Paget's disease

Contributed by Dr Rod Hughes, consultant rheumatologist at St Peter's Hospital, Chertsey.

Section 1: Aetiology and epidemiology
Paget's disease is a condition of increased but uncontrolled bone turnover that leads to excessive, but weak, bone formation. It was first described by Sir James Paget in 1877. He published a series of remarkable early illustrations of a patient with Paget's disease of the bone, showing the characteristic bowing of the tibia. He called the condition 'osteitis deformans'.1

Prevalence
Paget's disease rarely affects patients aged under 40 years. The overall prevalence in the UK is estimated at 5 per cent but the risk of developing the disease doubles every 10 years after the age of 50.2 The prevalence of Paget's disease may be in decline.3

The condition is 50 per cent less prevalent in France than the UK, and 25 per cent less prevalent in Germany, Ireland and Spain. Prevalence varies with latitude. It is more common in the north of the US than the south, and is rare in Sub-Saharan Africa, south-east Asia and the Middle East. It is estimated that the prevalence in Japan is as low as 5 per million.

Paget's disease demonstrates family clustering. Patients with an affected family member have a 10-fold increased risk, and patients with at least one family member affected in an autosomal dominant pattern have a 40 per cent increased risk. The disease affects three men for every two women.

Aetiology
The cause of Paget's disease remains unclear. An explanation first put forward in the early 1970s is that it develops secondary to a slow virus infection.

This was suggested when intranuclear and intracytoplasmic inclusions were found in the giant osteoclasts of pagetoid bone. Electron microscopic images revealed central structures within the osteoclast nucleus resembling an array of nucleocapsids from measles or similar RNA paramyxoviruses.

Similar structures have now been demonstrated in bone from patients with other conditions.

Immuno-staining methods have found nucleocapsid antigens of measles virus and respiratory syncytial virus (RSV) in osteoclasts from patients with Paget's disease.

Studies have found measles virus and canine distemper virus mRNA in the bone of patients with Paget's disease, giving rise to the unproven hypothesis that Paget's disease may be associated with close contact with dogs.

Transverse fracture in the upper outer shaft of the femur in Paget'sSection 2: Making the diagnosis
Paget's disease is diagnosed on the basis of clinical features including symptoms of bone pain, serum elevation of bone alkaline phosphatase (AP) and characteristic X-ray results.4, 5

Paget's disease can affect any bone but it is mostly found in the pelvis, lumbar spine, femur, thoracic spine, sacrum, skull, tibia and humerus.

Only 5 per cent of patients with Paget's disease are symptomatic. It is often diagnosed when X-rays are taken for an unrelated reason, especially when the pelvis or the spine is affected. Of those patients who are symptomatic, 80 per cent have bone or joint pain.

The high cell turnover in patients with the condition may be associated with hyperuricaemia and gout.

Bone deformation
Excessive bone vascularity in patients with Paget's disease can cause the bone to be warm to the touch.

Pagetoid bone is thicker than healthy bone but is weak and can fracture spontaneously or cause stress-deformity in weight-bearing bones. This can give rise to bowing of the tibia, skull bossing, and jaw and dental deformity.

Bone growth in the skull can result in cranial nerve entrapment producing deafness or vertebrobasilar insufficiency. Patients with periarticular Paget's disease in the pelvis can develop premature distortion and degeneration of the hip.

Histological tests will show focal bone resorption and formation at up to 45 times the normal speed. Multinuclear osteoclasts are found in early Paget's disease together with rapid bone lysis, vascular hypertrophy and medullary fibrosis. This results in growth of disorganised trabecular and cortical bone.

Blood tests
Active osteoblasts release bone AP and AP measurement remains the most reproducible biochemical test for the condition, although AP levels are sometimes normal in patients with Paget's disease. AP release from some bone sites, such as the skull, are higher than others, such as the pelvis and hips.

Serum calcium levels are only elevated in Paget's disease if the patient is bed-bound or immobilised. Bone turnover markers reflect excessive bone formation but are not clinically helpful.

Imaging
Paget's disease can be identified using either plain X-ray or technetium99 isotope bone scanning. In addition, X-rays can be used to classify Paget's disease into osteoblastic, osteolytic or mixed type, depending on the nature and duration of the local disease process.

X-rays of patients in the early stages of Paget's disease will reveal osteolysis with an advancing front of bone lysis travelling at 8mm per year across an individual bone such as the tibia. Paget's can be confined to one bone or there may be several bones involved, but Paget's lesions do not travel across bone boundaries.

An X-ray characteristic of the later stages of the disease will reveal expanded bone and cortical thickening, especially in the skull and pelvis. They will also show increased porosity of the cortex, and thickening of the trabeculae with a lace-like appearance.

Biopsy
Bone biopsies are not necessary to diagnose Paget's disease but can be used to distinguish between Paget's lesions and malignancy. Biopsy of affected bone will reveal increased trabecular bone volume and a raised number of osteoclasts.

Section 3: Managing the condition
Many patients with asymptomatic Paget's disease do not require treatment.

Indications for treatment include bone pain, fracture and skull or long bone deformity.

The goal of treatment for Paget's disease is to 'tame the wild osteoclasts' and reduce bone turnover.

Many treatments are therefore the same as treatments for osteoporosis.4-6.

In addition, some patients require NSAID treatment or other analgesia to help control symptoms.

Best treatments
Osteoclast activity can be reduced by treatment with calcitonin or with bisphosphonates.

Injectable salmon calcitonin is approved as an anti-osteoclast treatment for Paget's disease. However, it is now rarely used because of inconvenience, limited efficacy and side-effects.

Oral bisphosphonate treatment with etidronate 400mg daily for six months, alendronate 40mg daily for six months or risedronate 30mg daily for two months can normalise AP levels and reduce bone pain. Risedronate is the most effective of the oral bisphosphonates.

The injectable amino-bisphosphonates pamidronate and zoledronate are both licensed for use in Paget's disease and are more effective than the oral treatments.

Studies have shown that alkaline phosphatase levels are normalised in over 90 per cent of those treated with 5mg IV zoledronate administered once yearly, compared with between 50 and 75 per cent of those treated with oral risedronate. Efficacy is maintained for over a year.

Recommended initial treatment for Paget's disease is with either oral risedronate or IV zoledronate, and should continue depending on response.

Guidelines
In 2002 the Bone and Tooth Society of Great Britain and the National Association for the Relief of Paget's Disease produced guidelines for the treatment of Paget's disease. These guidelines give a further evidence base for treatment decisions.4

The cost of diagnosis, investigation and effective treatment of Paget's disease means that the annual managed healthcare costs for Paget's patients are double those for a matched 'healthy' population.7

An analysis of a US managed healthcare database showed that in spite of treatment guidelines many patients are treated with less effective oral bisphosphonates, such as alendronate or etidronate, given in incorrect doses for longer than suggested.

This results in wasted resources and a suboptimal response to treatment.

Indications for treatment in Paget's disease

  • Bone pain.
  • Skull or long bone deformity.
  • Fracture.
  • Cranial nerve entrapment.
  • Periarticular Paget's.
  • Asymptomatic rapidly. progressive Paget's of vertebrae, skull or long bone with risk of ensuing symptoms.
  • High output cardiac failure due to extensive disease.

Osteosarcoma of hemi-pelvis showing a lytic lesion in the iliac boneSection 4: Complications and monitoring
In most cases, Paget's disease is a benign condition that requires modest treatment at most.

However, when the disease affects more than one bone, and in advanced cases, it can give rise to a number of complications apart from bone pain and fracture.

Cardiac failure
Patients with Paget's disease affecting extensive areas of the skeleton involving more than 30 per cent of their bone have a high level of osteoblastic activity that results in increased vascular flow to the bone tissue. This can lead to high output biventricular cardiac failure.

This complication is rare but needs to be considered within the differential diagnosis of heart failure in the older patient. Treatment for heart failure needs to be accompanied by treatment for the underlying Paget's disease.

Vascular steal syndrome
If there is major involvement of the skull, there can be extra blood flow to the bone tissue of the head from the external carotid artery at the expense of blood flow to the brain. Affected patients become listless.

Patients with Paget's lesions in the spine can suffer from a similar diversion of spinal artery blood to vertebral bodies, reducing blood flow to the spinal cord. This can give rise to spinal cord lesions and paralysis. Such complications are rare and require urgent treatment for Paget's disease.

Malignant transformation
Untreated or persistent long-term Paget's disease can lead to the development of bone malignancy, most commonly osteosarcoma. The chances of developing osteosarcoma of the skull, facial bones and humerus is 30 times greater for a patient with Paget's disease than for an unaffected individual but it is still rare, occurring in under 0.5 per cent of patients.

Any unusual bone symptoms in Paget's patients, such as increased local pain or bony swelling, should prompt tests for osteosarcoma. The investigation can involve MRI or CT scan and bone biopsy.

Sarcoma transformation is independent of treatment for Paget's.

Deafness
Cranial nerve entrapment can lead to deafness in some patients with Paget's disease. Treatment for the condition has little effect on the progression of established deafness.

It is advisable to treat significant Paget's disease of the skull-base to prevent the onset of deafness.

Patients with Paget's disease can also suffer from depression and a general lowering of health status.

Monitoring
Clinical change in Paget's disease activity can be monitored through AP measurement. Repeat isotope bone scanning is insensitive to disease change.

A fall of 25 per cent in AP level is considered a significant treatment response.

Patients' AP levels should be measured three and six months after treatment and then at six month intervals.

Some patients will require re-treatment. There is no evidence to suggest repeated courses of treatment lose their subsequent effect.

Retreatment needed if

  • Symptoms persist.
  • Patients relapse and have indicators of persistent disease activity such as raised AP levels or X-rays showing progression of the disease.
  • Patients suffer a biochemical relapse (an increase of 25 per cent total AP level above the nadir after treatment).

Resources

Useful websites:

References

1. Paget J. On a form of chronic inflammation of bones (osteitis deformans). Trans Med-Chir Soc, 1877; 60: 37-63.

2. Barker D, Clough P, Guyer P, et al. Paget's disease of bone in 14 British towns. BMJ 1977; 1: 1,181-3.

3. Cooper C, Schafheutle K, Dennison E et al. The epidemiology of Paget's disease in Britain: Is the prevalence decreasing? J Bone Miner Res 1999; 14: 192-7.

4. Selby P, Davie M, Ralston S, et al. Guidelines on the management of Paget's Disease of the Bone. Bone 2002; 31: 366-73.

5. Klippel J, Dieppe P (eds). Rheumatology (second edition). Mosby Int, London, 1998.

6. Kanis J A. Pathophysiology and treatment of Paget's Disease of the bone (second edition) Dunitz, London, 1998.

7. Dolgitser M, Stern L, Katz L, et al. Bisphosphonate use in the treatment of Paget's disease of the bone: analysis of claims in a large database. Manag Care Interface 2007; 20: 33-40.

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