RANKL and OPG are principally produced by osteoblasts and marrow stromal cells [142, 143]. OPG competitively inhibits the binding of RANKL to RANK on osteoclasts and their precursors. This results in inhibition

of the fusion of osteoclast precursor cells, blockade of the activation of mature osteoclasts, and induction of osteoclast apoptosis. OPG is a powerful inhibitor of bone resorption that could have been used clinically [144, 145]. However, because OPG also binds to the cytotoxic ligand Selleck BX-795 TRAIL and other members of the TNF family, a specific fully human antibody against RANKL has been developed (Amgen). This antibody, named denosumab, has been shown to specifically bind to RANKL with a very high affinity, preventing its interaction with the receptor RANK. Moreover, animal studies showed that this antibody had pharmacokinetic and pharmacodynamic advantages as compared Dinaciclib to an OPG construct. Denosumab has a very long circulating half-life (1–1.5 months), and administration of a single dose by the subcutaneous route induces a rapid (12 h), marked (decrease in uNTX >80%) and prolonged (>6 months)

inhibition of bone resorption in postmenopausal women [146]. The interest for using denosumab to counteract postmenopausal bone loss was enhanced by the knowledge that disequilibrium of the balance between RANKL and OPG plays a major role in the pathogenesis of osteoporosis. RANKL expression is increased after menopause, whereas estrogens stimulate OPG production [147]. RANKL expression is indeed significantly higher in bone marrow cells isolated from early untreated postmenopausal women than in cells obtained from pre- or postmenopausal women treated with estrogens [148]. A phase 2 study has been conducted in 412 postmenopausal women with low bone mass. Various therapeutic schedules of denosumab Metalloexopeptidase were tested against placebo and against

alendronate as a positive control. After 1 and 2 years, BMD changes with denosumab 30 mg every 3 months and >60 mg every 6 months were similar to, or in some cases greater than, the changes obtained with alendronate. Denosumab tended to produce greater bone density increments than alendronate at skeletal sites enriched for cortical bone. The drug was well tolerated. The only concern was the occurrence of six cases (in 314 patients) of infections associated with hospitalizations [149, 150]. This concern was not confirmed in a phase III study where there were no significant differences between denosumab and placebo in prespecified adverse events, selleck including infections [151]. The antifracture efficacy of denosumab has been evaluated in a placebo-controlled phase 3 trial including 7,868 postmenopausal osteoporotic women who received 60 mg denosumab every 6 months or matching placebo for a total of 3 years (the FREEDOM trial).