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.

Chronic heart failure (CHF) is a major public health problem causing considerable morbidity and mortality. Recently, plasma homocysteine (HCY) has been suggested to be increased in CHF patients potentially representing a newly recognized risk marker. This manuscript reviews the existing literature regarding hyperhomocysteinemia (HHCY) and CHF. Clinical data indicate that HHCY is associated with an increased incidence of CHF as well as with the severity of the disease. Mechanistic studies of HHCY and CHF are rare. However, preliminary results suggest that HHCY causes adverse cardiac remodelling characterized by interstitial and perivascular fibrosis resulting in increased myocardial stiffness. In addition, HHCY seems to affect the pump function of the myocardium. The mechanisms leading from an elevated HCY level to reduced pump function and adverse cardiac remodelling are a matter of speculation. Existing data indicate that direct effects of HCY on the myocardium as well as NO independent vascular effects are involved. In conclusion, HHCY might be a potential aetiological factor in CHF. Future studies need to clarify the mechanistic role of HHCY in CHF as a useful paradigm with most interesting therapeutic implications, because HCY lowering therapy could favourably influence the prognosis in CHF patients.

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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 ‫؍‬

Hyperhomocysteinemia (HHCY) has been linked to fragility fractures and osteoporosis. Folate and vitamin B 12 deficiencies are among the main causes of HHCY. However, the impact of these vitamins on bone health has been poorly studied. This study analyzed the effect of folate and vitamin B 12 deficiency on bone in rats. We used two groups of rats: a control group (Co, n = 10) and a vitamin-deficient group (VitDef, n = 10). VitDef animals were fed for 12 wk with a folate-and vitamin B 12 -free diet. Co animals received an equicaloric control diet. Tissue and plasma concentrations of homocysteine (HCY), S-adenosyl-homocysteine (SAH), and S-adenosyl-methionine (SAM) were measured. Bone quality was assessed by biomechanical testing (maximum force of an axial compression test; F max ), histomorphometry (bone area/total area; B.Ar./ T.Ar.], and the measurement of biochemical bone turnover markers (osteocalcin, collagen I C-terminal crosslaps [CTX]). VitDef animals developed significant HHCY (Co versus VitDef: 6.8 ± 2.7 versus 61.1 ± 12.8 mM, p < 0.001) that was accompanied by a high plasma concentration of SAH (Co versus VitDef: 24.1 ± 5.9 versus 86.4 ± 44.3 nM, p < 0.001). However, bone tissue concentrations of HCY, SAH, and SAM were similar in the two groups. Fmax, B.Ar./T.Ar., OC, and CTX did not differ between VitDef and Co animals, indicating that bone quality was not affected. Folate and vitamin B 12 deficiency induces distinct HHCY but has no effect on bone health in otherwise healthy adult rats. The unchanged HCY metabolism in bone is the most probable explanation for the missing effect of the vitamin-free diet on bone.