Association of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism with Bone Mineral Density in Postmenopausal Japanese Women

Abstract

The pathogenesis of osteoporosis is controlled by genetic and environmental factors. Considering the high prevalence of osteoporosis in homocystinuria, abnormal homocysteine metabolism would contribute to the pathogenesis of osteoporosis. It is known that the polymorphism of methylenetetrahydrofolate reductase (MTHFR), the enzyme catalyzing the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, correlates with hyperhomocysteinemia. In this study, we examined the association of this polymorphism with bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry (DXA) in 307 postmenopausal women. MTHFR A/V polymorphism was analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). We compared BMD, clinical characteristics, and bone metabolic markers among MTHFR groups (AA, AV, VV). The groups did not differ in terms of baseline data. The values of lumbar spine BMD and total body BMD were as follows: lumbar spine: AA, 0.91 +/- 0.18, AV, 0.88 +/- 0.16, VV, 0.84 +/- 0.14 g/cm(2); total body: AA, 0.97 +/- 0.11, AV, 0.96 +/- 0.11, VV, 0.93 +/- 0.09 g/cm(2). In the VV genotype, lumbar spine BMD values were significantly lower than those of the women with the AA genotype (P = 0.016) and total body BMD was significantly lower than those of the women with AA genotype (P = 0.03) and AV genotype (P = 0.04). This is the first report that suggests that the VV genotype of MTHFR is one of the genetic risk factors for low BMD.

Relation between homocysteine and biochemical bone turnover markers and bone mineral density in peri- and post-menopausal women

“…Based on our results, an increase from 10 to 15 mmol/L would only cause a marginal increase in DPD of approximately 1.5 pmol/mmol. Similar results were found in all other studies reported (21)(22)(23). In view of the discrepancy between our results and the clinical data, it can be speculated that the stimulation of bone matrix degradation by Hcy is of limited clinical relevance and that use of the currently available bone turnover markers is not appropriate for monitoring the biochemical effects of Hcy or B-vitamin deficiencies on bone metabolism.…”

“…Bode et al reported a relation with comparable strength between Hcy and collagen I C-terminal cross-links, another well-established bone resorption marker, in patients with coronary artery disease (21). Miyao et al found higher DPD levels in 57 subjects with a homozygous MTHFR C677T genotype, which is known to be associated with higher Hcy levels (22). Unfortunately, they did not measure Hcy, which limits the comparability with our results.…”

“…Even if their clinical use is still a matter of debate (19), these markers could be a useful tool in demonstrating a relation between Hcy and bone metabolism. At present, few data exist regarding the relation between Hcy and biochemical bone turnover markers (21)(22)(23). Moreover, nothing is known about Hcy and the osteoprotegerin (OPG)/sol- Normal BMD, t-score at hip and lumbar spine )y1.5; osteopenic, BMD t-score at hip or lumbar spine between y1.5 and y2.5); osteoporotic, BMD t-score at hip or lumbar spine -y2.5.…”

B-vitamins and bone in health and disease: the current evidence

“…Epidemiological studies investigating the relationship between the MTHFR 677C T polymorphism and bone health add further evidence to support the view that impaired folate metabolism (and the related phenotypes of elevated homocysteine and lower folate concentrations (19,20) ) may be implicated in adverse outcomes (Table 3) (39,(47)(48)(49)(50)(51)(52)(53) . Convincingly evidence from a recent meta-analysis of twenty studies (3525 cases and 17 909 controls) found that the 677C T polymorphism was associated with BMD at all measured sites, and with a 23 % increased risk for all fractures in individuals with the MTHFR 677TT genotype compared with those with the CT or CC genotypes (13) .…”

Association of the methylenetetrahydrofolate reductase C677T polymorphism and fracture risk in Chinese postmenopausal women

“…A point mutation in the MTHFR gene (C677T), which induces a substitution of valine for alanine, is a common variant, which is associated with reduced enzyme activity and with increased homocysteine levels. Some studies reported this polymorphism to be associated with either an increased risk of osteoporotic fractures [9,10] or lower BMD [11][12][13][14]. However, other studies fail to confirm this association.…”