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New agents, data highlight year of developments in bone research
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LOS ANGELES — The approval of new agents for postmenopausal women with osteoporosis at high risk for fracture and for children and adults with a rare, inherited form of rickets were two of several exciting developments in bone research during the past year, according to a speaker here.
“The year in bone was a very significant year in 2018,” Pauline M. Camacho, MD, FACE, professor of medicine in the division of endocrinology and metabolism at Loyola University Medical Center and director at the Loyola University Osteoporosis and Metabolic Bone Disease Center, said during a presentation at the AACE Annual Scientific and Clinical Congress. “We have a new anabolic agent, romosozumab, for the treatment of postmenopausal osteoporosis at high risk for fracture. For denosumab, we have 10-year data showing that the agent continues to be efficacious and safe. Abaloparatide, followed by 2 years of alendronate, shows a persistent effect in increasing [bone mineral density] further, and finally, for rare metabolic bone disease, we have a new agent for X-linked hypophosphatemia, an FGF23 inhibitor, burosumab.”
Camacho highlighted several developments in bone research in 2018 and 2019:
Romosozumab – In April, the FDA approved the monoclonal antibody romosozumab (Evenity, Amgen), indicated for women with a history of osteoporotic fracture or multiple risk factors for fracture, or those who cannot take other osteoporosis therapies or for whom other osteoporosis therapies have failed. The approval includes a boxed warning on its labeling stating that it may increase risks for myocardial infarction, stroke and cardiovascular death and should not be taken by patients who experienced a CV event within the previous year.
Romosozumab works by binding and inhibiting the activity of the protein sclerostin and, as a result, has a dual effect on bone, both increasing bone formation and decreasing bone breakdown. One dose of romosozumab consists of two injections, one immediately following the other, given once a month by a health care professional. The bone-forming effect of romosozumab wanes after 12 doses, so more than 12 doses should not be used. If osteoporosis therapy is needed after the 12 doses, patients should begin an osteoporosis treatment that reduces bone breakdown, according to the FDA.
Camacho noted that the drug’s approval was based on the FRAME and ARCH studies. In FRAME, 1 year of treatment with romosozumab lowered the risk for new vertebral fracture by 73% compared with placebo. This benefit was maintained during the second year of the trial when romosozumab was followed by 1 year of denosumab (Prolia, Amgen) compared with placebo followed by denosumab. In the second trial, 1 year of treatment with romosozumab followed by 1 year of alendronate reduced the risk for a new vertebral fracture by 50% compared with 2 years of alendronate alone. Romosozumab followed by alendronate also reduced the risk for nonvertebral fractures compared with alendronate alone.
“We are excited about this because a lot of us have already maxed out on 2 years of abaloparatide therapy, therefore, and when we want more anabolic agents, we have nothing else to offer,” Camacho said. “This is going to be a great addition to our armamentarium.”
Denosumab – Postmenopausal women with osteoporosis assigned denosumab therapy for up to 10 years saw sustained gains in BMD and reductions in bone turnover with low fracture incidence vs. women assigned to placebo, according to an analysis of 10-year data from the FREEDOM extension trial.
“Yearly incidence of new vertebral fractures and nonvertebral fractures remained low through 10 years, and similar to the first 3 years, bone density increased by 21% in the lumbar spine, 9% at the total hip and femoral neck and 2.7% in the radius through 10 years,” Camacho said. “Adverse events actually decreased, from 165 to 95, and there were two atypical fractures and 13 cases of [osteonecrosis of the jaw].”
Abaloparatide – Postmenopausal women treated with abaloparatide (Tymlos, Radius Health) for 18 months followed by 2 years of alendronate therapy saw a significant reduction in both vertebral and nonvertebral fractures through 3.5 years compared with patients assigned placebo followed by alendronate, according to findings from the ACTIVExtend study.
At the 43-month time point, women treated with abaloparatide saw an 84% RR reduction in the incidence of new vertebral fractures (P < .0001) and a 39% RR reduction in nonvertebral fractures (P = .038) compared with women who received placebo followed by alendronate. Additionally, women assigned abaloparatide experienced increases in BMD at the lumbar spine, total hip and femoral neck that were sustained during alendronate therapy, as well as decreased levels of C-terminal telopeptide (CTX) and procollagen type 1 N-terminal propeptides (P1NP).
“Highlights would be that 18 months of abaloparatide followed by 2 years of alendronate reduced the risk for vertebral, nonvertebral, clinical and major osteoporotic fractures,” Camacho said. “There were further increases in bone density during the 24 months, so you have a nice increase at 18 months, and you increase further when you switch to alendronate.”
Burosumab – In April 2018, the FDA approved the monoclonal antibody burosumab (Crysvita, Ultragenyx), a fibroblast growth factor 23 (FGF23)-blocking antibody indicated for X-linked hypophosphatemia in children and adults, the most common cause of inherited rickets. The condition, also known as XLH, causes low levels of phosphorus in the blood caused by excess FGF23 production, leading to impaired bone growth and development in children and adolescents and problems with bone mineralization throughout a person’s life. Pediatric dosing starts at 0.8 mg/kg body weight, rounded to the nearest 10 mg every 2 weeks (minimum of 10 mg, maximum of 90 mg), Camacho said. Adult dosing starts at 1 mg/kg body weight up to 90 mg every 4 weeks. Serum phosphorus levels should be monitored every 4 weeks, with dosing adjusted accordingly, Camacho said.
“It is very important if you are going to use this that you discontinue your conventional therapies,” Camacho said. “Calcitriol, phosphorus supplements get patients off of those drugs for 1 month prior to start of this agent. We don’t want any unnecessary hyperphosphatemia.” – by Regina Schaffer
Reference:
Camacho P. Disease state network year in review. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles.
Disclosure: Camacho reports no relevant financial disclosures.