Osteomalacia drug-induced

Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the isotretinoin population. While causality to isotretinoin has not been established, an effect cannot be ruled out. Physicians should use caution when prescribing isotretinoin to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsants. 

Clinical trials have demonstrated that the use of the bisphosphonates, nasal calcitonin, or human rPTH combined with calcium and vitamin D supplementation is effective in preventing drug-induced osteoporosis. Thus, individuals receiving over the long term any medication that can induce osteomalacia should also take one of these compounds and have periodic bone density determinations. 

Drug induced osteomalacia has been reported with the simultaneous use of phenytoin. 

Zhou C, Assem M, Tay JC, et al. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest 2006 116(6) 1703-1712. 

Xu YjHashizume T, Shuhart MC, Davis CL, Nelsos WL, Sakaki T, Kalhorn TF, Watkins PB, Schuetz EG, Thununel KE. Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1 alpha,25-dihydroxyvitamin D-3 Imphcations for drug-induced osteomalacia. Molec. Pharmacol. 2006 69 56-65. 

Metabolic changes over a long period may induce disease, e.g. thiazide diuretics (diabetes meUitus), adrenocortical hormones (osteoporosis), phenytoin (osteomalacia). Drugs may also enhance their own metabolism, and that of other drugs (enz5mie induction). 

Anticonvulsants (barbiturates and phenytoin) and other drugs that induce liver enzymes (such as rifampicin) can accelerate the hepatic catabolism of vitamin D and can lead to reduced serum concentrations of calcifediol and osteomalacia. Prophylactic vitamin D treatment of patients taking long-term enzyme inducers can be helpful and should be given at least in cases of anticonvulsant-drug-induced osteomalacia (74,75). 

D Erasmo E, Ragno A, Raejntroph N, Pisani D. Drug induced osteomalacia. Recent Prog Med 1998 89(10) 529-33. 

Drugs induce osteomalacia through various mechanisms. Phenyt-oin, primidone, phenobarbital, carbamazepine, rifampin, and some hypnotic medications may cause osteomalacia, potentially through... 

Pascussi, J. M., Robert, A., Nguyen, M., Walrant-Debray, O., Garabedian, M., Martin, P., Pineau, T., Saric, J., Navarro, F., Maurel, P., etal. (2005) Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J. Clin. Invest. 

EIahn TJ and EIalstead LR (1979) Anticonvulsant drug-induced osteomalacia alterations in mineral metabolism and response to vitamin D administration. Calcif Tissue Int 27 13 — 18. 

The application of 1,2S- OH)2D3, its analog la-OH-D3, and 25-OH-D3 to these diseases is, therefore, evident. Certainly l,25-(OH)2D3 or la-OH-D3 would be effective in renal osteodystrophy, hypoparath3 oidism, vitamin D dependency rickets, and drug induced osteomalacia. It is very promising as a treatment for various forms of osteoporosis. A review of the clinical literature related to this is beyond the scope of this chapter, but interested readers are directed elsewhere for this information... 

Wang Z, Lin YS, Dickmann LJ, Poulton F-J, Eaton DL, Lampe JW, Shen DD, Davis CL, Shuhart MC, Thummel KE (2013) Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin Dj through CYP3A4 induction in vitro and in vivo implications for drug-induced osteomalacia. J Bone Miner Res 28 1101-1116... 

Epileptic patients taking drugs that are enz5mtie inducers can develop osteomalacia (adults) or rickets (children). This may be due to enzyme induction increasing vitamin D metabolism and causing deficiency, or there may be inhibition of one of the hydroxylations that increase biological activity. 

Before leaving the subject of calcium homeostasis, it is perhaps worth mentioning that some inducers of the hepatic hydroxylating enzymes involved in detoxication (see below) can cause osteomalacia on chronic administration. Such enzyme inducers include the antioxidant ethoxyquin and some anticonvulsant drugs. Their mode of action is far from clear but possibly results from their effects on metabolism of vitamin D in the liver. 

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