Paget disease of bone

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Paget disease is a local remodelling disorder, not generalised osteoporosis. Ask about deep focal bone pain, warmth, limb bowing, increasing hat size, headache, hearing change, dental fit, joint-related pain, radicular symptoms, gait disturbance, fractures and family history. Examine skull contour, hearing, spinal neurology, limb alignment, local warmth, adjacent joint range and gait. Most affected adults are older than 50, and calcium and phosphate are normally preserved unless another disorder or prolonged immobilisation intervenes.

The diagnostic sequence separates confirmation, mapping and activity. A targeted radiograph establishes characteristic structure: coarsened trabeculae, cortical thickening, expansion, mixed lysis and sclerosis, or a blade-of-grass lytic front. Total ALP with liver tests is the usual biochemical screen. Once confirmed, radionuclide scintigraphy identifies other active sites. A normal ALP cannot exclude a small monostotic lesion, so bone-specific markers help when liver disease or limited burden obscures signal.

Treatment is driven mainly by Paget-attributable bone pain and selected complications, not by normalising every marker. Zoledronic acid produces prolonged suppression, but osteoarthritis, fixed deformity or nerve compression may persist despite falling ALP. Joint replacement, fixation, decompression, hearing support and ordinary analgesia remain important. Evidence does not support routine bisphosphonate solely to reduce bleeding before Pagetic bone surgery.

Key points

Paget disease is focal accelerated bone turnover producing enlarged, disorganised and mechanically weak bone; pelvis, spine, femur, tibia and skull are common sites.
Many cases are incidental after isolated raised ALP or characteristic radiography; confirm suspected sites with plain films and check total ALP with liver tests.
After radiographic diagnosis, radionuclide bone scintigraphy maps the full extent of metabolically active disease; uptake is sensitive but not specific.
Normal total ALP does not exclude monostotic disease; bone-specific ALP, PINP or urinary NTX can support activity assessment when liver disease confounds interpretation.
Treat bone pain attributable to active Paget disease with a bisphosphonate; one zoledronic-acid 5 mg infusion provides the most durable response and favourable pain effect.
Do not treat an ALP value alone or pursue complete biochemical normalisation in every asymptomatic patient; decide whether a lesion explains symptoms or threatens a defined complication.
Pain may instead arise from secondary osteoarthritis, fissure fracture, nerve compression, spinal stenosis or malignancy, each needing its own management.
Check calcium, vitamin-D status and kidney function before potent bisphosphonate treatment and warn that fever and myalgia commonly follow first zoledronate infusion.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Genetic susceptibility

Familial clustering and variants affecting osteoclast regulation, especially SQSTM1, contribute substantially; family history often predicts earlier onset and more extensive involvement.

Age and geography

Disease is uncommon before 50 and becomes more prevalent with age; frequency varies geographically and has declined in severity in several historically high-prevalence regions.

Uncertain environmental triggers

Environmental influences have been proposed, but no single infection or exposure is established as the direct cause and routine antimicrobial investigation has no role.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Excess osteoclast activity
Focally increased osteoclast number and activity creates rapid disorganised resorption; early lesions may be predominantly lytic and advance through affected bone.
2
Chaotic compensatory formation
Osteoblasts replace resorbed bone quickly but lay woven and lamellar tissue in a mosaic pattern rather than normal aligned architecture.
3
Enlarged weak bone
Resulting bone can be expanded, hypervascular and mechanically abnormal; it may bow, fissure or fracture despite appearing sclerotic and dense.
4
Local structural effects
Expansion and deformity alter adjacent joint loading and can narrow neural foramina, compress spinal or cranial nerves and complicate surgery through abnormal anatomy.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Incidental biochemical signal

An isolated raised ALP with normal liver markers in an older adult commonly triggers investigation, although the value reflects total active skeletal burden.

Focal bone pain

Pagetic pain is often deep, localised and present at rest, sometimes with warmth; mechanical adjacent-joint pain follows movement and loading.

Long-bone deformity

Anterior tibial or lateral femoral bowing changes gait and concentrates tensile stress, increasing fissure and complete fracture risk.

Skull involvement

Increasing hat size, frontal bossing, headache and progressive hearing impairment suggest skull disease, while cranial neuropathy signals complicated expansion.

Spinal involvement

Back pain, stenotic claudication, radiculopathy or myelopathy can result from enlarged vertebrae, degeneration, fracture or epidural compromise.

Malignant warning change

New relentless pain, rapid enlargement, focal swelling or a mass within known Pagetic bone is atypical and requires urgent malignancy assessment.

Red flags requiring action

Rapidly increasing focal bone pain, enlarging swelling, a soft-tissue mass or new destructive imaging requires urgent assessment for sarcomatous transformation or another malignancy.
New weakness, gait disturbance, sensory loss, bladder or bowel dysfunction, dysphagia or brainstem symptoms may indicate neural compression and needs expedited cross-sectional imaging.
Sudden severe limb or hip pain with deformity or inability to bear weight suggests pathological fracture through Pagetic bone.
Marked hypercalcaemia, dehydration, confusion or kidney injury during immobilisation is unusual but can occur with extensive active disease and requires acute treatment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line total ALP and liver testsFirst stepFirst line
Why
Screen for increased bone turnover and distinguish a likely skeletal source from hepatobiliary ALP elevation.
Interpretation and limitations
Raised ALP with otherwise normal liver tests supports active skeletal turnover but is nonspecific; normal ALP may occur in monostotic or quiet disease.
02
Confirmatory targeted radiographsConfirmatory
Why
Demonstrate expansion, cortical thickening, trabecular coarsening, lysis and sclerosis at a suspected site.
Interpretation and limitations
Characteristic films usually establish diagnosis; aggressive permeative destruction, cortical breakthrough or soft-tissue mass requires tumour referral.
03
Extent-defining bone scan
Why
Map additional metabolically active sites after radiographic confirmation and guide dedicated anatomical imaging.
Interpretation and limitations
Focal uptake is sensitive but also occurs with metastasis, fracture and arthritis; correlate each unexpected focus with radiography or cross-sectional imaging.
04
Alternative turnover markers
Why
Assess activity when total ALP is normal despite limited disease or cannot be interpreted due to liver pathology.
Interpretation and limitations
Bone-specific ALP, PINP or urinary NTX can reflect remodelling; use the same marker for follow-up without substituting it for clinical outcome.
05
CT or MRI for complications
Why
Define neural compression, occult fracture, skull-base anatomy, malignant change or complex surgical relationships.
Interpretation and limitations
MRI demonstrates marrow and neural structures; CT shows cortex and mineralised anatomy; urgency follows neurological deficit or aggressive change, not ALP concentration.
06
Pre-bisphosphonate safety tests
Why
Prevent hypocalcaemia and kidney injury and identify another metabolic explanation.
Interpretation and limitations
Check adjusted calcium, phosphate, vitamin D and creatinine clearance; correct deficiencies and avoid intravenous zoledronate below its licensed renal threshold.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Metastasis or sarcoma

Focal sclerosis, lysis and pain can be malignant; aggressive destruction, soft-tissue mass, disproportionate pain or atypical scan pattern needs oncological imaging and biopsy planning.

Osteoarthritis

Hip, knee or spinal osteoarthritis commonly coexists and may generate the pain; joint-line pattern and targeted imaging prevent treatment of an incidental Pagetic site.

Hyperparathyroid bone disease

Hyperparathyroidism can raise ALP and remodel bone diffusely, but calcium, PTH and distribution differ; Paget disease is usually focal with normal calcium.

Fibrous dysplasia

Fibrous dysplasia also expands abnormal bone, often presenting earlier with ground-glass matrix; age, distribution and radiographic boundaries guide distinction.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First-line diagnosisConfirm locally, map globallyFirst stepFirst lineFocal abnormal imaging, compatible pain or unexplained bone-source ALP elevation raises suspected Paget disease.

1Take a site-specific history and examination, check total ALP with liver profile, calcium, phosphate, kidney function and vitamin D, and obtain targeted radiographs.
2Once films are characteristic, arrange radionuclide scintigraphy to define distribution and image unexpected high-uptake sites anatomically when uncertain.
3Use bone-specific ALP or another marker if monostotic disease is likely or hepatic ALP obscures activity, reserving biopsy for diagnostic or malignant uncertainty.
4For each site, decide whether symptoms arise from active bone, adjacent osteoarthritis, fracture, deformity or neural compression.

02Preferred symptom treatmentSuppress painful active remodellingPreferredDeep focal pain is attributable to active Paget disease and no urgent structural complication dominates.

1Correct vitamin-D deficiency and hypocalcaemia, verify creatinine clearance, review dental and pregnancy context, and explain the transient acute-phase reaction.
2Offer one 5 mg intravenous zoledronic-acid infusion when suitable because UK guidance identifies it as most likely to give a favourable pain response.
3Use oral risedronate 30 mg daily for two months when intravenous treatment is unsuitable but swallowing, absorption and renal function permit.
4Review pain and baseline marker after treatment; never repeat solely because ALP has not reached the middle of the reference range.

03Complication escalationTreat anatomy rather than markerEscalationFracture, deformity, joint failure, hearing impairment or neurological compression causes disability or threatens function.

1Use urgent fracture stabilisation and spinal or neurosurgical assessment for instability or neurological loss; remodelling suppression is not decompression.
2Refer disabling secondary hip or knee osteoarthritis for arthroplasty and alert surgeons to deformity, anatomy, vascularity and bone-quality considerations.
3Arrange audiology and hearing support because bisphosphonate has not reliably prevented hearing-loss progression.
4Do not give bisphosphonate routinely solely to reduce operative blood loss; let the surgical team plan anatomy, vascularity and haemostasis.

04Urgent malignancy routeInvestigate aggressive changeEscalationKnown or suspected Paget disease develops rapidly escalating pain, swelling, a mass or destructive imaging.

1DefinitiveObtain urgent radiography and MRI or CT of the whole lesion, avoiding unplanned biopsy that could compromise definitive tumour surgery.
2Refer through a bone-sarcoma service so staging and image-guided biopsy occur along an oncologically safe tract.
3Continue analgesia and protect weight-bearing bone while malignancy, fracture and infection are differentiated; ALP alone cannot resolve them.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Preferred bisphosphonate for Paget-attributable bone pain because it provides strong durable turnover and pain responses.

Zoledronic acid

Give 5 mg by intravenous infusion over at least 15 minutes as a single treatment, with adequate hydration, calcium and vitamin D; retreatment follows clinical relapse rather than a fixed calendar.

Avoid creatinine clearance below 35 mL/min, hypocalcaemia and pregnancy. Correct vitamin-D deficiency, check creatinine and warn about transient fever, myalgia and headache; jaw and femur complications are rare.

Licensed oral alternative when bisphosphonate treatment is indicated but intravenous zoledronate is unsuitable or not preferred.

Risedronate sodium

Take 30 mg orally once daily for two months, at least 30 minutes before food, drink except water, or another medicine; remain upright for at least 30 minutes.

Avoid hypocalcaemia, severe renal impairment, oesophageal emptying disorders and inability to remain upright; separate calcium, iron and antacids and avoid during pregnancy.

Treats coexisting mechanical or fracture-related pain while its anatomical source is defined; it does not suppress Pagetic remodelling.

Paracetamol

Use 500 mg–1 g orally at intervals of at least four hours when needed, maximum 4 g in 24 hours for a suitable adult, with a lower ceiling for low weight, frailty or liver risk.

Avoid duplicate combination products and reduce exposure with hepatic disease or excess alcohol; persistent pain requires diagnostic reassessment rather than automatic escalation.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Deformity and fracture

Bowing of femur or tibia, skull enlargement and fissure or complete pathological fractures arise because enlarged mosaic bone is mechanically inefficient.

Secondary osteoarthritis

Altered alignment and subchondral change increase load across hips, knees and spine, causing degenerative pain that may persist after biochemical suppression.

Neurological and hearing loss

Skull or vertebral expansion can produce hearing impairment, cranial neuropathy, spinal stenosis, cord compression or rarely skull-base and hydrocephalus complications.

Rare sarcomatous change

Osteosarcoma or another sarcoma is uncommon but aggressive; escalating pain, swelling, a mass or new lytic destruction must not be dismissed as turnover.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Document pretreatment pain location and character so improvement in deep bone pain is not confused with unchanged osteoarthritis or radicular symptoms.
Repeat the chosen turnover marker, often total ALP, around three to six months after bisphosphonate treatment and use its nadir as a comparator.
Review sooner for new weakness, gait change, hearing symptoms, deformity, focal swelling or rapidly changing pain regardless of the latest ALP.
After zoledronate, distinguish the expected short acute-phase reaction from persistent fever, focal infection, symptomatic hypocalcaemia or kidney injury.
Long-term follow-up can be symptom-led with periodic biochemical review; biochemical relapse without symptoms does not automatically mandate retreatment.
Maintain falls, joint, hearing and mobility support because fixed structural consequences may persist after turnover suppression.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

ALP measures burden

Total ALP rises more in extensive active disease and may remain normal in one small lesion; it is neither a pain scale nor cancer test.

Scan and film differ

Scintigraphy sensitively maps activity, whereas radiography establishes Pagetic structure; a hot focus alone is not specific enough for diagnosis.

Pain needs attribution

An affected pelvis beside an arthritic hip creates two possible generators; examination and correlated imaging prevent futile biochemical treatment.

Dense is not strong

Pagetic bone can look sclerotic while its mosaic architecture and deformity make it susceptible to fissure and complete fracture.

New pain may be malignant

Rare sarcoma is dangerous enough that a rapid qualitative change in pain, swelling or imaging deserves urgent specialist evaluation.

11Common pitfallsFrequent interpretation and management errors.

01
Do not diagnose Paget disease from raised ALP alone; confirm a skeletal source, image characteristically and consider liver disease, fracture and malignancy.
02
Do not use radionuclide uptake as a stand-alone diagnosis because metastasis, arthritis and healing fracture can all be active.
03
Do not assume every painful joint next to Pagetic bone responds to bisphosphonate; secondary osteoarthritis often needs joint-directed care.
04
Do not chase biochemical normalisation in an asymptomatic person without a defined clinical objective.
05
Do not let normal ALP reassure against cord compression, fracture or sarcoma when new structural or neurological features are present.
06
Do not give zoledronate before correcting hypocalcaemia or important vitamin-D deficiency and confirming renal suitability.