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ENDOCRINOLOGY BOARD REVIEW MANUAL

Endorsed by the Association for HospitalMedical Education

The Association for Hospital Medical Educationendorses HOSPITAL PHYSICIAN for the pur-pose of presenting the latest developments inmedical education as they affect residency pro-grams and clinical hospital practice.

Endocrinology Volume 2, Part 3 1

PUBLISHING STAFFPRESIDENT, PUBLISHER

Bruce M.White

EXECUTIVE EDITORDebra Dreger

ASSOCIATE EDITORDaryl A. Kovalich

ASSISTANT EDITORLaurie Garrison

SPECIAL PROGRAMS DIRECTORBarbara T.White, MBA

PRODUCTION DIRECTORSuzanne S. Banish

PRODUCTION ASSOCIATESTish Berchtold Klus

Christie Grams

PRODUCTION ASSISTANTMary Beth Cunney

ADVERTISING/PROJECT MANAGERPatricia Payne Castle

Table of Contents

Copyright 2000, Turner White Communications, Inc., 125 Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. 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 WhiteCommunications, Inc., will not be liable for any errors of omission or inaccuracies in this publication. Opinions expressed are those of theauthors and do not necessarily reflect those of Turner White Communications, Inc.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Review of Normal Bone and Vitamin DMetabolism . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Etiology and Pathophysiology of Osteomalacia . . . . . . . . . . . . . . . . . . . . . . . 4

Diagnosis of Osteomalacia . . . . . . . . . . . . . . . 6

Treatment of Osteomalacia. . . . . . . . . . . . . . 10

Suggested Readings . . . . . . . . . . . . . . . . . . . 11

Cover Illustration by Andrew Grivas, MA, CMI

NOTE FROM THE PUBLISHER:This publication has been developed with-out involvement of or review by theAmerican Board of Internal Medicine.

OsteomalaciaSeries Editor: Bart L. Clarke, MD, FACPAssistant Professor of MedicineMayo Medical SchoolSenior Associate ConsultantMayo ClinicRochester, MN

Contributing Author: Stephen F. Hodgson, MD, FACP, MACEProfessor of MedicineMayo Medical SchoolConsultantMayo ClinicRochester, MN

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INTRODUCTION

Osteomalacia is a disorder of adult lamellar bonecaused by the abnormal mineralization of bone matrix.Osteomalacia is not a specific disease but is the skele-tal manifestation of several systemic and genetic disor-ders. Rickets is a similar disorder of growing bone,which is characterized by the abnormal mineralizationof matrix. Like osteomalacia in adults, rickets involvesnewly formed trabecular and cortical bone. Unlikeosteomalacia, rickets occurs in children and also in-volves the growth plates.

Osteomalacia often remains asymptomatic for monthsto years. The signs and symptoms of osteomalacia do notbecome clinically manifest until completion of multiplebone remodeling cycles, each several months in duration.

Clinical osteomalacia, therefore, takes months to years toevolve. The initial clinical presentation often is dominat-ed by the underlying disorder, and the diagnosis fre-quently remains unrecognized for a prolonged period oftime. A diagnosis of osteomalacia can be confirmed onlyby bone biopsy using undecalcified bone histomorphom-etry after double tetracycline labeling, although inadvanced cases the diagnosis can be made on clinicalgrounds.

The accurate diagnosis and treatment of osteoma-lacic bone disease are highly dependent on an aware-ness of the conditions that lead to abnormal mineral-ization and a thorough understanding of bone andmineral homeostasis. Thus, this review focuses on nor-mal bone metabolism as well as the pathogenesis of themost commonly encountered forms of acquired osteo-malacia.

ENDOCRINOLOGY BOARD REVIEW MANUAL

Osteomalacia

Series Editor: Bart L. Clarke, MD, FACPAssistant Professor of Medicine

Mayo Medical SchoolSenior Associate Consultant

Mayo ClinicRochester, MN

Contributing Author: Stephen F. Hodgson, MD, FACP, MACE

Professor of MedicineMayo Medical School

ConsultantMayo Clinic

Rochester, MN

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REVIEW OF NORMAL BONE AND VITAMIN DMETABOLISM

NORMAL BONE REMODELING

All structural changes in adult skeletal tissue occurthrough the process of bone remodeling, a coordinated,sequential system of bone cell activity that underlies theskeletal renewal and repair of adult lamellar bone.Normal bone remodeling involves a sequence of eventsthat initially removes old mineralized bone and replacesit with new bone matrix protein that mineralizes severaldays following its deposition. The biochemical basis ofbone mineralization is poorly understood. However, it isknown that appropriate extracellular concentrations ofcalcium and phosphorous are required at local siteswhere bone mineralization is occurring.

Resorptive Phase

Bone remodeling is carried out by the coordinatedactivity of teams of bone cells (ie, bone remodelingunits) at discrete sites throughout the skeleton. Boneresorbing osteoclasts initiate cellular activity at each site.These large, multinucleated cells simultaneously resorbthe organic and mineralized components of bone over10 to 30 days, leaving excavations (ie, resorption lacu-nae) that are of roughly uniform area and volume.During the latter part of the resorptive phase, the ex-posed lacunar surface becomes populated with a layer ofcontiguous mononuclear osteoblasts that synthesizetype I procollagen, a helical, triple-stranded structurethat is unique to type I collagen. Osteoblasts secrete pro-collagen into the resorption lacunae where it undergoesproteolytic cleavage to form tropocollagen, the basicstructural unit of type I collagen. The resulting collagenfibers line the resorption lacunae and form a layer, orseam, of unmineralized osteoid that accumulates andthickens at a rate of approximately 0.7 µm/day.

Mineralization Phase

Over several days, intermolecular crosslinking be-tween tropocollagen units forms hydroxypyridiniumcrosslinks and results in a staggered array of tropocolla-gen molecules whose ends are separated by “gaps” ofabout 400 Å. After further biochemical maturation,which requires additional crosslinking over the suc-ceeding 14 to 21 days, the deepest and oldest layer ofthe osteoid bone mineralization front becomes con-ducive to the deposition of calcium phosphate crystalswithin the intermolecular gaps in the collagen fibers.

Under normal conditions, the secretion of collagen byosteoblasts and the subsequent maturation of collagenresult in the formation of a layer of mineralized colla-gen that is less than 12 µm in mean thickness.

A slower, more comprehensive secondary mineral-ization of the collagen bundles occurs over the next6 months. In 30 to 90 days, bone formation normallyfills the resorption lacunae, after which osteoblasts be-come inactive and form a loose surface layer of cover-ing cells and collagen (ie, the lamina limitans). Theadvancing layer of mineralizing osteoid thus reachesthe surface layers of osteoid, completing the localprocess of bone remodeling (Figure 1). Under normalsteady state conditions, the amount of bone removed bybone resorption is completely replaced by bone forma-tion and net bone volume remains constant.

During the process of mineral deposition, foreignmolecules such as tetracycline or aluminum may becomeentrapped by chelation along the advancing mineraliza-tion front. When tetracycline is entrapped, its fluorescentproperty permits the microscopic localization and char-acterization of the mineralization process (Figure 1).Tetracycline does not inhibit mineral deposition, andmultiple intermittent exposures can be used to assess therate at which mineralization, and by inference bone for-mation, occurs. If disease or exposure to toxic substancesinterferes with mineralization, however, entrapment oftetracycline will not occur. In contrast to tetracycline, alu-minum and other substances that are toxic to bone alsoare deposited within the mineralization front and causeprimary mineralization to cease while matrix depositionproceeds.

Summary

The remodeling process serves several biologic func-tions and manifests in the following ways:

1. Bone mineral is released into the bloodstreamto buffer variations in plasma concentrationsof calcium and phosphorus.

2. Bone collagen is degraded, resulting in theproduction and excretion of several degrada-tion products (eg, crosslinks, N-telopeptide).

3. Osteoclasts and osteoblasts release enzymesand noncollagenous proteins whose concen-trations reflect bone cell activity (eg, acid phos-phatase by osteoclasts, osteocalcin, and alka-line phosphatase [ALP] by osteoblasts).

4. The skeletal architecture is changed due to thefocal remodeling of bone tissue.

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VITAMIN D NUTRITION AND METABOLISM

Vitamin D is a secosteroid synthesized by the skinthrough exposure to ultraviolet light. In the skin,7-dehydrocholesterol, the precursor of cholesterol,absorbs solar radiation (energies of 290 to 315 nm) toform provitamin D3, which is transformed spontaneous-ly to vitamin D3 (cholecalciferol). The ability to photo-synthesize vitamin D declines with age and is dependentupon the availability of solar radiation. At northern lati-tudes, vitamin D3 cannot be photosynthesized duringwinter months and nutritional requirements must bederived from stored vitamin D and from dietary sourcesof vitamin D3 or vitamin D2 (ergocalciferol). Vitamin D2

and vitamin D3 are biologically indistinguishable and arefound sparingly in nature. Vitamin D2 is found in someplants and in yeast; nutritional sources of vitamin D3 arelimited to fatty fish and fish oils. Foods that have beenfortified (eg, milk, cereals, bread products) are a majornutritional source of vitamin D in the United States andCanada. Adult nutritional requirements for vitamin D inthe 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 smallintestine and requires normal biliary function and bile saltformation. Vitamin D enters the circulation, is bound tovitamin D–binding protein, and can circulate or be storedin fat or the liver. Thus, biliary disease, cholestatic liver dis-ease, and small bowel disease can lead to vitamin D andother fat-soluble vitamin malabsorption and deficiency.

Vitamin D is a precursor molecule that has no bio-logic activity. It requires hydroxylation—first in theliver at the 25 position, and then at the 1 position inthe kidney—to become the biologically active metabo-lite 1,25-dihydroxyvitamin D [1,25(OH)2D]. The mostimportant function of 1,25(OH)2D is to help maintainnormal serum calcium concentrations. 1,25(OH)2Daccomplishes this by increasing intestinal calciumabsorption. 1,25(OH)2D has no direct role in bonemineralization but aids the process by maintainingappropriate local concentrations of calcium and phos-phorous.

Vitamin D is transported to the liver where theenzyme vitamin D-25-hydroxylase stimulates hydroxyla-tion at the 25 position, producing 25-hydroxyvitamin D[25(OH)D]. This reaction is imprecisely regulated, andconcentrations of 25(OH)D, the most prevalent circu-lating metabolite, reflect the relative nutritional abun-dance of the vitamin. The biologic activity of 25(OH)Dis very low in physiologic concentrations, although highconcentrations of this metabolite can be achieved afteringestion of excessive doses of vitamin D and are re-

sponsible for vitamin D toxicity. Thus, measurement of25(OH)D is clinically relevant in all suspected abnor-malities of vitamin D metabolism.

Hydroxylation of 25(OH)D at the 1 position pre-dominately occurs in the kidney, but the enzyme re-sponsible for this reaction, 1α-hydroxylase, is expressedin other tissues including the skin and placenta. Renalproduction of 1,25(OH)2D is the most importantsource, however, because anephric individuals are un-able to generate concentrations of the metabolite suf-ficient to support calcium homeostasis. 25(OH)D 1α-hydroxylase is regulated by several mechanisms but mostdirectly in response to changes in intracellular phos-phorous concentrations. Thus, low phosphate con-centrations stimulate 1α-hydroxylation and increasedconcentrations inhibit 1α-hydroxylation. Parathyroidhormone (PTH) indirectly stimulates 1α-hydroxylaseactivity by decreasing intracellular phosphate levelsthrough its renal phosphate wasting function. In addi-tion, 1,25(OH)2D regulates its own production througha strong negative feedback mechanism. Thus, undernormal physiologic conditions, a reciprocal relationshipexists between serum phosphorous levels and circulat-ing concentrations of 1,25(OH)2D.

Other factors such as hormones (eg, prolactin,growth hormone) renal failure, and age also influencethe regulation of 1,25(OH)2D. Circulating concentra-tions of the metabolite do not correlate closely with clin-ical disease. Therefore, measurement of 1,25(OH)2Doften is of limited diagnostic usefulness. (The case of vitamin D–dependent osteomalacia described onpage 6, however, is a notable exception.)

ETIOLOGY AND PATHOPHYSIOLOGY OFOSTEOMALACIA

ETIOLOGY

Although many specific congenital and acquired dis-orders are associated with the development of osteo-malacia, most cases encountered in clinical practice canbe attributed to 2 fundamental underlying conditions:1) abnormalities of vitamin D nutrition, metabolism, orresponsiveness; and 2) sustained hypophosphatemia.Less common causes of osteomalacia include an inhibi-tion of bone mineral deposition by specific substancesthat are toxic to bone. Rare forms of osteomalacia alsoexist for which the etiology is multifactorial or un-known. A detailed differential diagnosis of osteomalaciaand rickets is found in Table 1.

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PATHOPHYSIOLOGY

Under conditions that interfere with normal bonemineralization, bone resorption and formation continuebut mineralization stops. Because osteoclasts cannotresorb unmineralized tissue, bone remodeling is initiat-ed only at mineralized sites, resulting in the progressivereplacement of mineralized bone by unmineralizedbone. Thus, the amount of skeletal surface that is avail-able to the forces of mineral homeostasis is vastly re-duced. Osteoid seams become abnormally thickened(> 12.5 µm), and the mineralization lag time (ie, the timeit takes for new collagen to become mineralized) exceeds100 days. Ultimately, defective mineralization produces askeleton of poor structural quality that responds poorlyto the requirements of mineral homeostasis, characteris-tics that underlie the clinical, biochemical, and radio-graphic manifestations of osteomalacia and rickets.

When vitamin D insufficiency impairs intestinal calci-um absorption, PTH levels increase to supernormal lev-els to maintain normal serum calcium levels, and sec-ondary hyperparathyroidism results. Osteoclasts begin toaggressively invade mineralized surfaces and to tunnel

under unmineralized osteoid seams. After severalremodeling cycles, mineralized bone becomes progres-sively covered by unmineralized osteoid and therefore isinaccessible to the forces of mineral homeostasis. Theskeleton becomes an inefficient reservoir for maintainingserum calcium levels, resulting in an eventual decrease inserum calcium concentration. Additional manifestationsof secondary hyperparathyroidism may eventuallybecome evident and include hypophosphatemia (with orwithout magnesium deficiency), reduced urinary calci-um excretion, accelerated bone turnover with increasingserum ALP levels, and osteitis fibrosa cystica. The remain-ing skeletal tissue progressively demineralizes, becomesweak, distorts under a mechanical load, and may frac-ture. Advanced vitamin D–dependent osteomalacia maymanifest as various clinical signs and symptoms, includ-ing bone pain and muscle weakness (causing an antalgic,waddling gait), neuromuscular irritability (manifesting astetany, seizures, or choreoathetoid movement), osteo-penia, radiologic blurring of trabecular patterns (causinga radiographic “ground glass” appearance), and pseudo-fractures.

Endocrinology Volume 2, Part 3 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)2D, 1α-hydroxylase)

Vitamin D–resistant rickets type II (abnormal intracellular binding of 1,25(OH)2D)

Drug induced

Phenytoin

Phenobarbital

1,25(OH)2D = 1,25-dihydroxyvitamin D.

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)

O s t e o m a l a c i a

Hypophosphatemic osteomalacia usually is causedby a phosphate transport defect and its associated renalphosphate leak, or by phosphate malabsorption due tothe ingestion of phosphate binding antacids. Unlike vitamin D–deficient osteomalacia, calcium absorptionand serum calcium levels are consistently normal, andhyperparathyroidism usually is not present. Clinicalsigns and symptoms, therefore, generally reflect fea-tures of mechanical failure, including bone pain, sym-metric bowing of weight-bearing bones, and fracturingdue to poor bone quality. Hyperparathyroidism is not afactor in hypophosphatemic forms of osteomalacia;therefore, osteopenia is not prominent and bone den-sity usually is normal.

DIAGNOSIS OF OSTEOMALACIA

PATIENT 1: VITAMIN D–DEPENDENT OSTEOMALACIAInitial Presentation

A 58-year-old woman is referred to a specialist inmetabolic bone disease for evaluation of an underly-ing cause of a chronic incomplete fracture of the leftfemur.

History

The patient has experienced progressive, often poor-ly localized musculoskeletal pain for at least 8 years, dur-ing which she was diagnosed as having various con-ditions, including arthritis, connective tissue disease, apsychiatric disorder, and chronic pain syndrome. Herpain has been variable over this time period, with someimprovement during the summer months. Althoughpresent when lying down or sitting, the patient’s general-ized musculoskeletal pain is aggravated by weight bear-ing to the extent that ambulation is severely impaired.Muscle cramps also have been a problem over this 8-yearperiod. The patient recalls a particular incident of severehand cramping that occurred during an episode of in-tense crying.

Approximately 4 years ago, the patient developed afracture of the inferior aspect of the right femoral neckthat failed to heal with conservative therapy. A bonemineral density measurement revealed a T score of–3.7 standard deviations below the sex-matched youngadult mean at the lumbar spine. A decalcified bonebiopsy at that time suggested the presence of an in-flammatory process, and the patient subsequentlyunderwent antibiotic therapy and open surgical fixa-tion and stabilization of the right femoral neck frac-

ture. Four months ago, the patient developed an iden-tical lesion of the left femur that was again resistant toconservative therapy and resulted in the current refer-ral to a specialist in metabolic bone disorders.

The patient’s medical history includes extreme andlong-standing obesity for which she underwent an in-testinal bypass procedure approximately 16 years ago.This procedure resulted in a 100 lb weight loss, approx-imately 35 lb of which she has regained over the years.A diagnosis of vitamin B12 deficiency was made 3 yearsafter intestinal surgery, requiring the subsequent use ofmonthly vitamin B12 injections. There is no family his-tory of symptoms or signs of metabolic bone disease.The patient takes no medications that affect skeletal tis-sue (eg, glucocorticoids, anticonvulsants, antacids, hep-arin) and does not use mineral or vitamin supplements.Aside from her musculoskeletal complaints, the patientconsiders herself to be in good health.

Physical Examination

The patient is 65" tall and weighs 194 lb. Blood pres-sure is 134/80 mm Hg, and pulse is 74 bpm. The pa-tient has a waddling gait and has difficulty rising from asitting to a standing position. An antecubital ecchymo-sis is evident. The patient experiences significant dis-comfort when moving about the examination table.Proximal muscle weakness is evident. An abdominalsurgical scar is present. The liver is not enlarged. Theexamination 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, 3500 × 103/mm3 (normal, 3500 to

10,500 × 103/mm3)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)2D, 47 pg/mL (normal, 15 to 60 pg/mL)Bone-specific ALP, 520 U/L (normal, 24 to

146 U/L)

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Protein electrophoresis reveals mild hypoalbumine-mia but otherwise is normal. No abnormalities are notedon electrolyte assay, urinalysis, or electrocardiography.Chest radiography reveals several thoracic compressiondeformities and evidence of previous rib fractures.

Bone Biopsy

Percutaneous transiliac bone biopsy after double tetra-cycline labeling reveals a marked increase in the extent oftrabecular surfaces covered by unmineralized osteoid andan increased thickness of osteoid seams (Figure 2). Theabsence of clear linear fluorescent labels confirms thepresence of a mineralization defect. Prolonged mineral-ization lag time confirms osteomalacia.

• What clinical evidence supports a diagnosis of osteo-malacia?

A clinical diagnosis of osteomalacia should be sus-pected from the patient’s history and physical examina-tion findings. Her history of intestinal bypass surgeryfollowed by massive weight loss and the absence of sub-sequent vitamin replacement therapy suggest a settingin which fat malabsorption is likely. Malabsorption anddeficiency of fat-soluble vitamins A, D, E, and K also maybe expected. This diagnosis is supported by the pres-ence of an ecchymosis at the site of minor trauma,which suggests vitamin K deficiency, and perhaps by theimprovement in her symptoms during the summermonths, when cutaneous production of vitamin D ismaximal.

The patient’s pain pattern, muscle weakness, andwaddling gait are highly characteristic of osteomalaciaand reflect true bone pain. (True bone pain is poorlylocalized, proximal in location, and made worse withweight bearing, in contrast to the focal and stereotypi-cal pain of arthritis. If a patient points with a finger to afocus of pain that “always hurts,” the pain is not likely tobe due to metabolic bone disease.) This patient’s prox-imal muscle weakness likely results from a combinationof reduced mobility and hypophosphatemia.

Several laboratory findings in this patient supportthe diagnosis of osteomalacia. Hypocalcemia in thepresence of hypophosphatemia, several-fold increasedconcentrations of bone-specific ALP, reduced calciumexcretion, and secondary hyperparathyroidism are vir-tually diagnostic of osteomalacia due to vitamin D defi-ciency. A low concentration of 25(OH)D confirms anutritional deficiency of vitamin D. The concentrationof 1,25(OH)2D is within the normal physiologic rangebut is inappropriately low in the presence of hypophos-phatemia and marked elevations of PTH.

Finally, the patient’s chest radiograph indicates thepresence of osteopenia and compression fractures, whichare clear manifestations of skeletal structural weaknessand compromise. The double-labeled bone biopsy con-firms the diagnosis of osteomalacia.

PATIENT 2: HYPOPHOSPHATEMIC OSTEOMALACIAInitial Presentation

A 71-year-old woman is referred to the departmentof endocrinology for evaluation of suspected metabolicbone disease.

History

The patient developed proximal muscle weaknessand pelvic girdle pain with ambulation approximately8 months prior to her referral. Her symptoms beganinsidiously and progressed steadily. The patient wasthought to have an underlying malignancy but hadexperienced no other symptoms. Computed tomogra-phy scans of the abdomen and pelvis were negative, buta bone scan of the entire skeleton revealed multiplefocal areas of uptake that were thought to representmetastatic disease. A subsequent search for a primarymalignancy, including upper and lower gastrointestinalstudies and mammography, failed to reveal any neo-plasms. The patient was referred for a diagnostic biopsyof 1 of the lesions. However, preliminary review of thechanges noted in her initial bone scan was inconclusivefor malignancy, and the patient was referred to thedepartment of endocrinology for further evaluation.

Physical Examination

The patient is significantly overweight, with a height of 66" and weight of 198 lb. Blood pressure is130/90 mm Hg, and pulse is 78 bpm. Upon examina-tion, the patient appears comfortable at rest but expe-riences significant pain with change of position. Shehas a waddling gait. Proximal muscle (pelvic and shoul-der girdle) weakness is evident. There is slight asym-metry of the wrists but no palpable abnormality or evi-dence of functional impairment of the hands or wrists.Multiple small lipomas are noted over the trunk andupper proximal extremities. The neurologic examina-tion 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)

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A B

A B

A B

Figure 1. Microscopic appearance of normal bone. (A) Toluidin blue–stained section showing mineralized trabecular bone surround-ed by osteoid (OS) of normal thickness. (B) Fluorescence microscopy after double tetracycline labeling (TL) showing normal tetracy-cline labels.

Figure 2. Microscopic appearance of bone affected by vitamin D–dependent osteomalacia. (A) Toluidin blue–stained section showingsurfaces 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 label-ing revealing the absence of well-resolved fluorescent labels, indicating the presence of a mineralization defect and confirming the diag-nosis of osteomalacia.

Figure 3. Microscopic appearance of bone affected by hypophosphatemia-associated osteomalacia. (A) Osteoid (OS) seams areextensive and thickened. Aggressive osteoclastic resorption and marrow fibrosis are conspicuously absent. (B) No tetracyclinelabels are present.

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24-Hour urinary phosphorous, 12,000 mg (normal,< 11,000 mg)

Whole-molecule PTH, 5.0 pmol/mL (normal, 1.0 to5.2 pmol/L)

25(OH)D, 22 ng/mL (normal, 14 to 42 ng/mL)1,25(OH)2D, 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, thyroid-stimulating 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 axialskeleton suggests diffuse osteopenia and reveals com-pression fractures of several vertebrae and fractures of arib and the right inferior pubic ramus. No areas suspi-cious for metastatic disease are apparent. Review of thepreviously obtained bone scan reveals multiple areas ofuptake that correlate with the fractures noted on thenew radiographs as well as degenerative changes andfoci of uptake in the left scapula, ribs, and sacrum.

Bone Biopsy

A bone biopsy after double tetracycline labeling revealsincreased osteoid surfaces, increased osteoid seam thick-ness, and absence of well-defined tetracycline labels(Figure 3). Evidence of secondary hyperparathyroidism isconspicuously absent, and the total amount of bone (tra-becular bone volume) is normal.

• What clinical evidence supports a diagnosis of osteo-malacia?

This patient’s history of slowly developing bone painand weakness combined with the physical findings ofproximal weakness and characteristic gait are consistentwith the presence of metabolic bone disease. Hypophos-phatemia in this clinical setting always is significant andshould arouse suspicion of osteomalacia. The presenceof fractures, bony deformities, or both are frequent find-ings in osteomalacia, but bone density tends to be nor-mal in hypophosphatemic osteomalacia. Although abone scan often is unnecessary for diagnostic purposesand may often be misleading, in this case it is not incon-sistent with the diagnosis of osteomalacia.

Bone biopsy after tetracycline labeling reveals anincrease in bone surfaces covered by osteoid, an increasein the relative volume of unmineralized bone, and amarked increase in the thickness of osteoid seams. Theabsence of well-defined fluorescent labels on bone biop-

sy confirms the presence of a mineralization defect.There is no evidence of hyperparathyroidism, and theamount of bone present is not reduced. These histolog-ic features differentiate hypophosphatemic osteomalaciafrom vitamin D–dependent forms of osteomalacia.

The biochemical findings in this case are characteris-tic of hypophosphatemic osteomalacia. They includehypophosphatemia, renal phosphate wasting, normalconcentrations of 25(OH)D, very high concentrations ofbone-specific ALP, and normal concentrations of calci-um and PTH. The low concentration of 1,25(OH)2D inthe presence of normal levels of 25(OH)D, however, isnot typical of hypophosphatemic forms of osteomalacia.Rather, it is highly characteristic, if not pathognomonic,of a specific hypophosphatemic disorder called tumor-induced osteomalacia or oncogenic osteomalacia. This unusualform of hypophosphatemic osteomalacia occurs in asso-ciation with small mesenchymal tumors, and successfulremoval of the tumors results in the rapid resolution ofall biochemical and physical evidence of the disease.There is strong evidence that the disease is caused byphosphatonin, a humoral product that is secreted fromthe tumors. Phosphatonin appears to have multiple ef-fects on proximal renal tubule function, including caus-ing alterations in phosphate transport, inhibition of 1α-hydroxylase activity, and secretion of amino acids in theurine. The tumors often are small, may develop any-where in the body, and frequently are difficult to localize.

• What radiographic and laboratory findings are sug-gestive of advanced osteomalacia?

In mild, early cases of osteomalacia, skeletal radio-graphs may be normal or reveal a spectrum of reducedbone mass (ie, osteopenia or osteoporosis). In advancedcases, skeletal radiography may reveal the presence ofbilateral symmetrical lucent fracture defects (ie, pseudo-fractures) in characteristic locations near circumflex ornutrient arteries (Figure 4). These pseudofractures arelate developments that are virtually pathognomonic ofadvanced osteomalacia of any cause. An additional find-ing 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 anunderlying vitamin D deficiency. However, in practicethese radiographic signs are seen infrequently.

Prominent laboratory findings of hyperparathy-roidism include an increased 24-hour urinary calciumexcretion (normal, 20 to 275 mg) and an increased (by

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2- to 10-fold) whole-molecule concentration of PTH.Phosphaturia relative to the serum phosphorous con-centration and, therefore, the filtered phosphorousload invariably is present. Elevated concentrations of bio-chemical markers of bone turnover (eg, bone-specificALP) 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 D2

daily for 1 month and weekly thereafter. She is advisedto take 1500 mg/day of elemental calcium and todrink 1 quart of skim milk daily, which contains about1 g of calcium and an equal amount of phosphorus.Maintenance doses of vitamin D are determined byperiodic measurements of serum concentrations of25(OH)D.

• What are the treatment options for patients with vitamin D–dependent osteomalacia?

The underlying metabolic defects that cause othertypes of osteomalacia are varied, and therapeutic programs must be tailored to the specific disorder.Therapeutic strategies for patients with abnormalities

of vitamin D nutrition or metabolism have 2 goals:1) correction of the underlying disease, and 2) correc-tion of the intrinsic deficiencies and abnormalities ofcalcium-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 to2000 mg/day) may be given indefinitely. If the under-lying disease is reversible, vitamin D2 (8000 to50,000 IU/day) should be administered initially. Aftercalcium homeostasis has been restored, as indicated bynormalization of PTH and of serum concentrations ofminerals and 25(OH)D, the dose of vitamin D2 shouldbe reduced to 400 to 2000 IU/day.

Restoration of normal calcium homeostasis may re-quire several months. If normal gastrointestinal as-similation of vitamin D cannot be restored, vitamin D2

in peanut oil (50,000 IU/month) can be given intra-muscularly. The dose should be titrated against normalserum concentrations of 25(OH)D. The more polarcompounds 25(OH)D (30 µg/day) and 1,25(OH)2D(0.25 to 0.5 µg/day) may be useful in patients with fatmalabsorption. Solar or ultraviolet light exposure alsomay be of supplemental benefit in patients who areunable to assimilate orally administered vitamin D.

PATIENT 2: HYPOPHOSPHATEMIC OSTEOMALACIA

The patient is diagnosed with hypophosphatemicosteomalacia on the basis of a history of slowly progres-sive pain characteristic of true bone pain; the presenceof hypophosphatemia, a normal 25(OH)D level, and avery low 1,25(OH)2D level; and findings of a minerali-zation defect on bone biopsy. Wrist asymmetry noted onphysical examination leads to the decision to use mag-netic resonance imaging, which identifies a tumor inthe flexor tendon sheath of the patient’s wrist. Removalof the lesion, a sclerosing hemangioma, results in com-plete resolution of the patient’s osteomalacia.

• What are the treatment options for patients withhypophosphatemic osteomalacia?

Therapy for sustained and persisting hypophos-phatemia requires phosphate replacement in divideddoses of 1 to 4 g/day. Complications of phosphate thera-py include the induction of hypocalcemia with resultantsecondary hyperparathyroidism. Diarrhea is a frequentearly side effect that may require reduced doses initially.Vitamin D metabolites also are employed to increasephosphate absorption and to suppress secondary hyper-parathyroidism by increasing calcium absorption. Severalmetabolites have been used with success, but 1,25(OH)2D

10 Hospital Physician Board Review Manual

Figure 4. Radiograph of the proximal fibula showing pseudo-fracture near the fibular artery.

O s t e o m a l a c i a

(calcitriol) generally is used in North America. Doses de-pend on the underlying cause of osteomalacia and thepatient’s response to treatment.

In patients with persistent tumor-induced osteoma-lacia, in whom other metabolites do not appear to healthe bone disease, calcitriol (0.25 to 1.5 µg/day) andphosphorus (1 to 4 g/day) may be sufficient to nor-malize the biochemical abnormalities and effect partialhealing of the mineralization defect. Hypercalciuria,hypercalcemia, nephrocalcinosis, and nephrolithiasisare potential complications.

SUGGESTED READINGS

Cai Q, Hodgson SF, Kao PC, et al: Brief report: inhibition ofrenal phosphate transport by a tumor product in a patient withoncogenic osteomalacia. N Engl J Med 1994;330:1645–1649.

Clarke BL, Wynne AG, Wilson DM, Fitzpatrick LA: Osteo-malacia associated with adult Fanconi’s syndrome: clinical anddiagnostic fractures. Clin Endocrinol (Oxf) 1995;43:479–490.

Econs MJ, McEnery PT: Autosomal dominant hypophos-phatemic rickets/osteomalacia: clinical characterization of anovel renal phosphate-wasting disorder. J Clin Endocrinol Metab1997;82:674–681.

Hodgson SF, Hurley DL: Acquired hypophosphatemia.Endocrinol Metab Clin North Am 1993;22:397–409.

Holick MF: Vitamin D: photobiology, metabolism, mecha-nisms of action, and clinical applications. In Primer on theMetabolic Bone Diseases and Disorders of Mineral Metabolism, 4thed. Favus MJ, ed. Philadelphia: Lippincott Williams & Wilkins;1999:92–98.

Parfitt AM: Osteomalacia and related disorders. In MetabolicBone Disease and Clinically Related Disorders. Avioli LV, Krane SM,eds. Philadelphia: WB Saunders; 1990:326–369.

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