Paget's disease of bone
Encyclopedia
Paget's disease is a chronic disorder that can result in enlarged and misshapen bones. The excessive breakdown and formation of bone tissue causes affected bone to weaken, resulting in pain, misshapen bones, fractures, and arthritis in the joints near the affected bones. Paget's disease typically is localized, affecting just one or a few bones, as opposed to osteoporosis
, for example, which affects all the bones in the body.
Decisions about treating Paget's disease can be complicated because: 1) no two people are affected in exactly the same way by the disease, and 2) it is sometimes difficult to predict whether a person with Paget's disease who shows no signs of the disorder will develop symptoms or complications, such as a bone fracture, at a later date.
Although there is no cure for Paget's disease, medications (bisphosphonates and calcitonin) can help control the disorder and lessen pain and other symptoms. Paget's disease experts recommend that these medications be taken by people with Paget's disease who:
have bone pain, headache, back pain, or a nerve-related symptom (such as "shooting" pains in the leg) that is directly associated with the disease;
have elevated levels of serum alkaline phosphatase (SAP) 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 (spine);
have the disease in bones located next to major joints, placing them at risk of developing osteoarthritis;
develop a rare condition called hypercalcemia that occurs when a person with several bones affected by Paget's disease and a high SAP level is immobilized.
Today's medications, especially when started before complications begin, are often successful in controlling the disorder.
Paget's disease is rarely diagnosed in people less than 40 years of age. Women are more commonly affected than men. Prevalence of Paget's disease ranges from 1.5 to 8.0 percent, depending on age and country of residence. Prevalence of familial Paget's disease (where more than one family member has the disease) ranges from 10 to 40 percent in different parts of the world. 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.
infection (i.e., paramyxoviruses) present for many years before symptoms appear.
Contamination has been suggested to have played a role in producing past positive results.
of Paget's disease is described in 3 stages, which are:
i. Osteoclast
ic activity
ii. Mixed osteoclastic-osteoblast
ic activity
iii. Exhaustive (burnt out) stage
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. New evidence suggests he may have been correct and that a paramyxovirus
infection is the underlying cause of Paget's disease. No infectious virus has yet been isolated as a causative agent, however, and other evidence suggests an intrinsic hyperresponsive reaction to vitamin D and RANK ligand is the cause. Further research is therefore necessary.
, a form of bone cancer
, is an extremely rare complication that occurs in less than one percent of all patients.
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.
s, and otolaryngologists are generally knowledgeable about treating Paget's disease, and may be called upon to evaluate specialized symptoms.
s 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.
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.
, 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.
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, for example, which affects all the bones in the body.
Decisions about treating Paget's disease can be complicated because: 1) no two people are affected in exactly the same way by the disease, and 2) it is sometimes difficult to predict whether a person with Paget's disease who shows no signs of the disorder will develop symptoms or complications, such as a bone fracture, at a later date.
Although there is no cure for Paget's disease, medications (bisphosphonates and calcitonin) can help control the disorder and lessen pain and other symptoms. Paget's disease experts recommend that these medications be taken by people with Paget's disease who:
have bone pain, headache, back pain, or a nerve-related symptom (such as "shooting" pains in the leg) that is directly associated with the disease;
have elevated levels of serum alkaline phosphatase (SAP) 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 (spine);
have the disease in bones located next to major joints, placing them at risk of developing osteoarthritis;
develop a rare condition called hypercalcemia that occurs when a person with several bones affected by Paget's disease and a high SAP level is immobilized.
Today's medications, especially when started before complications begin, are often successful in controlling the disorder.
Paget's disease is rarely diagnosed in people less than 40 years of age. Women are more commonly affected than men. Prevalence of Paget's disease ranges from 1.5 to 8.0 percent, depending on age and country of residence. Prevalence of familial Paget's disease (where more than one family member has the disease) ranges from 10 to 40 percent in different parts of the world. Because early diagnosis
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
and treatment is important, after age 40, siblings and children of someone with Paget's disease may wish to have an alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
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
Bone scan
A bone scan or bone scintigraphy is a nuclear scanning test to find certain abnormalities in bone which are triggering the bone's attempts to heal. It is primarily used to help diagnose a number of conditions relating to bones, including: cancer of the bone or cancers that have spread to the bone,...
, or X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
can be performed.
Etymology
The term osteitis deformans is now considered technically incorrect, and the preferred term is osteodystrophia deformans.Viral
Paget's disease may be caused by a slow virusSlow virus
A slow virus is a virus, or a viruslike agent, etiologically associated with a disease having a long incubation period of months to years with a gradual onset frequently terminating in severe illness and/or death....
infection (i.e., paramyxoviruses) present for many years before symptoms appear.
- MeaslesMeaslesMeasles, also known as rubeola or morbilli, is an infection of the respiratory system caused by a virus, specifically a paramyxovirus of the genus Morbillivirus. Morbilliviruses, like other paramyxoviruses, are enveloped, single-stranded, negative-sense RNA viruses...
, though recent evidence has cast some doubt upon the measles association.
- Canine distemper virus
- Respiratory syncytial virus
Contamination has been suggested to have played a role in producing past positive results.
Genetic
There is also a hereditary factor. Associations include:| Name | OMIM | Locus | Gene |
|---|---|---|---|
| PDB1 | 6p | ? | |
| PDB2 | 18q22.1 | RANK RANK Receptor Activator of Nuclear Factor κ B , also known as TRANCE Receptor, is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding... |
|
| PDB3 | 5q35 | SQSTM1 | |
| PDB4 | 5q31 | ? |
Pathogenesis
The pathogenesisPathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of Paget's disease is described in 3 stages, which are:
i. Osteoclast
Osteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...
ic activity
ii. Mixed osteoclastic-osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
ic activity
iii. Exhaustive (burnt out) stage
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
Osteoporosis circumscripta
Osteoporosis Circumscripta Cranii refers to a highly circumscribed lytic lesion of the skull bone as seen on X-ray in patients with Paget's disease of bones. This focal lesion can be fairly large. This finding is highly specific for Paget's disease of bones....
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. New evidence suggests he may have been correct and that a paramyxovirus
Paramyxovirus
Paramyxoviruses are viruses of the Paramyxoviridae family of the Mononegavirales order; they are negative-sense single-stranded RNA viruses responsible for a number of human and animal diseases.-Genera:*Subfamily Paramyxovirinae**Genus Avulavirus Paramyxoviruses (from Greek para-, beyond, -myxo-,...
infection is the underlying cause of Paget's disease. No infectious virus has yet been isolated as a causative agent, however, and other evidence suggests an intrinsic hyperresponsive reaction to vitamin D and RANK ligand is the cause. Further research is therefore necessary.
Symptoms
Many patients do not know they have Paget's disease because they have a mild case with no symptoms. Sometimes, symptoms may be confused with those of arthritis or other disorders. In other cases, the diagnosis is made only after complications have developed. Symptoms can include:- Bone painBone painBone pain is a debilitating form of pain emanating from the bone tissue. It occurs as a result of a wide range of diseases and/or physical conditions and may severely impair the quality of life for patients who suffer from it...
Diagnosis
Paget's disease may be diagnosed using one or more of the following tests:- Pagetic bone has a characteristic appearance on X-rayX-rayX-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
s. A skeletal surveySkeletal surveyA skeletal survey is a series of X-rays of all the bones in the body, or at least the axial skeleton and the large cortical bones. A very common use is the diagnosis of multiple myeloma, where tumour deposits appear as "punched-out" lesions...
is therefore indicated. - An elevated level of alkaline phosphataseAlkaline phosphataseAlkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
in the blood in combination with normal calciumCalciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
, phosphatePhosphateA phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
, and aminotransferase levels in an elderly patient are suggestive of Paget's disease. - Bone scanBone scanA bone scan or bone scintigraphy is a nuclear scanning test to find certain abnormalities in bone which are triggering the bone's attempts to heal. It is primarily used to help diagnose a number of conditions relating to bones, including: cancer of the bone or cancers that have spread to the bone,...
s are useful in determining the extent and activity of the condition. If a bone scan suggests Paget's disease, the affected bone(s) should be X-rayed to confirm the diagnosis.
Prognosis
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 sarcomaOsteosarcoma
Osteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid...
, a form of bone cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, is an extremely rare complication that occurs in less than one percent of all patients.
Associated medical conditions
Paget's disease may lead to other medical conditions, including:- Arthritis may be caused by bowing of long bones in the leg, distorting alignment and increasing pressure on nearby joints. In addition, pagetic bone may enlarge, causing joint surfaces to undergo excessive wear. In these cases, pain may be due to a combination of Paget's disease and osteoarthritis.
- Loss of hearing in one or both ears may occur when Paget's disease affects the skull and the bone that surrounds the inner ear. Treating the Paget's disease may slow or stop hearing loss. Hearing aidHearing aidA hearing aid is an electroacoustic device which typically fits in or behind the wearer's ear, and is designed to amplify and modulate sound for the wearer. Earlier devices, known as "ear trumpets" or "ear horns", were passive funnel-like amplification cones designed to gather sound energy and...
s may also help. - Cardiovascular diseaseCardiovascular diseaseHeart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
can result from severe Paget's disease (i.e. with more than 15% skeletal involvement). Arteriovenous connections can often form in the bone, and so the heart has to work harder (pump more blood) to ensure adequate oxygen supply to the tissues. This increase in cardiac output can lead to calcification of the aortic valve, and the resulting aortic stenosis causes left ventricular hypertrophy and eventually high-output congestive failure. - Kidney stoneKidney stoneA kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...
s are somewhat more common in patients with Paget's disease. - Pagetic bone can cause nervous systemNervous systemThe nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
problems, such as pressure on the brain, spinal cordSpinal cordThe spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, or nerves, and reduced blood flow to the brain and spinal cord. - Rarely, Paget's disease is associated with the development of osteosarcomaSarcomaA sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
(malignant tumor of bone). When there is a sudden onset or worsening of pain, sarcoma should be considered. - When Paget's disease affects the facial bones, the teeth may become loose. Disturbance in chewing may occur.
- Rarely, when the skull is involved, the nerves to the eyeHuman eyeThe human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
may be affected, causing some loss of vision. - Angioid streaksAngioid streaksAngioid streaks, also called Knapp streaks or Knapp striae are small breaks in Bruch's membrane, an elastic tissue containing membrane of the retina that can become calcified and crack....
may develop, possibly as a result of calcification of collagen or other pathological deposition.
Paget's disease is not associated with osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. 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
Endocrinologists (internists who specialize in hormonal and metabolic disorders), rheumatologists (internists who specialize in joint and muscle disorders), orthopedic surgeons, neurologistNeurologist
A neurologist is a physician who specializes in neurology, and is trained to investigate, or diagnose and treat neurological disorders.Neurology is the medical specialty related to the human nervous system. The nervous system encompasses the brain, spinal cord, and peripheral nerves. A specialist...
s, and otolaryngologists are generally knowledgeable about treating Paget's disease, and may be called upon to evaluate specialized symptoms.
Drug therapy
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 the following treatments for Paget's disease:Bisphosphonates
Five bisphosphonateBisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
s are currently available. In general, the most commonly prescribed are: risedronic acid (Actonel), alendronic acid (Fosamax) and pamidronic acid
Pamidronic acid
Pamidronic acid or pamidronate disodium , pamidronate disodium pentahydrate is a nitrogen containing bisphosphonate, used to prevent osteoporosis. It is marketed by Novartis under the brand name Aredia.-Uses:...
(Aredia). Etidronic acid
Etidronic acid
Etidronic acid or 1-hydroxyethane 1,1-diphosphonic acid is a bisphosphonate used in detergents, water treatment, cosmetics and pharmaceutical treatment....
(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.
- Etidronate disodium (Didronel) in tablet form is available in 200–400 mg doses. The approved regimen is once daily for six months; the higher dose (400 mg) 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 (Aredia) in intravenous form: the approved regimen uses a 30 mg infusion over four hours on each of three consecutive days, but a more commonly used regimen is 60 mg over two to four hours for two or more consecutive or nonconsecutive days.
- Alendronate sodium (Fosamax) is given as tablets of 40 mg 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 (patient may sit).
- Tiludronate disodium (Skelid) in two tablets of 200 mg are 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 (Actonel) as a 30 mg 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 (patient may sit).
- Zoledronic acid (Reclast, Aclasta) is given as an intravenous infusion; a single dose (5 mg over 15 minutes) is effective for two years.
Calcitonin
- Miacalcin is administered by injection; 50 to 100 units daily or three times per week for 6–18 months. Repeat courses can be given after brief rest periods. Miacalcin may be appropriate for certain patients, but is seldom used. The nasal spray form of this drug is not approved for the treatment of Paget's disease.
Surgery
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.- Fractures — Surgery may allow fractures to heal in a better position.
- Severe degenerative arthritis — If disability is severe and medication and physical therapy are no longer helpful, joint replacement of the hips and knees may be considered.
- Bone deformity — Cutting and realignment of pagetic bone (osteotomy) may help painful weight bearingWeight bearingIn orthopedics, weight-bearing is the amount of weight a patient puts on the leg on which surgery has been performed. In general, it is described as a percentage of the body weight, because each leg of a healthy person carries the full body weight when walking, in an alternating fashion.After...
joints, especially the knees.
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
In general, patients with Paget's disease should receive 1000–1500 mg of calciumCalcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
, adequate sunshine
Sunlight
Sunlight, in the broad sense, is the total frequency spectrum of electromagnetic radiation given off by the Sun. On Earth, sunlight is filtered through the Earth's atmosphere, and solar radiation is obvious as daylight when the Sun is above the horizon.When the direct solar radiation is not blocked...
, and at least 400 units of vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
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
Weight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
, and maintaining joint mobility. Since undue stress on affected bones should be avoided, patients should discuss any exercise program with their physicians before beginning.