A Short Treatment With an Antibody to Sclerostin Can Inhibit Bone Loss in an Ongoing Model of Colitis

Abstract

Chronic inflammation leads to bone loss, and increased fracture rates have been reported in a number of human chronic inflammatory conditions. The study reported here investigates the skeletal effects of dosing a neutralizing antibody to the bone regulatory protein sclerostin in a mouse model of chronic colitis. When dosed prophylactically, an antibody to sclerostin (Scl-AbI) did not reduce the weight loss or histological changes associated with colitis but did prevent inflammation-induced bone loss. At the end of the experiment, Scl-AbI-treated animals had a significantly higher femoral BMD (+27%, p < 0.05) than control antibody (Cntrl-Ab)-treated animals. In a second experiment, treatment with Scl-AbI was delayed until colitis had developed, by which time the mechanical properties of femurs in colitic animals were significantly worse than those of healthy age-matched control mice (maximum load, -26%, p < 0.05; energy, -37%, p < 0.05; ultimate strength, -33%, p < 0.05; elastic modulus, 217%, p < 0.05). A short treatment with Scl-AbI halted bone loss and reversed the decline of both intrinsic and extrinsic mechanical properties of the femur such that, after 19 days of treatment, the bone mechanical properties in the Scl-AbI-treated animals were not significantly different from those of noncolitic age-matched controls. Serum markers of bone formation and resorption suggested that the antibody to sclerostin stimulated osteoblast activity and inhibited osteoclastmediated bone resorption.

Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone

“…Osteocalcin levels ( Figure 5B) and PINP levels (results not shown) were measured again at week 6 and, by this point, they were no longer elevated. We have previously noted that the rate at which BMD increases in Scl-AbI-treated animals declines with time (19), which may help explain the failure to see elevated bone formation markers at the later time point in this study. In both DEX treatment groups, osteocalcin and PINP levels were significantly lower than those in mice not receiving DEX.…”

“…DEX and methylcellulose were obtained from Sigma UK. The Scl-AbI antibody and isotypematched control antibody (Ctrl-Ab) have been previously described (19).…”

“…This test allows the calculation of a number of bone mechanical properties, including resistance to bending under load (stiffness), the maximum load that a bone can sustain (maximum load), and the maximum stress that a bone can sustain and the amount of energy the bone can absorb before failure (toughness). The mechanical testing was carried out at MDS Pharma, as previously described (19).…”

“…Sclerostin has been reported to antagonize signaling in the bone morphogenetic protein pathway (17), but it is currently believed that inhibition of the Wnt pathway is more important for the activity of sclerostin on bone formation in vivo (18). Antibodies to sclerostin increase bone strength, bone formation, and bone healing in a range of animal models (19)(20)(21)(22), and a monoclonal antibody to sclerostin was recently evaluated for its clinical effects (23).…”

Sclerostin: A gem from the genome leads to bone-building antibodies

“…(86) In a mouse model of chronic colitis, short-term treatment with Scl-Ab had no anti-inflammatory effects but increased bone formation and reversed both inflammationinduced bone loss and the inflammation-induced decline in bone mechanical properties. (87) Circulating TRACP5b levels were decreased, suggesting that administration of Scl-Ab also reduced osteoclast-mediated bone resorption. Scl-Ab treatment also has been found to prevent the systemic bone loss seen in a mouse collagen-induced arthritis model (M Marenzana, personal communication).…”