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The use of diphosphonates in the treatment of primary hyperparathyroidism
152
Abstracts: Bone and Tooth Society and British Endocrine Society Joint Meeting
3. EVIDENCE FOR EXTRARENAL GENERATION OF 1,25-DIHYDROXY AND 24,25-DIHYDROXYVITAMIN D3 IN MAN L.J. Fraher,‘S. Adami,‘S.E. Papapoulos,’ H.L. Sudan,’ R.J. McGonigle,2 V. Parsons2 and J.L.H. O’Riordan’ ‘Department of Medicine, The Middlesex Hospital, London Wl, UK ‘The Renal Unit, Dulwich Hospital, London, UK Although the important role of the kidney in the genesis of the active metabolites of vitamin D3 is well documented, recent animal studies both in vitro and in vivo have indicated that other tissues may possess vitamin D l- and 24-hydroxylase activity. To study this we have measured five of the polar metabolites of vitamin D,, including 1,25- and 24,25(OH)2D, in 4 patients on chronic dialysis (3 of whom had been surgically nephrectomized) both before and during administration of large doses of vitamin D3. Serum samples were extracted using acetonitrile and Cl8 silica, and the vitamin D, metabolites were fractionated on a high performance HPLC system (Zorbax-SIL eluted with hexane:methanol:isopropanol, 94:3:3 by volume at 3.0 mllmin). 25(OH)D, was measured using a rat serum CPBA, 24,25(OH),D3, 25(0H)D,-lactone, and 25,26(OH),D, by RIA using antiserum 02282 and 1,25(OH),D, by RIA using a selective antiserum S-11. The circulating concentrations of these metabolites were followed in the patients for between 3 and 6 weeks of ingestion of 40,000 IU/d of vitamin D, and compared to IO untreated normal controls whose samples were randomly measured in the same assays. In the 4 patients serum 25(OH)D, initially ranged from 5.3 to 17.6 nglml (controls 3.4-29) and this range rose on therapy to become 28-75 nglml. Circulating 25,26(OH),D3, which was initially 110-204 pglml (controls 150-1078) increased in a similar manner to reach a range of 600-1700 pg/ml. 24,25(OH),D, was detectable in all 4 of the patients prior to therapy but was low, ranging from0.08t00.12 ng/ml (controlsO.l-4.1); this rosemoreslowly to range from 0.2 to 2.8 nglml at the end of the study. The recently described metabolite 25(0H)D,-lactone was undetectable in all the patients before treatment (controls 60-165 pglml) but increased through the limit of detection to rangefrom 130 to480 pg/ml, and circulating 1,25(OH),D,, which wasalso undetectable in these patients prior to treatment (controls 20-57 pglml), became measurable in 3 of the 4. These studies suggest that extrarenal l- and 24-hydroxylases may be found in man and lend support to previous animal studies.
4. THE USE OF DIPHOSPHONATES IN THE TREATMENT OF
PRIMARY HYPERPARATHYROIDISM A.J.P. Yates, A.D. Paterson, C.J. Preston, K.I. Mundy, R.C. Percival, R.G.G. Russell, and J.A. Kanis Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Beech Hill Road, Sheffield, SlO ZRX, UK Medical treatment of hyperparathyroidism with inhibitors of bone resorption could be of value in suppressing hyperparathyroid bone disease either before surgery or in patients in whom parathyroidectomy is contraindicated. We have studied the effects of the diphosphonates CI,MDP (clodronate) and EHDP (etidronate) in 16 patients with primary hyperparathyroidism in order to evaluate their mode of action and therapeutic potential. CI,MDP (1 .O-3.2 g daily) was given to 9 patients. Bone resorption decreased in all patients, as judged by a fall
in fasting urinary calcium/creatinine ratio and hydroxyproline/ creatinine ratio. All patients were initially hypercalcemic. Serum calcium fell in response to treatment to values near the upper end of the normal range. Hypercalcemia and hypercalciuria recurred when treatment with CI,MDP was stopped. This suggests that CI,MDP acts primarily by inhibiting bone resorption and that renal tubular reabsorption of calcium remains increased in these patients. In the 3 patients treated with CI,MDP for longer than 19 weeks, the reduction of serum calcium was not fully sustained, suggesting the recoupling of bone formation with bone resorption. In contrast, the effects of EHDP (1 g daily) given to 7 patients were less marked, but there were significant reductions in urinary calcium/creatinine and hydroxyprolinelcreatinine ratios. However, no significant depression of plasma calcium was noted. Plasma phosphate concentrations and TmPlGFR increased, suggesting that the drug was effectively absorbed. The lack of response of serum calcium to EHDP may be due to the mineralization defect induced by this agent, offsetting the effect of decreased bone resorption These results suggest that CI,MDP, but not EHDP, could prove of value in the medical management of primary hyperparathyroidism.
5. EARLY EFFECTSOF SEX STEROIDSON CALCIUM METABOLISMAND PATIENTSWITH PRIMARY HYPERPARATHYROIDISM P.L. Selby, M. Peacock, and W.B. Brown MRC Mineral Metabolism Unit, The General Infirmary, Leeds, LS13EX, UK Sex steroid treatment reduces urinary calcium in postmenopausal women. We have shown that this is initially accompanied by a decrease in calcium absorption (Selby and Peacock: C/in. Sci. 64:65, 1983). In order to examine the role of PTH on this response we studied the early effects of sex steroid hormone replacement therapy in 7 postmenopausal patients with primary hyperparathyroidism. Four women were given ethinyloestradiol30 pgld and three norethisterone 5 mg/d. The results were compared with those obtained in 8 normal women given ethinyloestradiol and 6 given norethisterone. Patients were studied basally and after 1 and 3 weeks of treatment, when blood was drawn for estimation of Ca, PO,, PTH, vitamin D metabolities, and vitamin D binding protein concentrations. Urine was obtained for the estimation of Ca, PO,, hydroxyproline, and CAMP excretion. Calcium excretion was decreased from 10.41 + 1 .Ol (SE) mmol/day to 7.87 + 0.85 mmol/day over the first week (P < 0.01). This was also seen in the fasting calcium excretion, which continued to fall throughout the study period. A similar fall was seen in urinary hydroxyproline excretion. Plasma calcium and radiocalcium absorption were decreased by treatment. The only difference seen between the patients treated with norethisterone and those treated with ethinyloesteradiol is that the latter show an increase in plasma 1,25(OH),D from 103.5 + 12.3 pmol/l to 143.6 + 19.1 pmolll (P c 0.001) at 3 weeks. This was entirely explicable by a rise in vitamin D binding protein, which rose from 388 + 28 mgll to 535 f 15 mgll (P < 0.01) over the same period. There was no change in the calculated free 1 ,25(OH)2 vitamin D concentrations. These changes were not seen in the norethisterone-treated group. We conclude that the early effects of sex steroid therapy in patients with primary hyperparathyroidism are similar to those seen in normal postmenopausal women and are, therefore, uninfluenced by the
Abstracts: Bone and Tooth Society and British Endocrine Society Joint Meeting
3. EVIDENCE FOR EXTRARENAL GENERATION OF 1,25-DIHYDROXY AND 24,25-DIHYDROXYVITAMIN D3 IN MAN L.J. Fraher,‘S. Adami,‘S.E. Papapoulos,’ H.L. Sudan,’ R.J. McGonigle,2 V. Parsons2 and J.L.H. O’Riordan’ ‘Department of Medicine, The Middlesex Hospital, London Wl, UK ‘The Renal Unit, Dulwich Hospital, London, UK Although the important role of the kidney in the genesis of the active metabolites of vitamin D3 is well documented, recent animal studies both in vitro and in vivo have indicated that other tissues may possess vitamin D l- and 24-hydroxylase activity. To study this we have measured five of the polar metabolites of vitamin D,, including 1,25- and 24,25(OH)2D, in 4 patients on chronic dialysis (3 of whom had been surgically nephrectomized) both before and during administration of large doses of vitamin D3. Serum samples were extracted using acetonitrile and Cl8 silica, and the vitamin D, metabolites were fractionated on a high performance HPLC system (Zorbax-SIL eluted with hexane:methanol:isopropanol, 94:3:3 by volume at 3.0 mllmin). 25(OH)D, was measured using a rat serum CPBA, 24,25(OH),D3, 25(0H)D,-lactone, and 25,26(OH),D, by RIA using antiserum 02282 and 1,25(OH),D, by RIA using a selective antiserum S-11. The circulating concentrations of these metabolites were followed in the patients for between 3 and 6 weeks of ingestion of 40,000 IU/d of vitamin D, and compared to IO untreated normal controls whose samples were randomly measured in the same assays. In the 4 patients serum 25(OH)D, initially ranged from 5.3 to 17.6 nglml (controls 3.4-29) and this range rose on therapy to become 28-75 nglml. Circulating 25,26(OH),D3, which was initially 110-204 pglml (controls 150-1078) increased in a similar manner to reach a range of 600-1700 pg/ml. 24,25(OH),D, was detectable in all 4 of the patients prior to therapy but was low, ranging from0.08t00.12 ng/ml (controlsO.l-4.1); this rosemoreslowly to range from 0.2 to 2.8 nglml at the end of the study. The recently described metabolite 25(0H)D,-lactone was undetectable in all the patients before treatment (controls 60-165 pglml) but increased through the limit of detection to rangefrom 130 to480 pg/ml, and circulating 1,25(OH),D,, which wasalso undetectable in these patients prior to treatment (controls 20-57 pglml), became measurable in 3 of the 4. These studies suggest that extrarenal l- and 24-hydroxylases may be found in man and lend support to previous animal studies.
4. THE USE OF DIPHOSPHONATES IN THE TREATMENT OF
PRIMARY HYPERPARATHYROIDISM A.J.P. Yates, A.D. Paterson, C.J. Preston, K.I. Mundy, R.C. Percival, R.G.G. Russell, and J.A. Kanis Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Beech Hill Road, Sheffield, SlO ZRX, UK Medical treatment of hyperparathyroidism with inhibitors of bone resorption could be of value in suppressing hyperparathyroid bone disease either before surgery or in patients in whom parathyroidectomy is contraindicated. We have studied the effects of the diphosphonates CI,MDP (clodronate) and EHDP (etidronate) in 16 patients with primary hyperparathyroidism in order to evaluate their mode of action and therapeutic potential. CI,MDP (1 .O-3.2 g daily) was given to 9 patients. Bone resorption decreased in all patients, as judged by a fall
in fasting urinary calcium/creatinine ratio and hydroxyproline/ creatinine ratio. All patients were initially hypercalcemic. Serum calcium fell in response to treatment to values near the upper end of the normal range. Hypercalcemia and hypercalciuria recurred when treatment with CI,MDP was stopped. This suggests that CI,MDP acts primarily by inhibiting bone resorption and that renal tubular reabsorption of calcium remains increased in these patients. In the 3 patients treated with CI,MDP for longer than 19 weeks, the reduction of serum calcium was not fully sustained, suggesting the recoupling of bone formation with bone resorption. In contrast, the effects of EHDP (1 g daily) given to 7 patients were less marked, but there were significant reductions in urinary calcium/creatinine and hydroxyprolinelcreatinine ratios. However, no significant depression of plasma calcium was noted. Plasma phosphate concentrations and TmPlGFR increased, suggesting that the drug was effectively absorbed. The lack of response of serum calcium to EHDP may be due to the mineralization defect induced by this agent, offsetting the effect of decreased bone resorption These results suggest that CI,MDP, but not EHDP, could prove of value in the medical management of primary hyperparathyroidism.
5. EARLY EFFECTSOF SEX STEROIDSON CALCIUM METABOLISMAND PATIENTSWITH PRIMARY HYPERPARATHYROIDISM P.L. Selby, M. Peacock, and W.B. Brown MRC Mineral Metabolism Unit, The General Infirmary, Leeds, LS13EX, UK Sex steroid treatment reduces urinary calcium in postmenopausal women. We have shown that this is initially accompanied by a decrease in calcium absorption (Selby and Peacock: C/in. Sci. 64:65, 1983). In order to examine the role of PTH on this response we studied the early effects of sex steroid hormone replacement therapy in 7 postmenopausal patients with primary hyperparathyroidism. Four women were given ethinyloestradiol30 pgld and three norethisterone 5 mg/d. The results were compared with those obtained in 8 normal women given ethinyloestradiol and 6 given norethisterone. Patients were studied basally and after 1 and 3 weeks of treatment, when blood was drawn for estimation of Ca, PO,, PTH, vitamin D metabolities, and vitamin D binding protein concentrations. Urine was obtained for the estimation of Ca, PO,, hydroxyproline, and CAMP excretion. Calcium excretion was decreased from 10.41 + 1 .Ol (SE) mmol/day to 7.87 + 0.85 mmol/day over the first week (P < 0.01). This was also seen in the fasting calcium excretion, which continued to fall throughout the study period. A similar fall was seen in urinary hydroxyproline excretion. Plasma calcium and radiocalcium absorption were decreased by treatment. The only difference seen between the patients treated with norethisterone and those treated with ethinyloesteradiol is that the latter show an increase in plasma 1,25(OH),D from 103.5 + 12.3 pmol/l to 143.6 + 19.1 pmolll (P c 0.001) at 3 weeks. This was entirely explicable by a rise in vitamin D binding protein, which rose from 388 + 28 mgll to 535 f 15 mgll (P < 0.01) over the same period. There was no change in the calculated free 1 ,25(OH)2 vitamin D concentrations. These changes were not seen in the norethisterone-treated group. We conclude that the early effects of sex steroid therapy in patients with primary hyperparathyroidism are similar to those seen in normal postmenopausal women and are, therefore, uninfluenced by the