Paget’s Disease

  • AKA Osteitis Deformans described by Sir James Paget 1877

Definition

  • Disorder of bone turnover & remodelling of unknown aetiology
    • Disturbance of rate of bone turnover
  • 1. OsteoLytic phase (Osteoclastic)
  • 2. OsteoSclerotic phase (Osteoblastic)
  • 3. Burnt out phase
  • Polyostotic or monostotic
  • Most asymptomatic
    • Incidental XR finding

Epidemiology

  • mostly > 50 years old
    • 5% of people > 50
    • 8% of people > 80
  • M3 > F2
  • Geographic variations
    • wide geographic variation between countries & even cities, e.g. foci of Paget’s in Lancashire & in Malta
    • 10-15% of elderly patients in Northern Europe
    • virtually non-existent in Japan
  • Temporal clusters
  • Familial clustering
    • may be autosomal dominant inheritance
    • relative risk in 1st degree relatives is 7
    • Family History 15%
  • Most common sites
    • Spine
    • Femur
    • Skull
    • Pelvis

Aetiology

Pathophysiology

  • Two Phases (classically divided into 3 parts)
    • Active
      • Osteolytic (osteoclastic)
        • Starts at one end of long bone
        • Osteoclasts hyperactive
        • Leads to ↑ bone resorption / destruction with
        • Resorption stimulates osteoblastic activity
        • Woven bone produced rapidly absorbed on both endosteal & periosteal surfaces
        • excessive & pathologic (disorganised immature) bone formation by osteoblasts
        • Bone soft
      • Osteosclerotic (osteoblastic)
        • Osteoblastic activity > osteoclastic activity
        • Sclerotic ivory-hard bone produced
        • abnormal bone remodelling
    • Inactive (“burnt out”)
      • Bone remodelling & turnover decreases to normal
      • Remaining bone is
        • Enlarged
        • Brittle
        • Sclerotic
        • Deformed

Pathology

Gross

  • Distorted bone
    • Bowed because structurally weak
  • Spongy bone with generalised enlargement
  • Thick cortices
  • Coarse trabeculae
  • Immature woven appearance

Histology

  • Irregular segments of mature (lamellar) bone with ↑ cells
  • 1. Osteolytic phase
    • X-ray
      • an advancing wedge of osseous rarefaction
    • Marked ­ osteoclastic resorption
      • Multinucleated osteoclasts with nuclear inclusion bodies line the trabeculae
      • Extremely vascular fibrous tissue fills the marrow spaces (osteoporosis circumscripta)
      • Inflammatory cells absent
      • Cancellous bone
        • Trabeculae slender & sparse
      • Cortical bone
        • Large resorption cavities seen
    • Prominent osteoblasts occur concurrently
      • Appositional new bone formation
      • Woven bone
    • Both ↑ osteoclastic & osteoblastic activity seen on the same trabeculae
    • Process occurs on both endosteal & periosteal surfaces ® bone ↑ in thickness but is structurally weak ® deformity
    • Frenetic cell activity difficult to differentiate from hyperparathyroidism (osteitis fibrosa cystica)
  • 2. Osteoblastic phase
    • New bone formation predominates over resorption
    • Trabeculae are broad & the cortical bone thickens with sclerosis
      • Neither cortical nor cancellous in architecture
      • No abnormality of mineralisation but may see wide osteoid seams
      • Widened lamellae & disorganised cement lines
        • Gives diagnostic “Mosaic Pattern”
    • Alteration in architecture together with ↑ cement lines leads to structural weakness & facilitates propagation of cracks
    • Normal fatty or haematopoietic marrow replaced with fibrovascular connective tissue
  • 3. “Burnt-out” phase
  • 4. ?sarcoma

Clinical Features

  • Usually asymptomatic or pain & deformity
  • Monostotic in 17% & polyostotic in 83%
    • pelvis 70%
    • Lumbar spine 50%
    • femur 50%
    • skull 45%
    • tibia 30%
    • humerus 30%
    • clavicle 13%
    • hand & foot 3 – 5%)
  • Asymptomatic (incidental finding)
    • 20% asymptomatic
      • diagnosed from XR taken post trauma
      • ­alkaline phosphatase
  • Pain in Pagetoid bone
    • » “BANISH”
      • Bone pain
        • Deep, constant & aching
        • Due to
          • metabolic activity
          • periosteal stretching
          • vertebra compression Fracture
        • If worse at night
          • ? sarcoma, impending Fracture
      • Arthritis
        • Due to
          • Abnormal subchondral bone
            • Abnormal biomechanics due to deformity
          • Usually Medial Hip Osteoarthritis
            • Cf. Superior pole with primary Osteoarthritis
      • Neurological impingement
        • Stenosis
          • Central or Lateral Recess
        • Cranial Nerve
      • Impending fracture
        • Pain on weight bearing
      • Sarcoma
        • Severe night pain
      • Hypercalcaemia
  • Deformity
    • Characterised by
      • Increased size & abnormal shape of bones
        • Thicker cortex
        • Bow along stress lines
        • Femora bow anterior & lateral
        • Tibia bow anterior & lateral – Saber Shin
      • Skull enlargement
        • Occiput & frontal areas
        • Hats don’t fit
      • Thoracic Kyphosis
      • Arthrokatadysis
  • Pathological Fracture
    • Incidence of 10%
    • Most frequent in
      • Femoral neck
      • Subtrochanteric femur
      • Tibia
    • Usually transverse
    • On convex side (cf. Looser zones in osteomalacia)
    • Tension side of bone may have painful stress fractures
    • This fracture usually begins as a transverse line on the convexity or tension side of the bone & progresses across the cement lines. The transverse radiolucent line is described as a pseudofracture
    • Patients with pseudofracture are usually managed with protected weight bearing & immobilisation in a cast until there is relief of pain. Prophylactic nailing is made problematic by the associated deformity
    • “Fracture healing can be impaired, resulting in delayed union & nonunion” (Dee 1997)
  • Neurological Compromise
    • Cranial Nerve entrapment in foramina
    • Neurosensory & Conductive deafness
      • Cochlear compressed & ossicle ankylosis both lead to deafness
      • 50% of patients deaf
    • Softening & basilar invagination with vascular compression
    • Brain stem or Cerebellar compression
      • Blockage CSF flow with hydrocephalus
    • Spinal Stenosis may require surgical decompression
  • CVS Compromise
    • High-output cardiac failure
    • Steal syndrome
      • Shunting of blood can cause cerebral hypoxia & spinal cord ischaemia
  • Malignant Change
    • 1%
    • More common in polyostotic form (5%)
    • Men twice as likely as women to see malignant change
      • 70yo
        • 30% bone sarcomas secondary to Paget’s
        • Osteosarcoma followed by MFH most common forms
        • Survival for Enneking IIB is 15%
    • Suspect if previously affected bone painful, swollen & tender
    • Large rise in Alk Phos level often seen
  • ­ skin temperature
    • due to ­ vascularity of bone

Laboratory Investigations

Paget's Disease, radiograph of paget disease of the right hip bone
Radiograph of Paget disease of the right hip bone. Image by Jmarchn, Wikimedia Commons, CC BY-SA 4.0.
  • Uses
    • Confirm diagnosis
    • Monitor treatment
    • CaPO4 & PTH are normal
    • Occasionally hypercalcaemic after immobilise
  • Alkaline Phosphatase (ALP)
    • Hallmark of active disease

Up to ­ 20-30 Times Normal

  • 10% of patients with Pagets will have levels within the normal range
  • Located in the plasma membrane of osteoblasts
  • Reflects
    • ­ bone formation
    • number & functional state of osteoblasts; that is the level of bone formation
  • Correlates roughly with the extent of skeletal involvement
  • Serial determinations provide biochemical index of disease activity
  • measure annually to monitor disease
    • Measure of osteoblastic activity
    • Dependent on extent of disease
    • May be normal with localised Paget’s
    • Rapid ↑ may indicate sarcomatous change
    • 50% of ALP is of hepatic origin
      • Is There Now Bone Specific ALP?
    • Can distinguish Hepatic cause by
      • Assessment of other LFT
      • Urine Hydroxyproline
  • Urinary Hydroxyproline
    • Marker of osteoclastic activity
    • Reflects collagen turnover
    • 24hr urine level measured
    • Disadvantage lack of sensitivity
      • Useful for extent & progress of disease
    • Rapidly reflects response to treatment
  • Pyridinium Crosslinks
    • New measure of bone resorption
    • Measures urinary excretion
      • Of hydroxypyridinium crosslinks of collagen
    • Derived from degradation of mature bone collagen
    • More specific marker than Hydroxyproline

Differential Diagnosis

Radiology

XR

  • Focal bone resorption & formation
    • Radiolucencies
    • Radiodensities
  • Overall bone size enlarged
  • Coarse trabecular pattern

Active Stage

  • Skull
    • Sharp radiolucent areas (Osteoporosis Circumscripta)
  • Long bones
    • Flame-shaped osteolytic front extending from ends (Flame Sign)
      • “flame” advances along the bone
        • 1cm/year in untreated patients

Inactive Stage

  • Skull
    • Fluffy thick sclerotic bone (Cotton Wool Skull)
  • Spine
    • Cortical Sclerosis (Picture Frame Vertebra)
    • Uniform sclerosis with ivory vertebra (Ivory Body)
    • ­ size of the vertebra
  • Long bones
    • Sclerosis with cortical thickening & coarse trabeculae
    • Widened deformed bone
    • Coxa Vara
    • Anterolateral bowing
    • Chalk Stick
  • Pelvis
    • Patchy osteolytic/ osteoblastic changes
    • Thickening of pelvic brim & iliopectineal line (Brim Sign)
    • Protrusio
  • Secondary Osteoarthritis

Bone Scan

  • High turnover/ active phase
    • May show markedly ↑ uptake in the area
  • With treatment & inactive (burnt out) phase
    • May be less hot or cold
  • Useful
    • Confirm diagnosis
    • As baseline
  • Cold in Hot » Consider Pagetoid Sarcoma
  • Gallium scans
    • hot with tumours but not with Paget’s

CT Scan

  • Diagnose or exclude sarcomatous change

MRI

  • Shows new cortical destruction
  • Soft tissue mass
  • Spinal Stenosis

Management

  • Most patients never need treatment
  • All patients
    • Stage the disease
  • No treatment
    • Most
    • Asymptomatic patients with near normal body chemistry whose weight bearing bones are not involved

Indications

  • Medical Treatment
    • Pain
    • Neurological complications
      • Spinal Stenosis
      • Deafness
    • Repeated fractures
    • Deformity
    • Mild Osteoarthritis
    • Before & after bone surgery
    • Hypercalcaemia due to immobilisation
    • High-output cardiac failure
  • Surgery
    • Severe Osteoarthritis
    • Severe malalignment pain
    • Pathological fracture
    • Sarcomatous degeneration
  • Neurosurgery
    • Stem or cord compression

Medical Treatment

  • Indication is mainly pain
  • Aim is to retard osteoclasts
    • Hence works best in active disease
  • Simple Analgesia
    • Use in normal turnover & mild pain
  • Calcitonin
    • Small polypeptide hormone from the parafollicular cells of thyroid
    • Potent inhibitor of osteoclastic activity (direct inactivation of osteoclasts)
    • Salmon form most potent
    • Expensive
    • Nasal Spray or IVI
      • Start with 100u daily
      • Reduce to weekly after response
      • If no response in 3/12 stop
    • N & V
    • Relapse 30% of patients
    • 10% have antibody-mediated resistance
      • » Use human form
    • Reserve for
      • Severe pain due to rapid turnover
      • Impending fracture, fracture & post ORIF
      • Ie. Diphosphonates contraindicated
  • Diphosphonates
    • Pyrophosphate analogue
    • Decouples osteoblast-osteoclast interaction
    • Inhibit normal bone resorption & mineralisation
      • With low dose inhibition of bone resorption predominates
      • with chronic use or high dose inhibition of mineralisation predominates
        • Thus can cause focal osteomalacia
          • May lead to pathological fracture
    • » Contraindicated if impending fracture or fracture & postoperative (due to risk of nonunion)
    • Use in high turnover disease with pain
    • Advantages
      • Oral
      • Cheaper
      • Less relapse than Calcitonin
Etidronate
  • Older form
More Risk Osteomalacia
  • Etidronate impairs mineralisation at the doses used for Paget’s disease
  • Prolonged or high dose courses cause osteomalacia and raise fracture risk
  • Courses limited to 5 mg/kg/day for up to six months
  • Superseded by more potent bisphosphonates such as zoledronic acid
Alendronate
  • Newest
  • Least Osteoblasts effects
  • Empty stomach
  • Upright 1/2 hr
  • Pamidronate
    • Given IV
    • Used by RBH

Serial Management

  • Alternate Calcitonin & Bisphosphonate (Alendronate)
  • Enhances effects
  • Decreases side effects
  • Try medical treatment first with spinal stenosis
  • May ↓ ‘steal’ syndrome
  • Mithramycin
    • Antibiotic with cytotoxic properties
    • Potent osteoclast inhibitor
    • Rapidly relieves pain from Pagets
    • Causes hypocalcaemia
    • Main indication due to severe side-effects is Pagets Paraplegia
  • Surgery
    • Stress Fractures
      • Try bracing & NWB
      • Prophylactic ORIF if not healed 3/12
      • Earlier if NOF fracture on tension side
  • Complete fracture
    • Most commonly occur in
      • Femur
      • Tibia
      • Humerus
      • Radius
      • Ulna
    • Fracture may be the first sign of Paget’s disease in 2/3 of patients
    • Classically transverse orientation with disruption of the periosteal sleeve & comminution
    • Most fractures will heal with abundant callus
    • Non-union common
      • Correct deformity prior ORIF
        • May require osteotomy for femoral shaft or subtrochanteric fracture
      • Femoral neck fracture
        • Subcapital/ Transcervical
          • Hemiarthroplasty preferable
          • Almost 100% non-union with internal fixation
          • If protrusio consider THR
        • Subtrochanteric/ Intertrochanteric
          • More common
          • Tend to unite after internal fixation
          • Higher non-union with Subtrochanteric
        • Higher nonunion seen in
          • Subtrochanteric fracture
          • Sclerotic phase
          • Usually heal with callus +++
        • Calcitonin useful to promote healing
  • Varus deformity of shaft will make Intramedullary nailing difficult & may require osteotomy
  • Arthritis
    • TJR – Good success rates
    • Slight ↑ risk loosening
    • Pagets & TJA
      • No difference from other primary THR if cemented with respect to aseptic loosening
      • No studies for TKR
      • Always correct proximal deformity first (eg hip if knee affected)
  • Total Hip Arthroplasty
    • Similar indications as non-Pagetoid disease
    • Preoperative
      • Need to ensure that pain from the joint disease & not bone disease
        • Painful joint with Pagets
          • Bone pain with active Pagets
          • Insufficiency Fracture
          • Osteosarcoma
          • Arthritis
          • Neurological compression
          • Proximal problem
            • Eg. with painful knee consider hip or spine
      • Essential to get long leg, weight-bearing films
      • ALP
        • If ALP > 700 then need to control medically prior to OT
        • » Increased bleeding
        • » Catastrophic hypercalcaemia
      • Endocrinology Review
      • Anaesthetic review
    • Intraoperative
      • Deformity
        • Coxa Vara
          • » Tendency varize stem
            • May need femoral osteotomy to allow insertion of stem
            • Always get full length films
        • Protrusio Acetabuli
      • Increased bleeding
        • Cross match blood
      • Sclerotic
        • Difficult reaming
          • Sharp reamers
    • Postoperative
      • HO
        • 52% vs 5 % in normal patients (Merkow et al 1984)
        • Treat with NSAID
      • Early loosening
        • Not substantiated (Halliday says similar results to primary THR in non-Pagetoid bone)
  • Osteotomy
    • Performed to
      • Improve deformity
      • Improve mechanics of weight bearing joint
    • Good results with HTO
    • Intertrochanteric hip osteotomy less reliable
    • Slow healing if sclerotic phase
    • Hugh English advises strongly against this…
    • Not advised to do osteotomy » fails to heal » high nonunion rate
  • Spinal Stenosis
    • Middle-aged man with increasing paresis over a year
    • Usually multiple levels

Principles

  • There are three principal classes of drugs all are primarily inhibitors of bone resorption
  • each induces a rapid fall in hydroxy proline values within the first few days of treatment & this is followed by a later fall in alkaline phosphatase
  • Disease monitoring with Alkaline phosphatase levels
  • normal = 30-120 units/L (analytical error 9u/L)
  • Course of therapy usually continues six months, & 60% achieve remission without relapse for 5 years
  • If relapse occurs
    • recommence therapy
  • For surgery should commence 3 months prior to surgery & continue for six weeks post surgery

Bisphosphonates

  • Action
    • Potent inhibitors of bone resorption
    • Bind to hydroxyapatite crystals – poisons osteoclasts; induces apoptosis & decreases their recruitment
    • New bone formed during treatment is lamellar
  • goal of treatment i
    • to achieve / maintain a mid-range normal level of SAP
    • Treatment is restarted when the SAP climbs to 25% higher than this
  • Agents
  • alendronate (Fosamax)
    • agent of choice
    • orally
    • doesn’t cause osteomalacia
    • more effective than etidronate or calcitonin
    • 40mg orally daily for six months
    • Compare with dose for osteoporosis (10mg/day)
    • Side effects
      • oesophagitis
        • patient should remain upright for 30mins after taking the tablet
  • Pamidronate (Aredia)
    • intravenously
    • 60mg over four hours every 8-12 months
    • Side effects
      • iridocyclitis or a flu like illness
Calcitonin
  • Obsolete now
  • Binds to adenylate cyclase & turns off osteoclasts
  • Dosage: 50-100U intranasally daily then three times weekly
  • Causes fall in serum calcium & ↓ resorption of bone
  • Urinary hydroxyproline decreases in a matter of days
  • Long term benefits
    • -Relief of bone pain – occurs in a couple of weeks
    • -Reduction in cardiac output
    • -May reverse neurological deficits
    • -Healing of osteolytic lesions
    • -Reduction of bleeding associated with surgery
  • Side effects
    • -Nausea & flushing (up to 30%)
    • -Diarrhoea
    • -Pain at injection site
    • -Resistance can develop (up to 20% in patients treated with salmon calcitonin)
  • Treatment needs to be continued long term

Orthopaedic Surgical Procedures

Fractures
  • most common complication
  • 10% of patients with extensive Paget’s disease will suffer pathologic fracture, usually of the femur, tibia, or forearm
  • High complication rate
    • Delayed union or non-union
      • 15-40% nonunion
      • ­
        • sclerotic phase of the disease
        • subtroch femurs
  • Often fracture through sarcoma
    • 5-20% of pagetoid fractures!
  • Stress or pseudofractures
    • Commonly
      • tibia
      • proximal femur
      • convex side of bone
    • Treatment
      • protected weight bearing
      • If pain persists for more than 3-6 months prophylactic surgical treatment is warranted
  • Completed fractures
    • Diaphyseal
      • transverse or short oblique – chalk stick
      • Treatment
        • IM
          • Passage of an intramedullary device may be technically difficult because of the disordered architecture of the pagetic bone
    • Femoral neck fractures
      • Subcapitals
        • nonunion rate of 75-90%
        • Low threshold for hemiarthroplasty
      • Intertrochanteric fractures
        • will usually unite
    • With these exceptions, fractures in Paget’s disease tend to heal with abundant callus
    • Delayed union or nonunion is more common in the sclerotic burned-out phase of the disease. Even after successful union, protective bracing may be needed for 3–6 months to allow for remodelling, which is slow
  • Corrective osteotomies are frequently required
Elective Orthopaedics
Hip Replacement
  • Preoperative
    • Referred pain
      • ? cause of pain hip vs spine
      • many patients also have involvement of the lumbar spine
      • carefully separate possible lumbar spine pain from hip pain before undertaking arthroplasty of the hip
      • Diagnostic block should be considered
    • Medical referral
      • Bisphosphonates
      • Not in active phase
  • Intraoperative
    • Pelvic
      • 25% rate of protrusio
    • Femoral
      • Varus deformity
      • Anterolateral bowing of the femur (usually not a major problem because the femoral canal is widened)
      • Distorted medullary canal
    • Prosthesis
      • Uncemented preferred
        • Cement should not be used
          • Because of active remodelling
    • Increased blood loss
      • should pre treat with bisphosphonates
    • Difficulty in reaming sclerotic bone
  • Postoperative
    • Rate of loosening is ↑ (10-15% at 10 years)
    • Heterotopic ossification – up to 50%

Reviewed by Professor Phong Tran, Head of Orthopaedic Surgery, Western Health. Last updated 10 October 2026.