Vitamin B₁₂ Deficiency Stimulates Osteoclastogenesis via Increased Homocysteine and Methylmalonic Acid

The risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B₁₂ 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 B₁₂, Hcy, and MMA on differentiation and activity of bone cells. B₁₂ deficiency did not affect the onset of osteoblast differentiation, maturation, matrix mineralization, or adipocyte differentiation from human mesenchymal stem cells (hMSCs). B₁₂ 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 B₁₂, Hcy, and MMA on the formation of multinucleated tartrate-resistant acid phosphatase–positive osteoclasts from mouse bone marrow. We observed that B₁₂ 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 B₁₂ deficiency may lead to decreased bone mass by increased osteoclast formation due to increased MMA and Hcy levels.