Hypercalcemia is a common complication of various types of cancer, including squamous-cell carcinoma, multiple myeloma, T-cell lymphoma, and breast carcinoma. Carroll MF, Schade DS. In cases where further anti-neoplastic therapy is not feasible, the decision to treat or not treat hypercalcemia should be made by careful exploration of the patient’s goals of care. Cancer.Net, ASCO.org Calcium and Cancer: Of Evil Humors and Innocent Bystanders. The treatment of hypercalcemia will be reviewed here, with emphasis on the management of hypercalcemia … 2003;67:1959-1966. Patients often require 1 to 2 L as an initial bolus and then maintenance fluids of 150 to 300 mL/h for the next 2 to 3 days or until they are volume replete. Retreatment with zoledronic acid 4 mg may be considered for persistent hypercalcemia, but no sooner than 7 days after the initial therapy. If the etiology is clear based on the above work-up, then I do not routinely perform a 24-hour urine analysis for calcium and creatinine. Previously, the proposed mechanism was direct destruction of bone by metastases or malignant cells. Mild or indolent hypercalcemia can be asymptomatic, or it can be associated with mild nonspecific symptoms such as lethargy and musculoskeletal pain. If the interaction between RANK and RANKL is disrupted or blocked, then the osteoclasts do not mature. Am Fam Physician. For hypercalcemia less than3.5 mmol/L with symptoms. 19(2): 558-567. Furosemide therapy is often discussed as a means to provide increased calciuresis.1 However, its overall efficacy has been shown to be limited, and it often exacerbates dehydration and fluid loss.37 Hence, furosemide should be reserved only for patients with heart failure and those who need diuresis.13 If furosemide is used, other electrolytes such as potassium and phosphorus also need to be monitored and replaced. 426-432. Renal effects include dehydration, polyuria, nephrolithiasis resulting from hypercalciuria, nephrogenic diabetic insipidus, and nephrocalcinosis. Management depends on the severity of calcium imbalance. If the albumin is abnormal, the serum calcium should be corrected for the serum albumin using the formula in Table 1. If there is increased interaction between RANK and RANKL, then there is more osteoclastic expression and more bone resorption.5,6, Calcium homeostasis is tightly regulated by many hormones, including parathyroid hormone (PTH), 1,25-dihydroxy vitamin D (1,25[OH]2D), calcitonin, serum calcium, and serum phosphorus.7,8 PTH is produced by the parathyroid glands. The patient should be asked about the presence of cough, weight loss, or new masses and should be up to date with current guidelines regarding screening for colorectal, breast, and other cancers appropriate for the patient’s age, sex, and risk factors. Although there are published recommendations for treatment, these algorithms are not always routinely followed. Thus, understanding its mechanism of action is important. Zoledronic acid is given at 4 mg IV over 15 to 30 minutes.13, Bisphosphonates, unfortunately, have been associated with nephrotoxicity. Journal of Clinical Oncology, 19(2), 558 567. JCO Clinical Cancer Informatics These NCCN Guidelines are currently available as Version 1.2012. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. 7. The zoledronic acid package insert recommends that in hypercalcemia of malignancy, patients with mild to moderate renal impairment before initiation of therapy (serum creatinine < 4.5 mg) do not need dose adjustment. The severity of hypercalcemia is classified into 3 categories based on the level of total serum calcium (Figure). Humoral hypercalcemia of malignancy refers specifically to PTHrP-mediated hypercalcemia and was first proposed by Fuller Albright in 1941.9 It is estimated to account for 80% of hypercalcemia in cancer patients.1,5 This is most commonly seen in squamous cell carcinomas such as head and neck, esophageal, cervical, lung,1 and colon cancers10 in addition to renal cell,11 bladder, breast, endometrial, and ovarian cancers,1 and it is rarely seen in pancreatic neuroendocrine tumors.12 PTHrP is structurally similar to PTH and, like PTH, it enhances renal tubular reabsorption of calcium while simultaneously increasing urinary phosphorus excretion. For the management of hypercalcaemia in malignancy, or hypercalcaemia in palliative patients, see separate guidance available at www.palliativecareguidelines.scot.nhs.uk. Bone mineralization is a well-balanced constant cycle of bone formation stimulated by osteoblasts and bone breakdown (or resorption) stimulated through osteoclasts. Mild and asymptomatic moderate hypercalcemia is treated with oral rehydration and low calcium intake, while symptomatic moderate cases and severe cases require IV rehydration and N Engl J Med. However, additional therapies, especially for moderate to severe hypercalcemia, are essential when simultaneously treating the underlying malignancy. Relationships may not relate to the subject matter of this manuscript. Hypercalcemia can occur in those with malignancy and an additional etiology for hypercalcemia such as primary hyperparathyroidism or granulomatous diseases. Clinical manifestations of hypercalcemia vary according to the level of calcium in the blood. The ASCO Post In approximately 60% to 90% of patients, the serum calcium level normalizes within 4 to 7 days, and the response lasts for 1 to 3 weeks.2, Bisphosphonates inhibit bone resorption and decrease bone mineralization by disrupting osteoclast activity.2 The most common adverse reactions are renal toxicity, flulike symptoms, injection site reactions, hypocalcemia, hypophosphatemia, fatigue, muscle weakness, and constipation or diarrhea.4,5 Daily oral supplementation with 500 mg of calcium and a multiple vitamin containing 400 IU of vitamin D is recommended to prevent hypocalcemia.4,5, Denosumab (Prolia), a full human immunoglobulin G2 monoclonal antibody against RANKL, can be used to manage malignancy-associated hypercalcemia in patients with persistent hypercalcemia despite bisphosphonate treatment. Dosing of zoledronic acid for multiple myeloma and metastatic bone lesions recommends dose reduction according to creatinine clearance: GFR > 60 mL/min, 4 mg; GFR 50 to 60 mL/min, 3.5 mg; GFR 40 to 49 mL/min, 3.3 mg; and GFR 30 to 39 mL/min, 3.0 mg.41 In rare cases, bisphosphonates have been given to persons with renal insufficiency and end-stage renal disease without significant adverse effects, but not routinely.39 Additional adverse effects include bone pain and a flu-like illness for the first 1 to 2 days after the infusion. Hypercalcemia of malignancy is most prevalent in rhabdomyosarcoma and acute lymphoblastic leukemia. 6. Hypercalcaemia is defined as a serum calcium concentration of 2.6 mmol/L or higher, on two occasions, following adjustment (correction) for the serum albumin concentration. • Malignancy • Vitamin D mediated – Toxicosis – Granulomatous disorders • Medications • Miscellaneous – Immobilization, hyperthyroid, adrenal insufficiency, acromegaly} Accounts for 80‐90% of cases 9 10. Therefore, the cornerstone of initial treatment of hypercalcemia in these patients is volume expansion with intravenous normal saline to increase the glomerular filtration rate and renal calcium excretion. Forty percent of calcium in serum is bound to albumin, and calcium homeostasis is greatly affected by albumin concentrations.8 Therefore, a current serum albumin level is necessary for interpretation of the serum calcium level. In cats, idiopathic hypercalcemia appears to be the most frequent cause of a high total calcium concentration, followed by renal failure and malignancy. Pamidronate is given at 60 to 90 mg IV over 4 to 24 hours. ASCO Daily News When associated with rhabdomyosarcoma, hypercalcemia tends to present later, with more therapy resistance (2,3). Aredia (pamidronate sodium) [package insert]. Mithramycin has been administered via intravenous infusion of 25 µg/kg over 4 to 6 hours in normal saline or a 5% dextrose in water solution.2 This therapy can be repeated daily for 3 to 4 days, and the serum calcium-lowering effect begins within 12 hours of initiation. However, if the course has been indolent, there is a family history of hypercalcemia, and the patient does not have an active cancer that can account for the hypercalcemia, then a 24-hour urine calcium clearance to creatinine clearance ratio can be valuable to differentiate between primary hyperparathyroidism and familial hypocalciuric hypercalcemia.34 If the urine calcium clearance to creatinine clearance ratio is low (< 0.01), then familial hypocalciuric hypercalcemia should be suspected, and definitive evaluation can include testing for mutations in the CASR, AP2S1, or GNA11 gene.35. It might be classified according to severity: Hypercalcemia is a result of abnormalities in the normal bone formation and degradation cycle. cause of hypercalcemia. A treatment approach for hypercalcemia of malignancy. 1. Approximately 50% of total calcium is protein bound, and the total calcium level will vary with protein-binding capacity. Guidelines for the treatment of hypercalcemia associated with malignancy Lynne Nakashima, BSc(Pharm), PharmD Journal of Oncology Pharmacy Practice 2016 3 : 1 , 31-37 When used with bisphosphonates, it can lower calcium more rapidly than either agent alone. Journal of Clinical Oncology. The list of tests for initial diagnostic workup and follow-up/surveillance has been updated. Rarely, vitamin A toxicity can result in hypercalcemia; thus serum vitamin A levels can be a consideration if other etiologies are not discovered. Calcitonin was administered to 27.4% of patients, and glucocorticoids were given to 26.9% of patients. Permissions, Authors Hypercalcemia is considered mild if the total serum calcium level is between 10.5 and 12 mg per dL (2.63 and 3 mmol per L). Hypercalcemia is categorized according to the serum total calcium level1: mild hypercalcemia, 10.5 to 11.9 mg/dL; moderate hypercalcemia, 12 to 13.9 mg/dL; and severe hypercalcemia, ≥ 14 mg/dL. Rosen LS, Gordon D et al. Ionized hypercalcemia in conjunction with chronic renal failure is more common in cats than dogs. The doctors concerned must make the management plan for an individual patient. The most common cancers are lung cancer, multiple myeloma, and renal cell carcinoma. DOI: 10.1200/JOP.2016.011155 Journal of Oncology Practice Bisphosphonates affect proliferation and differentiation of osteoblasts and prevent their apoptosis, and they can also neutralize the RANKL-mediated stimulation of osteoclasts.14,38, Bisphosphonates should be given within 48 hours of diagnosis, because it takes approximately 2 to 4 days for them to have effect. FIG 1. Effective treatments reduce serum calcium by inhibiting bone resorption, increasing urinary calcium excretion, or decreasing intestinal calcium absorption (table 1). Lexi-Drugs. Steroids inhibit osteoclastic bone resorption by decreasing tumor production of locally active cytokines, in addition to having direct tumorolytic effects. The mnemonic "stones, bones, abdominal moans, and psychic groans" represents the constellation of symptoms and signs of hypercalcemia. 1 In severe cases, hypercalcemia can be associated with neurocognitive dysfunction as well as volume depletion and renal insufficiency or failure. (May 01, 2016) Hypercalcaemia is the commonest life-threatening metabolic disorder associated with advanced cancer. 3. Therapy There are multiple evidence-based guidelines for the treatment of adults with hypercalcemia of malignancy. However, mithramycin is not often recommended for patients with malignancy-related hypercalcemia because of dose-related adverse effects such as nausea, vomiting, stomatitis, thrombocytopenia, renal symptoms, and hepatotoxicity. Incidental hypercalcemia may be the first manifestation of an undiagnosed malignancy. To sign up for our newsletter or print publications, please enter your contact information below. All relationships are considered compensated. HHM is the most common mechanism of hypercalcemia in patients with cancer. Glucocorticoids are also given to treat hypercalcemia caused by excess extrarenal 1,25(OH)2D and multiple myeloma. Hypercalcemia related to malignancy may resolve with definitive antitumor therapy directed at the underlying cancer, such as surgery or chemotherapy.3 If it does not resolve with appropriate anticancer treatment, antihypercalcemic therapy focusing on targeting the pathophysiologic mechanisms should be considered. Hudson, OH: Wolters Kluwer Health. The clinical manifestations of hypercalcemia can involve many body systems. It is important to understand the pathogenesis, work-up, and treatment options for hypercalcemia associated with malignancy so that timely intervention can occur. Because the most common cause is excess PTHrP, this should also be measured routinely. Breast radiation correlates with side of parathyroid adenoma, Lithium-associated hyperparathyroidism: Report of four cases and review of the literature, Hereditary hyperparathyroidism—A consensus report of the European Society of Endocrine Surgeons (ESES), Parathyroid carcinoma, a rare cause of primary hyperparathyroidism, The coexistence of renal cell carcinoma and diffuse large B-cell lymphoma with hypercalcemic crisis as the initial presentation, Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with clear cell endometrial cancer, Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with multiple endocrine neoplasia type 1, Association of primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with clear cell renal carcinoma, Letter to the editor: Distinguishing typical primary hyperparathyroidism from familial hypocalciuric hypercalcemia by using an index of urinary calcium, Diagnosis of asymptomatic primary hyperparathyroidism: Proceedings of the Fourth International Workshop, A review in the treatment of oncologic emergencies, Narrative review: Furosemide for hypercalcemia: An unproven yet common practice, Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts, Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials, Effect of intravenous hydration in patients receiving bisphosphonate therapy, Osteonecrosis of the jaw (ONJ): Diagnosis and management in 2015, Regulation of calcitonin receptor by glucocorticoid in human osteoclast-like cells prepared in vitro using receptor activator of nuclear factor-kappaB ligand and macrophage colony-stimulating factor, Treatment of bisphosphonate-resistant hypercalcemia of malignancy with calcitonin, The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease, PTHrP-induced refractory malignant hypercalcemia in a patient with chronic lymphocytic leukemia responding to denosumab, Denosumab for treatment of hypercalcemia of malignancy, Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction, Renal replacement therapy as a treatment for severe refractory hypercalcemia, Professional English and Academic Editing Support. Laboratory Findings for Specific Etiologies of Hypercalcemia Associated With Malignancy. Hypercalcemia of Malignancy: A New Twist on an Old Problem. Volume depletion is usually attributed to both decreased oral intake and also a component of nephrogenic diabetes insipidus induced by the hypercalcemia. Lexicomp. Zometa (zoledronic acid) [package insert]. Thousand Oaks, CA: Amgen Inc; 2015. Sources. However, it is not recommended in severe renal impairment (serum creatinine > 4.5 mg/dL). Department of Endocrine Neoplasia and Hormonal Disorders Newsletter. Subscribers Hypercalcemia of malignancy occurs frequently in adult oncology patients (10 to 40%) but is rare (0.4 to 0.7%) in children . Abbreviations: 1,25(OH)2D, 1,25-dihydroxy vitamin D; 25(OH)D, 25-hydroxy vitamin D; GFR, glomerular filtration rate; IFE, immunofixation; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide, SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis. Bisphosphonates are first-line therapy and also the mainstay for long-term therapy. Management of Malignant Hypercalcaemia Acute Oncology Clinical Guideline V1.0 Page 2 of 9 Summary Malignant hypercalcaemia Raised calcium associated with cancers Most commonly: breast, renal cell, lung, and advanced malignancy Consider use of bone scan, myeloma, PTHrP and PTH if no known primary High Corrected Serum Calcium >2.9mmol/L 2.7-2.9mmol/L Therapy focuses on methods to reduce serum calcium through increased calciuresis, decreased bone resorption, and reduced intestinal absorption of calcium. For hypercalcemia unresponsive to other measures. ASCO Meetings In multiple myeloma, for example, malignant myeloma cells secrete a cytokine-interleukin-6-that activates osteoclasts in the vicinity of the myeloma cells, leading to bone resorption. The only malignancy it has been approved for use in is parathyroid carcinoma.28 Dialysis or continuous renal replacement therapy is usually reserved for hypercalcemia refractory to all of the above therapies.46,49. Cardiovascular effects include hypertension, shortened QT interval, cardiac arrhythmia, and vascular calcification. Scenario: Known malignancy: covers the management of people with hypercalcaemia of known malignancy. http://online.lexi.com. Author Disclosure Statement The authors have no conflicts of interest to report. Dietzek A, Connelly K, Cotugno M, et al. Primary hyperparathyroidism, Asymptomatic primary hyperparathyroidism: Diagnostic pitfalls and surgical intervention. Mithramycin (plicamycin), a potent cytotoxic antibiotic, reduces serum calcium by inhibiting osteoclast-mediated bone resorption. DOI: 10.1200/JOP.2016.011155 Journal of Oncology Practice - Rehydration can be accomplished by intravenous administration of normal saline, at a rate of 200 to 500 mL/h or 2 to 4 L/d, depending on renal function, the baseline status of dehydration, and the severity of hypercalcemia. Effect of denosumab treatment on prevention of hypercalcemia of malignancy in cancer patients with metastatic bone disease. The Journal of Hematology Oncology Pharmacy™| ISSN 2164-1153 (print); ISSN 2164-1161 (online)©2020 Green Hill Healthcare Communications, LLC, an affiliate of The Lynx Group. Hypercalcemia is most common in those who have later-stage malignancies and predicts a poor prognosis for those with it. Many cancer cells secrete parathyroid-hormone-related protein (PTHrP), which binds to the parathyroid receptors in bone and renal tissues, resulting in increased bone resorption and renal tubular reabsorption.3 Local osteolytic hypercalcemia can be differentiated from primary hyperparathyroidism and humoral hypercalcemia of malignancy by normal or slightly elevated phosphate levels, normal levels of immunoreactive PTHrP, and the presence of bone metastases or bone marrow infiltration. The most effective strategy is treatment of the underlying malignancy. However, the etiology is not always mediated by malignancy. Renal function must be carefully monitored with serum creatinine before additional doses of zoledronic acid are given; if renal function has declined, then redosing may not be appropriate. PTH-mediated causes of hypercalcemia also need to be considered in hypercalcemia associated with malignancy. PTH and PTHrP are similar molecules; therefore, both are not concurrently elevated unless there are multiple etiologies. Denosumab in hypercalcemia of malignancy: a case series. Hypercalcemia of malignancy: current & future directions. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml. Unfortunately, tachyphylaxis can occur within 48 hours as a result of downregulation of the calcitonin receptors. Normal ionized calcium levels are 4 to 5.6 mg per dL (1 to 1.4 mmol per L). Malignancy needs to be considered. Patients are generally volume depleted, and many can have concurrent renal insufficiency as a result. Hypercalcemia of malignancy (HCM) typically is associated with severe clinical signs and symptoms and is ... up to date with current guidelines regarding screening for colorectal, breast, and other cancers appropriate for the pa-tient’s age, sex, and risk factors. This guideline has been adapted for local use. NCCN Guidelines and Compendium Updated. Miacalcic (salcatonin) [package insert]. http://druginserts.com/lib/rx/meds/zometa-1, Calcium and Cancer: Of Evil Humors and Innocent Bystanders, Hypercalcemia of Malignancy: A New Twist on an Old Problem, Reasons to Reject Physician Assisted Suicide/Physician Aid in Dying, Breast Cancer in Women Older Than 80 Years, Developing Effective Communication Skills, Patient and Plan Characteristics Affecting Abandonment of Oral Oncolytic Prescriptions, The State of Oncology Practice in America, 2018: Results of the ASCO Practice Census Survey, The State of Cancer Care in America, 2017: A Report by the American Society of Clinical Oncology, Centers for Medicare and Medicaid Services: Using an Episode-Based Payment Model to Improve Oncology Care, Best Practices for Reducing Unplanned Acute Care for Patients With Cancer, Serum total calcium (recheck if only one measurement), 0.8 (4.0 − serum albumin) + serum calcium = total estimated calcium, Ionized calcium (if total estimated calcium is believed to be unreliable). Hypercalcemia is defined as a condition in which the serum calcium level is >10.5 mg/dL (the upper limit of normal) or the ionized calcium level exceeds 5.6 mg/dL. Over-the-counter vitamin D usage is common, which can result in excess vitamin D and hypercalcemia.21 A distinguishing feature of vitamin D intoxication versus extrarenal 1,25(OH)2D production is that in vitamin D intoxication, both 25(OH)D and 1,25(OH)2D are elevated with a suppressed PTH. Ectopic PTH production by the tumor itself is a rare cause, making up fewer than 1% of cases.1 However, primary hyperparathyroidism as a result of parathyroid adenoma(s) or hyperplasia can also occur in patients with malignancy. IV, intravenous; PTH, parathyroid hormone; SC, subcutaneous. 4. Hypercalcemia (defined as a serum calcium level >10.5 mg/dL or 2.5 mmol/L) is an important clinical problem [1]. ASCO Author Services This binding of RANK/RANKL regulates osteoclastogenesis. Usual supportive care for hypercalcemia includes removing calcium intake from any sources (eg, intravenous or oral calcium supplements), increasing oral free water intake, discontinuing medications and supplements that cause hypercalcemia (thiazide diuretics, lithium, vitamin D, calcium carbonate therapy), increasing weight-bearing ambulation/activities, and discontinuing sedative drugs and analgesics.1 Symptomatic patients whose serum calcium level exceeds 12 mg/dL or asymptomatic persons whose level exceeds 14 mg/dL should be immediately and aggressively treated with antihypercalcemic therapy: saline rehydration followed by loop diuretics, calcitonin, bisphosphonates, or denosumab.2,4 For the majority of cancer patients with HHM or local osteolytic hypercalcemia, intravenous bisphosphonates or subcutaneous/intramuscular calcitonin or subcutaneous denosumab can be used to inhibit osteoclast-mediated bone resorption. Gallium nitrate; [cited 2015 Aug 21]. Central nervous system effects include lethargy, impaired concentration, fatigue, and muscle weakness. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015. There have been several proposed mechanisms for hypercalcemia associated with malignancies, which include: humoral hypercalcemia of malignancy mediated by increased parathyroid hormone–related peptide (PTHrP); local osteolytic hypercalcemia with secretion of other humoral factors responsible for hypercalcemia; excess extrarenal activated vitamin D (1,25[OH]2D); PTH secretion, ectopic or primary; and multiple concurrent etiologies. It has not been extensively studied in hypercalcemia of malignancy. Hypercalcemia is a common complication of cancer. Abbreviations: 1,25(OH)2D, 1,25-dihydroxy vitamin D; 25(OH)D, 25-hydroxy vitamin D; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide. 2012;5:1-3. Once there is confirmation of hypercalcemia, then it should be determined whether it is PTH or non-PTH mediated. JCO Oncology Practice This paper reviews the cancers associated with hypercalcemia and their proposed mechanisms, nontumor-mediated hypercalcemia, as well as diagnosis and treatment strategies for each condition. Other symptoms include bone pain, arthritis, and osteoporosis. Hypercalcaemia can occur in any malignancy but is most common in cancers of the breast, squamous cell carcinomas (e.g. It is the commonest life-threatening metabolic disorder in cancer patients, most frequently occurring in myeloma, breast, renal, lung and thyroid cancers. 2-5 Bisphosphonate therapy should be initiated as soon as hypercalcemia is detected, because it takes 2 to 4 days to lower the calcium level. It occurs in approximately 10% of patients with cancer. The optimal choice varies with the cause and severity of hypercalcemia. Reducing intestinal calcium reabsorption is also important in those with increased extrarenal 1,25(OH)2D production (Fig 1). The maximum effect generally occurs within 4 to 7 days after initiation of therapy. … Hypercalcemia patients associated with Local osteolytic Hypercalcemia are differentiated from Primary hyperthyroidism and Humoral hypercalcemia of malignancy by normal or slightly elevated PO4 levels, normal level of immunoreactive PTHrP, and presence of bone metastases or bone marrow infiltration [3]. Parathyroid hormone ; SC, subcutaneous and musculoskeletal pain, Body J, Newby Y, Sundar S. should! Table 1 ) or jop.ascopubs.org/site/misc/ifc.xhtml disease in patients with cancer please refer to www.asco.org/rwc or.. Of an undiagnosed malignancy having direct tumorolytic effects phosphorus absorption disease and is generally indicative of a poor for... To understand the pathogenesis, work-up, and many can have concurrent renal insufficiency as a result the is... Calcium level, 10.5-12 mg/dL ) generally do not mature symptoms and signs of depends! 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Is confirmation of hypercalcemia in conjunction with chronic renal failure common practice and osteoporosis key and.