What this means
Methylmalonic acid (MMA) is a functional marker of vitamin B12 insufficiency and an emerging metabolic factor associated with skeletal aging and osteoporosis. This review synthesizes epidemiological, experimental, and mechanistic evidence linking the vitamin B12-MMA axis to impaired bone homeostasis.
A plain-English summary is on its way. Until then, this is the start of the authors' own summary.
- Who it was tested in
- People
- Kind of research
- A summary of earlier studies
The science
- Original title
- Methylmalonic Acid in Skeletal Aging and Osteoporosis: Linking Vitamin B12 Metabolism to Mitochondrial Dysfunction.
- Authors
- Ji T, Pei T, Yang J et al.
- Journal
- Calcified tissue international
- Published
- Oct 20, 2026
- Study type
- Review · in humans
- PMID
- 42900397 ↗
Abstract
Methylmalonic acid (MMA) is a functional marker of vitamin B12 insufficiency and an emerging metabolic factor associated with skeletal aging and osteoporosis. This review synthesizes epidemiological, experimental, and mechanistic evidence linking the vitamin B12-MMA axis to impaired bone homeostasis. Population studies associate elevated circulating MMA with lower bone mineral density, higher odds of osteoporosis, and lower knee extensor strength, while disturbed vitamin B12 metabolism has also been linked to altered bone turnover. Experimental MMA exposure and models of methylmalonyl-CoA mutase (MMUT) deficiency reveal context-dependent abnormalities in mitochondrial respiration, energy metabolism, redox balance, and quality control. These findings provide a rationale for investigating skeletal effects, but the broader consequences of vitamin B12 deficiency and inherited metabolic defects should be distinguished from direct MMA actions in bone cells. Concurrent homocysteine accumulation and reduced S-adenosylmethionine availability may further impair collagen cross-linking, epigenetic regulation, and skeletal remodeling. These pathways support a metabolic-mitochondrial framework in which functional vitamin B12 deficiency contributes to bone loss through coordinated effects on bioenergetics, redox balance, cell fate, and extracellular matrix quality. MMA may therefore complement vitamin B12, homocysteine, renal function, and conventional bone markers in the assessment of skeletal metabolic risk. Prospective human studies, bone-specific mechanistic experiments, and intervention trials are needed to establish causality, clinically useful thresholds, and the skeletal benefits of correcting vitamin B12 deficiency or targeting mitochondrial dysfunction.
Ji T, Pei T, Yang J et al. Methylmalonic Acid in Skeletal Aging and Osteoporosis: Linking Vitamin B12 Metabolism to Mitochondrial Dysfunction. Calcified tissue international. 2026. doi:10.1007/s00223-026-01622-7. PMID: 42900397. https://pubmed.ncbi.nlm.nih.gov/42900397/
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