StuartH. Ralston

COMPARISON OF THREE INTRAVENOUS BISPHOSPHONATES IN CANCER-ASSOCIATED HYPERCALCAEMIA

Three intravenous bisphosphonates were compared in the treatment of cancer-associated hypercalcaemia. 48 patients were randomly allocated to one of three treatment groups (each with 16 subjects)--30 mg pamidronate or 600 mg clodronate, both as single intravenous infusions; or etidronate as three infusions of 7.5 mg/kg per day for three consecutive days. Patients were rehydrated with normal saline before bisphosphonate treatment. All three bisphosphonates lowered serum calcium by inhibiting bone resorption; pamidronate was the most potent in this respect. By comparison with the other groups, more patients in the pamidronate group became normocalcaemic, and the effect on serum calcium was apparent sooner and lasted longer.

COMPARISON OF AMINOHYDROXYPROPYLIDENE DIPHOSPHONATE, MITHRAMYCIN, AND CORTICOSTEROIDSICALCITONIN IN TREATMENT OF CANCER-ASSOCIATED HYPERCALCAEMIA

Thirty-nine patients with cancer-associated hypercalcaemia were randomly allocated to receive aminohydroxypropylidene diphosphonate (APD), mithramycin, or corticosteroids and salmon calcitonin. Corticosteroids/calcitonin had the fastest calcium-lowering effect, owing mainly to an acute reduction in renal tubular calcium reabsorption; continued therapy over 9 days failed to suppress accelerated bone resorption, however, and most patients remained hypercalcaemic. Mithramycin also substantially reduced serum calcium within 24 h. A further dose on day 2 generally controlled hypercalcaemia until day 6 by reducing both bone resorption and renal tubular calcium reabsorption. By day 9, however, about 50% of the mithramycin-treated patients had started to relapse as bone resorption increased again. With APD serum calcium levels fell more slowly but progressively owing to effective suppression of bone resorption; by day 9 the control of hypercalcaemia was significantly better than in the other treatment groups. Symptoms of hypercalcaemia were greatly relieved, especially by APD.

Mineralisation defects with pamidronate therapy for Paget's disease

Bone biopsy samples were taken from 20 patients with Pagets disease before and after intravenous pamidronate therapy. In 10 patients given 180 or 360 mg during 6 or 9 weeks, bone turnover decreased as measured biochemically and histologically, but osteomalacia developed in 1 patient and mineralisation defects in 3. 10 other patients received 45 mg every 3 months for 1 year. Bone turnover decreased biochemically but not histologically, and osteoid thickness increased, suggesting impaired mineralisation. Despite overall efficacy, pamidronate has a narrow therapeutic range between resorption inhibition and mineralisation defects. Short courses given to achieve biochemical remission should be administered with caution.

THE PATHOGENESIS OF HUMORAL HYPERCALCAEMIA OF MALIGNANCY

The syndrome of humoral hypercalcaemia of malignancy (HHM) is characterised by end-organ manifestations of parathyroid-hormone (PTH)-like effects such as abnormalities of renal tubular calcium and phosphate transport, increased nephrogenous cyclic AMP and 1,25 dihydroxyvitamin D production, and increased osteoclastic bone resorption. Despite this, true ectopic PTH production has seldom been documented in HHM. A number of bone-resorbing factors, including prostaglandins, prostaglandin-stimulating factors, lymphokines, growth factors, and vitamin-D-like sterols, have been implicated as causes of HHM, but none can reproduce the PTH-like biochemical features characteristic of the syndrome. PTH-related peptides have recently been isolated from tumours associated with HHM. These substances are the most likely putative humoral mediators of HHM, since they are structurally similar to PTH in the aminoterminal region and interact with the PTH receptor in vitro. However, the remainder of the molecule is quite distinct from PTH, which accounts for the absence of PTH immunoreactivity in serum and tumour extracts from HHM patients. Since these factors seem to act by binding to the PTH receptor, synthetic PTH antagonists may in the future be a means of treating HHM.

Immobilization-related hypercalcaemia--a possible novel mechanism and response to pamidronate.

Immobilization-related hypercalcaemia is an uncommon but important condition being associated not infrequently with both urolithiasis and osteoporosis. In this study 5 patients who had been immobilized for a mean of 3 months and had a mean adjusted serum calcium of 3.15 mmol/l were treated with doses of intravenous pamidronate ranging between 10 mg and 45 mg. All patients became normocalcaemic by day 3. Patients 1-3 mobilized shortly after treatment and remained normocalcaemic. In those patients who continued to be immobile hypercalcaemia recurred after an interval of several weeks. Retreatment with pamidronate again resulted in normocalcaemia. No side effects were noted with treatment. All of the patients studied had increased rates of bone resorption as shown by elevated urinary hydroxyproline/creatinine ratios (median:range) of 0.101:0.045-0.180 (normal less than 0.033) and elevated calcium/creatinine ratios of 2.50:0.69-3.63 (normal less than 0.50). None of the patients in this study had any of the usual risk factors for developing immobilization-related hypercalcaemia though all 5 patients had problems with significant sepsis which we postulate may have lead to cytokine release which in turn contributed to the development of hypercalcaemia. We conclude that pamidronate (at doses as low as 10 mg) is safe and effective in immobilization-related hypercalcaemia and suggest that sepsis should be added to the list of risk factors for development of this syndrome.

Hypercalcaemia and metastatic bone disease: is there a causal link?

The relation between serum calcium and the extent of metastatic bone disease as judged by radionuclide bone scan was examined in a consecutive series of 195 patients with malignant disease. Of 87 patients with hypercalcaemia, 40% had no evidence of skeletal metastatic bone disease and serum calcium values. Of 160 patients judged to have bone-scan evidence of metastatic skeletal involvement, only 32.5% were significantly hypercalcaemic. Further, a negative correlation was found between the extent of metastatic bone disease and serum calcium value. The development of hypercalcaemia in malignancy is not directly related to the presence or extent of metastatic bone disease. It is suggested that the development of hypercalcaemia may depend on an alternative mechanism, such as the production of a humoral substance by tumour tissue, having its effect on calcium metabolism at sites or organs distant from local areas of tumor involvement.

Clinical experience with pamidronate in the treatment of Paget's disease of bone.

Bisphosphonates have been shown to be effective in treating the increased bone turnover associated with Pagets disease of bone. In this study two groups of patients were treated with pamidronate by intravenous infusion. In group 1 (n = 15) 30 mg of pamidronate was given once a week for six weeks. A subgroup (group 1A, n = 6) of more severely affected patients (pretreatment serum alkaline phosphatase (ALP) greater than 1000 U/l, normal range 80-280 U/l) received a further 60 mg weekly for three weeks. Group 2 (n = 24) received 45 mg of pamidronate every three months for one year. In both groups the level of ALP in serum samples decreased steadily throughout the year. In group 1 the level decreased to a mean value of 230 U/l (95% confidence interval 188-281) and in group 2 to 297 U/l (227-389). Four of the six patients in group 1A achieved normal ALP, whereas ALP remained at an increased level in all of the 10 patients in group 2 whose pretreatment ALP was greater than 1000 U/l, suggesting that a dose-response effect exists. The lowest hydroxyproline to creatinine ratios (normal ratio less than 0.033) were observed at the end of treatment in group 1, with a mean ratio of 0.022 (range 0.015-0.033) and at three months after the start of treatment in group 2 with a mean ratio of 0.029 (range 0.022-0.037). There was a significant decrease in the turnover of bone, as measured by whole body retention of radiolabelled bisphosphonate, from a mean of 49.3 to 41.0% (p less than 0.01). These data confirm that pamidronate is effective in the management of Pagets disease of bone. For patients with levels of ALP in serum samples of up to four times above the upper limit of the normal reference range, an effective and convenient regimen is 45 mg every three months for one year. For patients with higher levels of ALP higher doses may be more effective.

COMPARISON OF INTESTINAL CALCIUM ABSORPTION AND CIRCULATING 1,25‐DIHYDROXYVITAMIN D LEVELS IN MALIGNANCY‐ASSOCIATED HYPERCALCAEMIA AND PRIMARY HYPERPARATHYROIDISM

The relation between circulating 1,25‐dihydroxyvitamin D (l,25(OH)2D) levels and intestinal calcium absorption–as determined by an oral calcium load test–was studied in 16 patients with hypercalcaemia of malignancy (HM) and 16 with hypercalcaemic primary parathyroidism (HPT). In the HPT group serum calcium rose significantly after the oral calcium load and the increment correlated significantly with 1,25(OH)2D levels. While 1,25(OH)2D levels were raised to within the hyperparathyroid range in a number of HM patients, there was no correlation between change in serum calcium and 1,25(OH)2D level in the HM group and serum calcium did not rise significantly after the oral calcium load. HM patients with detectable or raised 1,25(OH)2D levels typically had few, or no, bone metastases in association with squamous lung cancers. A high proportion of these patients exhibited other aspects of hyperparathyroid‐like activity such as increased renal tubular calcium reabsorption, depressed renal tubular phosphate reabsorption and elevated urinary cyclic AMP excretion. Conversely, HM patients with undetectable 1,25(OH)2D levels typically had extensive metastatic bone disease in association with breast carcinoma and were less likely to exhibit other hyperparathyroid‐like features. It is postulated that in the former, the ‘inappropriately’ detectable or raised 1,25(OH)2D levels may have been due to enhanced renal la‐hydroxylase activity stimulated by the parathyroid hormone (PTH)‐like effect of a non‐PTH ectopic humoral mediator. In the latter the suppressed 1,25(OH)2D levels would be the predicted result of a non humorally mediated hypercalcaemia. It is currently unclear why intestinal calcium absorption was depressed in all HM patients when 1,25(OH)2D levels were normal or raised in some cases. It is possible, however, that in HM there is ‘end organ’ resistance to the effects of 1,25(OH)zD due to a generalized malabsorptive process.