Hyperhomocysteinemia (HHCY) has been suggested as a new risk factor for osteoporosis. Recent epidemiological, clinical and experimental studies provide a growing body of data, which is reviewed in this article. Epidemiological and (randomized) clinical trials suggest that HHCY increases fracture risk, but has minor effects on bone mineral density. Measurement of biochemical bone turnover markers indicates a shift of bone metabolism towards bone resorption. Animal studies confirm these observations showing a reduced bone quality and stimulation of bone resorption in hyperhomocysteinemic animals. Homocysteine (HCY) has been found to accumulate in bone by collagen binding. Cell culture studies demonstrate that high HCY levels stimulate osteoclasts but not osteoblasts, indicating again a shift of bone metabolism towards bone resorption. Regarding B-vitamins, only a few in vivo studies with equivocal results have been published. However, two large cell culture studies confirm the results obtained with exogenous HCY administration. In addition, HHCY seems to have adverse affects on extracellular bone matrix by disturbing collagen crosslinking. In conclusion, existing data suggest that HHCY (and possibly B-vitamin deficiencies) adversely affects bone quality by a stimulation of bone resorption and disturbance of collagen crosslinking.

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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 ‫؍‬

Homocysteine (HCY) has recently been linked to fragility fractures. Moreover, HCY activates osteoclasts. Little is known about the effect of HCY on activity of human osteoblasts (OBs). We hypothesized that HCY decreases the activity of OBs. Osteoblasts obtained from tra-becular human bone specimens of eight donors were cultured with conditioned medium. Culture medium was adjusted to 0, 100, 500, 1000 and 2000 μM HCY. After 14 days alkaline phosphatase (AP) activity, pro-collagen type I N-terminal peptide (PINP) and osteocalcin (OC) secretion in the supernatant were measured. After 20 days the formation of mineralized matrix was analyzed. HCY-stimulated AP activity gradually (100 μM HCY: 118%, P= 0.006; 500 μM HCY: 125%, P < 0.001). At 1000 and 2000 μM HCY the increase of AP activity was reversible (1000 μM HCY: 106%, P= 0.317; 2000 μM HCY: 102%, P < 0.737). The PINP secretion was also stimulated by HCY reaching a maximum of 260 ± 154 μg/l at 500 μmol/l versus 205 ± 94 μ,g/l in controls. After 20 days of culture the formation of bone matrix was increased at 100 and 500 μM HCY. OC secretion was not significantly changed. The results of the present study consistently demonstrate a moderate stimulation of primary human OB activity by increasing concentrations of HCY. However, the magnitude of this effect seems to be less pronounced than recent observations on primary human osteoclasts, suggesting a dysbalance between OBs and osteoclasts in favour of osteoclasts

B-vitamin supplementation had no consistent effects on bone turnover or BMD. However, the situation may be different in patients with hyperhomocysteinemia.