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PubMed1999

Comparative tolerability of drug therapies for hypercalcaemia of malignancy.

The bisphosphonates are the treatment of choice in hypercalcaemia of malignancy. However, plicamycin (mithramycin) an calcitonin treatment may still be of value should bisphophonate treatment fail, and gallium nitrate has recently been introduced as an alternative therapy. We analysed the tolerability of different treatments based on articles identified in a Medline search covering the period 1979 through September 1998. Articles were included if they met two criteria: (i) quantitative assessment of adverse effects; (ii) inclusion of > or = 10 patients. Although bisphosphonates are generally well tolerated, elevation of serum creatinine level, nausea/vomiting and fever have been reported following their application. Patients receiving etidronate (n = 268) or clodronate (n = 127) more frequently experienced creatinine elevation (8 and 5%, respectively) than did patients receiving pamidronate (n = 424; 2%), aledronate (n = 79; 0%), or ibandronate (n = 203; <1%). The difference in the frequency of reported creatinine level elevations reached statistical significance only for etidronate (z-test: p < 0.001 versus pamidronate; p < 0.02 versus alendronate; p < 0.001 versus ibandronate). With regard to the frequency of creatinine level elevations, clodronate treatment did not differ significantly from treatment with pamidronate, alendronate and ibandronate. An exception among the bisphosphonates is tiludronate, which has been reported on s a treatment of hypercalcaemia in only 1 study (n = 19) resulting in 1 case of lethal and 1 case of manageable acute renal failure. Nausea and vomiting are rare adverse effects of bisphosphonate treatment but seem to be more frequent with first generation drugs: etidronate (8%) and clodronate (7%) versus pamidronate (2%) [p < 0.001 and 0.009, respectively] and versus ibandronate (<1%) [p< 0.002 and 0.02, respectively]. Bisphosphonates containing a nitrogen atom were associated with an acute phase reaction leading to reported fever in 16% of pamidronate, 20% of aledronate, and 11% of ibandronate-treated patients. The most frequently reported adverse effects of treatment with the cytostatic drug plicamycin were hepatotoxicity (26%), nausea/vomiting (23%), and serum creatinine level elevation (5%). Furthermore. plicamycin application was associated with bone marrow suppression and a bleeding tendency due to abnormalities in multiple clotting factors and platelet dysfunction. The use of calcitonin is limited more by the short duration of its therapeutic effect than by toxicities (most frequent: nausea/vomiting in 16% of treated cases). The few publications on gallium nitrate in the treatment of hypercalcaemia of malignancy characterise it as an efficient drug, which is, however, associated with a higher frequency of renal toxicity (10%) and of nausea and vomiting (14%) than are the bisphosphonates.

Acute-Phase Reaction↗
PubMed1989

Treatment of hypercalcemia.

Severe hypercalcemia is a potentially life-threatening complication of several diseases. Most commonly it is caused by cancers that enhance bone resorption. Impaired renal calcium excretion resulting from a combination of volume contraction and calcium-induced renal injury (nephrocalcinosis) plays a critical role in the genesis and aggravation of hypercalcemia. Treatment of hypercalcemia is based on treating the underlying disease, restoring extracellular volume, correcting electrolyte deficiencies (potassium and magnesium), and reducing bone resorption. Several measures are available to reduce bone resorption, of which the most efficacious are the bisphosphonates and plicamycin (mithramycin). One of these agents in combination with volume expansion can reduce serum calcium concentrations to near normal in most patients within 3 to 6 days. Because of the delayed hypocalcemic action of these agents, they should be administered early. Calcitonin has a more modest hypocalcemic action than the bisphosphonates or plicamycin but has a more rapid effect. Combining calcitonin with plicamycin or a bisphosphonate can enhance the rate of decline of the serum calcium level. Bone resorption also can be reduced by getting patients out of bed to stand or walk. Glucocorticoids may be effective in patients with hypercalcemia associated with high levels of vitamin D, such as sarcoidosis, some lymphomas, or vitamin D intoxication. Patients with mild to moderate hypercalcemia may be asymptomatic. Therapy in these patients should be directed at the primary disease as well as at preventing complications that could raise the level of serum calcium. Efforts should be made to prevent volume contraction and prolonged bed rest. Sedatives and narcotic analgesics, by reducing activity and oral intake, can raise serum calcium levels. In the future it may be possible to predict which patients with cancer are likely to develop accelerated local tumor-mediated or humorally mediated osteolysis. For example, high circulating levels of PTH-like peptides in patients with lung cancer might suggest a greater risk of developing hypercalcemia. These patients could be monitored more closely by periodically measuring urinary calcium. Another prophylactic approach would be to treat patients at risk of developing hypercalcemia with drugs, such as the bisphosphonates, that inhibit bone resorption.

Humans↗
PubMed1993

Pathophysiology and management of severe hypercalcemia.

The principal pathophysiologic alteration in severe hypercalcemia accompanying hyperparathyroidism and malignancy is enhanced osteoclastic bone resorption. Hypercalcemia impairs renal mechanisms that lead to sodium and calcium excretion; PTH and PTHrP acting on renal tubules enhance further calcium reabsorption. Although rehydration is often necessary as an initial therapy of hypercalcemia, the cornerstone of therapy is to inhibit osteoclastic bone resorption. The bisphosphonates, plicamycin, gallium, and calcitonin all inhibit osteoclastic bone resorption. Calcitonin is the most rapidly acting agent. Toxicities of calcitonin are minimal, yet its therapeutic efficacy is limited by lack of potency and tachyphylaxis. The second-generation bisphosphonates such as pamidronate represent a class of compounds that are extremely effective in inhibiting the metabolic function of the osteoclast. Given in a single infusion, a significant majority of patients will have normalization of corrected serum calcium lasting, on average, 1-2 weeks. Therapeutic benefit will be of greater duration because most patients remain only minimally symptomatic until corrected serum calcium rises above 11.5 mg/dL. Side effects of low-grade fever, hypophosphatemia, hypomagnesemia, and hypocalcemia may occur. Gallium nitrate is a potent inhibitor of bone resorption and may be of increased clinical value when more efficient administration protocols can be developed. Plicamycin, available for two decades, has cumulative toxicities and is less potent than the aminobisphosphonates. Renal insufficiency often accompanies severe hypercalcemia. The nephrotoxicity of gallium nitrate and plicamycin should preclude their use when there is moderate impairment of renal function, and amino bisphosphonates become the treatment of choice in these patients. Although several authors have advocated individualized approaches to the management of hypercalcemia, the potency and duration of action of the aminobisphosphonates make them a reasonable treatment choice for most patients with symptomatic hypercalcemia. Most importantly, the most effective therapy for hypercalcemia is to recognize and treat the underlying disease. Acute primary hyperparathyroidism requires surgery. The effective treatment of hypercalcemia of malignancy allows the introduction of tumor-specific therapy, limits morbidity, and shortens and deintensifies hospitalization. At times, the most appropriate and compassionate decision (particularly in patients with malignancy who have exhausted all therapeutic options and have relentless bone pain) is to withhold therapy for hypercalcemia. Future therapies directed at the osteoclast, such as more potent later-generation bisphosphonates; inhibitors of osteoclast attachments and inhibitors of peptides, which stimulate osteoclastic bone resorption, may permit safe, easily administered, outpatient therapies that will improve the quality of life for hypercalcemic patients.

Diagnosis, Differential↗
PubMed1989

Medical treatment of hypercalcemia.

Calcium homeostasis and the symptoms, etiology, and general medical management of hypercalcemia are reviewed. Hypercalcemia, an elevation in total serum calcium concentration, may produce neurologic, gastrointestinal, renal, and cardiovascular disturbances; it may also cause calcification in extraskeletal tissue. Hyperparathyroidism and malignancy cause more than 90% of cases of this potentially fatal disorder. When correction of the underlying cause of hypercalcemia is impossible, calcium-lowering therapy is necessary. Acute management of hypercalcemia often involves rehydration, mobilization of the patient, and furosemide-induced diuresis. These measures may be followed by intravenous administration of etidronate, plicamycin, or calcitonin. Agents used in the long-term management of hypercalcemia include oral phosphates, oral etidronate, intermittent intravenous plicamycin, and, in selected patients, corticosteroids and nonsteroidal anti-inflammatory agents. Investigational calcium-lowering agents include gallium nitrate, ethiofos, dichloromethylene diphosphonate, and aminohydroxyproline diphosphonate. Many agents are available for the treatment of hypercalcemia. Therapy can be individualized by integrating knowledge of the physiologic causes of hypercalcemia, the mechanism of action of calcium-lowering drugs, and the patient's other disease states. Further studies are needed to define the role of investigational calcium-lowering agents.

Adrenal Cortex Hormones↗
PubMed1992

Gallium nitrate.

OBJECTIVE: To evaluate the therapeutic role of gallium nitrate in the treatment of hypercalcemia associated with malignancy and related disease states. DATA SOURCES: A literature search of English-language studies involving gallium nitrate for the period 1966-1991 using MEDLINE and the bibliographies of relevant articles. STUDY SELECTION: Because of the limited number of studies, all clinical trials were reviewed, with particular emphasis on Phase III comparative trials. Related investigative studies on the pharmacology, pharmacokinetics, and toxicity of gallium nitrate were also reviewed. DATA EXTRACTION: Two appraisers independently abstracted data from available clinical trials and evaluated trial quality. RESULTS OF DATA SYNTHESIS: Two Phase III comparative trials evaluating gallium nitrate in the treatment of hypercalcemia of malignancy have been completed. Gallium nitrate was shown to be superior to both calcitonin and etidronate disodium, based on the comparative percentage of patients achieving normocalcemia and the subsequent duration of normocalcemia. Both trials employed similar methodology. Positive therapeutic effects of gallium nitrate have also been demonstrated in small, noncomparative trials for hypercalcemia associated with parathyroid carcinoma, Paget's disease of bone, and osteolytic bone metastases. CONCLUSIONS: Gallium nitrate is effective in the treatment of hypercalcemia associated with malignancy and is appropriate for formulary addition. In certain clinical situations, it may be clearly advantageous over such agents as calcitonin, plicamycin, and etidronate. Further investigation is needed to define the limitations of nephrotoxicity and the therapeutic potential for other indications. Further comparative clinical trials of gallium nitrate versus bisphosphonates and plicamycin could also help define its relative clinical benefit.

Gallium↗
PubMed2002

Treatment of malignant hypercalcaemia.

Hypercalcaemia is a common paraneoplastic syndrome caused by the production by tumours of several factors which affect bone resorption and/or tubular calcium reabsorption. Antihypercalcaemic therapy in cancer patients involves rehydration manoeuvres, as well as the use of a variety of available drugs which inhibit bone resorption, namely plicamycin, calcitonin, bisphosphonates and gallium nitrate. While plicamycin is currently out of use because of its considerable toxicity, bisphosphonates have become the standard therapy in hypercalcaemia of malignancy (HM). These compounds are potent inhibitors of bone resorption but they do not affect tubular calcium reabsorption, which limits their efficacy in humoral HM (HHM) cases. In these patients, gallium nitrate should be the therapy of choice. Among the available bisphosphonates, pamidronate administered in a single infusion of 90 mg, normalises serum calcium levels in > 90% of HM patients. A recently introduced bisphosphonate, zoledronate, is likely to replace pamidronate as a first-line therapy in these patients. The effectiveness of calcitonin in HM treatment is limited, although it seems to be useful at the outset in cases with severe symptomatic hypercalcaemia. Future treatment options of HM are likely to include new bone resorption inhibitors, for example, naturally-occurring osteoprotegerin, or alternate approaches aimed at reducing the tumour production of parathyroid hormone-related protein with noncalcaemic analogues of calcitriol or ras-isoprenylation inhibitors. The development of putative therapeutic agents targeted to inhibit distal calcium reabsorption should be valuable in the management of HHM cases.

Diphosphonates↗
PubMed1989

Pharmacologic management of Paget's disease.

The pathogenesis, clinical features, indications for therapy, and current pharamacologic management of Paget's disease are reviewed. Paget's disease is a bone disorder of unknown etiology primarily affecting the elderly. Overactive bone resorption leads to the accelerated formation of disorganized, weak bone. Pain and fractures are common clinical features. Neurologic, cardiovascular, metabolic, and neoplastic complications are also reported. Because most patients are asymptomatic, the disease is often detected during routine roentgenography or laboratory tests. Primary indications for pharmacologic intervention include bone pain, neural compression, immobilization hypercalcemia or hypercalciuria, cardiac failure, and orthopedic surgery. Recurrent or non-healing fractures and rapidly progressing complications are additional indications. Drugs used in the management of Paget's disease include calcitonin, etidronate disodium, and plicamycin. Although these agents are efficacious, each has disadvantages. Clinical resistance to animal calcitonins may develop, and the cost of therapy may be prohibitive. Etidronate may induce ostemalacia. The use of plicamycin is limited by potentially severe toxicities. Dichloromethylene and aminohydroxypropylidene are promising diphosphonate compounds but are still investigational In those patients who are unresponsive to single-agent regimens, combination therapy may prove effective. Although many patients with Paget's disease do not require pharmacologic therapy, calcitonin and etidronate are the agents of choice when it is indicated.

Humans↗
PubMed2006

Mithramycin A activates Fas death pathway in leukemic cell lines.

Mithramycin A (MMA, trade name Plicamycin) can facilitate TNFalpha- (Tumor Necrosis Factor) and Fas ligand-induced apoptosis. Besides, several drugs play their anticancer effect through Fas apoptotic pathway. So we investigated the effect of MMA on Fas signaling. In this study we show that MMA induces apoptosis in Fas sensitive Jurkat cells and Fas resistant KG1a cells. This effect involves Fas apoptotic pathway: cell exposure to MMA leads to Fas clustering at the cell surface, DISC (Death Inducing Signaling Complex) formation and caspase cleavage. This phenomenon is independent of Fas ligand/Fas interaction and blockade of Fas death pathway partially inhibits MMA-induced apoptosis. Moreover the activation of Fas apoptotic pathway by MMA is correlated to the modulation of c-Flip(L) expression. Finally, pre-treatment with sub-lethal doses of MMA sensitizes KG1a cells to chemotherapeutic agents. Thus all these results may have important implications to improve clinical treatments.

Antineoplastic Agents↗
PubMed2001

Conventional treatment of hypercalcemia of malignancy.

Treatment of hypercalcemia of malignancy (HCM) is briefly reviewed, available treatments are compared, and treatment guidelines are presented. The most effective strategy is treatment of the underlying malignancy. For patients who have a poor prognosis and no viable treatment options, the most humane course may be no treatment at all since encephalopathy will cloud their consciousness. Patients with mild hypercalcemia (corrected serum calcium concentration < 12 mg/dL) may respond to oral hydration, salt restriction, and ambulation, which encourage the normal bone remodeling process. Patients with moderate (corrected serum calcium concentration 12.0-13.5 mg/dL) to severe (> 13.5 mg/dL) hypercalcemia may require rehydration with 0.9% sodium chloride injection. Furosemide may be indicated to counteract fluid overload from rehydration measures or in patients at risk of developing congestive heart failure. For patients with renal failure not caused by dehydration, dialysis with a calcium-free or low-calcium solution is the treatment of choice. The calciuric effect of rehydration lasts only two to three days, and antiresorptive therapy is indicated for patients who require a longer duration of effect. Calcitonin is useful if a rapid decrease in serum calcium is necessary, but tachyphylaxis limits its use. Corticosteroids should be used only in patients with tumors that produce 1,25-dihydroxycholecalciferol. The use of plicamycin is limited because of adverse effects. Before the availability of zolendronic acid, pamidronate disodium was the treatment of choice, because of its longer duration of action than etidronate disodium and potential safety advantages. Zolendronic acid (discussed elsewhere in this supplement) is likely to supercede pamidronate disodium as the drug of choice for HCM, but the presence of symptoms, the rate of rise in serum calcium concentration, and the overall status of the patient are important considerations in selecting therapy.

Calcitonin↗
PubMed1996

Acute management of cancer-related hypercalcemia.

OBJECTIVE: To review the pathogenesis and pharmacologic treatment of acute hypercalcemia associated with malignancy. DATA SOURCES: A MEDLINE search (1966 to 1995) of the English-language literature pertaining to acute hypercalcemia was performed. Additional literature was obtained from reference lists of articles identified through the search. STUDY SELECTION AND DATA EXTRACTION: All articles discussing the etiology and medical management of cancer-related acute hypercalcemia were considered in this review. Clinical trials reporting efficacy and safety of antihypercalcemic agents were also included. Information selected in the review was based on the discretion of the authors. DATA SYNTHESIS: Hypercalcemia is a life-threatening disorder associated with malignancy. It occurs in approximately 10-20% of patients with cancer. A variety of medications have been used in the management of hypercalcemia including bisphosphonates, calcitonin, furosemide, gallium nitrate, glucocorticoids, NaCl 0.9%, and plicamycin. Each of these agents has been reviewed with consideration of pharmacologic mechanism of action, evaluation of clinical trials, recommended dosages, efficacy, safety, cost, and role in treating cancer-related acute hypercalcemia. CONCLUSIONS: Immediate management of cancer-related acute hypercalcemia to prevent death and provide symptomatic relief is warranted. Severity determined by symptoms, calcium concentrations, and the overall status of the patient are important considerations in selecting appropriate therapy. Although the specific role of individual agents may vary, hydration remains the cornerstone of therapy. NaCl 0.9%, calcitonin, and pamidronate disodium have established roles as dominant first-line agents for the management of acute hypercalcemia associated with malignancy.

Calcitonin↗
PubMed2001

Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons.

Global inhibitors of RNA or protein synthesis such as actinomycin D or cycloheximide abrogate neuronal apoptosis induced by numerous pathological stimuli in vitro and in vivo. The clinical application of actinomycin D or cycloheximide to human neurological disease has been limited by the toxicities of these agents. To overcome these toxicities, strategies must be developed to inhibit selectively the expression of deleterious proapoptotic proteins, while leaving the expression of antiapoptotic, proregeneration, and other critical homeostatic proteins unperturbed. Mithramycin A (trade name Plicamycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers. This class of agents is believed to act, in part, by selectively inhibiting gene expression by displacing transcriptional activators that bind to G-C-rich regions of promoters. Here we demonstrate that mithramycin A and its structural analog chromomycin A3 are potent inhibitors of neuronal apoptosis induced by glutathione depletion-induced oxidative stress or the DNA-damaging agent camptothecin. We correlate the protective effects of mithramycin A with its ability to inhibit enhanced DNA binding of the transcription factors Sp1 and Sp3 to their cognate "G-C" box induced by oxidative stress or DNA damage. The protective effects of mithramycin A cannot be attributed to global inhibition of protein synthesis. Together, these results suggest that mithramycin A and its structural analogs may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence-selective DNA-binding drugs as neurological therapeutics.

Animals↗
PubMed1991

Nephrotoxicity from chemotherapy: prevention and management.

Among the most devastating effects of antineoplastic chemotherapy is nephrotoxicity. This article discusses the effects of plicamycin, methotrexate, mitomycin C, nitrosoureas, 5-azacytidine, cisplatin, ifosfamide, carboplatin, and gallium nitrate on kidney function when these drugs are used either alone or in combination with each other and/or other agents. The importance of adequate hydration during chemotherapy in preventing and reversing drug-induced nephrotoxicity is also discussed.

Antineoplastic Agents↗
PubMed1986

Hypercalcemia of malignancy: diagnosis and therapy.

Therapy should be individualized on the basis of patient symptoms, severity of hypercalcemia, and prospects for inducing a remission in the underlying malignancy. We have found the most effective approach to be vigorous hydration of the patient, usually intravenously with normal saline at a rate of 300 to 500 mL/h. Intravenous furosemide is given as needed to prevent fluid overload. If the patient is volume replete and if hypercalcemia persists after 24 to 48 hours of intravenous hydration, calcitonin, 200 MRC units subcutaneously every 12 hours plus prednisone, 20 mg orally four times daily, are added. In most cases, a response is seen shortly after institution of this therapy. Meanwhile, attempts to treat the malignancy are initiated, including palliative radiation therapy for bony metastases. If the patient is still hypercalcemic and symptomatic after seven days of this therapy, treatment with plicamycin is given unless the patient's condition is clearly terminal. At present, use of prostaglandin synthetase inhibitors is not recommended, and bisphosphonates are available only for investigational use.

Calcitonin↗
PubMed1994

An algorithmic approach to the treatment of Paget's disease of the spine.

An algorithmic approach to the treatment of Paget's disease of the spine is based on the authors' collective experience in managing 70 patients and a review of the literature. For patients with active disease, even if asymptomatic, cyclical treatment with etidronate is recommended until normalization of biochemical parameters is achieved. For patients with back pain and/or neurologic dysfunction, cyclical etidronate treatment in the blastic and mixed phase is advocated. Those who fail to respond to calcitonin in the lytic phase should be given the new generation of bisphosphonates and gallium nitrate. No antipagetic drug therapy is indicated for the sclerotic phase. Surgery for complications of Paget's disease should be preceded by intravenous therapy to minimize intraoperative bleeding. For cases of spinal stenosis with impending paraplegia, the new bisphosphonates, mithramycin (plicamycin), or gallium nitrate should be used. If conservative treatment fails, surgery should not be delayed.

Algorithms↗
PubMed1993

Associations and dissociations between serum bone Gla protein and alkaline phosphatase in skeletal metabolism.

Serum bone Gla protein (BGP) and alkaline phosphatase (AP) activity were compared for the assessment of skeletal status in 11 normal pregnant women, 12 normal women on days 3 and 13 of the menstrual cycle, five postmenopausal women before and after 1 month of treatment with ethinyl estradiol (20 micrograms/day), five patients with cancer and hypercalcemia during treatment with calcitonin, and one patient with Paget disease during treatment with Plicamycin. BGP and AP correlated with each other only in the pregnant women. In all other circumstances, there was no correlation between these two serum osteoblast products. Furthermore, there were conditions in which the two measurements became discordant. These studies demonstrate that BGP and AP commonly are dissociated when used as measurements of skeletal status. Although both are osteoblast products, BGP and AP probably reflect different aspects of osteoblast differentiation and function.

Adult↗
PubMed2001

Paget's disease of the spine and its management.

A review of the literature was conducted to study the pathomechanics by which Paget's Disease of bone (PD) alters the spinal structures that result in distinct spinal pathologic entities such as pagetic spinal arthritis, spinal stenosis, and other pathologies, and to assess the best treatment options and available drugs. The spine is the second most commonly affected site with PD. About one-third of patients with spinal involvement exhibit symptoms of clinical stenosis. In only 12-24% of patients with PD of the spine is back pain attributed solely to PD, while in the majority of patients back pain is either arthritic in nature or a combination of a pagetic process and coexisting arthritis. Neural element dysfunction may be attributed to compressive myelopathy by pagetic bone overgrowth, pagetic intraspinal soft tissue overgrowth, ossification of epidural fat, platybasia, spontaneous bleeding, sarcomatous degeneration and vertebral fracture or subluxation. Neural dysfunction can also result from spinal ischemia, when blood is diverted by the so-called "arterial steal syndrome". Because the effectiveness of pharmacologic treatment for pagetic spinal stenosis has been clearly demonstrated, surgical decompression should only be instituted after failure of antipagetic medical treatment. Surgery is indicated as a primary treatment when neural compression is secondary to pathologic fractures, dislocations, spontaneous epidural hematoma, syringomyelia, platybasia, or sarcomatous transformation. Since, in the majority of cases with pagetic spinal involvement, there are also coexisting osteoarthritic changes, antipagetic medical treatment alone may be disappointing. Therefore, one must be careful before attributing low back pain to PD alone. Five classes of drugs are available for the treatment of PD: bisphosphonates, calcitonins, mithramycin (plicamycin), gallium nitrate, and ipriflavone. Bisphosphonates are the most popular, and several forms have been investigated, but only the following forms have been approved for clinical use: disodium etidronate, clodronate, aledronate, risedronate, neridronate, pamidronate, tiludronate, ibadronate, aminohydroxylbutylidene bisphosphonate, olpadronate, and zoledronate. Several of these forms are still under investigation.

Humans↗
PubMed1987

Therapy of hypercalcemia of malignancy.

An appreciation of the pathogenesis of the hypercalcemia of malignancy is essential to its management. At the outset, since most patients with symptomatic hypercalcemia of malignancy are dehydrated, infusion of 2 to 3 liters of saline per day will at least partially reduce serum calcium levels. Induction of calciuresis by infusing larger volumes of saline simultaneously with parenteral administration of furosemide may reduce the serum calcium concentration to normal in the short term. Of major importance in long-term therapy, however, are drugs that inhibit bone resorption, a major cause of hypercalcemia. These include calcitonin, plicamycin, glucocorticoids, prostaglandin synthetase inhibitors, and the diphosphonates. These agents may provide long-term control of hypercalcemia in many patients. Reduction of intestinal calcium absorption by dietary means or by glucocorticoid therapy is often effective in the rare subset of patients with increased serum levels of 1,25-dihydroxyvitamin D. Oral and intravenous phosphorus therapy may be effective via unknown mechanisms in some patients. The diphosphonates, in particular, should greatly facilitate management of both acute and chronic hypercalcemia of malignancy. Daily intravenous infusion of etidronate disodium (etidronate) with saline over a period of three to six days, for example, appears to be a safe and effective means of restoring serum calcium concentrations to the normal range. Study results have shown that more than 90 percent of patients have a response to etidronate. Oral administration of the drug has been demonstrated to maintain normal serum calcium concentrations.

Bone Resorption↗
PubMed1991

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.

Amino Acid Sequence↗