Phenytoin inhibition of parathyroid hormone induced bone resorption in vitro.

1 A study is reported of the effects of phenytoin and phenobarbitone on bone calcium mobilization by parathyroid hormone in vitro.2 In a therapeutic concentration (15 mug/ml), phenytoin significantly inhibited parathyroid hormone-induced calcium release from bone.3 The inhibitory effect of phenytoin on bone calcium mobilization could play a role in the maintenance of hypocalcaemia in epileptic patients on long-term anticonvulsant drug therapy.

The effect of uraemic metabolites on parathyroid extract-induced bone resorption in vitro.

A study is reported of the effects of both pre- and post-dialysis serum and some of the known uraemic metabolites on parathyroid extract-induced bone resorption using an in vitro organ culture system. Serum from uraemic patients prior to haemodialysis was shown to inhibit the action of parathyroid hormone on bone and this inhibitory effect was not present after dialysis. Some of the uraemic metabolites studied and also phosphate exerted an inhibitory effect but the metabolites caused their inhibition at higher concentrations than those which are known to occur in uraemic patients. It is concluded that if uraemic metabolites play a role in vivo then it is probably due to a cumulative phenomenon.

Hepatic mixed function oxidase induction during rifampicin/isoniazid therapy in Indian vegetarians.

To determine the effect of rifampicin therapy on hepatic oxidase activity in animal protein deficient patients antipyrine and quinine t 1/2 and 6B-hydroxycortisol (6B-OHF) excretion was studied in 8 Indian vegetarians during treatment for tuberculosis. In 4 patients at the start of treatment rifampicin/streptomycin caused a steady decline in by time antipyrine t 1/2 which was complete in 3 weeks, in one patient introduction of isoniazid produced a temporary reversal. After 4 months rifampicin/isoniazid 6B-OHF excretion was increased 2 to 10 fold in all patients although one followed serially showed a marked fall when isoniazid was begun. Decline in antipyrine t 1/2 persisted in 4 patients at the end of 18 months therapy and in one of these concurrent quinine t 1/2 confirmed partial isoniazid reversal of this decline. Rifampicin-mediated mixed function oxidase induction appeared similar to that reported for non-vegetarians and largely persists with combination therapy throughout treatment. Isoniazid can act as a competitive inhibitor of hepatic oxidase activity in some patients.

Plasma gamma glutamyltransferase levels during rifampicin therapy for tuberculosis.

A possible effect of rifampicin enzyme induction on microsomally derived plasma gamma glutamyltransferase (gamma GT) during treatment for tuberculosis patients with spinal bone disease and pulmonary or lymph node involvement was studied. Of 10 patients with bone disease 5 had raised levels prior to therapy (greater than 60 IU/l) and none were alcohol consumers. Gamma GT is not known to be present in bone and this probably represents an indirect effect on the liver. Changes in gamma GT in the first 2 months of rifampicin/isoniazid treatment were variable and will not serve as an index of response to therapy. Of 69 patients with lung or lymph node disease 15 had raised levels during treatment and 9 had a high alcohol intake, when the alcohol group were excluded there was no significant difference from controls who had completed treatment (p greater than 0.1). We conclude that plasma gamma GT, a standard clinical estimation of liver dysfunction, is a useful index of suspicion for alcoholics among the tuberculous group but the disease itself can produce similar levels. It did not reflect the known hepatic microsomal inducing properties of rifampicin and thus differs from the anticonvulsant model. Clinical value would be enhanced if specific liver isoenzymes in plasma were identified which separated tissue injury, enzyme induction and the effect of extrahepatic infection on the liver.

Note on the enzyme assay for urinary D-glucaric acid and correlation with rifampicin-induced mixed function oxidase activity.

The enzyme assay for urinary D-glucaric acid is the simplest specific procedure for measuring drug-mediated hepatic enzyme induction in an ordinary laboratory without complex equipment. The problem of lactone conversion and interfering substances in the urine is examined. The normal range showed no significant difference between males (mean +/- SD = 42.60 +/- 19.80 mumol/day) and females (mean +/- SD = 40.40 +/- 31.50 mumol/day). Storage of urine at -20 degrees C longer than 6 months caused a decline in recovery probably due to further breakdown of D-glucarate. During rifampicin/streptomycin treatment a negative correlation was found between decline in antipyrine half-life (t1/2), a measure of mixed function oxidase activity, and rise in urinary D-glucaric acid (r = -0.7614, p less than 0.05). However, in 63 patients receiving rifampicin/isoniazid therapy no rise in D-glucaric acid was detected. Isoniazid appears to be an inhibitor of the glucuronic acid pathway in man at the level of uronlactonase or glucuronolactone dehydrogenase.

Metabolic balance studies of mineral supplementation in osteoporosis.

1. We studied the effect of mineral supplementation and its duration in osteoporosis by analysing the calcium and phosphorus balances of 49 treated osteoporotic patients whose median length of calcium treatment was 19 weeks with a range of 8 days to over 4 years. Forty-four studies satisfied statistical criteria of reproducibility and included 35 women (10 also receiving oestrogen replacement therapy) and nine men. 2. Mean calcium balance was positive in women taking calcium supplements alone, +1.9 +/- 2.5 mmol daily (P less than 0.002), and was significantly more positive (P less than 0.05) in women also taking oestrogens, +4.2 +/- 2.1 mmol daily. Calcium balance was not significantly positive in men. 3. Calcium balance correlated negatively with duration of supplementation, but significantly, only when duration of supplementation was expressed logarithmically (r = -0.401, P less than 0.01) giving the regression equation y = 4.2-1.6 log x, where y = calcium balance in mol/day and x = duration of supplementation in weeks. Theoretical net calcium retention, without allowance for dermal loss, could be calculated by integration. 4. Mean phosphorus balance was significantly positive in both groups of women and in the whole population. Although its correlation with duration of supplementation did not reach statistical significance (P less than 0.1), the ratio of the regression slopes for calcium and phosphorus, 1.5:1, corresponded to their molar ratio in bone. 5. These statistics are, we believe, the first to describe an exponential decline in calcium balance during mineral treatment of osteoporosis, but they firmly suggest that such treatment, with or without oestrogen therapy, conveys temporary benefit.

Fluoride therapy in osteoporosis: acute effects on parathyroid and mineral homoeostasis.

1. Acute metabolic effects of sodium fluoride therapy were analysed among 41 osteoporotic patients already receiving large calcium supplements, 33 of whom underwent simultaneous metabolic balance studies. 2. Mean serum calcium fell transiently within 24-48 h by 0.03 +/- 0.07 (SD) mmol/l (P less than 0.01) and phosphorus by 0.06 +/- 0.08 (SD) mmol/l (P less than 0.001). In a subgroup, ionized calcium fell and biologically active parathyroid hormone (bio-PTH) rose more than fivefold (P less than 0.01). Urine calcium rose after an insignificant fall. 3. Pretreatment calcium and phosphorus balances were significantly positive and did not change overall during the first 8 days of treatment. However, on analysing balances in two groups relative to serum changes, in patients whose serum levels changed least sodium fluoride increased faecal calcium (P less than 0.025) and phosphorus (P less than 0.01) and reduced calcium balance (P less than 0.01), giving a mean balance difference between the two groups of 2.1 mmol daily (P less than 0.001). 4. Very small changes in serum levels therefore indicate well-marked metabolic responses: sodium fluoride acutely stimulates bio-PTH activity and must also enhance mineral uptake from circulation into tissue(s). By separate and opposing action(s) it inhibits intestinal calcium and phosphorus absorption, predominantly in those whose serum levels remain stable. All these effects may be relevant to long-term therapeutic results.

Fluoride therapy and parathyroid hormone activity in osteoporosis.

1. To determine the relationships between parathyroid hormone activity and long-term sodium fluoride therapy in osteoporosis, cytochemical bioassays (for biologically active parathyroid hormone) were performed in 22 osteoporotic control patients and in 18 patients after 15 +/- 10 months of treatment (60 mg of sodium fluoride daily). Ten patients were studied longitudinally by repeated metabolic balances and were therefore common to both groups. All patients were receiving mineral supplements. 2. Cross-sectional data showed a fourfold mean increase in biologically active parathyroid hormone on fluoride treatment (P less than 0.005) together with a 51% increase in serum alkaline phosphatase (P less than 0.005). Longitudinal data showed, in addition, a significant increase in the calcium balance of 2.4 +/- 1.2 (SEM) mmol daily (P less than 0.05) and the development of a positive phosphorus balance (P less than 0.02). 3. Fluoride-treated patients were then analysed in two groups according to the level of biologically active parathyroid hormone. Thirty-two per cent of values were above the upper limit of normal (18 pg/ml). The mean serum alkaline phosphatase level in this group showed no elevation above that of the control patients, the overall rise being accounted for entirely by patients with normal levels of biologically active parathyroid hormone. High levels of biologically active parathyroid hormone were also associated with relative hypophosphataemia (P less than 0.01), relative hypercalciuria (P less than 0.05) and an increased urine/faecal calcium ratio (P less than 0.025). 4. Results show that long-term fluoride and calcium therapy increase biologically active parathyroid hormone in osteoporosis and that excessive parathyroid hormone activity may account for certain features of the refractory state.