Usually, hypercalcemia is reported as elevation of total plasma calcium levels rather than ionized calcium levels. Approximately 50% of total calcium is protein-bound, and total calcium level will vary with protein-binding capacity. This phenomenon may rarely result in pseudohypercalcemia—for example, in patients with hyperalbuminemia secondary to dehydration and in some patients with multiple myeloma. More commonly, lowering of total calcium levels is observed in patients with low levels of binding proteins (hypoalbuminemia). This physiology requires that the total plasma calcium level be corrected for the albumin level. Normal calcium levels may range from 8.5 to 10.5 mg/d assuming an albumin level of 4.5 g/dL, and. The calcium concentration usually changes by 0.8 mg/dL for every 1.0 g/dL change in plasma albumin concentration. Thus, the formula below estimates true total plasma calcium:

Corrected Ca = Total Ca + 0.8 x (4.5 - albumin level)

Acidosis decreases the amount of calcium bound to albumin, whereas alkalosis increases the bound fraction of calcium. A small amount of calcium (about 6%) is complexed to anions such as citrate and sulfate. The remainder is ionized calcium that is biologically active.

The most common causes of hypercalcemia, affecting 90% of all patients, are primary hyperparathyroidism (HPT) and malignancy. Other causes are summarized in Table 1.

Normal extracellular calcium concentration is necessary for normal neuromuscular function, and neurologic dysfunction is the major feature of hypercalcemic states. Changes vary from slight difficulties in concentrating to depression, confusion, and coma. Some of these symptoms may resolve or improve after correction of the hypercalcemia.¹ Muscle weakness is another clinical manifestation.

Chronic hypercalcemia may result in formation of renal calculi. Hypercalciuria is the main factor in stone formation, but increased calcitriol production in HPT also plays a role.
Nephrogenic diabetes insipidus resulting in polydipsia and polyuria is seen in about 20% of patients. Mechanisms include downregulation of water channels (aquaporin 2) and tubulointerstitial injury caused by calcium deposition.² Renal tubular acidosis and renal insufficiency are rare. Chronic hypercalcemic nephropathy may continue to worsen after correction of hypercalcemia.

Hypertension is seen with increased frequency in patients with hypercalcemia and may be caused by renal insufficiency and/or calcium-mediated vasoconstriction.³ Hypertension may or may not resolve after correction of hypercalcemia. Cardiac effects are reflected mostly in short QT intervals, which may increase sensitivity to digitalis. Deposition of calcium in heart valves, myocardium, or coronary arteries is also seen.

Constipation, anorexia, nausea, and vomiting are often prominent symptoms, whereas acute pancreatitis (via activation of trypsinogen in pancreatic parenchyma) and peptic ulcer disease (via stimulation of gastrin secretion) are unusual. Fatigue, musculoskeletal weakness, and pain are the only symptoms known to correlate with increasing levels of serum calcium.

The underlying pathophysiology of HPT is caused by excessive secretion of parathyroid hormone (PTH) that leads to increased bone resorption by osteoclasts, increased intestinal calcium absorption, and increased renal tubular calcium reabsorption. The consequent hypercalcemia is also often accompanied by low-normal or decreased serum phosphate levels because PTH inhibits proximal tubular phosphate reabsorption.

Most cases of HPT (80%) are discovered accidentally by automated blood sample analyzers that were initially introduced into clinical practice in the 1970s. These cases have minimal or no symptoms, and calcium levels are only mildly elevated (<12 mg/dL). Patients with HPT can present with any of the clinical manifestations summarized in Table 2, and this diagnosis needs to be considered especially in any patient presenting with kidney stones, bone disease, or hypercalcemic crisis.

Renal calculi are seen in 15% to 20% of patients with HPT, and conversely, about 5% of patients with renal calculi have HPT. Some of these patients may have calcium levels in the upper range of normal. Most calculi are made of calcium oxalate, and the main factor in pathogenesis is hypercalciuria. Although PTH stimulates calcium reabsorption in the distal tubule, the kidney is overwhelmed by the increase in the amount of filtered calcium from incresed serum calcium levels.⁵ Patients with increased vitamin D levels are more likely to have hypercalcemia and nephrolithiasis.

Classic bone disease of HPT presents with brown tumors, osteitis fibrosa cystica, and subperiostal resorption on the radial aspect of middle phalanges. These findings are present only in severe and long-standing disease, and today are seen very rarely, usually when disease is caused by parathyroid carcinoma and in secondary/tertiary HPT associated with chronic renal insufficiency.⁶ Low bone mineral density is found in some patients with HPT, but it is unclear if this is happening more often than in the normal population. Some studies showed decreased bone mineral density in untreated cases⁶ but others did not.⁷ However, most studies showed an increased risk for vertebral fractures in patients with HPT. Hip fractures were studied in a cohort of 1,800 patients in Uppsala, Sweden, and revealed no extra risk for women but an increased risk in men.⁸

Hypercalcemic crisis is a rare presentation and is characterized by calcium levels usually above 15 mg/dL and severe symptoms of hypercalcemia, particularly CNS dysfunction. Abdominal pain, pancreatitis, peptic ulcer disease, nausea, and vomiting are also seen more commonly in these patients. The mechanism by which a crisis develops is not clear, but dehydration, intercurrent illness, and possibly infarction of parathyroid adenoma in some patients all play a role. Treatment consists of rapid correction of the hypercalcemia (see section, Therapy of Hypocalcemia, below) and surgical parathyroidectomy.

Several studies found excessive mortality in patients with HPT, with most of the excess due to cardiovascular disease. The largest study included 4,461 patients and measured an increased mortality risk of 1.71 for men and 1.85 for women.⁹

The diagnosis of HPT requires elevated serum calcium with simultaneous demonstration of PTH levels that are elevated (in 80% to 90% of patients) or within normal limits (in 10 to 20% of patients). Note that patients with hypercalcemia should have PTH level suppressed and that "normal" level is inappropriately high in these patients. The PTH should be determined by an assay that measures the intact PTH molecule. Phosphorus may be low but is usually just in the low-normal range. Urinary calcium excretion is measured by 24-hour urine collection that should also specify total volume and urine creatinine levels; hypercalciuria should be considered with urinary calcium >400 mg/d. In addition, low calcium excretion (<150 mg/d) may signify familial hypercalcemic hypocalciuria, which is not surgically treatable.

A careful family history is paramount for recognition of familial forms of primary HPT. In these situations, urinary screening for catecholamine overproduction is important before surgical treatment.

Localization of abnormal parathyroid glands preoperatively by means of ultrasound, ⁹⁹Tc-sestamibi scintigraphy, or MRI may offer a possibility for a less invasive surgical approach. The accuracy of these radiologic modalities is variable. They are not required for diagnosis of HPT, but serve mainly as guides for surgical strategy, and the selection of these tests should be left to the surgeon.

Removal of the abnormal and hyperfunctioning parathyroid tissue results in a long-term cure of HPT in 96% of patients. Because most patients with HPT are asymptomatic and because there is a lack of reliable predictive indices regarding the development of HPT-related clinical problems, the following criteria were proposed as indications for parathyroidectomy:

1. Serum Ca >1 mg/dL above the upper limit of normal.
2. Marked hypercalciuria of >400 mg/d.
3. Creatinine clearance reduced >30% compared with age-matched controls.
4. Reduction in bone mineral density of the femoral neck, lumbar spine, or distal radius of more than 2.5 standard deviations below peak bone mass (T-score less than -2.5).
5. Age younger than 50 years.
6. Patients for whom medical surveillance is not desirable or possible.

Above are the latest published guidelines from the workshop on asymptomatic primary HPT.¹⁰ The Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism, sponsored by the National Institutes of Health¹¹ included the following additional criteria:

7. Presence of any complications (ie, nephrolithiasis, overt bone disease).
8. An episode of hypercalcemic crisis.

In recent years, parathyroid procedures have been developed using smaller incisions under sedation and local anesthesia, with the opportunity for outpatient surgery as well. Minimally invasive parathyroid surgery has become more frequently requested by patients and primary care physicians alike even though it does not represent a uniform set of techniques. Depending on regional practices, minimally invasive parathyroid surgery can include "laparoscopic," radio-guided, or, most frequently, only unilateral neck surgery. The success of these approaches in curing HPT and minimizing complications is relatively unknown because clinical follow-up periods are still short. Minimally invasive parathyroid surgery is appropriate only for patients who have a clearly defined parathyroid abnormality on ultrasound and/or sestamibi scan, and when parathyroid hormone levels can be monitored intraoperatively. Bilateral neck exploration is mandatory in all other cases and for patients with familial or genetic syndromes.

The literature suggests that up to 10% of cases of primary HPT are hereditary forms. Recognition is important as management of many patients and their families may be affected.

The most common form is associated with multiple endocrine neoplasia syndrome type I (MEN-I). In this disorder, primary HPT is almost invariably present (in >95% of patients) by the age of 65, but it may be diagnosed in children and even infants. Indications for surgical intervention are generally the same as in sporadic cases. Pancreatic tumors are present in 30% to 80% of patients. These are usually islet cell tumors secreting gastrin and causing Zollinger-Ellison syndrome in about two thirds of cases. The second most common pancreatic tumor is insulinoma. Tumors secreting a variety of substances have been described.

Pituitary adenomas affect 15% to 50% of patients and are mostly prolactinomas, although tumors causing acromegaly and Cushing's disease also occur. Adrenocortical hyperplasia is seen in about one third of patients.

MEN-I is caused by autosomal dominant mutation of the menin gene on chromosome 11. Genetic testing is cumbersome, and screening of the family members should be done by means of serum calcium levels. Some patients develop MEN-1-associated lesions as late as age 35 years.

MEN-II is characterized by the development of medullary thyroid carcinoma, which occurs in virtually all patients. Hyperparathyroidism occurs in about one half of affected individuals; most are asymptomatic. Pheochromocytoma or adrenal medullary hyperplasia is an associated feature. The mutated gene is the RET proto-oncogene. Genetic testing of family members is feasible and desirable because it clearly identifies individuals at risk, and timely thyroidectomy is life-saving.

Other familial syndromes are rare and include the HPT-jaw tumor syndrome and familial isolated primary HPT.

This is a rare familial condition caused by an inactivating disorder of calcium-sensing receptors that is expressed in many tissues, but has a major function in regulating calcium metabolism through effects in parathyroid tissue and on handling of renal calcium. The disorder is autosomal dominant with high penetrance. Several mutations are described, but all of them decrease the sensitivity of receptors to calcium, requiring higher calcium levels to suppress PTH secretion. Heterozygous patients present with hypercalcemia, hypocalciuria, and mild hypermagnesemia. Fractional excretion of calcium is <1% despite hypercalcemia. The PTH level is normal or slightly elevated (up to twice normal in our clinical experience).

The clinical significance of this disease lies mostly in mistaken diagnosis of HPT and referral for parathyroidectomy. A commonly performed subtotal parathyroidectomy cannot correct hypercalcemia, and these patients sometimes undergo multiple surgeries.¹³

Genetic testing is not routinely available and usually is not necessary. Patients are free of symptoms, a family history will uncover more family members with hypercalcemia, and urinary calcium excretion is low (about 75% of patients excrete <100 mg/d). Such a low calcium excretion in the face of hypercalcemia indicates increased renal tubular calcium absorption and low calcium clearance. Ratio of calcium clearance to creatinine clearance may be used for diagnosis of FHH using the following formula:

ClCa/ClCr = (Ca_u x Cr_s)/(Cr_u X Ca_s)

Ca_u = Urinary Ca concentration
Cr_s = Serum Cr concentration
Cr_u = Urinary Cr concentration
Ca_s = Serum Ca concentration

The ratio of 0.01 or less is typically seen in individuals with FHH.

Humoral hypercalcemia of malignancy (HHM) is a clinical syndrome in which elevated calcium levels are caused by the action of the humoral factor manufactured by the tumoral process. Classically, this name is applied to the cases with excessive tumoral production of PTH-related peptide (PTHrP). However, rare cases characterized by excessive production of PTH and calcitriol have also been described.¹⁴ Patients with HHM constitute about 80% of all patients with hypercalcemia associated with malignancy.

PTHrP and PTH share the same receptor but there are some differences in clinical presentation. HHM patients have a markedly larger degree of renal calcium excretion (PTH potently stimulates tubular calcium resorption and hypercalciuria is less pronounced). HHM is usually associated with low serum calcitriol levels (PTH stimulates calcitriol production and its level is usually elevated). Also, PTH stimulates bone resorption and formation, whereas PTHrP stimulates only bone resorption, with very low osteoblastic activity and thus usually normal alkaline phosphatase levels.

And, of course, these patients have suppressed levels of immunoreactive PTH, whereas immunoreactive PTHrP is elevated. In addition, patients with HHM are usually dehydrated, in part because of hypercalcemia and in part because of poor oral intake.

Patients with HHM usually have clinically obvious malignant disease and have poor prognosis (survival is measured in weeks or months). The only exceptions to this rule are those with small, well-differentiated endocrine tumors (pheochromocytomas or islet cell tumors). However, these tumors constitute a minority of cases, and HHM is most commonly seen with squamous cell carcinomas (lung, esophagus, cervix, head and neck, and so forth), renal, bladder, and ovarian cancers.

The therapy of HHM is aimed at reducing the tumor burden, reducing osteoclastic resorption of the bone, and increasing calcium excretion through the urine. See Therapy of Hypercalcemia section.

Most of the hypercalcemia cases associated with Hodgkin's disease and about one third of those seen in non-Hodgkin's lymphoma are caused by increased production of calcitriol by the malignant cells. Hypercalcemia usually responds well to treatment with corticosteroids.

Multiple myeloma affects the skeleton extensively in almost all patients. In addition, common malignant tumors (breast, prostate and lung) frequently metastasize to the bone. Most bone metastases are destructive to the bone tissue (osteolytic).

Bone involvement in multiple myeloma may be in the form of discrete lesions or can diffusely affect the axial skeleton. Bone involvement is responsible for pathologic fractures, bone pain (about 80% patients first present with bone pain), and hypercalcemia (seen in 20% to 40% of patients in the course of disease). Myelomas cause bone destruction by means of cytokine secretion that activates osteoclasts. The exact nature of the responsible cytokines is unknown. In vitro, lymphotoxin produced by myeloma cells accounts for the major portion of bone resorption activity. Interleukin-1, interleukin-6, and PTHrP may also be involved in the process in some patients. The fact that most patients with multiple myeloma demonstrate extensive bone destruction whereas many fewer develop hypercalcemia may be explained by impaired glomerular filtration (a result of nephropathy caused by Bence-Jones protein, uric acid nephropathy, amyloidosis, or infection) and the inability to excrete calcium efficiently in those who do develop hypercalcemia.

The treatment of hypercalcemia in these patients is complicated by renal failure. Calcitonin is not nephrotoxic and thus can be used freely. Treatment of myeloma with corticosteroids and alkylating agents is also effective in correcting hypercalcemia. A combination of calcitonin and corticosteroids is frequently used. It is important to recognize that corticosteroids may have detrimental effects on bone metabolism, but it is used in these patients in whom prognosis is poor and the goal is to prevent symptomatic hypercalcemia.

Treatment with bisphosphonates improves hypercalcemia but also inhibits bone resorption and decrease bone fragility. Intravenous (IV) pamidronate or zolendronate is effective in correcting hypercalcemia in practically every patient, and is also approved by the US Food and Drug Administration for the treatment of patients with multiple myeloma who do not have hypercalcemia. Which bisphosphonate is most effective, which dose is optimal, and how often to treat are questions that await answers.

Osteolytic bone metastases from solid tumors are another important cause of bone fragility and hypercalcemia. The prototypical example is bone metastasis of breast cancer. Metastatic mass in bone is affected by bone microenvironment, and recent data showed excessive production of PTHrP by breast cancer cells inside the bone (but not by primary tumor), which is induced by bone-derived peptide-transforming growth factor-ß released in response to bone resorption, establishing a vicious cycle.¹⁵ It is likely that various other substances are also involved in this process.

The principles of therapy are the same as for other patients with hypercalcemia of malignancy. Bisphosphonates have been shown to diminish the size of bone metastases from breast cancers in mice.¹⁶ No such data are available for human disease.

Although sarcoidosis is probably most commonly associated with hypercalcemia, virtually all granulomatous diseases can lead to abnormal calcium elevation (Table 3).

With these disorders, the predominant mechanism for development of hypercalcemia and hypercalciuria is increased intestinal absorption of calcium induced by elevated calcitriol levels. Calcitriol-mediated increase in bone resorption may play a role as well. In addition, PTHrP production by granulomas in some patients with sarcoidosis has been documented.¹⁷

The macrophage/monocyte line of immune cells expresses the identical 1-alpha-hydroxylase expressed in the kidneys that converts 25-(OH) vitamin D to 1,25-(OH) vitamin D. Activity of this enzyme is under negative feedback control in normal tissues. However, in granulomatous disorders, normal feedback inhibition is abolished, probably by the effects of interferon gamma.¹⁸ An abnormality in calcitriol production is seen even in patients who do not develop hypercalciuria or hypercalcemia.

Marked differences in the proportion of patients developing hypercalcemia or hypercalciuria exist between different geographic areas. This is likely caused by the differences in dietary vitamin D and calcium intake and the amount of sun exposure. Increase in all these is associated with development of hypercalcemia.

Therapy is aimed at diminishing intestinal calcium absorption by limiting calcium intake, eliminating vitamin D supplementation, and limiting sun exposure. Corticosteroid treatment (10 to 30 mg of prednisone in cases of sarcoidosis and more in cases of lymphoma) will diminish production of 1,25-(OH) vitamin D (calcitriol) in the macrophages. This, in turn, results in a gradual decrease in the serum calcium level, usually starting after 2 days of treatment and reaching full response in 7 to 10 days.

Antimalarial medications such as chloroquine and the less toxic hydroxychloroquine could be used to diminish calcitriol production in macrophages as well. However, use of these medications should be left to endocrinologists.

Bisphosphonates have been used with good success in patients not responding to the above measures. See Therapy of Hypercalcemia section.

The risk of renal calculi formation can be diminished by dietary oxalate restriction to prevent hyperoxaluria. It is important to note that thiazide diuretics should not be used for renal calculi prevention (by means of inhibition of renal calcium excretion) in these patients because they can lead to marked hypercalcemia.

Both 25-(OH) vitamin D and 1,25-(OH) vitamin D are circulating in blood partially bound to vitamin D-binding protein. In cases of ingestion of large amounts of vitamin D (which is converted to 25-(OH) vitamin D in the liver) or 25-(OH) vitamin D itself, calcitriol will be displaced from the binding protein, resulting in increased free calcitriol levels (the total level can be low since calcitriol production is inhibited). Elevated free calcitriol levels, in turn, will cause hypercalcemia because of increased intestinal calcium absorption and increased bone resorption. This mechanism is seen also with use of the topical vitamin D analog, calcipotriol, used in some dermatologic disorders. A hypercalcemic episode is usually prolonged and often requires therapy with corticosteroids and bisphosphonates along with routine nonspecific measures.

Another form of vitamin D intoxication is excessive use of calcitriol as a treatment of hypoparathyroidism, and as treatment of hypocalcemia and secondary HPT in patients with renal insufficiency. In these patients, the total calcitriol level in serum is increased, and the hypercalcemia is short-lived after discontinuation of calcitriol because of calcitriol's short half-life. Ensuring adequate hydration is usually enough for fast correction of hypercalcemia.

Most of the hypercalcemia cases associated with pheochromocytoma are caused by concomitant primary HPT.

However, in some cases, resection of the adrenal tumor resolves the hypercalcemia. Most of these cases are caused by tumoral production of PTHrP. Hypercalcemia is usually seen with adrenal insufficiency during the adrenal crisis, but the underlying pathophysiology is not clear. It is possible that simple volume contraction and hemoconcentration are responsible. Hypercalcemia usually responds to volume and glucocorticoid replacement.

Measures undertaken to treat hypercalcemia may be divided into nonspecific therapies aimed mainly at increasing renal calcium excretion and decreasing intestinal absorption of calcium, those specifically aimed at slowing bone resorption, those directly removing calcium from circulation, and those aimed at controlling the underlying diseases causing hypercalcemia.

Calcium is passively reabsorbed (by the favorable electrochemical gradient created by sodium and chloride reabsorption) in the proximal tubule and in the thick ascending limb of the loop of Henle. Calcium is actively reabsorbed (via PTH action) in the distal tubule. Excretion of calcium can be achieved by inhibition of proximal tubular and loop sodium reabsorption. This is best achieved by volume expansion using IV normal saline infusion (1 to 2 L for 1 hour). This will result in a marked increase in sodium, calcium, and water delivery to the loop of Henle. Using a loop diuretic (furosemide 20 to 40 mg IV every 2 hours) it is possible then to block transport of sodium in the loop. These actions will result in a marked increase in urinary excretion of calcium, but also of sodium, potassium, chloride, magnesium, and water. It is important to continuously replace water, sodium, potassium, and chloride and, if this regimen is prolonged for >10 hours, to replace magnesium (15 mg/h). Urinary flow should exceed 250 mL/h during this time, and the serum calcium level will start decreasing within 2 to 4 hours and approach normal range in 12 to 24 hours. Recurrent hypovolemia should be avoided.¹⁹

In cases of hypercalcemia with high calcitriol levels, the intestinal absorption may be the main mechanism responsible for hypercalcemia. Increased calcitriol production in cases with activated macrophages (granulomatous diseases and lymphomas) can be diminished using corticosteroids (10 to 30 mg/d of prednisone, or higher in cases of lymphoma. If this is ineffective, ketoconazole, chloroquine, and hydroxychloroquine could be used to block calcitriol production.

Intestinal calcium absorption can be partially blocked by ingestion of phosphate-containing drugs (250 to 500 mg four times per day; the dose should be adjusted to prevent diarrhea), which form insoluble calcium phosphate complexes and prevent absorption. Reducing calcium intake to 400 mg/d or less is also beneficial.

When bone resorption is the main source of calcium, inhibition of this process results in lowering of serum calcium. Drugs used for this purpose include gallium nitrate, plicamycin (formerly mithramycin), calcitonin, and bisphosphonates. Gallium nitrate is potent but nephrotoxic, it requires prolonged infusion (usually 5 days), and only limited experience with it exists in clinical practice. This compound cannot be recommended for routine use. Plicamycin use is limited by its toxicity, particularly in patients with renal, liver, or bone marrow disease. Calcitonin can be given subcutaneously or intramuscularly every 12 hours (4 IU/kg). Its action is rapid (4 to 6 hours), and calcium is usually lowered by 1 to 2 mg/dL. However, calcitonin is effective in only 60% to 70% of patients, and most of them develop tachyphylaxis in 48 to 72 hours, most likely due to receptor downregulation.

Bisphosphonates are a group of medications that accumulate in bone and powerfully inhibit osteoclast-mediated bone resorption. They very effectively lower serum calcium. Their maximum effect is seen in 2 to 4 days. The duration of effect is usually several weeks and varies between patients and with the type of bisphosphonate. Pamidronate, etidronate, alendronate, and zolendronate are currently available in the United States. Zolendronate appears to have the longest-lasting effect (1 to 1.5 months); it is given in a 15-minute IV infusion (4 mg); and it is approved for use only in the hypercalcemia of malignancy. Pamidronate is used most commonly. It is given by IV infusion over 4 to 24 hours. The initial dose varies: 30 mg if the calcium level is <12 mg/dL, 60 mg if calcium is 12 to 13.5 mg/dL, and 90 mg above that level. A subsequent dose should not be given until after 7 days. Because of the lag in the onset of effect, bisphosphonates should be combined with faster-acting therapeutic modalities such as IV saline infusion and calcitonin injections. Risedronate is another bisphosphonate that is currently being evaluated in oral form for the treatment of hypercalcemia. Bisphosphonates also appear to be promising in prevention of hypercalcemia in patients with breast carcinomas.

Hemodialysis or peritoneal dialysis with low calcium levels in the dialysis fluid is very effective for removing calcium from the circulation. These methods are used in patients with renal insufficiency and congestive heart failure when saline infusion is not feasible. Chelation of ionized calcium using ethylenediaminetetraacetic acid (EDTA) and IV phosphate has an immediate effect on calcium levels, but toxicity limits their use, and these methods have been practically abandoned.

Interventions aimed at correcting underlying disease are described in the chapter sections that summarized these disorders.

1. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med. 1994;96:101-106.
   
   
2. Goldfarb S, Agus ZS. Mechanism of the polyuria of hypercalcemia. Am J Nephrol. 1984;4:69-76.
   
   
3. Lafferty FW. Primary hyperparathyroidism: Changing clinical spectrum, prevalence of hypertension, and discriminant analysis of laboratory tests. Arch Intern Med. 1981;141:1761-66.
   
   
4. Wermers RA, Khosla S, Atkinson EJ, et al. The rise and fall of primary hyperparathyroidism: a population based study in Rochester, Minnesota, 1965-1992. Ann Intern Med. 1997;126:433-40.
   
   
5. Parks J, Coe F, Favus M. Hyperparathyroidism in nephrolithiasis. Arch Intern Med. 1980;140:1479-1481.
   
   
6. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res. 1989;4:283-91.
   
   
7. Grey AB, Evans MC, Stapleton JP, Reid IR. Body weight and bone mineral density in postmenopausal women with primary hyperparathyroidism. Ann Intern Med. 1994;121:745-9.
   
   
8. Larsson K, Ljunghall S, Krusemo UB, Naessen T, Lindh E. Persson I. The risk of hip fractures in patients with primary hyperparathyroidism: a population-based cohort study with a follow-up of 19 years. J Intern Med. 1993;234:585-93.
   
   
9. Hedback G, Oden A. Increased risk of death from primary hyperparathyroidism-an update. Eur J Clin Invest. 1998;28:271-276.
   
   
10. Bilezikian JP, Potts JT Jr, Fuleihan Gel-H, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab. 2002;87:5353-61.
    
    
11. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus Development Conference statement. Ann Intern Med. 1991;114:593-97.
    
    
12. Clark OH. How should patients with primary hyperparathyroidism be treated? J Clin Endocrinol Metab. 2003;88:3011-14.
    
    
13. Heath H 3rd. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am. 1989;18:723-40.
    
    
14. Rosol TJ, Capen CC. Mechanisms of cancer-induced hypercalcemia. Lab Invest. 1992;67:680-702.
    
    
15. Guise TA, Jin JJ, Taylor SD, et al. Evidence for causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest. 1996;98:1544-9.
    
    
16. Sasaki A, Boyce BF, Story B, et al. The bisphosphonate Risedronate reduces Metastatic human breast cancer burden in bone in nude mice. Cancer Res. 1995;55:3551-7.
    
    
17. Zeimer HJ, Greenway TM, Slavin J, et al. Parathyroid-hormone-related protein in sarcoidosis. Am J Pathol. 1998;152:17-21.
    
    
18. Basile JN, Liel Y, Shary J, Bell NH. Increased calcium intake does not suppress circulating 1,25-dihydroxyvitamin D in normocalcemic patients with sarcoidosis. J Clin Invest. 1993;91:1396-1398.
    
    
19. Bilezikian JP. Clinical review 51: Management of hypercalcemia. J Clin Endocrinol Metab. 1993;77:1445-49.

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