Relative contribution of humoral and metastatic factors to the pathogenesis of hypercalcaemia in malignancy.

Some relations between metastatic bone disease and calcium homoeostasis were determined in a consecutive series of 81 patients with solid malignant tumours attending for radionuclide bone scans. Biochemical evaluation showed that bone resorption from metastatic disease was generally not enough to account for hypercalcaemia. While skeletal metastases were present in about half of the patients who developed hypercalcaemia, biochemical indices of bone resorption in these subjects were greatly increased and disproportionate to the extent of metastatic disease detected by the bone scans. Furthermore, a reduced renal phosphate threshold and increased tubular calcium reabsorption were generally observed in hypercalcaemic patients when compared with their normocalcaemic counterparts. These findings suggest that in most cases malignancy associated hypercalcaemia may be caused by the release of a humoral factor by tumour tissue which exhibits "parathyroid-hormone-like" activity with regard to bone resorption, renal phosphate threshold, and renal calcium handling. It may be postulated that this putative humoral mediator predisposes to hypercalcaemia both by stimulating generalised osteolysis and in most cases also by impairing the renal excretion of the resultant increase in filtered calcium load. While hypercalcaemia may arise as a result of metastatic bone disease alone, these data indicate that this may be the exception rather than the rule. Hence the term "metastatic hypercalcaemia" should probably be reserved for patients with extensive skeletal tumour disease in whom biochemical evaluation fails to yield evidence of an underlying humorally mediated cause.     

Clinical Problems: Hypercalcaemia in Patients with Advanced Mammary Cancer

Hypercalcaemia and hypercalciuria are common complications of advanced mammary cancer. Of 127 patients with the disease 63 (49·5%) had some abnormality of calcium balance. Eighteen (14%) of these patients developed severe progressive hypercalcaemia and became acutely ill.Most patients had skeletal metastases, and the usual cause of hypercalcaemia was rapid destruction of bone by the cancer. One patient with severe uncontrollable hypercalcaemia and minimal skeletal involvement probably developed the complication due to inappropriate secretion of a parathyroid-hormone-like substance by massive hepatic deposits.Severe hypercalcaemia was controlled successfully in 13 of the 18 patients, the serum calcium levels returning to normal and the acute symptoms disappearing. Unfortunately, successful correction of the hypercalcaemia rarely was followed by prolonged survival from the underlying malignant disease. The incidence of subsequent objective response to pituitary ablation was less than usual, and only three patients survived for more than one year after the episode of hypercalcaemia.     

Modulation of tumour-induced bone resorption by bisphosphonates.

Tumour cells produce systemic or local factors which can stimulate osteoclast development and activity leading to increased bone resorption. The clinical consequences are bone pain, fractures and hypercalcaemia. Inhibitors of osteoclast-mediated bone resorption, such as the bisphosphonates, are now the treatment of choice for tumour-induced hypercalcaemia. Recent evidence indicates that these compounds, especially the newer ones, reduce skeletal morbidity in patients with metastatic bone disease and improve their quality of life. Better understanding of the mechanisms underlying tumour-induced bone resorption and development of more potent and less toxic bisphosphonates will lead to improved management of patients with malignant diseases involving the skeleton.     

Renal Effects of Calcitonin

Porcine calcitonin in a slow-release gelatin vehicle was given by intramuscular injection to 10 patients—four with primary hyperparathyroidism, four with Paget''s disease, and two with carcinoma of the breast and hypercalcaemia. All cases showed a fall in serum calcium with an immediate rise in urine calcium. All except three patients with primary hyperparathyroidism showed a fall in serum phosphorus, but an immediate rise in urine phosphorus occurred in all cases. Urine hydroxyproline output fell in three patients with severe Paget''s disease. Urine sodium rose in all cases, but the effects on potassium, magnesium, water, and pH were not appreciably different from results obtained in four control subjects who were given the gelatin vehicle alone.The data suggest that calcitonin caused a decrease in the tubular resorption of calcium and phosphorus. The hypocalcaemic effect appeared to be due to a decrease in bone resorption in the patients with Paget''s disease but in the remaining cases could be accounted for in part or entirely by the rise in urine calcium.     

Immobilization hypercalcaemia in patients on regular haemodialysis.

Immobilization of normal people causes reabsorption of calcium from bone, a small rise in serum ionized calcium, and, rarely, frank hypercalcaemia. The hazard is increased when patients with renal osteodystrophy are immobilized because of pathological fractures.     

Familial hypocalciuric hypercalcaemia and acute pancreatitis.

Four families with familial hypocalciuric hypercalcaemia were studied. The probands presented with abdominal pain, which in three was due to acute pancreatitis; in two the condition was life threatening. Serum concentrations of calcium, magnesium, phosphate, and immunoassayable parathyroid hormone, urinary calcium excretion, and the rate of renal tubular reabsorption of phosphate were measured; the findings were compared with results in 10 patients with primary hyperparathyroidism matched for serum calcium concentration to establish differences between the diseases. Familial hypocalciuric hypercalcaemia should be suspected in patients with hypercalcaemia in whom daily urinary calcium excretion is below 5 mmol (200 mg) provided renal insufficiency, vitamin D deficiency, and ingestion of drugs that reduce calcium excretion have been excluded. Most cases appear to run a benign course, but some may suffer considerable morbidity. Surgical treatment should be reserved for patients with severe complications, when all parathyroid tissue should be removed.     

Parathyroid hormone related protein and hypercalcaemia in breast cancer.

OBJECTIVE--To see whether parathyroid hormone related protein has a humoral role in breast cancer. DESIGN--Plasma concentrations and tumour expression of parathyroid hormone related protein were determined (by two site immunoradiometric assay and immunohistochemistry respectively) in women with breast cancer and related to the presence of bone metastases and serum calcium concentrations. SUBJECTS--Plasma concentrations of parathyroid hormone related protein were measured in 57 women with early breast cancer without apparent bone metastases, 28 women with bone metastases, and 13 women with bone metastases and hypercalcaemia. Tissue positivity for parathyroid hormone related protein was determined retrospectively in 106 primary breast tumours from women without apparent bone metastases and 72 tumours from women with bone metastases, 25 of whom subsequently developed hypercalcaemia. RESULTS--Plasma parathyroid hormone related protein concentrations were detectable (greater than 0.23 pmol/l) in 12 (92%) of the 13 hypercalcaemic patients with bone metastases compared with 10 (36%) of the 28 normocalcaemic patients with bone metastases and five (9%) of the 57 normocalcaemic patients without bone metastases. Parathyroid hormone related protein concentrations were significantly higher in hypercalcaemic than normocalcaemic patients with bone metastases. Tumour staining was positive for parathyroid hormone related protein in 22 (88%) of the 25 primary breast cancers from patients with bone metastases. Tumour staining was positive for parathyroid hormone related protein in 22 (88%) of the 25 primary breast cancers from patients with bone metastases who later developed hypercalcaemia compared with 25 (53%) of the 47 from women in this group who remained normocalcaemic and 55 (52%) of the 106 early breast cancers from women without known metastases. CONCLUSION--Tumour derived parathyroid hormone related protein may have an important humoral role in hypercalcaemia associated with metastatic breast cancer.     

Bone resorption and circulating PTH-like bioactivity in an animal model of hypercalcaemia of malignancy

An in vivo model of humoral hypercalcaemia of malignancy has been used to examine the role of circulating PTH-like bioactivity in the development of bone resorption and hypercalcaemia. After inoculation of cells from a renal carcinoma cell line into nude mice, circulating PTH-like bioactivity as measured by the sensitive renal and metatarsal cytochemical bioassays for PTH was elevated in only 18% and 53% of the mice respectively. Bone resorption was elevated in all the mice investigated irrespective of the level of PTH-like bioactivity. Thus, in this model, while the circulating PTH-like moiety is more potent when acting on bone, it did not correlate with the degree of bone resorption suggesting that it may not be the sole cause of the hypercalcaemia.     

Hypophosphataemia after parathyroidectomy in chronic renal failure.

Out of 24 patients receiving haemodialysis who were subjected to parathyroidectomy, 13 developed hypophosphataemia; this persisted for 3-52 weeks (mean 10.6 weeks). Before operation these 13 patients had had significantly higher plasma alkaline phosphatase activities (p less than 0.01) and significantly higher values in iliac crest bone biopsy samples for active resorption surface and active formation surface (p less than 0.05 in each case) than the group who remained normophosphataemic. Significantly more of the patients who remained normophosphataemic had shown periarticular calcification in preoperative skeletal radiographs (p less than 0.001). Hypophosphataemia may result from reduced mobilisation of phosphate from bone or its increased accretion into bone, and resorption of phosphate from periarticular mineral deposits may protect against development.     

Renal handling of calcium in hypoparathyroidism.

Treatment of hypoparathyroidism usually requires the use of pharmacological doses of parent vitamin D or near physiological amounts of the hydroxylated metabolites, calcitriol or alphacalcidol. Vitamin D intoxication and hypercalcaemia may be a problem but can be minimised by the use of small doses of vitamin D or its metabolites combined with large amounts of oral calcium. The response to treatment can be easily monitored by measuring serum and urinary calcium and creatinine concentrations. This allows the derivation of two simple indices reflecting calcium load presented to the kidney (calcium excretion in mmol/l glomerular filtrate) and renal tubular calcium reabsorption (TmCa/GFR). These can be used to predict the requirement of calcium supplements and also identify those patients at particular risk of hypercalcaemia.     

RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis

The emergence of the molecular triad osteoprotegerin (OPG)/Receptor Activator of NF-kB (RANK)/RANK Ligand (RANKL) has helped elucidate a key signalling pathway between stromal cells and osteoclasts. The interaction between RANK and RANKL plays a critical role in promoting osteoclast differentiation and activation leading to bone resorption. OPG is a soluble decoy receptor for RANKL that blocks osteoclast formation by inhibiting RANKL binding to RANK. The OPG/RANK/RANKL system has been shown to be abnormally regulated in several malignant osteolytic pathologies such as multiple myeloma [MM, where enhanced RANKL expression (directly by tumour cells or indirectly by stromal bone cells or T-lymphocytes)] plays an important role in associated bone destruction. By contrast, production of its endogenous counteracting decoy receptor OPG is either inhibited or too low to compensate for the increase in RANKL production. Therefore, targeting the OPG/RANK/RANKL axis may offer a novel therapeutic approach to malignant osteolytic pathologies. In animal models, OPG or soluble RANK was shown both to control hypercalcaemia of malignancy and the establishment and progression of osteolytic metastases caused by various malignant tumours. To this day, only one phase I study has been performed using a recombinant OPG construct that suppressed bone resorption in patients with multiple myeloma or breast carcinoma with radiologically confirmed bone lesions. RANK-Fc also exhibits promising therapeutic effects, as revealed in animal models of prostate cancer and multiple myeloma. If the animal results translate to similar clinical benefits in humans, using RANK-Fc or OPG may yield novel and potent strategies for treating patients with established or imminent malignant bone diseases and where standard therapeutic regimens have failed.     

Decreased levels of ionized calcium one year after hemithyroidectomy: importance of reduced thyroid hormones

BACKGROUND: Previously we have found reduced levels of total serum calcium and 1,25(OH)2D3 despite an unaltered stimulated parathyroid hormone (PTH) secretion 1 year after hemithyroidectomy. The present study was undertaken to elucidate the possible relationship between calcium homeostasis, thyroid hormones and bone resorption in a group of 45 consecutive patients subjected to hemithyroidectomy because of a solitary nodule. All patients had free T4 and T3 levels within normal range preoperatively. METHODS: Thyroid hormones, bone mineral and biochemical variables known to reflect calcium homeostasis were studied. Patients were divided into three separate groups depending on their pre- and postoperative thyroid hormone status. RESULTS: One year postoperatively, serum levels of free T4 were decreased and that of thyrotropin (TSH) increased in the entire group of patients. The concentration of ionized calcium was reduced from 1.25 +/- 0.05 to 1.22 +/- 0.04 (p < 0.001) despite an unaltered PTH value (2.8 +/- 1.0 vs. 3.1 +/- 1.5, p = 0.50). A significant reduction in C-terminal telopeptide type 1 collagen (1CTP) indicated decreased bone resorption 1 year after surgery (p < 0.05). Subgroup analysis showed that a reduction in ionized calcium was seen only among patients with a postoperative decrease in free T4. Patients with subclinical hyperthyroidism preoperatively presented the lowest postoperative levels of ionized calcium, significantly reduced levels of 1CTP and increased levels of phosphate and creatinine. Multiple linear regression analysis showed that age (p < 0.05) and postoperatively changed serum levels of TSH (p < 0.05), creatinine (p < 0.05), phosphate (p < 0.001) and FT4 (p < 0.01) were independently associated with altered levels of ionized calcium. CONCLUSION: We conclude that the reduction in ionized calcium 1 year after hemithyroidectomy was not due to PTH deficiency. Instead our results suggest that the reduced effects of thyroid hormones on bone and kidney function is essential.     

Hypercalcemia in glucocorticoid withdrawal

We found severe hypercalcemia in the course of hydrocortisone withdrawal in a patient who had undergone unilateral adrenalectomy to resect a cortisol-hypersecreting adenoma. Serum calcium gradually but progressively increased after unilateral adrenalectomy. Severe hypercalcemia developed on the 77th postoperative day (the 15th day after discontinuing hydrocortisone replacement). The serum concentration of calcium, PTH, 25(OH)D, and 1,25(OH)2D were 8.0 mEq/l, less than 100 pg/ml, 10.1 ng/ml and 29.6 pg/ml, respectively. This hypercalcemia was accompanied by marked urinary hydroxyproline excretion and less calcium excretion in the urine than the prevailing level of serum calcium. Serum concentrations of 25(OH)D, 1,25(OH)2D and PTH were not elevated during the severe hypercalcemia. We concluded that the hypercalcemia in this patient was due in part to enhanced bone resorption and increased renal tubular reabsorption of calcium as a result of glucocorticoid withdrawal, but not to the elevation of serum PTH or serum 25(OH)D and serum 1,25(OH)2D.     

Abnormal calcium metabolism in normocalcaemic sarcoidosis.

In studies of calcium metabolism in 13 unselected patients with untreated sarcoidosis all were normocalcaemic but five had hypercalcuria. All had normal renal function. Calcium absorption was indexed by a double isotope test. 45Ca hyperabsorption occurred in six patients. Ten kinetic studies were carried out with 47Ca and in six bone turnover was increased. 45Ca absorption correlated well with the calculated bone uptake rate of calcium, and with urine calcium excretion. These results suggest that in sarcoidosis abnormalities in calcium metabolism are fairly common although they rarely result in sustained hypercalcaemia.     

Transient and Persistent Hypercalcaemia in Patients Treated by Maintenance Haemodialysis

In a group of 32 patients with terminal renal failure the initial hypocalcaemia was corrected after two months'' adequate maintenance haemodialysis. In seven patients hypercalcaemia occurred with a peak incidence after about six months'' treatment. In six of these patients hypercalcaemia was transient and the plasma calcium became normal with haemodialysis alone. In one patient the hypercalcaemia was persistent and the plasma calcium reverted to normal only after subtotal parathyroidectomy. This patient had no radiological bone disease, a normal alkaline phosphatase, and no metastatic calcification of the soft tissues.It is concluded that in some patients with terminal renal failure treated with maintenance haemodialysis autonomy of the parathyroids becomes evident in the absence of bone disease or a raised plasma alkaline phosphatase, and that subsequently with continued dialysis there is a spontaneous involution towards normal parathyroid function.     

Paraneoplastic hypercalcaemia in ovarian carcinoma.

Five patients were seen in whom a raised serum calcium concentration was associated with ovarian carcinoma (clear cell in two cases, cystadenocarcinoma in three). None showed evidence of metastases in bone. The hypercalcaemia occurred as a paraneoplastic phenomenon, but biochemical studies suggested the production of a parathyroid-hormone-like substance. One patient remained free of symptoms of her hypercalcaemia throughout. Paraneoplastic hypercalcaemia due to ovarian carcinoma may be more common than generally recognised and present as a life threatening condition requiring urgent treatment.     

Evidence for decreased tubular reabsorption of calcium in glucocorticoid-treated asthmatics

Fasting urine calcium excretion was measured in 15 asthmatic patients receiving long-term glucocorticoid therapy (steroid group) and in age- and sex-matched asthmatics not receiving these drugs. In the steroid group, the mean urinary calcium/creatinine ratio and the mean calcium excretion per liter of glomerular filtrate (CaE) were both approximately twice the control values (p less than 0.005). When CaE was plotted as a function of serum calcium it more often exceeded the mean normal value in the steroid-treated patients than in the controls (p less than 0.05), suggesting a reduction in tubular calcium reabsorption. Calculation of the tubular maximum for calcium reabsorption confirmed a significant reduction in the glucocorticoid-treated patients (p less than 0.005). It is concluded that glucocorticoid drugs probably inhibit the tubular reabsorption of calcium and that this is likely to contribute to the development of osteoporosis in patients receiving this treatment.     

Osteoblasts suppress high bone turnover caused by osteolytic breast cancer in-vitro

The skeleton is the most common site of breast cancer metastasis, which can occur in up to 85% of patients during their lifetime. The morbidity associated with bone metastases in patients with breast cancer includes pathological fractures, bone pain, hypercalcaemia, and spinal cord compression. When breast cancer metastasizes to bone, the balance of bone resorption (mediated by osteoclasts) and bone formation (mediated by osteoblasts) favors bone resorption, which leads to net bone destruction (i.e., osteolysis). Anti-resorptive agents such as bisphosphonates are commonly used to treat bone resorption in osteoporosis or osteolytic cancer patients. However, bisphosphonates by themselves are unable to rebuild lost bone tissue, and can cause severe side effects. In this study, we developed a bovine bone explant culture system and have observed that murine osteoblasts can modulate the activity of osteotropic human breast cancer cells on this substrate. Using markers of bone metabolism, we observe diminished bone turnover in organ culture following the addition of exogenous osteoblasts. The data presented in this study supports further investigation into the use of cytotherapies to limit breast cancer mediated osteolysis.     

Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer

Objective To review the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients with bone metastases.Data sources Electronic databases, scanning reference lists, and consultation with experts and pharmaceutical companies. Foreign language papers were included.Study selection Included trials were randomised controlled trials of patients with malignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care. All trials measured at least one outcome of skeletal morbidity.Results 95 articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted ≥ 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001; combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival. Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates.Conclusions In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event. Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant.     

Handling of induced hypercalcaemia in hyperthyroidism

The mean serum calcium of 13 hyperthyroid patients was found to be significantly higher than that of controls matched for sex and age, though none of the patients'' values were outside the normal range. Nevertheless, these patients responded very promptly to hypercalcaemia (induced by an intravenous calcium load), and their serum calcium returned to normal much more rapidly compared with the matched controls. There was also increased retention of intravenous calcium load, possibly owing to increased calcitonin production. Calcium infusion may be useful in treating bone diseases in which increased bone resorption exceeds bone accretion.