Paget's Disease of Bone

Synonym: osteitis deformans

Sir James Paget described Paget's disease of bone in 1877.¹ There is increased bone turnover in focal areas of the skeleton and one or many bones can be affected.²

• There is a lytic phase to the disease process with an increase in bone resorption and abnormal osteoclast activity. This leads to a rapid increase in bone formation by osteoblasts. In the sclerotic phase, the focus is on bone formation. The structure of this new bone is disorganised and it is mechanically weaker, more bulky, less compact, more vascular, and liable to pathological fracture and deformity.³
• Burnt out Paget's disease is when the abnormal activity and hypercellularity dies down.³
• Paget's disease can affect any bone but is commonest in the axial skeleton, long bones, and the skull. The usual sites are the pelvis, lumbar spine, femur, skull and tibia.²
• The thoracic spine, sacrum and humerus may also be affected. The hands and feet are rarely affected.³

Juvenile Paget's disease is a separate disease (please refer to the Juvenile Paget's Disease article for more details).⁴

There is also a separate condition known as Paget's disease of the breast/nipple (please refer to the separate article Paget's Disease of Breast for more details).

• Affects 1-2% of white adults over the age of 55.²
• It is very rare in young adults.
• The UK has the highest prevalence of Paget's disease of bone in the world.²
• Paget's disease is very rare in Asian countries.³
• There is a male preponderance of 3:2.³

• Both genetic and environmental factors are thought to play a role.
• About 15% of people with Paget's disease have a family history.^5,6
• Autosomal dominant inheritance has also been described in some families.^5,6,7
• Mutations have been identified in four genes that cause Paget's disease, of which Sequestosome 1 (SQSTM1) mutation is the most important.² Patients carrying this mutation seem to be severely affected by Paget's disease and there is a high degree of penetrance.
• The mechanisms underlying the focal nature of the disease are unclear. Mechanical stress may play a role.
• Paramyxovirus infection (including measles and respiratory syncytial virus)³ has been suggested as a possible trigger but this has been disputed.²

• It is commonly asymptomatic and is discovered by the incidental finding of an elevated serum alkaline phosphatase or characteristic abnormality on x-ray.
• When symptoms occur, the most common complaints are bone pain and/or deformity.
• Pain may be present at rest, at night and on movement but does not tend to be focused around a joint.²
• Other presentations include pathological fractures or one of the other complications listed below.
• Skin temperature may be increased over areas of active disease.²
• It is monostotic (affecting 1 bone) in a third of cases and polyostotic (affecting 2 or more bones) in the remaining two thirds.³

Complications from Paget's disease depend on the site affected and the activity of the disease.

• Common:
  • Bone pain
  • Bone deformity (including sabre tibia (bowing of the tibia), kyphosis, frontal bossing of the skull, an enlarged maxilla, an increase in head size)
  • Pathological fractures (may produce heavy bleeding from the very vascular bone)
  • Osteoarthritis (due to Paget's disease around a joint)
  • Deafness and tinnitus⁸ (due to compression of cranial nerve VIII and cochlear dysfunction)³
• Less common:
  • Spinal stenosis
  • Nerve compression syndromes and cauda equina syndrome
• Rare:
  • Hypercalcaemia (with immobilisation, usually due to dehydration)
  • Hydrocephalus
  • High output cardiac failure (due to increased blood flow through affected bone)
  • Paraplegia (can occur in disease affecting the spine)
  • Osteosarcoma (rare, incidence thought to be 0.10-1.15%)^9,10

• Osteoarthritis
• Osteoporosis
• Osteomalacia
• Malignant skeletal metastases

• Bone specific alkaline phosphatase (BSAP) levels are raised.
• Urinary excretion of deoxypyridinoline and N-telopeptide are elevated. Non-isomerised C-telopeptide fragments are highly sensitive markers for monitoring disease activity and treatment efficacy.¹¹
• Serum calcium, phosphorus, and parathyroid hormone levels are usually normal but immobilisation may lead to hypercalcaemia.
• X-rays may show a number of signs:
  • Both osteolysis (seen as radiolucency) and excessive bone formation occur.
  • There are specific x-ray features of Paget's disease that include:
    • A classical V-shaped pattern between healthy and diseased long bones known as "the blade of grass" lesion.
    • The "cotton wool" pattern in the skull is also characteristic (multifocal sclerotic patches).¹²
  • Osteosarcomas also have a distinct radiological appearance.
• Radionuclide bone scans can show the extent of the disease.
• Bone biopsy may be needed of malignant change is suspected.

• The objectives of treatment are control of pain and to reduce or prevent disease progression and complications.
• There is debate as to when to start medical treatment. Some start treatment if alkaline phosphatase levels are raised; others only start treatment if there are symptoms.
• One study showed no clinical benefit of bisphosphonate treatment in patients who were randomly assigned this to return alkaline phosphatase concentrations to normal compared with those given symptomatic treatment for bone pain.¹³
• Specific treatment is required for complications.
• Because of the risk of osteosarcoma, patients should be monitored indefinitely. Presentation of osteosarcoma is classically with increased bone pain that is poorly responsive to medical treatment, local swelling, and possibly a pathological fracture.² X-ray and bone biopsy can help to confirm the diagnosis (see above).

Non-drug treatment

• Orthotic devices, sticks and walkers may be useful for disease of the legs if it causes problems with walking.
• Patients taking bisphosphonates should maintain an adequate intake of calcium and vitamin D.³

Drug treatment

• NSAIDs and paracetamol may be effective for pain.
• Anti-resorptive therapy is with either bisphosphonates or calcitonin (now rarely used).
• Bisphosphonates:
  • Oral or intravenous bisphosphonates are the mainstay of treatment.
  • They are thought to reduce bone turnover, improve bone pain, promote healing of osteolytic lesions and restore normal bone histology.²
  • However, one study showed that disease progression occurred in 28% of patients over a 5-year follow-up despite treatment with etidronate.¹⁴
  • Newer bisphosphonates such as zoledronic acid may help to better achieve metabolic control of the disease and so improve these statistics.^2,15
  • Pamidronate, risedronate, and zoledronic acid are preferred by many.²
  • Any calcium and vitamin D deficiency needs to be corrected before starting a bisphosphonate to avoid hypocalcaemia.²
  • Osteonecrosis of the jaw has been reported in patients taking bisphosphonates for Paget's disease.¹⁶
• Serial monitoring of alkaline phosphatase is used to monitor the effects of treatment and disease activity.

Surgery

• Bone deformity, osteoarthritis, pathological fractures and nerve compression may necessitate surgery.
• Bisphosphonates, should be used preoperatively to try to reduce disease activity in order to prevent severe bleeding during surgery.
• After surgery, bone healing may be prolonged, and lengthy rehabilitation may be necessary.
• Amputation may be necessary for osteosarcoma of long bones.
• Decompressive laminectomies may be necessary if medical therapy fails to help those with neurological problems from spinal cord compression.¹⁷

• This depends on the extent and degree of disease activity.
• Remission may be possible with successful treatment.
• Those who develop osteosarcoma have a very poor prognosis and most die within 3 years.³

• James Paget was born in Great Yarmouth in Norfolk in 1814.
• At 16 he became apprentice to a local surgeon and apothecary, and 4 years later he entered St. Bartholomew's Hospital, London, to which he was associated throughout his life and where he studied or worked from 1834 to 1871.
• He is regarded as one of the great founders of modern pathology.
• In 1854 he became surgeon extraordinary to Queen Victoria and, a few years later, surgeon ordinary to the Prince of Wales.
• He became professor of anatomy and surgery at the Royal College of Surgeons of England (1847-1852) and was elected fellow of the Royal Society in 1851 and became its vice president in 1873-1874 and president in 1875.
• He was honorary vice chancellor of the University of London, and was named doctor of honour of law at the universities of Oxford, Cambridge and Edinburgh.