Chronic administration of Cl‐amidine, a pan‐peptidylarginine deiminase inhibitor, does not reverse bone loss in two different murine models of osteoporosis

Abstract Recent in vitro studies have shown a role for the peptidyl‐arginine deiminases (PADs) in bone resorption. However, it is unknown whether these enzymes are involved in bone loss in vivo. Thus, we evaluated the antiresorptive effect of a pan‐PAD inhibitor in two murine models of osteoporosis: (a) primary osteoporosis induced by ovariectomy (OVX); and (b) secondary osteoporosis associated to Type‐1 diabetes induced by streptozotocin (STZ, 50 mg/kg, i.p., five daily administrations). Five weeks after OVX and 15 weeks after injections of STZ, mice received daily administrations of Cl‐amidine (3 or 10 mg/kg, i.p.) or vehicle for 30 consecutive days. At the end of the treatment, femur and vertebra were harvested for microCT analysis. Blood samples were collected for determination of antibodies against cyclic citrullinated peptides (anti‐CCP) by enzyme‐linked immunosorbent assay. Serum levels of anti‐CCP antibodies from diabetic mice were not significantly different compared to control mice. However, a significant loss of both trabecular bone at the femoral neck and cortical bone at the femoral diaphysis was found in diabetic mice, and Cl‐amidine did not reverse the diabetes‐induced bone loss. Mice with OVX had significantly lower serum levels of anti‐CCP compared to mice with sham surgery. OVX resulted in significant loss of both trabecular bone at the L5 vertebra and distal femoral metaphysis. Cl‐amidine did not block the OVX‐induced bone loss. Our results suggest that chronic treatment with Cl‐amidine at the doses and period of time administered is not long enough to inhibit bone loss in two different murine models of osteoporosis.