The role of hyperhomocysteinemia as well as folate, vitamin B(6) and B(12) deficiencies in osteoporosis: a systematic review

Clin Chem Lab Med. 2007;45(12):1621-32. doi: 10.1515/CCLM.2007.362.


Hyperhomocysteinemia (HHCY) has been suggested as a new risk factor for osteoporosis. Recent epidemiological, clinical and experimental studies provide a growing body of data, which is reviewed in this article. Epidemiological and (randomized) clinical trials suggest that HHCY increases fracture risk, but has minor effects on bone mineral density. Measurement of biochemical bone turnover markers indicates a shift of bone metabolism towards bone resorption. Animal studies confirm these observations showing a reduced bone quality and stimulation of bone resorption in hyperhomocysteinemic animals. Homocysteine (HCY) has been found to accumulate in bone by collagen binding. Cell culture studies demonstrate that high HCY levels stimulate osteoclasts but not osteoblasts, indicating again a shift of bone metabolism towards bone resorption. Regarding B-vitamins, only a few in vivo studies with equivocal results have been published. However, two large cell culture studies confirm the results obtained with exogenous HCY administration. In addition, HHCY seems to have adverse affects on extracellular bone matrix by disturbing collagen crosslinking. In conclusion, existing data suggest that HHCY (and possibly B-vitamin deficiencies) adversely affects bone quality by a stimulation of bone resorption and disturbance of collagen crosslinking.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Animals
  • Bone Density
  • Folic Acid Deficiency / complications*
  • Fractures, Bone / complications
  • Humans
  • Hyperhomocysteinemia / complications*
  • Osteoporosis / complications*
  • Vitamin B 12 / metabolism
  • Vitamin B 6 / metabolism
  • Vitamin B Deficiency / complications*


  • Vitamin B 6
  • Vitamin B 12