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Section XI Extraskeletal (Ectopic) Calcification and Ossification

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Section XI Extraskeletal (Ectopic) Calcification and Ossification Section XI Extraskeletal (Ectopic) Calcification and Ossification Michael P. Whyte Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital and Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis, Missouri INTRODUCTION somewhat higher value because they have greater serum phos- phate concentrations compared with adults. However, this is A significant number and variety of disorders cause extraskel- not well established.(5) etal deposition of calcium and phosphate (Table 1). In some, The material that comprises metastatic calcification may be mineral is precipitated as amorphous calcium phosphate or as amorphous calcium phosphate initially, but hydroxyapatite is crystals of hydroxyapatite; in others, osseous tissue is formed. deposited soon after.(2) The anatomic pattern of deposition The pathogenesis of ectopic mineralization is generally attrib- varies somewhat between hypercalcemia and hyperphos- uted to one of three mechanisms (Table 1). First, a supranormal phatemia, but occurs irrespective of the specific underlying “calcium-phosphate solubility product” in extracellular fluid condition or mechanism for the disturbed mineral homeostasis. can cause metastatic calcification. Second, mineral may be Additionally, there is a predilection for certain tissues. deposited as dystrophic calcification into metabolically im- Hypercalcemia is typically associated with mineral deposits paired or dead tissue despite normal serum levels of calcium in the kidneys, lungs, and fundus of the stomach. In these and phosphate. Third, ectopic ossification (or true bone forma- “acid-secreting” organs, a local alkaline milieu may account tion) occurs in a few disorders for which the pathogenesis is for the calcium deposition. In addition, the media of large becoming increasingly understood. arteries, elastic tissue of the endocardium (especially the left Discussed briefly in this introduction are these three mech- atrium), conjunctiva, and periarticular soft tissues are often anisms for extraskeletal calcification or ossification. Subse- affected. However, why these sites are predisposed is not well quently, there follows a description of disorders that illustrate understood. In the kidney, hypercalciuria may cause calcium each pathogenesis. phosphate casts to form within the tubule lumen, or calculi to develop in the calyces or pelvis. Furthermore, calcium phos- MECHANISMS FOR EXTRASKELETAL phate may precipitate in peritubular tissues. In the lung, calci- CALCIFICATION AND OSSIFICATION fication affects the alveolar walls and the pulmonary venous Calcium and inorganic phosphate are normally present in system. Well-established causes of metastatic calcification me- serum or extracellular fluid at concentrations that form a “meta- diated by hypercalcemia include the milk-alkali syndrome, stable” solution. That is, their levels are too low for spontane- hypervitaminosis D, sarcoidosis, and hyperparathyroidism (Ta- ous precipitation but sufficiently great to cause hydroxyapatite ble 1). [Ca10(PO4)6(OH)2] formation once crystal nucleation has be- gun.(1) In health, the presence of a variety of inhibitors of TABLE 1. DISORDERS ASSOCIATED WITH EXTRASKELETAL CALCIFICATION mineralization, such as inorganic pyrophosphate, helps to pre- OR OSSIFICATION vent ectopic calcification.(2) The pathogenesis of metastatic and dystrophic calcification A. Metastatic calcification at the cell level is partially understood. Both processes typi- I. Hypercalcemia cally involve mineral accumulation within matrix vesicles and a. Milk-alkali syndrome sometimes within mitochondria.(2) Conversely, the mecha- b. Sarcoidosis nisms which initiate ectopic ossification are less clear, but d. Hyperparathyroidism studies of progressive osseous heteroplasia (POH) identified e. Renal failure deactivating mutations in GNAS (which also causes pseudohy- II. Hyperphosphatemia poparathyroidism type IA).(3) Calcification and ossification a. Tumoral calcinosis within the vasculature is now being investigated intensely.(4) b. Hypoparathyroidism Metastatic calcification can occur from significant hypercal- c. Pseudohypoparathyroidism cemia or hyperphosphatemia (especially both) of any etiology d. Cell lysis after chemotherapy for leukemia (Table 1). In fact, therapy with phosphate supplements during e. Renal failure mild hypercalcemia or treatment with vitamin D or calcium B. Dystrophic calcification during mild hyperphosphatemia may trigger this problem. Min- I. Calcinosis (universalis or circumscripta) eral deposition can also occur ectopically from hyperphos- a. Childhood dermatomyositis phatemia despite concomitant hypocalcemia.(5) b. Scleroderma Direct precipitation of mineral occurs when the calcium– c. Systemic lupus erythematosis phosphate solubility product in extracellular fluid is exceeded. II. Post-traumatic A value of 75 (mg/dl ϫ mg/dl) is commonly taken as the limit C. Ectopic ossification that, if surpassed, causes mineral precipitation. However, the I. Myositis ossificans (post-traumatic) critical value for renal calcification is not precisely defined and a. Burns may vary with age.(5) In adults, some consider 70 to be the b. Surgery (joint replacement) maximal safe level for the kidney. Possibly, children tolerate a c. Neurologic injury II. Fibrodysplasia (myositis) ossificans progressiva (FOP) III. Progressive osseous heteroplasia (POH) IV. Osteoma cutis The author has reported no conflicts of interest. 436 © 2006 American Society for Bone and Mineral Research TUMORAL CALCINOSIS / 437 Hyperphosphatemia of sufficient severity to cause metastatic lesions of calcinosis are small or medium-sized hard nodules calcification occurs in idiopathic hypoparathyroidism or that can cause muscle atrophy and contractures. Other etiolo- pseudohypoparathyroidism and with the massive cell lysis (re- gies for calcinosis include metastases or trauma that produce lease of cellular phosphate) that can follow chemotherapy for necrotic tissue. leukemia (Table 1). Renal insufficiency is commonly associ- Ectopic ossification is associated with two principal etiolo- ated with metastatic calcification—the mechanism may involve gies. It occurs sporadically with the fasciitis that follows neu- hyperphosphatemia, hypercalcemia, or both.(6) Of interest (but rological injury, surgery, burns or trauma, when it is called unexplained), ectopic calcification is more common in myositis ossificans. It also occurs as the major feature of a pseudohypoparathyroidism (type I) than in idiopathic hypopar- separate, heritable entity—fibrodysplasia (myositis) ossificans athyroidism despite comparable elevations in serum phosphate progressiva—where the pathogenesis is becoming understood. levels. Furthermore, the location of ectopic calcification in Some ascribe the ectopic bone formation in this latter, genetic pseudohypoparathyroidism and hypoparathyroidism (e.g., ce- disorder to be a muscle abnormality (myositis ossificans pro- rebral basal ganglion) is different from observations in hyper- gressiva), whereas others favor a connective tissue defect (fi- calcemia. With hyperphosphatemia, calcification of periarticu- brodysplasia ossificans progressiva). In all of these conditions, lar subcutaneous tissues is characteristic and may be related to osseous tissue is formed. The bone is lamellar, is actively tissue trauma from the movement of joints.(6) remodeled by osteoblasts and osteoclasts, has haversian sys- Dystrophic calcification occurs despite a normal serum tems, and sometimes contains marrow. Apparently, the injured calcium–phosphate solubility product.(7) Injured tissue of any or diseased tissue has the necessary inductive signals and kind is predisposed to this type of extraskeletal calcification. precursor cells to form cartilage and bone. Apparently, tissues can release material that has nucleating Described in the following chapters are tumoral calcinosis, properties. One classic example is the caseous lesion of tuber- dermatomyositis, fibrodysplasia ossificans progressiva (FOP), culosis. However, what local factor predisposes to the precip- and vascular diseases, which represent the principal examples itation of calcium salts is unknown. Indeed, several mecha- of each type of ectopic mineralization. nisms seem likely. It is clear that mineral precipitation into injured tissue is even more striking and more severe when REFERENCES either the calcium or phosphate level in extracellular fluid is also increased. The deposited mineral, as for metastatic calci- 1. Fawthrop FW, Russell RGG 1993 Ectopic calcification and ossification. fication, may be either amorphous calcium phosphate or crys- In: Nordin BEC, Need AG, Morris HA (eds.) Metabolic Bone and Stone Disease, 3rd ed. Churchill Livingstone, Edinburgh, UK, pp. 325–338. talline hydroxyapatite. 2. Anderson HC 1983 Calcific diseases: A concept. Arch Pathol Lab Med The term “calcinosis” refers to an important type of dystro- 107:341–348. phic calcification that commonly occurs in (or under) the skin 3. Eddy MC, Jan de Beur SM, Yandow SM, McAlister WH, Shore EM, from connective tissue disorders—particularly dermatomyosi- Kaplan FS, Whyte MP, Levine MA 2000 Deficiency of the ␣-subunit of tis, scleroderma, or systemic lupus erythematosus.(7) As the the stimulatory G protein and severe extraskeletal ossification. J Bone Miner Res 15:2074–2083. symptoms and the inflammatory process in the subcutaneous 4. Collett GD, Canfield AE 2005 Angiogenesis and pericytes in the initiation tissues from the acute connective tissue disease
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