ENDOCRINOLOGY BOARD REVIEW MANUAL. Osteomalacia

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1 ENDOCRINOLOGY BOARD REVIEW MANUAL PUBLISHING STAFF PRESIDENT, PUBLISHER Bruce M.White EXECUTIVE EDITOR Debra Dreger ASSOCIATE EDITOR Daryl A. Kovalich ASSISTANT EDITOR Laurie Garrison SPECIAL PROGRAMS DIRECTOR Barbara T.White, MBA PRODUCTION DIRECTOR Suzanne S. Banish PRODUCTION ASSOCIATES Tish Berchtold Klus Christie Grams PRODUCTION ASSISTANT Mary Beth Cunney ADVERTISING/PROJECT MANAGER Patricia Payne Castle NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Internal Medicine. Endorsed by the Association for Hospital Medical Education The Association for Hospital Medical Education endorses HOSPITAL PHYSICIAN for the purpose of presenting the latest developments in medical education as they affect residency programs and clinical hospital practice. Osteomalacia Series Editor: Bart L. Clarke, MD, FACP Assistant Professor of Medicine Mayo Medical School Senior Associate Consultant Mayo Clinic Rochester, MN Contributing Author: Stephen F. Hodgson, MD, FACP, MACE Professor of Medicine Mayo Medical School Consultant Mayo Clinic Rochester, MN Table of Contents Introduction Review of Normal Bone and Vitamin D Metabolism Etiology and Pathophysiology of Osteomalacia Diagnosis of Osteomalacia Treatment of Osteomalacia Suggested Readings Cover Illustration by Andrew Grivas, MA, CMI Copyright 2000, Turner White Communications, Inc., 125 Strafford Avenue, Suite 220, Wayne, PA , All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications, Inc. The editors are solely responsible for selecting content. Although the editors take great care to ensure accuracy, Turner White Communications, Inc., will not be liable for any errors of omission or inaccuracies in this publication. Opinions expressed are those of the authors and do not necessarily reflect those of Turner White Communications, Inc. Endocrinology Volume 2, Part 3 1

2 ENDOCRINOLOGY BOARD REVIEW MANUAL Osteomalacia Series Editor: Bart L. Clarke, MD, FACP Assistant Professor of Medicine Mayo Medical School Senior Associate Consultant Mayo Clinic Rochester, MN Contributing Author: Stephen F. Hodgson, MD, FACP, MACE Professor of Medicine Mayo Medical School Consultant Mayo Clinic Rochester, MN INTRODUCTION Osteomalacia is a disorder of adult lamellar bone caused by the abnormal mineralization of bone matrix. Osteomalacia is not a specific disease but is the skeletal manifestation of several systemic and genetic disorders. Rickets is a similar disorder of growing bone, which is characterized by the abnormal mineralization of matrix. Like osteomalacia in adults, rickets involves newly formed trabecular and cortical bone. Unlike osteomalacia, rickets occurs in children and also involves the growth plates. Osteomalacia often remains asymptomatic for months to years. The signs and symptoms of osteomalacia do not become clinically manifest until completion of multiple bone remodeling cycles, each several months in duration. Clinical osteomalacia, therefore, takes months to years to evolve. The initial clinical presentation often is dominated by the underlying disorder, and the diagnosis frequently remains unrecognized for a prolonged period of time. A diagnosis of osteomalacia can be confirmed only by bone biopsy using undecalcified bone histomorphometry after double tetracycline labeling, although in advanced cases the diagnosis can be made on clinical grounds. The accurate diagnosis and treatment of osteomalacic bone disease are highly dependent on an awareness of the conditions that lead to abnormal mineralization and a thorough understanding of bone and mineral homeostasis. Thus, this review focuses on normal bone metabolism as well as the pathogenesis of the most commonly encountered forms of acquired osteomalacia. 2 Hospital Physician Board Review Manual

3 REVIEW OF NORMAL BONE AND VITAMIN D METABOLISM NORMAL BONE REMODELING All structural changes in adult skeletal tissue occur through the process of bone remodeling, a coordinated, sequential system of bone cell activity that underlies the skeletal renewal and repair of adult lamellar bone. Normal bone remodeling involves a sequence of events that initially removes old mineralized bone and replaces it with new bone matrix protein that mineralizes several days following its deposition. The biochemical basis of bone mineralization is poorly understood. However, it is known that appropriate extracellular concentrations of calcium and phosphorous are required at local sites where bone mineralization is occurring. Resorptive Phase Bone remodeling is carried out by the coordinated activity of teams of bone cells (ie, bone remodeling units) at discrete sites throughout the skeleton. Bone resorbing osteoclasts initiate cellular activity at each site. These large, multinucleated cells simultaneously resorb the organic and mineralized components of bone over 10 to 30 days, leaving excavations (ie, resorption lacunae) that are of roughly uniform area and volume. During the latter part of the resorptive phase, the exposed lacunar surface becomes populated with a layer of contiguous mononuclear osteoblasts that synthesize type I procollagen, a helical, triple-stranded structure that is unique to type I collagen. Osteoblasts secrete procollagen into the resorption lacunae where it undergoes proteolytic cleavage to form tropocollagen, the basic structural unit of type I collagen. The resulting collagen fibers line the resorption lacunae and form a layer, or seam, of unmineralized osteoid that accumulates and thickens at a rate of approximately 0.7 µm/day. Mineralization Phase Over several days, intermolecular crosslinking between tropocollagen units forms hydroxypyridinium crosslinks and results in a staggered array of tropocollagen molecules whose ends are separated by gaps of about 400 Å. After further biochemical maturation, which requires additional crosslinking over the succeeding 14 to 21 days, the deepest and oldest layer of the osteoid bone mineralization front becomes conducive to the deposition of calcium phosphate crystals within the intermolecular gaps in the collagen fibers. Under normal conditions, the secretion of collagen by osteoblasts and the subsequent maturation of collagen result in the formation of a layer of mineralized collagen that is less than 12 µm in mean thickness. A slower, more comprehensive secondary mineralization of the collagen bundles occurs over the next 6 months. In 30 to 90 days, bone formation normally fills the resorption lacunae, after which osteoblasts become inactive and form a loose surface layer of covering cells and collagen (ie, the lamina limitans). The advancing layer of mineralizing osteoid thus reaches the surface layers of osteoid, completing the local process of bone remodeling (Figure 1). Under normal steady state conditions, the amount of bone removed by bone resorption is completely replaced by bone formation and net bone volume remains constant. During the process of mineral deposition, foreign molecules such as tetracycline or aluminum may become entrapped by chelation along the advancing mineralization front. When tetracycline is entrapped, its fluorescent property permits the microscopic localization and characterization of the mineralization process (Figure 1). Tetracycline does not inhibit mineral deposition, and multiple intermittent exposures can be used to assess the rate at which mineralization, and by inference bone formation, occurs. If disease or exposure to toxic substances interferes with mineralization, however, entrapment of tetracycline will not occur. In contrast to tetracycline, aluminum and other substances that are toxic to bone also are deposited within the mineralization front and cause primary mineralization to cease while matrix deposition proceeds. Summary The remodeling process serves several biologic functions and manifests in the following ways: 1. Bone mineral is released into the bloodstream to buffer variations in plasma concentrations of calcium and phosphorus. 2. Bone collagen is degraded, resulting in the production and excretion of several degradation products (eg, crosslinks, N-telopeptide). 3. Osteoclasts and osteoblasts release enzymes and noncollagenous proteins whose concentrations reflect bone cell activity (eg, acid phosphatase by osteoclasts, osteocalcin, and alkaline phosphatase [ALP] by osteoblasts). 4. The skeletal architecture is changed due to the focal remodeling of bone tissue. Endocrinology Volume 2, Part 3 3

4 VITAMIN D NUTRITION AND METABOLISM Vitamin D is a secosteroid synthesized by the skin through exposure to ultraviolet light. In the skin, 7-dehydrocholesterol, the precursor of cholesterol, absorbs solar radiation (energies of 290 to 315 nm) to form provitamin D 3, which is transformed spontaneously to vitamin D 3 (cholecalciferol). The ability to photosynthesize vitamin D declines with age and is dependent upon the availability of solar radiation. At northern latitudes, vitamin D 3 cannot be photosynthesized during winter months and nutritional requirements must be derived from stored vitamin D and from dietary sources of vitamin D 3 or vitamin D 2 (ergocalciferol). Vitamin D 2 and vitamin D 3 are biologically indistinguishable and are found sparingly in nature. Vitamin D 2 is found in some plants and in yeast; nutritional sources of vitamin D 3 are limited to fatty fish and fish oils. Foods that have been fortified (eg, milk, cereals, bread products) are a major nutritional source of vitamin D in the United States and Canada. Adult nutritional requirements for vitamin D in the absence of sunlight are 400 IU/day until age 71, after which 600 IU/day are required. Absorption of vitamin D occurs in the upper small intestine and requires normal biliary function and bile salt formation. Vitamin D enters the circulation, is bound to vitamin D binding protein, and can circulate or be stored in fat or the liver. Thus, biliary disease, cholestatic liver disease, and small bowel disease can lead to vitamin D and other fat-soluble vitamin malabsorption and deficiency. Vitamin D is a precursor molecule that has no biologic activity. It requires hydroxylation first in the liver at the 25 position, and then at the 1 position in the kidney to become the biologically active metabolite 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. The most important function of 1,25(OH) 2 D is to help maintain normal serum calcium concentrations. 1,25(OH) 2 D accomplishes this by increasing intestinal calcium absorption. 1,25(OH) 2 D has no direct role in bone mineralization but aids the process by maintaining appropriate local concentrations of calcium and phosphorous. Vitamin D is transported to the liver where the enzyme vitamin D-25-hydroxylase stimulates hydroxylation at the 25 position, producing 25-hydroxyvitamin D [25(OH)D]. This reaction is imprecisely regulated, and concentrations of 25(OH)D, the most prevalent circulating metabolite, reflect the relative nutritional abundance of the vitamin. The biologic activity of 25(OH)D is very low in physiologic concentrations, although high concentrations of this metabolite can be achieved after ingestion of excessive doses of vitamin D and are responsible for vitamin D toxicity. Thus, measurement of 25(OH)D is clinically relevant in all suspected abnormalities of vitamin D metabolism. Hydroxylation of 25(OH)D at the 1 position predominately occurs in the kidney, but the enzyme responsible for this reaction, 1α-hydroxylase, is expressed in other tissues including the skin and placenta. Renal production of 1,25(OH) 2 D is the most important source, however, because anephric individuals are unable to generate concentrations of the metabolite sufficient to support calcium homeostasis. 25(OH)D 1αhydroxylase is regulated by several mechanisms but most directly in response to changes in intracellular phosphorous concentrations. Thus, low phosphate concentrations stimulate 1α-hydroxylation and increased concentrations inhibit 1α-hydroxylation. Parathyroid hormone (PTH) indirectly stimulates 1α-hydroxylase activity by decreasing intracellular phosphate levels through its renal phosphate wasting function. In addition, 1,25(OH) 2 D regulates its own production through a strong negative feedback mechanism. Thus, under normal physiologic conditions, a reciprocal relationship exists between serum phosphorous levels and circulating concentrations of 1,25(OH) 2 D. Other factors such as hormones (eg, prolactin, growth hormone) renal failure, and age also influence the regulation of 1,25(OH) 2 D. Circulating concentrations of the metabolite do not correlate closely with clinical disease. Therefore, measurement of 1,25(OH) 2 D often is of limited diagnostic usefulness. (The case of vitamin D dependent osteomalacia described on page 6, however, is a notable exception.) ETIOLOGY AND PATHOPHYSIOLOGY OF OSTEOMALACIA ETIOLOGY Although many specific congenital and acquired disorders are associated with the development of osteomalacia, most cases encountered in clinical practice can be attributed to 2 fundamental underlying conditions: 1) abnormalities of vitamin D nutrition, metabolism, or responsiveness; and 2) sustained hypophosphatemia. Less common causes of osteomalacia include an inhibition of bone mineral deposition by specific substances that are toxic to bone. Rare forms of osteomalacia also exist for which the etiology is multifactorial or unknown. A detailed differential diagnosis of osteomalacia and rickets is found in Table 1. 4 Hospital Physician Board Review Manual

5 Table 1. Differential Diagnosis of Osteomalacia and Rickets Abnormalities of vitamin D nutrition, metabolism, or responsiveness Nutritional insufficiency Dietary deficiency Intestinal malabsorption Celiac disease Whipple s disease Short gut syndrome Pancreatic insufficiency Hepatobiliary (cholestatic) disease Abnormal metabolism Hereditary Vitamin D resistant rickets type I (defect in 1,25(OH) 2 D, 1α-hydroxylase) Vitamin D resistant rickets type II (abnormal intracellular binding of 1,25(OH) 2 D) Drug induced Phenytoin Phenobarbital Sustained hypophosphatemia Overuse of phosphate binders (antacids, aluminum hydroxide) Acquired renal tubular disorders Tumor-induced osteomalacia Light chain dysproteinemia Drug induced (lead, cadmium) Hereditary renal tubular disorders Hypophosphatemic vitamin D resistant rickets (X-linked inborn error of phosphate transport) Fanconi s syndrome Drug induced, toxic Aluminum (renal failure) Fluoride Bisphosphonates (eg, high-dose etidronate) Anticonvulsants Multiple mechanisms Renal osteodystrophy Other causes Axial osteomalacia (rare) 1,25(OH) 2 D = 1,25-dihydroxyvitamin D. PATHOPHYSIOLOGY Under conditions that interfere with normal bone mineralization, bone resorption and formation continue but mineralization stops. Because osteoclasts cannot resorb unmineralized tissue, bone remodeling is initiated only at mineralized sites, resulting in the progressive replacement of mineralized bone by unmineralized bone. Thus, the amount of skeletal surface that is available to the forces of mineral homeostasis is vastly reduced. Osteoid seams become abnormally thickened (> 12.5 µm), and the mineralization lag time (ie, the time it takes for new collagen to become mineralized) exceeds 100 days. Ultimately, defective mineralization produces a skeleton of poor structural quality that responds poorly to the requirements of mineral homeostasis, characteristics that underlie the clinical, biochemical, and radiographic manifestations of osteomalacia and rickets. When vitamin D insufficiency impairs intestinal calcium absorption, PTH levels increase to supernormal levels to maintain normal serum calcium levels, and secondary hyperparathyroidism results. Osteoclasts begin to aggressively invade mineralized surfaces and to tunnel under unmineralized osteoid seams. After several remodeling cycles, mineralized bone becomes progressively covered by unmineralized osteoid and therefore is inaccessible to the forces of mineral homeostasis. The skeleton becomes an inefficient reservoir for maintaining serum calcium levels, resulting in an eventual decrease in serum calcium concentration. Additional manifestations of secondary hyperparathyroidism may eventually become evident and include hypophosphatemia (with or without magnesium deficiency), reduced urinary calcium excretion, accelerated bone turnover with increasing serum ALP levels, and osteitis fibrosa cystica. The remaining skeletal tissue progressively demineralizes, becomes weak, distorts under a mechanical load, and may fracture. Advanced vitamin D dependent osteomalacia may manifest as various clinical signs and symptoms, including bone pain and muscle weakness (causing an antalgic, waddling gait), neuromuscular irritability (manifesting as tetany, seizures, or choreoathetoid movement), osteopenia, radiologic blurring of trabecular patterns (causing a radiographic ground glass appearance), and pseudofractures. Endocrinology Volume 2, Part 3 5

6 Hypophosphatemic osteomalacia usually is caused by a phosphate transport defect and its associated renal phosphate leak, or by phosphate malabsorption due to the ingestion of phosphate binding antacids. Unlike vitamin D deficient osteomalacia, calcium absorption and serum calcium levels are consistently normal, and hyperparathyroidism usually is not present. Clinical signs and symptoms, therefore, generally reflect features of mechanical failure, including bone pain, symmetric bowing of weight-bearing bones, and fracturing due to poor bone quality. Hyperparathyroidism is not a factor in hypophosphatemic forms of osteomalacia; therefore, osteopenia is not prominent and bone density usually is normal. DIAGNOSIS OF OSTEOMALACIA PATIENT 1: VITAMIN D DEPENDENT OSTEOMALACIA Initial Presentation A 58-year-old woman is referred to a specialist in metabolic bone disease for evaluation of an underlying cause of a chronic incomplete fracture of the left femur. History The patient has experienced progressive, often poorly localized musculoskeletal pain for at least 8 years, during which she was diagnosed as having various conditions, including arthritis, connective tissue disease, a psychiatric disorder, and chronic pain syndrome. Her pain has been variable over this time period, with some improvement during the summer months. Although present when lying down or sitting, the patient s generalized musculoskeletal pain is aggravated by weight bearing to the extent that ambulation is severely impaired. Muscle cramps also have been a problem over this 8-year period. The patient recalls a particular incident of severe hand cramping that occurred during an episode of intense crying. Approximately 4 years ago, the patient developed a fracture of the inferior aspect of the right femoral neck that failed to heal with conservative therapy. A bone mineral density measurement revealed a T score of 3.7 standard deviations below the sex-matched young adult mean at the lumbar spine. A decalcified bone biopsy at that time suggested the presence of an inflammatory process, and the patient subsequently underwent antibiotic therapy and open surgical fixation and stabilization of the right femoral neck fracture. Four months ago, the patient developed an identical lesion of the left femur that was again resistant to conservative therapy and resulted in the current referral to a specialist in metabolic bone disorders. The patient s medical history includes extreme and long-standing obesity for which she underwent an intestinal bypass procedure approximately 16 years ago. This procedure resulted in a 100 lb weight loss, approximately 35 lb of which she has regained over the years. A diagnosis of vitamin B 12 deficiency was made 3 years after intestinal surgery, requiring the subsequent use of monthly vitamin B 12 injections. There is no family history of symptoms or signs of metabolic bone disease. The patient takes no medications that affect skeletal tissue (eg, glucocorticoids, anticonvulsants, antacids, heparin) and does not use mineral or vitamin supplements. Aside from her musculoskeletal complaints, the patient considers herself to be in good health. Physical Examination The patient is 65" tall and weighs 194 lb. Blood pressure is 134/80 mm Hg, and pulse is 74 bpm. The patient has a waddling gait and has difficulty rising from a sitting to a standing position. An antecubital ecchymosis is evident. The patient experiences significant discomfort when moving about the examination table. Proximal muscle weakness is evident. An abdominal surgical scar is present. The liver is not enlarged. The examination is otherwise unremarkable. Laboratory and Radiographic Evaluation Initial laboratory studies reveal the following findings: Hemoglobin, 12.5 g/dl (normal, 12.0 to 15.5 g/dl) Leukocyte count, /mm 3 (normal, 3500 to 10, /mm 3 ) Erythrocyte sedimentation rate (ESR), 28 mm/h (normal, 0 to 20 mm/h) Serum creatinine, 0.8 mg/dl (normal, 0.6 to 0.9 mg/dl) Urinary calcium excretion, 13 mg/24 h (normal, 20 to 275 mg/24 h) Total serum calcium, 8.2 mg/dl (normal, 8.9 to 10.1 mg/dl) Serum phosphorous, 2.4 mg/dl (normal, 2.5 to 4.5 mg/dl) Whole-molecule PTH, 38 pmol/l (normal, 1.0 to 5.2 pmol/l) 25(OH)D, 4 ng/ml (normal, 14 to 42 ng/ml) 1,25(OH) 2 D, 47 pg/ml (normal, 15 to 60 pg/ml) Bone-specific ALP, 520 U/L (normal, 24 to 146 U/L) 6 Hospital Physician Board Review Manual

7 Protein electrophoresis reveals mild hypoalbuminemia but otherwise is normal. No abnormalities are noted on electrolyte assay, urinalysis, or electrocardiography. Chest radiography reveals several thoracic compression deformities and evidence of previous rib fractures. Bone Biopsy Percutaneous transiliac bone biopsy after double tetracycline labeling reveals a marked increase in the extent of trabecular surfaces covered by unmineralized osteoid and an increased thickness of osteoid seams (Figure 2). The absence of clear linear fluorescent labels confirms the presence of a mineralization defect. Prolonged mineralization lag time confirms osteomalacia. What clinical evidence supports a diagnosis of osteomalacia? A clinical diagnosis of osteomalacia should be suspected from the patient s history and physical examination findings. Her history of intestinal bypass surgery followed by massive weight loss and the absence of subsequent vitamin replacement therapy suggest a setting in which fat malabsorption is likely. Malabsorption and deficiency of fat-soluble vitamins A, D, E, and K also may be expected. This diagnosis is supported by the presence of an ecchymosis at the site of minor trauma, which suggests vitamin K deficiency, and perhaps by the improvement in her symptoms during the summer months, when cutaneous production of vitamin D is maximal. The patient s pain pattern, muscle weakness, and waddling gait are highly characteristic of osteomalacia and reflect true bone pain. (True bone pain is poorly localized, proximal in location, and made worse with weight bearing, in contrast to the focal and stereotypical pain of arthritis. If a patient points with a finger to a focus of pain that always hurts, the pain is not likely to be due to metabolic bone disease.) This patient s proximal muscle weakness likely results from a combination of reduced mobility and hypophosphatemia. Several laboratory findings in this patient support the diagnosis of osteomalacia. Hypocalcemia in the presence of hypophosphatemia, several-fold increased concentrations of bone-specific ALP, reduced calcium excretion, and secondary hyperparathyroidism are virtually diagnostic of osteomalacia due to vitamin D deficiency. A low concentration of 25(OH)D confirms a nutritional deficiency of vitamin D. The concentration of 1,25(OH) 2 D is within the normal physiologic range but is inappropriately low in the presence of hypophosphatemia and marked elevations of PTH. Finally, the patient s chest radiograph indicates the presence of osteopenia and compression fractures, which are clear manifestations of skeletal structural weakness and compromise. The double-labeled bone biopsy confirms the diagnosis of osteomalacia. PATIENT 2: HYPOPHOSPHATEMIC OSTEOMALACIA Initial Presentation A 71-year-old woman is referred to the department of endocrinology for evaluation of suspected metabolic bone disease. History The patient developed proximal muscle weakness and pelvic girdle pain with ambulation approximately 8 months prior to her referral. Her symptoms began insidiously and progressed steadily. The patient was thought to have an underlying malignancy but had experienced no other symptoms. Computed tomography scans of the abdomen and pelvis were negative, but a bone scan of the entire skeleton revealed multiple focal areas of uptake that were thought to represent metastatic disease. A subsequent search for a primary malignancy, including upper and lower gastrointestinal studies and mammography, failed to reveal any neoplasms. The patient was referred for a diagnostic biopsy of 1 of the lesions. However, preliminary review of the changes noted in her initial bone scan was inconclusive for malignancy, and the patient was referred to the department of endocrinology for further evaluation. Physical Examination The patient is significantly overweight, with a height of 66" and weight of 198 lb. Blood pressure is 130/90 mm Hg, and pulse is 78 bpm. Upon examination, the patient appears comfortable at rest but experiences significant pain with change of position. She has a waddling gait. Proximal muscle (pelvic and shoulder girdle) weakness is evident. There is slight asymmetry of the wrists but no palpable abnormality or evidence of functional impairment of the hands or wrists. Multiple small lipomas are noted over the trunk and upper proximal extremities. The neurologic examination is unremarkable. Laboratory and Radiographic Evaluation Initial laboratory studies reveal the following findings: Serum calcium (2 measurements), 9.6 and 9.3 mg/dl (normal, 8.9 to 10.1 mg/dl) Serum phosphorous, 1.5 mg/dl (normal, 2.5 to 4.5 mg/dl) Endocrinology Volume 2, Part 3 7

8 A Figure 1. Microscopic appearance of normal bone. (A) Toluidin blue stained section showing mineralized trabecular bone surrounded by osteoid (OS) of normal thickness. (B) Fluorescence microscopy after double tetracycline labeling (TL) showing normal tetracycline labels. B A B Figure 2. Microscopic appearance of bone affected by vitamin D dependent osteomalacia. (A) Toluidin blue stained section showing surfaces covered with osteoid (OS), thickened osteoid seams, aggressive osteoclastic bone resorption (OC), and marrow fibrosis (F). Marrow fibrosis strongly suggests the presence of hyperparathyroidism. (B) Fluorescence microscopy after double tetracycline labeling revealing the absence of well-resolved fluorescent labels, indicating the presence of a mineralization defect and confirming the diagnosis of osteomalacia. A B Figure 3. Microscopic appearance of bone affected by hypophosphatemia-associated osteomalacia. (A) Osteoid (OS) seams are extensive and thickened. Aggressive osteoclastic resorption and marrow fibrosis are conspicuously absent. (B) No tetracycline labels are present. 8 Hospital Physician Board Review Manual

9 24-Hour urinary phosphorous, 12,000 mg (normal, < 11,000 mg) Whole-molecule PTH, 5.0 pmol/ml (normal, 1.0 to 5.2 pmol/l) 25(OH)D, 22 ng/ml (normal, 14 to 42 ng/ml) 1,25(OH) 2 D, undetectable (normal, 15 to 60 pg/ml) Bone-specific ALP, 772 U/L (normal, 24 to 146 U/L) No abnormalities are noted on other laboratory tests (ie, electrolytes, glucose, creatinine, liver function, thyroidstimulating hormone, urinalysis, first voided urinary ph, 24-hour calcium excretion, 24-hour creatinine excretion, serum protein electrophoresis, complete blood count, ESR, lipid profile) or on electrocardiography. A radiographic survey of all long bones and the axial skeleton suggests diffuse osteopenia and reveals compression fractures of several vertebrae and fractures of a rib and the right inferior pubic ramus. No areas suspicious for metastatic disease are apparent. Review of the previously obtained bone scan reveals multiple areas of uptake that correlate with the fractures noted on the new radiographs as well as degenerative changes and foci of uptake in the left scapula, ribs, and sacrum. Bone Biopsy A bone biopsy after double tetracycline labeling reveals increased osteoid surfaces, increased osteoid seam thickness, and absence of well-defined tetracycline labels (Figure 3). Evidence of secondary hyperparathyroidism is conspicuously absent, and the total amount of bone (trabecular bone volume) is normal. What clinical evidence supports a diagnosis of osteomalacia? This patient s history of slowly developing bone pain and weakness combined with the physical findings of proximal weakness and characteristic gait are consistent with the presence of metabolic bone disease. Hypophosphatemia in this clinical setting always is significant and should arouse suspicion of osteomalacia. The presence of fractures, bony deformities, or both are frequent findings in osteomalacia, but bone density tends to be normal in hypophosphatemic osteomalacia. Although a bone scan often is unnecessary for diagnostic purposes and may often be misleading, in this case it is not inconsistent with the diagnosis of osteomalacia. Bone biopsy after tetracycline labeling reveals an increase in bone surfaces covered by osteoid, an increase in the relative volume of unmineralized bone, and a marked increase in the thickness of osteoid seams. The absence of well-defined fluorescent labels on bone biopsy confirms the presence of a mineralization defect. There is no evidence of hyperparathyroidism, and the amount of bone present is not reduced. These histologic features differentiate hypophosphatemic osteomalacia from vitamin D dependent forms of osteomalacia. The biochemical findings in this case are characteristic of hypophosphatemic osteomalacia. They include hypophosphatemia, renal phosphate wasting, normal concentrations of 25(OH)D, very high concentrations of bone-specific ALP, and normal concentrations of calcium and PTH. The low concentration of 1,25(OH) 2 D in the presence of normal levels of 25(OH)D, however, is not typical of hypophosphatemic forms of osteomalacia. Rather, it is highly characteristic, if not pathognomonic, of a specific hypophosphatemic disorder called tumorinduced osteomalacia or oncogenic osteomalacia. This unusual form of hypophosphatemic osteomalacia occurs in association with small mesenchymal tumors, and successful removal of the tumors results in the rapid resolution of all biochemical and physical evidence of the disease. There is strong evidence that the disease is caused by phosphatonin, a humoral product that is secreted from the tumors. Phosphatonin appears to have multiple effects on proximal renal tubule function, including causing alterations in phosphate transport, inhibition of 1αhydroxylase activity, and secretion of amino acids in the urine. The tumors often are small, may develop anywhere in the body, and frequently are difficult to localize. What radiographic and laboratory findings are suggestive of advanced osteomalacia? In mild, early cases of osteomalacia, skeletal radiographs may be normal or reveal a spectrum of reduced bone mass (ie, osteopenia or osteoporosis). In advanced cases, skeletal radiography may reveal the presence of bilateral symmetrical lucent fracture defects (ie, pseudofractures) in characteristic locations near circumflex or nutrient arteries (Figure 4). These pseudofractures are late developments that are virtually pathognomonic of advanced osteomalacia of any cause. An additional finding is the blurring of skeletal trabecular patterns or a ground glass appearance of the microarchitecture. Evidence of prolonged secondary hyperparathyroidism, including subperiosteal resorption, chondrocalcinosis, bone cysts, and brown tumors, strongly suggests an underlying vitamin D deficiency. However, in practice these radiographic signs are seen infrequently. Prominent laboratory findings of hyperparathyroidism include an increased 24-hour urinary calcium excretion (normal, 20 to 275 mg) and an increased (by Endocrinology Volume 2, Part 3 9

10 Figure 4. Radiograph of the proximal fibula showing pseudofracture near the fibular artery. 2- to 10-fold) whole-molecule concentration of PTH. Phosphaturia relative to the serum phosphorous concentration and, therefore, the filtered phosphorous load invariably is present. Elevated concentrations of biochemical markers of bone turnover (eg, bone-specific ALP) reflect events at the cellular level in bone. TREATMENT OF OSTEOMALACIA PATIENT 1: VITAMIN D DEPENDENT OSTEOMALACIA The patient is treated with 50,000 IU of vitamin D 2 daily for 1 month and weekly thereafter. She is advised to take 1500 mg/day of elemental calcium and to drink 1 quart of skim milk daily, which contains about 1 g of calcium and an equal amount of phosphorus. Maintenance doses of vitamin D are determined by periodic measurements of serum concentrations of 25(OH)D. What are the treatment options for patients with vitamin D dependent osteomalacia? The underlying metabolic defects that cause other types of osteomalacia are varied, and therapeutic programs must be tailored to the specific disorder. Therapeutic strategies for patients with abnormalities 10 Hospital Physician Board Review Manual of vitamin D nutrition or metabolism have 2 goals: 1) correction of the underlying disease, and 2) correction of the intrinsic deficiencies and abnormalities of calcium-phosphorous homeostasis whenever possible. All patients require initial replacement of calcium, phosphorous, and vitamin D. Replacement of calcium (1500 to 2000 mg/day) and phosphorous (1000 to 2000 mg/day) may be given indefinitely. If the underlying disease is reversible, vitamin D 2 (8000 to 50,000 IU/day) should be administered initially. After calcium homeostasis has been restored, as indicated by normalization of PTH and of serum concentrations of minerals and 25(OH)D, the dose of vitamin D 2 should be reduced to 400 to 2000 IU/day. Restoration of normal calcium homeostasis may require several months. If normal gastrointestinal assimilation of vitamin D cannot be restored, vitamin D 2 in peanut oil (50,000 IU/month) can be given intramuscularly. The dose should be titrated against normal serum concentrations of 25(OH)D. The more polar compounds 25(OH)D (30 µg/day) and 1,25(OH) 2 D (0.25 to 0.5 µg/day) may be useful in patients with fat malabsorption. Solar or ultraviolet light exposure also may be of supplemental benefit in patients who are unable to assimilate orally administered vitamin D. PATIENT 2: HYPOPHOSPHATEMIC OSTEOMALACIA The patient is diagnosed with hypophosphatemic osteomalacia on the basis of a history of slowly progressive pain characteristic of true bone pain; the presence of hypophosphatemia, a normal 25(OH)D level, and a very low 1,25(OH) 2 D level; and findings of a mineralization defect on bone biopsy. Wrist asymmetry noted on physical examination leads to the decision to use magnetic resonance imaging, which identifies a tumor in the flexor tendon sheath of the patient s wrist. Removal of the lesion, a sclerosing hemangioma, results in complete resolution of the patient s osteomalacia. What are the treatment options for patients with hypophosphatemic osteomalacia? Therapy for sustained and persisting hypophosphatemia requires phosphate replacement in divided doses of 1 to 4 g/day. Complications of phosphate therapy include the induction of hypocalcemia with resultant secondary hyperparathyroidism. Diarrhea is a frequent early side effect that may require reduced doses initially. Vitamin D metabolites also are employed to increase phosphate absorption and to suppress secondary hyperparathyroidism by increasing calcium absorption. Several metabolites have been used with success, but 1,25(OH) 2 D

11 (calcitriol) generally is used in North America. Doses depend on the underlying cause of osteomalacia and the patient s response to treatment. In patients with persistent tumor-induced osteomalacia, in whom other metabolites do not appear to heal the bone disease, calcitriol (0.25 to 1.5 µg/day) and phosphorus (1 to 4 g/day) may be sufficient to normalize the biochemical abnormalities and effect partial healing of the mineralization defect. Hypercalciuria, hypercalcemia, nephrocalcinosis, and nephrolithiasis are potential complications. SUGGESTED READINGS Cai Q, Hodgson SF, Kao PC, et al: Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia. N Engl J Med 1994;330: Clarke BL, Wynne AG, Wilson DM, Fitzpatrick LA: Osteomalacia associated with adult Fanconi s syndrome: clinical and diagnostic fractures. Clin Endocrinol (Oxf) 1995;43: Econs MJ, McEnery PT: Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab 1997;82: Hodgson SF, Hurley DL: Acquired hypophosphatemia. Endocrinol Metab Clin North Am 1993;22: Holick MF: Vitamin D: photobiology, metabolism, mechanisms of action, and clinical applications. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 4th ed. Favus MJ, ed. Philadelphia: Lippincott Williams & Wilkins; 1999: Parfitt AM: Osteomalacia and related disorders. In Metabolic Bone Disease and Clinically Related Disorders. Avioli LV, Krane SM, eds. Philadelphia: WB Saunders; 1990: Copyright 2000 by Turner White Communications Inc., Wayne, PA. All rights reserved. Endocrinology Volume 2, Part 3 11