Paget's disease of bone | |
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Other names | osteitis deformans, Paget's disease |
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"This 92 year-old male patient presented for assessment of sudden inability to move half his body. An incidental finding was marked thickening of the calvarium. The diploic space is widened and there are ill-defined sclerotic and lucent areas throughout. The cortex is thickened and irregular. The findings probably correspond to the 'cotton wool spots' seen on plain films in the later stages of Paget's disease." | |
Pronunciation |
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Specialty | Rheumatology ![]() |
Named after | James Paget |
Paget's disease of bone (commonly known as Paget's disease or, historically, osteitis deformans) 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. [1] These structural changes cause the bone to weaken, which may result in deformity, pain, fracture or arthritis of associated joints. [1]
The exact cause is unknown, although leading theories indicate both genetic and acquired factors (see Causes). Paget's disease may affect any one or several bones of the body (most commonly pelvis, tibia, femur, lumbar vertebrae, and skull), but never the entire skeleton, [1] [2] [3] and does not spread from bone to bone. [4] 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 (bisphosphonates and calcitonin) 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. [5] [6] It is primarily diagnosed in older people and is rare in people less than 55 years of age. [7] Men are more commonly affected than women (3:2). [8] The disease is named after English surgeon Sir James Paget, who described it in 1877.
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. [7] Overall, the most common symptom is bone pain. [7] 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. [9]
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 [7] 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. [7]
Paget's disease is a frequent component of multisystem proteinopathy. Advanced Paget's disease may lead to other medical conditions, including:
Paget's disease is not associated with osteoporosis. Although Paget's disease and osteoporosis can occur in the same patient, they are different disorders. Despite their marked differences, several treatments for Paget's disease are also used to treat osteoporosis.
Paget's disease may be caused by a slow virus infection (i.e., paramyxoviridae) present for many years before symptoms appear. Associated viral infections include respiratory syncytial virus, [13] canine distemper virus, [14] [15] and the measles virus. [16] [17] However, recent evidence has cast some doubt upon the measles association. [18] Laboratory contamination may have played a role in past studies linking paramyxovirus (e.g. measles) to Paget's disease. [19]
There is a hereditary factor in the development of Paget's disease of bone. [20] [21] 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. [9]
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 (bone cells). [7] However, about 10–15 percent of people that develop the disease without any family history also have a mutation in the SQSTM1 gene. [7]
Paget's disease of bone is associated with mutations in RANK. Receptor Activator of Nuclear Factor κ B (RANK), which is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding. [22] Additional genetic associations include:
Name | OMIM | Locus | Gene |
---|---|---|---|
PDB1 | 167250 | 6p | ? |
PDB2 | 18q22.1 | RANK | |
PDB3 | 5q35 | SQSTM1 | |
PDB4 | 606263 | 5q31 [23] | ? |
The pathogenesis of Paget's disease is described in four stages: [24]
Initially, there is a marked increase in the rate of bone resorption in localized areas, caused by large and numerous osteoclasts. Radiographs at this phase show lucency in the affected bone. These localized areas of pathological destruction of bone tissue (osteolysis) are seen radiologically as an advancing lytic wedge in long bones or the skull. When this occurs in the skull, it is called osteoporosis circumscripta. The osteolysis is followed by a compensatory increase in bone formation and increase in alkaline phosphatase levels induced by the bone-forming cells, called osteoblasts, that are recruited to the area. This is associated with accelerated deposition of lamellar bone in a disorganized fashion. Woven bone, rather than lamellar bone, predominates and mineralization occurs at twice the normal rate. [5] This intense cellular activity produces a chaotic picture of trabecular bone ("mosaic" pattern), rather than the normal linear lamellar pattern. The resorbed bone is replaced and the marrow spaces are filled by an excess of fibrous connective tissue with a marked increase in blood vessels, causing the bone to become hypervascular. The bone hypercellularity may then diminish, leaving a dense "pagetic bone", also known as burned-out Paget's disease. A later phase of the disease is characterized by the replacement of normal bone marrow with highly vascular fibrous tissue. [25]
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, [7] 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.[ citation needed ] Further research is therefore necessary. [26]
The first clinical manifestation of Paget's disease is usually an elevated alkaline phosphatase in the blood. [7]
Paget's disease may be diagnosed using one or more of the following tests:
Condition | Calcium | Phosphate | Alkaline phosphatase | Parathyroid hormone | Comments |
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Osteopenia | unaffected | unaffected | normal | unaffected | decreased bone mass |
Osteopetrosis | unaffected | unaffected | elevated | unaffected [ citation needed ] | thick dense bones also known as marble bone |
Osteomalacia and rickets | decreased | decreased | elevated | elevated | soft bones |
Osteitis fibrosa cystica | elevated | decreased | elevated | elevated | brown tumors |
Paget's disease of bone | unaffected | unaffected | variable (depending on stage of disease) | unaffected | abnormal bone architecture |
Although initially diagnosed by a primary care physician, endocrinologists (internal medicine physicians who specialize in hormonal and metabolic disorders), rheumatologists (internal medicine physicians who specialize in joint and muscle disorders), 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 (such as a bone fracture) in the future.[ citation needed ]
The goal of treatment is to relieve bone pain and prevent the progression of the disease. [9] These medications are usually recommended for people with Paget's disease who:[ citation needed ]
Five bisphosphonates are currently available. In general, the most commonly prescribed are risedronic acid, alendronic acid, and pamidronic acid. Etidronic acid and other bisphosphonates may be appropriate therapies for selected patients but are less commonly used. In one study it was reported that people experienced side effects when taking bisphosphonates for six months, however the quality of evidence was low. [27] None of these drugs should be used by people with severe kidney disease.[ citation needed ]
Salcatonin, also called calcitonin-salmon is a synthetic copy of a polypeptide hormone secreted by the ultimobranchial gland of salmon. Miacalcin is administered by injection, three times per week or daily, for 6–18 months. Repeat courses can be given after brief rest periods. Miacalcin may be appropriate for certain patients but is seldom used. Calcitonin was putatively linked to increased chance of cancer. [29] The European Medicines Agency (EMA) recommended that calcitonin be used only on a short-term basis for 3 conditions for which it had previously been approved in the European Union: Paget's disease, acute bone loss resulting from sudden immobilization, and hypercalcemia caused by cancer. As a solution for injection or infusion, calcitonin should be administered for no more than 4 weeks to prevent acute bone loss resulting from sudden immobilization, and normally for no more than 3 months to treat Paget's disease, the EMA said. The agency did not specify a time frame for the short-term use of calcitonin for treating hypercalcemia caused by cancer. The EMA based its recommendations on a review of the benefits and risks of calcitonin-containing medicines. Conducted by the agency's Committee for Medicinal Products for Human Use (CHMP), the review encompassed available data from the companies that market these drugs, postmarketing safety data, randomized controlled studies, 2 studies of unlicensed oral calcitonin drugs, and experimental cancer studies, among other sources. [30]
In 2014, the FDA noted the risk imbalances in the prescribing information for Miacalcin but declined to label this product with a boxed warning as a causal association was not identified. [31]
A more recent meta-analysis determined that a causal link between calcitonin and cancer is both unlikely and antithetical to known biology, although a weak association was not definitively excluded. [32] The available studies for analysis were inconsistent and nonspecific, with one study [33] noting an increased risk of liver cancer and decreased risk of breast cancer. This was not replicated in any other study.[ citation needed ]
Additionally, there is question of the overall efficacy of calcitonin-containing nasal sprays. A phase III trial found no difference between placebo and nasal calcitonin sprays on lumbar bone mineral density in osteoporosis. [34] It did find a significant increase in bone mineral density with oral calcitonin. This result was replicated in another study, [35] but this study found that the bone mineral density increase did not significantly impact fracture risk. However, these studies were only inclusive of osteoporosis.
Medical therapy prior to surgery helps to decrease bleeding and other complications. Patients who are having surgery should discuss treatment with their physician. There are generally three major complications of Paget's disease for which surgery may be recommended. [9]
Complications resulting from enlargement of the skull or spine may injure the nervous system. However, most neurologic symptoms, even those that are moderately severe, can be treated with medication and do not require neurosurgery.[ citation needed ]
In general, patients with Paget's disease should receive 1000–1500 mg of calcium, adequate sunshine, and at least 400 units of vitamin D daily. This is especially important in patients being treated with bisphosphonates; however, taking oral bisphosphonates should be separated from taking calcium by at least two hours, because the calcium can inhibit the absorption of the bisphosphonate. Patients with a history of kidney stones should discuss calcium and vitamin D intake with their physicians. [36]
Exercise is very important in maintaining skeletal health, avoiding weight gain, and maintaining joint mobility. Since undue stress on affected bones should be avoided, people with Paget's disease of bone should discuss any exercise program with their physicians or physical therapists before beginning.[ citation needed ]
The disease is progressive and slowly worsens with time, although people may remain minimally symptomatic. Treatment is aimed at controlling symptoms, but there is no cure. Any bone or bones can be affected, but Paget's disease occurs most frequently in the spine, skull, pelvis, femur, and lower legs. Osteogenic sarcoma, a form of bone cancer, is a rare complication of Paget's disease occurring in less than one percent of those affected. The development of osteosarcoma may be suggested by the sudden onset or worsening pain.[ citation needed ]
Paget's disease of bone is the second most common metabolic bone disorder, after osteoporosis. [37] The overall prevalence and severity of Paget's disease are decreasing; the cause for these changes is unclear. [38] Paget's disease is rare in people less than 55 years of age, [7] and the prevalence increases with age. [38] Evidence from studies of autopsy results have demonstrated Paget's disease in about 3 percent of people older than 40 years of age. [38] Paget's disease is more common in males than females. [8] Rates of Paget's disease are about 50 percent higher in men than in women.
About 15 percent of people with Paget's disease also have a family member with the disease. [7] In cases where the disease is familial, it is inherited in an autosomal dominant fashion, although not all people that inherit the affected version of the genes will express the disease (incomplete penetrance). [7]
The incidence of Paget's disease varies considerably with geographic location. [38] Paget's predominantly affects people of European descent, whereas people of African, Asian, or Indian descent are less commonly affected. [7] Paget's disease is less common in Switzerland and Scandinavia than in the rest of Western Europe. [38] Paget's disease is uncommon in the native populations of North and South America, Africa, Asia, and the Middle East. When an individual from these regions does develop Paget's disease, there is typically some European ancestry present.[ citation needed ]
The condition was initially described by Dr. James Paget. In a paper published in 1877, Paget told of five patients with "a rare disease of bones" which presented with slowly progressive bone deformities in the 4th and 5th decades of age. [39] Strikingly, the first patient was described to have many of the classic complications of the disease, including arthritis related to abnormal bone mechanics, cranial nerve palsies associated with an enlarging skull, and malignant transformation of a tumor of the radius which ultimately proved fatal. Paget's post-mortem autopsy evaluation showed "bones of the vault of this skull were in every part increased to about four times the normal thickness," and microscopic evaluation showed evidence of both bone erosion and abnormal remodeling. Although he incorrectly attributed the findings to a process of chronic inflammation, having ruled out tumor and hypertrophy as alternative etiologies, these prescient observations of a mixed destructive/regenerative process correspond to the modern understanding of the disease.
Holding, then, the disease to be an inflammation of bones, I would suggest that, for brief reference, and for the present, it may be called, after its most striking character, Osteitis deformans. A better name may be given when more is known of it.
— James Paget, Paget J. On a form of chronic inflammation of bone (osteitis deformans). Medico-cirurgical Transactions of London 1887;60:37-63.
Paget's disease of bone was originally termed osteitis deformans, because it was thought to involve an inflammatory process, which is implied by the suffix -itis . Now, that term is considered technically incorrect, and the preferred term is osteodystrophia deformans. [40]
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in fracture risk.
Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).
Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.
Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they have two phosphonate groups. They are thus also called diphosphonates.
Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementation, and lifestyle changes.
Zoledronic acid, also known as zoledronate and sold under the brand name Zometa among others, by Novartis among others, is a medication used to treat a number of bone diseases. These include osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, Paget's disease of bone and Duchenne muscular dystrophy (DMD). It is given by injection into a vein.
Bone pain is pain coming from a bone, and is caused by damaging stimuli. It occurs as a result of a wide range of diseases or physical conditions or both, and may severely impair the quality of life.
Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteoporosis. In 2010, 43 million older adults in the US had osteopenia. Unlike osteoporosis, osteopenia does not usually cause symptoms, and losing bone density in itself does not cause pain.
Renal osteodystrophy is currently defined as an alteration of bone morphology in patients with chronic kidney disease (CKD). It is one measure of the skeletal component of the systemic disorder of chronic kidney disease-mineral and bone disorder (CKD-MBD). The term "renal osteodystrophy" was coined in 1943, 60 years after an association was identified between bone disease and kidney failure.
Osteitis fibrosa cystica is a skeletal disorder resulting in a loss of bone mass, a weakening of the bones as their calcified supporting structures are replaced with fibrous tissue, and the formation of cyst-like brown tumors in and around the bone. Osteitis fibrosis cystica (OFC), also known as osteitis fibrosa, osteodystrophia fibrosa, and von Recklinghausen's disease of bone, is caused by hyperparathyroidism, which is a surplus of parathyroid hormone from over-active parathyroid glands. This surplus stimulates the activity of osteoclasts, cells that break down bone, in a process known as osteoclastic bone resorption. The hyperparathyroidism can be triggered by a parathyroid adenoma, hereditary factors, parathyroid carcinoma, or renal osteodystrophy. Osteoclastic bone resorption releases minerals, including calcium, from the bone into the bloodstream, causing both elevated blood calcium levels, and the structural changes which weaken the bone. The symptoms of the disease are the consequences of both the general softening of the bones and the excess calcium in the blood, and include bone fractures, kidney stones, nausea, moth-eaten appearance in the bones, appetite loss, and weight loss.
Hypercalciuria is the condition of elevated calcium in the urine. Chronic hypercalciuria may lead to impairment of renal function, nephrocalcinosis, and chronic kidney disease. Patients with hypercalciuria have kidneys that excrete higher levels of calcium than normal, for which there are many possible causes. Calcium may come from one of two paths: through the gut where higher than normal levels of calcium are absorbed by the body or mobilized from stores in the bones. After initial 24 hour urine calcium testing and additional lab testing, a bone density scan (DSX) may be performed to determine if the calcium is being obtained from the bones.
Osteonecrosis of the jaw (ONJ) is a severe bone disease (osteonecrosis) that affects the jaws. Various forms of ONJ have been described since 1861, and a number of causes have been suggested in the literature.
Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology.
Orthopedic pathology, also known as bone pathology is a subspecialty of surgical pathology which deals with the diagnosis and feature of many bone diseases, specifically studying the cause and effects of disorders of the musculoskeletal system. It uses gross and microscopic findings along with the findings of in vivo radiological studies, and occasionally, specimen radiographs to diagnose diseases of the bones.
Bone disease refers to the medical conditions which affect the bone.
A pathologic fracture is a bone fracture caused by weakness of the bone structure that leads to decrease mechanical resistance to normal mechanical loads. This process is most commonly due to osteoporosis, but may also be due to other pathologies such as cancer, infection, inherited bone disorders, or a bone cyst. Only a small number of conditions are commonly responsible for pathological fractures, including osteoporosis, osteomalacia, Paget's disease, Osteitis, osteogenesis imperfecta, benign bone tumours and cysts, secondary malignant bone tumours and primary malignant bone tumours.
Medication-related osteonecrosis of the jaw is progressive death of the jawbone in a person exposed to a medication known to increase the risk of disease, in the absence of a previous radiation treatment. It may lead to surgical complication in the form of impaired wound healing following oral and maxillofacial surgery, periodontal surgery, or endodontic therapy.
An endocrine bone disease is a bone disease associated with a disorder of the endocrine system. An example is osteitis fibrosa cystica.
Bone metastasis, or osseous metastatic disease, is a category of cancer metastases that result from primary tumor invasions into bones. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing sarcoma are rare; the most common bone tumor is a metastasis. Bone metastases can be classified as osteolytic, osteoblastic, or both. Unlike hematologic malignancies which originate in the blood and form non-solid tumors, bone metastases generally arise from epithelial tumors and form a solid mass inside the bone. Bone metastases, especially in a state of advanced disease, can cause severe pain, characterized by a dull, constant ache with periodic spikes of incident pain.
Oral manifestations of systematic disease are signs and symptoms of disease occurring elsewhere in the body detected in the oral cavity and oral secretions. High blood sugar can be detected by sampling saliva. Saliva sampling may be a non-invasive way to detect changes in the gut microbiome and changes in systemic disease. Another example is tertiary syphilis, where changes to teeth can occur. Syphilis infection can be associated with longitudinal furrows of the tongue.
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