Paget's disease

Paget's disease of bone (PDB) is a chronic, nonmalignant skeletal disorder characterized by focal areas of excessive and disorganized bone remodeling.[1][2] The disease progresses through three recognized pathologic phases: an initial osteolytic (incipient-active) phase dominated by osteoclastic resorption, a mixed (active) phase in which osteoblastic repair is superimposed on resorption, and a late osteosclerotic (inactive) phase in which osteoblasts predominate.[3][4] The resulting bone is structurally disorganized, mechanically weak, and expanded.[2][4]

Pathogenesis remains incompletely understood. Genetic susceptibility is well established, with pathogenic variants in SQSTM1 (encoding p62 in the NF-κB signaling pathway) identified in 40–50% of familial cases.[5][6] A slow paramyxoviral infection in genetically susceptible individuals has been proposed but remains debated.[2][7] In the jaws, the maxilla is affected more often than the mandible, and involvement is typically part of polyostotic disease with concurrent skull changes.[8] The signature imaging pattern in the jaws is a mixed lytic-sclerotic process with cotton-wool radiopacities, bone expansion, and loss of normal trabecular architecture.[3][8] Management centers on bisphosphonate therapy, with intravenous zoledronic acid as the treatment of choice.[1][9]

The current accepted name is Paget's disease of bone (PDB). The eponymous designation honors Sir James Paget, who described the condition in 1877. The Latin synonym osteitis deformans remains in wide use and appears in many classification systems.[4] The alternative term osteodystrophia deformans is encountered in older European literature but is now largely obsolete. PDB should be distinguished from Paget's disease of the breast (an unrelated malignancy) and from juvenile Paget's disease (familial hyperphosphatasia), a rare autosomal recessive condition with a distinct pathogenesis.[8][10]

• Age: PDB is rare before age 55; prevalence approximately doubles each decade thereafter. Peak incidence of histologically proven disease falls between 70 and 80 years.[5][11]
• Sex: Males are affected more commonly than females (approximately 1.4:1).[5]
• Ethnicity: Predominantly affects individuals of European descent. The disease is common in the United Kingdom, France, Spain, Italy, and among European-descended populations in Australia, New Zealand, and North America. It is rare in Scandinavia, Asia, and the Indian subcontinent.[1][5]
• Prevalence trends: Both incidence and severity have declined in recent decades across most regions, possibly reflecting changes in environmental exposures.[1][12]
• Skeletal distribution: The pelvis, femur, lumbar spine, skull, and tibia are the most frequently affected sites. The skull is involved in an estimated 25–65% of cases. The jaws are affected in a reported 17% of cases, with the maxilla involved more often than the mandible. Isolated mandibular involvement is very rare.[1][3][8][12][13][14]

Presentation and symptoms

Most patients with PDB are asymptomatic; the disease is often discovered incidentally through an elevated serum alkaline phosphatase (ALP) or characteristic radiographic findings.[1][4] Only an estimated 5–10% of affected individuals come to medical attention.[1]

When the jaws are involved, common clinical findings include:

• Progressive alveolar enlargement: Symmetric or asymmetric expansion of the maxilla or mandible, which may cause ill-fitting dentures, spacing of teeth, or facial deformity[4][8]
• Bone pain: Deep, aching, and often worse at night; present in a minority of patients[1][4]
• Dental complications: Hypercementosis, loss of lamina dura, and dense sclerotic bone make tooth extractions difficult, with increased risk of hemorrhage and postoperative infection[8][15]
• Increased warmth: Palpable warmth over affected bone due to increased vascularity[4]

Complications and red flags

• Cranial nerve involvement: Hearing loss (most common neurologic complication) results from cochlear damage rather than direct nerve compression. Other cranial neuropathies may occur with skull base involvement.[4][8]
• Sarcomatous transformation: Rare.[1][3][4]
• Giant cell tumor: Very rare; overrepresented in patients of Italian descent carrying ZNF687 mutations.[5][16]
• Dental problems were reported by 93% of patients with maxillomandibular involvement in a national survey, compared with only 10% of those with disease at distant sites.[15]

Laboratory findings

• Isolated elevation of serum total ALP is the hallmark biochemical finding; calcium and phosphate levels are typically normal[1][7]
• Normal ALP does not exclude the diagnosis, particularly in monostotic disease[1]

The radiographic appearance of PDB in the jaws reflects the underlying pathologic phase and is often characteristic when multiple features coexist.[3][5]

Location and distribution

• The maxilla is affected more frequently than the mandible. Jaw involvement is almost always seen in the context of polyostotic disease with concurrent calvarial changes.[3][8][13][14]
• Isolated mandibular PDB is very rare; when present, it may involve the entire mandible diffusely.[14]
• Skull involvement characteristically includes progressive thickening of the diploe and base, with extension into the sphenoid, orbital, and frontal bones.[8]

Periphery and shape

• In the early lytic phase, well-defined areas of radiolucency (termed osteoporosis circumscripta in the calvarium) appear as large, geographic zones of bone loss.[3][8]
• In the mixed and sclerotic phases, margins become indistinct as sclerotic bone merges with adjacent normal bone. There is no discrete corticated border separating pagetic from unaffected bone.[3][5]

Internal architecture

• Cotton-wool pattern: The hallmark appearance in the mixed and sclerotic phases consists of irregular, patchy radiopaque masses of varying size and density scattered throughout the affected bone, producing the characteristic "cotton-wool" appearance. This pattern is most readily recognized on panoramic and skull radiographs.[3][8]
• Trabecular coarsening: Normal fine trabeculation is replaced by thickened, disorganized trabeculae.[1][5]
• Osteosclerosis: In the late blastic phase, diffuse sclerosis may predominate, with loss of distinction between cortex and medulla.[3][5]
• Loss of normal trabecular pattern: The granular or ground-glass quality seen in fibrous dysplasia is absent; instead, the internal pattern is coarser and more heterogeneous.[5]

Effects on teeth and adjacent structures

• Hypercementosis: Characteristic finding in teeth within pagetic bone; roots appear bulbous with irregular cementum deposition.[8]
• Loss of lamina dura: The periodontal ligament space may become indistinct or obliterated as pagetic bone encroaches on the tooth socket.[8]
• Tooth spacing and displacement: Progressive alveolar expansion may cause diastema formation and tilting of teeth.
• Root resorption: Occasional; less prominent than in some other expansile jaw lesions.
• Alveolar ridge widening: Generalized expansion of the alveolar process is common when the jaw is involved, visible as symmetric or asymmetric thickening on panoramic radiographs.[4][8]

Cortical involvement and extent

• Cortical thickening is a characteristic feature, often marked in the jaws and calvarium.[1][5]
• Loss of corticomedullary distinction: The boundary between cortex and medulla becomes obscured as pagetic bone replaces both compartments.[3][5]
• Bone expansion: Affected bones enlarge—a feature that distinguishes PDB from osteosclerotic metastases, which do not cause bone expansion.[17]
• In the skull, progressive thickening may lead to basilar invagination.[5]

Growth pattern

• PDB advances at an estimated rate of approximately 8 mm per year in long bones. In the jaws, the disease tends to involve the entire affected bone diffusely rather than presenting as a discrete focal mass.[4][14]
• The process is slowly progressive; radiographic changes evolve over years to decades.[4]

Recognized variants by phase

• Lytic phase: Predominant radiolucency; osteoporosis circumscripta in the calvarium[3][8]
• Mixed phase: Coexisting lytic and sclerotic areas producing the cotton-wool pattern; bone expansion and cortical thickening become apparent[3][8]
• Sclerotic (burned-out) phase: Diffuse osteosclerosis with marked bone enlargement; metabolic activity may be reduced[3][4]

Radionuclide bone scintigraphy

Tc-99m methylene diphosphonate bone scintigraphy is the most sensitive method for determining the full extent of skeletal involvement and is recommended at the time of diagnosis.[4][5] Affected sites show intense, homogeneous tracer uptake in all active phases of the disease.[5] Bone scintigraphy detects more lesions than plain radiography, although scans may be negative in burned-out sclerotic lesions.[5] The technique is valuable for identifying asymptomatic sites and for monitoring treatment response.[5][18]

Medical CT

CT is not routinely indicated for diagnosis but is useful for evaluating complications.[5] In the skull, CT demonstrates cortical thickening, trabecular coarsening, and loss of corticomedullary distinction concordant with radiographic findings.[3][5] CT can help differentiate PDB from fibrous dysplasia of the skull: symmetric cranial involvement and thick cortices favor PDB, whereas ground-glass density and involvement of the sinuses, sphenoid, orbit, and nasal cavity favor fibrous dysplasia.[5] CT is the preferred modality for assessing suspected sarcomatous transformation, which appears as focal cortical destruction with an associated soft-tissue mass.[3]

MRI

MRI is not recommended for routine diagnosis.[5] Pagetic bone most commonly shows signal intensity similar to fat on T1-weighted sequences, with a 100% negative predictive value for excluding neoplasm when fat signal is maintained.[19][20] Active disease may show high signal on T2-weighted images reflecting fibrovascular marrow replacement.[19] MRI is the modality of choice for evaluating basilar invagination, spinal stenosis, and suspected secondary neoplasm.[5][19][20]

The combination of cotton-wool radiopacities, bone expansion, cortical thickening, and loss of corticomedullary distinction in an older patient is usually diagnostic. However, individual features overlap with several conditions.

The highest-risk diagnostic pitfall is failure to recognize sarcomatous transformation within existing PDB. A sudden change in pain, rapid swelling, focal cortical destruction with a soft-tissue mass, or a sharp rise in ALP should prompt urgent cross-sectional imaging and biopsy.[1][3][25]

Microscopic findings

The histologic hallmark of PDB is the mosaic pattern (jigsaw-puzzle pattern) of cement (reversal) lines, reflecting repeated cycles of resorption and formation.[2][10][17] Key features vary by disease phase:

• Lytic phase: Numerous abnormally large, hypernucleated osteoclasts (often containing >20 nuclei) with prominent Howship lacunae; marrow fibrosis and increased vascularity[2][4]
• Mixed phase: Active osteoclastic resorption and osteoblastic formation coexist; woven bone is deposited in a disorganized pattern interspersed with lamellar bone, producing the mosaic of cement lines[2]
• Sclerotic phase: Osteoblastic activity predominates; dense, disorganized bone with prominent mosaic pattern; reduced cellularity[4]

Nuclear inclusion bodies

Pagetic osteoclasts may contain characteristic intranuclear microcylindrical inclusion bodies that resemble paramyxovirus nucleocapsids. These inclusions are not specific to PDB and have been reported in other conditions.[2]

Radiologic-pathologic correlation

The cotton-wool radiopacities correspond to irregular islands of dense, disorganized bone with prominent mosaic cement lines. Bone expansion reflects the overproduction of mechanically weak bone. The increased radionuclide uptake on scintigraphy correlates with the high metabolic activity and increased vascularity of pagetic lesions.[3][17] Hypercementosis of teeth within pagetic bone reflects the same disorganized cementoblastic activity affecting the periodontal structures.[8]

Molecular findings relevant to classification

• SQSTM1 mutations (most commonly affecting the ubiquitin-binding domain of p62) are found in 40–50% of familial and 5–10% of sporadic cases; they activate RANKL-induced NF-κB signaling and increase osteoclast activity.[5][6]
• ZNF687 mutations (particularly P937R) are associated with severe PDB and giant cell tumor complication; combined molecular analysis of H3F3A and ZNF687 can distinguish conventional giant cell tumor from PDB-associated giant cell tumor.[5][16]

Workup and referral

• Serum total ALP is the primary biochemical marker for diagnosis and monitoring; bone-specific ALP or procollagen type I N-terminal propeptide (P1NP) may be used when liver disease confounds interpretation.[1][7]
• Radionuclide bone scan is recommended at diagnosis to define the full extent of disease.[4][5]
• Targeted radiographs of the skull, facial bones, abdomen, and tibias detect approximately 93% of lesions.[5]
• Referral to an endocrinologist or metabolic bone specialist is appropriate for confirmed PDB. Dental specialists should coordinate with the treating physician before invasive oral procedures.[4][8]

Bisphosphonate therapy

Bisphosphonates are the mainstay of treatment, indicated for symptomatic bone pain attributable to increased metabolic activity, preparation for surgery at a pagetic site, and disease at sites at risk for complications (including the skull and jaws).[1][9][26]

• Zoledronic acid (single intravenous infusion of 5 mg) is the treatment of choice, achieving ALP normalization in approximately 89% of patients with sustained remission for years.[1][27][28]
• Oral alternatives include risedronate (30 mg daily for 2 months) and alendronate (40 mg daily for 6 months), though these are less efficacious than zoledronic acid.[1][5]
• Calcium and vitamin D repletion is mandatory before and during bisphosphonate therapy to prevent hypocalcemia.[26]

Dental and surgical considerations

• Tooth extractions in pagetic bone carry increased risk of hemorrhage (due to increased bone vascularity) and postoperative infection; hypercementosis and dense sclerotic bone make extractions technically difficult.[8]
• Preoperative bisphosphonate therapy is recommended before elective surgery at a pagetic site to reduce vascularity and bleeding risk.[4]
• The risk of medication-related osteonecrosis of the jaw (MRONJ) in patients receiving bisphosphonates for PDB is very low (reported incidence 0.0004–0.06% for oral bisphosphonates), substantially lower than in oncologic settings.[12][29]

Prognosis and surveillance

• PDB is a chronic, slowly progressive condition. Bisphosphonate therapy effectively controls metabolic activity but has not been conclusively shown to prevent long-term complications such as deformity, fracture, or deafness.[2][30][31]
• Sarcomatous transformation occurs in fewer than 1% of patients but carries a poor prognosis, with less than 50% surviving 5 years.[5][11][16]
• Monitoring with serial ALP measurements is recommended to detect biochemical relapse; retreatment with zoledronic acid is effective in relapsing patients.[32][33]

Familial screening and genetic testing

Approximately 15% of patients with classic PDB report a positive family history, with autosomal dominant inheritance and incomplete penetrance.[1][5] The Zoledronate in the Prevention of Paget's Disease (ZiPP) trial has investigated whether genetic testing for SQSTM1 mutations in at-risk relatives, followed by prophylactic zoledronic acid in carriers, can prevent disease progression.[6][31] This approach may represent a future paradigm for early intervention in genetically susceptible individuals.

Bisphosphonate therapy and dental implants

Given the very low risk of MRONJ in PDB patients receiving bisphosphonates, dental implant placement is not absolutely contraindicated but should be undertaken with caution, appropriate informed consent, and coordination with the patient's treating physician.[12][29] The altered bone quality in pagetic jaws may affect osseointegration.