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HypercalcemiaA Review

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Importance  Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma.

Observations  Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival.

Conclusions and Relevance  Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

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Article Information

Corresponding Author: Elizabeth Shane, MD, Columbia University Irving Medical Center, 180 Ft Washington Ave, Ninth Floor, Room 910, New York, NY 10032 (es54@cumc.columbia.edu).

Accepted for Publication: September 17, 2022.

Author Contributions: Dr Shane had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Walker.

Drafting of the manuscript: Walker.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Walker.

Conflict of Interest Disclosures: Dr Walker reported receiving payments from Springer for editing a textbook on hypercalcemia and receiving royalties from Springer for that textbook. Drs Walker and Shane reported receiving research support from Amgen. Dr Shane reported receiving royalties from UpToDate for chapters on hypercalcemia.

Minisola  S , Pepe  J , Piemonte  S , Cipriani  C .  The diagnosis and management of hypercalcaemia.   BMJ. 2015;350:h2723. doi:10.1136/bmj.h2723PubMedGoogle ScholarCrossref
Palmér  M , Jakobsson  S , Akerström  G , Ljunghall  S .  Prevalence of hypercalcaemia in a health survey: a 14-year follow-up study of serum calcium values.   Eur J Clin Invest. 1988;18(1):39-46. doi:10.1111/j.1365-2362.1988.tb01163.xPubMedGoogle ScholarCrossref
Gastanaga  VM , Schwartzberg  LS , Jain  RK ,  et al.  Prevalence of hypercalcemia among cancer patients in the United States.   Cancer Med. 2016;5(8):2091-2100. doi:10.1002/cam4.749PubMedGoogle ScholarCrossref
Balasubramanian  P , Majumdar  SK .  Albumin-corrected calcium and the prevalence and categories of hypercalcemia in hospitalized patients with 1-year follow-up of undiagnosed cases.   Endocr Pract. 2021;27:279-285. doi:10.1016/j.eprac.2020.09.005Google ScholarCrossref
Dent  DM , Miller  JL , Klaff  L , Barron  J .  The incidence and causes of hypercalcaemia.   Postgrad Med J. 1987;63(743):745-750. doi:10.1136/pgmj.63.743.745PubMedGoogle ScholarCrossref
Heedman  PA , Stenström  G .  Clinical findings in patients with hypercalcaemia: a preliminary investigation based on biochemical screening.   Acta Med Scand. 1973;193(3):167-173.PubMedGoogle Scholar
Vautour  L , Goltzman  D . Regulation of calcium homeostasis. In: Bilezikian  JP , Bouillon  R , Clemens  T ,  et al, eds.  Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Wiley; 2018:163-172.
Silva  BC , Bilezikian  JP .  Parathyroid hormone: anabolic and catabolic actions on the skeleton.   Curr Opin Pharmacol. 2015;22:41-50. doi:10.1016/j.coph.2015.03.005PubMedGoogle ScholarCrossref
Schwarz  P , Sørensen  HA , Transbøl  I , McNair  P .  Regulation of acute parathyroid hormone release in normal humans: combined calcium and citrate clamp study.   Am J Physiol. 1992;263(2 pt 1):E195-E198. doi:10.1152/ajpendo.1992.263.2.E195PubMedGoogle ScholarCrossref
Pirklbauer  M , Mayer  G .  The exchangeable calcium pool: physiology and pathophysiology in chronic kidney disease.   Nephrol Dial Transplant. 2011;26(8):2438-2444. doi:10.1093/ndt/gfr207PubMedGoogle ScholarCrossref
de Groot  T , Lee  K , Langeslag  M ,  et al.  Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation.   J Am Soc Nephrol. 2009;20(8):1693-1704. doi:10.1681/ASN.2008080873PubMedGoogle ScholarCrossref
Sato  T , Courbebaisse  M , Ide  N ,  et al.  Parathyroid hormone controls paracellular Ca2+ transport in the thick ascending limb by regulating the tight-junction protein Claudin14.   Proc Natl Acad Sci U S A. 2017;114(16):E3344-E3353. doi:10.1073/pnas.1616733114PubMedGoogle ScholarCrossref
van de Graaf  SF , Boullart  I , Hoenderop  JG , Bindels  RJ .  Regulation of the epithelial Ca2+ channels TRPV5 and TRPV6 by 1α,25-dihydroxy vitamin D3 and dietary Ca2+.   J Steroid Biochem Mol Biol. 2004;89-90(1-5):303-308. doi:10.1016/j.jsbmb.2004.03.029PubMedGoogle ScholarCrossref
Goltzman  D .  Pathophysiology of hypercalcemia.   Endocrinol Metab Clin North Am. 2021;50(4):591-607. doi:10.1016/j.ecl.2021.07.008PubMedGoogle ScholarCrossref
David Roodman  G , Silbermann  R .  Mechanisms of osteolytic and osteoblastic skeletal lesions.   Bonekey Rep. 2015;4:753. doi:10.1038/bonekey.2015.122PubMedGoogle ScholarCrossref
Hewison  M , Kantorovich  V , Liker  HR ,  et al.  Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages.   J Bone Miner Res. 2003;18(3):579-582. doi:10.1359/jbmr.2003.18.3.579PubMedGoogle ScholarCrossref
Beall  DP , Scofield  RH .  Milk-alkali syndrome associated with calcium carbonate consumption: report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia.   Medicine (Baltimore). 1995;74(2):89-96. doi:10.1097/00005792-199503000-00004PubMedGoogle ScholarCrossref
Machado  MC , Bruce-Mensah  A , Whitmire  M , Rizvi  AA .  Hypercalcemia associated with calcium supplement use: prevalence and characteristics in hospitalized patients.   J Clin Med. 2015;4(3):414-424. doi:10.3390/jcm4030414PubMedGoogle ScholarCrossref
Griebeler  ML , Kearns  AE , Ryu  E ,  et al.  Thiazide-associated hypercalcemia: incidence and association with primary hyperparathyroidism over two decades.   J Clin Endocrinol Metab. 2016;101(3):1166-1173. doi:10.1210/jc.2015-3964PubMedGoogle ScholarCrossref
El Masri  D , Jamil  Y , Eid Fares  J .  Sodium-glucose co-transporter protein 2 inhibitors induced hypercalcemia: a case series and literature review.   AACE Clin Case Rep. 2021;8(1):30-33. doi:10.1016/j.aace.2021.07.002PubMedGoogle ScholarCrossref
Zhang  J , Huan  Y , Leibensperger  M , Seo  B , Song  Y .  Comparative effects of sodium-glucose cotransporter 2 inhibitors on serum electrolyte levels in patients with type 2 diabetes: a pairwise and network meta-analysis of randomized controlled trials.   Kidney360. 2022;3(3):477-487. doi:10.34067/KID.0006672021PubMedGoogle ScholarCrossref
Wanchoo  R , Sakhiya  V , Jhaveri  KD .  Immune checkpoint inhibitor-associated electrolyte disorders: query of the Food and Drug Administration Adverse Event Reporting System.   Kidney Int. 2021;100(4):945-947. doi:10.1016/j.kint.2021.06.001PubMedGoogle ScholarCrossref
Ferris  RL , Blumenschein  G  Jr , Fayette  J ,  et al.  Nivolumab for recurrent squamous-cell carcinoma of the head and neck.   N Engl J Med. 2016;375(19):1856-1867. doi:10.1056/NEJMoa1602252PubMedGoogle ScholarCrossref
Ryder  M , Callahan  M , Postow  MA , Wolchok  J , Fagin  JA .  Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution.   Endocr Relat Cancer. 2014;21(2):371-381. doi:10.1530/ERC-13-0499PubMedGoogle ScholarCrossref
Rambhia  PH , Reichert  B , Scott  JF ,  et al.  Immune checkpoint inhibitor-induced sarcoidosis-like granulomas.   Int J Clin Oncol. 2019;24(10):1171-1181. doi:10.1007/s10147-019-01490-2PubMedGoogle ScholarCrossref
Uppal  NN , Workeneh  BT , Rondon-Berrios  H , Jhaveri  KD .  Electrolyte and acid-base disorders associated with cancer immunotherapy.   Clin J Am Soc Nephrol. 2022;17(6):922-933. doi:10.2215/CJN.14671121PubMedGoogle ScholarCrossref
Deligiorgi  MV , Panayiotidis  MI , Trafalis  DT .  Parathyroid hormone related protein (PTHrP)-mediated hypercalcemia in malignancy associated with anti-PD-1 immune checkpoint inhibitor treatment and related inflammatory reactions.   Int Immunopharmacol. 2019;77:105942. doi:10.1016/j.intimp.2019.105942PubMedGoogle ScholarCrossref
Kobari  Y , Kondo  T , Takagi  T , Omae  K , Nakazawa  H , Tanabe  K .  Rapid progressive disease after nivolumab therapy in three patients with metastatic renal cell carcinoma.   In Vivo. 2017;31(4):769-771. doi:10.21873/invivo.11129PubMedGoogle ScholarCrossref
Horiuchi  K , Kobayashi  E , Mizuno  T , Susa  M , Chiba  K .  Hypercalcemia following discontinuation of denosumab therapy: a systematic review.   Bone Rep. 2021;15:101148. doi:10.1016/j.bonr.2021.101148PubMedGoogle ScholarCrossref
Kallala  R , Haddad  FS .  Hypercalcaemia following the use of antibiotic-eluting absorbable calcium sulphate beads in revision arthroplasty for infection.   Bone Joint J. 2015;97-B(9):1237-1241. doi:10.1302/0301-620X.97B9.34532PubMedGoogle ScholarCrossref
Tarar  MY , Toe  KKZ , Javed  K , Shah  N , Khalid  A .  The risk of iatrogenic hypercalcemia in patients undergoing calcium sulphate beads implantation in prosthetic joint surgery: a systematic review.   Cureus. 2021;13(10):e18777. doi:10.7759/cureus.18777PubMedGoogle ScholarCrossref
Pamart  D , Otekpo  M , Asfar  M , Duval  G , Gautier  J , Annweiler  C .  Hypercalcemia as a biomarker of poor prognosis in frail elderly patients with COVID-19.   J Nutr Health Aging. 2021;25(10):1140-1144. doi:10.1007/s12603-021-1690-7PubMedGoogle ScholarCrossref
Li  APZ , Thomas  S , Gokmen  R , Kariyawasam  D .  Rhabdomyolysis and severe biphasic disturbance of calcium homeostasis secondary to COVID-19 infection.   BMJ Case Rep. 2021;14(5):14. doi:10.1136/bcr-2020-239611PubMedGoogle ScholarCrossref
Mesland  JB , Collienne  C , Laterre  PF , Hantson  P .  Immobilization-related hypercalcemia in a COVID-19 patient with prolonged intensive care unit stay.   Am J Phys Med Rehabil. 2022;101(1):61-63. doi:10.1097/PHM.0000000000001907PubMedGoogle ScholarCrossref
Bray  A , Reyes  JVM , Tarlin  N , Stern  A .  Case series: hypercalcemia from granulomatous silicosis developing after COVID-19 infection.   J Investig Med High Impact Case Rep. 2021;9:23247096211051206. doi:10.1177/23247096211051206PubMedGoogle ScholarCrossref
Mertz  P , Jeannel  J , Guffroy  A ,  et al.  Granulomatous manifestations associated with COVID19 infection: is there a link between these two diseases?   Autoimmun Rev. 2021;20(6):102824. doi:10.1016/j.autrev.2021.102824PubMedGoogle ScholarCrossref
Hawkes  CP , Roy  SM , Dekelbab  B ,  et al.  Hypercalcemia in children using the ketogenic diet: a multicenter study.   J Clin Endocrinol Metab. 2021;106(2):e485-e495. doi:10.1210/clinem/dgaa759PubMedGoogle ScholarCrossref
Senda  M , Hamano  T , Fujii  N ,  et al.  Exercise-induced hypercalcemia and vasopressin-mediated bone resorption.   Osteoporos Int. 2021;32(12):2533-2541. doi:10.1007/s00198-021-06030-1PubMedGoogle ScholarCrossref
Carroll  MF , Schade  DS .  A practical approach to hypercalcemia.   Am Fam Physician. 2003;67(9):1959-1966.PubMedGoogle Scholar
Payne  RB , Little  AJ , Williams  RB , Milner  JR .  Interpretation of serum calcium in patients with abnormal serum proteins.   Br Med J. 1973;4(5893):643-646. doi:10.1136/bmj.4.5893.643PubMedGoogle ScholarCrossref
Smith  JD , Wilson  S , Schneider  HG .  Misclassification of calcium status based on albumin-adjusted calcium: studies in a tertiary hospital setting.   Clin Chem. 2018;64(12):1713-1722. doi:10.1373/clinchem.2018.291377PubMedGoogle ScholarCrossref
Lian  IA , Åsberg  A .  Should total calcium be adjusted for albumin? a retrospective observational study of laboratory data from central Norway.   BMJ Open. 2018;8(4):e017703. doi:10.1136/bmjopen-2017-017703PubMedGoogle ScholarCrossref
Eastell  R , Brandi  ML , Costa  AG , D’Amour  P , Shoback  DM , Thakker  RV .  Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop.   J Clin Endocrinol Metab. 2014;99(10):3570-3579. doi:10.1210/jc.2014-1414PubMedGoogle ScholarCrossref
Endres  DB , Villanueva  R , Sharp  CF  Jr , Singer  FR .  Immunochemiluminometric and immunoradiometric determinations of intact and total immunoreactive parathyrin: performance in the differential diagnosis of hypercalcemia and hypoparathyroidism.   Clin Chem. 1991;37(2):162-168. doi:10.1093/clinchem/37.2.162PubMedGoogle ScholarCrossref
Walker  MD , Cong  E , Lee  JA ,  et al.  Low vitamin D levels have become less common in primary hyperparathyroidism.   Osteoporos Int. 2015;26(12):2837-2843. doi:10.1007/s00198-015-3199-6PubMedGoogle ScholarCrossref
Nussbaum  SR , Zahradnik  RJ , Lavigne  JR ,  et al.  Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia.   Clin Chem. 1987;33(8):1364-1367. doi:10.1093/clinchem/33.8.1364PubMedGoogle ScholarCrossref
Firek  AF , Kao  PC , Heath  H  III .  Plasma intact parathyroid hormone (PTH) and PTH-related peptide in familial benign hypercalcemia: greater responsiveness to endogenous PTH than in primary hyperparathyroidism.   J Clin Endocrinol Metab. 1991;72(3):541-546. doi:10.1210/jcem-72-3-541PubMedGoogle ScholarCrossref
Lowe  H , Cusano  NE , Binkley  N , Blaner  WS , Bilezikian  JP .  Vitamin D toxicity due to a commonly available “over the counter” remedy from the Dominican Republic.   J Clin Endocrinol Metab. 2011;96(2):291-295. doi:10.1210/jc.2010-1999PubMedGoogle ScholarCrossref
Malihi  Z , Wu  Z , Stewart  AW , Lawes  CM , Scragg  R .  Hypercalcemia, hypercalciuria, and kidney stones in long-term studies of vitamin D supplementation: a systematic review and meta-analysis.   Am J Clin Nutr. 2016;104(4):1039-1051. doi:10.3945/ajcn.116.134981PubMedGoogle ScholarCrossref
Rizzoli  R .  Vitamin D supplementation: upper limit for safety revisited?   Aging Clin Exp Res. 2021;33(1):19-24. doi:10.1007/s40520-020-01678-xPubMedGoogle ScholarCrossref
Donovan  PJ , Sundac  L , Pretorius  CJ , d’Emden  MC , McLeod  DS .  Calcitriol-mediated hypercalcemia: causes and course in 101 patients.   J Clin Endocrinol Metab. 2013;98(10):4023-4029. doi:10.1210/jc.2013-2016PubMedGoogle ScholarCrossref
Mundy  GR , Guise  TA .  Hypercalcemia of malignancy.   Am J Med. 1997;103(2):134-145. doi:10.1016/S0002-9343(97)80047-2PubMedGoogle ScholarCrossref
Blaine  J , Chonchol  M , Levi  M .  Renal control of calcium, phosphate, and magnesium homeostasis.   Clin J Am Soc Nephrol. 2015;10(7):1257-1272. doi:10.2215/CJN.09750913PubMedGoogle ScholarCrossref
Silverberg  SJ , Shane  E , Jacobs  TP ,  et al.  Nephrolithiasis and bone involvement in primary hyperparathyroidism.   Am J Med. 1990;89(3):327-334. doi:10.1016/0002-9343(90)90346-FPubMedGoogle ScholarCrossref
Bilezikian  JP , Silverberg  SJ , Bandeira  F ,  et al.  Task force #8: management of primary hyperparathyroidism.   J Bone Miner Res. 2022. doi:10.1002/jbmr.4682PubMedGoogle ScholarCrossref
Wilhelm  SM , Wang  TS , Ruan  DT ,  et al.  The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism.   JAMA Surg. 2016;151(10):959-968. doi:10.1001/jamasurg.2016.2310PubMedGoogle ScholarCrossref
Allendorf  J , DiGorgi  M , Spanknebel  K , Inabnet  W , Chabot  J , Logerfo  P .  1112 consecutive bilateral neck explorations for primary hyperparathyroidism.   World J Surg. 2007;31(11):2075-2080. doi:10.1007/s00268-007-9068-5PubMedGoogle ScholarCrossref
Kazaure  HS , Thomas  S , Scheri  RP , Stang  MT , Roman  SA , Sosa  JA .  The devil is in the details: assessing treatment and outcomes of 6,795 patients undergoing remedial parathyroidectomy in the Collaborative Endocrine Surgery Quality Improvement Program.   Surgery. 2019;165(1):242-249. doi:10.1016/j.surg.2018.03.026PubMedGoogle ScholarCrossref
Khan  AA , Bilezikian  JP , Kung  AW ,  et al.  Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial.   J Clin Endocrinol Metab. 2004;89(7):3319-3325. doi:10.1210/jc.2003-030908PubMedGoogle ScholarCrossref
Gucalp  R , Theriault  R , Gill  I ,  et al.  Treatment of cancer-associated hypercalcemia: double-blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone.   Arch Intern Med. 1994;154(17):1935-1944. doi:10.1001/archinte.1994.00420170079008PubMedGoogle ScholarCrossref
Warrell  RP  Jr , Israel  R , Frisone  M , Snyder  T , Gaynor  JJ , Bockman  RS .  Gallium nitrate for acute treatment of cancer-related hypercalcemia: a randomized, double-blind comparison to calcitonin.   Ann Intern Med. 1988;108(5):669-674. doi:10.7326/0003-4819-108-5-669PubMedGoogle ScholarCrossref
Major  P , Lortholary  A , Hon  J ,  et al.  Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.   J Clin Oncol. 2001;19(2):558-567. doi:10.1200/JCO.2001.19.2.558PubMedGoogle ScholarCrossref
Pecherstorfer  M , Steinhauer  EU , Rizzoli  R , Wetterwald  M , Bergström  B .  Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate.   Support Care Cancer. 2003;11(8):539-547. doi:10.1007/s00520-003-0477-1PubMedGoogle ScholarCrossref
Hu  MI , Glezerman  IG , Leboulleux  S ,  et al.  Denosumab for treatment of hypercalcemia of malignancy.   J Clin Endocrinol Metab. 2014;99(9):3144-3152. doi:10.1210/jc.2014-1001PubMedGoogle ScholarCrossref
Kristensen  B , Ejlertsen  B , Holmegaard  SN , Krarup-Hansen  A , Transbøl  I , Mouridsen  H .  Prednisolone in the treatment of severe malignant hypercalcaemia in metastatic breast cancer: a randomized study.   J Intern Med. 1992;232(3):237-245. doi:10.1111/j.1365-2796.1992.tb00578.xPubMedGoogle ScholarCrossref
Selby  PL , Davies  M , Marks  JS , Mawer  EB .  Vitamin D intoxication causes hypercalcaemia by increased bone resorption which responds to pamidronate.   Clin Endocrinol (Oxf). 1995;43(5):531-536. doi:10.1111/j.1365-2265.1995.tb02916.xPubMedGoogle ScholarCrossref
Massagli  TL , Cardenas  DD .  Immobilization hypercalcemia treatment with pamidronate disodium after spinal cord injury.   Arch Phys Med Rehabil. 1999;80(9):998-1000. doi:10.1016/S0003-9993(99)90050-3PubMedGoogle ScholarCrossref
Jansson  S , Tisell  LE , Lindstedt  G , Lundberg  PA .  Disodium pamidronate in the preoperative treatment of hypercalcemia in patients with primary hyperparathyroidism.   Surgery. 1991;110(3):480-486.PubMedGoogle Scholar
Gibbs  CJ , Peacock  M .  Hypercalcaemia due to sarcoidosis corrects with bisphosphonate treatment.   Postgrad Med J. 1986;62(732):937-938. doi:10.1136/pgmj.62.732.937PubMedGoogle ScholarCrossref
Pecherstorfer  M , Ludwig  H , Schlosser  K , Buck  S , Huss  HJ , Body  JJ .  Administration of the bisphosphonate ibandronate (BM 21.0955) by intravenous bolus injection.   J Bone Miner Res. 1996;11(5):587-593. doi:10.1002/jbmr.5650110506PubMedGoogle ScholarCrossref
Pecherstorfer  M , Herrmann  Z , Body  JJ ,  et al.  Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy.   J Clin Oncol. 1996;14(1):268-276. doi:10.1200/JCO.1996.14.1.268PubMedGoogle ScholarCrossref
Khan  AA , Gurnani  PK , Peksa  GD , Whittier  WL , DeMott  JM .  Bisphosphonate versus bisphosphonate and calcitonin for the treatment of moderate to severe hypercalcemia of malignancy.   Ann Pharmacother. 2021;55(3):277-285. doi:10.1177/1060028020957048PubMedGoogle ScholarCrossref
Eremkina  A , Krupinova  J , Dobreva  E ,  et al.  Denosumab for management of severe hypercalcemia in primary hyperparathyroidism.   Endocr Connect. 2020;9(10):1019-1027. doi:10.1530/EC-20-0380PubMedGoogle ScholarCrossref
Kuchay  MS , Mathew  A , Kaur  P , Mishra  SK .  Denosumab can be used successfully as a bridge to surgery in patients with severe hypercalcemia due to primary hyperparathyroidism.   Arch Endocrinol Metab. 2021;65(5):669-673. doi:10.20945/2359-3997000000408PubMedGoogle ScholarCrossref
Martin  M , Bell  R , Bourgeois  H ,  et al.  Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid.   Clin Cancer Res. 2012;18(17):4841-4849. doi:10.1158/1078-0432.CCR-11-3310PubMedGoogle ScholarCrossref
Vellanki  P , Lange  K , Elaraj  D , Kopp  PA , El Muayed  M .  Denosumab for management of parathyroid carcinoma-mediated hypercalcemia.   J Clin Endocrinol Metab. 2014;99(2):387-390. doi:10.1210/jc.2013-3031PubMedGoogle ScholarCrossref
Jiang  L , Cui  X , Ma  H , Tang  X .  Comparison of denosumab and zoledronic acid for the treatment of solid tumors and multiple myeloma with bone metastasis: a systematic review and meta-analysis based on randomized controlled trials.   J Orthop Surg Res. 2021;16(1):400. doi:10.1186/s13018-021-02554-8PubMedGoogle ScholarCrossref
Cicci  JD , Buie  L , Bates  J , van Deventer  H .  Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction.   Clin Lymphoma Myeloma Leuk. 2014;14(6):e207-e211. doi:10.1016/j.clml.2014.07.005PubMedGoogle ScholarCrossref
Adams  JS , Sharma  OP , Diz  MM , Endres  DB .  Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia.   J Clin Endocrinol Metab. 1990;70(4):1090-1095. doi:10.1210/jcem-70-4-1090PubMedGoogle ScholarCrossref
Saggese  G , Bertelloni  S , Baroncelli  GI , Di Nero  G .  Ketoconazole decreases the serum ionized calcium and 1,25-dihydroxyvitamin D levels in tuberculosis-associated hypercalcemia.   Am J Dis Child. 1993;147(3):270-273. doi:10.1001/archpedi.1993.02160270032013PubMedGoogle ScholarCrossref
Tachamo  N , Donato  A , Timilsina  B ,  et al.  Hypercalcemia associated with cosmetic injections: a systematic review.   Eur J Endocrinol. 2018;178(4):425-430. doi:10.1530/EJE-17-0938PubMedGoogle ScholarCrossref
Tebben  PJ , Milliner  DS , Horst  RL ,  et al.  Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy.   J Clin Endocrinol Metab. 2012;97(3):E423-E427. doi:10.1210/jc.2011-1935PubMedGoogle ScholarCrossref
Hosadurg  D , Srirangalingam  U .  Seasonal hypercalcaemia.   QJM. 2018;111(9):645-646. doi:10.1093/qjmed/hcy092PubMedGoogle ScholarCrossref
Willows  J , Sayer  JA .  Seasonal hypercalcaemia; consider CYP24A1 mutation.   QJM. 2019;112(5):393. doi:10.1093/qjmed/hcy265PubMedGoogle ScholarCrossref
Chukir  T , Liu  Y , Hoffman  K , Bilezikian  JP , Farooki  A .  Calcitriol Elevation is associated with a higher risk of refractory hypercalcemia of malignancy in solid tumors.   J Clin Endocrinol Metab. 2020;105(4):105. doi:10.1210/clinem/dgz278PubMedGoogle ScholarCrossref
Chandran  M , Bilezikian  JP , Lau  J ,  et al.  The efficacy and safety of cinacalcet in primary hyperparathyroidism: a systematic review and meta-analysis of randomized controlled trials and cohort studies.   Rev Endocr Metab Disord. 2022;23(3):485-501. doi:10.1007/s11154-021-09694-6PubMedGoogle ScholarCrossref
Sheehan  M , Tanimu  S , Tanimu  Y , Engel  J , Onitilo  A .  Cinacalcet for the treatment of humoral hypercalcemia of malignancy: an introductory case report with a pathophysiologic and therapeutic review.   Case Rep Oncol. 2020;13(1):321-329. doi:10.1159/000506100PubMedGoogle ScholarCrossref
Bech  A , Smolders  K , Telting  D , de Boer  H .  Cinacalcet for hypercalcemia caused by pulmonary squamous cell carcinoma producing parathyroid hormone-related peptide.   Case Rep Oncol. 2012;5(1):1-8. doi:10.1159/000335676PubMedGoogle ScholarCrossref
Thillainadesan  S , Twigg  SM , Perera  N .  Prevalence, causes and associated mortality of hypercalcaemia in modern hospital care.   Intern Med J. 2022;52(9):1596-1601. doi:10.1111/imj.15402PubMedGoogle ScholarCrossref
Ramos  REO , Perez Mak  M , Alves  MFS ,  et al.  Malignancy-related hypercalcemia in advanced solid tumors: survival outcomes.   J Glob Oncol. 2017;3(6):728-733. doi:10.1200/JGO.2016.006890PubMedGoogle ScholarCrossref
Westerdahl  J , Bergenfelz  A .  Unilateral versus bilateral neck exploration for primary hyperparathyroidism: five-year follow-up of a randomized controlled trial.   Ann Surg. 2007;246(6):976-980. doi:10.1097/SLA.0b013e31815c3ffdPubMedGoogle ScholarCrossref
Udelsman  R .  Six hundred fifty-six consecutive explorations for primary hyperparathyroidism.   Ann Surg. 2002;235(5):665-670. doi:10.1097/00000658-200205000-00008PubMedGoogle ScholarCrossref
Silverberg  SJ , Shane  E , Jacobs  TP , Siris  E , Bilezikian  JP .  A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery.   N Engl J Med. 1999;341(17):1249-1255. doi:10.1056/NEJM199910213411701PubMedGoogle ScholarCrossref
Bollerslev  J , Jansson  S , Mollerup  CL ,  et al.  Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial.   J Clin Endocrinol Metab. 2007;92(5):1687-1692. doi:10.1210/jc.2006-1836PubMedGoogle ScholarCrossref
Lundstam  K , Heck  A , Mollerup  C ,  et al; SIPH Study Group.  Effects of parathyroidectomy versus observation on the development of vertebral fractures in mild primary hyperparathyroidism.   J Clin Endocrinol Metab. 2015;100(4):1359-1367. doi:10.1210/jc.2014-3441PubMedGoogle ScholarCrossref
Rubin  MR , Bilezikian  JP , McMahon  DJ ,  et al.  The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years.   J Clin Endocrinol Metab. 2008;93(9):3462-3470. doi:10.1210/jc.2007-1215PubMedGoogle ScholarCrossref
Axelsson  KF , Wallander  M , Johansson  H ,  et al.  Analysis of comorbidities, clinical outcomes, and parathyroidectomy in adults with primary hyperparathyroidism.   JAMA Netw Open. 2022;5(6):e2215396. doi:10.1001/jamanetworkopen.2022.15396PubMedGoogle ScholarCrossref
Pretorius  M , Lundstam  K , Heck  A ,  et al.  Mortality and morbidity in mild primary hyperparathyroidism: results from a 10-year prospective randomized controlled trial of parathyroidectomy versus observation.   Ann Intern Med. 2022;175(6):812-819. doi:10.7326/M21-4416PubMedGoogle ScholarCrossref
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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