Henry Ford Hospital Medical Journal

Volume 31 Number 4 Article 11

12-1983

Osteomalacia

Boy Frame

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Recommended Citation Frame, Boy (1983) "," Henry Ford Hospital Medical Journal : Vol. 31 : No. 4 , 213-216. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol31/iss4/11

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Henry Ford Hosp Med J Vol 31, No 4,1983

Osteomalacia

Boy Frame, MD"

fd. Note - This overview was originally presented at the Recent advances in laboratory methods and techniques International Symposium on Clinical Disorders of Bone related to bone and mineral metabolism have provided a and Mineral Metabolism, May 9-13, 1983. The following detailed study of factors important in bone formation. list indicates the presentations given in this session at the Osteomalacia results from a disturbance in mineraliza­ Symposium and the contents ofthe corresponding chap­ tion of bone matrix. Theoretically, bone matrix may fail ter in the Proceedings of the Symposium published by to mineralize because of abnormalities in collagen and Excerpta Medica. The numbers in parentheses refer to matrix proteins, or because of an alteration in mineral pages in this volume. Complete information about the metabolism at the mineralization front. The result is an contents ofthe Proceedings can be found at the back of accumulation of increased quantities of unmineralized this issue. bone matrix (osteoid) over bone surfaces.

Spatial distributions of aluminum, phosphorus and cal­ Rickets is more apparent in children who have otherwise cium in mineralizingepiphy seal growth plates of aluminum- normal growth patterns, including that of the cartilage treated rats by electron spectroscopic imaging. A.L. present in the growth plates of long bones. Likewise, Arsenault, F.P. Ottensmeyer, and A.B. Hodsman (220) osteomalacia is less apt to occur when normal bone matrix formation is deficient. In order for a defect in tfistologic evolution of vitamin-D depletion in patients bone mineralization to be fully expressed, adequate with intestinal malabsorption of dietary deficiency. D.S. bone matrix must first be deposited. Rao, A. Villanueva, M. Matthews, B. Pumo, B. Frame, M. Kleerekoper, and A.M. Parfitt (224) The Table lists some of the factors currently considered to be possibly significant in the formation of bone matrix Primary biliary cirrhosis and alcoholic cirrhosis as exam­ and mineralization. ples of chronic liver disease associated with bone dis­ ease. R.R. Recker, W. Maddrey, H. Herlong, M. Sorrell, Recent studies suggest that itself may be and R. Russell (227) important as an initiating event for osteoblast formation and function in the bone remodeling unit (BMU). A high Chronic hypophosphatemia without osteomalacia. M.C. molecular weight polypeptide which has been isolated de Vernejoul, P.J. Marie, L. Miravet, and A. Ryckewaert from tissue cultures and demineralized human bone (232) matrix, stimulates osteoblast proliferation and matrix in patients receiving total parenteral nutri­ formation. Impaired release or other defect in this cou­ tion. S.M. Ott, N.A. Maloney, G.L. Klein, A.C. Alfrey, pling or skeletal growth factor could theoretically influ­ M.E. Ament, J.W. Coburn, and D.J. Sherrard (237) ence subsequent osteoblast vigor and function.

The pathogenesis of tumor-induced osteomalacia: A Collagen synthesis is the initial, major component of new perspective. P.C. Brazy, B. Lobuagh, K.W. Lyles, and bone matrix formation. Maturation of collagen, which M.K. Drezner (242) appears to be important for mineralization, is character­ ized by increasing intra- and extrafibrillar cross-linking of collagen fibers. Some defects in mineralization may result from an abnormality in collagen structure. For instance, in the rare skeletal disorder known as fibro-

•Department of Internal Medicine, Bone and Mineral Metabolism Division, Henry Ford Hospital Address reprint requests to Dr. Frame, Bone and Mineral Metabolism Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, Ml 48202.

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genesis imperfecta ossium, marked distortion of the zation. Osteoblast influence is less important in this lat­ normally polarized collagen fibers appears to result in ter phase of mineral deposition. impaired mineralization and increased numbers of widened osteoid seams. A number of precisely timed chemical and physiological factors must interact for mineralization to proceed nor­ The chronologic age of the person as well as the age of mally. Ambient concentrations of and particu­ the osteoblasts may influence the rate and extent of larly of phosphate are important. Since osteomalacia matrix formation. Decreases in the matrix appositional occurs in many patients with chronic hypophosphate­ rate correlates with age and distance from the cement mia, other modulating factors are also important. In this line in individual BMUs. Only insulin and growth hor­ section, M.C. de Vernejoul and associates (pp. 232 ff.) mone, the latter via somatomedin, directly stimulate report on 19 male patients with chronic hypophos­ bone collagen synthesis. Other hormones primarily play phatemia due to a renal phosphate leak independent of a modulating role in collagen formation. . Whilethere was noosteoid accum­ ulation, decreased osteoblast appositional rate was never­ Recently, noncollagenous bone matrix proteins have theless present. As in rickets, normal growth of bone been evaluated as possible causes of defective minerali­ matrix may be necessary before a mineralization defect zation. Osteocalcin (gla protein) has been extensively can be fully expressed. studied, but its ultimate role in bone metabolism is still to be determined. Osteocalcin has an affinity for binding to Relatives of patients with X-linked hypophosphatemic hydroxyapatite but only after the latter's maturation rickets and osteomalacia may exhibit hypophosphate­ from an initial amorphous mineral phase. Another bone mia without apparent bone involvement. However, matrix protein, osteonectin appears to facilitate the many of these patients have not had careful bone biopsy nucleation of calcium phosphate mineral onto the sur­ studies with current histomorphometric techniques to face of type I collagen. exclude a defect in mineralization. Chronic hypocalce­ mia appears to result in rickets and osteomalacia only Proteoglycans and glycoproteins are other important extracollagenous proteins in bone matrix. While their role in mineralization needs further clarification, they do TABLE have a high binding affinity for calcium, which appar­ Factors Influencing Bone Matrix ently depends on the presence of a large number of free Formation and Mineralization acidic groups. Theoretically, excessive calcium binding Bone resorption in bone remodeling units (BRUs) to proteoglycans might interfere with normal mineral • Release of a coupling factor that stimulates osteoblasts deposition at the mineralization front. In fact, certain Osteoblast function rare forms of osteomalacia may be related to a defect in • Collagen formation and maturation concentration or function of one or more of the matrix 1. Chronologic age of person proteins. One form of osteomalacia that could result 2. Insulin 3. Growth hormone (via somatomedin) from such a defect is axial osteomalacia. In this skeletal • Bone matrix proteins affliction, osteomalacia of the axial skeleton (exhibiting a 1. Osteocalcin (Gla protein) coarsened trabecular pattern on skeletal x-rays) is not 2. Osteonectin associated with any obvious disturbance in mineral or 3. Proteoglycans metabolism. An abnormality in one of the Mineralization at the mineralization front extracollagenous matrix proteins could account for this • Ambient Ca, PO^ concentrations mineralization defect. • pH at mineralization front • Amorphous Ca, PO.,(ACP) preceding Because methods of study are available, most identified hydroxyapatite formation (?) • Vitamin D metabolites forms of osteomalacia have been related to disturbances 1. Maintain adequate ambient Ca, PO,, levels in mineral and vitamin D metabolism. After appropriate 2. (?) Direct effect on osteoblasts and/or mineralization front maturation of bone matrix overa period of 10 to 15 days, • Parathyroid hormone primary mineralization occurs, and about 80% of the • Piezoelectric fields (exercise and stress) mineral is deposited in the first few days. This primary • Inhibitors of mineralization 1. Pyrophosphates ) destroyed by mineralization is largely controlled by the osteoblasts 2. ATP (adenosine triphosphate) V phosphatases and nearby osteoid osteocytes. The remainder of the 3. Foreign ions, such as aluminum \ and ATPases mineral is deposited at a slower rate over a six-month • Matrix vesicles period or more, a process known as secondary minerali­ 1. Facilitates mineral and enzyme concentration at the mineralization front

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rarely. Examples are seen primarily in rapidly growing minerals and enzymes, appearing at the initial site of children who have subsisted on a calcium deficient diet. mineral deposition. Hydrogen ion concentration appears to bean important Bone matrix formation and its mineralization is a complex clinical factor at the mineralization front. Chronic sys­ process, and many possibilities exist for metabolic defects temic acidosis, as occurs in patients who have under­ which may lead to impaired mineralization. Further use gone ureterosigmoidostomy, can result in osteomala­ of electron spectroscopic imaging, as described by Arse­ cia, even in the presence of normal serum levels of nault and associates (pp. 220 ff.) should help define the calcium and phosphorus. factors important for mineral deposition. These authors demonstrated that an increased concentration of alumi­ Most theories of suggest that crystalline num at the zone of calcification in the growth plate hydroxyapatite is preceded by an amorphous noncrystal­ retards normal mineralization in aluminum-treated rats. line calcium phosphate complex, although recent studies Other studies have demonstrated the importance of have questioned the validity of this concept. aluminum in inhibiting mineralization, both in the treat­ The role of several vitamin D metabolites in bone miner­ ment resistant osteomalacia observed in alization is discussed extensively elsewhere in this Pro­ patients with renal and in patients who ceedings. The importance of these metabolites in main­ have been maintained on total parenteral nutrition. The taining adequate serum concentrations of calcium and use of electron probes in association with histochemical phosphorus is unquestioned. Whether they have an techniques offers promise in the study of the mineraliza­ additional direct effect on osteoblasts or on mineraliza­ tion process. One day we may have a detailed map ofthe tion is hotly debated. osteoid seam, where the concentrations of all important factors needed for normal mineralization can be meas­ Parathyroid hormone appears to directly affect or ured, and variations from normal can be detected. enhance the availability of minerals at the mineraliza­ tion front. In some patients with renal osteodystrophy Bone histomorphometry with the use of double tetracy­ decreased parathyroid function appearsto increase the cline labeling techniques and undecalcified bone sec­ tendency toward a form of osteomalacia that resists the tions has come of age. An absence of osteomalacia, or at usual treatment. the other extreme, florid osteomalacia, can readily be identified by most established calcified tissue laborato­ Exercise by initiating shearing forces on mineral crystals ries. However, there is less agreement on criteria for the induces electrical fields (piezoelectrical) that may influ­ earliest histomorphometric signs of osteomalacia, espe­ ence bone formation. Fracture non-union is now being cially when accompanied by secondary hyperparathyroid­ successfully treated in some instances by application of ism. International agreement should be sought in estab­ low-grade pulsed electrical currents. The importance of lishing histodynamic criteria forall stages of osteomalacia such electrical fields in the process of normal matrix so that studies from different clinical research centers can formation and mineralization may be important but is be compared more readily. Rao and others (pp. 224 ff.) in difficult to prove. Parfitt's laboratory at Henry Ford Hospital addressed this Just as important as the factors that enhance mineraliza­ problem. As kinetic criteria in making the diagnosis of tion of bone matrix are the inhibitors of mineralization osteomalacia, these investigators use a mean osteoid that have been identified in bone. Both pyrophosphates seam width of greater than 15.0/ym and a mineralization and ATP are known to impede different phases of mineral lag time of greater than 100 days. They stressed that the formation and deposition, and removing these inhibitors early effects of hypovitaminosis D are mainly those of by endogenous pyrophosphatases (phosphatases) and secondary . As vitamin D deficient ATPases encourages mineralization. In hypophosphata- osteopathy progresses, the mineralization defect becomes sia, a condition with a deficiency of alkaline phosphatase more apparent, with a progressive accumulation of osteoid. and an increase in the inhibitor phosphoethanolamine, mineralization inhibitors may play an important role in is a common problem in patients the development of rickets and osteomalacia. with chronic liver disease. Patients with chronic biliary tract obstruction are more likely to have osteomalacia Much current investigation is centered on the role of and patients with chronic diffuse hepatocellular disease matrix vesicles in mineralization of cartilage and bone are more likely to have . I mportant etiologic matrix. These structures are detected by ultrastructural factors are defective vitamin D and 25 hydroxyvitamin D examination at mineralizing sites in cartilage and bone. absorption, impaired synthesis of 25 hydroxyvitamin D, They consist of membrane-bound concentrations of the deleterious effects of chronic alcoholism on the skel-

215 Frame

eton, hypoproteinemia, and other ill-defined nutritional further evidenceof a tumor-induced alteration of vitamin deficiencies. In view of this, the findings of Recker and D metabolism which may cause a urinary phosphate associates (pp. 227 ff.) in patients with primary biliary and leak. The tumor-producing agent that interferes with alcoholic cirrhosis were somewhat surprising. They found renal 1-hydroxylation of 25 hydroxyvitamin D has so far no evidence of vitamin D deficiency or osteomalacia, eluded identification. and bone histologic changes in both groups of patients were indistinguishable from those patients with post­ Identifiable causes of osteomalacia continue to increase. menopausal osteoporosis. Notsurprisingly,foreign ions deposited at the mineral­ ization front can interfere with normal mineralization. Much work still needs to be done to determine the Ott and associates (pp. 237 ff.) presented evidence that pathogenesis of the bone disease in patients with chronic the etiology ofthe metabolic bone disease observed in liver disorders. The type, degree, and duration of liver patients receiving total parenteral nutrition (TPN) is disease needs to be correlated with defects in mineral somewhat similar to the resistant form of osteomalacia and vitamin D metabolism as well as with histomorpho­ observed in some patients with renal osteodystrophy metric changes in the skeleton. The results of Recker and who have been maintained on hemodialysis. In both associates are discouraging with respect to the possibility conditions, aluminum from exogenoussources appears of effective treatment in patients with metabolic bone to interfere with normal mineral deposition. Removal disease due to chronic liver failure, no matter what the of the aluminum after the use of desferrioxamine underlying etiology. allows normal matrix mineralization to be restored. In bone disease associated with total parenteral nutrition, Many believe that sporadic hypophosphatemic osteo­ aluminum contamination ofthe casein used in the TPN malacia in the adult is almost always related toan under­ solution may be the culprit. Steps should be taken to lying tumor, usually mesenchymal. Such tumors may be insure that TPN solutions do not contain aluminum or quite small and difficult to detect, but the effort to find other potentially toxic trace elements that can impair the m is worthwhile, since successful removal often normal mineralization. If this approach is effective, improves or cures the underlying osteomalacia. Renal perhaps the painful disabling bone disease seen in phosphate wastage and hypophosphatemia appear to these patients will no longer be observed. However, it cause osteomalacia in such patients. should be remembered that not all workers have had a Studies reported by Drezner and associates (pp. 242 ff.) similar experience with regard to aluminum as an etio­ shed further light on this paraneoplastic syndrome of logic agent in TPN bone disease. This bone disorder tumor-induced osteomalacia. Their studies suggested may have more than one cause.

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