Denosumab (Prolia): A human IgG2 monoclonal antibody that binds to RANKL (or receptor activator of nuclear factor kappa-B ligand), preventing RANKL from activating its receptor (RANK) on the surface of osteoclasts

New Molecular Entity: Denosumab (Prolia) was approved in June as a treatment for postmenopausal osteoporosis in women at high risk for fracture.

Denosumab 60 mg in a 1-mL solution for subcutaneous injection was approved by FDA in June 2010, as a treatment of postmenopausal osteoporosis in women at high risk for fracture (defined as a history of osteoporotic fractures, multiple risk factors for fracture, or failure/intolerance of other therapies). It is estimated that 10 million Americans have osteoporosis, of which 80% are women. Consequently, 1 of every 2 women aged >50 years will break a bone in their lifetime due to osteoporosis.

Efficacy. Denosumab's efficacy in the treatment of postmenopausal osteoporosis was evaluated in a 3-year, randomized, double-blind, placebo-controlled trial. The trial enrolled 7,808 women aged 60 to 91 who had a baseline bone mineral density (BMD) T-score between –2.5 and –4.0 at either the lumbar spine or total hip. Denosumab, administered at a dose of 60 mg subcutaneously every 6 months (along with oral calcium and vitamin D) was found to significantly increase BMD at all anatomic sites out to 3 years. As a result, denosumab statistically significantly (P<.0001) reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years. Absolute risk reduction, or ARR, was 4.8% and relative risk reduction (RRR) was 68% at year 3. Denosumab resulted in a significant reduction in the incidence of nonvertebral fractures at year 3 as well (ARR=1.5%, RRR=20%; P<.05 for both).

Safety. In the above-mentioned randomized trial, the most common side effects of denosumab (occurring in >5% of participants and more commonly in treatment than placebo) included back pain, pain in extremities, hypercholesterolemia, musculoskeletal pain, and cystitis. The most worrisome side effects of denosumab include hypocalcemia (particularly in those with a history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, or a creatinine clearance <30 mL per minute or receiving dialysis), serious infection (skin, abdomen, urinary tract, ear), dermatologic reactions (dermatitis, eczema, rashes), and osteonecrosis of the jaw.