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Calcinosis Cutis Circumscripta
Last Updated: November 2, 2001 |
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| Synonyms and
related keywords: cutaneous calcinosis, cutaneous calculi |
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AUTHOR
INFORMATION |
Section
1 of 10 
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| Author: Julia
R Nunley, MD, Program Director, Associate Professor,
Department of Dermatology, Medical College of Virginia
Coauthor(s): Lydia
M E Jones, MD, Staff Physician, Department of
Dermatology, Virginia Commonwealth University
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| Julia R Nunley, MD, is a member of the following
medical societies: American Academy
of Dermatology, American
College of Physicians, American
Society of Nephrology, International
Society of Nephrology, Medical
Society of Virginia, and National
Kidney Foundation
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| Editor(s): James W Patterson, MD,
Director of Dermatopathology, Professor of Pathology and
Dermatology, Departments of Pathology and Dermatology, University
of Virginia Medical Center; Richard Vinson, MD,
Chief, Department of Dermatology, William Beaumont Medical Center;
Rosalie Elenitsas, MD, Director of
Dermatopathology, Associate Professor, Department of Dermatology,
University of Pennsylvania; Catherine Quirk, MD,
Clinical Assistant Professor, Department of Dermatology, Brown
University; and William D James, MD, Program
Director, Vice-Chair, Albert M Kligman Professor, Department of
Dermatology, University of Pennsylvania School of Medicine |
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INTRODUCTION |
Section
2 of 10 
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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, and tumoral calcinosis.
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 exist which allow 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.
Frequency:
 | Internationally: Dystrophic
calcinosis cutis is most common. Specific incidence and frequency data
are unavailable. |
Mortality/Morbidity: Calcinosis cutis
generally is a benign process. However, when present, morbidity relates 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.
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. |
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| Calcinosis cutis universalis occurs in the second
decade of life. |
| Tumoral calcinosis usually arises in the first or
second decade of life. |
History: Most lesions of calcinosis cutis develop
gradually and are asymptomatic. However, the history and evolution of the
lesions depend upon 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 prior trauma or disease. Those who
develop iatrogenic calcinosis cutis generally have a history of recent
hospitalization.
Physical: The clinical presentation of
calcinosis cutis can vary according to the diagnosis and underlying
process. However, 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 yellowish-white gritty substance. Not infrequently, the
lesions may spontaneously ulcerate and extrude a chalky white material.
Most lesions are asymptomatic, though some may be tender and others may
restrict joint mobility. Vascular calcification, when severe, may cause
diminished pulses and cutaneous gangrene.
| Dystrophic calcinosis cutis: Calcification usually is
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. |
Causes: 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 factors.
Table 1. Causes of Dystrophic Calcinosis Cutis
 | Localized
 | Trauma
| Inflammatory processes
| Acne
| Insect bites |
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| Varicose Veins
| Infections
| Tumors
| Pilomatricoma
| Fat cell tumors
| Epithelial cysts
| Syringomas
| Melanocytic nevi |
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| Generalized
| Connective tissue diseases
| Dermatomyositis
| Lupus erythematosus
| Systemic sclerosis
| CREST* |
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| Subcutaneous fat necrosis of the newborn
| Pancreatic calcification
| Inherited disorders
| Ehlers-Danlos syndrome
| Werner syndrome
| Pseudoxanthoma elasticum
| Rothmund-Thompson syndrome |
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*Calcinosis cutis, Raynaud phenomenon, esophageal
dysfunction, sclerodactyly, telangiectasias
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| Trauma and inflammatory processes/tumors/infections
| Extraosseal calcification can occur in the
setting of many local and destructive processes, including
burns, arthropod bites, acne lesions, varicose veins, and
rhabdomyolysis.
| Both benign and malignant tumors may develop
calcification. Pilomatrixoma, or calcifying epithelioma of
Malherbe, is the most common tumor to calcify. Epithelial cysts
and syringomas also have a significant tendency to calcify. Foci
of calcification commonly are seen in histologic sections of
basal cell carcinomas. Rarely, melanocytic nevi, malignant
melanoma, atypical fibroxanthoma, hemangioma, pyogenic granuloma,
seborrheic keratoses, neurilemomas, and trichoepitheliomas have
shown foci of calcification.
| Necrotic tissue produced by an infectious
process may subsequently calcify. Some infectious granulomas
also may produce 1,25 vitamin D. Infections that may result in
calcinosis cutis include onchocerciasis, cysticercosis,
histoplasmosis, cryptococcosis, and intrauterine herpes simplex. |
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| Connective tissue diseases
| Dermatomyositis: Calcification occurs 3 times
more commonly in juvenile dermatomyositis than the adult-onset
form and may be seen in 30-40% of patients. Calcification is
accentuated over joints, sparing the digits. Aggressive
corticosteroid therapy has decreased the incidence of
calcification.
| Lupus erythematosus: Calcification occurs
rarely in lupus and usually is an insignificant incidental
radiologic finding. Calcification occurs more frequently in
patients 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.
| Scleroderma: Systemic scleroderma and CREST
syndrome (calcinosis cutis, Raynaud phenomenon, esophageal
dysfunction, sclerodactyly, telangiectasias) are related
diseases frequently associated with the late development of
tissue calcification. |
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| Panniculitis
| Subcutaneous fat necrosis of the newborn: This
condition typically affects full-term 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 calcify. The
cause is unknown. Possible inciting events include obstetric
trauma, maternal pre-eclampsia or diabetes, or neonatal
hypothermia or hypoxia.
| Pancreatic calcification: 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. |
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| Inherited disorders
| Ehlers-Danlos syndrome: 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: In this inherited disorder of
premature aging, soft tissue calcification may occur involving
ligaments, tendons, synovia, vasculature, and subcutaneous
tissue.
| Pseudoxanthoma elasticum: In this disorder of
abnormal elastic fibers, calcification occurs within these
elastic fibers causing rupture. Late in the disease, collagen
fibers also may become calcified.
| Rothmund-Thomson syndrome: Small yellow papules
of calcification may be numerous on the extremities. |
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| Hyperparathyroidism may be primary or secondary. 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 gastrointestinal calcium absorption as well as renal
calcium reabsorption giving rise to hypercalcemia. This 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. Multiple factors
in calcium metabolism are affected by chronic renal failure.
Hyperphosphatemia due to decreased renal clearance occurs relatively
early. Hypocalcemia occurs as a direct result of this
hyperphosphatemia and is worsened by renal-failure–induced vitamin
D deficiency. As a compensatory measure, excessive parathyroid
hormone is produced. This augmentation of parathyroid hormone
results in an increase in 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 most commonly affecting patients with end-stage renal
disease. Calcification occurs within 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 include renal failure, hypercalcemia,
hyperphosphatemia, and hyperparathyroidism. |
| Idiopathic calcinosis of the scrotum/penis/vulva:
Calcification may occur following trauma or may occur in the absence
of known tissue injury. Calcinosis cutis of the penis may also
result from calcification of an epidermal cyst.
| Milialike idiopathic calcinosis cutis: Many cases
have been associated with Down syndrome and/or syringoma formation.
Lesions usually are multiple and occur on the trunk, limbs, and
face. The etiology remains controversial, but some evidence of sweat
gland calcium deposition is present.
| Subepidermal calcified nodule: These lesions
usually develop in early childhood and are usually solitary, though
multiple lesions may be present. They occur most commonly on the
face though they may occur anywhere. The pathogenesis is unknown,
but it may be due to calcification of components of adnexal
structures. |
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| Tumoral calcinosis may be caused by an error in
renal phosphate metabolism resulting in hyperphosphatemia. General
characteristics of the calcified nodules include large size,
juxta-articular location, progressive enlargement, a tendency to
recur after surgical removal, and the ability to encase adjacent
normal structures. The most common locations of calcification are
the hip, elbow, scapula, foot, leg, knee, and hand. Tumoral
calcinosis frequently is familial and the hereditary pattern
suggests that it is an autosomal recessive trait. |
| Calcinosis cutis circumscripta and calcinosis
universalis are very 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 usually is more widespread. Both have been
associated with trauma, foreign body reaction, and, on occasion,
scleroderma. |
| Parenteral administration of calcium or phosphate:
Intravenous administration of solutions containing calcium or
phosphate may cause calcium salt precipitation and lead to
calcification.
| 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 electroencephalogram,
electromyography, and brain stem auditory evoked potential, may
result in calcium deposition at the placement site. |
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DIFFERENTIALS |
Section
4 of 10
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Milia
Molluscum Contagiosum
Mycetoma
Osteoma Cutis
Warts, Genital
Xanthomas
Other Problems to be Considered:
Gouty tophi
Progressive osseous hyperplasia
Subcutaneous cholesterol crystals
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Lab Studies:
| Serum calcium, inorganic phosphate, alkaline
phosphatase, and albumin |
| An elevation in serum calcium and alkaline
phosphatase with a decrease in inorganic phosphate 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 is needed to interpret the significance
of hypo- or hypercalcemia. Calcium is highly protein bound, and
abnormalities in albumin concentration may cause clinically
insignificant abnormalities of calcium concentration. |
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| Serum blood urea nitrogen (BUN) and creatinine to
measure renal function |
| Complete blood count (CBC) with differential:
Hematologic abnormalities may suggest an underlying malignancy or
lupus erythematosus. |
| Plasma bicarbonate or arterial pH: If milk-alkali is
suspected, these values will indicate the presence of a metabolic
alkalosis. |
| Parathyroid hormone is a direct measurement for
hyperparathyroidism. |
| Creatine phosphokinase (CPK) and aldolase may be
significantly abnormal in dermatomyositis, myositis, or rhabdomyolysis. |
| Serum amylase or lipase: Both are markers of
pancreatic disease. |
| Antinuclear antibody (ANA) is helpful in screening
for lupus erythematosus. |
| SCL-70 (topoisomerase): In scleroderma, the presence
of this antibody portends a poorer prognosis. |
| Vitamin D level to evaluate for excess Vitamin D. |
| Twenty-four–hour urinary excretion of calcium
and/or inorganic phosphate |
Imaging Studies:
| Plain films: Radiologic examination may document the
extent of tissue calcification. |
| Bone scintigraphy with radiolabeled phosphate
compounds (technetium-99m methylene diphosphonate [MDP]) is useful in
evaluating nonvisceral soft tissue calcification and is more sensitive
than plain films. |
| Computed tomography allows identification of visceral
and nonvisceral calcification. This has been used infrequently in
evaluating calcinosis cutis and primarily in tumoral calcinosis. |
| Magnetic resonance imaging is of limited utility in
evaluating calcified structures, but calcific deposits display
characteristic patterns. The granulomatous foreign body reaction in
tumoral calcinosis is evident. |
Procedures:
| Biopsy and histopathologic examination of a cutaneous
lesion are diagnostic. |
| Fine-needle aspiration cytology of a skin nodule may
also be diagnostic. |
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 by Von
Kossa and alizarin red stains.
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TREATMENT |
Section
6 of 10
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Medical Care:
| Medical therapy of calcinosis cutis is of limited and
variable benefit. When identified, correct the underlying problem.
| Intralesional corticosteroids may be beneficial due
to the anti-inflammatory effect and inhibitory effect on fibroblast
activity. |
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| Probenecid and colchicine have been beneficial in
some individuals. |
| Magnesium or aluminum antacids may be effective
phosphate binders in patients with hyperphosphatemia. However, use 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. |
| Warfarin has shown benefit in some. |
| There have been variably beneficial effects with the
use of the calcium-channel blocker diltiazem over a period of at least
5 years. The therapeutic effect of this is believed to be the
antagonism of the calcium-sodium ion pump. |
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 a large excision is pursued. Following excision, however,
recurrence is common. |
Consultations:
| Nephrologic, rheumatologic, and hematologic
consultations should be pursued as indicated by the presence of an
underlying disease. |
Diet:
| Dietary alteration is of minor benefit in most cases.
However, the following changes may be tried. |
| Restrict dietary phosphorous when hyperphosphatemia
is present. |
| Restrict dietary calcium when hypercalcemia is
present. |
| A ketogenic diet that stresses consumption of free
fatty acids may be helpful in some individuals. Accumulation of
ketoacids, the metabolic product of fatty acids, may lower tissue pH
and prevent crystallization. |
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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MEDICATION |
Section
7 of 10
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Medical therapy generally has limited benefit. The following medications
may be tried.
Drug Category: Antacids -- Inorganic salts have
the capacity to bind phosphate in the GI tract and prevent absorption.
Drug Name
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Aluminum
carbonate (Basaljel) -- Increases gastric pH above 4 and inhibits
proteolytic activity of pepsin. Does not coat mucosal lining but
may have local astringent effect. May also increase lower
esophageal sphincter tone.
| Adult Dose |
400-1800 mg PO
tid with meals
| Pediatric Dose |
Not established
| Contraindications |
Documented
hypersensitivity
| Interactions |
Decreases
effects of allopurinol, chloroquine, corticosteroids, diflunisal,
digoxin, ethambutol, iron salts, H2-antagonists, isoniazid,
penicillamine, phenothiazines, tetracyclines, thyroid hormones,
and ticlopidine; increases effects of benzodiazepines and
dicumarol
| Pregnancy |
B - Usually safe
but benefits must outweigh the risks.
| Precautions |
Use in patients
with renal insufficiency may result in aluminum toxicity; nausea
and constipation are frequent adverse effects; aluminum ions
inhibit smooth muscle contraction, thus inhibiting gastric
emptying; caution in patients with gastric outlet obstruction; may
cause dose-related rebound hyperacidity by increasing gastric
secretion or serum gastrin levels; prolonged use of
aluminum-containing antacids in renal failure may result in or
worsen dialysis osteomalacia; elevated tissue aluminum levels
contribute to development of dialysis encephalopathy and
osteomalacia syndromes
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Drug Name
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Aluminum
hydroxide (ALternaGEL, Alu-Cap, Amphojel, Dialume) -- Effective
phosphate binder; not considered first-line therapy due to
potential for toxicity.
| Adult Dose |
320-1800 mg PO
tid with meals
| Pediatric Dose |
50-150 mg/kg/d
PO divided q4-6h; titrate to maintain normal serum phosphorus
levels
| Contraindications |
Documented
hypersensitivity
| Interactions |
Tetracyclines,
ranitidine, ketoconazole, benzodiazepines, penicillamine,
phenothiazines, digoxin, indomethacin, isoniazids, and
corticosteroids decrease effects of aluminum in hyperphosphatemia;
absorption of dicumarol and benzodiazepines may increase if
administered concurrently
| Pregnancy |
B - Usually safe
but benefits must outweigh the risks.
| Precautions |
Caution in
patient with recent massive upper GI hemorrhage; renal failure may
cause aluminum toxicity
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Drug Name
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Magnesium oxide
(Maox, Mag-ox) -- Treats magnesium deficiencies or magnesium
depletion from malnutrition, restricted diet, alcoholism, or
magnesium-depleting drugs.
| Adult Dose |
140-420 mg PO
tid with meals
| Pediatric Dose |
Administer as in
adults
| Contraindications |
Documented
hypersensitivity
| Interactions |
Decreases
effects of benzodiazepines, chloroquine, corticosteroids, digoxin,
H-2 antagonists, hydantoins, nitrofurantoin, tetracyclines, iron
salts, ticlopidine, phenothiazines, iron salts; increases the
effects of dicoumarol, quinidine, and sulfonylureas
| Pregnancy |
B - Usually safe
but benefits must outweigh the risks.
| Precautions |
Hypermagnesemia
and toxicity may occur in renal impairment when >50 mEq
magnesium is given qd due to decreased clearance of magnesium ion;
approximately 5-20% of orally administered magnesium salts can be
absorbed systemically
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Drug Category: Diphosphonates -- Use to inhibit
bone turnover in order to lower serum calcium and phosphate levels. These
agents also can absorb hydroxyapatite crystal and inhibit growth.
Drug Name
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Etidronate
disodium (Didronel) -- Reduces bone formation and does not alter
renal tubular reabsorption of calcium. Does not affect
hypercalcemia in patients with hyperparathyroidism.
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BRTS
