Pathophysiology of hypercalcemia and the therapeutic role of bisphosphonates

When hypercalcemia is found in patients with malignancy, it is necessary to measure circulating parathyroid hormone -related peptide concentrations and to search for bone lesions. Because accelerated bone resorption mainly contributes to malignancy associated hypercalcemia, bisphosphonates, which strongly suppress osteoclastic resorption, is most effective. Upon administration of bisphosphonates, serum calcium begins to fall within two days, reaches the bottom after one week, and the effects disappear after two or three weeks. In case of need to lower the serum calcium concentration rapidly, calcitonin should be used at the same time.     

Current Management Strategies for Hypercalcemia

The two most common causes of hypercalcemia are primary hyperparathyroidism and neoplastic disease. Parathyroidectomy is the only curative intervention for the former condition. In the rare cases of patients with primary hyperparathyroidism who present with clinical symptoms due to their hypercalcemia, pharmacological treatment may be required. Fluid repletion and intravenous (IV) administration of bisphosphonates are recommended in the literature. Calcium receptor agonists (calcimimetic agents) are at the present time only available for use within clinical trials. Cancer patients usually present with symptoms of hypercalcemia. Rapid institution of antihypercalcemic treatment is essential in preventing life-threatening deterioration. Fluid repletion and administration of bisphosphonates are the treatment mainstays in hypercalcemia of malignancy. Five bisphosphonates are currently licensed in Europe for treatment of tumor-associated hypercalcemia: etidronate, clodronate, pamidronate, ibandronate, and zoledronate. In the US, pamidronate and zoledronate are licensed for use in this indication. Bisphosphonates containing nitrogen atoms (e.g. pamidronate, ibandronate, and zoledronate) are more potent than those without (e.g. etidronate, clodronate, and tiludronate). In patients with malignant hypercalcemia, the efficacy of the individual bisphosphonate depends on dose administered and initial serum calcium concentration. At present, pamidronate has been studied in the greatest number of investigations and in the largest number of patients. In the literature, the efficacy of pamidronate in restoring normocalcemia ranges between 40% and 100%, depending on the dose used and baseline serum calcium concentration. More recently, one study reported that pamidronate was inferior to zoledronate. In this study, the duration of response was also longer in the two zoledronate groups (30 and 40 days) than in the pamidronate group (17 days). The most serious adverse events of bisphosphonates concern renal function. Increases in serum creatinine levels have been more frequently reported following treatment of tumor-associated hypercalcemia with etidronate (8%) and clodronate (5%) than with the nitrogen-containing bisphosphonates pamidronate (2%) and ibandronate (1%). The frequency of increases in serum creatinine levels following treatment with zoledronate is difficult to estimate. Administration of the nitrogen-containing bisphosphonates has been associated with transient (usually mild) fever, lymphocytopenia, malaise, and myalgias. These events occur within 36 hours of the first dose and are self-limiting. Hypocalcemia occurs in up to 50% of patients treated with bisphosphonates for hypercalcemia of malignancy, although symptomatic hypocalcemia is rare. The toxicity and low efficacy of plicamycin (mithramycin) mean that use of this agent should be restricted to patients with hypercalcemia of malignancy who fail to respond to IV bisphosphonates. Calcitonin is characterized by good tolerability but poor efficacy in normalizing the serum calcium level. However, a major advantage of calcitonin is the acute onset of the hypocalcemic effect, which contrasts with the delayed but more pronounced effect of bisphosphonates. Combination calcitonin and bisphosphonate treatment may therefore be of value when rapid reduction of serum calcium is warranted. Gallium nitrate may be a valuable treatment for hypercalcemia of malignancy. It is characterized by high efficacy and few adverse events apart from renal toxicity (10% of cases). However, data are very limited and further trials are necessary.     

Hypercalcemia of malignancy: pathophysiology, diagnosis and treatment

Malignancy is the most frequent cause of hypercalcemia in hospitalized patients. The pathophysiology of hypercalcemia of malignancy (HM) is complex. Increased bone resorption is involved in most cases caused either by extensive local bone destruction or by humoral factors. Tumor extracts from patients with humoral hypercalcemia of malignancy (HHM) often contain PTH-like bioactivity. Recently, cDNAs coding for a PTH-related protein (PTH-rP) has been cloned. The N-terminal amino acid sequence of this protein shows a considerable homology with human PTH. However, other bone resorbing factors including prostaglandins, transforming growth factors, colony stimulating factors, leucocyte cytokines and 1,25-dihydroxyvitamin D may be involved in different types of malignancy. HM is usually progressive with troublesome symptoms and a high mortality. Several treatment alternatives are available including rehydration, bisphosphonates, calcitonin, plicamycin, phosphate, and glucocorticoids. Others are under investigation. Treatment should be individualized taking into account the pathophysiological mechanisms involved, the extent of hypercalcemia and renal failure, and the prognosis related to the malignant disease.     

Metabolic effects of gallium nitrate administered by prolonged infusion

Gallium nitrate was recently found to be effective treatment for resistant cancer-related hypercalcemia. In vitro and in vivo experiments have suggested that the drug directly inhibits calcium resorption from bone; however, the overall effects of gallium nitrate on calcium balance were unknown. We have completed metabolic balance studies in four patients who received this drug by prolonged infusion. All patients were in positive calcium balance while receiving the drug. Each patient also showed a substantial decrease in urinary calcium excretion. Serum phosphorus decreased in all four patients. There was no change in phosphorus, sodium, chloride, or magnesium balance or in creatinine clearance. We conclude that prolonged infusions of gallium nitrate reduce urinary calcium excretion and that the hypocalcemic effect of this drug is primarily due to inhibition of calcium resorption from bone. Thus, the drug may prove useful in reducing accelerated bone resorption in patients with bone metastases or chronic cancer-related hypercalcemia.     

Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride

The efficacy of intravenous aminohydroxypropylidene bisphosphonate as treatment for the hypercalcemia of malignancy was examined in a phase II multicenter study in 132 patients with a large variety of primary tumors. This provided an opportunity for an analysis of the separate influences of bone resorption and renal calcium handling on the genesis and maintenance of hypercalcemia. The results demonstrated that increased bone resorption is the major contributory factor and that inhibition with bisphosphonate normalizes the serum calcium concentration within five days in more than 90 percent of patients. Hypercalcemia is sustained by an inability of the kidney to deal efficiently with a chronically increased calcium load. This is influenced by the requirements of volume regulation in the presence of a sodium diuretic effect of hypercalcemia and is very sensitive to induced variations of sodium load. In addition, in a minority of patients, direct renal actions of tumor-derived humoral factors adversely reduce the ability to excrete calcium. For optimal treatment of tumor-induced hypercalcemia, bisphosphonate treatment should be combined with intravenous administration of saline solution.     

Vitamin D intoxication causes hypercalcaemia by increased bone resorption which responds to pamidronate

OBJECTIVE Vitamin D intoxication is a relatively rare but treatable cause of hypercalcaemia. In the past this has been undertaken using corticosteroids. Previous observations have suggested that there is increased bone resorption in hypervitaminosis D. If this were to be the case, specific inhibitors of bone resorption might provide more effective treatment. We have therefore studied the mechanisms of hypercalcaemia and response to therapy in a group of patients with vitamin D intoxication. DESIGN Vitamin D metabolites were measured in six patients with vitamin D intoxication; in five of these the components of hypercalcaemia were calculated. These measurements were repeated following treatment with corticosteroids (two patients) or the bisphosphonate, pamidronate (three patients). RESULTS In each case the serum 25-hydroxyvitamin D was grossly elevated and there was a more modest elevation in serum 1,25-dihydroxyvitamin D. The components of hypercalcaemia suggest that there was a significant degree of bone resorption in all six patients and that this Is the major determinant of hypercaicaemia. Pamidronate treatment resulted in a brisk reduction in plasma calcium concentration. Following corticosteroids the return of calcium to normal was more delayed. CONCLUSION The hypercalcaemia of vitamin D intoxication is mediated by Increased bone resorption and bisphosphonates have a role in its management.     

Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use

All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.     

Therapy of malignancy-associated hypercalcemia: 1983

Hypercalcemia is common among patients with cancer and may be due to secretion by tumors of a humoral, calcemic, bone-resorbing factor or, alternatively, to skeletal metastases. In each case, hypercalcemia ultimately results from osteoclastic bone resorption. Therapy should be aimed at (1) reducing or eliminating tumor burden, (2) increasing renal calcium clearance, and (3) inhibiting osteoclastic bone resorption. Hydration with saline infusion and augmentation of calciuresis with furosemide should be the initial modes of therapy in most patients. Oral phosphorus should be used in hypophosphatemic patients. Glucocorticoids, calcitonin, and prostaglandin synthetase inhibitors may be effective in reducing bone resorption in selected patients. Mithramycin reliably induces a fall in serum calcium but long-term use is usually complicated by toxicity. A new class of drugs that inhibit osteoclastic bone resorption, the diphosphonates, is being employed in clinical trials in patients with malignancy-associated hypercalcemia. Results have been particularly promising with dichloromethylene diphosphonate.     

Prolonged, symptomatic hypocalcemia with pamidronate administration and subclinical hypoparathyroidism

A 62-yr-old woman with thyroid carcinoma metastatic to bone, and a history of subclinical hypoparathyroidism was admitted to the hospital in hypocalcemic crisis 5 wk after receiving iv pamidronate. The patient had tetany and laryngospasm. An electrocardiogram showed junctional rhythm with QT segment prolongation. The patient had previously maintained a lownormal serum calcium on 500–750 mg of calcium carbonate and 600 IU of vitamin D daily. One week after pamidronate administration the patient’s calcium and vitamin D supplementation were inadvertently discontinued. She continued to take daily intranasal calcitonin. At the time of her hospitalization for hypocalcemia, the patient’s serum calcium was 4.3 mg/dL. The patient received aggressive calcium and vitamin D supplementation. However, her serum calcium remained below 6 mg/dL for a 2-wk period, and took another week to return to the normal range. In this article, we discuss the counterregulatory responses necessary to maintain calcium homeostasis following osteoclast inhibition by bisphosphonates. We also review the risk factors for hypocalcemia following bisphosphonate administration. Pamidronate and other bisphosphonates are becoming an integral part of the management of normocalcemic patients with malignant bone disease. Therefore, awareness of risk factors for hypocalcemia and familiarity with avenues available for protection from potentially catastrophic hypocalcemia are both crucial.     

Elderly patient presenting with severe thyrotoxic hypercalcemia

An 81-year-old woman with Graves' disease and osteoporosis was referred to the hospital because of anorexia over one month and impaired consciousness. She also presented with low-grade fever and emaciation. Laboratory tests revealed marked hypercalcemia (corrected serum calcium level of 12.4 mg/dL), which was initially suspected to result from vitamin D toxicity, because she had been taking vitamin D3 (alphacalcidol of 0.5 µg/day) for the treatment of osteoporosis. However, discontinuation of vitamin D3 and fluid infusion did not ameliorate hypercalcemia one week later. After excluding hyperparathyroidism and malignancy-related hypercalcemia, hypercalcemia was considered to be attributable to the exacerbation of hyperthyroidism (free T4 of 6.69 ng/dL, free T3 of 13.27 pg/mL and thyroid stimulating hormone (TSH) <0.015 µIU/mL) with increased bone resorption. Finally, the increased dose of thiamazole (30 mg/day) normalized serum calcium level and thyroid function three months later. Laboratory tests suggested that normal bone formation in spite of increased bone resorption contributed to hypercalcemia in hyperthyroid state.     

Mechanism of the hypocalcemic effect of mithramycin.

Mithramycin is effective in the treatment of hypercalcemia. The mechanism of its hypocalcemic effect was studied in six patients with hypercalcemia by serum 85Sr or 45Ca kinetic techniques. Mithramycin was given at two dosage levels (25 or 50 microgram/kg iv). Mithramycin at the low dosage had little effect on the rate of bone accretion. However, at both dosage levels, mithramycin caused an upward shift of the slope of the specific activity curve, indicating an inhibitory effect on bone resorption. This effect started 6-12 h after a 25-microgram/kg dose of mithramycin and lasted from 4-6 days. It appears that mithramycin has a preferential effect on bone resorption.     

Clodronate. A randomized study in the treatment of cancer-related hypercalcemia

Malignancy-associated hypercalcemia is a common and recalcitrant problem. Current modes of therapy are often ineffective or prohibitively toxic. Clodronate disodium is a diphosphonate capable of inhibiting bone resorption resulting in a hypocalcemic effect. In this randomized, placebo-controlled study, we investigated the effect of hydration only (Rx-1) vs the effect of hydration plus either intravenously administered clodronate disodium, 4 mg/kg of body weight per day for three days (Rx-2) or intravenously administered clodronate disodium, 12 mg/kg of body weight given once only (Rx-3). By the third day of observation, Rx-2 produced a significant 2.8 mg/dL (0.70 mmol/L) reduction in serum calcium levels, whereas Rx-1 and Rx-3 did not produce a significant hypocalcemic effect when compared with baseline values. There were no toxicities observed. Intravenously administered clodronate appears to be an excellent agent for the acute treatment of malignancy-associated hypercalcemia.     

Thionapthene-2-carboxylic acid: a new antihypercalcemic agent

Thiophene-2-carboxylic acid (TCA) was previously shown to be hypocalcemic in the rat. We have compared TCA with thionapthene-2-carboxylic acid (TNCA), an analog which is a more potent inhibitor of bone resorption in vitro, for the ability to decrease serum calcium concentration in vivo. In normocalcemic rats on a low calcium diet, TNCA (2 mmol/kg) produced a larger and more prolonged decrease in calcium concentration than TCA. In rats bearing the Walker 256 carcinosarcoma, which became hypercalcemic, TNCA produced a dose-related decrease in serum calcium concentration at 0.3-1.2 mmol/kg. TNCA reduced serum calcium concentration in 4-6 h, and the effects were sustained for up to 72 h. TNCA was effective after oral as well as sc administration. Unlike calcitonin which produced only a transient reduction in serum calcium followed by escape, the effects of TNCA (0.6 mmol/kg) were sustained for 1 week and were accompanied by a decrease in mortality in tumor-bearing animals. We conclude that TNCA is a potent hypocalcemic action which has a rapid and prolonged effect without evidence of escape. This and related compounds should be tested further for use in treatment of hypercalcemia and other states characterized by excessive bone resorption.     

Management of osteoporosis, fat-soluble vitamin deficiencies, and hyperlipidemia in primary biliary cirrhosis

Osteoporosis is several times more common in patients with PBC compared with the general population. Maintaining adequate intake of calcium and vitamin D is important for prevention of bone loss. The use of bisphosphonates or vitamin K to improve bone mineral density in osteopenic patients seems promising and needs to be further evaluated. Patients with PBC may develop fat-soluble vitamin deficiencies, especially vitamins A and D; serum levels should be investigated in patients considered at risk with the aim of recommending appropriate replacement therapy. Finally, hyperlipidemia in PBC does not seem to be associated with an increased risk of atherogenesis. New therapies in this patient population are currently under investigation.     

The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy

Humoral hypercalcemia of malignancy (HHM) is mediated primarily by skeletal and renal responses to tumor-derived PTHrP. PTHrP mobilizes calcium from bone by inducing the expression of receptor activator for nuclear factor-kappaB ligand (RANKL), a protein that is essential for osteoclast formation, activation, and survival. RANKL does not influence renal calcium reabsorption, so RANKL inhibition is a rational approach to selectively block, and thereby reveal, the relative contribution of bone calcium to HHM. We used the RANKL inhibitor osteoprotegerin (OPG) to evaluate the role of osteoclast-mediated hypercalcemia in two murine models of HHM. Hypercalcemia was induced either by sc inoculation of syngeneic colon (C-26) adenocarcinoma cells or by sc injection of high-dose recombinant PTHrP (0.5 mg/kg, s.c., twice per day). In both models, OPG (0.2-5 mg/kg) caused rapid reversal of established hypercalcemia, and the speed and duration of hypercalcemia suppression were significantly greater with OPG (5 mg/kg) than with high-dose bisphosphonates (pamidronate or zoledronic acid, 5 mg/kg). OPG also caused greater reductions in osteoclast surface and biochemical markers of bone resorption compared with either bisphosphonate. In both models, hypercalcemia gradually returned despite clear evidence of ongoing suppression of bone resorption by OPG. These data demonstrate that osteoclasts and RANKL are important mediators of HHM, particularly in the early stages of the condition. Aggressive antiresorptive therapy with a RANKL inhibitor therefore might be a rational approach to controlling HHM.     

Pathogenesis of hypercalcemia in lymphosarcoma cell leukemia: Role of an osteoclast activating factor-like substance and a mechanism of action for glucocorticoid therapy

The pathogenesis of hypercalcemia and mode of action of glucocorticoid therapy was examined in a patient with lymphosarcoma cell leukemia. Circulating neoplastic cells were cultured in vitro and secreted a bone-resorbing factor. The bone-resorbing factor was partially purified with the use of a bioassay for bone resorption, and was found to be chromatographically and pharmacologically similar to osteoclast activating factor (OAF), which is produced by normal mitogen-activated peripheral blood lymphocytes. Other factors which stimulate bone resorption, such as parathyroid hormone, prostaglandins and the vitamin D metabolites, were excluded by criteria which included dose-response curves, radioimmunoassays, extraction in organic solvents and failure of glucocorticoids to inhibit bone-resorbing activity.The patient's hypercalcemia responded rapidly to prednisone therapy. The effects of the bone-resorbing factor secreted by the neoplastic cells on bone cultures to which cortisol was added were examined. Cortisol inhibited bone resorption directly at low doses (10^?8 M), which suggests that prednisone may have lowered the serum calcium in this patient by direct inhibition of bone resorption.     

Hypercalcemia of malignancy: clinical features, diagnosis and treatment

Hypercalcemia associated with malignancies is reported in up to 20 to 30% of patients with cancer during the course of the disease, and points to a poor prognosis. Symptoms related to the central nervous system, as progressive mental impairment, stupor and coma, predominate. Alterations in kidney function (water-concentrating defect leading to polyuria) and gastrointestinal tract (anorexia, nausea, vomiting) corroborate to dehydration and a further increase in serum calcium. Cancer-induced hypercalcemia may be classified as: 1) local osteolytic hypercalcemia (LOH), due to marked increase in osteoclastic bone resorption in areas surrounding the malignant cells within the marrow space; 2) humoral hypercalcemia of malignancy, caused by the secretion of parathyroid hormone-related protein (PTHrP) by the malignant tumor; 3) ectopic hyperparathyroidism; 4) 1,25(OH)2 D-secreting tumors. Adequate control of hypercalcemia is necessary to give the patient time to respond to anti-cancer therapy. Volume expansion with saline will correct dehydration, improve glomerular filtration and increase urinary calcium excretion, which may be further stimulated by loop diuretics. Intravenous bisphosphonates are the most effective agents to control hypercalcemia, as they block osteoclastic osteolysis and also have antitumoral effects, decreasing bone metastases. New approaches to control the skeletal manifestations of malignancies are anti-PTHrP and anti-RANKL antibodies, osteoprotegerin, and also proteasome inhibitors in the case of multiple myeloma.     

Glucocorticoid-induced osteoporosis in patients with sarcoidosis

BACKGROUND: Patients with sarcoidosis are at risk for osteoporosis caused by glucocorticoid therapy. However, because of potential hypercalciuria and hypercalcemia, the usual conservative treatment for low bone mass, calcium and vitamin D supplements, may not be well tolerated. METHODS: Patients with sarcoidosis referred to a metabolic bone clinic were compared with other sarcoidosis patients studied prospectively and patients with chronic obstructive pulmonary disease (COPD) or asthma. The subjects underwent bone mineral density (BMD) testing, and the sarcoidosis patients underwent mobility testing and measurements of serum and urine chemistries, vitamin D levels, bone turnover markers, and sex hormone levels. RESULTS: The subjects were mostly male African Americans in the 6th decade of life. Many took chronic oral glucocorticoid therapy and often used home oxygen therapy. Low hip BMD was common among the referred group, comparable with patients with COPD. Surprisingly, hypercalciuria and hypercalcemia were uncommon, and serum testosterone levels were frequently low. The use of calcium supplements, multivitamins containing vitamin D, and glucocorticoids had no impact on serum or urine calcium levels. From univariate analysis, potential risk factors for low hip BMD were low weight, low body mass index (BMI), advanced age, and current use of glucocorticoids. However, in stepwise multiple regression analysis, only low BMI predicted about 40% of hip BMD. CONCLUSIONS: Despite calcium and vitamin D supplements, this group of patients with sarcoidosis had low BMD but relatively infrequent hypercalciuria and hypercalcemia. No prediction model of BMD was adequate. Therefore, we conclude that each patient needs to be assessed individually, including measurement of BMD, serum and urine calcium, and sex steroid status.     

Tumorinduzierte Hyperkalzämie

Hypercalcemia is in many cases a symptom of advanced stage malignant diseases due to increased resorption and reduced secretion. A slightly increased hypercalcemia is mostly asymptomatic but high calcium levels are associated with neurological, gastrointestinal, cardiac and renal symptoms. Important diagnostic tools are the determination of serum albumin and ionized calcium levels. Therapeutic intervention depends on the clinical symptoms as well as calcium levels. Furthermore, increase over time and duration of hypercalcemia has to be taken into account. The principles of treatment are sufficient fluid replacement and maintaining adequate diuresis. In addition, calcitonin, bisphosphonates and steroids are effective and widely used to decrease plasma calcium levels.     

Calcium and salmon calcitonin in treatment of osteoporosis.

Calcitonin has been considered of therapeutic value in osteoporosis because of its effects in tissue culture. In the whole animal, however, the predominant result seems to be hypocalcemia, which might be expected to have the opposite effect of stimulating parathyroid hormone secretion and therefore resorption of bone. Indeed, in a short term study of 3- and 4-month duration in osteoporotic women, this was found to be so. A combination of calcium and calcitonin was therefore considered a more promising therapeutic alternative for this disease. Calcium was given to 26 patients, alone or with vitamin D, for a period of 15 months, and the effects on serum and urine calcium and phosphorus and on bone resorption and formation were evaluated. Calcium and vitamin D decreased serum parathyroid hormone levels, reduced bone resorption, and increased urinary calcium. The addition of calcitonin to the calcium and vitamin D did not seem to change these effects. Neither form of treatment resulted in change of bone mass. Calcium, with or without vitamin D supplements, may prevent the development of osteoporosis, but it seems unlikely that calcitonin has any additional desirable effect in the disease.