Bone Abstracts

Loss of the gene encoding the secreted Wnt antagonist sclerostin results in increased bone mass in humans and mice. Administration of antibodies to sclerostin (Scl-Ab) has been shown to increase bone mineral density (BMD) by increasing bone formation and decreasing bone resorption, in both animal studies and human clinical trials. In these studies, the magnitude and rate of increase in bone formation markers, and the rate of increase of BMD, diminishes upon repeat dosing with Scl-Ab despite a continuous and progressive increase in BMD.

In this study, we investigated whether increased expression of secreted antagonists of Wnt signalling could be a contributory factor to the apparent attenuated response in markers of bone formation following repeat dosing of Scl-Ab.

Treatment of female Balb/c mice (8–10 weeks old) with Scl-Ab for five weeks (10 mg/kg weekly, s.c.) increased DXA whole body BMD by 9.4%±2.0% compared with vehicle control. Serum P1NP, a bone formation marker, was measured 4 days after one, three or five doses of Scl-Ab. After the first dose of Scl-Ab, serum P1NP significantly increased versus vehicle control (165%±9%) whilst the increase was less pronounced after the third or fifth dose of Scl-Ab (56%±11% or 21%±6%, respectively).

In order to investigate the mechanism of this attenuated response, mRNA expression of several secreted Wnt antagonists was determined in femurs collected from mice following five weeks of Scl-Ab or vehicle treatment. Expression of SOST, SOST-DC1, DKK1, DKK2, SFRP2, FRZB, SFRP4, SFRP5 and WIF1 transcripts was significantly increased (approximately 2–3.5 fold) upon Scl-Ab treatment compared with vehicle controls.

Continuous administration of Scl-Ab is associated with up-regulation of several Wnt antagonists. This could represent a negative feedback to increased Wnt signalling induced by Scl-Ab and may help explain the attenuation in the bone formation response and in bone density increase over time.