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
          • Osteoporosis
          • Fibrovascular hyperplasia
        • Resorption stimulates osteoblastic activity
        • Woven bone produced rapidly absorbed on both endosteal & periosteal surfaces
        • excessive & pathologic (disorganized immature) bone formation by osteoblasts
        • Bone soft
      • Osteosclerotic (osteoblastic)
        • Osteoblastic activity > osteoclastic activity
        • Sclerotic ivory-hard bone produced
        • abnormal bone remodeling
    • 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 generalized enlargement
  • Thick cortices
  • Coarse trabeculae
  • Immature woven appearance

Histology

  • Irregular segments of mature (lamellar) bone with ↑ cells
  • 1. Osteolytic phase
    • Xray
      • 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 mineralization but may see wide osteoid seams
      • Widened lamellae & disorganized cement lines
        • Gives diagnostic “Mosaic Pattern”
    • Alteration in architecture together with ↑ cement lines leads to structural weakness & facilitates propagation of cracks
    • Normal fatty or haematopoeitic 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
    • Characterized 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 & immobilization 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

  • Uses
    • Confirm diagnosis
    • Monitor treatment
    • CaPO4 & PTH are normal
    • Occasionally hypercalcaemic after immobilize
  • 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 localized 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

  • Osteitis Fibrosa cystica
  • Fibrous Dysplasia
  • Osteoblastic secondaries
  • Osteopetrosis
  • Hyperparathyroidism
  • Lymphoma

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 tumors 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
      • full body bone scan
      • XR of affected regions
  • 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 immobilization
    • 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
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 affects
  • 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 maybe 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 principle 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 lamella
  • goal of treatment i
    • to achieve / maintatin 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%)
    • -Diarrhea
    • -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 remodeling, 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 remodeling
    • 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%