An osteoporosis drug, romosozumab, is found to have significantly reduced the risk of new vertebral and clinical fractures in postmenopausal women in a phase 3 clinical trial. The study was led by Felicia Cosman, MD, who is affiliated with Columbia University and Helen Hayes Hospital. The results are presented at the Annual Meeting of the American Society for Bone Mineral Research (ASBMR) in Atlanta on 18th September, 2016.
Romosozumab, produced by Amgen and UCB Pharma is a monoclonal antibody which binds with a protein; sclerostin produced in osteocytes bone cells to inhibit the deleterious effects on the bone tissue formation.
The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) recruited a total of 7,180 patients out of whom 6,390 patients completed the 12-month trial while 6,026 patients completed the 24-month trial.
The results of this international, randomized, double-blind, placebo-controlled trial were published recently by theNew England Journal of Medicine (NEJM). This extensive international study, funded by Amgen, ran in collaboration with experts from the US, Canada, Hong Kong, Switzerland, Poland, Brazil, Japan and UCB Pharma Brussels, Belgium.
It is estimated that over 200 million adults are living with osteoporosis worldwide which is increasingly impacting the unsustainable cost linked with disability, fracture management, hospitalization and treatment. While the conventional therapeutics for osteoporosis have some limitations to their use, the use of a novel therapeutic target “sclerostin” shows promising prospects.
Although romosozumab is not the first drug to target the bone forming proteins, it certainly is the first anti-sclerostin drug that is injected subcutaneously once a month.
However, another drug, also marketed by Amgen Inc, Prolia (generic name: denosumab), received FDA’s approval in 2010 which is a monoclonal antibody that binds to RANKL protein. This protein is involved in the formation, function and survival of bone cells that trigger bone resorption. This drug is associated with improving bone mineral density and reducing the fracture risk in postmenopausal women.
Out of the widely categorized osteoporosis patients, postmenopausal osteoporosis is relatively common. Marked by high risk for fractures and bone fragility, it is said that about 20% of bone loss takes place in 5 to 7 years right after menopause onset. Startlingly, about 1 in every 2 women after the age of 50 are reported to have at least one bone fracture, which increases their vulnerability to having more such episodes.
As a person grows over the age of 30 years, the process of building of new bones slows down and the bone breakdown starts to begin. To make matters worse, by the age of reaching menopause, due to a lack of estrogen hormone, the process of bone resorption speeds up and leads to a loss of bone mass, making the bone brittle and prone to fractures.
Sclerostin is a negative regulator of bone formation which interferes with the Wnt-signaling which regulates the development and function of bone cells. The SOST gene which encodes sclerostin has dual functions: increased bone formation and reduced bone resorption (breakdown and removal of old bone tissues). With time, it becomes important for the body to have a balance between the formation of new bone tissues and resorption. Though bone formation inhibition is required to have bones of correct shape, size and density, increased activity of sclerostin leads to self-destruction of bone cells.
In this trial, the postmenopausal women who received a certain score for bone density test were only recruited. T-score of -2.5 and below are indicative of bone density corresponding to having osteoporosis, thereby the research participants recruited had a T score of -2.5 to -3.5, at the total hip or femoral neck. These participants were randomly assigned either the experiment group or the control group. The participants in the experiment group received 210 mg of romosozumab monthly and the control group participants received placebo for a period of 12 months. Both groups were later given a 60mg dose of demosumab for 12 months and the incidence of new vertebral fractures were measured at 12 months and 24 months, respectively.
Upon the completion of first 12 months, 16 new vertebral (spinal) fractures were recorded in the romosozumab group out of 3,321 patients (0.5%), while in the placebo group, 59 of 3,322 (1.8%) showed new vertebral fractures. This leads to a lower risk of fractures in the romosozumab group by a significant 73%.
Similarly, the incidence rate of clinical fractures also showed a striking contrast. In romosozumab group, clinical fractures were recorded in 58 of 3,589 patients (1.6%), while in the placebo group the rate was 90 of 3,591 (2.5%), translating into 36% reduced risk in the experiment group. Thirdly, in the romosozumab group, 56 of 3,589 patients (1.6%) and in the placebo group, 75 of 3,591 (2.1%) had a non-vertebral fracture.
As the trial reached its 24 months, it was found that the effects of denosumab was significantly different in the experiment and control groups. The risk of fractures in the experiment group was 75% lower than the placebo group, in this case.
Subsequently, it was also reported that the use of romosozumab led to substantial gains in bone mineral density at the spine and hip which in turn helped better results in the use of denosumab and overall bone health outcome.
By the end of this trial, the researchers observed the adverse effects which were found to be consistent in both groups. With an exception of one incident of typical femoral fracture and two incidents of osteonecrosis of the jaw (the bone in the jaw begins to weaken and starve from lack of blood) in the experiment group, other side effects, which included hyperostosis, osteoarthritis, cardiovascular events and cancer, remained balanced in both groups.
With these significant outcomes, the researchers hope that this investigated drug gets the approval and reaches the osteoporosis patients who remained deprived of pharmacologic treatments of the condition. This study also went on to say that fewer than 25% of osteoporosis patients receive treatment which is a negative indication to contain clinical burden of bone fragility and fractures.
To complement these positive results of the trial, the executive vice president of Research and Development at Amgen Sean E Harper, MD, said, “We are pleased to see nearly 15 years of sclerostin antibody research reinforced with these phase 3 data.
Romosozumab, with its dual effect as a bone builder and anti-resorptive, has the potential to play a distinct and important role in the treatment of women with postmenopausal osteoporosis at increased risk of fracture.” He added that the results from FRAME study led them to submit their Biological Licensing Application to FDA in July and that they are hopeful for a positive response from the regulatory authority.