SUN-532 Interferon Gamma-1b Does Not Increase Markers of Bone Resorption in Autosomal Dominant Osteopetrosis

Abstract

In autosomal dominant osteopetrosis type 2 (ADO2) CLCN7 mutations cause impaired osteoclast function. Severe consequences include skeletal fragility despite high bone mass, osteomyelitis, osteonecrosis, bone marrow failure, and severe cranial nerve impingement. There is no effective medical treatment for ADO2. We recruited subjects with ADO2 into a 14-week, open-label, pilot clinical trial of interferon gamma-1b. Doses were titrated based on tolerability and if fasting serum C-telopeptide (CTX) was <25% above baseline at week 8, targeting doses of 100 mcg/m2 three times a week. The primary outcomes were change from baseline in CTX and N-telopeptide/creatinine ratio (NTX/Cr) at week 14. Secondary outcomes included changes in urine calcium/creatinine ratio, bone formation markers and tolerability. Nine adults and 3 children were recruited. Severe manifestations of ADO2 included histories of fractures (100%), osteomyelitis (16.7%), vision loss attributable to ADO2 (50%), and anemia (58.3%). Baseline CTX and NTX/Cr were in the normal range, though frequently in the lower half of the normal range. Procollagen type I N-terminal propeptide (P1NP) was elevated or in the upper normal range in 11/12 (91.6%) subjects. Elevations of AST, and LDH were common (each 75%). One subject withdrew due to rash. Five subjects achieved doses of 50 ug/m2 three days a week, while 6 reached the full dose of 100 ug/m2 three days a week. Only 3/11 (27.3%) completing subjects achieved the primary outcome of increasing CTX ≥25% above baseline at week 14. The mean change from baseline in CTX at week 14 was +2.2% (SD 43.2%, p=0.86). Likewise, there was no significant change in NTX/Cr (mean change -2.1%, p=0.81). Interferon gamma-1b was poorly tolerated. Most subjects had adverse events, and the Mental Health and Mental Component Scales of the SF-36v2 declined slightly, but significantly (p<0.05). Over 14 weeks, interferon gamma-1b failed to significantly increase bone turnover markers in ADO2 and was poorly tolerated. Consequently, effects to decrease bone mass by increasing osteoclastic bone resorption in ADO2 are unlikely.