Paget's disease of bone

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Paget's disease of bone
Classification and external resources
Pagets skull.jpg
"This 92 year-old male patient presented for assessment of acute hemiparesis. 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."
ICD-10M88
ICD-9731.0
OMIM602080
DiseasesDB9479
MedlinePlus000414
eMedicinemed/2998 radio/514 pmr/98
MeSHD010001
 
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Paget's disease of bone
Classification and external resources
Pagets skull.jpg
"This 92 year-old male patient presented for assessment of acute hemiparesis. 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."
ICD-10M88
ICD-9731.0
OMIM602080
DiseasesDB9479
MedlinePlus000414
eMedicinemed/2998 radio/514 pmr/98
MeSHD010001

Paget's disease of bone or Paget disease of bone (/ˈpæɨt/, rhymes with "gadget") is a chronic disorder that can result in enlarged and misshapen bones. Paget's is caused by the excessive breakdown and formation of bone, followed by disorganized bone remodeling. This causes affected bone to weaken, resulting in pain, misshapen bones, fractures, and arthritis in the joints near the affected bones. Often Paget's disease is localized to only a few bones in the body. The pelvis, femur, and lower lumbar vertebrae are the most commonly affected bones.

Paget's disease typically is localized, affecting just one or a few bones, as opposed to osteoporosis, for example, which usually affects all the bones in the body.

Decisions about treating Paget's disease may be complicated because people are often affected very differently by Paget's disease, and it is sometimes difficult to predict whether a person with Paget's disease who shows no signs or symptoms of the disorder will develop symptoms or complications (such as a bone fracture) in the future. Although there is no cure for Paget's disease, medications (bisphosphonates and calcitonin) can help control the disorder and lessen pain and other symptoms. These medications are usually recommended for people with Paget's disease who

Medications are often successful in controlling the disorder, especially when started before complications begin. Paget's disease is rare in people less than 55 years of age.[1] Men are more commonly affected than women (3:2).[2] The prevalence of Paget's disease ranges from 1.5 to 8.0 percent, depending on age and country of residence. Because early diagnosis and treatment is important, after age 40, siblings and children of someone with Paget's disease may wish to have an alkaline phosphatase blood test every two or three years. If the alkaline phosphatase level is above normal, other tests such as a bone-specific alkaline phosphatase test, bone scan, or X-ray can be performed.

Etymology[edit]

The term osteitis deformans is now considered technically incorrect, and the preferred term is osteodystrophia deformans.

Causes[edit]

Viral[edit]

Paget's disease may be caused by a slow virus infection (i.e., paramyxoviruses) present for many years before symptoms appear. Associated viral infections include respiratory syncytial virus,[3] canine distemper virus,[4][5] and the measles virus.[6][7] However, recent evidence has cast some doubt upon the measles association.[8] Laboratory contamination may have played role in past studies linking paramyxovirus (e.g. measles) to Paget's disease.[9]

Genetic[edit]

About 40-50% of people with the inherited version of Paget's disease have a mutation in the gene SQSTM1, which encodes a protein involved in regulating osteoclast functioning, called p62.[1] About 10-15 percent of people that develop the disease without any family history also have a mutation in the SQSTM1 gene.[1]

There is also a hereditary factor.[10][11] Associations include:

NameOMIMLocusGene
PDB11672506p ?
PDB218q22.1RANK
PDB35q35SQSTM1
PDB46062635q31[12] ?

Pathogenesis[edit]

Micrograph showing Paget's disease of the bone with the characteristic jigsaw puzzle-like/mosaic pattern, H&E stain

The pathogenesis of Paget's disease is described in 4 stages:

  1. Osteoclastic activity
  2. Mixed osteoclastic - osteoblastic activity
  3. Osteoblastic activity
  4. Malignant degeneration

Initially, there is a marked increase in the rate of bone resorption at localized areas caused by large and numerous osteoclasts. These localized areas of osteolysis are seen radiologically as an advancing lytic wedge in long bones or osteoporosis circumscripta in the skull. The osteolysis is followed by a compensatory increase in bone formation induced by osteoblasts recruited to the area. This is associated with accelerated deposition of lamellar bone in a disorganized fashion. 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.

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,[1] 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.[13]

Signs and symptoms[edit]

Many patients with Paget's disease do not know they have the disease, because they have a mild case with no symptoms. In addition, when symptoms do occur, they may be confused with those of arthritis or other disorders. In other cases, the diagnosis is made only after complications have developed. About 35 percent of patients with Paget's have symptoms related to the disease when they are first diagnosed.[1]

The first manifestation of Paget's disease is usually an elevated alkaline phosphatase in the blood.[1] Overall, the most common symptom is bone pain.[1]

Loss of hearing in one or both ears may occur when Paget's disease affects the skull[1] and the bone that surrounds the inner ear. Treating the Paget's disease may slow or stop hearing loss. In rare cases, involvement of the skull may lead to compression of the nerves that supply the eye, leading to vision loss. Paget's may also cause gross deformities in the bones.[1]

Diagnosis[edit]

Paget's disease may be diagnosed using one or more of the following tests:

Comparison of bone pathology
ConditionCalciumPhosphateAlkaline phosphataseParathyroid hormoneComments
Osteoporosisunaffectedunaffectednormalunaffecteddecreased bone mass
Osteopetrosisunaffectedunaffectedelevatedunaffectedthick dense bones also known as marble bone
Osteomalacia and ricketsdecreaseddecreasedelevatedelevatedsoft bones
Osteitis fibrosa cysticaelevateddecreasedelevatedelevatedbrown tumors
Paget's disease of boneunaffectedunaffectedvariable (depending on stage of disease)unaffectedabnormal bone architecture

Prognosis and complications[edit]

The outlook is generally good, particularly if treatment is given before major changes in the affected bones have occurred. Any bone or bones can be affected, but Paget's disease occurs most frequently in the spine, skull, pelvis, femur, and lower legs. In general, symptoms progress slowly, and the disease does not spread to normal bones. Treatment can control Paget's disease and lessen symptoms, but is not a cure. Osteogenic sarcoma, a form of bone cancer, is an extremely rare complication that occurs in less than one percent of all patients.

In rare cases, Paget's disease can lead to the growth of a malignant bone cancer, called osteosarcoma. The development of osteosarcoma may be suggested by the sudden onset or worsening of pain.

Associated medical conditions[edit]

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.

Treatment[edit]

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, podiatrists, and otolaryngologists are generally knowledgeable about treating Paget's disease, and may be called upon to evaluate specialized symptoms.

Drug therapy[edit]

The goal of treatment is to relieve bone pain and prevent the progression of the disease. The U.S. Food and Drug Administration has approved several treatments for Paget's disease.

Bisphosphonates[edit]

Five bisphosphonates are currently available. In general, the most commonly prescribed are risedronic acid (Actonel), alendronic acid (Fosamax), and pamidronic acid (Aredia). Etidronic acid (Didronel) and other bisphosphonates may be appropriate therapies for selected patients but are less commonly used. As a rule, bisphosphonate tablets should be taken with 200-250 mL (6–8& oz) of tap water (not from a source with high mineral content) on an empty stomach. None of these drugs should be used by people with severe kidney disease.

Calcitonin[edit]

Calcitonin, 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 is also linked to increased chance of cancer. Due to the increased risk of cancer, 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.

In the United States, 2 nasal-spray versions of calcitonin are FDA-approved for treating postmenopausal osteoporosis in women: Fortical (Upsher-Smith Laboratories) and Miacalcin (Novartis). Neither of the labels for the 2 drugs contains restrictions on how they should be used or a warning about the risk for cancer.

The EMA said it 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.

CHMP found that "a higher proportion of patients treated with calcitonin for long periods of time develop cancer of various types, compared with patients taking placebo." The increase in cancer rates ranged from 0.7% for oral formulations to 2.4% for the nasal formulation. CHMP concluded that the benefits of calcitonin for osteoporosis did not exceed the risks. The nasal spray's only indication is for osteoporosis, thus justifying the drug's removal from the market.

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.

Surgery[edit]

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.

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.

Diet and exercise[edit]

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.

Exercise is very important in maintaining skeletal health, avoiding weight gain, and maintaining joint mobility. Since undue stress on affected bones should be avoided, patients should discuss any exercise program with their physicians before beginning.

Epidemiology[edit]

The overall prevalence and severity of Paget's disease are decreasing; the cause for these changes is unclear.[14] Paget's disease is rare in people less than 55 years of age,[1] and the prevalence increases with age.[14] Evidence from studies of autopsy results have demonstrated Paget's disease in about 3 percent of people older than 40 years of age.[14] Paget's disease is more common in males than females.[2] 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.[1] 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).[1]

The incidence of Paget's disease varies considerably with geographic location.[14] Paget's predominantly affects people of European descent, whereas people of African, Asian, or Indian descent are less commonly affected.[1] Paget's disease is less common in Switzerland and Scandinavia than in the rest of Western Europe.[14] 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.

In culture[edit]

The Ugly Duchess - portrait by Quentin Matsys. Michael Baum, emeritus professor of surgery at University College London, suggested that the sitter suffered from Paget's disease of bone.[15]

References[edit]

  1. ^ a b c d e f g h i j k l m Ralston, Stuart H. (Feb 14, 2013). "Paget's Disease of Bone". New England Journal of Medicine 368 (7): 644–650. doi:10.1056/NEJMcp1204713. PMID 23406029. 
  2. ^ a b Kumar and Clark, Parveen and Micheal (2009). [Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=9780702029936&ID=HC010583 Welcome to Kumar and Clark's Clinical Medicine 7E]. Elsiver. p. 565. ISBN 978-0-7020-2993-6. 
  3. ^ Mills BG, Singer FR, Weiner LP, Holst PA (February 1981). "Immunohistological demonstration of respiratory syncytial virus antigens in Paget disease of bone". Proc. Natl. Acad. Sci. U.S.A. 78 (2): 1209–13. doi:10.1073/pnas.78.2.1209. PMC 319977. PMID 6940136. 
  4. ^ Hoyland JA, Dixon JA, Berry JL, Davies M, Selby PL, Mee AP (May 2003). "A comparison of in situ hybridisation, reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ-RT-PCR for the detection of canine distemper virus RNA in Paget disease". J. Virol. Methods 109 (2): 253–9. doi:10.1016/S0166-0934(03)00079-X. PMID 12711070. 
  5. ^ Gordon MT, Anderson DC, Sharpe PT (1991). "Canine distemper virus localised in bone cells of patients with Paget disease". Bone 12 (3): 195–201. doi:10.1016/8756-3282(91)90042-H. PMID 1910961. 
  6. ^ Friedrichs WE, Reddy SV, Bruder JM et al. (January 2002). "Sequence analysis of measles virus nucleocapsid transcripts in patients with Paget's disease". J. Bone Miner. Res. 17 (1): 145–51. doi:10.1359/jbmr.2002.17.1.145. PMID 11771661. 
  7. ^ Baslé MF, Fournier JG, Rozenblatt S, Rebel A, Bouteille M (May 1986). "Measles virus RNA detected in Paget disease bone tissue by in situ hybridization". J. Gen. Virol. 67 (5): 907–13. doi:10.1099/0022-1317-67-5-907. PMID 3701300. 
  8. ^ Matthews BG, Afzal MA, Minor PD et al. (April 2008). "Failure to detect measles virus ribonucleic acid in bone cells from patients with Paget's disease". J. Clin. Endocrinol. Metab. 93 (4): 1398–401. doi:10.1210/jc.2007-1978. PMID 18230662. 
  9. ^ Ralston SH, Afzal MA, Helfrich MH et al. (April 2007). "Multicenter blinded analysis of RT-PCR detection methods for paramyxoviruses in relation to Paget disease of bone". J. Bone Miner. Res. 22 (4): 569–77. doi:10.1359/jbmr.070103. PMID 17227218. 
  10. ^ Ralston SH, Langston AL, Reid IR (July 2008). "Pathogenesis and management of Paget disease of bone". Lancet 372 (9633): 155–63. doi:10.1016/S0140-6736(08)61035-1. PMID 18620951. 
  11. ^ Whyte MP (April 2006). "Paget disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kappaB signaling". Ann. N. Y. Acad. Sci. 1068: 143–64. doi:10.1196/annals.1346.016. PMID 16831914. 
  12. ^ Laurin N, Brown JP, Lemainque A et al. (September 2001). "Paget Disease of Bone: Mapping of Two Loci at 5q35-qter and 5q31". Am. J. Hum. Genet. 69 (3): 528–43. doi:10.1086/322975. PMC 1235483. PMID 11473345. 
  13. ^ Basic Pathology, Kumar Abbas Fausto Mitchell, Saunders Elsevier
  14. ^ a b c d e Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine:Chapter 355. Paget's Disease and Other Dysplasias of Bone (18th ed.). New York: McGraw-Hill. ISBN 007174889X. 
  15. ^ Brown, Mark (2008-10-11). "Solved: mystery of The Ugly Duchess - and the Da Vinci connection". The Guardian. Retrieved 2012-04-30. 
  16. ^ "Paid Notice: Deaths DIMAGGIO, DOMINIC P". The New York Times. May 10, 2009. 

External links[edit]