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Paget's Disease of Bone

Paget's Disease


Definition

Condition characterised by high rates of bone resorption and disorganised immature new bone formation, leading to abnormal remodelling of bone.
First described by Sir James Paget in 1876 and evidence of the disease found in Neanderthal man.

Incidence

  • Affects more than 3% of population over 40 years of age
  • Around 2% of the population at age 40 to around 10% in the elderly (more than 80 years)
  • Only occasionally presents in people under 50 years
  • Relatively common in Anglo-Saxons, Britain, Germany and Australia
    • Britain has the highest recorded prevalence
    • In Australia the prevalence among British born immigrants is intermediate between the British rate and the native born Australians
    • Rare in Scandinavia, Russia, Italy, Asia, Africa and the Middle East
    • There is evidence of a decline in incidence of the disease in Britain and USA  
  • Affects American whites and blacks equally, which suggest environmental factor contributing to aetiology
  • Male : Female 7:6. Probably equal overall incidence but in younger individuals males slightly more frequent

Aetiology

The primary abnormality is thought to lie in the osteoclasts, but the precise cause remains unknown

Viral aetiology

  • Suggested by the isolation of viral intra-nuclear inclusion bodies in osteoclasts on EM which resemble those of measles (Rebel 1976, Mills 1976)
  • Antigen to measles virus, simian virus 5 and human parainfluenza virus type 3 detected in abnormal osteoclasts (Basle 1985)
  • Measles virus not detected (Gordon 1991)
  • Canine distemper virus (CDV) in 41% of Pagetic osteoclasts, osteocytes and osteoblasts (Gordon 1991)
  • Slow virus type aetiology consistent with familial incidence
  • Ralston, 1994 investigated Pagets and normal bone with reverse-transcriptase and polymerase chain reaction
    • No difference in IL-1, IL-6, TNF-alpha, TNF-beta, FGF, TGF, IGF-1
    • Possibility that Pagets bone turnover is due to local elaboration of other osteotropic factors
  • Birch (Ralston) 1994 was unable to detect measles and CDV aetiology for Pagets disease with PCR
  • Relationship to pets has been postulated, but not substantiated
  • Genetic, as family history, found in 15 - 20% of cases and the site and extent of disease similar in family members. Implies dominant inheritance with low penetrance (Sofaer 1983)
  • Extraordinary geographic variations in prevalence (see data on incidence)
    • Probably, Pagets disease is caused by infection with a common and widespread virus superimposed on genetic variation for susceptibility and perhaps severity of disease (Sofaer, 1983)
    • Interaction between hereditary and environmental factors
  • Geographical variations in the prevalence of Paget's disease remain unexplained and the viral hypothesis remains unproven
  • Also postulated :
    • Disorder of hormonal secretion
    • Vascular aetiology
    • Autoimmune disease, monoclonal IgM

Clinically

  • Variable picture with the majority being discovered incidentally following X-Ray or elevated alkaline phosphatase
  • Only a minority of patients become symptomatic (5%)
  • Monostotic in 17% and polyostotic in 83%
    • Pelvis 70%
    • Lumbar spine 50%
    • Femur 50%
    • Skull 45%
    • Tibia 30%
    • Humerus 30%
    • Clavicle with visible deformity in 13%
    • Hand and foot 3 - 5%
  • The disease may be localised to part or the whole of one bone for many years
  • Affected bones may remain asymptomatic or become painful (dull constant ache) and deformed
  • Pain is worse at night, but rarely severe, unless sarcoma or fracture supervene
  • Lesions detected on bone scan are usually painful, whereas many lesions seen on X-Ray are not
  • Bone looks bent, feels warm (may be 5° warmer than unaffected side) and thick (osteitis deformans)
  • If generalised may cause
    • Headache
    • Deafness (with impairment of hearing in 30 - 50% of cases)
    • Deformities
    • Stiffness
    • Limb pain 
    • Fracture 
    • Heart failure
    • Occasionally pressure on the optic nerve may cause blindness
    • Facial and trigeminal nerves may also be affected
    • Spinal stenosis may occur with root or cord problems infrequently
    • Vascular steal syndrome may cause spinal claudication
  • Features suggestive of pain of Pagetic origin in the back are :
    • Nonspecific low back pain without radiculopathy
    • Normal or minimal findings on examination
    • Vertebral sclerosis in radiographs
    • Isolated vertebral involvement in bone scan 
    • Enlarged vertebra and neural arch, normal facet joints and no bony impingement
  • Canal stenosis occurs gradually as the expanding vertebral body reduces the canal diameter, may be accompanied with kyphosis, and back ache. Radicular pain is common
  • Cardiac failure associated with arterial calcification and calcification of heart valves and myocardium as well as being a high output state
  • About 20% of Pagets patients have fractures which may be complete or incomplete and as many as 40% have delayed union or non-union
  • Tinnitus and vertigo are common complaints
  • Coxa vara is also a feature with considerable anterolateral bowing of the legs
  • When involves a joint may cause painful erosive arthritis due to altered stresses, secondary to deformity and abnormal subchondral bone

X-Rays

  • Early: osteoporosis circumscripta
  • Disease involvement usually seen at one end of the bone (generally proximal)
  • The bone as a whole is thick and bent
  • Density in the vascular stage is decreased and it is increased in the sclerotic stage
  • Trabeculae are coarse and widely separated
  • In vascular stage areas of porosis, shaped like a candle flame are seen in the cortex (arrow or flame sign)
  • Fine cracks may appear (stress fractures), which resemble Looser zones, may be evident, but occur on the convex surface
  • Acetabular involvement may cause protrusion
  • Cortical thickening lead to pelvic brim signs or framed picture appearance of vertebrae
  • Remodelling of the skull base may result in its invagination by the cervical vertebrae and platybasia
  • Only 65% of the lesions seen on bone scan will be seen on X-Rays
  • In Pagetic sarcoma, there is cortical disruption and soft tissue mass
  • Bone scan is hot, with variable intensities in different phases (less intense in sclerotic phase)

Investigations

  • Plasma alkaline phosphatase level is elevated in direct correlation with degree of bone involvement 
    • Reflects osteoblastic activity
    • 10% of patients with Pagets will have levels within the normal range
  • Urinary hydroxyproline is elevated and is a good indicator of collagen turnover (usually less than 50mg per 24 hrs)
    • Reflects increased osteoclastic activity
    • The urinaryhydroxy proline to creatinine ratio correlating well with disease activity
  • Hypercalcaemia seen with prolonged inactivity 
  • Hypermetabolic state associated with increased serum urate and gout
  • X-Rays and bone scans show typical appearance
  • Bone scan showing increased uptake in the region of Paget
    • Discrete decrease in the region of suspected tumour in association with gallium scan showing increase in the region of tumour is highly diagnostic

Pathology

  • Osteoclasts are increased in both size and number, containing greater than normal numbers of nuclei (more than 100 per cell, usually less than 20)
    • 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
  • Newly formed bone is coarse fibred 
    • This disorganised formation is architecturally abnormal and mechanically weak 
    • Marrow tends to become fibrous with scanty haemopoetic cells
    • Abnormal bone is rapidly resorbed by osteoclasts and bone turnover is greatly increased (up to 40 times normal)
  • Pagetoid tissue has been seen to invade cartilage directly, e.g. intervertebral disc
Active or Osteolytic Phase
  • Avid resorption of existing bone by large osteoclasts with increased nuclei
  • The excavations being filled with vascular fibrous tissue (osteoporosis circumscripta)
  • In adjacent areas osteoblastic activity produces new woven and lamellar bone
  • Process occurs on both endosteal and periosteal surfaces, so bone increases in thickness but is structurally weak and deforms
Mixed Phase

Resorption continues, but an osteoblastic response is mounted and woven bone is deposited

Inactive or Sclerotic Phase
  • Gradually, osteoclastic activity abates and the eroded areas fill with new lamellar bone, leaving an irregular patter of cement layer
  • These mark the limits of the old resorption cavities and causes marbled or mosaic appearance on microscopy
  • In the late osteoblastic stage the thickened bone becomes increasingly sclerotic and brittle, bone marrow reverts to fat and lining cells on the trabeculae are inactive

All three phases of the disease may be evident in the same specimen
Patients with Pagets disease have a 30 fold increase in the incidence of bone sarcoma (Price 1962)

Treatment

  • Most require no treatment
  • Fractures need ORIF and useful to straighten the bone if possible
  • Drugs which lower bone turnover such as calcitonin and diphosphonates are used in specific instances:
    • Persistent bone pain
    • Repeated fractures
    • Neurological complications
    • High output cardiac failure
    • Hypercalcaemia due to immobilisation
    • For some months before and after major bone surgery, where there is risk of excessive haemorrhage (3/12 before and 3/12 after)
  • Non steroidal anti-inflammatories and analgesics useful
  • There are three principle classes of drugs all are primarily inhibitors of bone resorption 
  • Each induces a rapid fall in hydroxyproline values within the first few days of treatment and 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, and 60% achieve remission without relapse for 5 years
  • If relapse occurs, recommence therapy
  • For surgery should commence therapy 3 months prior to surgery and continue for six weeks post surgery
Calcitonin
  • Polypeptide hormone with 32 aminoacids 
  • Inhibits osteoclastic resorption, decreases calcium iron release
  • Synthetic human like calcitonin is now available
  • Osteoclasts have receptor sites for calcitonin which reduces bone resorption by decreasing both their activity and number
  • Relieves the pain of Pagets in up to 80% of cases
  • Leads to 50% reduction in pre-treatment levels of the indicators of bone turnover (serum alkaline phosphatase and urinary hydroxy proline) which then plateau
    • Addition of a second agent may lead to further reduction in bone activity
    • When treatment is stopped, levels quickly return to pre treatment levels, but relief of pain may persist for several months
  • Side effects are common and limit the usefulness of calcitonin
    • Anaphylactic reaction
    • Gastrointestinal upset
    • Itching and flushing
    • Hypocalcaemia (rare)
  • Dose : 80 - 160 iu (porcine) or 50 - 100 iu (salmon) thrice weekly 
    • Initially daily for the first week then daily for 6 months, reducing then to thrice weekly for life
    • Must be administered parenterally
  • Synthetic form 100 iu as subcutaneous injection, nasal spray or suppository
  • Cost : $5 - 20 per dose ($1800 for first 6 months , $1200 per year)
Diphosphonates
  • Exact mechanism of action remains unclear
    • Blocks transformation of amorphous calcium phosphate to hydroxyappatite
    • Delaying aggregation of apatite crystals into larger crystals 
    • Slowing down dissolution of crystals
  • Effect is dose dependant 
  • Brings relief of pain in 60% of cases 
  • Short course of 1 - 6 months can cause prolonged remission (50% still in remission at 2 years)
  • Main disadvantage is impairment of bone mineralisation, especially at high doses, which is occasionally associated with increased bone pain and fractures
  • Narrow therapeutic range between resorption inhibition and mineralisation defects, therefore use with caution in patients with lytic lesions
  • Pamidronate may impair osteoblast function
  • Side effects: Use of Etidronate also associated with diarrhoea, nausea, irritation of gastric mucosa, gastritis, lymphocytopenia, pyrexia, osteomalacia
  • At RAH two diphosphonates are used
  • Pamidronate
    • Is the most common 
    • Given IV as a single dose (30-60 mg), daily or weekly infusion for a 5-10 dose course
    • Cost : $70 for 15 mg ($280 for single dose, may need several doses per year, $2800 per year)
  • Etidronate
    • 1 - 20 mg per kg per day IV or
    • 1.2 gm per day as oral dose for 6 months on, 6 months off and may be reqired for several years
    • Cost : $9 per dose ($1620 for 6 months, which is also the yearly cost)
Mithramycin
  • NOT CURRENTLY USED BECAUSE OF SIDE-EFFECTS
  • Specific effect on osteoclasts lowers plasma calcium
  • A cytotoxic antibiotic 
  • Produces impressive clinical responses, but its potential toxicity 
  • Side effects: Bone marrow, liver and kidney toxicity
  • Dose: 10 - 20 mg/kg/day IV for 10 days
  • Useful in patients with sever disease, who do not respond to other drugs or in patients with neurological complications
Other treatment
  • Saline (hyertonic saline) and diuretic for the treatment of hypercalcaemia in association with steroids and calcitonin
  • Joint replacement may be necessary for articular involvement; disease activity should be controlled before surgery

Differential Diagnosis

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

Complications

  • Pathological fractures are common
    • Especially in the femoral neck, where they are often vertical
    • Elsewhere the fractures are usually partly transverse and partly oblique
    • Bones with stress fractures are usually metabolically inactive
    • ORIF is recommended
  • Sarcomatous change usually in diffuse long standing disease
    • Occurs in less than 1% of all Paget's patients, probably about 0.5%
    • Osteogenic sarcoma is common, but also fibrosarcoma, chondrosarcoma and giant cell tumour
    • Sarcomatous change most common in the femur, humerus, pelvis, tibia
    • 50% osteosarcoma
    • Most in polystotic Pagets disease
  • Nerve compression may cause pain, blindness or deafness
  • Spinal canal stenosis
  • Arthritis of joints affected with Paget's (hip or knee)
    • Only if subarticular bone is involved
    • Bone can be either soft or brittle
  • High output cardiac failure due to prolonged increased bone blood flow
  • Hypercalcaemia may occur if the patient is immobilised for long periods
    • Treat with a saline diuresis (IV saline and a diuretic), steroids and calcitonin
  • Slightly higher incidence of aseptic loosening of joint implants than in primary osteoarthritis (15 - 17% before 10 years)

Recent Literature

  • Rapid Postoperative Osteolysis in Pagets Disease JBJS 76A, 274
  • Case report of rapid osteolysis after THR, responding to calcitonin
  • No calcitonin pre-op
  • Consider pre-op control of Pagets proir to THR
  • The Ilizarov External Fixator for Treatment of deformities in Paget's Disease CORR 323, 298
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