Paget's Disease of Bone

Synonym: Osteitis deformans.

Sir James Paget described the disease of bone in 1877.¹ It is a localised disorder of bone structure that begins with excessive bone resorption by osteoclasts, followed by increased bone formation by osteoblasts.
The structure of the bone is disorganised and it is mechanically weaker, more bulky, less compact, more vascular, and liable to pathological fracture.

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, thoracic spine, sacrum, skull, tibia, and humerus. The hands and feet are very rarely affected.

Paget's disease of bone must not be confused with Paget's disease of breast. Paget's disease of skin is the name sometimes given to an unusual condition when similar cells to those found in Paget's disease of breast are found in skin.

• Paget's disease is the second commonest disorder of bone in the elderly, after osteoporosis.
• Prevalence varies greatly, with the highest frequency in Europe, especially England, France, and Germany. It is also high in Australia and New Zealand. Paget's disease is very rare in Asia, the Middle East and Africa.
  In Europe, the prevalence for Paget's disease decreases from north to south, except for Norway and Sweden which have very low rates. The highest prevalence in Europe is found in England (4.6%) and France (2.4%) in hospital patients over 55 years. Other European countries, such as Ireland, Spain, Germany, Italy, and Greece, report prevalence rates ranging from 0.5% to around 2%.
• There is a male preponderance of 3:2.
• It is very rare in young adults although a juvenile form has been described. It probably starts around 40 and in England has an incidence of around 10% over 80 years old.

• The aetiology of the disease is unknown but both genetic² and environmental factors have been suggested. Ethnic and geographic clusters of Paget's disease occur, especially in Lancashire.³
• About 40% of patients with Paget's disease give a family history of the disease.⁴ Genetic heterogeneity is likely.⁵
• An environmental trigger has never been proved although several different viruses have been implicated.
• It is usually seen as a disease of old age but it can sometimes occur rather younger. Disease before the age of 40 tends to be more extensive but not more active than in later life.⁶

Symptoms

• It is monostotic (affecting 1 bone) in a third of cases and polyostotic (affecting 2 or more bones) in the remaining two thirds. It does not normally spread to other bones after diagnosis but it may progress if not treated.
• Most patients with Paget's disease are asymptomatic, and it is discovered by the incidental finding of an elevated serum alkaline phosphatase or characteristic abnormality on x-ray.
• When symptoms occur the commonest complaint is pain in the bone.
• Other presentations include pathological fractures, congestive heart failure, hearing loss, or symptoms from nerve root compression.

Signs

• There may be no abnormal physical findings.
• The bone may feel warm or there may be bowing of the bone with an abnormal gait.
• Osteoarthritis can occur in local joints.
• Hearing loss can result from compression of the acoustic nerve.
• The spine is the 2nd commonest site of the disease, after the pelvis. In the lumbar spine, spinal stenosis or kyphosis may develop. In the thoracic spine, spinal cord compression can occur.
• Disease of the skull may be asymptomatic but a third of patients have an increase in head size with or without deformity such as frontal bossing or enlarged maxilla along with headaches, hearing loss, and, rarely, nerve damage leading to loss of sensation.
• Facial deformity can occur if the facial bones are affected and, rarely, narrowing of the airway may result.
• Fracture of a diseased bone can be a serious complication and may be either traumatic or spontaneous. The femur is the most common site to fracture and it may bleed profusely. They heal normally.

• Osteoarthritis
• Osteoporosis
• Malignant skeletal metastases

• Bone specific alkaline phosphatase (BSAP) levels are raised. Total alkaline phosphatase levels have a sensitivity of only 78% for the detection of Paget's disease.⁷
• Urinary excretion of deoxypyridinoline and N-telopeptide are elevated. Non-isomerized C-telopeptide fragments are highly sensitive markers for monitoring disease activity and treatment efficacy.⁸
• 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 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 "brim sign," is the thickened iliopectineal line in the pelvis.
  • Osteoporosis circumscripta can occur in the frontal and occipital bones of the skull.
  • The "cotton wool" pattern in the skull is characteristic.
  • In the spine, enlargement of the vertebral bodies with thickened cortical shells and vertical striations produce the "framed vertebrae."
  • Osteosarcomas have a distinct radiological appearance.
• Radionuclide bone scans show the extent of the disease. If pain or BSAP levels increase or if pathological fractures occur, further imaging studies are important to exclude malignancy such as sarcomas and giant cell tumours.

The juvenile form⁹ of Paget's disease is very different from the adult version.

Juvenile Paget's disease is also called hyperphosphatasia. It is an autosomal recessive dysplasia, associated with dwarfism with progressive enlargement of the head, bowed limbs, pigeon breast deformity and weakness with premature shedding of the teeth.¹⁰ Radiologically, there is enlargement and thickening of the skull vault.

• The objectives of treatment are control of pain and to reduce or prevent disease progression and complications. There is no evidence that treating asymptomatic patients reduces later complications.¹¹
• Nevertheless, young patients and those with high levels of BSAP are often treated to avoid future complications.
• Treatment is required for complications, including bone pain, progressive skeletal deformity, high-output congestive heart failure, hypercalcaemia, compression of spinal cord and nerve roots, bone compression of the acoustic or optic nerve, recurrent renal calculi due to hypercalciuria, or fractures. When the disease occurs near a joint, treatment aims to prevent osteoarthritis.
• Because of the risk of malignancy, patients should be monitored indefinitely.

Non-Drug

Orthotic devices, including sticks and walkers, may be useful for disease of the legs if it causes problems with walking. No restriction of activity or dietary change is required but patients on bisphosphonates should maintain an adequate intake of calcium.

Drugs

• NSAIDs and paracetamol are effective for pain.
• Medical therapy includes bisphosphonates with serial monitoring of bone markers.¹² Bone markers should be rechecked 2 or 3 months after bisphosphonate treatment. These drugs can reduce bone turnover to normal¹³ but they have not been shown to reduce deafness, fracture or bone deformity.¹⁴
• Alendronate inhibits osteoclastic bone resorption. The usual dose is 40mg daily for 6 months. It should be taken with a large amount of water at least half an hour before any other food, drink or medication and the patient should stay upright. Risedronate is similar but the dose is 30mg daily for 2 months. It may be repeated after another 2 months.
• Pamidronate can be used for intravenous treatment but it does not appear to be any more effective than oral alendronate.¹⁵
• Calcitonin analogues also inhibit osteoclastic activity. Calcitonin is given by subcutaneous or intramuscular injection with a dose range of 50 units 3 times weekly to 100 units daily, in single or divided doses. Bisphosphonates are the mainstay of treatment and the role of calcitonin seems not yet clear.

Surgical

• Bone deformity, pathological fractures and nerve compression may demand 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.¹⁶

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

• When it occurs near a joint, osteoarthritis may be provoked. If the skull is involved, there may be deafness, vertigo, tinnitus, dental malocclusion, vertebral insufficiency, and cranial nerve involvement.
• Excess mortality is due most commonly to complications, related to fractures or sarcoma.
• Sarcoma occurs in about 1% and most patients with sarcoma die within 3 years of diagnosis.
• Fractures or surgery may produce heavy bleeding from the very vascular bone.
• Vertebral involvement from Paget's disease may cause serious complications, including nerve root compressions and cauda equina syndrome. Fractures are the most common complication of the disease and can have devastating consequences.

James Paget was born in Great Yarmouth in Norfolk in 1814 and the local district general hospital in Gorleston is named after him. 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 was created a baronet in 1877, the same year he described the bone disorder. 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, its vice president 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.