Hypercalcemia Treatment & Management
- Author: Mahendra Agraharkar, MD, MBBS, FACP; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Treatment depends on the severity of symptoms and the underlying cause.
Volume depletion results from uncontrolled symptoms leading to decreased intake and enhanced renal sodium loss. This tends to exacerbate or perpetuate the hypercalcemia by increasing Na+ reabsorption in the thick ascending limb of the loop of Henle (TALH). Thus, appropriate volume repletion with isotonic sodium chloride solution is an effective short-term treatment for hypercalcemia.
Once volume is restored, simultaneous administration of loop diuretics blocks Na+ and calcium reabsorption in the TALH. Replacing ongoing sodium, potassium, chloride, and magnesium losses is important if prolonged sodium chloride and loop diuretic therapy is contemplated.
Immobilization aggravates hypercalcemia. Whenever possible, weightbearing mobilization should be encouraged.
Reduction of dietary calcium and vitamin D intake is effective for treating hypercalcemia due to increased intestinal calcium absorption (eg, in idiopathic infantile hypercalcemia, ie, Williams syndrome). In vitamin D toxicity or extrarenal synthesis of 1,25(OH) D3 (eg, in sarcoidosis), prednisone may help reduce plasma calcium levels by reducing intestinal calcium absorption. Oral phosphate also can be used to form insoluble calcium phosphate in the gut.
Bisphosphonates inhibit osteoclastic bone resorption and are effective in the treatment of hypercalcemia due to conditions causing increased bone resorption and malignancy-related hypercalcemia. Pamidronate and etidronate can be given intravenously, while risedronate and alendronate may be effective as oral therapy. Calcitonin can be given intramuscularly or subcutaneously, but it becomes less effective after several days of use. Mithramycin blocks osteoclastic function and can be given for severe malignancy-related hypercalcemia. It has significant hepatic, renal, and marrow toxicity.
The US Food and Drug Administration (FDA) approved denosumab (Xgeva) for treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy in December 2014. Approval was based on results from an open-label, single-arm study that enrolled patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment. The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L.
The study achieved its primary endpoint with a response rate at day 10 of 63.6% in the 33 patients evaluated. The estimated median time to response (CSC < 11.5 mg/dL) was 9 days, and the median duration of response was 104 days.
Peritoneal dialysis or hemodialysis against calcium-free or lower calcium concentration dialysate solution is highly effective in lowering plasma calcium levels.
Surgical care is directed toward reversing the underlying cause of hypercalcemia or repairing the orthopedic damage, as follows[17, 18] :
Prolonged hypercalcemia due to hyperparathyroidism may warrant surgical neck exploration and removal of one or more parathyroid glands; this is particularly appropriate if evidence of nephrolithiasis, osteoporosis, reduction of renal function, neuromuscular symptoms, or radiographic bone disease is present
Hypercalcemia due to malignancy, especially a tumor that is producing parathyroid hormone – related peptide (PTHrP), may necessitate surgical resection of the tumor
Orthopedic complications of prolonged hypercalcemia (eg, osteoporosis), complications of Paget disease, or complications of bony metastases may require orthopedic or neurosurgical intervention
Consultation with a surgeon or orthopedist may be required, as indicated.
McKay CP, Portale A. Emerging topics in pediatric bone and mineral disorders 2008. Semin Nephrol. 2009 Jul. 29(4):370-8. [Medline].
Guarnieri V, Canaff L, Yun FH, et al. Calcium-Sensing Receptor (CASR) Mutations in Hypercalcemic States: Studies from a Single Endocrine Clinic Over Three Years. J Clin Endocrinol Metab. 2010 Feb 17. [Medline].
Nissen PH, Christensen SE, Wallace A, et al. Multiplex ligation-dependent probe amplification (MLPA) screening for exon copy number variation in the calcium sensing receptor gene: no large rearrangements identified in patients with calcium metabolic disorders. Clin Endocrinol (Oxf). 2009 Nov 11. [Medline].
Luna-Cabrera F, Justicia-Rull EA, Caricol-Pérez MP, et al. Incidence of hypercalcemia, hypercalciuria and related factors in patients treated with recombinant human parathyroid hormone (1-84). Minerva Med. 2012 Apr. 103(2):103-10. [Medline].
Vanstone MB, Oberfield SE, Shader L, Ardeshirpour L, Carpenter TO. Hypercalcemia in Children Receiving Pharmacologic Doses of Vitamin D. Pediatrics. 2012 Mar 12. [Medline].
Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest. 1996. 109(2):535-539. [Medline].
Griebeler ML, Kearns AE, Ryu E, Thapa P, Hathcock MA, Melton LJ 3rd, et al. Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades. J Clin Endocrinol Metab. 2016 Mar. 101 (3):1166-73. [Medline].
Vargas-Poussou R, Mansour-Hendili L, Baron S, et al. Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences. J Clin Endocrinol Metab. 2016 May. 101 (5):2185-95. [Medline].
Gastanaga VM, Schwartzberg LS, Jain RK, Pirolli M, Quach D, Quigley JM, et al. Prevalence of hypercalcemia among cancer patients in the United States. Cancer Med. 2016 Jun 5. [Medline].
Royer AM, Maclellan RA, Daniel Stanley J, Willingham TB, Heath Giles W. Hypercalcemia in the emergency department: a missed opportunity. Am Surg. 2014 Aug. 80(8):732-5. [Medline].
Cafforio P, Savonarola A, Stucci S, De Matteo M, Tucci M, Brunetti AE, et al. PTHrP produced by myeloma plasma cells regulates their survival and pro-osteoclast activity for bone disease progression. J Bone Miner Res. 2014 Jan. 29(1):55-66. [Medline].
Goldner W. Cancer-Related Hypercalcemia. J Oncol Pract. 2016 May. 12 (5):426-32. [Medline].
Alsirafy SA, Sroor MY, Al-Shahri MZ. Hypercalcemia in advanced head and neck squamous cell carcinoma: prevalence and potential impact on palliative care. J Support Oncol. 2009 Sep-Oct. 7(5):154-7. [Medline].
Makras P, Papapoulos SE. Medical treatment of hypercalcaemia. Hormones (Athens). 2009 Apr-Jun. 8(2):83-95. [Medline]. [Full Text].
Brooks M. FDA Approves New Indication for Denosumab (Xgeva). Medscape Medical News. Available at http://www.medscape.com/viewarticle/836252. Accessed: December 13, 2014.
Hu MI, Glezerman IG, Leboulleux S, Insogna K, Gucalp R, Misiorowski W, et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 2014 Sep. 99(9):3144-52. [Medline]. [Full Text].
Bergenfelz AO, Jansson SK, Wallin GK, et al. Impact of modern techniques on short-term outcome after surgery for primary hyperparathyroidism: a multicenter study comprising 2,708 patients. Langenbecks Arch Surg. 2009 Jul 18. [Medline].
Low TH, Clark J, Gao K, et al. Outcome of parathyroidectomy for patients with renal disease and hyperparathyroidism: predictors for recurrent hyperparathyroidism. ANZ J Surg. 2009 May. 79(5):378-82. [Medline].
Padhi D, Harris R. Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. Clin Pharmacokinet. 2009. 48(5):303-11. [Medline].
Marcocci C, Chanson P, Shoback D, et al. Cinacalcet reduces serum calcium concentrations in patients with intractable primary hyperparathyroidism. J Clin Endocrinol Metab. 2009 Jun 2. [Medline].
al Zahrani A, Levine MA. Primary hyperparathyroidism. Lancet. 1997 Apr 26. 349(9060):1233-8. [Medline].
Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003 May 1. 67(9):1959-66. [Medline].
Ganong CA, Kappy MS. Hypercalcemia. In: Berman S, ed. Pediatric Decision Making. 3rd ed. St. Louis, Mo: Mosby-Year Book; 1996:. 128-31.
Hoenderop JG, Nilius B, Bindels RJ. Molecular mechanism of active Ca2+ reabsorption in the distal nephron. Annu Rev Physiol. 2002. 64:529-49. [Medline].
Inzucchi SE. Management of hypercalcemia. Diagnostic workup, therapeutic options for hyperparathyroidism and other common causes. Postgrad Med. 2004 May. 115(5):27-36. [Medline].
Pearce SH. Calcium homeostasis and disorders of the calcium-sensing receptor. J R Coll Physicians Lond. 1998 Jan-Feb. 32(1):10-4. [Medline].
Strewler GJ. The physiology of parathyroid hormone-related protein. N Engl J Med. 2000 Jan 20. 342(3):177-85. [Medline].