J Am Soc Nephrol 12: S3–S9, 2001 Hypercalcemic Crisis

REINHARD ZIEGLER Medizinische Universitätsklinik und Poliklinik, Heidelberg, Germany.

Abstract. Hypercalcemia may decompensate from a more or program has to be followed either to prove or to exclude less chronic status into a critical and life-threatening condition, primary hyperparathyroidism. In the first case, surgical neck hypercalcemic crisis. In the majority of cases, primary hyper- exploration is the only way to avoid fatal outcome. The diag- parathyroidism is the cause; humoral hypercalcemia of malig- nostic program should be performed within hours; during this nancy or rarer conditions of hypercalcemia will decompensate time, serum should be lowered. Treatment of choice is less often. The leading symptoms that characterize the crisis hemodialysis against a calcium-free dialysate. Bisphospho- are oliguria and anuria as well as somnolence and coma. After nates could be useful as adjuvant drugs. a hypercalcemic crisis is recognized, an emergency diagnostic

Hypercalcemic crisis is a condition involving the decompen- patient received (in addition to intravenously administered sation of hypercalcemia, which could have existed for longer saline solution and furosemide) 300 mg of clodronate admin- periods or could be acute at the first instance of this electrolyte istered intravenously, 100 mg of prednisolone administered disturbance. Compensated hypercalcemia is caused by malig- intravenously, and 100 units of calcitonin administered subcu- nancies in 70% of cases, by primary hyperparathyroidism taneously. Because diuresis did not begin within 6 h, hemodi- (pHPT) in 20% of cases, and by other (rarer) conditions in the alysis was performed, using a calcium-free dialysate. After remaining 10% (1); the majority of cases of hypercalcemic 12 h, arteriovenous hemofiltration was performed for further crisis are caused by pHPT (2). The disease is then parathyro- lowering of the serum calcium concentrations, and then hemo- toxic crisis. The following case history should illustrate this dialysis was repeated. Clodronate (300 mg) administration was situation (3). repeated after 12 h, and calcitonin (100 U) was administered A 42-yr-old woman had experienced episodes of nausea and subcutaneously every 4 h. stomach pain for approximately 1 yr. Three months before Meanwhile, the diagnostic procedure led to the diagnosis of admission, she felt weak and lost initiative; these symptoms parathyroid toxicosis. There was no evidence for tumoral hy- were related to professional and familial stress. An outpatient percalcemia, and parathyroid hormone (PTH) levels, measured examination revealed increased alkaline phosphatase levels. in a fast assay, were 2.5-fold elevated. Neck surgery was Because other liver function test results were normal, the performed. The patient was asystolic for seconds when anes- alkaline phosphatase was thought to be of skeletal origin. thesia was initiated, but the operation could be performed. A Skeletal scintigraphy demonstrated only nonspecific spots near parathyroid adenoma of 8.3 g was found and removed. Post- the ankles. Further examinations were refused. The patient operatively, the patient again became asystolic. Despite all developed tiredness, vomiting, weight loss, and dehydration, efforts at resuscitation, the patient could not be revived. An and she needed to be admitted to the hospital. Clinical chem- autopsy revealed nephrocalcinosis and severe myocardial istry assays revealed extreme hypercalcemia of 5.9 mM, mild calcinosis. of 3.1 mM, and borderline creatinine and urea Approximately 20 yr ago, there were more reports of hyper- concentrations. Fluid supply for rehydration decreased the cal- calcemic crisis (2). It is evident that the current use of earlier cium concentration only to 5.4 mM; the patient was oliguric. fluid supply for critically ill patients and optimized strategies Three days later, she was transferred to our hospital, presenting for intensive care medicine have made hypercalcemic crisis a with hypercalcemic crisis. Renal insufficiency and somnolence rare event. However, the life-threatening condition requires were the primary symptoms. From the history of the patient, rapid action, to avoid a lethal course such as in this case. previous goiter resection must be noted. A diagnostic program to exclude causes other than pHPT was initiated. To decrease the calcium concentrations, the Pathophysiologic Features and Clinical Findings Calcium homeostasis has been a very stable system from early periods of evolution. Our extracellular fluid, including Correspondence to Dr. Reinhard Ziegler, Medizinische Universitätsklinik und the circulation, conserves the calcium content of the primordial Poliklinik, Bergheimer Strasse 58, D-69115 Heidelberg, Germany. Phone: ocean. When life left that ocean to live on land, systems for the 6221-568601; Fax: 6221-56522; E-mail: sekretariat_ziegler@med. uni-heidelberg.de maintenance of optimal calcium concentrations in body fluids 1046-6673/1202-0003 were developed. Calcium was no longer the content of the Journal of the American Society of Nephrology surrounding water; it needed to be taken in and conserved from Copyright © 2001 by the American Society of Nephrology food. The skeleton had the double tasks of taking up calcium S4 Journal of the American Society of Nephrology J Am Soc Nephrol 12: S3–S9, 2001 for stability and acting as a depot for times of poor calcium decreased and contributes to this hypercalcemia. This condi- supply. tion is a disturbance but not a disease. PTH is one of the principal factors in the prevention of Hypercalcemia induces functional disturbances in a group of . By decreasing calcium excretion, increasing organs, which are considered together as the “hypercalcemic calcium absorption (via calcitriol), and resorbing depot cal- syndrome” (2). Single components are often nonspecific and cium from the skeleton in cases of emergency, it is a major are also observed in many other diseases. If several compo- contributor to normocalcemia. If PTH is autonomously se- nents of the syndrome are present, hypercalcemia is suggested creted in excess, e.g., in pHPT, hypercalcemia develops. (Table 1). Because serum calcium concentration determina- Renal PTH effects are threefold. In addition to the increase tions are not very expensive, they should be performed in cases in calcium reabsorption, PTH stimulates phosphaturia. Phos- with single symptoms and in all cases of the syndrome. phate loss favors an increase in blood calcium levels via the Renal symptoms are polyuria and polydipsia. Diabetes hy- constancy of the calcium ϫ phosphorus ion product. Being a percalcemicus must be investigated in any case of polyuria, glandotrophic hormone, PTH activates renal 1-␣-hydroxylase especially when diabetes mellitus, diabetes insipidus, and tu- and increases the formation of calcitriol. Normal concentra- bulopathies have been excluded. Diuresis attributable to hy- tions of PTH stimulate bone turnover without bone loss, percalcemia is accompanied by potassium loss; hypercalcemia whereas PTH excess induces bone resorption to an extent that generally leads to hypokalemia. cannot be compensated for by new bone formation. In this Intestinal symptoms are nausea, vomiting, and constipation situation, the released calcium is needed for the prevention of more than diarrhea. The secretion of gastric acid and pancreatic hypocalcemia and is not recycled into the newly formed bone. enzymes is increased. The kidneys act as one of the regulatory elements of calcium Central nervous system symptoms are less characteristic, homeostasis by increasing or decreasing calciuria. If calciuria including tiredness, headache, components of an endocrine is abruptly stopped because of renal insufficiency, stored cal- psychologic syndrome (e.g., loss of initiative), and depression. cium may induce a phase of hypercalcemia until the other Cardiac symptoms also are nonspecific. The QT interval is regulatory links have adapted and counter-regulated levels. shortened, and tachycardias may be observed. The increased Intestinal calcium absorption is increased if higher levels of sensitivity to digitalis is relevant. The mechanism of hyperten- calcitriol are present. Whether increased calcitriol concentra- sion accompanying chronic hypercalcemia attributable to tions result from hyperparathyroidism or diseases with in- pHPT is unclear. Chondrocalcinosis (pseudogout) is occasion- creased calcitriol formation (sarcoidosis and other diseases) ally observed. does not make a difference. With the complexity of malignant When hypercalcemia reaches a critical level (Ͼ4mM),two diseases, several mechanisms may lead to hypercalcemia, in- organs are at risk for decompensation. Polyuria may develop cluding the paraneoplastic production and secretion of calcit- into oliguria and finally anuria, especially in case of exsiccosis. riol, the production of PTH-related peptide (PTHrP), and the Untreated hypercalcemic renal insufficiency is lethal. The production of hypercalcemic cytokines such as interleukin-1, other organ at risk is the brain. Psychologic disturbances may interleukin-6, tumor necrosis factor-␣, and prostaglandins (4). develop into somnolence and finally coma. For all patients In addition to these endogenous causes of hypercalcemia, with comas of questionable cause, a calcium-related coma exogenous factors may play causative roles. One factor con- must be excluded. sists of medications that induce hypercalcemia (vitamin D and When these symptoms of the hypercalcemic syndrome are its analogs and vitamin A). Another factor involves immobili- accompanied by additional symptoms that are characteristic of zation of individuals with labile calcium homeostasis. Immo- a causal disease, the final diagnosis is facilitated. The so-called bilization reduces the inflow of calcium into the skeletal tissue, organ manifestations of pHPT, such as renal stones, hyperpara- and calcium is released into the circulation. If the homeostatic thyroid bone disease, and recurrent peptic ulcers, may indicate capacity of a patient is already under stress because of preex- pHPT. Hyperthyroidism presents with its typical symptoms. isting diseases (severe osteoporosis, acute severe fractures, or Hypercalcemia of malignancy must be considered in cases with Paget’s disease of the bone), immobilization can be accompa- histories of, for example, previous breast cancer (for women) nied by hypercalcemia. Furthermore, endocrinopathies can be or lung cancer or myeloma (for both men and women). accompanied by hypercalcemia. Thyroid hormone in excess accelerates bone turnover; therefore, severe thyrotoxicosis can Diagnosis be accompanied by hypercalcemia. Glucocorticoids are in- The introduction of immunoassays for intact PTH-1–84 was volved in calcium homeostasis, with a calcium-lowering activ- a breakthrough in the diagnosis of hypercalcemic states. The ity (antagonism to PTH). If glucocorticoid levels are acutely simultaneous occurrence of hypercalcemia and increased (or decreased, hypercalcemia can result (acute Addison’s disease nonsuppressed) PTH levels proves the parathyroid origin of the or acute removal of adrenal tumors with hypercortisolism). hypercalcemia. The parathyroid glands are at least contribut- All of these conditions have the character of diseases; the ing, even if another cause may be involved. If intact PTH levels only exception is benign familial hypocalciuric hypercalcemia are low and suppressed, parathyroid involvement is excluded (FHH) (5). Because of an inherited defect of the calcium sensor and other possibilities must then be investigated (Table 2). As of parathyroid cells, the inhibitory feedback effects of calcium a rule, elevated PTH levels in hypercalcemia are caused by on PTH secretion begin only at hypercalcemia. Calciuria is pHPT. A variant is tertiary hyperparathyroidism after a history J Am Soc Nephrol 12: S3–S9, 2001 Hypercalcemic Crisis S5

Table 1. Symptoms of the hypercalcemic syndrome, organ manifestations of pHPT, and typical indications for other causes of hypercalcemiaa

Components of Hypercalcemic Syndrome Pathognomonic Organ Organ Manifestation of Findings for Other Disturbance Resulting Symptom or Destabilization to pHPT Hypercalcemic Hypercalcemic Diseases (Reversible) Complication Crisis

Kidney Hyposthenuria, Polyuria, polydipsia, Oliguria, anuria, Nephrolithiasis FHH: hypocalciuria hypercalciuria, exsiccosis, muscle azotemia (recurrent), sodium and weakness, arrhythmia nephrocalcinosis potassium loss 3 hypokalemia Intestine Increased gastric Loss of appetite, nausea, Increase Peptic ulcer Hyperthyroidism: acid secretion, vomiting, weight loss, (recurrent), weight loss pancreatic constipation pancreatitis enzyme (calcifying), secretion, cholelithiasis delayed intestinal transport Central Endocrine Weakness, tiredness, Somnolence, nervous psychologic loss of initiative, coma system syndrome, depression, dizziness, EEG changes loss of appetite Musculature Increases in Muscle weakness, Increase Hypercortisolism: level of weakened reflexes Cushing neuromuscular myopathy excitability Cardiovascular ECG: shortened Arrhythmia Cardiac arrest Rare calcinosis Hyperthyroidism: system QT time (hypertension) (avoid tachycardia, digitalis) hypertension (large amplitude) Skeleton Osteoporosis, ostitis Malignancies: bone fibrosa cystica metastases generalisata (von Recklinghausen) Ankles Chondrocalcinosis (pseudogout)

a pHPT, primary hyperparathyroidism; FHH, familial hypocalciuric hypercalcemia; EKG, electrocardiogram; EEG, electroencephalography.

of long-lasting renal insufficiency. Extremely rare is the para- tosis may produce PTHrP. If PTHrP levels are low, other neoplastic production of true PTH (6). FHH is sometimes a osteolytic factors may be produced by the tumor. Calcitriol trap. The lack of true symptoms and organ manifestations must levels are sometimes increased. Other cases demonstrate the be taken into consideration; the best diagnostic clue is the production of interleukin-1, -6, or -11, transforming growth calcium clearance/creatinine clearance ratio, which is Ͻ0.01 in factor-␣ or -␤, interferon, or granulocyte/macrophage colony- FHH. stimulating factor. We recommend only the measurement of Most patients who present with nonparathyroidal hypercal- PTHrP; the measurements of the other factors are expensive cemia suffer from a malignant disease. In cases in which there and not as reliable. The result is of no importance for the are no symptoms indicating pHPT, the search for a malignant treatment, which should be uniformly performed with disease should be initiated early. Approximately one-half of bisphosphonates. the patients have elevated blood levels of PTHrP. This finding The rare nonmalignant, non-parathyroid-related hypercalce- is observed in many cases of cancer of the lung, esophagus, mias generally provide some hints in the clinical findings. skin, kidney, pancreas, liver, colon, or ovary. Even hemoblas- Difficulties may arise in cases of iatrogenic hypercalcemia. If S6 Journal of the American Society of Nephrology J Am Soc Nephrol 12: S3–S9, 2001

Table 2. Diseases leading to hypercalcemia and indications for diagnosisa Category Condition Mechanism Indications for Diagnosis PTH-induced, pHPT Increased intestinal Ca2ϩ Ca2ϩ 1, PTH 1 parathyroid absorption, renal Ca2ϩ absorption, osteolysis Tertiary Same History: long-lasting secondary hyperparathyroidism hyperparathyroidism, Ca2ϩ 1, PTH 1 Lithium-induced (long-term Same History: long-lasting lithium treatment) treatment, Ca2ϩ 1, PTH 1 Nonparathyroid paraneoplastic Humoral hypercalcemia of Secretion of osteolytic factors Staging for malignancy, tumor malignancy like PTHrP, IL-1, IL-6, markers 1, PTHrP 1, calcitriol TNF, prostaglandins, and 1, PTH 2 calcitriol mechanical Immobilization at Calcium release from the History, x-rays, exclusion of pHPT preexisting bone diseases, skeleton attributable to (PTH 2) e.g., multiple fractures (in immobilization young patients), osteoporosis, Paget’s disease of bone, acute intermittent porphyria thyroidal Thyrotoxicosis Increase in bone turnover T3 1,T41, TSH suppression, PTH 2 corticoadrenal Acute disease in Lack of a PTH antagonist Glucocorticoid diagnostic tests, glucocorticoids, acute history, PTH 2 Addison’s disease, postoperatively in Cushing’s disease renal Acute renal insufficiency Decrease in calciuria History, renal function 2 Exsiccosis Decrease in calciuria History, renal function 2 FHH Decrease in calciuria Calciuria 2, phosphaturia normal, attributable to a calcium PTH normal or 1,Ca2ϩ sensor defect clearance/creatinine clearance, Ͻ0.01 Hard-water syndrome Dialysis using too great a Control of dialysate calcium gradient calcitriol-induced Sarcoidosis Overproduction of calcitriol X-ray of lungs, ACE 1, calcitriol 1 Tuberculosis, histoplasmosis Overproduction of calcitriol X-ray of lungs, tuberculosis (lepra) diagnostic tests, serologic findings, calcitriol 1 viral AIDS Osteolysis by viruses History, serologic findings PTHrP-induced Infantile idiopathic (PTHrP 1?) Age, exclusion of other causes, hypercalcemia PTH 2, PTHrP 1 iatrogenic/induced by Vitamin D intoxication Calcium absorption 1, History, calcidiol 1, PTH 2 medications osteolysis 1 Vitamin A intoxication Osteolysis History Thiazides (in conditions Calciuria 2 History prone to hypercalcemia) Tamoxifen in metastatic “Flare up” because of History breast cancer paradoxical receptor activation Theophylline ? History Salicylic acid intoxication ? History

a PTH, parathyroid hormone; PTHrP, PTH-related peptide; IL, interleukin; TNF, tumor necrosis factor; TSH, thyroid-stimulating hormone; ACE, angiotensin-converting enzyme. J Am Soc Nephrol 12: S3–S9, 2001 Hypercalcemic Crisis S7

Table 3. Symptomatic treatment of hypercalcemiaa

Side Effects, Type Measure/Substance Dosage Specific Indication Mode of Action Complications

Fast-acting diuretic Drinking of fluids 2 to 3 liters/d Universal Increase in None low in calcium calciuria IV infusion of saline 4 to 6 (10) Universal Increase in Volume expansion, liters/d calciuria (via hypokalemia, natriuresis) hypomagnesemia Furosemide 20 to 40 to 500 Universal in cases Increase in Hypomalemia, mg/d of fluid retention diuresis and hypomagnesemia calciuria 100 mg/hr 3 Same Direct stimulation Same 24 h of calciuria antiresorptive Bisphosphonates clodronate 300 mg iv in 6 Universal (in Inhibition of In cases of too fast to8hfor2to preference in osteolysis administration, 6 days HHM) renal insufficiency 400 to 3200 mg Same Same Rarely gastrointestinal orally for complaints days or weeks pamidronate 15 to 90 mg iv Same Same Same, occasionally in4to6h feverish reaction ibandronate 2 to 6 mg iv in Same Same None 2h Calcitonin 200 to 500 IU/d Universal (adjuvant Inhibition of Nausea, vomiting, drug) osteolysis escape phenomenon Mithramycin, mostly 25 ␮g/kg iv In preference in Inhibition of Thrombopenia, replaced by daily for 3 to HHM, parathyroid osteolysis leukopenia, liver bisphosphonates 4d carcinoma and kidney damage extractive Hemodialysis Ca2ϩ-free Hypercalcemic crisis Dialysis of Ca2ϩ Dialysis-related dialysate and renal from the insufficiency circulation Slow-acting anti-absorptive Diet low in Ca2ϩ Ͻ100 mg Universal Decrease in Ca2ϩ None and vitamin D Ca2ϩ/d supply and absorption Prednisone 40 to 100 mg/d Vitamin D Decrease in Ca2ϩ Iatrogenic Cushing’s intoxication, absorption, syndrome sarcoidosis (rarely increase in HHM) calciuria

a HHM, humoral hypercalcemia of malignancy; iv, intravenous. Digitalis and hydrochlorothiazides are contraindicated during hypercalcemia. the patient does not reveal that he or she took, for example, way. However, hypercalcemic crises require early treatment, vitamin D (as in Mu¨nchausen’s syndrome), diagnosis may be so that the life of the patient is not at risk. difficult (7). It is not too rare for hypercalcemia to be caused by Because hypercalcemic crises are predominantly parathyro- more than one disease (e.g., immobilization in osteopathies). In toxic crises, pHPT must be proven or excluded. Proven pHPT cases of severe hypercalcemia in which PTH levels are only requires emergency surgery performed by an experienced sur- mildly elevated, the possibility of a second diagnosis should be geon. Surgeons who do not often perform parathyroid explo- considered. There have been frequent reports of the coinci- ration should refer their patients elsewhere. dence of pHPT and sarcoidosis (8), thyrotoxicosis (9), and The following diagnostic program is recommended: (1) other conditions. careful history and examination; (2) x-rays of the head, thorax, In cases of compensated hypercalcemia without relevant vertebral column, pelvis, and long bones, to exclude osteolytic renal insufficiency, diagnoses can be made in a conventional lesions attributable to pHPT, metastases, myeloma, or lung S8 Journal of the American Society of Nephrology J Am Soc Nephrol 12: S3–S9, 2001 cancer; (3) ultrasound examination of the abdominal organs, to effects and which quickly becomes inactive because of the exclude hepatic, pancreatic, renal, or gynecologic tumors (oc- escape phenomenon (12). Because of the availability of the casionally, kidney stones or nephrocalcinosis indicates pHPT); highly potent bisphosphonates, mithramycin (which was of and (4) laboratory studies such as phosphate, potassium, cre- great utility in the pre-bisphosphonate period) is no longer atinine, urea, alkaline phosphatase, sedimentation rate, and needed. proteinuria measurements (hypercalcemia is known) and blood Hypercalcemias accompanying neoplasias are often chronic. smears. Fast PTH measurement is only occasionally available. It is then recommended that the bisphosphonate treatment be If all findings are generally normal and no tumor is found, accompanied by a reduction in the dietary calcium supply. pHPT should be suspected. Ultrasound examination of the Diets low in calcium and vitamin D are recommended. neck region is recommended; it reveals a hypoechogenic nod- Glucocorticoids exert a calcium-lowering effect by reducing ule, consistent with a parathyroid adenoma, in approximately calcium absorption. They are indicated only for rare hypercal- two-thirds of cases. Experienced surgeons are content with this cemias such as intoxicosis with vitamin D or its analogs. The result, but inexperienced surgeons are not more satisfied after treatment of some hemoblastoses, e.g., myeloma, also includes computed tomographic and magnetic resonance imaging ex- glucocorticoids. They may then exert “cytostatic” effects as aminations, which cause further delay. During this diagnostic procedure, the patient should be re- well as antiabsorptive effects in the gut. ceiving symptomatic treatment (see below). The combination Hypercalcemic crisis requires a special accelerated strategy. of calcium lowering within 12 to 24 h and emergency diag- The first question to answer is the following: is diuresis pos- nostic testing should permit surgical treatment of pHPT within sible and efficient? If yes, intravenous saline treatment, sup- 24 h. ported by furosemide, should be combined with a potent bisphosphonate. Treatment If diuresis is restricted and does not promise a relevant effect Except in cases of FHH, hypercalcemia is always a risk for within a few hours, hemodialysis is the treatment of choice. We patients. The risk is present even in cases of so-called asymp- recommend that hemodialysis be performed in a unit with tomatic pHPT. Observation of patients without surgery is per- sufficient expertise. The dialysis bath should be low in or free mitted (10); the guarantee of regular diuresis and the avoidance of calcium, depending on the individual situation. of additional factors such as immobilization cannot always be Contraindicated medications during hypercalcemia are dig- achieved. If patients are hypercalcemic, they must be warned italis and hydrochlorothiazides. Digitalis may produce cardiac that regular drinking of fluids low in calcium represents a kind arrest if administered during hypercalcemia. Thiazides reduce of life insurance. Patients should know all symptoms of the calciuria and thus contribute to the severity of hypercalcemia. hypercalcemic syndrome and should ask their doctors for cal- As mentioned, diagnostic testing should proceed in parallel cium control in case of any such symptoms. with the symptomatic calcium-lowering treatment. Hypercal- Ͼ If hypercalcemia is relevant ( 2.8 mM), fluid supply should cemic crisis is a situation that requires improvement within be defined. Patients should drink approximately 3 liters/d, to hours. produce a urinary volume of 2 to 2.5 liters. Diuresis in this range requires the control of potassium (as well as calcium) in the blood (Table 3). Conclusions When the calcium concentration increases above 3 mM, Hypercalcemic crisis is a life-threatening condition that is often drinking is no longer sufficient. Nausea and even vom- currently rather rare; however, it presents the risk that medical iting may begin; the intravenous infusion of saline solution is action may be too slow. Most cases of hypercalcemic crisis are the treatment of choice. Again, potassium substitution must be attributable to decompensating pHPT. They require neck sur- considered. gery performed by an experienced endocrine surgeon. Diuresis can be increased with furosemide. Lower doses stimulate natriuresis, which is accompanied by calciuresis. A Within 12 to 24 h, two problems must be solved. On one direct calciuretic effect of furosemide should be expected at hand, a short diagnostic program should lead to the exclusion high doses of 100 mg/h (11). of neoplasias producing hypercalcemia. On the other hand, Especially in cases of humoral hypercalcemia of malig- those hours should also be used to lower serum calcium levels. nancy, the administration of bisphosphonates should be con- One method is forced diuresis combined with the use of highly sidered early. Available preparations are clodronate, pamidr- potent bisphosphonates; in cases of impaired renal function, onate, and ibandronate. Table 3 documents the increase in calcium-free hemodialysis is the treatment of choice. Hyper- potency in this family of drugs. The advantage of the more- calcemic crisis should be treated in a unit with appropriate potent bisphosphonates is the need for smaller amounts, which expertise. means that the infusion time can be shortened. In cases with normal renal function, ibandronate can even be administered as a bolus; without time pressures, we prefer to perform infusions Acknowledgment in 1 to 2 h. We think that the highly potent bisphosphonates This work was presented at the 6th Colloquium Dresden, Intensive limit the requirement for calcitonin, which may produce side Care Nephrology 2000, May 26 to 27, 2000. J Am Soc Nephrol 12: S3–S9, 2001 Hypercalcemic Crisis S9

References 7. Ziegler R, Delling G: Clinical observations in lethal vitamin D or 1. Burkhardt E, Kistler HJ: Hypercalciämie bei hospitalisierten DHT intoxication. In: Vitamin D and Problems to Uremic Bone Patienten. Schweiz Med Wschr 111: 2017–2023, 1981 Disease, Berlin, Walter de Gruyter & Co., 1995, pp 689–695 2. Binstock ML, Mundy GR: Effect of calcitonin and glucocorti- 8. Papapoulos SE, Clemens TL, Fraher JG, Lewin LM, Sandler JL, coids in combination on the hypercalemia of malignancy. Ann O’Riordan LH: 1,25-Dihydroxycholecalciferol in the pathogen- Intern Med 93: 269–272, 1980 esis of the hypercalcemia of sarcoidosis. Lancet 1: 627–630, 1979 3. Raue F, Blind E, Schuler G, Otto G, Ziegler R: Parathyreo- 9. Maxon HR, Apple DJ, Goldsmith RE: Hypercalcemia in thyro- toxische Krise mit letalem Ausgang: Was lernen wir daraus? toxicosis. Surg Gynecol Obstet 147: 694–696, 1978 Med Klin 87: 495–497, 1992 10. Consensus Development Conference Panel: Diagnosis and man- 4. Mundy GR, Guise TA: Hypercalcemia of malignancy. Am J Med agement of asymptomatic primary hyperparathyroidism: Con- 103: 134–135, 1997 sensus Development Conference Statement. Ann Intern Med 114: 5. Marx SJ: Familial hypocalciuric hypercalcemia. In: Primer on 593–597, 1991 the Metabolic Bone Disease and Disorders of Mineral Metabo- 11. Suki WN, Yium JJ, Von Minden M, Saller-Hebert C, Eknoyan lism, edited by Favus MJ, Philadelphia, Lippincott Williams & G, Martinez-Maldonado M: Acute treatment of hypercalcemia Wilkins, 1999, pp 195–198 with furosemide. N Engl J Med 283: 836–840, 1970 6. Iguchi H, Miyagi C, Tomita K, Kawauchi S, Nozuka Y, 12. Ralston SH, Dryburgh FJ, Cowan RA, Gardner MD, Jenkins Tsuneyoshi M, Wakasugi H: Hypercalcemia caused by ectopic AS, Boyle IT: Comparison of aminohydroxyprolidene diphos- production of parathyroid hormone in a patient with papillary phate, mithramycin and corticosteroids/calcitonin in treat- adenocarcinoma of the thyroid gland. J Clin Endocrinol Metab ment of cancer-associated hypercalcemia. Lancet 2: 907–910, 83: 2653–2657, 1998 1985