title: Raloxifene preserves phenytoin and sodium valproate induced bone loss by modulating serum estradiol and TGF-β3 content in bone of female mice.
abstract: Antiepileptic drugs (AEDs)-induced adverse consequences on bone are now well recognized. Despite this, there is limited data on the effect of anti-osteoporotic therapies on AEDs-induced bone loss. We hypothesize that estrogen deprivation following phenytoin (PHT) and sodium valproate (SVP) therapy could lead to adverse bony effects. Both PHT and SVP inhibit human aromatase enzyme and stimulate microsomal catabolism of oestrogens. Estrogen deficiency states are known to reduce the deposition of transforming growth factor-β (TGF-β3), a bone matrix protein, having anti-osteoclastic property. Thus, an attempt was made to investigate the effect of raloxifene, a selective oestrogen receptor modulator, in comparison with calcium and vitamin D3 (CVD) supplementation, on PHT and SVP-induced alterations in bone in mice and to unravel the role of estradiol and TGF-β3 in mediation of bony effects by either AEDs or raloxifene. Further, the effect of raloxifene on seizures and on the antiepileptic efficacy of PHT and SVP was investigated. Swiss strains of female mice were treated with PHT (35 mg/kg, p.o.) and SVP (300 mg/kg, p.o.) for 120 days to induce bone loss as evidenced by reduced bone mineral density (BMD) and altered bone turnover markers (BTMs) in lumbar bones (alkaline phosphatase, tartarate resistant acid phosphatase, hydroxyproline) and urine (calcium). The bone loss was accompanied by reduced serum estradiol levels and bone TGF-β3 content. Preventive and therapeutic treatment with raloxifene ameliorated bony alterations and was more effective than CVD. It also significantly restored estradiol and TGF-β3 levels. Deprived estrogen levels (that in turn reduced lumbar TGF-β3 content) following PHT and SVP, thus, might represent one of the various mechanisms of AEDs-induced bone loss. Raloxifene preserved the bony changes without interfering with antiepileptic efficacy of these drugs, and hence raloxifene could be a potential therapeutic option in the management of PHT and SVP-induced bone disease if clinically approved.
authors.affiliation: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, Hamdard University, New Delhi 110062, India.
authors.forename: Md Jamir
authors.initials: MJ
authors.lastname: Anwar
authors.affiliation: Department of Clinical Research, National Institute of Nutrition (NIN), Tarnaka, Hyderabad 500007, India.
authors.forename: K V
authors.initials: KV
authors.lastname: Radhakrishna
authors.affiliation: Institute of Genomics and Integrative Biology, Sukhdev Vihar, Mathura Road, New Delhi 110025, India.
authors.forename: Abhay
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, Hamdard University, New Delhi 110062, India. Electronic address: dvohra@jamiahamdard.ac.in.
authors.forename: Divya
authors.initials: D
authors.lastname: Vohora
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001847:Bone Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D005260:Female; D051379:Mice; D010672:Phenytoin; D020849:Raloxifene Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D012640:Seizures / Q000188:drug therapy; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D053782:Transforming Growth Factor beta3 / Q000378:metabolism; D014635:Valproic Acid
chemical_list: D000927:Anticonvulsants; D050071:Bone Density Conservation Agents; D020845:Selective Estrogen Receptor Modulators; D053782:Transforming Growth Factor beta3; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D014635:Valproic Acid; D010672:Phenytoin
keywords: Bone turnover markers; Estradiol; Phenytoin; Raloxifene; Sodium valproate; TGF-β3