By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

In April, the FDA approved a first-in-its-class sclerostin inhibitor for the treatment of postmenopausal osteoporosis. Romosozumab is a humanized monoclonal antibody directed at sclerostin, a glycoprotein involved in bone metabolism. Romosozumab is produced using recombinant DNA technology and is distributed as Evenity.

INDICATIONS

Romosozumab is prescribed to treat osteoporosis in postmenopausal women at high risk for fracture.1 This includes those with a history of osteoporotic fracture or multiple risk factors for fracture or those who have failed or are intolerant to other available osteoporosis therapy.1

DOSAGE

The recommended dose is 210 mg (administered as two separate subcutaneous injections, one after the other) once every month for 12 doses.1 The dose should be administered by a healthcare provider in the abdomen, thigh, or upper arm. Adequate calcium and vitamin D intake during treatment is recommended. Treatment is limited to up to 12 monthly doses as the effect gradually wanes after 12 doses.2 Romosozumab is available as a prefilled syringe each containing 105 mg/1.17 mL.

POTENTIAL ADVANTAGES

Romosozumab offers a drug with dual actions of increasing bone formation and, to a lesser degree, decreasing bone resorption.1

POTENTIAL DISADVANTAGES

Romosozumab may increase the risk of myocardial infarction, stroke, and cardiovascular death.1 A meta-analysis of major adverse cardiovascular events conducted by the FDA showed a hazard ratio of 1.38 (95% confidence interval, 0.96-1.99; 1.3% vs. 0.9%).2 Treatment should not be started in patients who had a myocardial infarction or stroke within the preceding year. Osteonecrosis of the jaw and atypical subtrochanteric and diaphyseal femoral fractures have been reported.1 Hypocalcemia can occur; therefore, correcting hypocalcemia prior to initiating romosozumab and adequately supplementing with calcium and vitamin D are recommended during treatment. Hypersensitivity reactions have been reported. Eighteen percent of subjects developed antibodies to romosozumab; 4.7% of these were neutralizing.1 Romosozumab targets the canonical Wnt/beta-catenin signaling pathway, which also is involved in hematopoietic and immune cell development.3 It is unclear whether or how a 12-month treatment with romosozumab affects these pathways.

COMMENTS

Sclerostin inhibits bone formation and enhances bone loss.4 Inhibition of sclerostin increases bone formation and decreases bone resorption. The efficacy and safety of romosozumab was evaluated in two clinical trials in women with postmenopausal osteoporosis with bone mineral density (BMD) T-score ≤ -2.5 at the total hip or femoral neck.1,5,6 In Study 1, approximately 18% of subjects had previous vertebral fractures and 22% had previous nonvertebral fractures.5 Subjects were randomized to romosozumab 210 mg monthly (n = 3,591) or placebo (n = 3,589) for 12 months. In the open-label period, after the treatment period, both groups received subcutaneous denosumab 60 mg every six months for 12 months. Subjects also received supplemental calcium (500 mg to 1,000 mg) and vitamin D (600 IU to 800 IU) daily. The coprimary endpoints were cumulative incidences of new vertebral fractures at 12 and 24 months. New vertebral fracture rates at month 12 were 0.5% for romosozumab vs. 1.8% for placebo and 0.6% vs. 2.5% at month 24, respectively. These reflect a 73% and 75% relative risk reduction. There were no significant differences in the incidence of nonvertebral fractures. BMD scores were significantly higher compared to placebo at month 12 (difference of 12.7% at lumbar spine, 5.8% at total hip, and 5.2% at femoral neck). After discontinuation of romosozumab, BMD returned to roughly baseline levels within 12 months.7

In Study 2, subjects were at a higher risk for fractures (96% with previous vertebral fractures and 38% with nonvertebral fractures).6 Subjects were randomized to romosozumab (n = 2,046) or alendronate 70 mg every week (n = 2,047) for 12 months. After the double-blind period, all subjects received open-label oral alendronate. The incidence of new vertebral fracture was assessed at month 24. Through month 24, the new vertebral fracture rate was was 4.1% for romosozumab vs. 8% for alendronate (50% relative risk reduction). There was a 19% lower risk of nonvertebral fractures (8.7% vs. 10.6%). Hip fractures were lowered by 38% (2.0% vs. 3.2%). BMD differences at month 12 were 8.7% for lumbar spine, 3.3% for total hip, and 3.2% for femoral neck in favor of romosozumab. Differences were similar at month 24. The authors of a meta-analysis concluded that romosozumab showed a greater reduction of fracture risk and an increase in BMD vs. alendronate and teriparatide.8 In an open-label, Phase III study, romosozumab was more effective in increasing BMD than teriparatide in postmenopausal women transitioning from an oral bisphosphonate after at least three years of treatment.9

CLINICAL IMPLICATIONS

Osteoporosis is a common disorder affecting more than 10 million Americans.10 In postmenopausal women at high risk for fracture, the Endocrine Society recommends bisphosphonates as initial treatment, with denosumab as an alternative for initial treatment in postmenopausal women at high risk for fractures.11 Teriparatide and abaloparatide are recommended for those at very high risk for fracture. Romosozumab offers a new treatment option for women with high to very high risk for fractures. Sequential treatment with romosozumab reduced the risk of fracture and produced the greatest BMD increase among currently available treatment at 24 months.12 Its shortcomings are that treatment is limited to one year and there are potential cardiovascular risks. The FDA requires the drug’s manufacturer to conduct postmarketing assessment of cardiovascular safety. The price of romosozumab is $1,825 a month or $21,900 for a full 12-month course.

REFERENCES

  1. Amgen Inc. Evenity Prescribing Information, April 2019. Available at: http://bit.ly/2XK31a7. Accessed April 24, 2019.
  2. U.S. Food & Drug Administration. FDA Briefing Document. Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee, Jan. 16, 2019. BLA 761062 Romosozumab Amgen, Inc. Available at: http://bit.ly/2vgMEWj. Accessed April 24, 2019.
  3. Chicana B, et al. Wnt antagonists in hematopoietic and immune cell fate: Implications for osteoporosis therapies. Curr Osteoporos Rep 2019;17:49-58.
  4. Canalis E. Management of endocrine disease: Novel anabolic treatments for osteoporosis. Eur J Endocrinol 2018;178:R33-R44.
  5. Cosman F, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375:1532-1543.
  6. Saag KG, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 2017;377:1417-1427.
  7. Horne AM, et al. Bone loss after romosozumab/denosumab: Effects of bisphosphonates. Calcif Tissue Int 2018;103:55-61.
  8. Liu Y, et al. Romosozumab treatment in postmenopausal women with osteoporosis: A meta-analysis of randomized controlled trials. Climacteric 2018;21:189-195.
  9. Langdahl B, et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: A randomised, open-label, phase 3 trial. Lancet 2017;390:1585-1594.
  10. U.S. Food & Drug Administration. FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture. April 9, 2019. Available at: http://bit.ly/2ZvRMnj. Accessed April 24, 2019.
  11. Eastell R, et al. Pharmacological management of osteoporosis in postmenopausal women: An Endocrine Society* Clinical Practice Guideline. J Clin Endocrinol Metab 2019;104:1595-1622.
  12. McClung MR. Romosozumab for the treatment of osteoporosis. Osteoporos Sarcopenia 2018;4:11-15.