential. The study enrolled a high-risk group; the mean age of participants was 74.3 years, 99.0% had a previous osteoporotic fracture, 96.1% had a prevalent vertebral fracture, and the mean bone mineral density T scores were -2.96 at the lumbar spine, -2.80 at the total hip, and -2.90 at the femoral neck.
After 24 months, subjects randomized to treatment with romosozumab followed by alendronate showed a 48% lower risk of new vertebral fractures than those receiving alendronate alone (6.2% vs. 11.9%; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.40-0.66), and a 27% lower risk of clinical fracture (9.7% vs. 13%; HR, 0.73; 95% CI, 0.61-0.88). Significantly fewer hip fractures occurred in the romosozumab-to-alendronate group (2% vs. 3.2%; HR, 0.62; 95% CI, 0.42-0.92). Women who received romosozumab also showed greater improvement in bone mineral density from baseline at all measured sites and at all time points. Romosozumab treatment increased levels of the bone-formation marker P1NP and decreased levels of the bone-resorption marker β-CTX within 12 months. In contrast, treatment with alendronate alone decreased both P1NP and β-CTX.
Although the incidences of adverse events and serious adverse events were similar overall between the two treatment groups, serious cardiovascular adverse events occurred more frequently in the romosozumab group (2.5% vs. 1.9%; significance not provided in the paper) during the 12-month randomization interval. The authors concluded that the results support the use of romosozumab in women at high risk of fragility fractures, with a decrease in fracture risk compared to bisphosphonate therapy alone.
Because of concerns regarding postmenopausal hormone replacement therapy, in the future we may find more women presenting with osteoporosis and vertebral fractures. How to best manage these women remains controversial. While effective at preventing bone loss, bisphosphonates do not stimulate bone formation, and concerns over atypical femoral fractures and osteonecrosis of the jaw have reduced the enthusiasm for their use. Rapid bone loss occurs at menopause due to the absence of estrogen-regulated modulation of bone remodeling. In addition to direct effects on bone, estrogen also has important effects on vitamin D metabolism, and the intestinal absorption and renal excretion of calcium.1 We have level 1A evidence that postmenopausal estrogen replacement therapy does prevent hip and other fractures.2,3 Although women using raloxifene had a reduction in spinal compression fractures, this important reduction in hip fracture was not observed.4,5 A reduction of nonvertebral fracture also has been reported with bazedoxifene, but the absolute number of hip fractures seen in the study was small and not different from placebo or raloxifene.6 Bisphosphonates have been shown to reduce vertebral and non-vertebral fracture risk, but the data are less convincing7 for primary prevention of hip fracture. This leads me to conclude that women at risk for fracture without contraindications to estrogen therapy should be strongly counseled to consider this benefit for primary prevention. Women with osteoporosis or prevalent fractures require enhanced therapy.
Romosozumab, a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation and decreases bone resorption. The development of romosozumab is a triumph of molecular biology. Scientists investigating sclerosteosis, a rare genetic disorder with high bone mass, determined that a mutation in SOST, the gene that encodes sclerostin caused of the disorder. Sclerostin is produced by osteocytes and inhibits bone formation and enhances bone resorption. Romosozumab promotes bone formation and slows resorption by blocking sclerostin activity.
In the placebo-controlled, Phase III, randomized Fracture Study in Postmenopausal Women with Osteoporosis (FRAME), one year of monthly romosozumab treatment increased bone mineral density at the lumbar spine by 13% and decreased the risk of new vertebral fracture by 73%.8 The study by Saag et al extends these observations by focusing on a group of women at extremely high risk of fracture. Although the results were impressive, the significance is blurred by the assessment of the primary endpoint at 24 months, after one year of use of alendronate. Still, the reduction in fracture incidence is impressive and deserves attention.
All new therapies carry the potential for risk and benefit. Our > 50-year experiment with estrogen and progestogen therapy leaves us well acquainted with these trade-offs. A major concern with romosozumab is the twofold increase in the risk of cardiovascular complications at one year. This increase was not seen in the placebo-controlled study. Although some evidence of a protective effect of alendronate exists, a potential mechanism for harm exists as sclerostin is expressed in vascular smooth muscle and may promote remodeling in vascular tissue.9 We also can expect that the cost associated with this injectable monoclonal antibody treatment to be significant. As is typical in medicine, there are no panaceas.
- Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
- Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712.
- Ensrud KE, Stock JL, Barrett-Connor E, et al. Effects of raloxifene on fracture risk in postmenopausal women: The Raloxifene Use for the Heart Trial. J Bone Miner Res 2008;23:112-120.
- Agnusdei D, Iori N. Raloxifene: Results from the MORE study. J Musculoskelet Neuronal Interact 2000;1:127-132.
- Silverman SL, Christiansen C, Genant HK, et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: Results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 2008;23:1923-1934.
- Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008;Jan 23:CD001155.
- Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375:1532-1543.
- Rosen CJ. Romosozumab — Promising or practice changing? N Engl J Med 2017;377:1479-1480.