Fall In Serum Calcium Research Articles

A cross-sectional study to find out the role of lipid peroxidation in the alteration of serum calcium and magnesium levels with aging

Background: In the forthcoming decades, there will be a tremendous increase in the elderly population in India. According to free radical theory, aging is a result of cumulative damage incurred by free radical reactions (reactive oxygen species [ROS]). Antioxidant system (superoxide dismutase, catalase, glutathione, etc.) performs the function of neutralizing of these ROS activities. Free radicals cause peroxidation of membrane lipids and serum malondialdehyde (MDA) can be used as a biomarker to assess the overall lipid peroxidation level. Lipid peroxidation will alter the membrane permeability to electrolytes/other ions and may lead to alteration in the electrolyte or mineral levels. Aims and Objectives: This study aims to compare the serum levels of calcium and magnesium in different age groups and to find out its correlation with serum MDA level. Materials and Methods: A total of 150 healthy subjects (20–90 years) were recruited and divided into three groups of 50 each; as young (20–30 years), middle aged (40–59 years), and the elderly (60–90 years). Serum MDA, calcium, and magnesium levels were determined and compared. The correlation between serum MDA and with calcium and magnesium levels was analyzed with appropriate statistical tests. Results: The present study revealed a significant fall in serum calcium and magnesium levels in the elderly. A negative correlation between serum MDA with calcium and magnesium was observed. Conclusion: It is evident that lipid peroxidation plays a role in alteration in the serum calcium and magnesium levels with aging.

Is hungry bone syndrome a cause of postoperative hypocalcemia after total thyroidectomy in thyrotoxicosis? A prospective study with bone mineral density correlation

Hungry bone syndrome is a well-established cause of postoperative hypocalcemia in thyrotoxicosis. To date, the incidence of hungry bone syndrome after total thyroidectomy is unclear. This prospective study examined the incidence of postthyroidectomy hungry bone syndrome and its correlation with preoperative bone mineral density. Forty thyrotoxic subjects (Group A; age: mean ± SD; 36.5 ± 9.8 years) and 40 euthyroid controls with benign thyroid nodules (Group B) undergoing total thyroidectomy were evaluated for preoperative bone mineral density and serum calcium, magnesium, phosphorus, parathyroid hormone, alkaline phosphatase, and 25-Hydroxy Vitamin D serially. At least 3 parathyroid glands were preserved. Both groups were age and sex matched. Thyrotoxic subjects had higher postoperative hypocalcemia (82.5% vs controls 22.5%, 95% confidence interval 37.9 to 75.4), low preoperative bone mineral density and raised alkaline phosphatase (each, P = .001). Among thyrotoxic subjects experiencing hypocalcemia (n = 33), 39.4% (13/33) exhibited hungry bone syndrome (characterized by simultaneous fall in serum calcium, magnesium, and phosphorus), 18.1% (6/33) had hypoparathyroidism and 12% had hypomagnesemia. Hypocalcemic subjects exhibiting hungry bone syndrome displayed further decreased preoperative bone mineral density in the spine (0.875 ± 0.138 vs 1.024 ± 0.149 g/cm2, P = .004) and low serum magnesium 72-hour postsurgery (0.57 ± 0.23 vs 0.88 ± 0.25 mmol/L, P = .013) than those not exhibiting hungry bone syndrome. Postoperative serum calcium correlated with preoperative bone mineral density in the spine (P = .013). In group B subjects experiencing hypocalcemia (n = 9), none exhibited hungry bone syndrome but 77.78% (7/9) had hypoparathyroidism. All but one was eucalcemic after 6 months. Hungry bone syndrome occurs exclusively in thyrotoxic subjects and constitutes the major cause of postoperative hypocalcemia after total thyroidectomy. Vertebral osteoporosis and hypomagnesemia within 72 hours after total thyroidectomy is associated with the risk of hungry bone syndrome.

Sequential changes in bone biochemical parameters and bone mineral density after renal transplant

To evaluate sequential changes in biochemical bone parameters, parathyroid hormone (iPTH), vitamin D levels and bone mineral density (BMD) over a period of 24 weeks after renal transplantation, we studied 75 patients (58 males, with a mean age of 35.4 years) who underwent their first renal transplantation without a past history of parathyroid surgery or fractures. Serum calcium, phosphorus and albumin were measured before transplant, then weekly for four weeks and monthly for the following 20 weeks. Serum iPTH and vitamin D levels and BMD were measured at baseline and 24 weeks after transplantation. After transplantation, there was a significant fall in serum calcium in the first week, followed by a gradual rise. At 12 and 24 weeks, respectively, 17.5% and 8% patients had hypercalcemia. Serum phosphorus decreased after transplant and at 24 weeks; 25% patients had hypophosphatemia. The iPTH levels declined significantly from 251 ± 218.2 pg/mL before transplant to 97 ± 142.8 pg/mL at the end of the study period. At 12 and 24 weeks, 42.7% and 51.3% patients, respectively, had persistent hyperparathyroidism (HPT). Elevated baseline iPTH levels and graft dysfunction were the risk factors for HPT at 12 weeks, while low vitamin D levels were the risk factor at 24 weeks. The BMD showed a significant decline of 2.7% after transplant, and it negatively correlated with the pre-transplant iPTH levels; the patients who received tacrolimus immunosuppression had a lower decline in BMD than the rest of the patients. No fractures were reported during the study period. We conclude that, after renal transplantation, hypercalcemia and hypophosphatemia are common, while a significant proportion of patients have persistent HPT and decline in bone mineral density.

Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones.

Mineral and bone metabolism are regulated differently in utero compared with the adult. The fetal kidneys, intestines, and skeleton are not dominant sources of mineral supply for the fetus. Instead, the placenta meets the fetal need for mineral by actively transporting calcium, phosphorus, and magnesium from the maternal circulation. These minerals are maintained in the fetal circulation at higher concentrations than in the mother and normal adult, and such high levels appear necessary for the developing skeleton to accrete a normal amount of mineral by term. Parathyroid hormone (PTH) and calcitriol circulate at low concentrations in the fetal circulation. Fetal bone development and the regulation of serum minerals are critically dependent on PTH and PTH-related protein, but not vitamin D/calcitriol, fibroblast growth factor-23, calcitonin, or the sex steroids. After birth, the serum calcium falls and phosphorus rises before gradually reaching adult values over the subsequent 24-48 h. The intestines are the main source of mineral for the neonate, while the kidneys reabsorb mineral, and bone turnover contributes mineral to the circulation. This switch in the regulation of mineral homeostasis is triggered by loss of the placenta and a postnatal fall in serum calcium, and is followed in sequence by a rise in PTH and then an increase in calcitriol. Intestinal calcium absorption is initially a passive process facilitated by lactose, but later becomes active and calcitriol-dependent. However, calcitriol's role can be bypassed by increasing the calcium content of the diet, or by parenteral administration of calcium.

Do newborns of epileptics on anticonvulsants develop biochemical signs of osteomalacia?

In a controlled prospective study performed in 16 pregnant epileptics and nine normal pregnant controls, biochemical indices of calcium homeostasis (serum calcium, serum magnesium, serum phosphate, and serum alkaline phosphatases) were determined after 18 weeks pregnancy, at birth, 8 days and 6 months after birth. Furthermore, the same indices were measured in their newborns in the first 6 months of life. In both groups of mothers the serum alkaline phosphatase rose significantly during the pregnancy (P less than 0.001), followed by a significant fall after the births (epileptics: P less than 0.05, controls: P less than 0.001), but the epileptic mothers had significantly higher initial serum alkaline phosphatase levels than the controls (P less than 0.05). In both groups of newborns a dramatical fall in serum calcium was observed in the first day of life (P less than 0.001), followed by a normalization after 1 month. The serum alkaline phosphatases doubled between day 8 and day 30 in both groups (P less than 0.001). In the standing debate whether epileptics should be treated prophylactically with vitamin D, the present study indicates that pregnancy in epileptics does not call for extra vitamin D supply, and their newborns do not develop more severe hypocalcemia than their controls.

A case of renal sarcoidosis: a special reference to calcium metabolism as a diagnostic and the therapeutic implications

Sarcoidosis is a systemic granulomatous disease of unknown etiology and is associated with a wide variety of renal disorders including nephrolithiasis, hypercalciuria, hypercalcemia, nephrocalcinosis, tubular defect, glomerulonephritis, and granulomatous interstitial nephritis. We report a case of renal sarcoidosis in which we could not detect any evidence of extrarenal involvements that was diagnosed by renal biopsy and abnormal calcium metabolism incompatible with chronic renal insufficiency. On laboratory findings, decreased creatinine clearance, proteinuria, hypercalcemia, hypercalciuria, and mildly elevated serum angiotensin-converting enzyme (ACE) were seen. Serum intact parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,alpha-25 vit D) were lower and higher than normal range, respectively, whereas the patient was already in chronic renal insufficiency. He was treated with oral corticosteroid. Serum ACE tended to fall, and 1,alpha-25 vit D level decreased with substantial fall of serum calcium and daily calcium excretion. In contrast, intact PTH increased slowly in accordance with a fall of serum calcium compatible with the level of renal impairment. Creatinine clearance and daily excretion of protein improved. The case reported here may propose that serial measurement of serum level of 1,alpha-25 vit D, calcium level, and magnitude of daily calcium excretion into urine is a simple and meaningful tool to detect the therapeutic response in sarcoidosis with abnormal calcium metabolism.

Changes in calcium homoeostasis in patients undergoing liver transplantation: effects of a single infusion of pamidronate administered pre-operatively

Bone turnover, bone loss and fracture risk increase after liver transplantation. It has been postulated that peri-operative administration of a bisphosphonate might prevent bone loss and reduce fracture rate. We studied the effects of a single pre-operative dose of pamidronate on biochemical parameters of skeletal metabolism in the first month after liver transplantation. In a randomized, single-blind study, six of 12 patients with chronic liver disease received 60 mg of pamidronate intravenously on a single occasion 1-30 days before transplantation. Six other patients undergoing transplantation received no pamidronate. We measured serum calcium, phosphate, albumin, bone-specific alkaline phosphatase, plasma parathyroid hormone and tartrate-resistant acid phosphatase before pamidronate infusion and at frequent intervals during the first 30 post-operative days. In treated patients, plasma parathyroid hormone increased 12-fold over baseline values and remained elevated in comparison with baseline at days 26-30; serum calcium and phosphate fell significantly, returning to normal at around day 14 post-operatively. There were no significant changes in any parameter in the untreated group. No changes in bone formation or resorption markers were observed in either group. The large increase in plasma parathyroid hormone concentrations in the treated group is probably secondary to the fall in serum calcium. The magnitude of the increase is much greater than that seen after pamidronate infusion in other patient groups. The lack of change in, or correlation of, serum calcium and plasma parathyroid hormone in the untreated group suggests that additional factors release calcium from bone after liver transplantation, presumably by increasing bone resorption.

A case report of hypo-parathyroidism with psychiatric complications

Hyper and hypo-parathyroidism both lead to psychiatric disorder. In the former the hypercal-caemia is responsible for an acute or chronic organic reaction, depending on the speed with which the calcium has risen. The hypocalcaemia of the latter is more likely to present as tetany, and enters into the differential diagnosis of hysterical over-breathing (Hill et al, 1987). Hypo-parathyroidism most commonly follows inadvertent parathyroidectomy during thyroiddectomy when an abrupt fall in serum calcium can precipitate psychiatric disturbance. The mental state is closely related to the serum calcium level. If this is borderline there may only be symptoms such as anxiety, depression and tension, but with lower levels acute confusion may result. More chronic symptoms occur in long standing hypo-parathyroidism, such as poor concentration, emotional lability and impaired intelligence (Kendall & Zealley, 1983).

Effect of bisphosphonate therapy and parathyroidectomy on the urinary excretion of galactosylhydroxylysine in primary hyperparathyroidism

In patients with mild or asymptomatic primary hyperparathyroidism a reliable index of bone resorption might be useful for appropriate management. Hydroxyproline is the most commonly used marker of bone resorption but its low specificity and sensitivity are known. Galactosylhydroxylysine, an amino acid mainly represented in bone collagen, has been proposed as a more suitable index of bone resorption. In this study we evaluated the sensitivity of galactosylhydroxylysine and hydroxyproline assays in following the changes of their urinary levels in 12 patients with mild primary hyperparathyroidism before and after treatment with bisphosphonate and surgery. Serum and fasting urine specimens were obtained from 12 women with mild primary hyperparathyroidism before and after bisphosphonate treatment (2.5 mg daily for 5 days, intravenously) and after a further 25 days; in 7 patients biochemical tests were also performed 1 and 6 days after parathyroidectomy. Galactosylhydroxylysine was assayed by an HPLC method and hydroxyproline by a RIA commercial kit. Baseline galactosylhydroxylysine urinary levels were far above the normal range in all the patients whilst in 8 of them baseline hydroxyproline levels were normal. Bisphosphonate treatment significantly decreased bone turnover as shown by a significant fall in serum calcium (from 2.9 to 2.6 mmol/l; P < 0.001) and in galactosylhydroxylysine and hydroxyproline (-55 and -31% respectively). Twenty-five days after the end of treatment, resorption increased again and serum calcium and galactosylhydroxylysine, but not hydroxyproline, rose significantly towards basal levels. One day after parathyroidectomy serum calcium, galactosylhydroxylysine and PTH showed reduction below normal ranges. PTH and galactosylhydroxylysine returned to normal values at day 6 after parathyroidectomy. No changes in hydroxyproline levels were seen. Galactosylhydroxylysine, but not hydroxyproline, correlated significantly with serum calcium and PTH. Galactosylhydroxylysine appears to be a sensitive index of bone resorption, useful in the clinical assessment of bone involvement and in the management of patients with mild primary hyperparathyroidism.

Treatment of malignant hypercalcaemia with aminohexane bisphosphonate (neridronate)

Twenty patients with hypercalcaemia due to malignancy, which persisted following rehydration, were treated with the bisphosphonate, aminohexane bisphosphonate (AHBP), which is structurally similar to pamidronate. The treatment given was a single infusion of 125 mg of AHBP in 500 ml of normal saline infused over 4 h. Serum and urine biochemistry were measured before and after treatment. Acute toxicity was evaluated with particular attention to gastrointestinal symptoms, acute-phase reaction and change in renal function, as judged by serum creatinine. The infusion of AHBP induced a rapid fall apparent by day 3 (P < 0.001), with a nadir at day 7. The serum calcium remained lower at days 14 and 28 than at day 0, but the numbers followed up were low (n = 5 and n = 4). In all 20 patients there was a fall in serum calcium after treatment, and in 13 (65%) normocalcaemia was achieved. Failure to respond completely to AHBP appeared to be associated with a renal mechanism of hypercalcaemia. Treatment was associated with a significant decrease in fasting urinary calcium excretion (P < 0.05). There was no change in white cell count or renal function following AHBP and only two cases of mild pyrexia after infusion. We conclude that aminohexane bisphosphonate is an effective agent in the treatment of tumour-induced hypercalcaemia, with rapid onset of effect and low toxicity.

Tumour induced hypercalcaemia: A case for active treatment

This paper reports a retrospective survey of the diagnosis, management and outcome of hypercalcaemia in patients admitted to a regional oncology centre over a 12-month period; 168 cases of tumour induced hypercalcaemia were identified. In 69 patients (41%) the presence of hypercalcaemia was not noted in the case records; in a further 15 patients (9%) a positive decision was made not to treat the condition, although some of these patients continued to receive other forms of active treatment. Of the remaining patients, 20 (12%) received intravenous fluids alone and 64 (38%) received bisphosphonate therapy. Of those patients with initial serum calcium >3 mmol/171% were treated with bisphosphonates. Median survival from onset of hypercalcaemia was only 2 months, but in the bisphosphonate treated group, 98% experienced a fall in serum calcium within a week of treatment. We believe that the symptomatic relief associated with a fall in serum calcium justifies active management even in the face of a poor prognosis. A large proportion of cases of tumour induced hypercalcaemia remain undiagnosed or untreated and we believe that this deserves further attention.

Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate

Thirty patients with hypercalcaemia due to malignancy that persisted following rehydration, were treated with a single dose of the bisphosphonate, clodronate. Clodronate (1.5 g) was administered intravenously in 500 ml normal saline over 4 h. Serum and urine biochemistry were measured before and after treatment and the results were compared with data from 15 patients given the recommended regimen 300 mg intravenous clodronate daily for 5 consecutive days. The single infusion induced a rapid and significant fall in serum calcium, apparent at day 3 (P < 0.0001) that persisted to the end of follow-up at day 10 (P < 0.001). Eighty per cent (24/30) of patients became normocalcaemic. The response was associated with a significant decrease in fasting urinary calcium excretion, and no change in renal function, as judged by serum creatinine. The same dose of clodronate, given as 5 daily infusions, induced a comparable decrease in serum calcium, but was less rapid in onset so that at day 3 the serum calcium was significantly lower with the single infusion (P = 0.02). The calcium lowering effect of both regimens depended on the tumour type. We conclude that the single infusion of 1500 mg clodronate is as effective in reducing serum calcium as the same dose given over 5 days. The single infusion has a more rapid onset of effect, is more convenient than multiple infusions, and has no adverse effect on renal function.

Levels of Parathyroid Hormone-Related Protein (PTHrP) in Hypercalcemia of Malignancy Are not Lowered by Treatment With the Bisphosphonate BM 21.0955

Parathyroid hormone-related protein (PTHrP) is a major cause of hypercalcemia in malignancy and serum levels are elevated in many patients suffering from this syndrome. In 10 patients with hypercalcemia of malignancy the levels of the midregional fragment of PTHrP in serum were determined by radioimmunoassay over 7 days during a calcium-lowering treatment with a single dose of the bisphosphonate BM 21.0955. PTHrP concentrations remained unchanged 6 days after administration of the drug as compared with pretherapeutic values, thus apparently excluding an effect of either the drug itself or the rapid fall in serum calcium on the release of PTHrP by the tumors or on its clearance from the circulation. In the patients with elevated midregional PTHrP levels (n = 6), the calcium-lowering effect of the drug was significantly less pronounced than in patients with normal PTHrP (n = 4) (mean serum calcium of 2.89 vs. 2.51 mmol/l at day 6), despite similar pretherapeutic concentrations. Of the six patients with elevated PTHrP, five were still hypercalcemic, whereas in the group with normal PTHrP one out of four patients remained hypercalcemic. In conclusion, PTHrP levels in hypercalcemia of malignancy remained unchanged after calcium-lowering therapy with bisphosphonates. High serum PTHrP levels were, however, predictive of a lesser effectiveness of the drug in lowering serum calcium.

Comparative effects of clodronate and calcitonin on bone in metastatic breast cancer: A histomorphometric study

We studied the effects of long-term treatment with clodronate, calcitonin or placebo on bone in 36 normocalcaemic women with osteolytic metastases due to breast cancer. Clodronate (1.6 g daily given to 12 patients) induced a significant decrease in osteoclast surface and osteoclast number, and a significant fall in serum calcium and urinary excretion of calcium and hydroxyproline, an effect not noted after treatment with calcitonin (100 U in 12 patients) or in 12 placebo-treated patients. Treatment with clodronate did not abnormally suppress bone turnover nor impair mineralisation, as measured by bone formation and mineral apposition rates.

Islet amyloid polypeptide: production by an osteoblast cell line and possible role as a paracrine regulator of osteoclast function in man

1. The recently discovered peptide islet amyloid polypeptide shows considerable sequence homology with calcitonin-gene-related peptide, itself an alternative product of the calcitonin gene. The possibility that islet amyloid polypeptide might affect calcium homoeostasis and bone cell function was investigated. 2. Islet amyloid polypeptide messenger RNA was found to be expressed by human HTb 96 osteoblast-like cells in culture, and islet amyloid polypeptide immunoreactivity was present in the cell culture medium. 3. Infusion of islet amyloid polypeptide (150 pmol min-1 kg-1) caused a fall in serum calcium and phosphate concentrations in five patients with Paget's disease of the bone. This was similar to that caused by infusion of calcitonin (50 pmol min-1 kg-1). 4. These findings raise the possibility that islet amyloid polypeptide may act as a local factor within bone, produced by osteoblasts and regulating osteoclast function. The possibility of an action of islet amyloid polypeptide on the renal handling of calcium seems unlikely but is not totally excluded.

Hypocalcemic Effect of Physiological Concentrations of Corticosterone in Adrenalectomized-Parathyroidectomized Rats*

We have confirmed the serum calcium-raising effect of adrenalectomy in young male rats 5-6 h after parathyroidectomy that was first observed by others many years ago. (The phenomenon has also been reported in cats, dogs, and mice.) In addition, we have shown that adrenalectomy raises the serum ionized calcium as well as total calcium and that the effect occurs in young female as well as in young male rats. Furthermore, we have found that the serum calcium-raising effect of adrenalectomy occurs if the adrenalectomy is performed several days before parathyroidectomy or 6 h after parathyroidectomy, as well as at the same time as the parathyroidectomy. When the rats were adrenalectomized 7-9 days before parathyroidectomy and given small daily life-maintaining doses of corticosterone or cortisone acetate, this glucocorticoid treatment did not reverse the adrenalectomy effect. This led us to think at first that the effect of adrenalectomy must be due to the loss of an unknown adrenal factor rather than to loss of glucocorticoid. Additional experiments, however, in which corticosterone or hydrocortisone was administered by continuous release pellets, demonstrated conclusively that a small continuous supply of corticosterone (within the physiological range as determined by immunoassay of plasma) was sufficient to reverse the adrenalectomy effect. The results with hydrocortisone were similar at even lower doses than of corticosterone. Somewhat higher doses of corticosterone or hydrocortisone reduced the serum calcium even below the parathyroidectomy level. In a preliminary investigation of the specificity of the glucocorticoid effect we found that aldosterone, dehydroepiandrosterone, or estradiol had no effect on serum calcium under similar conditions. We conclude that the fall in serum calcium after parathyroidectomy in rats is due in part to the hypocalcemic effect of endogenous corticosterone. Thus, the loss of corticosterone after adrenalectomy explains the serum calcium-raising effect of adrenalectomy in parathyroidectomized rats. These results also suggest that glucocorticoids at physiological levels have a significant effect on calcium metabolism in general.

Direct and indirect assessment of the parathyroid hormone response to pamidronate therapy in Paget's disease of bone and hypercalcaemia of malignancy

In patients with either Paget's disease or hypercalcaemia associated with malignancy (HCM) we have assessed the parathyroid response to pamidronate therapy, both by immunoassay of serum intact parathyroid hormone PTH (1–84) and by measurement of indirect parameters of PTH bioactivity, tubular maximum reabsorption of phosphate (TmPO 4/GFR) and nephrogenous cyclic AMP (NcAMP). In 12 patients with Paget's disease, therapy with pamidronate produced a small but significant decrease in adjusted serum calcium within the reference interval which was accompanied by a progressive increase in PTH (1–84) secretion and a corresponding fall in TmPO 4/GFR and increase in NcAMP. In 12 patients with HCM pretreatment, PTH (1–84) concentrations were suppressed, whilst mean TmPO 4/GFR was reduced and NcAMP was increased, compatible in most patients, with parathyroid hormone-related peptide (PTHrP) driven hypercalcaemia. Therapy with pamidronate produced the expected fall in serum calcium but caused an increase in PTH (1–84) secretion in the presence of absolute hypercalcaemia. The initial subnormal TmPO 4/GFR decreased further to a nadir on day 5, and there was a corresponding further increase in NcAMP. By day 7, however, when PTH (1–84) concentrations were maximal, there was a significant paradoxical rise in TmPO 4/GFR and a corresponding decrease in NcAMP. These data are consistent with a variable trigger point for PTH (1–84) secretion, one consequence of which is a reduction in the risk of hypocalcaemia following pamidronate. The results have major clinical implications for the interpretation of PTH (1–84) measurements in patients who are being treated or about to be treated for bone disease or for hypercalcaemia of malignancy (HCM). A pretreatment sample is essential in making the correct diagnosis in such patients, preventing confusion and possible unnecessary investigation.

Treatment of humoral hypercalcemia of malignancy in rats with inhibitors of carbonic anhydrase

The enzyme carbonic anhydrase has been suggested as a critical participant in osteoclast-mediated bone resorption. In humoral hypercalcemia of malignancy (HHM) intense osteoclastic bone resorption is principally responsible for the observed hypercalcemia. We therefore undertook to examine the effect of the carbonic anhydrase inhibitor acetazolamide on the hypercalcemia induced by the H500 Leydig cell tumor in Fisher rats, a well-described model of HHM. Acetazolamide treatment for 10 h at 10 mg/h resulted in a significant fall in serum calcium in the five drug-treated animals (14.2 +/- 0.9 to 11.5 +/- 0.1 mg/dl, p less than 0.05). Conversely, the six animals infused with vehicle alone showed a significant rise in serum calcium (12.5 +/- 0.5 to 13.8 +/- 0.1 mg/dl, p less than 0.05). At the end of the infusion, the acetazolamide-treated animals had a significantly lower mean serum calcium than those receiving vehicle alone (11.5 +/- 0.1 versus 13.8 +/- 0.1, p less than 0.05). There was no significant change in serum phosphorus, urine calcium, urine phosphorus, or nephrogenous cyclic AMP excretion between the two groups. Acetazaolamide and HTS 5-(3-hydroxybenzoyl)-2-thiophenesulfonamide, another carbonic anhydrase inhibitor, both significantly inhibited in vitro bone resorption induced by 5 X 10(-9) M 36Tyr(1-36)-PTHrP-amide (PTHrP, parathyroid hormone-related protein). Acetazolamide also inhibited the resorption induced by 10(-8) M (1-141)-PTHrP and 2.5 X 10(-9) M (1-74)-PTHrP. We conclude that acetazolamide is effective in lowering the serum calcium in animals with humoral hypercalcemia of malignancy. The data are consistent with the hypothesis that the mechanism of action for this effect is direct inhibition of osteoclast-mediated bone resorption.

REGULATION OF CALCIUM‐PARATHYROID HORMONE FEEDBACK IN PRIMARY HYPERPARATHYROIDISM: EFFECTS OF BISPHOSPHONATE TREATMENT

Dichloromethylene bisphosphonate (C12MBP), a powerful inhibitor of bone resorption, was administered to 27 patients with primary hyperparathyroidism. It was given by either intravenous infusion (six patients, 500-100 mg day), or by intramuscular injection (six patients, 100-200 mg/day) or by mouth (15 patients, 1600-2400 mg/day) for 20-180 days. Sustained suppression of bone resorption was observed in all patients, as judged by a fall in the urinary hydroxyproline excretion. In contrast, the hypocalcaemic effect was inconsistent and short-lived, particularly in the patients without overt bone disease. The fall in serum calcium seemed largely to be due to a transient dissociation between bone resorption and bone formation and was associated with increases in circulating parathyroid hormone (PTH). In ten patients given the bisphosphonate orally for 6 months, serum calcium was unchanged but serum PTH was significantly raised. These results suggest that C12MBP may be of use for short-term correction of severe hypercalcaemia due to hyperparathyroidism, particularly in the patients with overt bone disease. However, its long-term use should not be recommended because of increased PTH secretion.

Use of gallium to treat Paget's disease of bone: a pilot study

The effects of gallium nitrate on bone turnover were evaluated in four patients with active Paget's disease. Treatment with gallium nitrate (100 mg/m 2 daily for 5 days, intravenously in 5% glucose) significantly reduced serum calcium, serum phosphate, urinary calcium, and the ratio of maximum tubular reabsorption of phosphate to glomerular filtration rate in each patient. Serum parathyroid hormone levels rose. The findings suggest that the fall in serum calcium caused secondary hyperparathyroidism, resulting in a fall in serum phosphate. Serum alkaline phosphatase and urinary hydroxyproline levels fell substantially, showing that gallium effectively suppressed bone turnover. The fall in hydroxyproline excretion preceded that in serum alkaline phosphatase, suggesting that suppression of bone resorption by osteoclasts preceded that of bone formation by osteoblasts. Alkaline phosphatase levels remained low throughout follow-up (85-141 days), so the effect of gallium seems to be long-lasting.