Hyperparathyroidism

Hyperparathyroidism (HPT) is a systemic endocrine disorder of calcium metabolism characterized by excessive parathyroid hormone (PTH) secretion, which drives accelerated osteoclastic bone resorption and can produce a spectrum of osseous changes in the jaws.[1][2] Elevated PTH upregulates RANKL-mediated osteoclast activation, leading to generalized bone demineralization, subperiosteal resorption, and, in advanced disease, focal reparative giant-cell lesions known as brown tumors—collectively termed osteitis fibrosa cystica (OFC).[1][2] Jaw alterations may be the first clinical sign of undiagnosed HPT and can range from subtle loss of lamina dura and widened periodontal ligament spaces to expansile lytic lesions.[3][4] Management is directed at the underlying parathyroid disease; jaw lesions characteristically regress after normalization of PTH.[5][6]

• Primary hyperparathyroidism (PHPT): Autonomous PTH overproduction, most often from a solitary parathyroid adenoma (~80%) or multigland hyperplasia (15–20%); rarely parathyroid carcinoma.[1][7]
• Secondary hyperparathyroidism (SHPT): Compensatory PTH elevation driven by chronic kidney disease (CKD), vitamin D deficiency, or malabsorption.[8]
• Tertiary hyperparathyroidism: Autonomous parathyroid hyperfunction persisting after correction of the secondary stimulus, typically post–renal transplant.[8]
• Osteitis fibrosa cystica (OFC): The pathognomonic skeletal manifestation of advanced HPT, encompassing subperiosteal resorption, brown tumors, and bone cysts.[1][9]
• Brown tumor (osteoclastoma): A focal, non-neoplastic, reparative giant-cell lesion of bone arising from sustained PTH-driven osteoclastic activity; the term reflects the gross brown color from hemosiderin deposition.[2][10]
• Renal osteodystrophy: Skeletal manifestations of CKD-mineral and bone disorder, including osteitis fibrosa, adynamic bone disease, and mixed patterns.[11]

The WHO Classification of Head and Neck Tumours distinguishes the ossifying fibromas of hyperparathyroidism–jaw tumor (HPT-JT) syndrome from brown tumors and other fibro-osseous lesions.[12]

PHPT is the third most common endocrine disorder, affecting approximately 1% of adults, with peak prevalence (~2%) in postmenopausal women.[7][13] In regions with routine biochemical screening, most PHPT is discovered in an asymptomatic state; in areas without screening, symptomatic disease—including jaw manifestations—predominates.[1][3]

Clinically overt skeletal disease (OFC) now occurs in fewer than 5% of PHPT patients in Western countries.[9] Brown tumors develop in up to 3% of PHPT and 1.5–1.7% of SHPT patients.[2] In a systematic review of 245 patients with oral HPT manifestations, the mean age was 34 years, with a female-to-male ratio of 1.7:1.[14] Bony pathology occurred most often in the mandible (41%), followed by both jaws (30%) and the maxilla alone (29%).[14] A separate systematic review of 167 oral brown tumors confirmed the mandible as the most frequent oral location.[15]

Systemic presentation

The classic mnemonic "stones, bones, groans, and psychic moans" captures the multisystem effects of HPT: nephrolithiasis, skeletal pain and fractures, gastrointestinal complaints, and neurocognitive symptoms.[1] Most contemporary PHPT patients are asymptomatic at diagnosis.[1]

Oral and maxillofacial presentation

• Facial swelling and asymmetry are the most common presenting complaints in patients with jaw involvement, reported in approximately 78% of cases in a systematic review.[14]
• Oral pain is present in a minority of cases.[14]
• Brown tumors present as firm, slow-growing, bony-hard or occasionally fluctuant swellings of the alveolar ridge, palate, or body of the mandible; the overlying mucosa is typically intact but may appear brownish or violaceous.[15][16]
• Tooth mobility and malocclusion may develop secondary to alveolar bone loss or displacement by expanding lesions.[3][17]
• Neuropathy (e.g., inferior alveolar nerve paresthesia) is occasionally reported.[14][18]
• Leontiasis ossea—severe, symmetric facial bone expansion—is a rare, disfiguring manifestation of advanced SHPT.[3][11]

Red flags

A giant-cell lesion of the jaw in a young patient, multifocal jaw radiolucencies, or a jaw lesion accompanied by hypercalcemia should prompt immediate serum calcium and PTH evaluation to exclude HPT.[9][19]

The radiographic manifestations of HPT in the jaws encompass both generalized metabolic bone changes and focal lesions. Findings range from subtle alterations detectable only on careful inspection to dramatic expansile masses.

Generalized bone changes

• Loss of lamina dura: Resorption of the thin cortical plate lining the tooth sockets is a characteristic early finding, reflecting subperiosteal resorption at the alveolar level. Although classically described as pathognomonic, one systematic review found it was only the third most common radiographic presentation.[2][4][14]
• Widened periodontal ligament (PDL) space: Generalized widening of the PDL space around teeth correlates with serum PTH levels and may precede frank lamina dura loss.[4][17]
• Altered trabecular pattern: The normal fine trabecular architecture becomes coarsened or assumes a diffuse ground-glass appearance as secondary trabeculae are resorbed and primary (weight-bearing) trabeculae are accentuated. In advanced SHPT with renal osteodystrophy, a diffuse, ill-defined ground-glass pattern may involve both jaws symmetrically.[11][20]
• Cortical thinning of the mandible: Reduced cortical width at the inferior mandibular border is measurable on panoramic radiographs; the Parathyroid Mandibular Index and Klemetti Index are significantly worse in PHPT patients and correlate with systemic osteoporosis.[21][22]
• Soft-tissue and vascular calcifications: Metastatic calcifications may occasionally be visible on panoramic radiographs in patients with SHPT.[22]

Brown tumors (focal lesions)

• Brown tumors in the jaws most commonly involve the mandible, particularly the posterior body and ramus; the maxilla is the next most frequent site.[14][15]
• Lesions may be solitary or multifocal; when a brown tumor is detected in the maxilla or when multiple oral lesions are present, additional maxillofacial brown tumors should be suspected.[15]

• Brown tumors appear as well-defined radiolucent lesions with a narrow zone of transition to normal bone.[2]
• Margins are typically well corticated with sclerotic borders, though cortication may be incomplete in rapidly growing lesions.[2]
• Shape is round to ovoid; larger lesions may appear multilocular or "soap-bubble" in configuration.[2][23]

• The internal pattern is predominantly radiolucent (lytic), reflecting replacement of bone by vascularized fibrous tissue and giant cells.[2]
• Occasional internal septa create a multilocular or compartmentalized appearance.[2][23]
• There is no internal mineralization (no calcification or tooth-like structures), which helps distinguish brown tumors from odontogenic tumors with calcified components.

• Tooth displacement is common with larger lesions.[3]
• Root resorption may occur but is not a dominant feature.[23]
• Inferior alveolar canal displacement or encasement can be seen with mandibular lesions.[18]

• Cortical thinning and expansion are characteristic; the buccal and lingual cortices may be markedly thinned but typically remain intact without frank perforation.[2]
• Cortical breakthrough, when present, is better depicted on cross-sectional imaging, which also clarifies the three-dimensional extent of the lesion and its relationship to adjacent vital structures such as the inferior alveolar nerve, maxillary sinus, and nasal cavity.[24][25]

• Brown tumors enlarge by expansile remodeling rather than infiltrative destruction; there is no periosteal reaction.[2]

Osteitis fibrosa / renal osteodystrophy pattern

In advanced SHPT, a distinct pattern of diffuse, ill-defined, ground-glass radiopacity may replace normal jaw architecture bilaterally, sometimes with generalized jaw expansion.[11] This pattern differs from the focal, well-defined lytic appearance of brown tumors and may coexist with them.[11]

Tc-99m sestamibi scintigraphy (SPECT/CT)

Parathyroid scintigraphy with Tc-99m sestamibi is a standard preoperative localization modality for parathyroid adenomas; SPECT/CT achieves sensitivity approaching 90–97% for single-gland disease.[26][27] Brown tumors themselves demonstrate intense focal radiotracer uptake on bone scintigraphy, which can help distinguish them from myeloma lesions (which show minimal uptake).[2][28]

Ultrasound

Cervical ultrasonography is recommended as a first-line modality for parathyroid localization and concurrent thyroid assessment.[29] Sensitivity for lateralizing adenomas ranges from 76% to 87% depending on operator experience.[26][29]

MRI

MRI is not routinely required for jaw brown tumors but is valuable when lesions extend into critical compartments. Brown tumors show heterogeneous signal on T1- and T2-weighted sequences; areas of low T2 signal correspond to hemosiderin from prior hemorrhage, and cystic components are T2-hyperintense.[2] Fluid-fluid levels may be present.[2]

4D-CT and PET/CT

Four-dimensional CT and choline-based PET/CT are emerging modalities for parathyroid localization, particularly in cases with discordant or nonlocalizing conventional imaging.[30]

Brown tumors and the generalized osseous changes of HPT overlap radiographically with several entities. Serum calcium and PTH measurement is the single most important discriminator and should be obtained whenever a giant-cell lesion of the jaw is diagnosed histologically.[9][19]

The highest-risk diagnostic pitfall is misdiagnosing a brown tumor as a primary bone neoplasm or metastasis, leading to unnecessary radical surgery. Serum calcium and PTH should be measured before biopsy or surgical intervention for any giant-cell lesion of the jaw.[9][19]

Microscopic features of brown tumor

• Multinucleated osteoclast-like giant cells dispersed within a cellular fibrovascular stroma of mononuclear spindle-shaped cells.[2][10]
• Hemosiderin deposits from prior hemorrhage impart the characteristic brown color grossly.[2]
• Extravasated red blood cells and areas of hemorrhage are common.[32]
• Reactive woven bone or osteoid may be present at the periphery.[10]
• No cytologic atypia or mitotic activity beyond that expected in a reparative process.[32]

Radiologic-pathologic correlation

The well-defined radiolucent appearance corresponds to the replacement of normal bone by the giant-cell–rich fibrovascular tissue. Multilocular radiographic patterns reflect fibrous septa within the lesion. After treatment, progressive sclerosis on imaging corresponds to re-mineralization and new bone formation within the lesion bed.[5][6]

Key differential: central giant cell granuloma

Brown tumor and central giant cell granuloma (CGCG) are histologically indistinguishable; both show multinucleated giant cells in a mononuclear stromal background.[19][31] The distinction is made clinically and biochemically: brown tumor occurs in the setting of elevated PTH, whereas CGCG arises in normocalcemic patients. Recent identification of KRAS, FGFR1, and TRPV4 mutations in CGCG—absent in brown tumors—provides a molecular discriminator when needed.[31] Hotspot KRAS mutations have also been identified in some brown tumors of CKD, suggesting a more complex molecular landscape.[10]

Osteitis fibrosa / renal osteodystrophy

Histologically, osteitis fibrosa shows peritrabecular fibrosis, increased osteoclastic resorption, and woven bone formation without the focal giant-cell aggregation of brown tumors.[11]

Laboratory workup

Any jaw lesion yielding a histologic diagnosis of giant-cell granuloma or giant-cell lesion should prompt measurement of serum calcium, phosphorus, PTH, alkaline phosphatase, and renal function.[9][19] Elevated calcium with elevated or inappropriately normal PTH confirms PHPT; low calcium with elevated PTH and impaired renal function indicates SHPT.[8]

Parathyroid localization and definitive treatment

• Parathyroidectomy is the definitive treatment for PHPT and is indicated in symptomatic patients and asymptomatic patients meeting guideline criteria (age ≤50, serum calcium >1 mg/dL above normal, osteoporosis, nephrolithiasis, or reduced renal function).[8][29]
• Preoperative localization with ultrasound and Tc-99m sestamibi SPECT/CT guides minimally invasive parathyroidectomy.[26][29]
• For SHPT, management targets the underlying cause (vitamin D supplementation, phosphate binders, calcimimetics, dialysis optimization); parathyroidectomy is reserved for refractory cases.[8][11]

Management of jaw brown tumors

• Conservative management after parathyroidectomy is the preferred approach. Brown tumors characteristically undergo spontaneous re-mineralization and regression once PTH normalizes.[2][5][6]
• Bone regeneration at the tumor site occurs on average within 7 months after parathyroid surgery.[5]
• Surgical intervention (curettage, osteoplasty) on the jaw lesion is reserved for lesions causing significant functional impairment, facial deformity, failure to regress after PTH normalization, or patient preference for rapid resolution.[5][6]
• Corticosteroids have occasionally been used to reduce tumor size.[6]

Prognosis and surveillance

• Prognosis is excellent when the underlying HPT is corrected; brown tumors are non-neoplastic and do not recur once PTH is normalized.[2][5]
• Persistent or recurrent jaw lesions after parathyroidectomy should raise concern for incomplete parathyroid surgery, multigland disease, or parathyroid carcinoma.[9]
• Follow-up imaging demonstrates progressive sclerosis and eventual complete or near-complete ossification of the lesion bed.[16][34]
• Dental implant rehabilitation at former brown tumor sites has been reported after complete mineralization.[16]