Endocrine Abstracts

Current osteoporosis therapy is predominantly ‘anti-resorptive’. Oestrogen antagonises the action of RANK-Ligand, a potent cytokine for osteoclast differentiation. Amino-bisphosphonates inhibit the HMG CoA reductase pathway, reducing osteoclast activity and viability, while denosumab is a human monoclonal antibody that binds to RANKL. Denosumab treatment reduces fractures. In a study of 7868 women with postmenopausal osteoporosis, denosumab reduced new radiographic vertebral fracture risk (HR, 0.32; 95% CI, 0.26 to 0.41; P<0.001); hip fracture risk (HR, 0.60; 95% CI, 0.37 to 0.97), and nonvertebral fracture risk (HR, 0.80; 95% CI, 0.67 to 0.95). Importantly, there was no increase in the risk of cancer, infection (apart from cellulitis), cardiovascular disease, delayed fracture healing, or hypocalcemia, and no cases of osteonecrosis of the jaw. However, two subsequent cases have been reported. Denosumab increases BMD after alendronate therapy, and increased BMD more than alendronate in a head-to-head study. In elderly men on androgen deprivation for prostate cancer, denosumab reduced vertebral fractures by 62%, compared with placebo, after 3 years. Cathepsin-K is a collagenolytic enzyme, relatively specific for bone. It is an ‘uncoupling’ anti-resorptive that reduces osteoclast activity, but not viability. The cathepsin-K inhibitor, odanacatib, increases BMD and reduces bone resorption markers in a dose-dependent manner. Importantly, bone formation is only modestly and transiently reduced. Fracture data are awaited. A further cathepsin-K inhibitor, ONO-5334, is being assessed. A new drug family inhibits endogenous inhibitors of Wnt-dependent anabolic bone pathways e.g. anti-sclerostin and anti-dikkopf (Dkk-1) antibodies. Anti-sclerostin antibodies increased BMD, bone formation and doubled skeletal strength after only 2 months in primates. A phase-1 study in older women and men showed a single injection of anti-sclerostin antibodies resulted in large increases in bone formation and smaller decreases in bone resorption, resulting in increases in BMD after only 85 days, and may represent a paradigm shift in osteoporosis therapy.

Declaration of interest: The author declares that there is a conflict of interest.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.