Bisphosphonates in phenytoin-induced bone disorder

Chronic administration of phenytoin (PHT) has been associated with bone loss. Bisphosphonates [alendronate (ALD), ibandronate (IBD) and risedronate (RSD)] are potential candidates to prevent PHT-induced bone disorders, and the present study evaluated their effect on the antiepileptic efficacy of PHT. The PHT-induced depletion in folic acid (FA), vitamin B6 and vitamin B12 results in hyperhomocysteinemia. The elevated circulating homocysteine (hcy) could be a risk indicator for micronutrient-deficiency-related osteoporosis via generation of free radicals. Thus, an attempt was also made to unravel the PHT's and bisphosphonates' effect on hcy. Male mice received PHT (35 mg/kg, p.o.) for 90 days to induce bone loss. ALD, RSD and IBD were administered orally at doses 0.65 mg/kg, 0.33 mg/kg, and 0.17 mg/kg respectively, for prevention and 1.3 mg/kg, 0.65 mg/kg, and 0.33 mg/kg respectively, for treatment of PHT-induced bone loss. The bone loss was confirmed by bone mineral density (BMD) analysis and bone turnover markers. Serum levels of hcy and FA were estimated along with hydrogen peroxide levels and total antioxidant capacity in order to assess the antioxidant profile of bisphosphonates. The induction of bone loss by PHT was marked by lowered BMD and altered bone turnovers. ALD and RSD administration to PHT treated groups significantly reverted the bony adverse effects. No such effects were observed with IBD. In the bisphosphonates treated groups, hcy levels were statistically at par with the control group. PHT at 35 mg/kg, p.o. could compromise bone mass and thus, could be a model of bone demineralization in mice. The ALD, IBD and RSD have no pharmacodynamic interaction when administered along with PHT at the experimental level. Thus, their usage in the management of PHT-induced bone disease could be worthwhile if clinically approved.

Graphical AbstractProbable mechanism of hcy lowering effect of bisphosphonates
• The autoxidation of hcy to homocystine liberates HP, which can form free radicals.
• Bisphosphonates disrupt osteoclast activity and prevent the release of TRAP.
• They have been found to quench HP and free radicals.Figure optionsDownload high-quality image (327 K)Download as PowerPoint slideResearch Highlights
► Chronic administration of phenytoin can be used as a bone demineralization model in mice.
► Alendronate and risedronate but not ibandronate significantly reverts phenytoin-induced femoral bony changes.
► Bisphosphonates have no pharmacodynamic interaction with phenytoin at experimental level.
► Bisphosphonates possess anti-hyperhomocysteinemic and free radical scavenging property.