Hyperhomocysteinemia: Can't it account for retinoid-induced fracture proneness?

Mohammad Reza Namazi¹ , Amir Feily²

¹ Department of Dermatology, Comparative Medicine Research Center, Faghihi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
² Resident of Dermatology, Jondishapur, University of Medical Sciences, Ahvaz, Iran

Correspondence Address:
Amir Feily
Department of Dermatology, Resident of Dermatology, Jondishapur University of Medical Sciences, Ahvaz
Iran

Sir,

A substantial amount of animal studies ^[1],[2],[3] and some human studies have shown that retinoid use is associated with osteoporosis and an increased risk for bone fracture. ^[4],[5] The mechanism of this effect has been elusive. In 1986, McGuire and Lawson. ^[5] suggested a possible relationship of the retinoid use with elevation of some cytokines that can enhance maturation of the preosteoclasts. ^[5] Later on, histomorphometric evaluations revealed that activation of osteoclasts and increased subperiosteal osteoclastic bone resorption may be the mechanism of bone loss due to retinoids. ^[2],[3] Administration of retinol with alendronate sodium, a direct potent inhibitor of osteoclasts action, ^[3] lessened the preventive action of alendronate on the development of osteopenic changes in the skeletal system of ovariectomized rats. ^[6]

We herein suggest a hitherto unexplained mechanism for retinoid osteoporotic adverse effect and increasing risk of bone fractures that could lead to novel preventive strategies.

The aminoacid homocysteine (Hcy) is metabolized in the liver by cystathionine beta-synthase. ^[7] Hcy levels are shown to be elevated in patients on isotretinoin treatment for acne, which may be due to the inhibition of cystathionine beta-synthase by the drug and/or the drug-induced liver dysfunction. ^[7],[8] Elevated levels of Hcy have been linked to increased fracture in the elderly and have been suggested as a new risk factor for osteoporosis. ^[9],[10] Epidemiological and randomized clinical trials suggest that hyperhomocysteinemia increases fracture risk, but has minor effects on bone mineral density. Hcy has been found to accumulate in the bone by collagen binding and stimulate osteoclasts but not osteoblasts, thereby inducing a shift of bone metabolism toward resorption. In addition, hyperhomocysteinemia seems to have adverse effects on extracellular bone matrix by disturbing collagen crosslinking. ^[9]

So, putting these facts altogether, it could be suggested that retinoid-induced hyperhomocysteinemia may account for osteoclast overactivity, osteoporosis, and increased risk of bone fracture associated with retinoid use. Daily supplementation with vitamin B ₁₂ and folate, which are the cofactors of the enzymatic reactions involved in Hcy metabolism, can lower plasma levels of Hcy ^[7] and prevent osteoporosis ^[11] induced by retinoid and other potential untoward effects of hyperhomocysteinemia such as atherosclerosis.

1.	Hotchkiss CE, Latendresse J, Ferguson SA. Oral treatment with retinoic acid decreases bone mass in rats. Comp Med 2006;56:502-11. [Google Scholar]
2.	Wu B, Xu B, Huang TY, Wang JR. A model of osteoporosis induced by retinoic acid in male Wistar rats. Yao Xue Xue Bao 1996;31:241-5. [Google Scholar]
3.	Kneissel M, Studer A, Cortesi R, Susa M. Retinoid-induced bone thinning is caused by subperiosteal osteoclast activity in adult rodents. Bone 2005;36:202-14. [Google Scholar]
4.	Leachman SA, Insogna KL, Katz L, Ellison A, Milstone LM. Bone densities in patients receiving isotretinoin for cystic acne. Arch Dermatol 1999;135:961-5. [Google Scholar]
5.	McGuire J, Lawson JP. Skeletal changes associated with chronic isotretinoin and etretinate administration. Dermatologica 1987;175:169-81. [Google Scholar]
6.	Sliwiñski L, Janiec W, Pytlik M, Folwarczna J, Kaczmarczyk-Sedlak I, Pytlik W, et al. Effect of administration of alendronate sodium and retinol on the mechanical properties of the femur in ovariectomized rats. Pol J Pharmacol 2004;56:817-24. [Google Scholar]
7.	Polat M, Lenk N, Bingöl S, Oztaº P, Ilhan MN, Artüz F, et al . Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne: a prospective controlled study. J Dermatolog Treat 2008;19:229-32. [Google Scholar]
8.	Schulpis KH, Karikas GA, Georgala S, Michas T, Tsakiris S. Elevated plasma homocysteine levels in patients on isotretinoin therapy for cystic acne. Int J Dermatol 2001;40:33-6. [Google Scholar]
9.	van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, van der Klift M, de Jonge R, Lindemans J, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 2004;350:2033-41. [Google Scholar]
10.	Herrmann M, Peter Schmidt J, Umanskaya N, Wagner A, Taban-Shomal O, Widmann T, et al. 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;45:1621-32. [Google Scholar]
11.	Cashman KD. Homocysteine and osteoporotic fracture risk: A potential role for B vitamins. Nutr Rev 2005;63:29-36. [Google Scholar]