Supplemental arginine and high-dose folate may promote bone health by supporting the activity of endothelial-type nitric oxide synthase in bone

Med Hypotheses. 2005;64(5):1030-3. doi: 10.1016/j.mehy.2003.10.036.


The endothelial isoform of NO synthase promotes maintenance of bone density by stimulating osteoblastic activity while inhibiting bone catabolism; it appears to be a key mediator of the anabolic effects of mechanical loading, estrogens, and statin therapy on bone. This enzyme is susceptible to competitive inhibition by elevated systemic levels of asymmetric dimethylarginine (ADMA) encountered in vascular disorders associated with endotheliopathy; it may not be coincidental that reduced bone density has been observed in subjects afflicted with many of these disorders. Supplemental arginine has the potential to offset this adverse effect of ADMA. Superoxide production by osteoclasts may also impair bone NO synthase activity by oxidizing its cofactor tetrahydrobiopterin; high-dose folate has been shown to compensate for endothelial deficiency of this cofactor by effectively "pinch hitting" for it. These considerations suggest that supplementation with arginine as well as high-dose folate might aid maintenance of bone density by helping to preserve optimal NO synthase activity in bone cells.

MeSH terms

  • Arginine / administration & dosage*
  • Arginine / pharmacology
  • Bone and Bones / drug effects*
  • Bone and Bones / enzymology
  • Bone and Bones / physiology
  • Dose-Response Relationship, Drug
  • Folic Acid / administration & dosage*
  • Folic Acid / pharmacology
  • Humans
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type III


  • Folic Acid
  • Arginine
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III