Introduction

Along with osteoporosis, Paget disease of the bone (PDB) – aka osteitis deformans –  is a common degenerative bone disease. It affects up to 5% of the population in Anglo-Saxon societies.
PBD is a disorder of bone metabolism, whereby there is an increase rate of bone remodelling at localised sites (can be single or multiple). This remodelling causes reduced bone integrity resulting in pain and deformity, and less commonly – fracture.
It is typically discovered incidentally – either on blood tests with a raised alkaline phosphatase, or on x-ray performed for another reason.
It most commonly affects the skull, spine pelvis and long bones of the legs.
Symptomatic patients, or those with a high risk of fracture, are usually treated with bisphosphonates – most commonly a single IV dose of zolendronic acid. This is a highly effective treatment with remission achieved in up to 90% of patients.
Other treatments include physical aids to minimise disability from deformity, and simple analgesia.
 

Epidemiology and Aetiology

This is the second most common degenerative bone disorder (after osteoporosis), and affects >5% of the over 55’s in the UK. The prevalence varies between countries and races. It has an unusual geographic distribution – the UK has the highest incidence (particularly in the northwest), and there are also high incidences in Australia, New Zealand and North America – reflecting their Anglo-Saxon heritage. It is rare in Scandinavia, China and Japan.
  • M>F (slightly)
  • Increased incidence in Pet Owners
  • Genetic susceptibility – increased risk in a family history of the disease
    • Disease also often occurs in local geographical clusters
  • Essentially unknown aetiology; environmental factors in a predisposed individual (possibly viral infection is the environmental factor)
  • Incidence increases with age
    • Rare under 50

Clinical features

  • Chronic progressive disease
  • Often asymptomatic, and discovered incidentally with a raised ALP in the blood, or discovered incidentally on x-ray
  • Only 15-40% of cases have symptoms
  • Bone pain – the most common symptom
    • Occurs in 40% of presentations
      Pain is usually due to impingement on other localised structures
    • Bone pain is a late feature. It is typically a deep constant aching pain, worse with weight bearing, and may persist through the night
    • Consider Paget disease of the bone in elderly patients presenting with persist back pain
    • Bony deformity may cause warm skin overlying the lesion due to increased blood flow
  • Deformity – up to 30% of patients
  • May affect bones anywhere in the skeleton, but common sites include; pelvis, lumbar spine, femur, thoracic spine, sacrum, skull, tibia, humerus
  • Usually only affects one site – it is not ‘systemic’ like osteoporosis, and does not spread to other sites.
  • Osteoarthritis
  • Fractures – bones are prone to fracture because they become more brittle. Affect 15% of patients
  • Deafness / Headaches occurs in some patients due to compression of the vestibulocochlear nerve, when the skull is affected
    • More rarely there may be other non-specific neurological features – e.g. dizziness, altered gait
  • Osteosarcomaused to be more common, now only affects 1% of patients
  • Bowing deformity is seen in Paget disease of the long bones
    • This can cause altered gait, and may result in other joint pains, particularly of the hips and lower back
    • Traumatic fracture are also most likely to occur in Paget disease of the long bones

Pathology

  • Increased number of osteoclasts. Osteoclasts also often larger. The osteoblasts are normal, but are often over active, due to increased factors released by osteoclasts.
    • Osteoclasts are also often oversensitive to vitamin D
  • Essentially, an accelerated rate of bone turnover – with subsequent rapid new bone formation – and this new bone does not have a normal bone matrix – the matrix is disorganised
  • The bones increase in size, but become more brittle, and thus more prone to fracture.
  • Unclear why some areas of bone are affected and others are normal

Investigations & Diagnosis

Diagnosis is usually made radiologically. Blood tests and other investigations are suggestive or supportive of the x-ray findings.

Once diagnosis is confirmed, radionuclide bone scan is often performed to check for any other areas of involvement.

Bone biopsy is not usually required.

Blood tests

  • Raised alkaline phosphatase – ALP can be an indicator of osteoblastic activity
    • Remember to ask for bone specific ALP – increased ALP can also be of liver origin
    • Consider checking gamma-GT – to rule out a liver cause if bone specific ALP is not available
    • The level of ALP is correlated to the severity of the Paget disease
  • Serum calcium and phosphates are usually normal
  • Vitamin D levels are normal tested. This is for two reasons:
    • To help rule out another cause of raised ALP
    • To ensure levels are sufficient to undertake bisphosphonate therapy

X-ray

  • Widening of the cortical region – i.e. the hollow cortex at the centre of the bone (where marrow is produced) is wider
  • Mixed areas of sclerosis and lysis – on the x-ray will look like lots of opaque dark splodges in the bone
    • Seen in early disease
    • This can make differentiation between Paget Disease and malignancy difficult in the early stages of the disease
  • Bone thickening and enlargement
    • Seen in later disease
    • Easier to differentiate
  • Bone deformities
    • Bone bends anteriorly in the tibia
    • Bone bends laterally in the femur
  • May also show what appears to be localised osteoporosis in areas of very high osteoclast activity – called osteoporosis circumscripta – this is particularly apparent in the skull
  • MRI or CT may also be used to better define unusual bone lesions

Bone scan

  • Increased isotope uptake in affected bones
  • Often performed after the initial lesions has been diagnosed to assess the extend of the disease
  • Any areas that appear to show ‘uptake’ on a bone scan should then be further investigated with x-ray to confirm if there is Paget’s disease at these sites

Urine

May contain collagen due to very high bone resorption

Differentials

Treatment

Treatment aims to reduce pain and slow down the rate of bone remodelling. Knowing who and when to treat is the biggest problem. This decision is usually based on symptom severity. Asymptomatic disease does not often require treatment. Reasons to treat include:
  • Severe pain
  • Nerve compression from expanding bone, or other neurological complications
  • Fractures
  • Asymptomatic disease with significant biochemical abnormalities, e.g.
    • ALP >2x normal
    • Raised ALP and Paget Disease at a site that commonly results in fracture (e.g. long bones, vertebrae or base of skull)
  • In some cases it can be difficult to detainee if pain is arising from Paget Disease or osteoarthritis. In these patients, I trial of bisphosphonates may be indicated.

Bisphosphonates are the ‘mainstay’ of treatment. They inhibit osteoclast activity, and cause osteoclast apoptosis. They damage the cytoskeleton of the osteoclast, so the cell is then unable to bind to bone, and to perform its bone resorption duties.

Serum calcium and vitamin D levels should be checked before therapy is initiated and all patient should be started on supplemental vitamin D (1,000 international units daily) and calcium (this often comes combined).

Bisphosphonates are often able to induce disease remission. Typical regimen will last 2 months. The agents described below are sometimes called the “newer” bisphosphonates, or the “nitrogen containing bisphosphontes”. Older agents are less effective and rarely used.  Options include:

  • Zolendronic acid
    • Given via IV infusion – e.g. 5mg given on 15 minutes
    • Induces remission for up to 2-3 years after a single dose
    • Usually first line choice – more effective than oral agents
    • Up to 90% remission rate, <1% relapse rate
    • Resistance can develop after multiple doses
    • Can cause flu-like symptoms after first dose
    • Pamidronate is an alternative IV bisphosphonate but is less effective (“older” bisphosphonate). It may be considered if resistance has developed to zolendronate
  • Oral therapy – e.g. risedronate, alendronate
    • May be considered in younger patients or those with less severe disease
    • About 60% remission rate, 20% relapse rate
    • Usually oral doses are given daily for a limited period – e.g.:
      • Risedronate 30mg daily for 2 months
      • Allendronate 40mg daily for 3-6 months
    • Much more cumbersome dosing than the IV preparations:
      • Must be taken with water
      • No food should be taken for at least 30 minutes afterwards
      • Patients should not lie down for 2 hours after taking them to avoid oesophageal irritation and gastroesophageal reflux
    • Any required dental work should be performed before initiation of therapy as this reduces the risk of a rare but serious side effect of bisphosphonates – oestonecrosis of the jaw
  • Calictonin
    • Can be used in patents who do not tolerate bisphosphonates
    • Does not induce remission but can reduce disease progression
  • Adverse effects of bisphosphonates
    • Osteonecrosis of the jaw – extremely rare in the short durations of therapy used in Paget Disease. Approximate risk is 1 in 100 000
    • Bone Pain
    • Flu-like symptoms – transient, occurs in 25% of patients
Other management options include:
  • Simple analgesia – e.g. paracetamol 1g QID, ibuprofen 400mg TDS PRN
  • Orthoses – braces, usually plastic that support and protect a bone
  • Orthotics – show inserts that help to correct deformity and altered gait
  • Analgesia
  • Education
  • Treat the complications – e.g. joint replacement, hearing aids, physiotherapy

Ongoing Management

  • Consider repeating ALP at 3-6 months to assess the effectiveness of treatment
  • Repeat annually
  • Initiate treatment again when ALP starts to rise or patient becomes symptomatic again

Complications

  • Increased risk of bone tumours – particularly osteosarcoma
    • Incidence of up to 1% of PBD patients
    • Consider this in lesions that do not respond to medical therapy – particularly pain
    • If osteosarcoma develops it is often advanced and fatal
    • More common in long standing disease

References

Related Articles