Romosozumab for Osteoporosis: How Anti-Sclerostin Therapy Builds Bone and Prevents Fractures

What Is Sclerostin and Why Is Blocking It Important?

Sclerostin is a glycoprotein encoded by the SOST gene, primarily secreted by osteocytes, the most abundant cells in bone. Osteocytes act as mechanosensors, detecting physical stress on bone and coordinating the remodeling response. Sclerostin functions as a key negative regulator of the Wnt/beta-catenin signaling pathway, which is essential for osteoblast differentiation, proliferation, and survival. When sclerostin binds to LRP5/6 receptors on osteoblast precursors, it inhibits Wnt signaling and suppresses bone formation.

The therapeutic potential of sclerostin inhibition was discovered through the study of rare genetic conditions. Sclerosteosis and van Buchem disease are conditions caused by loss-of-function mutations in the SOST gene, resulting in absent or reduced sclerostin production. Individuals with these conditions have dramatically increased bone density and are essentially resistant to fractures. While the extreme skeletal overgrowth in these conditions is undesirable, the observation that reduced sclerostin leads to exceptionally strong bones provided the rationale for developing anti-sclerostin antibodies as osteoporosis treatments.

Romosozumab (Evenity), developed by Amgen and UCB, is a humanized monoclonal antibody that binds and neutralizes sclerostin. Its unique mechanism produces what is called the "open anabolic window" or "modeling-based bone formation": it simultaneously increases bone formation markers (such as P1NP, which rises within the first month) while decreasing bone resorption markers (such as CTX). This dual effect is fundamentally different from all other osteoporosis therapies, which either reduce resorption alone (bisphosphonates, denosumab) or increase formation alone (teriparatide, abaloparatide).

What Did the ARCH and FRAME Trials Show About Romosozumab?

Two pivotal phase 3 trials established the efficacy of romosozumab. The FRAME trial (FRActure study in postmenopausal woMen with ostEoporosis), published in the New England Journal of Medicine in 2016, randomized 7,180 postmenopausal women with osteoporosis to romosozumab 210 mg or placebo monthly for 12 months, followed by denosumab in both groups for 12 months. At 12 months, romosozumab reduced the risk of new vertebral fractures by 73% compared to placebo (0.5% vs 1.8%, p<0.001). The benefit persisted through month 24 after transition to denosumab.

The ARCH trial (Active-contRolled fraCture study in postmenopausal women with osteoporosis at High risk), published in the New England Journal of Medicine in 2017, was the first active-comparator superiority trial in osteoporosis. It randomized 4,093 postmenopausal women with osteoporosis and a fragility fracture to romosozumab 210 mg monthly for 12 months followed by alendronate, versus alendronate alone for the full study period. Through 24 months, the romosozumab-to-alendronate sequence reduced new vertebral fractures by 48% (6.2% vs 11.9%, p<0.001), clinical fractures by 27%, and nonvertebral fractures by 19% compared to alendronate alone.

The bone density gains with romosozumab are among the largest seen with any osteoporosis treatment. In the FRAME trial, BMD increased by 13.3% at the lumbar spine and 6.9% at the total hip over 12 months of romosozumab treatment. These gains exceeded those achieved with any other single agent in a 12-month period. However, the anabolic effect of romosozumab wanes after approximately 12 months due to a natural negative feedback mechanism that gradually increases sclerostin-independent Wnt pathway inhibition. This is why romosozumab is approved for a limited 12-month course.

How Should Romosozumab Be Used in Clinical Practice?

Romosozumab (Evenity) received FDA approval in April 2019 for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or failure or intolerance of other osteoporosis therapies. Each monthly dose consists of two subcutaneous injections of 105 mg each (210 mg total), administered by a healthcare provider or trained patient/caregiver. The treatment course is limited to 12 monthly doses.

A critical aspect of romosozumab treatment is the mandatory transition to antiresorptive therapy after the 12-month course. Without subsequent treatment, the bone density gains achieved with romosozumab are rapidly lost, similar to the rebound bone loss seen after discontinuing denosumab. The ARCH trial protocol transitioned patients to alendronate, while FRAME used denosumab. Both approaches maintained and extended the gains achieved during the romosozumab phase. Current expert opinion and the Endocrine Society 2024 guidelines recommend transitioning to denosumab to maximize bone density consolidation.

The FDA label carries a boxed warning regarding a potential increased risk of cardiovascular events (myocardial infarction, stroke, and cardiovascular death) observed in the ARCH trial, where the romosozumab group had numerically more cardiovascular serious adverse events than the alendronate group (2.5% vs 1.9%). Romosozumab should not be used in patients who have had a myocardial infarction or stroke within the preceding year, and the potential cardiovascular benefit of fracture reduction should be weighed against this risk. Common side effects include injection site reactions (5.2%) and arthralgia (12.4%). Hypocalcemia should be corrected before starting treatment.