The effect of carbamazepine on bone structure and strength in control and osteogenesis imperfecta (Col1a2^+/p.G610C) mice

AbstractThe inherited brittle bone disease osteogenesis imperfecta (OI) is commonly caused byCOL1A1andCOL1A2mutations that disrupt the collagen I triple helix. This causes intracellular endoplasmic reticulum (ER) retention of the misfolded collagen and can result in a pathological ER stress response. A therapeutic approach to reduce this toxic mutant load could be to stimulate mutant collagen degradation by manipulating autophagy and/or ER‐associated degradation. Since carbamazepine (CBZ) both stimulates autophagy of misfolded collagen X and improves skeletal pathology in a metaphyseal chondrodysplasia model, we tested the effect of CBZ on bone structure and strength in 3‐week‐old male OICol1a2+/p.G610Cand control mice. Treatment for 3 or 6 weeks with CBZ, at the dose effective in metaphyseal chondrodysplasia, provided no therapeutic benefit toCol1a2+/p.G610Cmouse bone structure, strength or composition, measured by micro‐computed tomography, three point bending tests and Fourier‐transform infrared microspectroscopy. In control mice, however, CBZ treatment for 6 weeks impaired femur growth and led to lower femoral cortical and trabecular bone mass. These data, showing the negative impact of CBZ treatment on the developing mouse bones, raise important issues which must be considered in any human clinical applications of CBZ in growing individuals.