Theodore J. Hahn

Effect of Chronic Anticonvulsant Therapy on Serum 25-Hydroxycalciferol Levels in Adults

Abstract A survey of 48 adult epileptic outpatients receiving chronic combined phenobarbital and diphenylhydantoin therapy demonstrated significant hypocalcemia in 19 per cent, and significantly decreased serum 25-hydroxycalciferol in 33 per cent of patients, as compared to 38 untreated controls. Similar but less marked changes were seen in a group of 13 patients given chronic therapy with either phenobarbital or diphenylhydantoin alone. Elevation of serum alkaline phosphatase in the patients receiving chronic therapy with either or both of these agents was attributable to increases in both the hepatic and bone isoenzyme fractions. Serum calcium correlated positively with serum 25-hydroxycalciferol in both the patient and the control groups. Serum 25-hydroxycalciferol also correlated positively with vitamin D intake in the patient and control groups, but at any given intake of vitamin D, mean serum levels were lower in the patient group. Lowest serum calcium and 25-hydroxycalciferol levels were seen in th...

Serum 25-Hydroxycalciferol Levels and Bone Mass in Children on Chronic Anticonvulsant Therapy

Abstract Fifty-six children with epilepsy receiving chronic therapy with phenobarbital or diphenylhydantoin or both and 51 controls were studied to determine the effects of anticonvulsant therapy o...

Competitive protein-binding radioassay of 24,25-dihydroxyvitamin D in sera from normal and anephric subjects

Abstract A competitive protein-binding radioassay for 24,25-dihydroxyvitamin D [24,25-(OH) 2 D] in human serum has been developed. Whereas small amounts of [ 3 H]24,25-(OH) 2 D must be biosynthesized in order to trace the efficiency of the extraction and chromatographic procedures, tritiated 25-hydroxyvitamin D 3 ([ 3 H]25-OHD 3 ) can be used as the assay tracer. Since 25-OHD 3 and 24,25-(OH) 2 D 3 are equipotent in their competitive displacement of [ 3 H]25-OHD 3 from rat serum, 25-OHD 3 can be used as the assay standard. Liquid-gel partition chromatography on small columns of Sephadex LH-20 can reliably isolate 24,25-(OH) 2 D by batch elution. The purity of biosynthesized [ 3 H]24,25-(OH) 2 D 3 and the 24,25-(OH) 2 D fraction isolated from serum was confirmed by high-pressure chromatography on 0.2 × 50 cm columns of 10-μm silica. Serum 24,25-(OH) 2 D levels averaged 16% of the serum 25-OHD concentrations in normal subjects. Since chronic hemodialysis patients, without kidneys, had normal serum 24,25-(OH) 2 D levels, significant extrarenal 25-hydroxycalciferol 24-hydroxylase activity occurs in these subjects. Since the present assay represents a reasonably simple extension of 25-OHD assay methodology, it should prove to be a useful technique in the analysis of clinical disorders of vitamin D metabolism.

Bone Complications of Anticonvulsants

SummaryAnticonvulsant drug-induced disorders in mineral and bone metabolism are apparently quite common. Current evidence indicates that these drugs derange bone metabolism, both through induction of increased hepatic catabolism of vitamin D and its biologically active products, as well as by direct effects on membrane cation transport systems.The significant clinical manifestations of the disorder include rickets with defective bone development, decreased bone mass with increased risk of pathological fracture and reductions in serum calcium levels which may predispose to increased seizure frequency. There is a broad range of clinical presentation with a number of factors — drug dose, duration of therapy, vitamin D intake, amount of sunlight exposure, degree of physical activity and presence of other concurrent diseases — which appear to determine the severity of the clinical manifestations. Current evidence indicates that appropriate vitamin D and calcium supplementation can significantly reduce the clinical manifestations of this disorder.All patients receiving chronic anticonvulsant drug therapy should be carefully evaluated for the presence of drug-induced osteomalacia and treated appropriately with vitamin D. This is especially important in those patients in whom the presence of multiple risk factors indicates an increased likelihood of deranged mineral metabolism.

Anticonvulsant drug-induced osteomalacia: Alterations in mineral metabolism and response to vitamin D3 administration

SummaryParameters of mineral metabolism were examined in 6 patients with moderately severe anticonvulsant drug-induced osteomalacia. Compared to 15 matched controls, the patients exhibited significantly reduced serum calcium, inorganic phosphate, and 25-hydroxyvitamin D concentration, elevated serum alkaline phosphatase and immunoreactive parathyroid hormone (iPTH) concentration, reduced intestinal47Ca absorption, reduced urinary calcium and increased urinary hydroxyproline excretion, and reduced forearm bone mass. Intestinal absorption of vitamin D3 was normal. Following 4 months of treatment with vitamin D3 (4000 units/day), serum 25-OHD concentration was increased to 3 times mean normal values and all parameters except serum iPTH, urinary calcium excretion, and forearm bone mass were returned to levels not significantly different from normal. Serum iPTH concentration was reduced by 39% (P<0.05); 24-h urinary calcium excretion rose by 98% (P<0.001), and forearm bone mass increased by 5.6% (P<0.05). It is concluded that moderate-dose vitamin D3 supplementation is effective in normalizing parameters of mineral metabolism in this disorder, despite evidence of resistance to the biologic effects of vitamin D.

Comparison of subacute effects of oxazacort and prednisone on mineral metabolism in man

SummaryProlonged therapeutic administration of prednisone or other corticosteroids frequently produces severe osteopenia with an increased incidence of bone fractures. Recent efforts to decrease the severity of corticosteroid-induced osteopenia have included the development of corticosteroid analogues designed to possess diminished bone-wasting effects relative to their anti-inflammatory activity. We compared the effects of an oxazoline derivative of prednisolone, oxazacort (azacortinol), with those of prednisone on mineral metabolism in man. After a 12-day equilibration period on a 600 mg/day calcium diet, normal volunteers were studied for 15 days during treatment with either prednisone (20 mg/day, 12 subjects) or oxazacort (25 mg/day, 10 subjects). There was no difference between the two groups with regard to the effects of each corticosteroid on serum ionized calcium, phosphate, alkaline phosphatase, immunoreactive parathyroid hormone (iPTH), and 25-hydroxyvitamin D (25OHD) concentrations. Both corticosteroids suppressed intestinal47Ca absorption to a similar degree after 15 days of treatment (prednisone: −28.5±7.5, oxazacort: −30.2±4.4% of initial values). Although both corticosteroids increased 24-h urinary calcium excretion significantly above pretreatment values, this effect was less marked in the oxazacort-treated subjects. The mean cumulative 15-day increase in urinary calcium excretion in the prednisone-treated group (+326 ± 54 mg/g creatinine/24 h) was more than twice as great as that in the oxazacort-treated group (+146 ± 48 mg/g creatinine/24 h), a difference significant atP<0.001. It is concluded that the increase in urinary calcium excretion, and presumably the negative calcium balance, produced by a 2-week administration of oxazacort is significantly less pronounced than that produced by an equivalent dose of prednisone.

Vitamin D metabolite-binding proteins in human tissue.

Serum and post-microsomal supernatants of human lymphocyte, erythrocyte, skeletal muscle and parathyroid adenoma homogenates were examined for specific binding of 25-hydroxycholecalciferol (25-OHD3) and 1, 25-dihydroxycholecalciferol (1,25-(OH)2D3). Muscle, lymphocytes and parathyroid adenomata extracts contained a 6-S 25-OHD3-binding protein which was not found in erythrocyte extracts, and which was distinct from the smaller serum transport alpha-globulin. A cathodal, 1, 25-(OH)2D3-binding protein, which sedimented at 3-4 S was also detected in parathyroid tissue. These observations suggest the possibility of direct physiologic interaction between vitamin D metabolites and nucleated human tissues other than intestine and bone.

Mixed-sclerosing-bone-dystrophy: Report of a case and review of the literature

We present clinical, laboratory, radiologic, genetic, and pathologic findings in a 49-year-old man with mixed-sclerosing-bone-dystrophy (MSBD), review the six cases previously reported as “MSBD”, and examine the nosology of this rare bone dysplasia. Our asymptomatic patient showed radiographic changes consistent with osteopoikilosis, osteopathia striata, and melorheostosis and had widespread osteosclerosis of the axial skeleton. Several previous reports of combined osteosclerotic disorders suggest the latter finding represents osteopetrosis, however, histologic examination of our patients iliac crest excluded that diagnosis. Limited radiographic surveys of his eight children were unremarkable except for isolated bone islands in two sons. Literature review revealed that “MSBD” has actually been used generically to describe the association of a variety of osteosclerotic bone dysplasias when they occur together in a single patient.

Vitamin D metabolites specific binding by rat intestinal cytosol

Abstract The intestine of ricketic rats, a recognized target tissue of vitamin D, contains s soluble macromolecule capable of specific in vitro binding of both 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol. Its sedimentation behavior on linear 5–20% sucrose gradients suggests as a molecular weight of approximately 100 000. The binding is specific for sterols possessing both an open B ring and 25-hydroxyl group, and is destroyed by pre-incubation with trypsin. The binding affinity for 25-hydroxycholecalciferol ( K A = 2 · 10 9 1/ mole ) was 2.8 times that for 1,25-dihydroxycholecalciferol.

Cortisol enhancement of PTH-stimulated cyclic AMP accumulation in cultured fetal rat long bone rudiments

SummaryCortisol in concentrations from 10 nM to 10 µM produced a dose-related inhibition of basal and PTH1-stimulated45Ca and [3H]-hydroxyproline release from cultured fetal rat forelimb rudiments. PTH-stimulated cyclic AMP generation however was not diminished by cortisol; in contrast, at a concentration of 1 µM cortisol produced a 57% increase in PTH-stimulated bone cyclic AMP content. The stimulatory effect of cortisol on cyclic AMP content appeared to be the result of reduced phosphodiesterase activity, since this effect was not seen in the presence of 10 mM theophylline. It is concluded that cortisol inhibition of PTH-induced resorption in long bones is not accompanied by reduced cyclic AMP generation.