But first, lets talk about bone remodeling (see also this tutorial). Bone constantly remodels through a delicate interplay between two types of cells on the bone surface: the bone-producing osteoblasts, and the bone-resorbing osteoclasts (One source suggests that approximately 10% of the adult skeleton turns over every year). Osteoclasts are activated in part by a signal made by osteoblasts called RANKL (receptor activator of NFkB ligand), which binds to its receptor on osteoclasts. Once activated, osteoclasts start resorbing bone by acidifying the section of bone immediately underneath them (called a resorptive pit) to help digest and release the protein matrix (mostly collagen) and free up calcium and phosphate.
Denosumab, sold under the tradename Prolia by Amgen (FDA approved June 2010), is a monoclonal antibody against RANKL. It thus prevents activation of osteoclasts and the initiation of resorption. Denosumab is given every six month subcutaneously. In a randomized trial (The Freedom trial), which enrolled over 7800 women between the ages of 60 and 90 with a T score on their dexa scan between -2.5 and -4.0, denosumab prevented the radiological evidence of vertebral fractures (primary endpoint), as well as reduced the risk of hip fractures and non-vertebral fractures, increased bone mineral density at the lumbar spine and hip, and did so with minimal adverse effects.
No patients with ESRD were included, though a stratification of patients based on renal function reveals 74 patients with CrCl 15-29 (avg Cr 1.5+/-0.3), 2817 patients with CrCl of 30-59 (avg Cr 0.9) and 4059 with CrCl 60-89 (avg Cr 0.8). Comparing the patients with severe renal impairement to those with mild, the first set of women were older (80 vs 71 yo), thinner (avg weight 53 vs 66 kg) and had worse femoral neck and hip BMD T scores (-2.8 vs -2.1 and -2.8 vs -1.8). Despite this perhaps less healthy population, the primary endpoint, radiological vertebral fractures, was reduced in this sub-group as well, with an incidence of 9.1% in the placebo group vs 3.2% in the active drug.
One major issue with this drug in this sub-group, was the increased incidence of serious infections: 11 in the denosumab group (31 pts received the drug, so the rate was ~30%) vs 4 in the placebo group (33 patients received placebo, for a rate of 12%). It appears that the infections are mostly cellulitis. While this difference was not statistically significant, it would give me pause. Given that the population in this trial was probably “healthier” (Calcium had to be normal for study entry; PTH was not checked), I think more data is needed before we can consider denosumab safe in patients with renal dysfunction.