Alendronate Treatment of the Brtl Osteogenesis Imperfecta Mouse Improves Femoral Geometry and Load Response Before Fracture but Decreases Predicted Material Properties and Has Detrimental Effects on Osteoblasts and Bone Formation

Abstract

Long courses of bisphosphonates are widely administered to children with osteogenesis imperfecta (OI), although bisphosphonates do not block mutant collagen secretion and may affect bone matrix composition or structure. The Brtl mouse has a glycine substitution in col1a1 and is ideal for modeling the effects of bisphosphonate in classical OI. We treated Brtl and wildtype mice with alendronate (Aln; 0.219 mg/kg/wk, SC) for 6 or 12 wk and compared treated and untreated femora of both genotypes. Mutant and wildtype bone had similar responses to Aln treatment. Femoral areal BMD and cortical volumetric BMD increased significantly after 12 wk, but femoral length and growth curves were unaltered. Aln improved Brtl diaphyseal cortical thickness and trabecular number after 6 wk and cross-sectional shape after 12 wk. Mechanically, Aln significantly increased stiffness in wildtype femora and load to fracture in both genotypes after 12 wk. However, predicted material strength and elastic modulus were negatively impacted by 12 wk of Aln in both genotypes, and metaphyseal remnants of mineralized cartilage also increased. Brtl femoral brittleness was unimproved. Brtl osteoclast and osteoblast surface were unchanged by treatment. However, decreased mineral apposition rate and bone formation rate/bone surface and the flattened morphology of Brtl osteoblasts suggested that Aln impaired osteoblast function and matrix synthesis. We conclude that Aln treatment improves Brtl femoral geometry and load to fracture but decreases bone matrix synthesis and predicted material modulus and strength, with striking retention of mineralized cartilage. Beneficial and detrimental changes appear concomitantly. Limiting cumulative bisphosphonate exposure of OI bone will minimize detrimental effects.

Effect of alendronate on the mandible and long bones: an experimental study in vivo

“…This may partly be explained by the fact that by inhibiting bone resorption, ALN alters the mechanism of bone modeling/remodeling at the level of the primary spongiosa, consequently affecting endochondral ossification. Our results are in contrast with reported findings in wild-type animals treated with a dose of ALN similar to the dose used in our study (30) but are partly in agreement with studies using ALN in wild-type mice (14) and clodronate in healthy rats (16). According to the results of the former study (14), only the high ALN dose (2.5 mg/kg) was found to affect long bone length, suggesting that low ALN doses would not result in such alterations.…”

“…Similar findings were observed in children treated with oral ALN (27)(28)(29). These clinical findings are supported by experimental animal studies on OI showing similar results, i.e., increased femoral and vertebral bone mineral density, bone volume, number of trabeculae (30), and cortical width (14).…”

Bone Material Properties in Osteogenesis Imperfecta

“…(96) Tissue mineralization density is not affected by pamidronate therapy in children with OI and material properties are not worsened. (97) Two groups have found an increase in nonenzymatic cross-linking after 3 years' bisphosphonate treatment in healthy beagles.…”

Osteogenesis imperfecta

“…This finding suggests that improving bone architecture may not be sufficient to overcome the increased fracture risk owing to altered bone material properties, particularly in more severely affected children. In fact, treatment with bisphospho nates increased bone brittleness in mouse models at the whole bone level, perhaps by impairing microcrack repair and decreased mineralization heterogeneity due to reduced bone turn over 173 . In addition, concerns have also arisen over the long cumulative half life of bisphos phonates, which are incorpor ated in the bone matrix, and their possible contribution to impaired healing of fractures and osteotomies, and delayed tooth eruption.…”