Hypercalcemia

Primary hyperparathyroidism is a generalized disorder resulting from excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands. It probably is the most common cause of hypercalcemia, particularly among patients who are not hospitalized. Incidence increases with age and is higher in postmenopausal women. It also occurs in high frequency ≥ 3 decades after neck irradiation. Familial and sporadic forms exist.

PTH increases serum calcium by increasing intestinal absorption of calcium; rapidly mobilizing calcium and phosphate from bone (bone resorption); enhancing renal distal nephron calcium reabsorption; and stimulating conversion of vitamin D to its most active form, calcitriol (which increases the percentage of dietary calcium absorbed by the intestine).

Familial forms due to parathyroid adenoma occur in patients with other endocrine tumors (see also Overview of Multiple Endocrine Neoplasia). Primary hyperparathyroidism causes hypophosphatemia and excessive bone resorption.

Although asymptomatic hypercalcemia is the most frequent presentation, nephrolithiasis is also common, particularly when hypercalciuria occurs due to long-standing hypercalcemia.

Histologic examination shows a parathyroid adenoma in about 85% of patients with primary hyperparathyroidism, although it is sometimes difficult to distinguish an adenoma from a normal gland. About 15% of cases are due to hyperplasia of ≥ 2 glands. Parathyroid cancer occurs in < 1% of cases.

The syndrome of familial hypocalciuric hypercalcemia (FHH) is transmitted as an autosomal dominant trait. FHH involves an inactivating mutation of the calcium-sensing receptor gene CASR (most commonly), GNA11, or AP2S1 (peptides related to control or expression of CASR), resulting in higher concentrations of serum calcium being needed to inhibit PTH secretion. Subsequent PTH secretion induces renal phosphate excretion. Persistent hypercalcemia (usually asymptomatic) and often from an early age, normal to slightly elevated concentrations of PTH, hypocalciuria, and hypermagnesemia occur. Renal function is normal, and nephrolithiasis is unusual. However, severe pancreatitis occasionally occurs. This syndrome, which is associated with parathyroid hyperplasia, is not relieved by subtotal parathyroidectomy.

Secondary hyperparathyroidism occurs most commonly in advanced chronic kidney disease when decreased formation of active vitamin D in the kidneys and other factors lead to hypocalcemia and chronic stimulation of PTH secretion. Hyperphosphatemia that develops in response to chronic kidney disease also contributes. Once the hyperparathyroidism is established, hypercalcemia or normocalcemia may occur. The sensitivity of the parathyroid to calcium may be diminished because of pronounced glandular hyperplasia and elevation of the calcium set point (ie, the amount of calcium necessary to reduce secretion of PTH).

Tertiary hyperparathyroidism results in autonomous hypersecretion of PTH regardless of serum calcium concentration. Tertiary hyperparathyroidism generally occurs in patients with long-standing secondary hyperparathyroidism, as in patients with end-stage renal disease of several years’ duration.

Cancer is a common cause of hypercalcemia, usually in hospitalized patients. Although there are several mechanisms, elevated serum calcium ultimately occurs as a result of bone resorption.

Humoral hypercalcemia of malignancy (ie, hypercalcemia with no or minimal bone metastases) occurs most commonly with squamous cell carcinoma, renal cell carcinoma, breast cancer, prostate cancer, and ovarian cancer. Many cases of humoral hypercalcemia of malignancy were formerly attributed to ectopic production of PTH. However, some of these tumors secrete a PTH-related peptide that binds to PTH receptors in both bone and kidney and mimics many of the effects of the hormone, including osteoclastic bone resorption.

Osteolytic hypercalcemia can be caused by metastatic solid tumors (eg, breast, prostate, non-small cell lung cancers) or hematologic cancers, most often multiple myeloma, but also certain lymphomas and lymphosarcomas. Hypercalcemia may result from local elaboration of osteoclast-activating cytokines or prostaglandins that stimulate osteoclasts to resorb bone, direct bone resorption by the tumor cells, or both. Diffuse osteopenia may also occur.

Vitamin D toxicity can be caused by high concentrations of endogenous 1,25(OH)2D. Although serum concentrations are low in most patients with solid tumors, patients with lymphomas or T-cell leukemia sometimes have elevated concentrations due to dysregulation of the 1-alpha-hydroxylase enzyme present in tumor cells. Exogenous vitamin D in pharmacologic doses causes excessive bone resorption as well as increased intestinal calcium absorption, resulting in hypercalcemia and hypercalciuria.

Granulomatous disorders, such as sarcoidosis, tuberculosis, leprosy, berylliosis, histoplasmosis, and coccidioidomycosis, lead to hypercalcemia and hypercalciuria. In sarcoidosis, hypercalcemia and hypercalciuria appear to be due to unregulated conversion of 25(OH)D to 1,25(OH)2D, presumably due to expression of the 1-alpha-hydroxylase enzyme in mononuclear cells within sarcoid granulomas. Similarly, elevated serum concentrations of 1,25(OH)2D have been reported in patients with hypercalcemia and tuberculosis or silicosis. Other mechanisms must account for hypercalcemia in some instances, because depressed 1,25(OH)2D concentrations occur in some patients with hypercalcemia and leprosy.

Immobilization, particularly complete prolonged bed rest in patients at risk (see table Principal Causes of Hypercalcemia), can result in hypercalcemia due to accelerated bone resorption. Hypercalcemia develops within days to weeks of onset of bed rest. Reversal of hypercalcemia occurs promptly on resumption of weight bearing. Young adults with several bone fractures and people with Paget disease of bone are particularly prone to hypercalcemia when at bed rest.

Idiopathic infantile hypercalcemia (Williams syndrome—see table Examples of Microdeletion Syndromes) is an extremely rare sporadic disorder with dysmorphic facial features, cardiovascular abnormalities, renovascular hypertension, and hypercalcemia. It leads to nephrocalcinosis in some patients. The cause of hypercalcemia is unknown.

In milk-alkali syndrome, excessive amounts of calcium and absorbable alkali are ingested, usually during self-treatment with calcium carbonate antacids for dyspepsia or to prevent osteoporosis, resulting in hypercalcemia, metabolic alkalosis, and renal insufficiency. The availability of effective medications for peptic ulcer disease and osteoporosis has greatly reduced the incidence of this syndrome.

Initial evaluation should include

• Review of the history, particularly of past serum calcium concentrations

• Physical examination

• Chest x-ray

• Laboratory studies, including electrolytes, BUN, creatinine, ionized calcium, phosphate, PTH, alkaline phosphatase, 25(OH)D, and serum protein immunoelectrophoresis

The cause is apparent from clinical data and results of these tests in ≥ 95% of patients. Patients without an obvious cause of hypercalcemia after this evaluation should undergo measurement of intact parathyroid hormone and 24-hour urinary calcium. When no cause is obvious, serum calcium < 11 mg/dL (< 2.75 mmol/L) suggests hyperparathyroidism or other nonmalignant causes, whereas serum calcium > 13 mg/dL (> 3.25 mmol/L) suggests cancer.

Asymptomatic hypercalcemia that has been present for years or is present in several family members raises the possibility of familial hypocalciuric hypercalcemia. Primary hyperparathyroidism generally manifests late in life but can be present for several years before symptoms occur.

Measurement of intact PTH levels help differentiate PTH-mediated hypercalcemia (eg, caused by hyperparathyroidism or familial hypocalciuric hypercalcemia), in which PTH levels are high or high-normal, from most other (PTH-independent) causes. In PTH-independent causes, levels are usually < 20 pg/mL (< 2.1 pmol/L).

The chest x-ray is particularly helpful, revealing most granulomatous disorders, such as tuberculosis, sarcoidosis, and silicosis, as well as primary lung cancer and lytic and Paget lesions in bones of the shoulder, ribs, and thoracic spine.

Chest and bone (eg, skull, extremity) x-rays can also show the effects on bone of secondary hyperparathyroidism, most commonly in patients receiving long-term dialysis. In osteitis fibrosa cystica (often due to primary hyperparathyroidism), increased osteoclastic activity from overstimulation by PTH causes rarefaction of bone with fibrous degeneration and cyst and fibrous nodule formation. Because characteristic bone lesions occur only with relatively advanced disease, bone x-rays are recommended only for symptomatic patients. X-rays typically show bone cysts, a heterogeneous appearance of the skull, and subperiosteal resorption of bone in the phalanges and distal clavicles.

In hyperparathyroidism, the serum calcium is rarely > 12 mg/dL (> 3 mmol/L), but the ionized serum calcium is almost always elevated. Low serum phosphate concentration suggests hyperparathyroidism, especially when coupled with elevated renal excretion of phosphate. When hyperparathyroidism results in increased bone turnover, serum alkaline phosphatase is frequently increased. Increased intact PTH, particularly inappropriate elevation (ie, a high concentration in the absence of hypocalcemia) or an inappropriate high-normal concentration (ie, despite hypercalcemia), is diagnostic.

Urinary calcium excretion is usually normal or high in hyperparathyroidism. Chronic kidney disease suggests the presence of secondary hyperparathyroidism, but primary hyperparathyroidism can also be present. In patients with chronic kidney disease, high serum calcium and normal serum phosphate suggest primary hyperparathyroidism, whereas elevated phosphate suggests secondary hyperparathyroidism.

Multiple endocrine neoplasia (MEN) should be considered in patients with primary hyperparathyroidism. Primary hyperparathyroidism is more common in women, occurs most commonly in people ages 30 to 50 years, and typically presents with a single abnormal gland, while MEN occurs equally in both sexes, typically occurs in younger adults, and frequently manifests with multiple abnormal glands as well as recurrent parathyroid adenomas.

Localization of parathyroid tissue before surgery on the parathyroid(s) is sometimes performed. High-resolution CT with or without CT-guided biopsy and immunoassay of thyroid venous drainage, MRI, high-resolution ultrasonography, digital subtraction angiography, and thallium-201–technetium-99 scanning all have been used and are highly accurate, but they have not improved the usually high cure rate of parathyroidectomy done by experienced surgeons. Technetium-99 sestamibi, a radionuclide agent for parathyroid imaging, is more sensitive and specific and may be useful for identifying solitary adenomas.

For residual or recurrent hyperparathyroidism after initial parathyroid surgery, imaging is necessary and may reveal abnormally functioning parathyroid glands in unusual locations throughout the neck and mediastinum. Technetium-99 sestamibi is probably the most sensitive imaging test. Use of several imaging studies (MRI, CT, or high-resolution ultrasonography in addition to technetium-99 sestamibi) before repeat parathyroidectomy is sometimes necessary.

A serum calcium measurement > 13 mg/dL (> 3.25 mmol/L) suggests some cause of hypercalcemia other than hyperparathyroidism. Urinary calcium excretion is usually normal or high in cancer. In humoral hypercalcemia of malignancy, PTH is often decreased or undetectable; phosphate is often decreased; and metabolic alkalosis, hypochloremia, and hypoalbuminemia are often present. Suppressed PTH differentiates humoral hypercalcemia of malignancy from primary hyperparathyroidism. Humoral hypercalcemia of malignancy can also be diagnosed by detection of PTH-related peptide in serum.

Multiple myeloma is suggested by simultaneous anemia, azotemia, and hypercalcemia or by the presence of a monoclonal gammopathy. Myeloma is confirmed by bone marrow examination.

FHH is very rare but should be considered in patients with hypercalcemia and elevated or high-normal intact PTH levels. FHH is distinguished from primary hyperparathyroidism by the

• Early age of onset

• Absence of symptoms

• Frequent occurrence of hypermagnesemia

• Presence of hypercalcemia without hypercalciuria in other family members

• Low fractional excretion of calcium, which is the ratio of calcium clearance to creatinine clearance (< 1% in FHH; 1 to 4% in primary hyperparathyroidism)

• Elevated or normal intact PTH

Altered feedback regulation of the parathyroid glands may be responsible for the elevated or normal intact PTH level.

Testing for mutations of the CASR, GNA11, or AP2S1 genes may identify the genetic cause of the autosomal dominant forms of the disease that affect specific families.

Clinical Calculators

Creatinine Clearance Estimate by Cockcroft-Gault Equation (SI units)

Clinical Calculators

Creatinine Clearance Estimate by Cockcroft-Gault Equation

Clinical Calculators

Glomerular Filtration Rate Estimate by the MDRD Equation (SI units)

In addition to a history of increased intake of calcium antacids, milk-alkali syndrome is recognized by the combination of hypercalcemia, metabolic alkalosis, and, occasionally, azotemia with hypocalciuria. The diagnosis can be confirmed when the serum calcium concentration rapidly returns to normal when calcium and alkali ingestion stops, although renal insufficiency can persist when nephrocalcinosis is present. Circulating PTH usually is suppressed.

Vitamin D toxicity is characterized by elevated 25(OH)D (calcifediol, calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D) concentration. In hypercalcemia due to sarcoidosis, other granulomatous disorders, and some lymphomas, serum concentration of 1,25(OH)2D (calcitriol, 1,25-dihydroxycholecalciferol, or 1,25-dihydroxyvitamin D) may be elevated.

In other endocrine causes of hypercalcemia, such as thyrotoxicosis and Addison disease, typical laboratory findings of the underlying disorder help establish the diagnosis. When Paget disease of bone is suspected, plain x-rays are done first and may show characteristic abnormalities.

In mild hypercalcemia (serum calcium < 11.5 mg/dL [< 2.9 mmol/L]), in which symptoms are mild or absent, treatment is deferred pending definitive diagnosis. After diagnosis, the underlying disorder is treated.

When symptoms are significant, treatment aimed at lowering serum calcium is necessary. Oral phosphate can be used. When taken with meals, phosphate binds some calcium, preventing its absorption. A starting dose is 250 mg of elemental phosphate (as sodium or potassium salt) 4 times a day. The dose can be increased to 500 mg 4 times a day as needed unless diarrhea develops.

Another treatment is increasing urinary calcium excretion by giving isotonic saline plus a loop diuretic. Initially, 1 to 2 L of saline is given over 2 to 4 hours unless significant heart failure is present because nearly all patients with significant hypercalcemia are hypovolemic. Furosemide 20 to 40 mg IV every 2 to 4 hours is given as needed to maintain a urine output of roughly 250 mL/hour (monitored hourly). Care must be taken to avoid volume depletion. Potassium and magnesium are monitored as often as every 4 hours during treatment and replaced IV as needed to avoid hypokalemia and hypomagnesemia. Serum calcium begins to decrease in 2 to 4 hours and falls to near-normal within 24 hours.

Moderate hypercalcemia (serum calcium > 11.5 mg/dL [> 2.88 mmol/L] and < 18 mg/dL [< 4.51 mmol/L]) can be treated with isotonic saline and a loop diuretic as is done for mild hypercalcemia or, depending on its cause, with medications that decrease bone resorption (usually bisphosphonates, calcitonin, or infrequently plicamycin or gallium nitrate), corticosteroids, or chloroquine.

Bisphosphonates inhibit osteoclasts. They are usually the drugs of choice for cancer-associated hypercalcemia. Zoledronic acid can be given as a one-time dose of 4 to 8 mg IV and lowers serum calcium very effectively for an average of > 40 days.

Pamidronate can be given for cancer-associated hypercalcemia as a one-time dose of 30 to 90 mg IV, repeated only after 7 days. It lowers serum calcium for ≤ 2 weeks.

Ibandronate as a one-time dose of 4 to 6 mg IV can be given for cancer-associated hypercalcemia; it is effective for about 14 days.

Etidronate 7.5 mg/kg IV once a day for 3 to 5 days is used to treat Paget disease and cancer-associated hypercalcemia. Maintenance dosage is 20 mg/kg orally once a day, but the dose must be reduced when glomerular filtration rate is low.

Repetitive use of IV bisphosphonates to treat hypercalcemia associated with metastatic bone disease or myeloma has been associated with osteonecrosis of the jaw. Some reports suggest this finding may be more common with zoledronic acid. Renal toxicity has been reported in patients receiving zoledronic acid. Oral bisphosphonates (eg, alendronate or risedronate) can be given to maintain calcium in the normal range but are not generally used for treating hypercalcemia acutely.

Denosumab, 120 mg subcutaneously every 4 weeks with additional doses on days 8 and 15 of the first month of treatment, is a monoclonal antibody inhibitor of osteoclastic activity that can be used for cancer-associated hypercalcemia that does not respond to bisphosphonates. Calcium and vitamin D are given as needed to avert hypocalcemia.

Calcitonin (thyrocalcitonin) is a rapidly acting peptide hormone normally secreted in response to hypercalcemia by the C cells of the thyroid. Calcitonin appears to lower serum calcium by inhibiting osteoclastic activity. A dosage of 4 to 8 IU/kg subcutaneously every 12 hours of salmon calcitonin is safe. Calcitonin can lower serum calcium levels by 1 to 2 mg/dL within a few hours. Its usefulness in the treatment of cancer-associated hypercalcemia is limited by its short duration of action with the development of tachyphylaxis (often after about 48 hours) and by the lack of response in ≥ 40% of patients. However, the combination of salmon calcitonin and prednisone may control serum calcium for several months in some patients with cancer. If calcitonin stops working, it can be stopped for 2 days (while prednisone is continued) and then resumed.

Corticosteroids (eg, prednisone 20 to 40 mg orally once a day) can help control hypercalcemia as adjunctive therapy by decreasing calcitriol production and thus intestinal calcium absorption in most patients with vitamin D toxicity, idiopathic hypercalcemia of infancy, and sarcoidosis. Some patients with myeloma, lymphoma, leukemia, or metastatic cancer require 40 to 60 mg of prednisone once a day. However, > 50% of such patients fail to respond to corticosteroids, and response, when it occurs, takes several days; thus, other treatment usually is necessary.

Chloroquine phosphate 500 mg orally once a day inhibits 1,25(OH)2D synthesis and reduces serum calcium concentration in patients with sarcoidosis. Routine ophthalmologic surveillance (eg, retinal examinations every 6 to 12 months) is mandatory to detect dose-related retinal damage.

Plicamycin 25 mcg/kg IV once a day in 50 mL of 5% dextrose in water over 4 to 6 hours is effective in patients with hypercalcemia due to cancer but is rarely used because other treatments are safer.

In severe hypercalcemia (serum calcium > 18 mg/dL [> 4.5 mmol/L] or with severe symptoms), hemodialysis with low-calcium dialysate may be needed in addition to other treatments. Although there is no completely satisfactory way to correct severe hypercalcemia in patients with renal failure, hemodialysis is probably the safest and most reliable short-term treatment.

IV phosphate (disodium phosphate or monopotassium phosphate) should be used only when hypercalcemia is life threatening and unresponsive to other methods and when short-term hemodialysis is not possible. No more than 1 g should be given IV in 24 hours; usually 1 or 2 doses over 2 days lower serum calcium for 10 to 15 days. Soft-tissue calcification and acute renal failure may result. (NOTE: IV infusion of sodium sulfate is even more hazardous and less effective than phosphate infusion and should not be used.)

Hypercalcemia of malignancy demands aggressive treatment due to its progressive nature and mortality risk. Saline (with or without furosemide, depending on volume status) may be used as initial treatment. Denosumab or an IV bisphosphonate is generally needed if hypercalcemia does not respond to fluid administration. Calcitonin can be added if hypercalcemia remains unresponsive. Hemodialysis is needed to lower calcium level acutely if other treatments are not successful (1).

Treatment for hyperparathyroidism depends on severity.

Patients with asymptomatic primary hyperparathyroidism with no indications for surgery may be treated conservatively with methods to ensure that serum calcium concentrations remain low. Patients should remain active (ie, avoid immobilization that could exacerbate hypercalcemia), follow a low-calcium diet, drink plenty of fluids to minimize the chance of nephrolithiasis, and avoid drugs that can raise serum calcium, such as thiazide diuretics. Serum calcium level and renal function are monitored every 6 months. Bone density is monitored every 12 months. However, subclinical bone disease, hypertension, and longevity are concerns. Osteoporosis is treated with bisphosphonates.

In patients with symptomatic or progressive hyperparathyroidism, surgery is indicated. The indications for surgery in patients with asymptomatic, primary hyperparathyroidism are controversial. Surgical parathyroidectomy increases bone density and may have modest effects on some quality of life symptoms, but most patients do not have progressive deterioration in biochemical abnormalities or bone density. Still, concerns about hypertension and longevity remain. Many experts recommend surgery in the following circumstances:

• Serum calcium 1 mg/dL (0.25 mmol/L) greater than the upper limits of normal

• Calciuria > 400 mg/day (> 10 mmol/day)

• Creatinine clearance < 60 mL/minute

• Peak bone density at the hip, lumbar spine, or radius 2.5 standard deviations below controls (T score = −2.5)

• Age < 50 years

• The possibility of poor adherence with follow-up

Surgery consists of removal of adenomatous glands. Parathyroid hormone concentration can be measured before and after removal of the presumed abnormal gland using rapid assays. A fall of ≥ 50% 10 minutes after removal of the adenoma indicates successful treatment. In patients with disease of > 1 gland, several glands are removed, and often a small portion of a normal-appearing parathyroid gland is reimplanted in the belly of the sternocleidomastoid muscle or subcutaneously in the forearm to prevent hypoparathyroidism. Parathyroid tissue is also occasionally preserved using cryopreservation to allow for later autologous transplantation in case persistent hypoparathyroidism develops.

When hyperparathyroidism is mild, the serum calcium concentration drops to just below normal within 24 to 48 hours after surgery; serum calcium must be monitored. In patients with severe osteitis fibrosa cystica, prolonged, symptomatic hypocalcemia may occur postoperatively unless 10 to 20 g elemental calcium is given in the days before surgery. Even with preoperative calcium administration, large doses of calcium and vitamin D are needed while bone calcium is repleted.

In patients with severe hypercalcemia with primary hyperparathyroidism who are unable to undergo parathyroidectomy, medical treatment is indicated. Cinacalcet, a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to extracellular calcium, may lower parathyroid hormone and calcium levels.

Hyperparathyroidism in patients with renal failure is usually secondary. Measures used for treatment can also be used for prevention. One aim is to prevent hyperphosphatemia. Treatment combines dietary phosphate restriction and phosphate binding agents, such as calcium carbonate or sevelamer. Despite the use of phosphate binders, dietary restriction of phosphate is needed. Aluminum-containing compounds have been used to limit phosphate concentration, but they should be avoided, especially in patients receiving long-term dialysis, to prevent aluminum accumulation in bone resulting in severe osteomalacia. Vitamin D administration is potentially hazardous in renal failure because it can increase phosphate absorption and contribute to hypercalcemia; administration requires frequent monitoring of calcium and phosphate levels. Treatment should be limited to patients with any of the following:

• Symptomatic osteomalacia (unrelated to aluminum)

• Secondary hyperparathyroidism

• Postparathyroidectomy hypocalcemia

Although oral calcitriol is often given along with oral calcium to suppress secondary hyperparathyroidism, the results are variable in patients with end-stage renal disease. The parenteral form of calcitriol, or vitamin D analogs such as paricalcitol, may better prevent secondary hyperparathyroidism in such patients, because the higher attained serum concentration of 1,25(OH)2D directly suppresses PTH release. Simple osteomalacia may respond to calcitriol 0.25 to 0.5 mcg orally once a day, whereas correction of postparathyroidectomy hypocalcemia may require prolonged administration of as much as 2 mcg of calcitriol orally once a day and ≥ 2 g of elemental calcium/day.

The calcimimetic, cinacalcet, modulates the set point of the calcium-sensing receptor on parathyroid cells and decreases PTH concentration in dialysis patients without increasing serum calcium. In patients with osteomalacia caused by having taken large amounts of aluminum-containing phosphate binders, removal of aluminum with deferoxamine is necessary before calcitriol administration reduces bone lesions.

Although FHH results from histologically abnormal parathyroid tissue, the response to subtotal parathyroidectomy is unsatisfactory. Because overt clinical manifestations are rare, treatment, other than calcium supplementation, is usually not required.

1. 1. El-Hajj Fuleihan G, Clines GA, Hu MI, et al. Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2023;108(3):507-528. doi:10.1210/clinem/dgac621