Experimental Hyperhomocysteinemia Reduces Bone Quality in Rats

Background: Recently, hyperhomocysteinemia (HHCY) has been suggested as a new risk factor for osteoporosis. This study investigated if HHCY is a causal osteoporotic factor in vivo. Methods: We used 3 groups of rats: a control group (n = 20), a moderate HHCY group (induced by a 2.4% methionine-enriched diet, n = 10), and an intermediate HHCY group (induced by a 2% homocystine-enriched diet, n = 10). We measured bone fragility [maximum force of an axial compression test (Fmax)], bone area as percentage of total area (BAr/TAr, histomorphometry), and biochemical bone turnover markers [osteocalcin (OC) and collagen I C-terminal crosslaps (CTx)]. Results: Compared with controls, 3 months of moderate or intermediate HHCY increased mean (SD) bone fragility at the femoral neck by 18% (6%) in methionine-fed ( P = 0.001) and 36% (13%) in homocystine-fed rats ( P <0.001). Mean (SD) BAr/TAr at the distal femur in methionine and homocystine groups was decreased by 45% (21%; P = 0.001) and 93% (9%; P = 0.001), respectively. At the femoral neck, BAr/TAr was decreased by 19% (11%; P <0.001) and 55% (19%; P <0.001). At the lumbar spine, the reduction of BAr/TAr was 17% (23%; P = 0.099) and 44% (19%; P <0.001). Plasma OC (bone formation marker) was decreased by 23% (20%; P = 0.006) and 34% (21%; P <0.001). Plasma CTx (bone resorption marker) did not differ between groups. Conclusion: Bone quality is consistently decreased in the presence of increased circulating homocysteine. The results provide evidence that HHCY is a causal osteoporotic factor.