The Effect of Discontinuing Treatment With Blosozumab: Follow-up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women With Low Bone Mineral Density

Abstract

Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1-year randomized, placebo-controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow-up; 88 women completed 1 year of follow-up. At the beginning of follow-up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow-up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow-up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C-terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti-drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis.

Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model

“…Post-menopausal osteoporotic women required continuous alendronate therapy to preserve bone mineral density in the spine following 1 year of PTH (1-84) [36]. Similarly, despite large BMD gains during 1 year of blosozumab anti-sclerostin treatment, anabolic gains were not fully sustained in the year following blosozumab cessation [38]. Our current study extends these observations to a pediatric model of OI, where low bone mass and quality contribute to a need for anabolic stimulus during growth to improve resistance to fracture.…”

“…Rapid decreases in resorption markers are also evident, but are more modest and variable [28, 31]. In the year following cessation of sclerostin antibody, a moderate increase in serum CTX corresponded with drug clearance and gradual return of bone mass toward pre-treatment levels [38]. These findings suggest an upregulation of bone resorption following SclAb cessation.…”

“…In osteoporosis, adults treated with PTH, the only clinically available anabolic agent, demonstrate a time-dependent recovery in remodeling indices following PTH cessation, requiring subsequent BP to protect gains in bone mass [36, 37]. Clinical studies suggest that SclAb similarly results in gradual loss of bone mass gains after withdrawal in osteoporotic patients [38], supporting a similar need for follow-on administration of an anti-resorptive agent. While PTH has been studied in adults with OI, there is no data in the literature describing cessation effects of anabolic bone drugs such as PTH or SclAb in OI patients—adults or children [14, 15]—or in any mouse model of the disease [16–21].…”

Bone biology, signaling pathways, and therapeutic targets for osteoporosis

“…To evaluate the effect of discontinuing blosozumab, women enrolled in the 1-year randomized, placebo-controlled phase 2 trial were followed for an additional year [85]. At the end of follow-up, lumbar spine and total hip BMD decreased, but remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks, and blosozumab 180 mg every 2 weeks.…”

CORR Insights®: Does Sclerostin Depletion Stimulate Fracture Healing in a Mouse Model?

“…Also, it would be interesting to determine whether this differential rate would occur with SclAb injections. Next, lumbar, total hip and femoral neck bone-mineral density remains elevated 1 year after discontinuing a year-long/biweekly regiment of blosozumab injections [12]. Does this benefit persist beyond a year?…”