Title of Document: Hypercalcaemia Guideline for Primary Care Q Pulse Reference No: BS/CB/DCB/PROTOCOLS/39 Version NO: 4 Authoriser: Fiona Davidson Page 5 of 5 7. *Treatment mechanism. 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. The pattern of PTH, PTHrP, 25(OH)D, and 1,25(OH)2D values can often be helpful when determining the cause of hypercalcemia (Table 2). The mnemonic "stones, bones, abdominal moans, and psychic groans" represents the constellation of symptoms and signs of hypercalcemia. 2015;21:143-147. 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. We will request your mailing address on the next page. Therapy focuses on methods to reduce serum calcium through increased calciuresis, decreased bone resorption, and reduced intestinal absorption of calcium. 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. 1 In severe cases, hypercalcemia can be associated with neurocognitive dysfunction as well as volume depletion and renal insufficiency or failure. 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. Incidental hypercalcemia may be the first manifestation of an undiagnosed 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. IV Zoledronic acid 4 mg in 100 mL NS over 15 minutes (note: see #7 initial dose modification if renal dysfunction) 5. 426-432. Steroids are usually given as hydrocortisone 200 to 400 mg/d for 3 to 4 days and then prednisone 10 to 20 mg/day for 7 days,1 or prednisone 40 to 60 mg/d for 10 days.14 If prednisone is not helpful after 10 days, it should be discontinued. 10. Contact Us PTH and PTHrP are similar molecules; therefore, both are not concurrently elevated unless there are multiple etiologies. Effective treatments reduce serum calcium by inhibiting bone resorption, increasing urinary calcium excretion, or decreasing intestinal calcium absorption (table 1). Because the most common cause is excess PTHrP, this should also be measured routinely. If the serum calcium is believed to be inaccurate, then ionized calcium can be used, but this also has its limitations and can be inaccurate. NCCN Guidelines and Compendium Updated. 19(2): 558-567. Serum phosphorus should also be measured because hypercalcemia can be associated with both hyper- and hypophosphatemia. Hypercalcemia of malignancy occurs frequently in adult oncology patients (10 to 40%) but is rare (0.4 to 0.7%) in children . The following represents disclosure information provided by authors of this manuscript. 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 Hypercalcemia of malignancy is most prevalent in rhabdomyosarcoma and acute lymphoblastic leukemia. bronchus, upper oesophagus), lymphoma, myeloma, kidney and bladder. Patients whose total serum calcium level is consistently between 12 mg/dL and 14 mg/dL may tolerate this level well, but the sudden development of hypercalcemia in this range or above may lead to dramatic changes in the patient's mental status. Furosemide blocks calcium reabsorption in the loop of Henle and increases urine output, which may necessitate increased saline administration, inducing further renal excretion of calcium.1, Two bisphosphonate agents were approved by the US Food and Drug Administration for the treatment of hypercalcemia of malignancy: pamidronate (Aredia) and zoledronic acid (Zometa).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. IV, intravenous; PTH, parathyroid hormone; SC, subcutaneous. Treatment of hypercalcemia of malignancy (HCM) is briefly reviewed, available treatments are compared, and treatment guidelines are presented. Society for Endocrinology Endocrine Emergency Guidance: … The document should be considered as a guideline only; it is not intended to determine an absolute standard of medical care. Hypercalcemia occurs in approximately 20% to 30% of patients with cancer at some time during the course of their disease, and is encountered predominantly among hospitalized patients, whereas primary hyperparathyroidism accounts for the majority of outpatient cases.1,2, There are 4 major types of hypercalcemia associated with cancer, including humoral hypercalcemia of malignancy (HHM), local osteolytic hypercalcemia, calcitriol-secreting lymphoma, and ectopic hyperparathyroidism.2. Calcitonin was administered to 27.4% of patients, and glucocorticoids were given to 26.9% of patients. To sign up for our newsletter or print publications, please enter your contact information below. 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. cause of hypercalcemia. Hypercalcaemia is a raised level of corrected calcium in the blood. (2003) Long-term Efficacy and Safety of Zoledronic Acid Compared with Pamidronate Disodium … Volume depletion is usually attributed to both decreased oral intake and also a component of nephrogenic diabetes insipidus induced by the hypercalcemia. Corrected calcium = Measured calcium +0.022 x (40 - serum albumin g/l) Effect of denosumab treatment on prevention of hypercalcemia of malignancy in cancer patients with metastatic bone disease. J Oncol Pharm Pract. 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. Because of the requirement for continuous intravenous infusion, gallium nitrate is not used frequently.2,7. 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. A treatment approach for hypercalcemia of malignancy. ASCO Meetings hypercalcemia associated with malignancies, which include: humoralhypercalcemiaofmalignancymediatedbyincreased parathyroid hormone–related peptide (PTHrP); local oste-olytic hypercalcemia with secretion of other humoral factors responsible for hypercalcemia; excess extrarenal activated vitamin D(1,25[OH] 2 D); PTH secretion, ectopicor primary; The most effective strategy is treatment of the underlying malignancy. The result is both hypercalcemia and hypophosphatemia.1,5 However, unlike PTH, PTHrP does not increase 1,25(OH)2D and thus does not increase intestinal absorption of calcium and phosphorus. About The most common cancers are lung cancer, multiple myeloma, and renal cell carcinoma. 9. 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. University of Nebraska Medical Center, Omaha, NE, Clinical practice. 7. IV Pamidronate 60 to 90 mg in 250 mL NS over 1 hour OR 4.1. 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. 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. JCO Precision Oncology, ASCO Educational Book If the etiology is not clear with the above laboratory tests, and the diagnosis of multiple myeloma is in question, then serum and urine protein electrophoresis or immunofixation along with a skeletal survey is indicated. Carroll MF, Schade DS. Denosumab, although expensive, is a valid option for patients with renal impairment. 3. This section addresses treatment options for hypercalcemia, including dose, frequency, and titration parameters; expected effects and anticipated time to resolution; special or target populations for specific therapies; and side effects and their management. It has not been extensively studied in hypercalcemia of malignancy. Relationships may not relate to the subject matter of this manuscript. Pamidronate is given at 60 to 90 mg IV over 4 to 24 hours. In advanced untreatable cancer, the decision to not treat hypercalcemia may be very appropriate. Lexi-Drugs. The total calcium level is low in patients with low levels of binding proteins (hypoalbuminemia) and higher in those with high levels of binding proteins. Macrophage inflammatory protein 1α was found to be elevated in the bone marrow of patients with active myeloma, and it is known to stimulate osteoclastic formation in human bone marrow cells.5,16 Local cytokines can also be released in the setting of metastatic breast cancer bone lesions, such as transforming growth factor β, which stimulate local production of PTHrP.17, Extrarenal production of 1,25(OH)2D by the tumor accounts for approximately 1% of cases of hypercalcemia in malignancy.1 In normal vitamin D metabolism, stored vitamin D (25[OH]D) in the liver is converted to 1,25(OH)2D under the influence of PTH by renal 1-α-hydroxylase in the kidneys. The list of tests for initial diagnostic workup and follow-up/surveillance has been updated. Among the causes of hypercalcemia, primary hyperparathyroidism (PHPT) and malignancy are most common, accounting for 80–90% of cases. Unfortunately, tachyphylaxis can occur within 48 hours as a result of downregulation of the calcitonin receptors. Zometa (zoledronic acid) [package insert]. In response to hypercalcemia, calcitonin is secreted by the parafollicular C cells. 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. This agent decreases serum calcium by inhibiting osteoclast activity. Am Fam Physician. 6. 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.