Vitamin B12 Deficiency Stimulates Osteoclastogenesis via Increased Homocysteine and Methylmalonic Acid

Abstract

The risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B 12 deficiency is especially prevalent in the elderly and causes increased homocysteine (Hcy) and methylmalonic acid (MMA) levels. These three factors have been recognized as risk factors for reduced bone mineral density and increased fracture risk, though mechanistic evidence is still lacking. In the present study, we investigated the influence of B 12 , Hcy, and MMA on differentiation and activity of bone cells. B 12 deficiency did not affect the onset of osteoblast differentiation, maturation, matrix mineralization, or adipocyte differentiation from human mesenchymal stem cells (hMSCs). B 12 deficiency caused an increase in the secretion of Hcy and MMA into the culture medium by osteoblasts, but Hcy and MMA appeared to have no effect on hMSC osteoblast differentiation. We further studied the effect of B 12 , Hcy, and MMA on the formation of multinucleated tartrate-resistant acid phosphatase-positive osteoclasts from mouse bone marrow. We observed that B 12 did not show an effect on osteoclastogenesis. However, Hcy as well as MMA were found to induce osteoclastogenesis in a dose-dependent manner. On the basis of these results, we conclude that B 12 deficiency may lead to decreased bone mass by increased osteoclast formation due to increased MMA and Hcy levels.Osteoporosis is a complex multifactorial disease with a strong genetic component, but lifestyle factors are also important for maintenance of bone mass. Nutrition is one of the factors that contributes to bone health. During the first decades of life, adequate intake of calcium and vitamin D is essential to establish peak bone mass (see [1,2] and references therein). It has also been observed that nutritional deficiencies can cause impaired growth and skeletal abnormalities during childhood [3], while in adults inadequate intake of nutrients such as proteins, vitamins, and minerals has been associated with loss of bone quality [2,4]. Nutritional deficiency is very common in the elderly, emphasizing that adequate nutrient intake may slow down the age-related loss of bone mass.A challenge in nutrition research is to identify food components that contribute to the maintenance of bone health. During the last years, vitamin B 12 has gained particular attention since a number of epidemiological studies have reported a correlation between B 12 status and bone quality and fracture risk [5][6][7][8][9]. The micronutrient B 12 is involved as a cofactor in two enzymatic reactions [10]. The enzyme methionine synthase requires B 12 for the remethylation of homocysteine (Hcy) into methionine. The other enzyme dependent on B 12 is methylmalonyl-CoA mutase, which catalyzes the conversion of methylmalonyl-CoA into succinyl-CoA. As a consequence of B 12 deficiency, these

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

“…Since this finding, further investigations have been limited but have been stimulated by a renewed interest in tHcy and more accessible methods for its measurement. 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].…”

The Application of Holotranscobalamin and Methylmalonic Acid in Hospital Patients and Total Vitamin B12 in Primary Care Patients to Assess Low Vitamin B12 Status

“…Interestingly MMA correlation analysis for adult patients with holoTC values between 25-70 pmol/L and eGFR ≥60 mL/min/1.73 m 2 in addition to significant correlations age, renal function and FBC markers revealed correlations with ALP. A number of studies have previously reported associations of vitamin B12 deficiency with ALP and bone metabolism [32][33][34][35][36][37]. The exact mechanisms by which B12 affects bone metabolism are not yet understood.…”

Poststroke Hip Fracture: Prevalence, Clinical Characteristics, Mineral-Bone Metabolism, Outcomes, and Gaps in Prevention

“…The poststroke subjects with higher vitamin B12 concentrations had significantly higher BAP levels and the lowest OC/BAP ratio, indicating that vitamin B12 may influence maturation of osteoblasts, which in turn may contribute to bone fragility and fractures. In vitro, vitamin B12 in low concentrations dose dependently increased alkaline phosphatase (ALP) activity of osteoblastic cells [151], while vitamin B12 deficiency did not affect the onset of osteoblast differentiation, maturation, and matrix mineralization [152] and had no influence on ALP expression in human osteoblasts [153] but increased homocysteine induced osteoclastogenesis in a dose-dependent manner [152]. These data indicates that vitamin B12 deficiency (when causing hyperhomocysteinaemia) may increase osteoclast formation and bone resorption, while higher B12 levels may affect osteoblast maturation.…”