Paget's disease of bone
Paget's disease of bone is a condition involving cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone remodeling at the microscopic level, specifically excessive bone breakdown and subsequent disorganized new bone formation. These structural changes cause the bone to weaken, which may result in deformity, pain, fracture or arthritis of associated joints.
The exact cause is unknown, although leading theories indicate both genetic and acquired factors. Paget's disease may affect any one or several bones of the body, but never the entire skeleton, and does not spread from bone to bone. Rarely, a bone affected by Paget's disease can transform into a malignant bone cancer.
As the disease often affects people differently, treatments of Paget's disease can vary. Although there is no cure for Paget's disease, medications can help control the disorder and lessen pain and other symptoms. Medications are often successful in controlling the disorder, especially when started before complications begin.
Paget's disease affects from 1.5 to 8.0% of the population, and is most common in those of British descent followed by Northern European and Northern Americans. It is primarily diagnosed in older people and is rare in people less than 55 years of age. Men are more commonly affected than women. The disease is named after English surgeon Sir James Paget, who described it in 1877.
Signs and symptoms
Mild or early cases of Paget's are asymptomatic, and so most people are diagnosed with Paget's disease incidentally during medical evaluation for another problem. Approximately 35% of patients with Paget's have symptoms related to the disease when they are first diagnosed. Overall, the most common symptom is bone pain. When symptoms do occur, they may be confused with those of arthritis or other disorders, and so diagnosis may be delayed. Paget's may first be noticed as an increasing deformity of a person's bones.Paget's disease affecting the skull may cause frontal bossing, increased hat size, and headaches. Often patients may develop loss of hearing in one or both ears due to auditory foramen narrowing and resultant compression of the nerves in the inner ear. Rarely, skull involvement may lead to compression of the nerves that supply the eye, leading to vision loss.
Associated conditions
Paget's disease is a frequent component of multisystem proteinopathy.Advanced Paget's disease may lead to other medical conditions, including:
- Osteoarthritis may result from changes in bone shape that alter normal skeletal mechanics. For example, bowing of a femur affected by Paget's may distort overall leg alignment, subjecting the knee to abnormal mechanical forces and accelerating degenerative wear.
- Heart failure is a rare, reported consequence of severe Paget's disease. The abnormal bone formation is associated with recruitment of abnormal blood vessels, forcing the cardiovascular system to work harder to ensure adequate circulation.
- Kidney stones are somewhat more common in patients with Paget's disease.
- Nervous system problems may occur in Paget's disease, resulting from increased pressure on the brain, spinal cord, or nerves, and reduced blood flow to the brain and spinal cord.
- When Paget's disease affects the facial bones, the teeth may become loose. Disturbance in chewing may occur. Chronic dental problems may lead to infection of the jaw bone.
- Angioid streaks may develop, possibly as a result of calcification of collagen or other pathological deposition.
Causes
Viral
Paget's disease may be caused by a slow virus infection present for many years before symptoms appear. Associated viral infections include respiratory syncytial virus, canine distemper virus, and the measles virus. However, recent evidence has cast some doubt upon the measles association. Laboratory contamination may have played a role in past studies linking paramyxovirus to Paget's disease.Genetic
There is a hereditary factor in the development of Paget's disease of bone. Two genes, SQSTM1 and RANK, and specific regions of chromosome 5 and 6 are associated with Paget's disease of bone. Genetic causes may or may not involve a family history of Paget's disease.About 40–50% of people with the inherited version of Paget's disease have a mutation in the gene SQSTM1, which encodes a protein, called p62, that is involved in regulating the function of osteoclasts. However, about 10–15 percent of people that develop the disease without any family history also have a mutation in the SQSTM1 gene.
Paget's disease of bone is associated with mutations in RANK. Receptor Activator of Nuclear Factor κ B, which is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding. Additional genetic associations include:
| Name | OMIM | Locus | Gene |
| PDB1 | 6p | ? | |
| PDB2 | 18q22.1 | RANK | |
| PDB3 | 5q35 | SQSTM1 | |
| PDB4 | 5q31 | ? |
Pathogenesis
The pathogenesis of Paget's disease is described in four stages:- Osteoclastic activity
- Mixed osteoclastic – osteoblastic activity
- Osteoblastic activity
- Malignant degeneration
Sir James Paget first suggested the disease was due to an inflammatory process. Some evidence suggests that a paramyxovirus infection is the underlying cause of Paget's disease, which may support the possible role of inflammation in the pathogenesis. However, no infectious virus has yet been isolated as a causative agent, and other evidence suggests an intrinsic hyperresponsive reaction to vitamin D and RANK ligand is the cause. Further research is therefore necessary.
Diagnosis
The first clinical manifestation of Paget's disease is usually an elevated alkaline phosphatase in the blood.Paget's disease may be diagnosed using one or more of the following tests:
- Pagetic bone has a characteristic appearance on X-rays. A skeletal survey is therefore indicated.
- An elevated level of alkaline phosphatase in the blood in combination with normal calcium, phosphate, and aminotransferase levels in an elderly patient are suggestive of Paget's disease.
- Markers of bone turnover in urine eg. Pyridinoline
- Elevated levels of serum and urinary hydroxyproline are also found.
- Bone scans are useful in determining the extent and activity of the condition. If a bone scan suggests Paget's disease, the affected bone should be X-rayed to confirm the diagnosis.
Differential diagnosis
Treatment
Although initially diagnosed by a primary care physician, endocrinologists, rheumatologists, orthopedic surgeons, neurosurgeons, neurologists, oral and maxillofacial surgeons, and otolaryngologists are generally knowledgeable about treating Paget's disease and may be called upon to evaluate specialized symptoms. It can sometimes be difficult to predict whether a person with Paget's disease, who otherwise has no signs or symptoms of the disorder, will develop symptoms or complications in the future.Medication
The goal of treatment is to relieve bone pain and prevent the progression of the disease. These medications are usually recommended for people with Paget's disease who:- have bone pain, headache, back pain, or a nerve-related symptom that is directly associated with the disease;
- have elevated levels of serum alkaline phosphatase in their blood;
- display evidence that a bone fracture will occur;
- require pretreatment therapy for affected bones that require surgery;
- have active symptoms in the skull, long bones, or vertebrae ;
- have the disease in bones located next to major joints, placing them at risk of developing osteoarthritis;
- develop hypercalcemia that occurs when a person, with several bones affected by Paget's disease and a high serum alkaline phosphatase level, is immobilized.
Bisphosphonates
- Neridronate
- Etidronate disodium The approved regimen is once daily for six months; a higher dose is more commonly used. No food, beverage, or medications should be consumed for two hours before and after taking. The course should not exceed six months, but repeat courses can be given after rest periods, preferably of three to six months duration.
- Pamidronate disodium in intravenous form: the approved regimen uses an infusion over four hours on each of three consecutive days, but a more commonly used regimen is over two to four hours for two or more consecutive or nonconsecutive days.
- Alendronate sodium is given as tablets once daily for six months; patients should wait at least 30 minutes after taking before eating any food, drinking anything other than tap water, taking any medication, or lying down.
- Tiludronate disodium is taken once daily for three months; they may be taken any time of day, as long as there is a period of two hours before and after resuming food, beverages, and medications.
- Risedronate sodium tablet taken once daily for 2 months is the prescribed regimen; patients should wait at least 30 minutes after taking before eating any food, drinking anything other than tap water, taking any medication, or lying down.
- Zoledronic acid is given as an intravenous infusion; a single dose is effective for two years. This is recommended for most people at high risk with active disease.