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The Spectrum of Orofacial Manifestations in Renal Osteodystrophy: Diagnostic Challenges of an Uncommon Presentation

The Spectrum of Orofacial Manifestations in Renal Osteodystrophy: Diagnostic Challenges of an Uncommon Presentation

Quintessence International

The spectrum of orofacial manifestations in renal : Diagnostic challenges of an uncommon presentation

Mahnaz Fatahzadeh, DMD MSD1

Renal osteodystrophy refers to a spectrum of bone diseases caused by pathologic alterations in the metabolism of , phosphate, and bone in the context of end-stage renal disease and secondary . Radiographic alterations affecting the jaw and facial skeleton are common and among the earliest signs of renal . also shares clinical, histologic, and radiologic similarities with several benign fibro-osseous conditions affecting the craniofacial region, and its recognition is critical to prevention, choice of therapy, and overall prognosis. The aim of this article is to review the craniofacial manifestations of renal osteodystrophy, describe the work-up of a patient with macrognathia and facial disfigurement caused by renal bone disease, discuss the challenges in arriving at a definitive diagnosis, and highlight an interdisciplinary approach to evaluation and timely diagnosis in overall management. (Quintessence Int 2011;42:e78–e88)

Key words: end-stage renal disease, renal osteodystrophy, uremic leonthiasis ossea

Chronic renal failure refers to the progres- fibrosa, the most frequent type of osseous sive and irreversible loss of renal function, change in renal osteodystrophy, is considered often culminating in end-stage renal disease a high-turnover bone disease affecting nearly and mandating chronic hemodialysis or kid- one-third of patients with end-stage renal ney transplantation for survival.1 The poten- disease.6–9 It frequently involves long bones, tial systemic complications associated with the ribs, and pelvis; however, jaw bones may chronic renal failure include hypertension, also be affected.6,10 Histopathologic features anemia, bleeding tendencies, metastatic of fibrosa include proliferation of both calcification, secondary hyperparathyroid- and , increased bone ism, and renal bone disease, known as resorption, osteoid formation, peritrabecular renal osteodystrophy.1,2 The latter affects fibrosis, and an overall increase in the rate of 90% of patients undergoing dialysis and bone remodeling.6,7,10–12 Clinical implications refers to the spectrum of bone diseases include and bone fractures.12 caused by pathologic alterations in metabo- , or brown tumors, lism of calcium, phosphate, and bone in the represent a delayed manifestation of renal context of end-stage renal disease.3,4 osteodystrophy, characterized by local- Microscopic and pathologic features of ized, often expansile, osteolytic lesions.13–15 renal osteodystrophy are variable, dynamic Histologically, brown tumors are character- in their progression, and broadly classified ized by proliferating osteoblasts and osteo- as high and low turnover diseases.3,5 Osteitis clasts, vascularity, hemosiderin deposits, multinucleated giant cells, and reactive fibrous stroma.4,16–18 Brown tumors may be detected in osseous tissues throughout the 1Associate Professor, Division of Oral Medicine, Department body as well as in the jaw.4,15,19,20 The pre- of Diagnostic Sciences, UMDNJ–New Jersey Dental School, dilection of cortical bone for brown tumors Newark, New Jersey, USA. may explain why mandible rather than the Correspondence: Dr Mahnaz Fatahzadeh, UMDNJ–New Jersey maxilla is more the frequently affected in the Dental School, 110 Bergen St, Newark, NJ 07103. Email: fatahza@ 13,14,21 umdnj.edu maxillofacial region. When affecting

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the maxilla, brown tumors may involve the 1. Radiographic features such as loss or orbits, ethmoid, or frontal bones, causing poor definition of mandibular cortex, inferior severe facial deformity and potential fatality alveolar nerve canal, alveolar crest, palatal by airway obstruction.4,22 suture, nasal floor, and maxillary sinus walls Low-turnover renal osteodystrophy is are often helpful to assess the severity of characterized by poor production and min- bone disease.4 eralization of osseous tissues and includes Although there is no statistically signifi- and adynamic bone disease.9,16 cant relationship between the radiographic In osteomalacia, diminished numbers and alterations in renal osteodystrophy and activity of osteoblasts and osteoclasts, sub- serum levels of phosphate or parathyroid normal osteoid production, and defective hormone, radiographic features become mineralization leads to greater volumes of more prominent as duration of the dis- unmineralized osteoid.9,12 Affected patients ease or hemodialysis increases.4 Kelly et al often suffer from osseous pain and musculo- reported a significant correlation between skeletal disability and are at risk for osteope- duration of dialysis in months and appear- nia, bone deformity, and fracture.12 ance of osseous alterations, such as loss Adynamic bone disease, the second of lamina dura and normal trabeculation, on variant of low-turnover renal osteodystro- radiographic surveys.32 In an observational phy, predominantly affects patients with study, patients receiving dialysis in excess end-stage renal disease without secondary of 6 years had measurable and more signifi- hyperparathyroidism.9,11,12 Microscopically, cant osseous alterations.33 This is because it is characterized by a low number of improved longevity by chronic hemodialysis osteoblasts and osteoclasts, deficient oste- also prolongs patient exposure to parathy- oid production, and nonspecific mineral- roid hormone and increases the risk of renal ization, resulting in areas of osteodystrophy.2,4 The potential increase and .9,11,12 Differentiation of in prevalence of renal osteodystrophy with osteomalacia from adynamic bone disease improved survival may be prevented by depends on the threshold of normal vs early diagnosis; the optimal period to pre- abnormal osteoid volume.9 Adynamic bone vent potentially irreversible osseous chang- disease is classified into nonaluminum and es in chronic renal failure is thought to be aluminum-induced forms.9 The latter form within 6 months of the start of hemodialysis.33 of adynamic bone disease is more often Diagnosis of renal osteodystrophy relies associated with osseous pain, hypercalce- on a thorough medical history as well mia, and fracture.9 The source of aluminum as a radiologic, histologic, and biochemi- is often traced to dialysis fluid or aluminum cal work-up.4 In practice, however, the salts used as phosphate binders, and alter- nature or severity of osteodystrophy can ations in end-stage renal disease therapy be determined only through bone , have reduced the incidence of aluminum- which remains the gold standard.34 The induced renal disease.12 most commonly used biochemical tests in Radiographic findings of renal osteo- diagnosis and monitoring of renal osteodys- dystrophy on the skeletal survey include trophy include serum , demineralization, brown tumors, and Rugger calcium, phosphate, and total alkaline Jersey spine (which refers to osteosclerosis phosphatase.3 Patients with secondary affecting the upper and lower margins of the hyperparathyroidism often present with vertebral body).4,8,23 Subperiosteal erosion is hypocalcamia, hyperphosphatemia, and the most frequently detected change2 and elevated parathyroid hormone.13 In general, the earliest radiographic sign when affecting the levels of bone terminal phalanges.3 Radiographic altera- are significantly higher in patients with high tions affecting the jaws and facial skeleton rather than low turnover renal osteodys- are also common and among the earliest trophy.35 There is also a good correlation signs of the renal bone disease.2 The poten- among levels of intact parathyroid hormone, tial osseous and dental findings on imaging total alkaline phosphatase, and bone alka- associated with renal osteodystrophy in the line phosphatase in patients with second- craniofacial region are summarized in Table ary hyperparathyroidism, allowing the use

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Table 1 Osseous and dental manifestations of renal osteodystrophy in the craniofacial region

Osseous alterations Dental anomolies Demineralization of osseous structures4,23,24 Delayed tooth eruption24,27,28 Salt-and-pepper trabecular appearance (mixed and sclerosis)2,8 Hypoplastic enamel24,29 Diffuse and generalized ground glass pattern of trabecula2,4,6,8,16,23,25,26 Absence of lamina dura2,4,6,8,13,16,23,25 Thickening of diploic space of calvarium8 Widening of periodontal ligament24 Loss of outer table of skull 8 Dental spacing8,24 Serpiginous channeling within bone25 Tooth mobility8,24,30 Osteitis fibrosa cystica (brown tumors)2,4,13,18,20 Dental erosions24,27 Depletion of cortical bone2,4,23,25,26 Narrowing of pulp chambers4,24,26,31 Jaw fracture (traumatic or iatrogenic)24 Obliteration of pulp chambers4,24 Loss of corticomedullary distinction of bone25 Poor definition of anatomical landmarks2,4,6,26 Expansion of jaw bone4,26 Abnormal healing of extraction sockets24 Metastatic soft tissue calcifications24

of bone alkaline phosphatase isoenzyme In younger patients, leontiasis ossea may as a sensitive marker of bone remodeling also lead to an increase in the size, weight, in these patients.35,36 In addition, the histo- and thickness of the cranium.39 The skin logic markers of bone remodeling appear overlying the prominent areas of facial bone to have a linear association with levels of may also be tightly stretched.43 When symp- intact parathyroid hormone with advanced tomatic, affected patients may present with histologic features of hyperparathyroidism cranial nerve palsy caused by overgrowth manifesting at parathyroid levels above 500 of bone and narrowing of cranial fissures pg/mL.37,38 In patients with chronic renal or foramina.44 Leontiasis ossea clinically failure and secondary hyperparathyroidism, and histologically resembles a common elevated levels of total alkaline phosphatase phenomenon referred to as big head dis- in conjunction with relevant histopathologic ease observed in mammals fed diets low in findings are consistent with a high turnover calcium and high in phosphorous.41,45,46 The bone disease such as osteitis fibrosa.6,13 biopsy specimens from both humans and Although osseous alterations associated animals affected by leontiasis ossea show with renal osteodystrophy are common, histologic changes consistent with osteitis macrognathia and facial disfigurement are fibrosa, a common high-turnover variant of not frequent.6,8,16 Leontiasis ossea is a renal osteodystrophy.41,47 clinical description applied to hyperostotic This facial deformity may be caused by changes in the size and shape of facial a number of benign fibro-osseous lesions bones that causes gradual, bilateral expan- such as fibrous dysplasia, Paget disease, sion of the malar processes and reduction or renal osteodystrophy.39,41 and uremic of the nasomaxillary angle, resulting in a leontiasis ossea in patients with chronic lionlike facial appearance.39,40 Clinical fea- renal failure receiving hemodialysis has tures of leontiasis ossea include hypertro- been previously described.39,41,48 We pres- phy of the maxilla and mandible, widening ent clinical, radiographic, histologic, and of the nares, flattening of the nasal bridge, biochemical findings of a patient with ure- increased palatal size, prominence of the mic leontiasis ossea and discuss the chal- cheekbones, and interdental spacing.41,42 lenges in arriving at a definitive diagnosis.

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Fig 1 Photographs of the patient showing cranial enlargement, prominence of midface, flattening of nasal bridge, widening of nares, and bimaxillary hypertrophy.

Case report Medical history was significant for long- standing end-stage renal disease related A 40-year-old man presented with a 2-year to congenital renal hypoplasia, hyperten- history of gradual, asymptomatic craniofa- sion, , , anemia, and cial deformity. Extraoral examination was secondary hyperparathyroidism diagnosed remarkable for expansion of the malar pro- 2 years prior to presentation. He received cesses, loss of nasomaxillary angle, widen- hemodialysis three times a week (and had ing of nares, and generalized macrognathia for the previous 8 years), and his medica- (Fig 1). Intraoral examination revealed a tions included clonidine, lanthanum carbon- symmetric and smooth enlargement of both ate, , and epoetin alpha. Due to jaws, generalized interdental spacing, and a refractory response of secondary hyper- prominent buldging of the hard palate (Fig parathyroidism to medical therapy, he had 2). The expansile areas were firm and pain- undergone a parathyroidectomy with no evi- less on palpation, and no tooth mobility was dence of glandular malignancy. Review of evident. The overlying mucosa was intact systems was significant for loss of 5 inches and without paresthesia but was erythema- in height, diffuse back pain, and vertebral tous and vascular. Interincisal opening was deformity necessitating the use of a cane. normal. The patient denied speech impaire- Panoramic and occlusal radiographs ment but reported mastication difficulties revealed abnormalities in the dentition as due to palatal swelling and a sensation well as in the size, trabecular texture, and of pressure and lip incompetence when anatomical features of the jaw (Fig 3). A non- attempting to close his mouth. He was also contrast computed tomography (CT) scan concerned about his facial appearance. of the skull also revealed marked changes

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Fig 2 Intraoral photographs depicting marked macognathia, palatal bulge, interdental spacing, and lip incompetence at rest.

Fig 3 Panoramic and occlusal radio- graphs showing expansion of both jaws with nearly homogenous or ground glass trabecular pattern. Note the loss of cortical outline for the inferior alveo- lar nerve canal, poor definition of crestal bone and inferior cortex of the man- dible, generalized interdental spacing and loss of lamina dura, narrowing of pulp chambers, and apical osteoscle- rosis of the mandibular left first molar.

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a

c Fig 4 (a) Sagittal CT of the skull revealing cranial and bimaxillary expansion with diffuse, hyperostot- ic, hazy, ground glass appearance of osseous tissues and maxillary sinuses. (b) Axial CT showing bilateral tickening of the cranial vault. (c) Radionuclide whole b body bone scan revealing intense uptake in the skull, maxilla, and mandibular bones.

in the volume and texture of osseous tis- and alkaline phosphatase consistent with sues (Figs 4a and 4b). The skeletal survey secondary hyperparathyroidism and high indicated intense uptake in the skull, maxilla, bone turnover (Table 2). and mandible (Fig 4c). Magnetic resonance An incisional biopsy from the anterior imaging (MRI) of the spine without contrast mandible revealed the fibrous nature of the revealed kyphoscoliosis, loss of vertebral grossly enlarged mandible in addition to height, and brown tumors. Tentative radio- histopathologic features consistent with a graphic diagnosis included renal osteodys- benign fibro-osseous lesion (Fig 5). Based trophy, fibrous dysplasia, and Paget disease. on medical history; clinical presentation; Review of recent blood work revealed and radiographic, biochemical, and histo- low red blood cell count (4.39 × 103 cells/ logic findings, a diagnosis of osteitis fibrosa mm3; normal, 4.7 to 6.0), hemoglobin (13.1 associated with secondary hyperparathy- g/dL; normal, 13.5 to 18.0), and hematocrit roidism was made. (39%; normal, 42 to 52), indicating anemia Two and half years after the parathy- as well as elevated serum creatinine (11.9 roidectomy, leonthiasis ossea facial disfig- mg/dL; normal, 0.7 to 1.5) and urea nitro- urement remains a concern for the patient. gen (117 mg/dL; normal, 7.0 to 20.0) con- During this period, parathyroid hormone sistent with chronic renal failure. Relevant levels have progressively declined, particu- biochemical assays also revealed hyper- larly with the start of cinacalcet therapy, but phosphatemia, normal calcium, and signifi- have not yet normalized (503.3 Pg/mL). The cantly high levels of parathyroid hormone massive craniofacial deformity, persistence

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Table 2 Sequential biochemical profile of the patient

Value (7 months after PTx and on Laboratory parameters Value (prior to PTx) presentation) Value (current) Normal range Calcium 10.2 mg/dL 8.8 mg/dL 8.6 mg/dL 8.4–10.2 mg/dL Phosphorus 6.2 mg/dL 5.6 mg/dL 5.0 mg/dL 2.5–4.5 mg/dL Parathyroid hormone > 5,000 pg/mL 3,193 pg/mL 503.3 pg/mL 15–65 pg/mL Alkaline phosphatase 1,199 U/L 1,332 U/L 202 U/L 38–126 U/L

PTx, parathyroidectomy.

a b

c d Fig 5 Histopathologic photomicrograph of the biopsy specimen from the anterior mandible revealing (a) moder- ately cellular fibrous stroma with woven bone trabeculae, scattered giant cells, and areas of interstitial hemorrhage (hematoxylin-eosin, original magnification ×100); (b) irregularly shaped and variable size of nonlamellar bone trabeculae (hematoxylin-eosin, original magnification ×100); (c) woven bone trabeculae lined by a continuous rim of osteoblasts along the edges (hematoxylin-eosin, original magnification ×400); (d) a cluster of multinucleated giant cells with scattered erythrocytes within connective tissue (hematoxylin-eosin, original magnification ×400).

and slow decline of parathyroid hormone Discussion levels, and alkaline phosphatase despite medical therapy and parathyroidectomy, in Renal osteodystrophy shares similar histo- addition to an overlap of diagnostic features logic and radiographic features with Paget between potential etiologic entities, renders disease and fibrous dysplasia.6 These this case interesting. benign fibro-osseous lesions have different

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clinical presentation and biologic behaviors tifocal activity, on skeletal survey55 and the from renal osteodystrophy.16 absence of radiographic corticomedullary Fibrous dysplasia is a developmental distinction25 as well as the late manifestation bone disorder with a broad spectrum of and symmetric nature of craniofacial defor- manifestations including skeletal anoma- mity did not support a fibrous dysplasia lies, endocrinopathy, and neurologic diagnosis. symptoms.39,49,50 The majority of cases are Paget disease of bone, or osteitis defor- monostatic fibrous dysplasia, affecting a mans, is a disorder of skeletal remodeling single bone.39,49–51 Polyostotic fibrous dys- characterized by extensive bone turnover plasia involves two or more skeletal sites, and abnormal osseous repair.56–58 A recent often located unilaterally throughout the article reports a 2.5% prevalence with few body.50 It may manifest at any age but is incident cases in an area known for high frequently detected by early adulthood.51,52 concentration of the disease.59 Paget dis- Monostotic lesions tend to stabilize after ease may affect any osseous segment, puberty, but the polyostotic form often con- although certain skeletal sites such as the tinues to progress beyond skeletal matu- pelvis, vertebra, femur, , skull, humer- rity.52 Due to the asymptomatic nature of us, and ribs are preferentially affected by minor lesions, the overall incidence of the the disease.56,58–61 Depending on the sever- monostatic form is not known,49 but it is ity of disease and the number of osseous considered rare among the general popula- segments affected, Paget disease may be tion. Its etiology involves genetic mutations categorized as monstotic or polyostotic.56,58 leading to abnormalities in osteoblastic Skeletal complications such as osseous differentiation and maturation,39,52,53 giving pain, deformity, fractures, arthritic changes rise to weak woven bone trabeculae and in nearby joints, and neoplastic transfor- fibrous, undermineralized matrix contain- mation often develop with the polyostotic ing an abundance of dysplastic spindle- form of the disease.56,57 Paget disease shaped cells.39,51,52 often inflicts middle-aged or elderly adults Both forms of fibrous dysplasia may of European heritage over 55 years of affect craniofacial structures and cause age.56,58,62 gradual asymmetric enlargement of the skull Microscopic features of Paget disease and facial bones.39,49,50,54 Cranial sclerosis include the presence of highly active giant and deformity of maxillofacial structures multinucleated osteoclasts, increased num- such as the sinuses and nasal cavities are ber of both osteoblasts and , frequent, and complications include head- osteosclerosis, and abnormal canalicular aches, cranial neuropathies, and occlusal patterns.56,57,63 Etiopathogenesis of Paget discrepancy caused by nerve compres- disease may involve an environmental sion or massive bony swellings.39,50,52 The infectious agent or somatic gene muta- biochemical profile of patients with fibrous tion.56,64,65 Diagnosis of Paget disease does dysplasia is within normal limits.2,55 not require a bone biopsy but often relies A thorough review of systems failed to on radiographic features and biochemi- reveal systemic of cal testing.56 The latter is characterized by polyostotic fibrous dysplasia in our patient. normal serum calcium and elevated alkaline The homogenous ground glass appearance phosphatase levels indicative of a high rate of the osseous tissues noted on imaging in of bone remodeling.56 our patient is common to renal osteodystro- Although frequently a silent condition, phy and fibrous dysplasia and was previ- osseous deformities affecting bones of the ously reported in some leontiasis ossea skull, face, and extremities are common- patients.23,25 Features such as variable size ly appreciable.56 Thickening of the skull and shape of woven bone trabeculae noted observed in advanced Paget disease is on histology also resemble features seen in the result of excessive bone deposition immature fibrous dysplasia. Nevertheless, along the inner and outer tables of the cra- a history of chronic dialysis biochemical nial vault.39 Our patient had visible cranial markers of secondary hyperparathyroid- expansion, symmetric facial deformity, jaw ism, diffuse rather than monostotic or mul- enlargement, and osseous changes con-

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firmed by CT and radionucleotide bone in dialysis patients,8,55,66 normalization of scans. While these features are shared by parathyroid hormone levels and reduction both uremic leontiasis ossea and Paget of bone turnover with medical therapy, disease, radiographic alterations in renal parathyroidectomy, or renal transplantation osteodystrophy are diffuse compared to frequently fail to resolve craniofacial defor- monostotic or multifocal changes in Paget mities necessitating surgical intervention disease.2 Both can lead to osseous verte- to restore normal size and contour.2,14,23,67 bral changes, back pain, and elevation of Despite progressive decline in markers of markers of bone turnover, all of which were bone turnover (see Table 2), it is unlikely that present in our patient.56 Elevated levels of massive craniofacial deformity in our patient alkaline phosphatase and its normalization will fully resolve after normalization of para- after parathyroidectomy have previously thyroid hormone or renal transplantation. been reported in patients with secondary Surgical recontouring may be necessary to hyperparathyroidism.2 Our patient did not improve esthetics. This case highlights the report any neurologic complications, had need to integrate clinical, radiographic, and negative family history of Paget disease, histologic data for definitive diagnosis of and did not meet the typical age and ethnic fibro-osseous lesions affecting the craniofa- profile for the same. cial region and emphasizes the importance Renal osteodystrophy associated with of timely diagnosis in overall management. secondary hyperparathyroidism may be pre- Recognition of early bone disease by vigi- vented or improved by supplementation of lant oral health care providers familiar with calcium and vitamin D together with treatment osseous and dental manifestations of renal of hyperphosphatemia using phosphate bind- osteodystrophy may help prevent or dimin- ing agents and strict adherence to a phos- ish morbid consequences through timely phate-restricted diet.2,4,13,19 When the disease medical intervention. This is particularly is resistant to medical therapy, removal of relevant as more patients with end-stage autonomous parathyroid glands is indicated.13 renal disease sustain life with hemodialysis. In these cases, autotransplantation of para- thyroid tissue elsewhere in the body allows maintenance of a baseline parathyroid func- tion for control of bone metabolism.4 Renal Conclusion transplantation often helps restore normal bone metabolism; however, in nearly 50% of The spectrum of changes affecting the jaw recipients, persistence of hyperpara- region in renal osteodystrophy is broad, thyroidism perpetuates renal osteodystrophy, including obliteration of pulp chambers and removal of overactive glands is still nec- impacting endodontic treatment, loss of essary.4 In addition, the status of bone dis- osseous support for dentition caused by ease at the time of transplantation influences altered trabecular structure, expansion and the prognosis of renal osteodystrophy.33 In pathologic jaw fracture due to advanced our patient, nearly 3 years after removal brown tumors as well as fibro-osseous of parathyroid-producing tissue, high levels deformities affecting the craniofacial region. of parathyroid hormone have significantly Oral health care practitioners should rec- declined but not yet normalized. This obser- ognize clinical and radiographic changes vation is unusual and may be attributed to associated with secondary hyperparathy- hypersensitivity of residual glandular tissues roidism in the maxillofacial area and con- to serum calcium and phosphorus. This pos- tribute to timely intervention. tulate is likely since a decline in parathyroid hormone levels was particularly evident after treatment with cinacalcet, a pharmacologic agent reducing sensitivity of residual parathy- roid tissue to serum calcium and phosphate. In spite of occasional reports describing the resolution of uremic leontiasis ossea with medical therapy or parathyroidectomy

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