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Metabolic & Endocrine Disorders in Orthopaedic Surgery

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

    • 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

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%

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