Antisclerostin Antibodies in the Treatment of Osteoporosis

Sclerostin is a glycoprotein encoded by the SOST gene and secreted almost exclusively by osteocytes — the mechanosensing cells buried within bone.

It binds the LRP5/6 co-receptors and thereby blocks canonical Wnt/β-catenin signalling, the master pathway for osteoblast differentiation and bone formation. Sclerostin is therefore a physiological brake on bone formation.

Sclerostin also increases RANKL and reduces osteoprotegerin, so blocking it reduces bone resorption as well as increasing formation.

Human proof of concept: loss-of-function mutations in SOST cause sclerosteosis and van Buchem disease — conditions of very high bone mass with strong, fracture-resistant bone, which established sclerostin as a drug target.

Mechanical loading and PTH suppress sclerostin; immobilisation, glucocorticoids and unloading increase it — this explains disuse osteoporosis at a molecular level.

Romosozumab is a humanised IgG2 monoclonal antibody against sclerostin and is currently the only anti-sclerostin agent in clinical use for osteoporosis.

It has a unique “dual effect”: it increases bone formation and simultaneously decreases bone resorption. This is different from teriparatide and abaloparatide, which increase both formation and resorption.

Dose: 210 mg subcutaneously once monthly (given as two 105 mg injections) for 12 months only. The anabolic window is self-limited — P1NP rises sharply then wanes by 9–12 months, while CTX stays suppressed.

It must be followed by an antiresorptive (a bisphosphonate or denosumab); otherwise the BMD gain is rapidly lost.

BMD gains are the largest of any currently available agent — roughly 13% at the lumbar spine and 6% at the total hip over 12 months, exceeding alendronate and teriparatide.

FRAME (postmenopausal osteoporosis): romosozumab versus placebo for 12 months, then denosumab in both arms — 73% reduction in new vertebral fractures at 12 months, with benefit maintained at 24 months.

ARCH (high fracture risk): romosozumab for 12 months then alendronate, versus alendronate throughout — 48% fewer new vertebral fractures, 27% fewer clinical fractures and 38% fewer hip fractures at 24 months. This trial also generated the cardiovascular safety signal.

STRUCTURE: in women already treated with bisphosphonates, romosozumab produced greater hip and spine BMD gains than teriparatide — relevant because prior antiresorptive use blunts teriparatide’s hip response.

BRIDGE: demonstrated efficacy in men with osteoporosis.

Boxed warning — cardiovascular risk. ARCH showed an excess of major adverse cardiovascular events (myocardial infarction, stroke, cardiovascular death) in the romosozumab arm. It is contraindicated within 12 months of a myocardial infarction or stroke, and cardiovascular risk must be assessed before starting.

Hypocalcaemia — correct calcium and vitamin D before starting and supplement throughout; use with caution in CKD, where the risk is higher.

Other adverse effects: injection-site reactions, arthralgia, headache, hypersensitivity and, rarely, osteonecrosis of the jaw and atypical femoral fracture (class effects of potent antiresorptive activity). A dental review before starting is prudent.

Indicated for postmenopausal women (and men) at very high or imminent fracture risk — a recent fracture, multiple vertebral fractures, a very low T-score, fractures occurring while on antiresorptive therapy, or high-dose glucocorticoid-induced osteoporosis.

Anabolic-first sequencing gives the best outcome. Starting with romosozumab and following with denosumab produces the highest probability of reaching a target T-score above −2.5; the reverse sequence (antiresorptive first) blunts the anabolic response, particularly at the hip.

In the Indian context, cost and availability remain the principal barriers. Teriparatide (including biosimilars) is the more accessible anabolic agent, with romosozumab reserved for selected very-high-risk patients in tertiary centres.