Calcinosis Cutis

Background

Calcinosis cutis is a term used to describe a group of disorders in which calcium deposits form in the skin. Virchow initially described calcinosis cutis in 1855. Calcinosis cutis is classified into 4 major types according to etiology: dystrophic, metastatic, iatrogenic, and idiopathic. A few rare types have been variably classified as dystrophic or idiopathic. These include calcinosis cutis circumscripta, calcinosis cutis universalis, tumoral calcinosis, and transplant-associated calcinosis cutis.^[1]

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Pathophysiology

In all cases of calcinosis cutis, insoluble compounds of calcium are deposited within the skin due to local and/or systemic factors. These calcium salts consist primarily of hydroxyapatite crystals or amorphous calcium phosphate. The pathogenesis of calcinosis cutis is not completely understood and a variety of factors allow for different clinical scenarios to occur.

Metabolic and physical factors are pivotal in the development of most cases of calcinosis. Ectopic calcification can occur in the setting of hypercalcemia and/or hyperphosphatemia when the calcium-phosphate product exceeds 70 mg²/dL², without preceding tissue damage. These elevated extracellular levels may result in increased intracellular levels, calcium-phosphate nucleation, and crystalline precipitation. Alternatively, damaged tissue may allow an influx of calcium ions leading to an elevated intracellular calcium level and subsequent crystalline precipitation. Tissue damage also may result in denatured proteins that preferentially bind phosphate. Calcium then reacts with bound phosphate ions leading to precipitation of calcium phosphate.

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Etiology

Disorders of calcinosis cutis may be categorized according to the type of calcification process, ie, dystrophic, metastatic, idiopathic, and iatrogenic.

Dystrophic calcification occurs in the setting of normal serum calcium and phosphate levels. The primary abnormality is damaged, inflamed, neoplastic, or necrotic skin. Tissue damage may be from mechanical, chemical, infectious, or other insults.

Localized tissue damage

Extraosseal calcification can occur in the setting of many local and destructive processes, including burns, arthropod bites, acne lesions, varicose veins, and rhabdomyolysis, among others.

Infections

Necrotic tissue produced by an infectious process may subsequently become calcified. Some infectious granulomas produce 1,25-vitamin D. Infections that may result in calcinosis cutis include onchocerciasis, cysticercosis, histoplasmosis, cryptococcosis, and intrauterine herpes simplex.

Tumors

Benign and malignant tumors may develop calcification. Pilomatrixoma, or calcifying epithelioma of Malherbe, is the most common tumor that becomes calcified. Epithelial cysts and syringomas also have a significant tendency to calcify. Foci of calcification commonly are seen in histologic sections of basal cell carcinomas. In rare cases, melanocytic nevi, malignant melanoma, atypical fibroxanthoma, hemangioma, pyogenic granuloma, seborrheic keratoses, neurilemomas, and trichoepitheliomas show foci of calcification.

Generalized tissue damage

Connective tissue diseases

Examples are dermatomyositis^{[2, 3]} ; lupus erythematosus^{[4, 5, 6, 7]} ; systemic sclerosis; and calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias (CREST) syndrome.

In dermatomyositis, calcification occurs 3 times more commonly in juvenile dermatomyositis than the adult-onset form and may be seen in 30-40% of patients. In the setting of dermatomyositis, calcinosis cutis is associated with longer disease duration, fingertip ulcers, and NXP-2 autoantibodies. There is a negative association with transcriptional intermediary factor 1-γ antibodies.^[8] Typically, calcification is accentuated over joints, sparing the digits. Aggressive corticosteroid therapy decreases the incidence of calcification.

In lupus erythematosus, calcification is rare and usually an insignificant incidental radiologic finding. Calcification occurs most frequently with long-standing systemic disease, and though calcification may develop in lesions of lupus profundus, it usually is not associated with panniculitis. However, an associated myositis may be present. Lesions characteristically are on the extremities.

Regarding scleroderma, systemic scleroderma and CREST syndrome are related diseases frequently associated with the late development of tissue calcification.

Panniculitis

Subcutaneous fat necrosis of the newborn typically affects full- or post-term newborns within the first few days to weeks of life. Necrosis of subcutaneous tissues, predominantly on the shoulders and buttocks, results in nodules and plaques that may become calcified. The cause is unknown. Possible inciting events are obstetric trauma, maternal pre-eclampsia or diabetes, or neonatal hypothermia or hypoxia. Pancreatitis or pancreatic malignancy may result in inflammation of the panniculus. The combination of fatty acids released by damaged fat cells and calcium may lead to calcium salt formation.

Inherited disorders

Examples are Ehlers-Danlos syndrome, Werner syndrome, pseudoxanthoma elasticum, and Rothmund-Thompson syndrome.

Ehlers-Danlos syndrome is a group of inherited disorders of collagen metabolism. Individuals with Ehlers-Danlos type I may develop calcification in healing surgical scars and subcutaneous nodules.

Werner syndrome is an inherited disorder of premature aging. Soft tissue calcification may involve the ligaments, tendons, synovia, vasculature, and/or subcutaneous tissue.

Pseudoxanthoma elasticum is a disorder of abnormal elastic fibers. Calcification occurs in the elastic fibers causing rupture. Late in the disease, collagen fibers may become calcified.

In Rothmund-Thomson syndrome, small, yellow papules of calcification may be numerous on the extremities.

Metastatic calcification

Metastatic calcification arises in the setting of abnormal calcium or phosphate metabolism and is generally associated with hypercalcemia and/or hyperphosphatemia.

Primary or secondary hyperparathyroidism

In primary hyperparathyroidism, the parathyroid glands become hyperplastic and autonomously overproduce parathyroid hormone. Secondary hyperparathyroidism is a functional response to hypocalcemia. The causes of hypocalcemia may be numerous, but the most common cause is chronic renal failure.

Paraneoplastic hypercalcemia

Hypercalcemia may occur as part of a malignancy syndrome due to bony metastases or the production of an abnormal hormone that directly affects calcium and bone metabolism.

Destructive bone disease

Malignancy and other conditions, such as Paget disease, may induce enough bone destruction to cause hypercalcemia.

Milk-alkali syndrome

Uncommon today, this syndrome is caused by excessive consumption of sodium bicarbonate and calcium-containing compounds. The result is a metabolic alkalosis with hypercalcemia, hyperphosphatemia, nephrocalcinosis, and renal failure.

Excessive vitamin D

Overconsumption of vitamin D may increase GI calcium absorption, as well as renal calcium reabsorption, giving rise to hypercalcemia. This mechanism is relatively uncommon.

Sarcoidosis

The sarcoidal granuloma may overproduce 1,25-vitamin D, with subsequent hypercalcemia and an elevated calcium-phosphate product.

Chronic renal failure

This is the most common setting in which metastatic calcification occurs. Chronic renal failure affects many factors in calcium metabolism. Hyperphosphatemia due to decreased renal clearance occurs relatively early. Hypocalcemia is the direct result of this hyperphosphatemia and worsened by vitamin D deficiency due to renal failure. As a compensatory measure, excessive parathyroid hormone is produced. This augmentation results in increased calcium and phosphate mobilization; an elevated solubility product; and, subsequently, the formation and precipitation of calcium salts.

Calciphylaxis

This is a poorly understood, highly morbid process that most commonly affects patients with end-stage renal disease. Calcification occurs in the intima of the blood vessels and subcutaneous tissue. Microthrombi formation is a frequent finding. The exact mechanism remains unknown, but the most common unifying disorders are renal failure, hypercalcemia, hyperphosphatemia, and hyperparathyroidism.

Idiopathic calcinosis cutis

Idiopathic calcinosis cutis occurs in the absence of known tissue injury or systemic metabolic defect.

Idiopathic calcinosis of scrotum, penis, or vulva

Calcification may occur after trauma, or it may occur in the absence of known tissue injury. Calcinosis cutis of the penis may also result from calcification of an epidermal cyst.

Milia-like idiopathic calcinosis cutis ^{[9, 10, 11, 12]}

Many cases have been associated with Down syndrome and/or syringoma formation. Lesions are usually multiple and occur on the trunk, limbs, and face. The etiology remains controversial, but some evidence of calcium deposition in the sweat glands is present.

Subepidermal calcified nodule

These lesions usually develop in early childhood and are typically solitary, though multiple lesions can also be present. The nodules most commonly occur on the face, though they may occur anywhere. The pathogenesis is unknown, but the lesions may be due to calcification of components of adnexal structures.

Tumoral calcinosis

This may be caused by an error in renal phosphate metabolism resulting in hyperphosphatemia. General characteristics of the calcified nodules are a large size, a juxta-articular location, progressive enlargement, a tendency to recur after surgical removal, and the ability to encase the adjacent normal structures. The most common locations of calcification are the hip, elbow, scapula, foot, leg, knee, and hand. Tumoral calcinosis is often familial, and the hereditary pattern suggests that it is an autosomal recessive trait. Vitamin D deficiency may also be associated with hyperphosphatemia.

Calcinosis cutis circumscripta and calcinosis universalis

These forms are rare and may be due to altered ground substances. Calcinosis cutis circumscripta generally occurs earlier and tends to involve the extremities, whereas calcinosis universalis occurs later and is usually more widespread. Both have been associated with trauma, foreign body reaction, and (on occasion) scleroderma.

Transplant-associated calcinosis cutis ^{[13, 14, 15]}

In addition to calciphylaxis, numerous cases of calcinosis cutis have been described in transplant recipients. Although calcinosis cutis appears to be most common after renal transplantation, it is also described in liver, heart, and lung transplantation. The etiology of this calcification is unknown. Perhaps patients are infused with large numbers of blood products containing citrate and calcium that create an environment that favors calcification. The role of other factors remains to be elucidated.

Iatrogenic calcinosis

Iatrogenic calcinosis cutis arises secondary to a treatment or procedure.^{[16, 17, 18, 19]}

Parenteral administration of calcium or phosphate

The intravenous administration of solutions containing calcium or phosphate may cause the precipitation of calcium salts and lead to calcification.

Parental inorganic phosphate

This has been implicated.

Tumor lysis syndrome

Cutaneous calcification associated with tumor lysis syndrome is due to several factors, including chemotherapy-induced tissue damage with resultant hyperphosphatemia, hypocalcemia, hyperuricemia, and the potential for acute renal failure. Hypocalcemia frequently requires parenteral calcium use, increasing the possibility of tissue calcification.

Repeated heel sticks in the newborn

Calcium salt deposition may occur in newborns at sites of repeated heel sticks.

Prolonged use of calcium-containing electrode paste

Prolonged placement of electrode pastes containing calcium on abraded skin in diagnostic procedures such as electroencephalography, electromyography, or brainstem auditory evoked potential testing may result in calcium deposition at the placement site.

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Epidemiology

Frequency

Dystrophic calcinosis cutis is most common. Specific incidence and frequency data are unavailable.

Race

Tumoral calcinosis is more common in blacks of South African heritage.

Sex

No sex predilection is documented.

Age

Subepidermal calcified nodules are more common in children. Calcinosis cutis circumscripta tends to arise in the second half of life. Calcinosis cutis universalis occurs in the second decade of life. Tumoral calcinosis usually arises in the first or second decade of life.

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Prognosis

The prognosis is determined by that of any underlying disease. Calcinosis cutis alone usually is benign. Severe complications are infrequent. When present, morbidity is related to the size and location of the calcification.

Lesions may become painful, limit mobility of an adjacent joint, or compress adjacent neural structures. Ulceration and secondary infection may occur. Vascular calcification may result in ischemia and necrosis of the affected organ.

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Patient Education

Patients should be educated about the underlying disease processes and natural history of their specific disorder.

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History

Most lesions of calcinosis cutis develop gradually and are asymptomatic. However, the history and evolution of the lesions depend on the etiology of the calcification. Patients with dystrophic calcification may provide a history of an underlying disease, a preexisting dermal nodule (which represents a tumor), or an inciting traumatic event. Patients with metastatic calcification most frequently have a history of chronic renal failure. Cases of idiopathic calcinosis cutis usually are not associated with previous trauma or disease. Those who develop iatrogenic calcinosis cutis generally have a history of recent hospitalization.

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Physical Examination

The clinical presentation of calcinosis cutis can vary according to the diagnosis and underlying process. In general, multiple, firm, whitish dermal papules, plaques, nodules, or subcutaneous nodules are found in a distribution characteristic for the specific disorder. At times, these lesions may be studded with a yellow-white, gritty substance. Not infrequently, the lesions spontaneously ulcerate, extruding a chalky, white material. Most lesions are asymptomatic, though some may be tender, and others may restrict joint mobility. When severe, vascular calcification can cause diminished pulses and cutaneous gangrene.

Note the images below.

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Calcinosis cutis appearing as an indurated and nodular subcutaneous plaque in a patient with systemic lupus erythematosus.

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Ulceration of a lesion of calcinosis cutis in a patient with systemic lupus erythematosus.

Note the following types and manifestations:

• Dystrophic calcinosis cutis: Calcification is usually localized to a specific area of tissue damage, though it may be generalized in some disorders.
• Metastatic calcinosis cutis: Calcium deposition frequently is widespread. Large deposits are frequently found around large joints, such as knees, elbows, and shoulders, in a symmetrical distribution. Visceral organ deposition of calcium in the lung, kidneys, blood vessels, and stomach actually occurs more frequently than deposition within the skin or muscle.
• Idiopathic calcinosis cutis: Calcification most commonly is localized to one general area.
• Iatrogenic calcinosis cutis: Calcification generally is located at the site of an invasive procedure, though diffuse deposition may occur.

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Complications

Complications of calcinosis cutis include pain, cosmetic disfigurement, ulceration, and mechanical compromise.

The plaques or nodules may impinge on adjacent structures such as joints, resulting in restricted mobility, and nerves, resulting in pain or paresthesia. Destruction of synovial tissue also may result. Vascular occlusion may result in gangrene. Ulceration may be complicated by bacterial infection.

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Laboratory Studies

Tests of serum calcium, inorganic phosphate, alkaline phosphatase, and albumin levels may be helpful. An elevation in serum calcium and alkaline phosphatase levels with a decrease in the inorganic phosphate level is suggestive of hyperparathyroidism. One can further calculate the calcium-phosphate product to determine if the threshold of 70 mg²/dL² is exceeded. An albumin value is needed to interpret the significance of hypocalcemia or hypercalcemia. Calcium is highly protein bound, and abnormalities in the albumin concentration may cause clinically insignificant abnormalities of calcium concentration.

Additionally, note the following:

• Serum blood urea nitrogen and creatinine concentrations can be obtained to measure renal function.
• On the complete blood cell count with differential, hematologic abnormalities may suggest an underlying malignancy or lupus erythematosus.
• If milk-alkali is suspected, the plasma bicarbonate or arterial pH value may indicate the presence of a metabolic alkalosis.
• The parathyroid hormone concentration is a direct measurement for hyperparathyroidism.
• Creatine kinase and aldolase value may be significantly abnormal in cases of dermatomyositis, myositis, or rhabdomyolysis.
• Serum amylase or lipase levels are markers of pancreatic disease.
• Antinuclear antibody testing is helpful in screening for lupus erythematosus.
• In patients with scleroderma, the presence of SCL-70 (topoisomerase) antibody portends a poor prognosis.
• Vitamin D levels should be determined to evaluate the possibility of vitamin D excess or deficiency.^[20]
• A test of the 24–hour urinary excretion of calcium and/or inorganic phosphate may be useful.

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Imaging Studies

Radiographic examination may demonstrate the extent of tissue calcification.

Bone scintigraphy with radiolabeled phosphate compounds (technetium Tc 99m methylene diphosphonate [MDP]) is useful in evaluating nonvisceral soft tissue calcification; this test is more sensitive than plain radiography.^{[21, 22]}

CT allows for the identification of visceral and nonvisceral calcification. CT is infrequently used in evaluating calcinosis cutis and primarily used in assessing tumoral calcinosis.

MRI is of limited utility in evaluating calcified structures, but calcific deposits have characteristic patterns. The granulomatous foreign body reaction in tumoral calcinosis is evident.

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Procedures

Findings on biopsy and histopathologic examination of a cutaneous lesion are diagnostic.

Results of fine-needle aspiration cytology of a skin nodule may also be diagnostic.

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Histologic Findings

On biopsy, granules and deposits of calcium are seen in the dermis, with or without a surrounding foreign-body giant cell reaction. Alternatively, massive calcium deposits may be located in the subcutaneous tissue. In areas of necrosis, calcium deposition is frequently found within the walls of small and medium-sized blood vessels. Calcium deposition may be confirmed on Von Kossa and alizarin red stains.

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Medical Care

Medical therapy of calcinosis cutis is limited and of variable benefit. When identified, the underlying problem should be corrected.^{[23, 24]}

Intralesional corticosteroids may be beneficial because of their anti-inflammatory and inhibitory effects on fibroblast activity.

Probenecid and colchicine have been beneficial in some individuals.

Magnesium or aluminum antacids may be effective phosphate binders in patients with hyperphosphatemia. However, the use of these agents in patients with renal insufficiency may result in magnesium or aluminum toxicity.

Sodium etidronate and diphosphonates may reduce bone turnover and inhibit the growth of ectopic hydroxyapatite crystals. However, prolonged treatment is necessary, and paradoxical hyperphosphatemia may result.

Myo-inositol hexaphosphonate is a dietary substance shown to inhibit the crystallization of calcium salts. Recent animal studies have demonstrated a reduction in calcinosis cutis lesions with topical myo-inositol hexaphosphate. This potentially could be of benefit in humans.^{[25, 26]}

Warfarin has shown benefit in some. Low-dose warfarin should not be used, as no benefit has been established.^[27]

Rituximab and tumor necrosis factor inhibitors may be beneficial alternatives in patients with dermatomyositis.^[27]

The use of the calcium-channel blocker diltiazem over at least 5 years has variable benefits. The therapeutic effect is believed to be the antagonism of the calcium-sodium ion pump.^{[28, 29, 30]}

Use of intravenous sodium thiosulfate should be considered as it has been shown to be effective in many cases of calciphylaxis. It would be considered off-label and experimental therapy.^[31]  Reports suggest that ulcerative calcinosis cutis and tumoral calcinosis may respond to topical or intralesional sodium thiosulfate 25%.^{[32, 33, 34, 35]}

Minocycline may be another treatment option. Nine patients with cutaneous calcification associated with limited systemic sclerosis were treated with 50-100 mg/day of minocycline. Improvement was noted within 1-7 months in 8 of the patients. Although lesional size was only moderately improved, ulceration and inflammation were markedly reduced.^[36]

Theoretically, in extraordinarily severe cases of calcinosis cutis, associated with one of several connective-tissues diseases, autologous hematopoietic stem cell transplantation (HSCT) may be considered. Risks and benefits must be thoroughly investigated, but studies exist that suggest remission of some connective-tissue diseases with HSCT, which, in theory should help with calcinosis cutis.^[37]

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Surgical Care

Indications for surgical removal include pain, recurrent infection, ulceration, and functional impairment. Because surgical trauma may stimulate calcification, initially treat a test site before pursuing a large excision. Recurrence is common after excision.

Electric shock wave lithotripsy is anecdotally successful in treating calcinosis cutis associated with dermatomyositis, as well as venous insufficiency and scleroderma.^{[38, 39]}  Although reduction in the size of the calcification was minimal, the patient's associated pain was completely relieved. The physiology for this effect is unknown.

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Consultations

A nephrologist, a rheumatologist, and/or a hematologist should be consulted, as indicated by the underlying disease.

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Diet

Dietary alteration is of minor benefit in most cases.

The following changes may be tried:

• Restrict dietary phosphorous when hyperphosphatemia is present.
• Restrict dietary calcium intake when hypercalcemia is present.
• A ketogenic diet that stresses the consumption of free fatty acids may be helpful in some individuals. An accumulation of ketoacids, the metabolic product of fatty acids, may lower tissue pH and prevent crystallization.

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Activity

Activity is affected only if the calcified plaques and/or nodules are large enough to restrict joint mobility or cause ischemia and/or ulceration.

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Prevention

Prevention or treatment of the underlying disease process, as well as prevention of trauma and factors associated with iatrogenic calcinosis, is optimal.

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Medication Summary

Medical therapy generally has limited benefit. The following medications may be tried.

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Aluminum hydroxide (ALternaGEL, Alu-Cap, Amphojel, Dialume)

• Dosing, Interactions, etc.

Clinical Context:  Aluminum hydroxide is an effective phosphate binder; it is not considered first-line therapy because of its potential for toxicity.

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Magnesium oxide (Maox, Mag-ox)

• Dosing, Interactions, etc.

Clinical Context:  Magnesium oxide treats magnesium deficiencies or magnesium depletion due to malnutrition, restricted diet, alcoholism, or magnesium-depleting drugs.

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Class Summary

Inorganic salts can bind phosphate in the GI tract and prevent absorption.

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Etidronate disodium (Didronel)

• Dosing, Interactions, etc.

Clinical Context:  Etidronate disodium reduces bone formation and does not alter renal tubular reabsorption of calcium. It does not affect hypercalcemia in patients with hyperparathyroidism.

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Class Summary

These agents are used to inhibit bone turnover to lower serum calcium and phosphate levels. These agents also can absorb hydroxyapatite crystal and inhibit growth.

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Diltiazem hydrochloride (Cardizem)

• Dosing, Interactions, etc.

Clinical Context:  Diltiazem hydrochloride is used for the management of angina, supraventricular tachycardia, and hypertension. During depolarization, it inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium.

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Class Summary

Antagonism of calcium-sodium pump may diminish the intracellular calcium concentration, decreasing crystal formation.

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Cinacalcet (Sensipar)

• Dosing, Interactions, etc.

Clinical Context:  Cinacalcet directly lowers parathyroid hormone (PTH) levels by increasing the sensitivity of the calcium-sensing receptor on the chief cell of the parathyroid gland to extracellular calcium. This also results in concomitant serum calcium decrease.

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Class Summary

These agents lower PTH levels by increasing sensitivity of calcium-sensing receptor on chief cell of parathyroid gland to extracellular calcium. Serum calcium also decreases.

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