Bone Abstracts

Objectives: Losartan is an angiotensin II receptor type 1 (AT1) antagonist. Losartan reduces circulating TGFb concentrations in a variety of myopathic models. We hypothesised that losartan administration to the murine osteogenesis imperfecta model OIM would result in lower circulating TGFb and CTX (bone resorption marker) and increase bone mass.

Methods: All procedures were approved by UConn Health Institutional Animal Care and Use Committee and performed in an AAALACi accredited facility. OIM mice were obtained from Jackson Labs (Bar Harbor, ME) on a mixed background (B6C3Fe a/a-Col1a2oim/J) for Study 1 and then rederived onto a C57BL6 background for Study 2. OIM mice were administered losartan via their drinking water at concentrations of 0 g/l, 0.6 g/l and 1.2 g/l for 4-weeks in study 1 or 0 g/l or 0.6 g/l for 8-weeks in study 2. Following termination, Serum TGFb and CTX were measured by ELISA and bone volume/integrity was measured in vertebral bodies by uCT. Data reported as mean (S.D.).

Results: In Study 1, 4 weeks’ losartan at 0.6 g/l, but not 1.2 g/l, was associated with a significant reduction in TGFb (ng/ml): losartan 0 g/l, 79.2 (14.6); 0.6 g/l, 60.0 (18.6) P=0.0440 vs 0 g/l; 1.2 g/l, 82.1 (18.7); and in CTX (ng/ml): Losartan 0 g/l, 275.9 (100.2); 0.6 g/l, 157.2 (128.2) P=0.0205 vs 0 g/l; 1.2 g/l, 263.1 (80.7). In Study 2, 8 weeks’ losartan treatment at 0.6 g/l vs 0 g/l was associated with significant differences in L3 vertebral body BV/TV%; 63.7 (40.0) vs 10.0 (2.0) P=0.0215; Tb. N. 0.019 (0.003) vs 0.014 (0.003) P=0.0158; Tb. Sp. 17.6 (17.4) vs 46.4 (5.3) P=0.0085; and Tb. Th 33.1 (20.8) vs 6.9 (0.2) P=0.0278. CTX and TGFb measured at 8 weeks were not significantly different between treated and control mice.

Conclusions: Losartan 0.6 g/l reduced bone turnover and TGFb at 4 weeks and increased vertebral trabecular bone mass at 8 weeks. The lack of difference in CTX and TGFb at 8 weeks suggests earlier reductions in bone turnover, resulting in increased retention of trabecular bone, that are carried through to 8 weeks of age when turnover is intrinsically lower in both treated and untreated animals. Further studies are needed to clarify the biological mechanisms and pathways involved.

Disclosure: NJB consults for Alexion, Mereo, UCB and Amgen, and receives grant support for clinical studies from Alexion and Amgen.