Milk-Alkali Syndrome 

Updated: Aug 09, 2017
Author: R Hal Scofield, MD; Chief Editor: George T Griffing, MD 



Milk-alkali syndrome is caused by the ingestion of large amounts of calcium and absorbable alkali, with resulting hypercalcemia. If unrecognized and untreated, milk-alkali syndrome can lead to metastatic calcification and renal failure. This syndrome was originally recognized in the 1920s during administration of the Sippy regimen, consisting of milk and bicarbonate, for treatment of peptic ulcer disease. (See Pathophysiology, Etiology, Prognosis, Presentation, and Workup.)[1]

With the development of nonabsorbable alkali and histamine-2 blockers for treatment of peptic ulcer disease, milk-alkali syndrome became a rare cause of hypercalcemia; however, with the increased use and promotion of calcium carbonate for dyspepsia and for calcium supplementation, a resurgence of milk-alkali syndrome has occurred. (See Etiology and Epidemiology.)

A few authors recommend changing the name of milk-alkali syndrome to calcium-alkali syndrome, since this name reflects the changing epidemiology. Calcium-alkali syndrome is now more common in postmenopausal women with the use of over-the counter (OTC) calcium and vitamin D supplements. Calcium- or milk-alkali syndrome is now the third most common cause of hypercalcemia in hospitalized patients.[2]  The name milk-alkali syndrome was first used by Fuller Albright (one of the most important figures in endocrinology in the 20th century) and his colleagues in the 1949 New England Journal of Medicine article describing chronic renal disease in milk alkali syndrome.[3]  This is the most cited article published about the condition with 251 citations in Web of Science as of June 2017 showing that the name milk-alkali syndrome has historical importance even if it does not reflect current pathogenesis. 

Milk-alkali syndrome can have an acute course with rapid induction of hypercalcemia and acute renal failure soon (within a week) after excess calcium carbonate is begun. A more chronic course also is observed. In this form, irreversible renal failure may ensue, but many patients have partial recovery with a timely diagnosis. (See Prognosis, Presentation, and Workup.)

Characteristics of hypercalcemia

Wide variations in symptoms occur among individuals with hypercalcemia, even among patients with similar levels of serum calcium. Some patients may be completely asymptomatic, with hypercalcemia found incidentally after a multiple chemistry panel.

Patients may have severe mental status changes that include obtundation and coma, especially as serum calcium levels rise higher than 15 mg/dL. (See Presentation and Workup.)

Hypercalcemia may produce EKG changes such as shortened QT/QTc interval and nonhypothermic J (or Osborn) waves.[4]

Patient education

The proper dose and the potentially harmful dose of calcium carbonate need to be discussed with the patient. Attention to ingredients in all medications should be stressed, because multiple over-the-counter (OTC) medications contain calcium carbonate. (See Treatment.)

Cases of calcium-alkali syndrome have been reported from calcium carbonate intake with 2-9 grams of elemental calcium per day. Comorbid illnesses like chronic kidney disease and/or use of diuretics can be predisposing factors.[5]


How oral intake of more than 2 g/day of elemental calcium with absorbable alkali results in hypercalcemia and alkalosis is not completely understood. Adaptation of intestinal calcium absorption to oral intake may play a role and help to explain individual variability in the development of milk-alkali syndrome. Some persons maintain a high fractional absorption of calcium even with a high intake, while other persons decrease fractional absorption with a high intake. The former are likely at risk of developing milk-alkali syndrome.

Calcium absorption is completed within 4 hours of intake. Avid absorption of large doses may lead to suppression of parathyroid hormone (PTH), which then leads to enhanced bicarbonate retention by the kidney. (The data are clear that PTH is suppressed in milk-alkali syndrome.) Continuing ingestion of calcium carbonate and bicarbonate retention leads to alkalosis, which causes increased calcium resorption in the distal collecting system of the kidney. Also, hypercalcemia produces a renal concentrating defect that can be considered a form of nephrogenic diabetes insipidus.

Resultant dehydration and volume depletion may worsen the hypercalcemia. PTH is further suppressed by hypercalcemia. This cyclic pathophysiology maintains hypercalcemia and alkalosis as long as calcium and alkali are taken in by mouth.

A low PTH level impairs gastrointestinal (GI) absorption of phosphate. Therefore, low PTH levels may be part of the mechanism by which phosphate levels either remain normal or rise abnormally high in many patients.

The milk-alkali syndrome from Sippy diet often was associated with hyperphosphatemia due to high phosphate content of milk with cream. However, in the new era of calcium-alkali syndrome, low or low normal serum phosphorus levels due to phosphate-binding properties of calcium carbonate are the norm. Low serum phosphate may be more prominent in elderly and patients with eating disorders with low intake of protein and phosphorus.[2]

Chronic milk-alkali syndrome can result in metastatic calcification due to high serum calcium levels and relatively high phosphate levels (calcium × phosphate). Irreversible renal failure may result. However, even severe renal failure may be completely reversible if milk-alkali syndrome is diagnosed early.


The cause of milk-alkali syndrome is ingestion of an inappropriately high amount of calcium carbonate. Ingestion of large amounts of milk or milk products is no longer a common feature of milk-alkali syndrome, and ingestion of milk and bicarbonate is now rare. One patient was reported to have developed milk-alkali syndrome during prolonged enteral tube feedings delivering 2.1 g of calcium daily.[6] Certainly more than 4 g/d of supplemental calcium can predispose to milk-alkali syndrome.

A myriad of OTC medicines have calcium carbonate as an ingredient.[7, 8] Patients may be acquiring it from more than 1 source. For example, a woman might take a 600 mg calcium carbonate tablet twice daily for calcium supplementation and additionally take 200 mg tablets marketed for dyspepsia treatment.

Thiazide diuretics can cause volume depletion and contraction alkalosis increasing renal calcium absorption. Angiotensin-converting enzyme inhibitors and NSAIDs decrease renal calcium excretion by decreasing GFR.[2]

While perhaps counterintuitive, the therapeutic index of calcium carbonate is small. The usual prescribed dose is 1200-1500 mg of elemental calcium for postmenopausal supplementation, while 2500-3000 mg of elemental calcium as the carbonate salt can produce milk-alkali syndrome.

A case report described a 64-year-old woman with recurrent hypercalcemia and milk-alkali syndrome with nicotine replacement gum and carbonated water as the source of excessive calcium intake.[9]

Milk-alkali syndrome in pregnancy

Milk-alkali syndrome has been reported in pregnancy. Pregnant women absorb calcium from the GI tract more avidly than do nonpregnant women. The serum level of PTH-RP is increased in pregnancy. Furthermore, pregnant women are prescribed calcium supplements and frequently have GI symptoms for which calcium carbonate–containing OTC preparations may be taken. (Milk-alkali syndrome has been treated with dialysis during pregnancy.)[10]

In one patient, milk-alkali syndrome was induced by ingestion of large amounts of calcium carbonate during hyperemesis gravidarum. The newborn of a pregnant woman with milk-alkali syndrome had hypocalcemia in the neonatal period, according to a report.

Iatrogenic milk-alkali syndrome

The author has reported iatrogenic milk-alkali syndrome in a patient with sepsis and acute renal failure who was given large doses of calcium carbonate as a phosphate-absorption blocker. As the renal failure resolved, calcium carbonate was continued and hypercalcemia developed.[11]


Occurrence in the United States

One older study indicated that milk-alkali syndrome causes less than 1% of hypercalcemia. However, a number of case reports over the last several years have suggested that milk-alkali syndrome is more common than previously observed or appreciated.

Moreover, in a study of patients hospitalized for emergent hypercalcemia, milk-alkali syndrome was the underlying cause in 6 (12%) of 49 of patients admitted over a 4-year period.[12] The syndrome was third behind hyperparathyroidism and solid malignancy as a cause of hypercalcemia requiring hospitalization and more common than multiple myeloma.

Another study, of patients hospitalized between 1998-2003 with hypercalcemia, found similar results.[13] Of 125 patients without end-stage renal disease, 11 (8.8%) had milk-alkali syndrome. Among 25 patients in the study with severely elevated calcium (serum calcium >14 mg/dL), milk-alkali syndrome was second only to malignancy, being present in 9 (25.7%) of these individuals.

International occurrence

International frequency is not known to be different than that observed in the United States. Occurrence should be related to the number of persons ingesting calcium carbonate. Areas of the world in which betel nut chewing is common may have an increased incidence of milk-alkali syndrome. Betel nut is a recreational drug used in Southeast Asia and India by an estimated 600 million persons daily. The meat of the betel nut is made into a paste (or quid) with dried oyster shell, wrapped in a betel nut leaf, and placed in the lateral buccal pouch. Because the paste contains calcium carbonate from oyster shell, milk-alkali syndrome can result from heavy use.[14]

Betel nut is addictive and causes oral cancer. Betel nut and related ingredients are available in areas of the West with large immigrant populations from Asia and India. The lips, tongue, and oral mucosa are stained a characteristic red in long-term users of betel nut.

Race-, sex-, and age-related demographics

No race predilection is recognized for milk-alkali syndrome, although Southeast Asians and Indians are potential users of betel nut, which can cause the syndrome.

In the era of calcium carbonate ingestion as the cause of milk-alkali syndrome, the average age among 65 patients with milk-alkali syndrome was 50.3 years, with a range of 24-95 years. Women are affected by milk-alkali syndrome more commonly than men and make up approximately 60% of patients. Older, postmenopausal women taking calcium supplementation may be at particularly high risk for the condition. Milk-alkali syndrome has been reported in children.

In the era of milk and bicarbonate as the etiology, milk-alkali syndrome was common in men with peptic ulcer disease. However, modern era calcium-alkali syndrome is more common in postmenopausal women, pregnant women, transplant recipients, dialysis patients, and patients with eating disorders like bulimia.[2]


The prognosis in milk-alkali syndrome usually is good, although this diagnosis is frequently missed. Reports indicate that some patients have been admitted with hypercalcemia several times before the diagnosis was made. A complete history of all medication use, including OTC medications, should prevent milk-alkali syndrome from escaping detection.

Once calcium carbonate is no longer being ingested and hypercalcemia has been treated acutely, further care specifically directed at the milk-alkali syndrome is not necessary.


Milk-alkali syndrome almost never results in death, but a significant number of patients may be left with permanent renal impairment. That is, chronic renal disease may result from milk-alkali syndrome. In reports from the last several years, 20 of 57 patients studied had a follow-up serum creatinine level of more than 1.5 mg/dL (see the Table below). Patients may have severe mental status changes that include obtundation and coma, especially as serum calcium levels rise higher than 15 mg/dL.

Table. Summary of 78 Consecutively Reported Adult Patients With Milk-Alkali Syndrome* (Open Table in a new window)

Mean Age

59.8 Years (Range, 24-95 y)


35 men and 43 women

Calcium source

Calcium carbonate in all but 1

Ingestion of bicarbonate

In 7 patients

Ingestion of milk

In 20 patients (plus one who ate yogurt)

Mean serum calcium

17. 2mg/dL (4.30mmol/L) (range, 11.1-27.5mg/dL)

High serum phosphorus

In 12 patients

Permanent renal insufficiency

In 20 of 57 patients eligible for evaluation

Parathyroid exploration

In 3 patients

Hypocalcemia with treatment

In 16 patients

*These data are derived from the 7 patients reported, plus the 28 reviewed in Beall and Scofield, 1995,[12] as well as additional patients reported by Gibbs and Lee, 1992;[15] Nakanishi et al, 1992[16] ; Brandwein and Sigman, 1994[17] ; Campbell et al, 1994[18] ; Duthie et al, 1995[19] ; Spital and Freedman, 1995[20] ; Fiorino, 1996[21] ; Lin et al, 1996[22] ; Muldowney and Mazbar, 1996[23] ; Sulkin and Krentz, 1999[24] ; Camidge and Peaston, 2000[25] ; George and Clark, 2000[26] ; Vanpee et al, 2000[27] ; Liu et al, 2002[28] ; Robertson, 2002[29] ; Morton, 2002[30] ; Kleinig and Torpy, 2004[6] ; Picolos et al, 2005[13] ; Gordon et al, 2005[31] ; Addington et al, 2006[10] ; Verburg et al, 2006[32] ; Ennen and Magann, 2006[33] ; Caruso et al, 2007[34] ; Dinnerstein et al, 2007[35] ; Javid et al, 2007; Kaklamanos and Perros, 2007[36] ; Shah et al, 2007[37] ; Irtiza-Ali et al, 2008[7] ; and Jousten and Guffens, 2008.[8]


Two of the patients were pregnant.




Milk-alkali syndrome is a diagnosis of history and of exclusion; other potential causes of hypercalcemia must be eliminated. A careful history of all medicines, including OTC medications, should be obtained. This includes actual inspection of bottles to determine ingredients, when needed.

Failure to diagnose milk-alkali syndrome is usually related to a failure to obtain a full history of OTC medications.[38] Moreover, in a series of 11 patients with milk-alkali syndrome, only 5 had the diagnosis made while hospitalized. The remaining 6 were diagnosed only with chart review in retrospect.[13] Patients discharged without a specific diagnosis are likely to continue excess intake of calcium carbonate and develop hypercalcemia again.

Three different progressive stages have been noticed. First, the toxemia (acute) stage occurs within 2-30 days after calcium ingestion begins and clinically patients present with irritability, vertigo, apathy, headaches, weakness, muscle aches, and/or vomiting. Second, the intermediate stage, or Cope syndrome, clinically has the above symptoms along with conjunctivitis. Third, the chronic stage, or Burnett syndrome, manifests as soft tissue calcification including conjunctivitis, band keratopathy of the cornea, musculoskeletal deposits, and nephrocalcinosis.[39]

No specific or characteristic physical findings are described for milk-alkali syndrome; the signs and symptoms are those of hypercalcemia from any cause. Central nervous system symptoms may include the following:

  • Fatigue

  • Depression

  • Malaise

  • Confusion/mental status changes

GI symptoms may include the following:

  • Nausea

  • Vomiting

  • Constipation

Genitourinary symptoms and signs may include the following:

  • Urinary frequency

  • Renal tubular defects

  • Renal failure

Cardiac symptoms and signs may include the following:

  • Electrocardiographic changes (short QT/QTc interval)[40]

  • Hypercalcemia can occasionally produce J (or Osborn) waves, which are typically seen in hypothermia. However, Osborn waves due to hypothermia and other conditions like haloperidol overdose and active cardiac ischemia are associated with prolonged QT/QTc interval in contrast to short QT/QTc interval in hypercalcemia.[4]

  • Arrhythmias



Diagnostic Considerations

Conditions other than milk-alkali syndrome that can cause hypercalcemia include the following:

  • Hyperthyroidism - Any condition causing hyperthyroidism can cause mild hypercalcemia

  • Primary or Tertiary Hyperparathyroidism

  • Ectopic hormone secretion - Secretion of authentic PTH is rare, but secretion of PTH-related peptide (PTH-RP) by squamous cell malignancies of the lung or head and neck is observed frequently; about 15% of renal cell carcinomas secrete PTH-RP, with hypercalcemia found in some of these patients[41]

  • Familial hypocalciuric hypercalcemia (FHH) - The hypercalcemia is mild and serum PTH is usually in the high-normal range or slightly above normal; fractional excretion of calcium is low in the autosomal dominant disease

  • Acquired hypocalciuric hypercalcemia – There are recent reports of autoantibodies binding the calcium receptor, a G-coupled receptor, and inducing a constellation of findings that mimic FHH.[42, 43]  The frequency of this disorder is not known.

  • Hematological malignancies - Almost every type of lymphoma and leukemia can produce hypercalcemia

  • Hypophosphatasia

  • Immobilization - Hypercalcemia can occur in the setting of increased bone turnover and immobilization, such as in Paget disease or in paralysis in a teenager

  • Lithium therapy - PTH secretion is stimulated

  • Solid malignancies - Virtually any cancer with metastatic bone lesions can produce hypercalcemia; squamous cell carcinomas of the lung or head and neck produce a humeral hypercalcemia via PTH-RP production

  • Vitamin D intoxication

With regard to hyperparathyroidism, mentioned in the list above, primary hyperparathyroidism can be caused by an adenoma or hyperplasia. Tertiary hyperparathyroidism is the persistence of high PTH levels and the onset of hypercalcemia after renal transplant in a patient with severe hyperparathyroidism secondary to renal failure. All forms of parathyroid-mediated hypercalcemia are associated with an inappropriately high serum PTH level for the elevated level of serum calcium, but serum PTH may be in the reported normal range. Parathyroid carcinoma is a very rare cause of hypercalcemia.

Rate of occurrence of differentials

A summary of the final diagnoses (ie, of conditions causing hypercalcemia) in 2 large series of patients (100 patients in series 1[12] and 125 patients in series 2[13] ) admitted for hypercalcemia is as follows:

  • Malignancy - 29% in series 1, 33.6% in series 2

  • Hyperparathyroidism - 49% in series 1, 29.6% in series 2

  • Milk-alkali syndrome - 12% in series 1, 8.8% in series 2

  • Multiple myeloma - 4% in series 1, not separated from other malignancies in series 2

  • Vitamin D intoxication - 4% in series 1, 6.8% in series 2

  • Unknown - 4% in series 1, 2.4% in series 2

With regard to the last item above, a diagnosis was not made in these patients, in whom hypercalcemia resolved. In addition, no diagnosis was made in a retrospective review of the chart. However, the use of OTC medicines was not well recorded in these patients. They may have had milk-alkali syndrome, but the diagnosis clearly was not considered during the admission.

Soyfoo et al retrospectively studied in a cancer center all consecutive hypercalcemic (Ca > 10.5 mg/dL) patients over an 8-year period. Of 699 evaluated patients, 642 were analyzed after exclusion of patients whose hypercalcemia resolved after rehydration or who had a normal calcium level after correction for protein concentrations. Clinical information was gathered on the type of cancer, its histology, whether the disease was active or in complete remission, and on the presence of bone metastases. Biochemical data included serum Ca, Pi, proteins in all patients, PTH in most patients, and PTHrP, 25OH-Vitamin D, 1,25(OH)2 –Vitamin D, TSH, and T4 in selected cases.

By order of decreasing frequency, the main causes of hypercalcemia were cancer (69.0%), primary hyperparathyroidism (24.6%), hyperthyroidism (2.2%), milk-alkali syndrome (0.9%), and sarcoidosis (0.45%). In cancer-related causes, bone metastases accounted for 53.0% of the cases, humoral hypercalcemia of malignancy (HHM) for 35.3% of cases, and 11.7% of cases were apparently due to both HHM and bone metastases. Hypercalcemia was not due to cancer in 97% (84/87) of the patients who were in complete remission. Even in patients with active neoplastic disease, the number of patients whose hypercalcemia was not due to cancer remained clinically relevant (115/555 = 20.5%). In the 158 patients with primary hyperparathyroidism, 92 patients were in complete remission and 66 patients had active neoplastic disease.[44]

Differential Diagnoses



Approach Considerations

The differential diagnosis of hypercalcemia is wide; many laboratory tests may be indicated in order to eliminate the possibilities. Based on the clinical circumstances, most of the studies may be needed in some patients, while in other patients, only a few may be required to secure the diagnosis.

Serum calcium

An elevated serum calcium level should initiate a workup that includes the possibility of milk-alkali syndrome. Serum calcium levels can range from a mild elevation to a severe, life-threatening elevation of higher than 18 mg/dL.

Serum calcium levels must be interpreted with regard to serum albumin levels, although use of the formula for correction of calcium for hypoalbuminemia is validated only in cirrhosis of the liver. Clearly, this correction is not valid during pregnancy or critical illness. Ionized calcium is useful to confirm true, physiologic elevated calcium.


Serum phosphorus concentration can be elevated in milk-alkali syndrome due to a low PTH level, although this finding is less prevalent in the present era than it was when ingestion of milk and bicarbonate caused the syndrome.

The product of serum calcium and phosphorus is an important predictor of the risk of metastatic calcification.

Creatinine/blood urea nitrogen

Kidney function can range from normal to severely compromised in patients with milk-alkali syndrome. Severe renal disease may alter the approach to therapy, because intravenous infusion of large amounts of saline may not be possible due of volume overload.

The combination of severe renal impairment and a high serum PTH level suggests secondary or tertiary hyperparathyroidism.

Thyroid-stimulating hormone/free levothyroxine and cortisol

Hyperthyroidism can cause elevated serum calcium levels due to high bone turnover. Adrenal failure also can be associated with high serum calcium levels, although the mechanism has not been fully explained.

If the clinical and laboratory picture is suggestive, adrenocortical function should be evaluated in a provocative manner, such as with an adrenocorticotropic hormone stimulation test. A single serum cortisol level is rarely useful in the diagnosis of adrenal insufficiency.

Other tests

Additional tests used in determining or excluding the presence of milk-alkali syndrome include the following:

  • Serum protein electrophoresis - Serum protein electrophoresis helps to identify a monoclonal gammopathy characteristic of multiple myeloma

  • Complete blood count (CBC) - Other lymphoproliferative diseases, such as leukemia and lymphoma, occasionally induce hypercalcemia

  • Chest radiography - This study is needed in patients with severe renal impairment. Lung cancer may be preliminarily or presumptively identified by this test

  • Electrocardiography - Potential findings are QT-interval shortening and ventricular arrhythmia

Serum Parathyroid Hormone

PTH is suppressed to below normal in patients with milk-alkali syndrome. The 4 important caveats in the measurement of serum PTH are as follows:

  • A high-quality, 2-antibody assay for the intact molecule must be used; many of these assays are based on immunoradiometric techniques; these assays do not cross-react with PTH-RP

  • The timing of measurement of PTH is critical

  • PTH should always be determined and interpreted with a simultaneous serum calcium or, more correctly, with ionized serum calcium

  • An elevated PTH may be found in the setting of milk-alkali syndrome with renal failure

As mentioned in the above list, the timing of measurement of PTH is critical, because in milk-alkali syndrome, but not in other forms of hypercalcemia, vigorous treatment of hypercalcemia with saline diuresis and loop diuretics may lead to hypocalcemia. This occurs within the first few days of treatment and is associated with a suppressed PTH level. With hypocalcemia, however, PTH will rise and may reach levels above the reference range. PTH levels should be determined before or at the initiation of treatment. If serum PTH is measured after treatment has started, the levels will be unpredictable and the results will be confusing. (See the image below.)

The hospital course of a patient with milk-alkali The hospital course of a patient with milk-alkali syndrome who, during treatment, developed symptomatic hypocalcemia with a markedly elevated serum parathyroid hormone level (PTH). Thirty days after discharge, the calcium and PTH levels were normal.

The elevated PTH that may occur in the setting of milk-alkali syndrome with renal failure is caused by severe secondary hyperparathyroidism. In general, however, a high PTH level suggests hyperparathyroidism, while a low PTH level is consistent with milk-alkali syndrome or hypercalcemia of malignancy.

Parathyroid hormone-related peptide

PTH-RP is produced by squamous cell malignancies of the lung or head and neck, as well as by renal cell cancers, resulting in a humeral hypercalcemia. Most of these tumors are clinically apparent, and the hypercalcemia is noted incidentally. No immunologic cross-reactivity occurs with the use of a high-quality PTH assay; ie, the serum level of PTH is suppressed.

PTH-RP is important for lactation and is produced during pregnancy. This may predispose pregnant women to milk-alkali syndrome. Very rarely, an occult malignancy presents with hypercalcemia. In this situation, determination of the serum level of PTH-RP is useful.

Serum Albumin and Globulin

Approximately 50% of serum calcium is bound to albumin; therefore, the total serum calcium level depends directly on the serum albumin level.

In low albumin states, the total serum calcium value may be normal while the ionized calcium value is high. That is, the patient is physiologically hypercalcemic but has a normal total serum calcium value.

Total calcium can be corrected for serum albumin. Every change in albumin of 1g/dL results in a change of 0.8mg/dL in serum calcium. As noted above, this calculation is known to be accurate in patients with low albumin from liver disease. In other situations, it may not be correct; the calculation has been proven to be inaccurate during pregnancy and critical illness.

Multiple myeloma may cause hypercalcemia. This disorder occasionally is suggested by an elevation in the serum globulin.

Vitamin D

Levels of 1,25-dihydroxyvitamin D are elevated in sarcoidosis and other granulomatous diseases associated with hypercalcemia, because of the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by cells in granulomatous tissue. Excess vitamin D ingestion is best assessed by measurement of 25-hydroxyvitamin D levels and should be measured in suspected vitamin D toxicity.

Serum PTH levels usually are low; therefore, vitamin D–related hypercalcemia may be readily confused with milk-alkali syndrome, although the 1,25-dihydroxyvitamin D level was low in one patient with milk-alkali syndrome.

Preventative Measures

General preventive measures include reducing the daily calcium intake including total diet plus supplements to less than 1.2-1.5g/day and avoiding absorbable alkali. Monitoring calcium levels periodically in patients on calcium and vitamin D supplementation is advisable.



Approach Considerations

Mild hypercalcemia

The only care required is discontinuation of calcium carbonate or reduction of the dose to no more than 1200-1500mg of elemental calcium daily. In most patients, calcium supplementation should be changed to a form of calcium other than calcium carbonate. Thus, absorbable alkali is avoided.

Severe hypercalcemia

The patient should be admitted to the hospital. Saline diuresis, produced by infusion of large volumes of intravenous isotonic sodium chloride solution, is the treatment of choice. Further calciuresis can be induced by treatment with intravenous loop diuretics, although the utility of loop diuretics for hypercalcemia has been questioned.[45]

The typical patient is volume depleted; therefore, volume should be replaced with saline prior to institution of diuretic therapy. Care should be taken to not induce volume depletion with the diuretics, because this may worsen the hypercalcemia.

Calcium carbonate should be stopped to resolve the pathophysiology that produced the hypercalcemia. As stated previously, however, patients with milk-alkali syndrome may become transiently hypocalcemic during treatment with intravenous saline and intravenous diuretics.

Because laboratory studies such as PTH measurements will not have returned to normal when therapy is instituted, the serum calcium level must be monitored closely.

Pamidronate has been used successfully in the treatment of hypercalcemia secondary to milk-alkali syndrome. However, treatment of milk-alkali syndrome with bisphosphonates was associated with hypocalcemia in one series; 6 of 11 patients with milk-alkali syndrome developed treatment-induced hypocalcemia, with 5 of the 6 patients having received bisphosphonates,[13] while in the author’s series of 6 patients, none of whom received bisphosphonate, only 1 developed hypocalcemia.[12]

Treatment-related hypocalcemia

If hypocalcemia develops in the course of treatment, this usually can be treated with oral calcium supplementation. A calcium source without absorbable alkali, such as calcium citrate, is preferred. Rarely, intravenous calcium might be required to treat severe hypocalcemia.

Diet and activity

A low-calcium, low-phosphorus diet is required during hypercalcemia. No activity restrictions are necessary.


Consultation with a nephrologist may be needed with severe renal disease and/or severe hypercalcemia, because dialysis sometimes is required. Consultation with an endocrinologist may be needed for interpretation of PTH and other laboratory studies.


Occasionally, dialysis may be required with severe renal impairment. With elevated serum calcium and phosphorus levels, dialysis may be needed to urgently lower these parameters. This may prevent ectopic calcification.



Medication Summary

The primary therapy for hypercalcemia in milk-alkali syndrome is intravenous volume replacement with isotonic sodium chloride solution. When ingestion of calcium carbonate has stopped, the pathophysiologic stimulus for hypercalcemia is no longer present. Hypercalcemia in this setting usually is rapidly corrected. Loss of calcium from urine can be increased with the use of a loop diuretic, but this therapy cannot be started until intravascular volume has been replenished. Renal dialysis has been used in a few patients, as has intravenous infusion of pamidronate.

Diuretics, Loop

Class Summary

Diuretics induce calciuresis. In patients with severe hypercalcemia, the individual typically is volume depleted, which means that volume should be replaced with saline prior to institution of diuretic therapy.

Furosemide (Lasix)

Furosemide inhibits the resorption of sodium and chloride in the loop of Henle and the proximal and distal tubules of the kidney. Its onset of action is rapid after an intravenous dose.

Calcium Metabolism Modifiers

Class Summary

These agents decrease the movement of calcium from bone to serum. Bisphosphonates are analogues of inorganic pyrophosphate and act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. They prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.

The newer bisphosphonates are not completely free of the risk of causing a mineralization defect, but their safe therapeutic window is much wider. They clearly are more potent than etidronate in reducing disease activity and normalizing alkaline phosphatase levels. Severe dental disease may be a contraindication for these agents.

Pamidronate (Aredia)

Pamidronate's main action is to inhibit the resorption of bone. The mechanism by which this inhibition occurs is not fully known. The drug is adsorbed onto calcium pyrophosphate crystals and may block the dissolution of these crystals, also known as hydroxyapatite, which are an important mineral component of bone. There is also evidence that pamidronate directly inhibits osteoclasts.

Zoledronate (Reclast, Zometa)

Zoledronate inhibits bone resorption. It inhibits osteoclastic activity and induces osteoclastic apoptosis