Osteomalacia anticonvulsants

Drugs have also been associated with osteomalacia. Anticonvulsants increase the hepatic cataboHsm of vitamin D metabolites, and produce end-organ resistance. Phosphatebinding antacids used for treatment of peptic ulcer disease cause osteomalacia by preventing the intestinal absorption of phosphate. Etidronate treatment (e.g., of Paget s disease, osteoporosis, or hypercalcemia of mafignancy) can cause a mineralization defect and result in osteomalacia. 

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. 

Long-term anticonvulsive therapy with diphenylhydantoin or phenobarbital is known to cause osteomalacia by influencing calcium metabolism (24,25). Alteration in the metabolism of vitamin D, presumably secondary to induction of hepatic microsomal enzymes, leads to the calcium and bone abnormalities (26). Patients on anticonvulsive therapy with phenytoin exhibit a decrease in serum 25-hydroxyvitamin D (27). Adequate dietary amounts of vitamin precursors or microsomal enzyme stimulators might prevent these effects of long-term therapy. 

Anticonvulsant treatment Fibrogenes imperfecta ossium Osteitis fibrosa cystica Osteomalacia Osteoporosis Osteopenia Osteosclerosis Renal osteodystrophy Rickets... 

Osteomalacia and rickets have been reported with long-term anticonvulsant therapy additional risk factors for these conditions (e.g., poor sunlight exposure) increases risk... 

Immunoreactive parathyroid hormone concentrations may be increased by anticonvulsants, while bone mineral content is reduced. Hypocalcemia and osteopenia can occur, despite normal serum concentrations of active vitamin D metabolites, suggesting that they may be independent of drug effects on vitamin D metabolism. Bone biopsies have shown increased osteoid but normal calcification front formation, accelerated rate of mineralization, and reduced mineralization lag time, suggesting increased skeletal turnover rather than osteomalacia (96). The risk of age-related fractures in drug-treated epileptic patients is not greatly increased (97). 

Hoikka V, Savolainen K, Alhava M, Sivenius J, Karjalainen P, Repo A. Osteomalacia in institutionalised epileptic patients on long term anticonvulsant therapy. Arch Dis Child 1981 56 446. 

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). 

Treatment of osteomalacia from vitamin D deficiency is vitamin D therapy, with dose depending on severity. Supplements of 800 to 4000 units/day or 50,000 units weekly for 8 weeks may be necessary. For sprue, a gluten-free diet is necessary. With intestinal malabsorption, high oral doses (50,000 to 100,000 units/day) or daily intramuscular injections of 10,000 units of vitamin D may be initially required. With disordered vitamin D metabohsm caused by anticonvulsants or rifampin, supplemental vitamin D (4000 units/day) can be effective. Sun exposure can also be useful. Serum calcium and 25(OH) vitamin D monitoring is necessary with high vitamin D doses. 

Serum alkaline phosphatase elevation and other indices, both biochemical and radiological, of rickets and osteomalacia are more common in patients receiving anticonvulsant drugs than in control subjects (B13, C16, C37, R16, TIO). The severity of these abnormalities has been reported to relate directly to the duration of therapy (K35, TIO), to the... 

Precocious puberty may be associated with polyostotic fibrous dysplasia, which causes hyperphosphatasemia (A5). Some patients with precocious puberty suffer from convulsive disorders (L17), for which they receive anticonvulsant medication, resulting in osteomalacia and elevated serum alkaline phosphatase activities. Precocious puberty has also... 

Tolman, K. G., Jubiz, W., Sannella, J. J., Madsen, J. A., Belsey, R. E., Goldsmith, R. S., and Preston, J. W., Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children. Pediatrics 56, 45-51 (1975). 

Some drugs, for example anticonvulsants phenytoin, phenobarbital and corticosteroids can lead to osteomalacia and rickets by depressing vitamin D dependent calcium uptake in the intestine. 

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. 

In addition to the classical environmental or nutritional cause of these diseases, both osteomalacia and rickets can have a pharmacological origin via chronic treatment with anticonvulsants (phenobarbital and phenytoin) or glucocorticoids. These agents interfere with intestinal absorption of calcium and, thereby, cause pseudohyperparathyroidism. As a result, an increase in bone turnover and a decrease in the formation of appropriately mineralized bone is observed. In these patients, treatment with vitamin D improves calcium absorption, ultimately enhancing mineralization of the bone. 

Mallette LE. Anticonvulsants, acetazolamide and osteomalacia. NEr lJMed(y91S) 293,668. 

Mallette LE. Acetazolamide-accelerated anticonvulsant osteomalacia. Arch Intern Med(1977) 137,1013-17. 

Other reports describe patients whose response to usual doses of vitamin D was poor, because of concurrent anticonvulsant treatment with pheny-toin and phenobarbital or primidone. " Other reports clearly show low serum calcium levels,low serum vitamin D levels, osteomalacia, and bone structure alterations in the presence of phenytoin. 

Mosekilde L, Melsen F. Anticonvulsant osteomalacia determined by quantitative analyses of bone changes. Population study and possible nskfactors. Acta MedScand(l9J6) 199,349-55. 

A condition in which there is decalcification of bone tissue. It occurs when there is reduced calcium or vitamin D intake, for instance in malabsorption. Osteomalacia can also occur as a result of treatment with anticonvulsant drugs which are thought to interfere with the metabolism of vitamin D. Low serum calcium levels occur along with high serum alkaline phosphatase levels, the latter being due to a secondary increase in osteoblastic activity. 

An anticonvulsant drug. Among its undesirable side-effects h that of osteomalacia. This is thought to be due to the stimulatior by the drug of hepatic enzymes which inactivate vitamin D resulting in decreased calcium absorption. Phenytoin also in terferes with folate metabolism and this may result in i megaloblastic anaemia. 

A deficiency of vitamin D results in rickets in children and osteomalacia in adults. It can occur as a result of malnutrition, or malabsorption. Deficiency can also occur when there is a failure to hydroxylate vitamin D. This is thought to occur in some types of renal disease and as a result of treatment with particular anticonvulsant drugs. These drugs are thought to stimulate liver enzymes which oxidize vitamin D to inactive metabolites. 

Anticonvulsants—Epileptic patients given these drugs for the prevention of seizures have sometimes developed softening and distortion of their lx>nes which may lead to rickets in children, or to softening of the lx>nes (osteomalacia) in adults. 0 Apparently, the drugs produce their harmful effects on the bones by provoking increased rates of destruction of vitamin D and its active metabolites, so that the absorption and utilization of dietary calcium is reduced. Sometimes, their effects have been overcome by... 

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. 

Regarding the effect of anticonvulsants on calcium metabolism, the potential size of the problem was highlighted by Richens and Rowe (34 ) who showed that 22.5% of epileptic patients in an adult residential centre had decreased serum calcium levels, and 29% had increased alkaline phosphatase levels. Lemaire et al. (24 ) studied a case of osteomalacia due to anticonvulsants using tritium-labelled vitamin D. It was shown that its metabolism was accelerated in comparison with deficiency type osteomalacia. This supports the hypothesis that anticonvulsants, acting via hepatic enzyme induction processes, cause increased transformation of vitamin D into inactive metabolites. Richens states that it is likely that anticonvulsant osteomalacia is caused by a disturbance of the hepatic hydroxylation of vitamin D3 to... 

Calcium absorption was studied in 28 adult male epileptics on chronic anticonvulsant therapy. In 16 patients on phenytoin alone calcium absorption was abnormal in 9. In 12 patients on both phenytoin and phenobarbitone calcium absorption was abnormal in 3. Hypocalcaemia (<8.5 mg/ 100 ml) occurred in only 2 patients, while serum alkaline phosphatase was elevated in 7 patients. The findings support the suggestion that rickets and osteomalacia reported in patients on chronic anticonvulsant therapy results from reduced calcium absorpion. The effect of these drugs appear to be the increased metabolism of vitamin D via enzyme induction, and an increase in the excretion of polar metabolites 25-hydroxycholecalciferol and 1,25-dihy-droxycholecalciferol which are necessary for normal calcium absorption (40 ). 

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