balicatib and Osteoporosis--Postmenopausal

Drug-induced scleroderma has been rarely reported, mostly with the features of diffuse scleroderma or acrosclerosis, and exceptionally with the characteristics of morphea. We report the case of an adult white woman, enrolled in a double-blind, placebo-controlled, multicentric trial evaluating the efficacy and safety of the cathepsin K inhibitor balicatib for osteoporosis. Typical morphea lesions developed on the patient's trunk 9 months after the beginning of therapy. Lesions completely resolved after drug withdrawal and a single brief course of systemic steroids. No recurrence occurred in a 2-year follow-up. Fifteen cases of drug-induced morphea could be retrieved from the literature. Drug withdrawal determined complete remission in only a few patients. Different drug classes have been implicated. Some of these, including balicatib, alter directly connective tissue metabolism.

Topics: Administration, Oral; Benzamides; Cathepsin K; Cathepsins; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Piperazines; Randomized Controlled Trials as Topic; Scleroderma, Localized

Balicatib, an inhibitor of the osteoclastic enzyme cathepsin K, was tested in ovariectomized monkeys, a model for osteoporosis. As expected, ovariectomy-induced bone mass changes were partially prevented by balicatib treatment. Bone turnover was significantly decreased at most sites, but unlike most bone resorption inhibitors, periosteal bone formation rates were increased.. Selective inhibitors of the osteoclastic enzyme cathepsin K have potential in osteoporosis treatment. This study evaluated the efficacy of balicatib (AAE581), a novel inhibitor of human cathepsin K, on bone mass and dynamic histomorphometric endpoints in ovariectomized monkeys.. Eighty adult female Macaca fascicularis underwent bilateral ovariectomies and were dosed twice daily by oral gavage with balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively). Approximately 1 month after treatment initiation, the 50 mg/kg dose was decreased to 30 mg/kg. Twenty animals underwent sham-ovariectomies (group S). Bone mass was measured at 3-6 month intervals. At 18 months, vertebra and femur were collected for histomorphometry.. In both spine and femur, group O animals lost BMD and all other groups gained BMD between 0 and 18 months. In balicatib-treated animals, BMD change in the spine was intermediate between group S and O, with groups L and M significantly different from group O. In femur, all three doses of balicatib significantly increased BMD gain relative to group O and group mean values were also higher than group S. Most histomorphometric indices of bone turnover in vertebra and femoral neck were significantly lower than group O with balicatib treatment, except that periosteal bone formation rates (Ps.BFR) were significantly higher. Ps.BFR in mid-femur was also significantly increased by treatment.. Balicatib partially prevented ovariectomy-induced changes in bone mass, inhibited bone turnover at most sites, and had an unexpected stimulatory effect on periosteal bone formation.

Topics: Animals; Benzamides; Body Weight; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Cathepsin K; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eating; Estradiol; Female; Femur; Humans; Lumbar Vertebrae; Macaca fascicularis; Organ Size; Osteogenesis; Osteoporosis, Postmenopausal; Ovariectomy; Periosteum; Piperazines; Uterus

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.

Topics: Animals; Azepines; Biphenyl Compounds; Cathepsin K; Cathepsins; Collagen; Cysteine Proteinase Inhibitors; Dogs; Fibroblasts; Humans; Models, Biological; Molecular Structure; Osteoporosis, Postmenopausal; Skin; Structure-Activity Relationship; Sulfones