Paget's disease of bone

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Paget's disease of bone

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou [2];

Synonyms and Keywords: Commonly known as Paget's disease; Historically known as osteitis deformans

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[3] Paget's disease of bone (PDB), also known as osteitis deformans, is a chronic, focal disorder of bone remodeling characterized by increased osteoclastic bone resorption followed by increased but disorganized osteoblastic bone formation. The resulting pagetic bone is structurally abnormal and may become enlarged, deformed, mechanically weak, and hypervascular. Disease may involve a single bone (monostotic) or multiple skeletal sites (polyostotic) and does not spread from one bone to another.

Epidemiology

PDB is one of the most common metabolic bone disorders after osteoporosis. Prevalence varies substantially with age and geographic region and increases markedly with advancing age. In historically high-prevalence populations, prevalence may reach several percent in older adults. PDB is most prevalent in the United Kingdom and populations of Northwest European ancestry and is uncommon in Scandinavia, the Indian subcontinent, and East Asia. Men are affected more often than women. Incidence and disease severity have declined in several historically high-prevalence regions.

Core pathophysiology

PDB is characterized by focal acceleration of bone turnover. Genetic susceptibility is important, particularly variants affecting SQSTM1, which encodes the p62 protein involved in NF-κB signaling and osteoclast activation. SQSTM1 mutations occur in up to approximately 40% of familial cases and approximately 5–10% of sporadic cases. Environmental factors appear to modify disease penetrance and severity, but the relevant environmental triggers remain incompletely defined.

A viral (paramyxovirus/"slow virus") etiology has long been proposed but remains unproven; current evidence centers on genetic susceptibility with modifying environmental factors that are not yet defined.

Clinical presentation

Most patients are asymptomatic, with PDB commonly detected incidentally because of an elevated serum alkaline phosphatase (ALP) concentration or an imaging abnormality. When symptomatic, bone pain is the most common presentation. Manifestations otherwise depend on skeletal sites involved and may include bone deformity, increased local warmth, fracture, secondary osteoarthritis, hearing loss, and nerve compression. The disease preferentially affects the axial skeleton and long bones, most frequently the pelvis (approximately 70%), femur (approximately 55%), lumbar spine (approximately 53%), skull (approximately 42%), and tibia (approximately 32%).

An isolated elevation of ALP with otherwise normal liver biochemical tests should raise suspicion for PDB in an older adult. Plain radiography is used to confirm characteristic skeletal involvement, while radionuclide bone scanning is used to define the distribution and extent of metabolically active disease.

Management principles

Management is individualized according to symptoms, disease activity, skeletal sites involved, and risk of complications. Nitrogen-containing bisphosphonates are the principal pharmacologic therapy. When treatment is indicated, a single 5-mg intravenous infusion of zoledronic acid is the preferred regimen and produces more complete and durable biochemical remission than oral risedronate.

Indications for treatment differ between guidelines; see the Medical therapy microchapter for treatment selection and the evidence surrounding symptom-directed versus treat-to-target approaches.

Total serum ALP is the principal biochemical marker used to assess treatment response and disease activity when it is elevated at baseline.

Major complications and prognosis

PDB may cause skeletal deformity, pathological fracture, secondary osteoarthritis, hearing impairment, and neurological compression. Malignant transformation to osteosarcoma is rare, occurring in approximately 0.3–1% of patients, but carries a poor prognosis; virtually all osteosarcomas occurring in adults older than 60 years arise in pagetic bone.

New focal or disproportionately severe pain, swelling, or a mass arising in a pagetic bone should prompt evaluation for a complication such as pathological fracture or malignant transformation.

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[5]

Original description

Paget's disease of bone (PDB) was first described by Sir James Paget in 1877 under the name osteitis deformans. Paget interpreted the disorder as a chronic inflammatory process based on the progressive skeletal deformities and histopathologic evidence of increased bone remodeling. Although the inflammatory interpretation was subsequently shown to be incorrect, his original clinicopathologic description remains the foundation of the modern recognition of PDB.

Paleopathologic studies have identified Paget-like skeletal lesions in historical European remains, including Roman and medieval skeletons. The geographic distribution of historical cases, together with genetic and epidemiologic observations, has contributed to the hypothesis that PDB originated in northwestern Europe and subsequently spread through migration. Interpretation of historical prevalence estimates remains difficult because of differences in skeletal preservation, ascertainment, and diagnostic criteria.

Evolution of etiologic theory

Following Paget's inflammatory hypothesis, infectious explanations were proposed. In 1974, electron-microscopic identification of inclusion bodies resembling paramyxoviral nucleocapsids led to the hypothesis that PDB was caused by a persistent or "slow" paramyxovirus infection. Subsequent studies produced conflicting evidence, and a causal viral etiology was never established. Thus, the paramyxovirus hypothesis is best regarded as an important historical stage in the evolution of PDB research rather than an established cause of disease.

The discovery of familial clustering and disease-associated genetic variants subsequently shifted the field toward a genetic model. Variants in SQSTM1 (encoding p62) were identified as an important genetic contributor, with additional susceptibility genes including TNFRSF11A, VCP, ZNF687, and PFN1. SQSTM1 variants occur in up to approximately 40% of familial cases and approximately 5% to 10% of sporadic cases.

The viral inclusion bodies described historically may represent aggregates of autophagy-related proteins rather than viral particles, providing a potential link between the historical viral hypothesis and subsequent recognition of abnormalities in the SQSTM1/p62-autophagy pathway. The precise relationship between these inclusions, genetic susceptibility, and disease initiation remains incompletely resolved.

History of therapy

Calcitonin was an early effective treatment for PDB, but its use was limited by the need for frequent administration, adverse effects such as flushing and nausea, and biochemical relapse after treatment discontinuation. The introduction of bisphosphonates represented a major therapeutic advance by providing more sustained suppression of pagetic bone turnover.

Etidronate was the first bisphosphonate used clinically for PDB. Its early use demonstrated the effectiveness of bisphosphonate-mediated suppression of abnormal bone turnover, but high doses could impair mineralization and cause osteomalacia. Subsequent development of nitrogen-containing bisphosphonates, including pamidronate, alendronate, and risedronate, improved therapeutic efficacy and safety.

The development of intravenous zoledronic acid marked a further major advance. In a landmark randomized trial, a single infusion produced normalization of alkaline phosphatase in approximately 89% of patients compared with 58% with oral risedronate at 6 months. Long-term follow-up demonstrated markedly more durable remission, with relapse occurring in approximately 0.7% after zoledronic acid compared with 20% after risedronate over 6.5 years.

Evolution of treatment philosophy

The PRISM and PRISM-EZ trials subsequently challenged the assumption that intensive biochemical suppression should be routinely pursued in established PDB. These randomized trials compared intensive treatment aimed at normalization of alkaline phosphatase with symptom-directed management and did not demonstrate reductions in fractures, orthopedic procedures, or quality of life. In PRISM-EZ, intensive treatment was additionally associated with a nonsignificant increase in fractures (hazard ratio 1.90; 95% CI, 0.91 to 3.98), orthopedic procedures, and serious adverse events, reinforcing the historical shift toward symptom-directed management.

More recent genetic prevention studies, including the Zoledronate in the Prevention of Paget's Disease (ZiPP) study, represent an emerging historical transition toward identifying genetically susceptible individuals and investigating whether early treatment can prevent clinical disease.

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[7]

Paget's disease of bone (PDB) has no single formally validated staging system. For clinical communication, it is best described along three complementary axes: anatomic extent, radiographic/metabolic phase, and genetic or syndromic subtype. These descriptors are not mutually exclusive; a patient may, for example, have polyostotic, mixed-phase, SQSTM1-associated familial PDB.

By anatomic extent

Classification	Definition
Monostotic	Involvement of a single bone.
Polyostotic	Involvement of two or more bones.

The anatomic distribution of PDB is generally established by the pattern of skeletal involvement rather than by a formal numerical stage. Pagetic change advances within an affected bone at approximately 1 cm (about 8 mm) per year but does not spread from one bone to another. Consequently, the skeletal distribution present at diagnosis generally remains fixed for life.

Familial disease is often associated with younger age at presentation and a greater likelihood of polyostotic involvement than sporadic disease.

By radiographic/metabolic phase

PDB lesions are traditionally described as progressing through an osteolytic, mixed, and late sclerotic or "burnt-out" phase. These phases represent differing relative activity of bone resorption and formation and are descriptive rather than formally validated clinical stages.

• Osteolytic phase — predominantly osteoclastic activity and active bone resorption.
• Mixed phase — active bone resorption together with disorganized new bone formation.
• Sclerotic/late phase — relatively predominant osteoblastic activity with increased sclerosis and remodeling.

The phase descriptors are radiographic-pathologic correlates rather than formal stages. Different phases may coexist in different bones, and a single affected bone may contain areas with differing activity.

Detailed radiographic appearances of these phases are described in the Other imaging findings chapter.

By genetic and syndromic subtype

Classic PDB includes sporadic and familial adult-onset disease. Familial PDB is usually inherited in an autosomal-dominant pattern with incomplete penetrance. SQSTM1 variants are the most important genetic contributor and are found in approximately 40% to 50% of familial cases and approximately 5% to 10% of sporadic cases.

Rare genetic forms can present with unusually early-onset, severe, or multisystem disease. Important examples include:

• ZNF687 and PFN1 variants, which have been associated with severe early-onset polyostotic PDB and increased risk of skeletal neoplasia.
• TNFRSF11A variants, associated with familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia.
• VCP variants, associated with multisystem proteinopathy that may include PDB, inclusion body myopathy, and frontotemporal dementia.

Juvenile Paget disease is a distinct rare disorder rather than simply an early-onset form of adult PDB. It is most commonly caused by loss-of-function variants in TNFRSF11B, resulting in osteoprotegerin deficiency and generalized high bone turnover beginning in childhood. Rare cases are caused instead by activating TNFRSF11A (RANK) variants or heterozygous SP7 (osterix) mutations, demonstrating genetic heterogeneity.

Clinical use of the classification

The three descriptors should be considered together when characterizing PDB:

• Extent — monostotic or polyostotic.
• Phase — osteolytic, mixed, or sclerotic/late.
• Subtype — classic sporadic/familial PDB or a rare genetic/syndromic form.

Early-onset, unusually severe or polyostotic disease, or PDB accompanied by myopathy, neurodegeneration, dementia, or childhood-onset skeletal disease should raise consideration of a syndromic or inherited form and may warrant genetic evaluation.

Monostotic disease may have a normal total alkaline phosphatase concentration; therefore, a normal biochemical marker does not exclude limited skeletal involvement. Approximately 15% of symptomatic patients—typically those with monostotic disease—have a normal serum total alkaline phosphatase. The extent of disease is assessed with appropriate skeletal imaging, particularly radionuclide bone scintigraphy when mapping the distribution is required.

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [8] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[9] Paget's disease of bone (PDB) is fundamentally a disorder of abnormal osteoclast function. Genetically susceptible osteoclasts are increased in number and size, hypernucleated, and hyperresponsive to osteoclastogenic signals, producing focal areas of accelerated bone resorption. Osteoblasts respond with increased bone formation, but the newly formed bone is disorganized, producing a characteristic mosaic of woven and lamellar bone. The process is accompanied by increased bone vascularity and marrow fibrosis. Dysregulated RANK–NF-κB signaling, particularly involving the SQSTM1/p62 pathway, is a central molecular feature of the disease, while osteoimmunologic and environmental factors may modify disease expression.

Osteoclast abnormality

The primary cellular abnormality in PDB is an increase in the number, size, and activity of osteoclasts. Pagetic osteoclasts are characteristically large and hypernucleated and show increased sensitivity to osteoclastogenic stimuli, including receptor activator of nuclear factor kappa-B ligand (RANKL), 1,25-dihydroxyvitamin D, and tumor necrosis factor alpha (TNF-α). They have increased bone-resorptive capacity and may exhibit impaired apoptosis. The pagetic bone marrow is also enriched in osteoclastogenic cytokines, particularly interleukin-6 (IL-6), contributing to a local microenvironment that promotes osteoclastogenesis.

SQSTM1 variants occur in approximately 40% to 50% of familial and 5% to 10% of sporadic PDB; most causal mutations impair the ability of p62 to bind ubiquitin, enhancing RANKL-induced NF-κB signaling and increasing the sensitivity of osteoclast precursors to RANKL.

Coupled but disorganized bone formation

Increased osteoclastic resorption is followed by increased osteoblastic bone formation through coupling mechanisms. Hyperactive osteoclasts release coupling signals that recruit and stimulate osteoblast-lineage cells, resulting in rapid deposition of disorganized woven and lamellar bone. Coupling of bone formation to resorption is mediated in part by the ephrin ligand-receptor pair EphB2 on osteoclasts and EphB4 on osteoblasts and may be further regulated by osteocytes.

The resulting bone is enlarged but structurally abnormal, with irregularly arranged trabeculae and a characteristic mosaic pattern of woven and lamellar bone. Although bone formation is increased, the newly formed bone is mechanically inferior to normally remodeled bone. Increased vascularity and marrow fibrosis accompany the active remodeling process.

SQSTM1/p62 and RANK–NF-κB signaling

SQSTM1, which encodes the scaffold protein p62, is the best-established susceptibility gene for classic PDB. p62 functions downstream of several osteoclastogenic receptors, including RANK, TNF receptors, and interleukin-1 receptors, and participates in signaling through TRAF6 and the IκB kinase/NF-κB pathway. Mutations affecting the ubiquitin-associated (UBA) domain of p62 can alter ubiquitin binding and enhance RANKL-induced NF-κB activation, increasing osteoclast precursor sensitivity to RANKL.

The molecular abnormalities identified in PDB are heterogeneous, but the genes implicated in classic disease converge on pathways regulating osteoclast differentiation and function, particularly the RANK–NF-κB signaling axis. Other genes implicated in PDB or PDB-like phenotypes include OPTN, CSF1, TNFRSF11A/RANK, TM7SF4/DC-STAMP, and RIN3. Syndromic forms involving genes such as VCP, ZNF687, PFN1, and TNFRSF11A further support the importance of dysregulated osteoclast signaling.

Autophagy and pagetic inclusion bodies

p62 also functions as an autophagy receptor. SQSTM1 mutations can interfere with autophagic flux and promote accumulation of ubiquitinated protein aggregates. The classic nuclear and cytoplasmic inclusion bodies described in pagetic osteoclasts, historically interpreted as evidence of paramyxovirus infection, may represent p62- and ubiquitin-containing protein aggregates related to altered autophagy rather than viral particles.

Osteoimmunology and osteocyte contribution

The pagetic bone microenvironment contains increased concentrations of osteoclastogenic cytokines, including IL-6, supporting sustained osteoclast formation and activity. Interactions among osteoclasts, osteoblasts, osteocytes, and immune-mediated signaling contribute to the focal remodeling abnormalities characteristic of PDB.

A proposed mechanism is that abnormal pagetic osteoclasts secrete high local concentrations of insulin-like growth factor 1 (IGF1), which induces osteocyte senescence. Senescent osteocytes in turn express RANKL; approximately 25% of osteocytes in pagetic lesions have been reported to be senescent/RANKL-positive, roughly three-fold more than in controls. This mechanism may help sustain local osteoclastogenesis and maintain the pagetic lesion, although the precise contribution of osteocytes to human PDB remains under investigation.

Environmental and viral hypotheses

Environmental factors may modify the expression of genetically susceptible PDB. A proposed viral mechanism involves the measles virus nucleocapsid protein (MVNP), which has been reported to induce a pagetic osteoclast phenotype in experimental systems through TBK1-dependent IL-6 production and p38 MAPK signaling and to interact with SQSTM1/p62 mutations in experimental models.

However, independent studies have failed to reproducibly detect paramyxoviral transcripts or antigens in human pagetic bone. Therefore, a viral cause of PDB remains unproven and controversial. The prevailing model is that genetic susceptibility, particularly abnormalities affecting osteoclast signaling, interacts with incompletely defined environmental factors.

Pathophysiologic basis of the Pagetic phenotype

The sequence of accelerated osteoclastic resorption followed by excessive but disorganized bone formation produces the characteristic high-turnover state of PDB. The resulting bone is often enlarged and highly vascular but structurally abnormal. These mechanisms explain the characteristic biochemical and imaging manifestations of active disease and provide the biologic rationale for therapies that suppress osteoclast activity.

The commonly described lytic, mixed, and sclerotic radiographic phases reflect different temporal patterns of the underlying remodeling process rather than distinct molecular stages of disease. Malignant degeneration is a complication of PDB rather than a stage in its pathophysiology.

Areas of uncertainty

The precise mechanisms linking genetic susceptibility to focal disease distribution remain incompletely understood. The contribution of environmental exposures, including the proposed viral mechanisms, remains unresolved. The mechanisms responsible for the abnormal coupling between bone resorption and formation and the full contribution of osteocytes to lesion maintenance are also still under investigation.

Causes / Etiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [10] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[11] Paget's disease of bone (PDB) is a multifactorial disorder caused by genetic susceptibility acting in combination with incompletely defined environmental factors. The dominant etiologic model has shifted from the historical "slow-virus" hypothesis toward a genetic model centered on SQSTM1 and multiple susceptibility loci that converge on pathways regulating osteoclast differentiation, particularly RANK–NF-κB signaling.

Genetic causes

SQSTM1 is the principal causal gene implicated in classic PDB. SQSTM1 encodes p62/sequestosome-1, and causal variants occur in approximately 40% to 50% of familial and 5% to 10% of sporadic cases. Most mutations cluster in the ubiquitin-associated (UBA) domain, with P392L being a prototype mutation. These variants impair p62 ubiquitin binding and enhance RANKL-induced NF-κB signaling. UBA-domain mutations are associated with more severe and extensive disease.

SQSTM1-related PDB follows an autosomal-dominant pattern with incomplete penetrance. Consequently, a pathogenic variant does not necessarily result in clinical disease, and absence of a family history does not exclude a genetic cause.

Other monogenic and syndromic causes

Several additional genes have been associated with early-onset, severe, or syndromic PDB and PDB-like phenotypes. These disorders generally converge on pathways involved in osteoclast differentiation or RANK–NF-κB signaling.

• TNFRSF11A encodes RANK and is associated with early-onset PDB and related expansile osteolytic syndromes.
• ZNF687 and PFN1 variants are associated with severe, early-onset, often polyostotic disease and may be associated with increased risk of neoplastic transformation.
• VCP mutations can cause multisystem proteinopathy characterized by inclusion-body myopathy, frontotemporal dementia, and PDB.
• TNFRSF11B encodes osteoprotegerin (OPG). Variants can increase susceptibility to classic PDB, while biallelic loss-of-function variants can cause juvenile Paget disease.

Polygenic susceptibility

Genome-wide association studies have identified multiple susceptibility loci in patients without SQSTM1 mutations. Seven major susceptibility loci have been described, including CSF1, OPTN, TNFRSF11A, TM7SF4/DC-STAMP, RIN3, PML, and NUP205. These variants increase susceptibility rather than acting as single-gene causes of PDB.

The implicated susceptibility genes predominantly participate in osteoclast differentiation, signaling, or cytoskeletal function, supporting a common biologic pathway underlying genetically heterogeneous PDB.

Collectively, these seven loci account for approximately 13% of the familial risk of PDB, and variants near CSF1, OPTN, TM7SF4, and TNFRSF11A explain the majority of the measurable genetic risk in replication cohorts.

Epigenetic factors

Epigenetic mechanisms, including DNA methylation and histone modification, influence genes involved in bone remodeling and osteoclast function, including RANKL, OPG, HDAC2, DNMT1, and SQSTM1. Blood-based DNA-methylation signatures have been shown to discriminate PDB cases from controls and to correlate with disease severity, with differentially methylated loci identified in or near SQSTM1, RIN3, and CSF1. These findings identify epigenetic variation as a potential contributor to disease expression and a potential biomarker, although its causal role remains under investigation.

Environmental factors

Several environmental exposures have been associated with PDB, including rural residence, animal or livestock contact, dog ownership, bovine meat consumption, wood-fired heating during childhood, tobacco exposure, environmental toxins such as arsenic, and low childhood calcium or vitamin D intake. However, these associations have not established a specific environmental exposure as a proven cause, and mechanisms linking these factors to disease remain incompletely defined.

The decline in incidence and severity of PDB in historically high-prevalence regions has been interpreted as indirect evidence that environmental factors may modify disease expression, but the specific responsible exposures remain uncertain.

Direct support for a gene–environment interaction comes from observations that younger first-degree relatives carrying the same SQSTM1 mutation as an affected parent develop PDB at substantially older ages and with milder disease, implying that declining exposure to an environmental trigger may reduce penetrance despite similar genetic susceptibility.

Infectious and paramyxovirus hypothesis

The historical infectious hypothesis arose from the observation of paramyxovirus-like nuclear and cytoplasmic inclusion bodies in pagetic osteoclasts. Measles virus, respiratory syncytial virus, and canine distemper virus have been proposed as possible infectious triggers.

Experimental studies have provided supportive evidence for a role of measles virus nucleocapsid protein (MVNP), particularly in models combining MVNP expression with mutant SQSTM1. However, human tissue studies have produced conflicting results, and paramyxoviral transcripts or antigens have not been reproducibly demonstrated in human pagetic bone. The viral hypothesis therefore remains unproven and should be regarded as a possible environmental trigger in genetically susceptible individuals rather than an established cause of PDB.

Clinically relevant implications

A family history of PDB should be specifically sought because familial disease is an important clue to inherited susceptibility.

SQSTM1 genetic testing may be considered in patients with familial disease or selected patients with early-onset, severe, or polyostotic disease. Interpretation should account for incomplete penetrance, and testing or screening of relatives should be addressed in the dedicated Screening and Other diagnostic studies chapters.

Very early onset, severe polyostotic disease, or syndromic features such as myopathy or dementia should raise consideration of rare genetic disorders involving genes such as VCP, ZNF687, or PFN1.

Areas of uncertainty

The precise mechanism by which germline genetic susceptibility produces focal skeletal lesions remains incompletely understood. Most familial cases do not have an identified single causal mutation, indicating that additional genetic determinants remain to be discovered.

The specific environmental exposures that contribute to PDB and their interaction with genetic susceptibility remain uncertain. The paramyxovirus hypothesis remains unresolved because experimental evidence is contrasted by inconsistent findings in human tissue.

Differentiating Paget's disease of bone from Other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [12] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[13] Paget's disease of bone (PDB) should be distinguished from disorders that produce focal osteolysis, osteosclerosis, mixed lytic-sclerotic lesions, bone expansion, or an isolated elevation of serum alkaline phosphatase (ALP). In most patients, the combination of characteristic radiographic findings, biochemical markers, and radionuclide bone scintigraphy permits the diagnosis without biopsy. The principal diagnostic challenge is distinguishing pagetic bone from osteoblastic or mixed metastases, primary bone tumors, fibrous dysplasia, osteomyelitis, and other metabolic bone disorders, while recognizing that an elevated total ALP may originate from liver or bone.

Sclerotic and mixed bone lesions

Disease	Distinguishing features from Paget's disease of bone	Useful diagnostic studies
Osteoblastic or mixed bone metastases	Often multifocal and ill-defined; prostate cancer commonly produces osteoblastic metastases, while breast cancer may produce mixed osteoblastic and osteolytic lesions. Metastases usually lack the characteristic combination of cortical thickening, coarse trabeculation, bone expansion, and remodeling seen in PDB.	Targeted radiographs/CT; bone scan or PSMA-PET when clinically indicated; CT/MRI to characterize indeterminate lesions; biopsy when imaging remains non-diagnostic.
Lymphoma	May produce lytic, mixed, or occasionally sclerotic lesions and is usually more marrow-based or permeative, with less characteristic bone expansion and cortical thickening than PDB.	MRI and CT for marrow and cortical assessment; systemic evaluation and biopsy when required.
Primary bone malignancy, particularly osteosarcoma	Aggressive cortical destruction, permeative or moth-eaten bone destruction, periosteal reaction, and/or a soft-tissue mass favor malignancy rather than uncomplicated PDB.	Radiographs followed by MRI; CT for cortical/mineralized matrix assessment; targeted biopsy when malignancy cannot be excluded.
Fibrous dysplasia	Typically demonstrates homogeneous ground-glass matrix and may cause bone expansion, but lacks the characteristic coarse trabeculation and marked cortical thickening of PDB. Craniofacial involvement may overlap with PDB.	Plain radiographs or CT; MRI when aggressive features or diagnostic uncertainty are present.
Chronic osteomyelitis, including chronic nonbacterial osteomyelitis	May produce sclerosis, cortical thickening, and bone expansion, creating substantial overlap with PDB. Sequestrum, sinus tract, inflammatory changes, multifocal lesions in characteristic locations, or clinical inflammatory features favor osteomyelitis.	Radiographs and MRI; inflammatory and microbiologic evaluation when appropriate; biopsy/culture when diagnosis remains uncertain.
Erdheim-Chester disease	Typically causes bilateral and symmetric osteosclerosis, especially of the long-bone metaphyseal and diaphyseal regions, usually without the focal bone enlargement and deformity characteristic of PDB.	Radiographs/CT and systemic imaging; diagnosis requires correlation with characteristic systemic findings and tissue confirmation when appropriate.

Bone scintigraphy is highly sensitive for metabolically active PDB but is not specific; intense uptake may also occur with metastases, infection, fibrous dysplasia, and other active skeletal lesions. Therefore, a positive bone scan should be interpreted together with the corresponding radiographic or cross-sectional appearance rather than being used alone to distinguish PDB from metastatic disease.

A specific modern imaging pitfall is prostate-specific membrane antigen (PSMA)-targeted PET. Pagetic bone may demonstrate focal PSMA uptake, including in the pelvis and proximal long bones, and can therefore mimic osseous metastatic prostate cancer. Correlation with CT or MRI demonstrating pagetic features such as coarsened trabeculae, cortical thickening, and bone hypertrophy can prevent erroneous metastatic staging.

Lytic lesions and primary bone tumors

PDB may develop areas of osteolysis, particularly in the early phase of disease or in advanced destructive lesions. Important lytic mimics include multiple myeloma, lymphoma, fibrous dysplasia, osteomyelitis, and primary bone tumors. Multiple myeloma typically produces discrete punched-out lytic lesions with little reactive sclerosis or bone expansion; serum and urine monoclonal protein studies should be considered when the clinical context is compatible.

Sarcomatous transformation of pagetic bone is uncommon but should be suspected when a previously stable pagetic lesion develops new focal pain, rapid progression, cortical destruction, or a soft-tissue mass. Focal cortical destruction extending through the cortex with an associated soft-tissue mass is particularly concerning for Paget-associated sarcoma.

MRI is particularly useful when malignant transformation is suspected. Preserved fat-equivalent marrow signal within pagetic bone strongly favors uncomplicated PDB, whereas marrow replacement by tumor and an associated soft-tissue mass are concerning for neoplasia. One imaging study reported a 100% negative predictive value for preserved fat signal in excluding neoplastic transformation in its study population; this finding should be interpreted in the context of the overall imaging appearance rather than as an absolute rule.

A rapidly progressive or disproportionate increase in ALP accompanied by new focal pain, neurologic deficit, or aggressive imaging findings should prompt urgent evaluation for neoplastic transformation. A lytic lesion with a soft-tissue component in pagetic bone may also represent a giant-cell tumor, which can mimic sarcoma radiologically and should be considered in the appropriate clinical and anatomic setting.

Cranial sclerotic lesions

Hyperostosis frontalis interna may mimic cranial PDB but is characteristically confined to the inner table of the frontal bone, with relative preservation of the diploë and outer table. PDB more often produces expansion, cortical thickening, and coarsened trabeculation involving the affected cranial bones. Fibrous dysplasia and meningioma-associated hyperostosis are additional considerations when cranial imaging is atypical.

Biochemical mimics of isolated elevated alkaline phosphatase

An isolated elevation of total ALP with otherwise unremarkable routine biochemistry is a common biochemical presentation of PDB, particularly in patients with metabolically active disease. However, elevated ALP is not specific for skeletal disease and may originate from the liver or biliary tract, other metabolic bone disorders, or skeletal malignancy.

Total ALP is the recommended first-line biochemical marker when assessing suspected PDB, but liver biochemical tests should be obtained concurrently because hepatobiliary disease is a common alternative source of ALP elevation.

The most useful routine discriminator between a hepatic and skeletal source of ALP is gamma-glutamyl transferase (GGT), with 5'-nucleotidase as an alternative. These enzymes are not produced by bone; a concomitant elevation supports a hepatobiliary source, whereas an elevated ALP with a normal GGT favors a skeletal source. GGT is not completely specific for hepatobiliary disease and should therefore be interpreted in the clinical context. In older adults, coexisting vitamin D deficiency and osteomalacia are important alternative causes of elevated bone ALP, so 25-hydroxyvitamin D should be assessed when clinically appropriate.

When total ALP is normal but clinical or radiographic suspicion for active PDB remains high, bone-specific ALP, procollagen type I N-terminal propeptide (PINP), or urinary N-terminal telopeptide (uNTX) may help assess bone turnover. A normal total ALP therefore does not completely exclude metabolically active or localized PDB.

Metabolic bone disease mimics

Disease	Typical biochemical pattern	Features favoring the alternative diagnosis
Paget's disease of bone	Usually elevated ALP with normal calcium and phosphate; PTH is generally normal.	Focal characteristic radiographic changes, bone expansion, cortical thickening, coarse trabeculation, and increased radionuclide uptake.
Osteomalacia / vitamin D deficiency	Elevated ALP; phosphate often low; calcium may be low or normal; PTH commonly elevated in secondary hyperparathyroidism; 25-hydroxyvitamin D may be low in vitamin D deficiency.	Diffuse skeletal symptoms and biochemical evidence of defective mineralization rather than a characteristic focal pagetic lesion.
Primary hyperparathyroidism / osteitis fibrosa cystica	Hypercalcemia, low or low-normal phosphate, elevated PTH; ALP may be elevated in severe skeletal disease.	Generalized skeletal manifestations, subperiosteal resorption, brown tumors, and biochemical evidence of hyperparathyroidism.
Osteopetrosis	Serum calcium, phosphate, PTH, and ALP may be normal or variable depending on subtype.	Diffuse skeletal sclerosis, bone-within-bone appearance, Erlenmeyer-flask deformity, and generalized rather than focal involvement favor osteopetrosis.

Biochemical patterns should not be interpreted in isolation because substantial overlap exists among metabolic bone disorders. The diagnosis should be based on the combination of biochemical findings, clinical context, and characteristic imaging.

When biopsy should be considered

Biopsy is not routinely required when the clinical presentation and imaging findings are characteristic of PDB. It should be considered when imaging is atypical or non-pathognomonic and the distinction from malignancy, infection, or another primary bone disorder cannot be made confidently.

Targeted biopsy is particularly appropriate when there is focal cortical destruction, a new soft-tissue mass, rapidly progressive osteolysis, or other features suggesting sarcomatous transformation. Biopsy should be directed to the most diagnostically informative abnormality and coordinated with appropriate CT or MRI characterization.

Practical diagnostic approach

• Focal sclerotic or mixed lesion: review the radiographic morphology for bone expansion, cortical thickening, coarse trabeculation, and characteristic distribution. Consider metastatic disease, lymphoma, fibrous dysplasia, and osteomyelitis when the appearance is atypical.
• Lytic or aggressive lesion in pagetic bone: assess for cortical destruction, periosteal reaction, soft-tissue mass, and marrow replacement. MRI is preferred when malignant transformation is suspected.
• Isolated elevated ALP: determine whether the source is hepatic or skeletal using liver biochemical tests, particularly GGT or 5'-nucleotidase, and assess for vitamin D deficiency when appropriate.
• Normal ALP with persistent suspicion: consider bone-specific ALP, PINP, or uNTX and correlate with imaging.
• Positive bone scan without characteristic radiographs: do not diagnose PDB from scintigraphic uptake alone; correlate with radiographs or cross-sectional imaging.
• Atypical or aggressive imaging: obtain CT/MRI as appropriate and consider targeted biopsy when malignancy or another diagnosis cannot be excluded.

The evidence supporting individual imaging features for distinguishing PDB from some uncommon mimics remains limited. Current guidelines emphasize integration of clinical, biochemical, radiographic, and scintigraphic findings rather than reliance on any single test.

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [14] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[15] Paget's disease of bone (PDB) is the second most common metabolic bone disease after osteoporosis. It predominantly affects older adults and shows marked geographic and ancestral variation, with the highest prevalence historically reported in populations of Northwest European ancestry. Contemporary epidemiology also demonstrates declining incidence and clinical severity in many historically high-prevalence regions, although this trend is not uniform across countries or populations.

Overall burden

Contemporary estimates suggest that approximately 1.5 million people in the United States have PDB, with prevalence around 1–2% among White adults older than 55 years. Historical US prevalence estimates derive largely from the NHANES-I pelvic-radiograph survey, which reported pelvic PDB in approximately 0.71% of participants overall and 2.3% among those aged 65–74 years, with similar rates in White and Black participants. No formal US population prevalence study comparable to NHANES-I has been performed since.

Across studied populations, reported prevalence has ranged from approximately 0.00028% in Japan to as high as 5.4% in the United Kingdom; these estimates are strongly age- and ascertainment-dependent and should not be interpreted as directly comparable general-population prevalence figures.

Age and sex distribution

PDB is uncommon before approximately 50–55 years of age. Incidence approximately doubles with each successive decade after age 50. In the United Kingdom, prevalence by the eighth decade has been reported at approximately 7.6% among men and 5.4% among women. Most contemporary patients are therefore older than 55 years.

The age at diagnosis has also increased over time, consistent with the changing clinical phenotype of the disease; contemporary patients were diagnosed at approximately 69 years compared with 59 years in a historical Quebec cohort.

PDB shows a modest male predominance, with an overall male-to-female ratio of approximately 1.4:1, although the magnitude of the sex difference varies between populations.

Geographic and ancestral distribution

PDB occurs predominantly in populations of Northwest European ancestry, particularly those of British descent. The highest prevalence has historically been reported in the United Kingdom, especially Northwest England. PDB is also reported in France, Spain, Italy, and populations of European descent in Australia, New Zealand, Canada, South Africa, and the United States.

The disease is uncommon in Scandinavia, the Indian subcontinent, China, Japan, Southeast Asia, and the Middle East. However, contemporary data indicate that PDB should not be considered exclusively a disease of White populations.

In a 2020 Greater Manchester database study, clinically diagnosed prevalence among individuals aged 60 years or older was 0.174% overall, including 0.195% in men and 0.155% in women. Prevalence was 0.344% among Black or Black British individuals, 0.179% among White individuals, and 0.048% among Asian or Asian British individuals. Prevalence also increased with socioeconomic deprivation.

Consistent with this finding, a 2024 Birmingham Veterans Affairs study in the southeastern United States found that, among veterans diagnosed with PDB, a significantly higher proportion were African American than White (0.51 vs 0.40 of cases), with African American patients diagnosed at a younger age (mean 64.6 vs 70.1 years). These are proportions within the diagnosed cohort rather than population prevalence rates.

These findings indicate substantial population variation but also demonstrate that ancestry alone should not be used to exclude PDB from the differential diagnosis.

Familial occurrence

Approximately 15–40% of patients with PDB report an affected first-degree relative. Familial PDB tends to present at a younger age and is more frequently polyostotic than apparently sporadic disease.

See also: Paget's disease of bone/Risk factors

Secular trends

The incidence and clinical severity of PDB have declined substantially in many historically high-prevalence regions. A UK primary-care analysis found that standardized incidence continued to fall from 0.75 to 0.20 per 10,000 person-years between 1999 and 2015, with incidence more than 30% higher in the most-deprived quintile and persistently highest in Northwest England.

A systematic review and meta-analysis of secular trends found an overall decline in prevalence, with a pooled odds ratio of approximately 0.64 (95% CI, 0.45–0.91). The largest reductions occurred in historically high-prevalence regions, including the United Kingdom, continental Europe, and New Zealand. In contrast, prevalence appeared relatively stable in the United States and Italy, and disease severity increased in some populations in southern Italy.

A 20-year population-based study from Quebec found that prevalence remained approximately stable at 0.43%, whereas incidence declined from 0.77 to 0.28 per 1000 population between 2000 and 2020.

Contemporary Quebec patients also demonstrate a milder clinical phenotype than historical cohorts. Compared with a historical cohort, contemporary patients had an older age at diagnosis (68.7 vs 58.5 years), more frequent monostotic disease (60.5%), lower alkaline phosphatase levels, and substantially fewer fractures (6.7% vs 36.7%) and deformities (13% vs 54%).

Clinically relevant demographic implications

• PDB should be considered primarily in adults older than 55 years, particularly when characteristic radiographic findings or otherwise unexplained isolated elevation of alkaline phosphatase are present.
• Contemporary disease is increasingly characterized by later presentation, monostotic involvement, lower biochemical activity, and fewer skeletal complications than historical disease.
• Northwest European ancestry increases epidemiologic suspicion, but PDB can occur in non-White populations and should not be excluded on ancestry alone.
• A first-degree family history is common and may be associated with younger age at presentation and polyostotic disease.

See also: Paget's disease of bone/Risk factors

See also: Paget's disease of bone/Diagnosis

Epidemiologic uncertainties

The secular decline in PDB is not uniform across geographic regions, and the reasons for the changing incidence and phenotype remain incompletely established. Epidemiologic data are substantially stronger for the United Kingdom and other historically high-prevalence European populations than for the United States and regions where PDB is uncommon.

Reported prevalence also varies substantially according to age distribution, ascertainment method, diagnostic criteria, and whether radiographic or clinically diagnosed disease is measured. Consequently, historical and contemporary prevalence estimates should not be compared without considering these methodological differences.

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [16] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[17]

Age

Paget's disease of bone (PDB) is uncommon before age 50 years, and its prevalence increases with advancing age. Incidence approximately doubles with each decade after age 50 in some populations.

Sex

PDB is generally more common in men, with a reported male-to-female ratio of approximately 1.4:1. However, the ratio varies across populations and studies, and some series report a more balanced sex distribution. A slight female predominance has been reported in the oldest age groups.

Ancestry and geographic origin

PDB is most prevalent in populations of Northwestern European ancestry and has historically been particularly common in the United Kingdom. It is also reported in other European populations and in people of European descent in countries including Australia, New Zealand, Canada, the United States, and South Africa. The disease is uncommon in many populations from Africa, the Indian subcontinent, and East Asia. These geographic differences may reflect a combination of genetic susceptibility and environmental influences; founder effects have been proposed as one explanation for its distribution.

Family history and inherited susceptibility

A positive family history is reported in approximately 15% of patients in contemporary series, although estimates vary across studies and populations. First-degree relatives of affected individuals have an approximately 7- to 10-fold increased risk of PDB compared with the general population. The risk may be substantially higher in families in which the affected individual has severe or early-onset disease, with estimates approaching 20-fold in these settings.

PDB susceptibility has a complex genetic basis, involving rare pathogenic variants with relatively large effects and common variants associated with smaller increases in risk. Inheritance and clinical expression vary, and genetic susceptibility does not invariably lead to clinically apparent disease.

Genetic risk factors

SQSTM1

Pathogenic variants in the SQSTM1 gene are the most frequently identified genetic cause of PDB. They are found in approximately 40–50% of familial cases and 5–10% of apparently sporadic cases. The gene encodes p62, a protein involved in intracellular signaling and regulation of osteoclast activity. The p.Pro392Leu (P392L) variant is the most frequently reported SQSTM1 variant and occurs within the ubiquitin-associated (UBA) domain.

Penetrance of SQSTM1 pathogenic variants is incomplete and age-dependent. In studied carriers, penetrance has been estimated at approximately 80–90% by the seventh decade, although it varies with the specific variant and population. Carriers may develop disease of differing severity and extent. The P392L variant has been observed on a shared founder haplotype in European-derived populations.

Other genetic determinants

Rare variants in several other genes have been associated with PDB or related skeletal phenotypes:

• TNFRSF11A, which encodes RANK, is associated with rare early-onset forms of PDB and familial expansile osteolysis.
• TNFRSF11B, which encodes osteoprotegerin, is associated with susceptibility to classic PDB through common polymorphic variants, with some evidence of a stronger association in women. Biallelic loss-of-function variants in this gene can cause juvenile Paget disease.
• ZNF687 and PFN1 variants have been associated with severe or aggressive forms of PDB, including early-onset disease.
• VCP variants cause inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD), a multisystem disorder distinct from typical isolated PDB.

Genome-wide association studies have identified common susceptibility loci near CSF1, OPTN, TM7SF4 (also known as DCSTAMP), and RIN3. These loci generally confer smaller increments in risk and should be distinguished from rare pathogenic variants responsible for monogenic forms of disease.

Environmental and other proposed associations

Environmental factors have been proposed to contribute to the development of PDB, potentially in combination with inherited susceptibility. Reported associations include childhood exposure to wood-fired heating, rural residence, contact with livestock or other animals, hunting, and residence near mines. In one study, childhood exposure to wood-fired heating was associated with increased odds of PDB (odds ratio 2.10; 95% confidence interval 1.13–3.90). A strong association with residence near a mine has also been reported in a familial PDB study, although the estimate was imprecise.

Other proposed factors include low childhood dietary calcium or vitamin D intake, mechanical loading, tobacco exposure, heavy metals such as lead or arsenic, and air pollution. These associations are not uniformly established and should be interpreted cautiously. A viral contribution, including hypotheses involving measles virus or canine distemper virus, has also been investigated, but a causal infectious agent has not been established.

The long-term decline in PDB incidence in several historically high-prevalence populations, together with a parallel decline in PDB-associated osteosarcoma, is consistent with the possibility that environmental determinants have changed. These observations do not establish a specific environmental cause.

Clinical implications

A family history of PDB, particularly in the setting of early-onset or severe disease, may increase clinical suspicion. However, most individual risk factors do not independently establish the diagnosis. Genetic testing and screening of relatives with a known familial pathogenic variant should be addressed in the Screening microchapter.

Areas of uncertainty

The relative contributions of genetic susceptibility and environmental exposures remain incompletely understood. Environmental associations are based largely on observational studies and do not establish causation. Estimates of disease prevalence, sex distribution, familial aggregation, and genetic penetrance vary according to population, age, and study design.

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [18] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[19] Routine population screening for Paget's disease of bone (PDB) is not recommended. Targeted screening may be considered for adult relatives of patients with a known pathogenic SQSTM1 variant. The Zoledronate in the Prevention of Paget's disease (ZiPP) trial supports further evaluation of a genetic screen-and-treat strategy, but prevention of clinical complications has not been established.

Population screening

Routine screening of asymptomatic adults, including older adults, is not recommended by major clinical guidelines.

Reasons include:

• Limited screening-test performance: In the Rotterdam population-based accuracy study of adults older than 55 years, elevated serum total alkaline phosphatase (ALP), with normal transaminases, had a sensitivity of 57.7% and specificity of 88.9% for PDB. The positive likelihood ratio was 5.19 and the negative likelihood ratio was 0.48. This sensitivity is insufficient for reliable population screening.
• Declining disease burden: The incidence and severity of PDB have declined in several historically high-prevalence populations, reducing the expected yield of untargeted screening.
• Uncertain clinical benefit: Early detection can identify asymptomatic skeletal lesions, but there is no established evidence that treating screen-detected asymptomatic disease prevents fractures, deformity, hearing loss, or other clinical complications. The 2019 guideline found no direct evidence addressing this question.

Serum ALP: case-finding rather than population screening

Serum total ALP, interpreted alongside liver function tests, is the recommended first-line biochemical test when PDB is suspected on clinical or radiographic grounds. This is case-finding, not population screening.

A normal ALP does not exclude PDB, particularly in monostotic disease or early lesions in SQSTM1 variant carriers. If suspicion remains despite a normal total ALP, bone-specific ALP, procollagen type I N-terminal propeptide (P1NP), or urinary N-terminal telopeptide (NTX) may be considered. These markers can also be normal in early disease and should not replace imaging when evaluating high-risk carriers.

Targeted screening of relatives

Pathogenic variants in SQSTM1 account for approximately 40–50% of familial cases and 5–10% of apparently sporadic cases. Penetrance is incomplete and age-dependent. Although older estimates suggested high lifetime penetrance, long-term follow-up of carriers has shown a much lower observed incidence over the study period.

For families with a known familial pathogenic variant, a targeted approach may include:

1. Genetic counseling and testing: Consider testing adult at-risk relatives for the known familial SQSTM1 variant. Testing is most interpretable when the pathogenic variant has first been identified in an affected family member.
2. Radionuclide bone scintigraphy: Consider a baseline bone scan in variant-positive relatives to detect asymptomatic skeletal lesions. Biochemical markers alone are insufficiently sensitive for early lesions.
3. Counseling after a negative result: Relatives who test negative for the known familial variant can generally be reassured regarding that familial variant, while recognizing that testing does not exclude every possible genetic cause of PDB.

In a 16-year follow-up study of unaffected relatives, no participants without an SQSTM1 mutation developed PDB, whereas the incidence among carriers was 7.1%. In the ZiPP cohort, approximately 9% of SQSTM1 variant carriers had asymptomatic lesions on baseline bone scintigraphy by approximately the fifth decade of life. Biochemical markers had poor sensitivity for detecting these lesions, and many carriers with lesions had normal marker levels.

Screen-and-treat: evidence from the ZiPP trial

The ZiPP randomized trial compared a single 5-mg intravenous dose of zoledronic acid with placebo in 222 SQSTM1 variant carriers without a prior clinical diagnosis of PDB. Some participants already had asymptomatic bone-scan lesions at baseline: 8.1% in the zoledronic acid group and 10.8% in the placebo group. Thus, enrollment did not require a lesion-free skeleton. Median follow-up was approximately 84 months.

The main findings were:

• New lesions (primary endpoint): No new lesions occurred in the zoledronic acid group, compared with two in the placebo group. The difference was not statistically significant (odds ratio 0.41; 95% confidence interval 0.00–3.43; p=0.25).
• Composite poor outcome: No participants in the zoledronic acid group versus eight in the placebo group had new, unchanged, or progressing lesions (odds ratio 0.08; 95% confidence interval 0.00–0.42; p=0.003). At study end, one participant in the zoledronic acid group and 11 in the placebo group had lesions.
• Biochemical response and safety: Bone-turnover markers were significantly reduced with zoledronic acid. Adverse events did not differ between groups, and one placebo participant required rescue zoledronic acid for symptomatic disease.

The trial authors concluded that genetic testing for pathogenic SQSTM1 variants coupled with zoledronic acid was well tolerated and favorably affected the progression of early PDB. However, the trial was not powered to demonstrate prevention of clinical complications such as pain, deformity, fracture, or deafness. The favorable composite endpoint should therefore not be interpreted as proof that screening and prophylactic treatment improve long-term patient-important outcomes.

Clinical recommendations and limitations

• Do not screen the general asymptomatic population for PDB.
• When PDB is suspected clinically or radiographically, measure serum total ALP with liver function tests; a normal result does not exclude disease.
• In families with a known SQSTM1 pathogenic variant, consider genetic counseling and targeted testing of adult at-risk relatives.
• In variant-positive relatives, bone scintigraphy is more useful than biochemical markers alone for identifying early asymptomatic lesions.
• Prophylactic zoledronic acid in variant carriers remains an emerging strategy, not established routine care. Decisions should account for uncertainty about clinical benefit and involve specialist input and shared decision-making.

The optimal age for targeted screening, the long-term clinical benefit of screening, and the role of prophylactic treatment require further study. Evidence is derived predominantly from European-ancestry populations, which may limit generalizability to other populations.

Natural History, Complications, and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [20] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[21]

Natural History

Paget's disease of bone (PDB) is a focal disorder of accelerated, disorganized bone remodeling that may affect one bone (monostotic disease) or multiple bones (polyostotic disease). The disease generally progresses slowly and does not spread from one bone to another. A lesion may extend within an affected bone, while additional sites identified during follow-up usually represent previously unrecognized involvement rather than true disease spread.

Most people with radiographic PDB remain asymptomatic or have limited symptoms. Fewer than 10% are estimated to come to clinical attention, and diagnosis is often incidental following an elevated serum alkaline phosphatase (ALP) level or imaging performed for another indication.

Commonly affected sites include the pelvis, femur, lumbar spine, skull, and tibia. Approximate site frequencies reported in clinical series are 70% for the pelvis, 55% for the femur, 53% for the lumbar spine, 42% for the skull, and 32% for the tibia; these estimates vary by study and population.

The incidence and clinical severity of PDB have declined in several historically high-prevalence populations. Contemporary presentations tend to involve fewer bones, lower ALP levels, and fewer pathologic fractures than in older cohorts. Disease onset has also been reported to occur later in SQSTM1 variant carriers than in previous generations, suggesting that environmental or other nongenetic modifiers may influence disease expression; the responsible factors remain uncertain.

Skeletal Complications

Bone pain

Bone pain is the most common symptom among patients who present clinically. A systematic review reported pain in approximately 73% of clinically presenting patients. However, pain correlates poorly with biochemical disease activity: approximately 46% of patients with elevated ALP may have no bone pain. Pain can arise from active pagetic lesions, bone deformity, fissure fracture, secondary osteoarthritis, or nerve compression; it should not automatically be attributed to increased bone turnover.

Bone deformity and fracture

Deformity was reported in approximately 21.5% of patients at initial presentation in the cited clinical evidence. Bowing of weight-bearing bones, particularly the femur and tibia, can alter limb alignment and gait and increase mechanical stress on adjacent joints.

Pagetic bone may develop fissure fractures or complete pathologic fractures. Fissure fractures typically occur along the convex surface of a bowed long bone; complete fractures may be transverse and are sometimes described as "chalk-stick" or "banana" fractures. Pathologic fracture was reported in approximately 8.5% of patients in historical series, although fracture frequency has declined alongside overall disease severity.

Clinical warning: Sudden or worsening focal pain in a bowed femur or tibia warrants prompt assessment and radiography to exclude a progressing fissure fracture or complete fracture. New, rapidly worsening pain also requires consideration of malignant transformation.

Secondary osteoarthritis

Bone expansion and deformity can alter joint mechanics and contribute to secondary osteoarthritis. In a UK population-based study, patients with PDB had approximately three times the odds of requiring hip arthroplasty compared with age-matched controls (odds ratio 3.1; 95% confidence interval 2.4–4.1).

Bleeding during surgery

Active pagetic lesions can be markedly hypervascular. Orthopedic procedures involving affected bone may therefore be complicated by substantial intraoperative blood loss. Surgical planning should account for this risk; perioperative treatment considerations are discussed in the medical therapy section.

Neurologic and Otologic Complications

Hearing loss

Hearing loss is an important complication of skull involvement and was reported as a presenting feature in approximately 8.9% of patients in the cited clinical evidence. The hearing impairment is typically sensorineural and may involve cochlear lesions, changes in the stria vascularis, and spiral ligament abnormalities rather than being explained solely by compression of the eighth cranial nerve. Audiologic assessment is appropriate when patients report hearing impairment.

Cranial nerve and spinal complications

Neurologic complications are uncommon but can be serious. Reported manifestations include cranial nerve deficits, basilar invagination, obstructive hydrocephalus, spinal canal stenosis, and, rarely, paraplegia or quadriplegia. Mechanisms include mechanical compression and, in some cases, vascular steal associated with hypervascular pagetic bone. New neurologic deficits require prompt evaluation; treatment details belong in the relevant medical or surgical therapy sections.

Cardiovascular and Metabolic Complications

High-output cardiac failure

High-output cardiac failure attributable to PDB is extremely rare and is mainly associated with extensive, highly active polyostotic disease and substantially increased skeletal blood flow. The previously cited threshold of greater than 40% skeletal involvement should not be treated as an established clinical cutoff.

Aortic stenosis, arteriosclerosis, and intracardiac calcification have also been reported in association with PDB. These findings do not establish that PDB directly causes each condition, and cardiovascular assessment should be guided by the patient's clinical presentation.

Hypercalcemia

Hypercalcemia is unusual in PDB. When present, it may occur in patients with extensive disease who become immobilized. Other causes, particularly concurrent primary hyperparathyroidism, should also be considered rather than attributing hypercalcemia to PDB alone.

Malignant Transformation

Paget-associated osteosarcoma

Osteosarcoma is a rare but serious complication of PDB, affecting approximately 0.3% of patients according to the 2019 multi-society guideline, although estimates as high as approximately 1% have been reported in older series. It arises predominantly in longstanding, often polyostotic disease, typically in the seventh decade, and may be multifocal or metachronous. Prognosis is poor even with aggressive treatment. Historically, virtually all osteosarcomas occurring in adults older than 60 years were reported to arise in pagetic bone. Paget-associated sarcomas most often involve the pelvis, femur, humerus, or skull and tend to spare the spine.

Warning features include new or rapidly worsening focal bone pain, a new soft-tissue mass, new osteolysis, or an abrupt unexplained rise in ALP. These findings warrant prompt investigation for malignant transformation, generally involving appropriate imaging and specialist-directed biopsy when indicated. Detailed imaging features and biopsy indications are covered in the relevant diagnostic chapters.

Giant cell tumor

Giant cell tumor is a very rare complication of PDB. In Italy, its estimated prevalence among patients with PDB has been reported at approximately 0.8%, with cases overrepresented among people of Campanian descent carrying ZNF687 variants. The complication appears to be much rarer elsewhere, and estimates may not generalize to other populations.

Prognosis

The overall prognosis of PDB is generally favorable, particularly in patients who do not develop major deformity, fracture, neurologic compromise, or malignant transformation. Many patients remain asymptomatic or minimally symptomatic for prolonged periods.

Bisphosphonate therapy can suppress excessive bone turnover and improve pagetic bone pain. Zoledronic acid is associated with a high rate of biochemical response and durable remission in many patients. However, biochemical improvement should not be equated with proven prevention of long-term complications, and treatment indications and monitoring should follow the recommendations discussed in the medical therapy section.

Paget-associated osteosarcoma is a major cause of PDB-specific mortality, although it is rare. The prognosis is substantially worse when malignant transformation occurs than in uncomplicated PDB.

Clinical Implications and Evidence Limitations

• Investigate sudden or escalating focal bone pain, a new mass, or an abrupt unexplained ALP rise to exclude fracture or malignant transformation.
• Obtain prompt radiography for new localized pain in a bowed femur or tibia when a fissure or complete fracture is suspected.
• Anticipate increased intraoperative bleeding when surgery involves active pagetic bone.
• In patients with PDB and hypercalcemia, assess for immobilization and alternative causes, particularly concurrent primary hyperparathyroidism.
• Reassure patients that PDB is usually focal and slowly progressive, while explaining that complications can occur depending on disease location and extent.

The PRISM and PRISM-EZ trials found that intensive treat-to-target treatment lowered ALP but did not improve clinical outcomes, including fractures, orthopedic procedures, hearing loss, or quality of life, compared with symptom-directed treatment over approximately seven years. In PRISM-EZ, intensive therapy was associated with a nonsignificant trend toward increased fractures (hazard ratio 1.90; 95% confidence interval 0.91–3.98), as well as more orthopedic procedures and serious adverse events. These findings do not establish that intensive therapy causes harm, but they reinforce that lowering ALP alone has not been shown to prevent long-term complications. The evidence underlies disagreement between guidelines: the 2014 Endocrine Society guideline takes a broader approach to treating active disease in patients considered at risk of complications, whereas the 2019 multi-society guideline emphasizes treatment for bone pain. Detailed trial results and treatment-indication recommendations belong in the medical therapy section.

The true frequency of several complications is uncertain because PDB is increasingly uncommon in many populations and estimates are often derived from historical cohorts. Reported frequencies may not reflect the risk in contemporary patients.

Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [22] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[23] Paget's disease of bone (PDB) should be suspected in adults with unexplained elevation of serum alkaline phosphatase (ALP), an incidentally identified characteristic bone lesion, or symptoms such as bone pain, deformity, or hearing loss. Diagnosis is established primarily by characteristic plain radiographs. Serum bone turnover markers help assess metabolic activity, while radionuclide bone scintigraphy defines the distribution of metabolically active disease. Bone biopsy is rarely required when clinical and radiographic findings are typical.

Diagnostic Approach

PDB is commonly identified in one of three settings: unexplained elevation of serum ALP with normal aminotransferases, an incidental characteristic bone lesion, or symptoms suggesting skeletal involvement.

The initial evaluation should include:

1. Serum total ALP and liver function tests to assess increased bone turnover and identify a possible hepatobiliary source of elevated ALP.
2. Plain radiographs of the symptomatic or suspicious skeletal region to confirm characteristic pagetic changes.
3. Radionuclide bone scintigraphy after radiographic diagnosis to assess the distribution of metabolically active disease.
4. Additional bone turnover markers, cross-sectional imaging, or bone biopsy when initial investigations are inconclusive or complications are suspected.

Laboratory Findings

Alkaline Phosphatase and Bone Turnover Markers

• Serum total alkaline phosphatase (ALP): Total ALP measured alongside liver function tests is the recommended first-line biochemical screening test for PDB. Elevated ALP with normal aminotransferases supports increased bone turnover but does not establish the diagnosis by itself.
• In the Rotterdam study, elevated total ALP with normal transaminases had a sensitivity of 57.7% and specificity of 88.9% for PDB. The reported frequency of elevated total ALP varies across sources: approximately 95% of untreated patients in one review, compared with 78-85% in another. These estimates reflect differences in the populations and evidence summarized. A normal total ALP does not exclude PDB, particularly in monostotic disease or metabolically inactive disease.
• Additional bone turnover markers: When total ALP is normal despite strong suspicion of active disease, bone-specific ALP (BALP), procollagen type I N-terminal propeptide (PINP), or urinary N-terminal telopeptide of type I collagen (uNTX) may be useful. BALP and PINP are also useful when coexisting hepatobiliary disease complicates interpretation of total ALP.
• Other laboratory investigations: Serum calcium, albumin, renal function, and 25-hydroxyvitamin D may be assessed as clinically appropriate. Calcium and phosphate are usually normal in uncomplicated PDB. Hypercalcemia is unusual and warrants evaluation for contributing factors such as immobilization or coexisting primary hyperparathyroidism.

Imaging Findings

Plain Radiography

Plain radiography is the principal confirmatory imaging investigation. The combination of characteristic findings is usually diagnostic.

Characteristic radiographic findings include:

• Osteolysis: Early disease may produce focal osteolytic lesions, including osteoporosis circumscripta in the skull and an advancing flame-shaped or blade-of-grass lesion in long bones.
• Cortical thickening: Thickening of the cortex with loss of the normal distinction between cortical and medullary bone.
• Trabecular coarsening: Thickened, disorganized trabeculae, often accompanied by sclerosis as the disease progresses.
• Bone expansion: Enlargement of the affected bone, an important feature when distinguishing PDB from osteoblastic metastases, which generally do not produce the same pattern of bone expansion.
• Deformity and fissures: Bowing of long bones and transverse fissure fractures, particularly along the convex aspect of a deformed bone.
• Skull changes: Early osteoporosis circumscripta may progress to a mixed, patchy sclerotic appearance classically described as cotton-wool skull.
• Spinal involvement: Cortical thickening may produce a picture-frame vertebra, while diffuse vertebral sclerosis may produce an ivory vertebra. These appearances require differentiation from osteoblastic metastases and other causes of vertebral sclerosis.

A focused radiographic approach has been studied against bone scintigraphy. An abdominal radiograph, including the lower ribs and femoral heads, detected approximately 79% of cases; adding skull and facial radiographs increased detection to approximately 89%, and adding upper tibial radiographs increased detection to approximately 93%. The extent of radiographic evaluation should be guided by the clinical context and the need to identify additional skeletal involvement.

Radionuclide Bone Scintigraphy

After radiographic confirmation, radionuclide bone scintigraphy using technetium-99m-labelled diphosphonates is recommended to define the extent of metabolically active disease and identify additional skeletal sites.

• Pagetic lesions typically demonstrate intense tracer uptake.
• Scintigraphy is more sensitive than plain radiography for identifying additional sites of active disease, but uptake is not specific to PDB. Osteoarthritis, fractures, metastases, and other disorders can produce increased uptake; scan-positive lesions should therefore be correlated with radiographs and the clinical context.
• Most additional sites identified by scintigraphy may be asymptomatic.
• A negative bone scan does not exclude PDB, particularly in sclerotic, metabolically inactive (burnt-out) lesions. Radiographs may demonstrate disease despite negative scintigraphy; approximately 3.7% of sites in the cited guideline evidence were radiograph-positive but scan-negative.

FDG-PET/CT may incidentally reveal pagetic lesions during investigations for malignancy. Pagetic bone can demonstrate increased FDG uptake and mimic malignant involvement. Such findings should be interpreted alongside the CT morphology, dedicated radiographs, and clinical context rather than being considered diagnostic of malignancy on uptake alone.

Computed Tomography and Magnetic Resonance Imaging

CT and MRI are not routinely required to diagnose uncomplicated PDB. They are used primarily to investigate suspected complications, clarify complex anatomical involvement, and assist surgical planning.

• CT: Provides detailed assessment of cortical thickening, trabecular coarsening, bone expansion, and complex skull or spinal involvement. It may assist in evaluating suspected fractures, structural complications, and lesions requiring further characterization.
• MRI: Is useful for assessing spinal canal compromise, neural compression, marrow abnormalities, and suspected malignant transformation. Loss of normal T1-weighted marrow fat signal in an osteolytic lesion, cortical destruction, or an associated soft-tissue mass should raise concern for sarcomatous transformation and prompt specialist assessment and consideration of biopsy.

Other Diagnostic Studies

Bone Biopsy

Bone biopsy is rarely necessary because the combination of characteristic clinical and radiographic findings generally establishes the diagnosis. Biopsy should be considered when:

• Imaging raises suspicion of a primary bone malignancy or metastatic disease.
• The clinical presentation or radiographic appearance is atypical for PDB.
• A previously stable lesion develops new destructive changes or other concerning features suggesting malignant transformation or an alternative diagnosis.

Histopathological findings may include disorganized woven and lamellar bone, irregular cement lines producing a mosaic pattern, enlarged multinucleated osteoclasts, increased osteoblastic activity, and prominent vascularity.

Additional Investigations

• Audiometry: Consider formal hearing assessment when the skull is involved or hearing impairment is suspected.
• Genetic testing: Testing for pathogenic variants in SQSTM1 may be considered in selected patients, particularly those with early-onset disease or a strong family history. It is not routinely required to diagnose typical sporadic PDB.

Differential Diagnosis

Conditions that may mimic PDB include:

• Osteosclerotic (osteoblastic) metastases, particularly from prostate or breast cancer.
• Primary bone tumors, including sarcomatous transformation in a pagetic bone.
• Fibrous dysplasia.
• Hyperostosis frontalis interna.
• Pustulotic arthro-osteitis.
• Other causes of elevated serum ALP, including hepatobiliary disease and disorders associated with increased bone turnover.

The differential diagnosis should be guided by the clinical presentation, radiographic pattern, biochemical findings, and, when indicated, histopathological assessment.

Diagnostic Pearls

• Characteristic plain radiographs establish the diagnosis in most patients; serum ALP and bone scintigraphy provide complementary information about metabolic activity and disease extent.
• Normal total ALP does not exclude PDB, particularly in monostotic or metabolically inactive disease.
• Bone expansion, cortical thickening, and coarse trabeculation support PDB in the appropriate clinical setting.
• A negative bone scan does not exclude inactive or sclerotic disease.
• FDG uptake in pagetic bone may mimic malignancy; correlate PET/CT findings with morphology and dedicated radiographs.
• CT and MRI are primarily used for suspected complications, atypical lesions, and surgical planning.
• New destructive changes or a soft-tissue mass warrant evaluation for malignant transformation or an alternative diagnosis.

Treatment

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [24] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[25] Paget's disease of bone (PDB) has no definitive cure, and established skeletal deformities generally cannot be reversed. Treatment aims to relieve bone pain attributable to metabolically active pagetic lesions and suppress excessive bone turnover. Bisphosphonates are the mainstay of medical therapy, with a single 5 mg intravenous infusion of zoledronic acid generally considered the preferred treatment when bisphosphonate therapy is indicated. Whether treating asymptomatic disease prevents long-term complications remains controversial.

Indications for Treatment

Major guidelines agree that symptomatic active PDB is an indication for treatment, particularly when bone pain is attributable to increased metabolic activity at a pagetic site. Recommendations differ regarding treatment of asymptomatic patients and prevention of future complications.

• 2019 international clinical guideline: Recommends a symptom-focused approach, with treatment primarily directed at relieving bone pain attributable to PDB. It does not recommend bisphosphonate treatment solely to normalize serum alkaline phosphatase (ALP) in asymptomatic patients, because randomized trials have not demonstrated that an intensive treat-to-target strategy reduces major clinical complications.
• 2014 Endocrine Society guideline: Recommends treatment for most patients with active disease, including selected asymptomatic patients with involvement of sites where progression could cause important complications, such as the skull, spine, weight-bearing long bones, or bones adjacent to major joints.
• 2024 SIOMMMS position paper: Supports a broader treatment strategy and suggests that most, or potentially all, patients may be offered treatment at diagnosis because of zoledronic acid's potency and durability. However, evidence that treatment prevents complications in asymptomatic patients remains limited.

Other potential indications include neurologic complications attributable to active disease and selected cases of immobilization-associated hypercalcemia in extensive polyostotic disease. The role of pretreatment before elective surgery at an active pagetic site is controversial because evidence that it reduces operative blood loss is insufficient; see the Surgery section below.

In practice, symptomatic metabolically active disease is a clear indication for treatment. For asymptomatic active disease, the decision should be individualized according to disease location and activity, age, comorbidities, patient preferences, and the uncertainty surrounding prevention of future complications.

First-Line Medical Therapy

Zoledronic Acid

Zoledronic acid is generally the preferred bisphosphonate for PDB because of its potent suppression of bone turnover, high biochemical response rate, and durable effect.

• Dose: Zoledronic acid 5 mg intravenously as a single infusion administered over at least 15 minutes.
• Efficacy: In a randomized trial comparing zoledronic acid with oral risedronate, ALP normalized by 6 months in approximately 89% of patients receiving zoledronic acid compared with 58% receiving risedronate. The therapeutic response rates were approximately 96% and 74%, respectively. Zoledronic acid also produced a more rapid response and favorable pain and quality-of-life outcomes.
• Durability: A single infusion can suppress disease activity for years. In open follow-up extending to 6.5 years, biochemical relapse occurred in 1 of 152 zoledronic acid-treated responders (0.7%) compared with 23 of 115 risedronate-treated responders (20%), with quality-of-life benefits maintained.

Before infusion, assess renal function, check serum calcium, correct pre-existing hypocalcemia, treat vitamin D deficiency, ensure adequate calcium intake, and confirm that the patient is adequately hydrated. The prescribing information recommends calcium and vitamin D supplementation after treatment, typically approximately 500 mg of calcium and 400 IU of vitamin D daily. Monitor serum calcium after infusion when clinically indicated, particularly in patients at increased risk of hypocalcemia, and counsel patients to report symptoms such as perioral tingling, muscle cramps, or spasms.

An acute-phase reaction, including fever, myalgia, and influenza-like symptoms, occurs in approximately one-quarter of patients after the first infusion. Acetaminophen or an appropriate NSAID, when not contraindicated, may reduce the frequency or severity of symptoms. Ocular inflammation, including uveitis, is an uncommon reported reaction. Patients developing acute eye pain, redness, photophobia, or visual changes require urgent ophthalmologic assessment.

Alternative Bisphosphonates

Alternative bisphosphonates may be considered when zoledronic acid is unavailable, unsuitable, or declined by the patient. Choice depends on renal function, gastrointestinal tolerance, treatment availability, and patient preference.

Drug	Typical regimen for PDB	Clinical considerations
Risedronate	30 mg orally once daily for 2 months	Effective oral alternative; generally less durable than zoledronic acid.
Alendronate	40 mg orally once daily for 6 months	Effective oral therapy that suppresses bone turnover and can promote healing of osteolytic lesions.
Pamidronate	Intravenous regimens using repeated infusions	An alternative in selected circumstances; generally less durable than zoledronic acid.
Etidronate and tiludronate	Agent-specific regimens	Older, less potent agents. Etidronate is largely obsolete because high-dose treatment can impair mineralization and cause osteomalacia.

Alendronate is generally not recommended when creatinine clearance is below 35 mL/min. Other bisphosphonates have agent-specific renal restrictions, which should be checked before prescribing.

Oral bisphosphonates should be taken according to the agent-specific instructions, generally with plain water on an empty stomach. Patients should remain upright for the required period after administration and avoid food or other medications during the specified fasting interval to reduce upper gastrointestinal adverse effects.

Pregnancy and Reproductive Considerations

Zoledronic acid may cause fetal harm and is not recommended during pregnancy. Before initiating treatment, verify pregnancy status when applicable and advise females of reproductive potential to use effective contraception during and after treatment, in accordance with the current prescribing information. Because bisphosphonates are retained in the skeleton for prolonged periods, potential fetal effects may remain relevant after treatment has ended. The risks and benefits should be considered carefully in younger patients and in individuals who may become pregnant.

Other Medical Therapies

Calcitonin

Calcitonin can suppress bone turnover and may relieve bone pain, but its effects are less durable than those of bisphosphonates. Frequent administration, adverse effects, and rapid recurrence of disease activity after discontinuation limit its role.

The 2019 clinical guideline reserves calcitonin for short-term pain control when bisphosphonates are contraindicated or unsuitable. Long-term calcitonin use has been associated with an increased risk of cancer. FDA labeling restricts injectable calcitonin to symptomatic moderate-to-severe PDB when alternatives are unsuitable and advises periodic reassessment of the need for continued treatment. Calcitonin is not a routine first-line treatment, and intranasal calcitonin is not approved for PDB in the United States.

Denosumab

Denosumab is not recommended for routine treatment of PDB because evidence of efficacy is limited largely to case reports. It may be considered in selected patients with an associated giant cell tumor when the tumor is unresectable, under specialist guidance.

If denosumab is used off-label, discontinuation may be followed by rebound increases in bone turnover. A plan for subsequent antiresorptive therapy may therefore be needed. This concern is based primarily on evidence from other bone disorders and limited rare-bone-disease literature; the optimal approach in PDB has not been established.

Analgesics and Other Symptom-Directed Therapy

Analgesics, NSAIDs, and selected neuropathic pain medications may be used as adjuncts according to the source of pain and the patient's comorbidities. Pain should not automatically be attributed to active PDB: coexisting osteoarthritis and other musculoskeletal disorders may be responsible and may not improve with bisphosphonate treatment.

Contraindications, Adverse Effects, and Precautions

Renal Function

Renal function should be assessed before intravenous zoledronic acid. Zoledronic acid is contraindicated in patients with creatinine clearance below 35 mL/min and in acute renal impairment. No dose adjustment is recommended for patients with creatinine clearance at or above 35 mL/min, although renal risk remains clinically relevant. Alendronate is generally not recommended when creatinine clearance is below 35 mL/min. Other bisphosphonates have agent-specific renal precautions, which should be checked before prescribing. Adequate hydration and adherence to the recommended infusion duration help reduce renal risk but do not eliminate it.

Hypocalcemia and Vitamin D Deficiency

Pre-existing hypocalcemia should be corrected before bisphosphonate administration. Vitamin D deficiency should be treated, and adequate calcium and vitamin D intake ensured, to reduce the risk of post-infusion hypocalcemia. Patients with risk factors for calcium or vitamin D deficiency may require closer biochemical monitoring after treatment.

Oral Bisphosphonate Precautions

Oral bisphosphonates may be unsuitable for patients with significant esophageal abnormalities, delayed esophageal emptying, or inability to remain upright for the required period after dosing. Correct administration is important to reduce upper gastrointestinal adverse effects.

Adverse Effects

• Acute-phase reaction: Fever, myalgia, and influenza-like symptoms can occur after intravenous zoledronic acid, particularly after the first infusion. Symptoms are usually self-limited over approximately 1–3 days and are less frequent with subsequent treatment. Acetaminophen or an appropriate anti-inflammatory agent may be used when clinically suitable.
• Ocular inflammation: Uveitis and other inflammatory ocular reactions are uncommon. Acute eye pain, redness, photophobia, or visual changes warrant urgent ophthalmologic assessment.
• Hypocalcemia: Risk is increased by vitamin D deficiency, inadequate calcium intake, renal dysfunction, and other relevant comorbidities.
• Osteonecrosis of the jaw and atypical femoral fractures: These are rare adverse effects associated with bisphosphonates, particularly in settings involving prolonged or high-intensity exposure.
• Other adverse effects: Oral agents may cause gastrointestinal irritation. Potential cardiovascular safety signals, including atrial fibrillation, have been reported with zoledronic acid; their clinical significance in PDB should be interpreted in context.

Monitoring and Retreatment

Total serum ALP is a convenient and commonly used biochemical marker for assessing disease activity and response to treatment. Bone-specific ALP, procollagen type I N-terminal propeptide (PINP), or bone resorption markers such as CTX or NTX may be useful when total ALP is normal despite suspected active disease, when monostotic disease is present, or when liver disease makes total ALP difficult to interpret.

• Initial assessment of response: Reassess symptoms and relevant biochemical markers approximately 3–6 months after treatment, recognizing that the timing of response varies by marker and patient.
• Long-term follow-up: After a durable response to zoledronic acid, biochemical monitoring at approximately 1–2-year intervals may be appropriate. More frequent monitoring may be needed after less durable therapies or when symptoms recur.
• Retreatment: Consider reassessment for recurrent symptoms or renewed biochemical activity. Suggested biochemical thresholds include ALP rising above the upper limit of normal or increasing substantially from the post-treatment nadir. These thresholds are not validated universal rules and should not automatically trigger retreatment in an otherwise asymptomatic patient.

The optimal monitoring interval and retreatment threshold depend on disease extent, baseline activity, symptoms, and the agent used. Evidence that treating an isolated biochemical rise in an asymptomatic patient improves clinical outcomes remains uncertain.

Surgery

Surgery addresses complications of PDB rather than the underlying bone-remodeling disorder. Procedures are generally similar to those used in patients without PDB and may include joint replacement for severe secondary osteoarthritis, osteotomy for selected symptomatic deformities, fixation of fractures, and decompression for selected cases of spinal stenosis or neural compression.

Perioperative Bisphosphonate Therapy

Active pagetic bone may be hypervascular. The 2014 Endocrine Society guideline suggests pretreatment with a bisphosphonate before elective surgery involving active pagetic bone to reduce operative blood loss. In contrast, the 2019 multi-society guideline concluded that the evidence was insufficient to recommend bisphosphonates specifically for reducing perioperative blood loss. The evidence is of very low quality, and the decision should be individualized rather than treated as a universal requirement.

Emerging Approach: Prevention in Genetically At-Risk Individuals

The Zoledronate in the Prevention of Paget's (ZiPP) trial evaluated prophylactic zoledronic acid in asymptomatic carriers of pathogenic variants in the SQSTM1 gene. The findings support further evaluation of genotype-guided prevention but do not establish routine prophylactic bisphosphonate treatment for all genetically at-risk individuals. Detailed trial results and implications for screening and prevention are addressed in the dedicated investigational-therapy and prevention chapters.

Key Clinical Points

• Zoledronic acid 5 mg IV as a single infusion is generally the preferred treatment for active PDB requiring bisphosphonate therapy.
• Treat bone pain attributable to active PDB, while evaluating other potential causes of pain, particularly coexisting osteoarthritis.
• Assess renal function and correct hypocalcemia and vitamin D deficiency before treatment. Ensure appropriate calcium and vitamin D supplementation and consider post-infusion calcium monitoring according to risk.
• Zoledronic acid may cause fetal harm. Verify pregnancy status when applicable and counsel females of reproductive potential regarding effective contraception during and after treatment in accordance with prescribing information.
• Counsel patients about acute-phase reactions and the rare possibility of ocular inflammation requiring urgent assessment.
• Calcitonin is reserved for selected short-term use when bisphosphonates are unsuitable; long-term use is limited by an associated cancer-risk signal. Denosumab is not routine therapy for PDB.
• Do not assume that normalizing ALP in every asymptomatic patient prevents complications. Guidelines differ on treatment of asymptomatic active disease.
• Consider surgery for established complications such as severe osteoarthritis, fracture, deformity, or neural compression.
• Prophylactic zoledronic acid in SQSTM1 variant carriers remains an emerging strategy and is not routine standard care.