B vitamins, homocysteine, and bone disease: Epidemiology and pathophysiology

Abstract

Observational studies indicate that mildly elevated homocysteine is a strong risk factor for osteoporotic fracture, yet there is no clear biologic mechanism for an effect of homocysteine on bone. The association could instead be attributed to B vitamins (folate, vitamin B(12), vitamin B(6)), as low levels of these nutrients are the primary determinants of homocysteine and may be associated with lower bone quality. Discovery of a direct effect of homocysteine or B vitamins on bone would be important in terms of interventions, as these factors can be modified with changes in diet or supplementation. This article reviews the connections of homocysteine and B vitamins to measures of bone quality and osteoporotic fracture. Although the literature suggests that these factors may be associated with bone health, most of the epidemiologic studies are observational, limiting conclusions regarding causality. More controlled -trials are needed to determine whether treatment with B vitamins would reduce fracture rates among community-dwelling cohorts.

Relation of plasma total homocysteine, folate and vitamin B12 levels to bone mineral density in Moroccan healthy postmenopausal women

“…These findings are in agreement with those of a recent study of 1,550 old American subjects, which concluded that neither serum nor red blood cell folate was related to BMD or osteoporosis [10], possibly because of a higher mean age and higher mean plasma folate concentration. However, several studies [5,23] have found a significant positive correlation of folate with BMD. The direct association between plasma tHcy and plasma folate with BMD is not well documented except in reports describing the development of osteoporosis in patients with inherited classical homocystinuria [25].…”

“…Osteoporosis is a well-recognized feature of homocystinuria, and many large general population cohort studies demonstrated positive relations between circulating tHcy levels and osteoporosis and hip fracture risk [3][4][5][6][7]. These findings raised the hope of reducing the burden of an enormous public health problem through B-vitamin therapy.…”

“…Homocysteine can be deleterious even at moderate levels, such as those achieved during aging or diets poor in vitamin B12 and folic acid, the necessary coenzymes for its metabolism [8,9]. Several observational studies suggested that poor dietary intakes and low blood concentrations of B vitamins may be associated with decreased BMD, greater bone loss, and higher risk of osteoporotic fracture [3,5,10].…”

Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus

“…A candidate for increased oxidative stress may be hyperhomocysteinemia. A moderately increased plasma homocysteine (Hcys) level in the general population may indicate a fracture risk that is independent of BMD [4,142]. McKusick first proposed that hyperhomocysteinemia might interfere with normal enzymatic collagen cross-link formation [143], and this proposed mechanism was confirmed indirectly in homocystinuric patients.…”

Nutrition, Bone, and Aging: An Integrative Physiology Approach

“…Homocysteine metabolism requires the presence of vitamin B 6 , vitamin B 12 , and folate; deficiency of any of these vitamins can lead to elevations in plasma homocysteine. Homocystinuria, a rare autosomal-recessive disorder causing elevated plasma homocysteine levels and severe vaso-occlusive disease, is associated with osteoporosis [67]. Hyperhomocysteinemia in the general population has been associated with a two-to fourfold increase in fracture risk [68,69], but studies of homocysteine and BMD are inconsistent [67].…”