Wednesday, September 21, 2016

Building strong bones with biologics- Romosozumab significantly decreases fracture risk in osteoporotic postmenopausal women.

Clinical Pearls:


  • Currently, no osteoanabolic treatment exists for osteoporosis, other than parathyroid hormone.
  • Romosozumab is the first humanized, osteoanabolic, anti-sclerostin monoclonal antibody which binds and inhibits sclerostin leading to increases in bone formation and decrease in bone reabsorption.
  • This regimen is a new approach in treating osteoporosis whereby patients received sequential anabolic therapy with two biologic agents-Romosozumab and Denosumab. 
  • One year of treatment with Romosozumab resulted in clinically significant lower risk of vertebral and clinical fractures in postmenopausal women and resulted in substantial gains in Bone Mineral Density (BMD) at the spine and hip. 

According to the statistics by International Osteoporosis Foundation (IOF) [1]It is estimated that osteoporosis affects 200 million women worldwide, affecting one tenth of women over the age of 60, one fifth over the age of 70, two-fifth over the age of 80 and nearly two-third over the age of 90.[2] 

Nearly 1 in 3 women over the age of 50 will suffer osteoporotic fractures during her life time. Fewer than 25% of patients suffering osteoporotic fractures receive treatment after the incidence and even among those who start the treatment, majority of the patients terminate it prematurely.

Currently, other than the parathyroid hormone analogs all treatments aimed at osteoporosis are antiresorptive. Researchers have spent resources on development of anabolic therapies, which led them to novel therapeutic approach in the treatment of osteoporosis - sclerostin inhibition. Sclerostin is secreted by osteocytes and acts by inhibiting Wnt signaling, thereby preventing osteoblast development and function.

Romosozumab is the first humanized, osteoanabolic, anti-sclerostin monoclonal antibody which binds and inhibits sclerostin leading to increases in bone formation and decrease in bone reabsorption.[3] 

The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) is an international, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial. The landmark study aims to evaluate the effect of 1 year of Romosozumab (at a dose of 210 mg, administered subcutaneously monthly) on development of fractures in post-menopausal women with osteoporosis. The FRAME trial recruited 7180 postmenopausal women between 55 -90 years of age and they were randomized to receive either 210 mg of Romosozumab placebo once a month for 12 months.

The study findings were presented at the at the American Society for Bone and Mineral Research (ASBMR) 2016 Annual Meeting.[4] The results were also published simultaneously in The New England Journal of Medicine.[5]

After I year of therapy with the monoclonal antibody treatment, patient received 2 doses of denosumab 60 mg subcutaneously at an interval of 6months. This regimen is a new approach in treating osteoporosis whereby patients received sequential anabolic therapy with two biologic agents.

The results were statistically significant since the relative risk of new vertebral fractures was reduced by 75% and the relative risk of a clinical fracture by 36% through 12 months compared to those receiving placebo.

The study met the coprimary end points of reducing the cumulative incidence of new vertebral fractures at the end of 1 year and 24 months. By reducing the incidence of clinical fractures (vertebral and non-vertebral) at the end of 12 months’ secondary end point werealso met, however when only incidence of non-vertebral fractures was analyzed, the study was short of meeting the goal.

In the study Romosozumab did reduce non-vertebral fractures but the data was not statistically significant. This was explained due to the geographical location of the study population. Majority of the study subjects were from Latin America were the incidence of non-vertebral fracture is extremely low. When the analysis was conducted after excluding the Latin American cohort, Romosozumab led to a significant 42% reduction in the risk of nonvertebral fractures over 1 year compared with placebo patients.

The clinical benefits seen in trials were also supported by lab results of increase in bone-formation marker P1NP and decrease in bone-resorption marker β-CTX during the 12 months’ period of therapy.

Adverse events were reported in control as well as placebo groups equally. Hypersensitivity reactions were more common in the Romosozumab group along with single incidence of jaw bone necrosis and atypical femoral fracture.

In an accompanying editorial, Dr Rosen and Dr Ingelfinger quote "The long-term treatment of osteoporosis remains challenging, and Romosozumab may be one answer. More trials are needed before we can embrace a new approach."

The study received funding from Amgen and UCB Pharma as well as Dr Cosman received personal fees from Amgen and other pharma company. The editorial authors are employee of NEJM.  





[1] https://www.iofbonehealth.org/facts-statistics
[2] Kanis JA (2007) WHO Technical Report, University of Sheffield, UK: 66.
[3] http://www.ncbi.nlm.nih.gov/pubmed/24842796
[4] http://www.asbmr.org/meetings/annualmeeting.aspx
[5] http://www.nejm.org/doi/full/10.1056/NEJMoa1607948#t=article

1 comment:

  1. Osteoporosis is a silent process of losing minerals from your bones. They become brittle and fracture easily.There is no pain unless you experience a fracture which is why it is important to look after your bone health with preventive measures.


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