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

A>Aetiology

Unknown – ? disorder of osteoclasts
Recent evidence Paramyxovirus
- Measles
- Respiratory Syncitial Virus
Probably, Pagets disease is caused by infection with a common & widespread virus superimposed on genetic variation for susceptibility
- Viral
  - slow virus
  - Virus intra-nuclear inclusion bodies in osteoclasts
  - measles (paramyxovirus) or adeno-type
  - Has never been grown
- Genetic
  - A candidate gene on chromosome 18q
  - familial clustering
    - positive family history in 15% to 30% of patients
- Human leukocyte antigen (HLA) patterns
Associations
- primary hyperparathyroidism
- DISH (14-30%)
- gout & pseudogout

P>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

Patholo>Pathology

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Distorted bone

Bowed because structurally weak

Spongy bone with generalized enlargement

Thick cortices

Coarse trabeculae

Immature woven appearance

Histolo>Histology

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Irregular segments of mature (lamellar) bone with ↑ cells

Osteoclasts, Osteoblasts, Fibroblasts
Osteoclasts
- activity
  - number & size
    - Osteoclasts are normally present in bone but are seen only rarely, only 0.1% of the bone surfaces should show active osteoclast resorption & only 5% of bone surfaces should show scalloped morphology
  - Nuclei are numerous & remarkably large
    - more than 100 per cell, usually less than 20
  - bone turnover is greatly ↑ (up to 40 times normal)
Osteoblasts
- activity
Peritrabecular fibrosis
- also seen in other hypermetabolic conditions such as hyperparathyroidism
Hypervascular
Cortex
- thickened
- Corticomedullary demarcation lost
Trabeculae
- both thick & thin
- Mosaic pattern
  - “Burned-out” sclerotic pagetic bone

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

Gradually osteoclastic activity abates & the eroded areas fill with new lamellar bone leaving an irregular patter of cement lies these mark the limits of the old resorption cavities ® marbled or mosaic appearance on microscopy
In the late osteoblastic stage the thickened bone becomes increasingly sclerotic & brittle, bone marrow reverts to fat & lining cells on the trabeculae are inactive
All three phases of the disease may be evident in the same specimen
Cell activity less intense & vascularity diminished
Rate of bone turnover not much greater than normal
Bones enlarged & sclerotic with deformity
Marrow may appear relatively normal

4. ?sarcoma

Some investigators would add a 4th phase to Paget’s disease: malignant degeneration into a sarcoma
Patients with Pagets disease have a 30 fold ↑ in the incidence of bone sarcoma (Price 1962)

Clinical Features

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

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

Normal
- Acid phosphatase
- Serum calcium & phosphate
Maybe
- Uric acid
LFTs
- should be done concurrently; if they are elevated then the bony isoenzyme can be isolated
Urine
- Hydroxyproline
  - reflection of osteoclasts function
    - good indicator of collagen turnover (usually less than 50mg per 24 hrs)
  - not done routinely
  - requires a meat-free diet & a 24-hour urine collection
  - urinary hydroxy proline to creatinine ratio correlating well with disease activity
- Pyridinoline cross links
  - can also be measured in the urine
- N-telopeptides
  - are another urinary measure of bone resorption. Crosslaps can be measured in the serum & provide a measure of bone resorption

Differential Diagnosis

Osteitis Fibrosa cystica
Fibrous Dysplasia
Osteoblastic secondaries
Osteopetrosis
Hyperparathyroidism
Lymphoma

Radiology

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Focal bone resorption & formation

Radiolucencies
Radiodensities

Overall bone size enlarged

Coarse trabecular pattern

Active Stage

Sku>Active Stagediolucent 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>Inactive stage 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

All patient>Bone Scanagnosis to define involved bones
Can be used to distinguish between areas of tumor & Paget’s
Only 65% of the lesions seen on bone scan will be seen on X-Rays

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 >CT Scanhange

MRI

Shows new cortical destr>MRIi>
Soft tissue mass
Spinal Stenosis

Management

Most patients nev>Managementt
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 Treatmen>Indications>
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>Medical Treatment>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 Ca>Serial Managementhonate (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 inhibi>Bisphosphonateson
- 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

Orthopaedic surgical proceduresommon 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%