1. http://www.nhs.uk/Conditions/Pagets-disease/Pages/Introduction.aspx Pagets disease is a condition where the normal cycle of bone renewal and repair is disrupted.

In some cases, this can cause the affected bone (or bones) to become weakened and deformed. Bone pain is the most common symptom of Pagets disease. It most commonly affects the pelvis or spine and it is usually worse when lying down. However, in many cases Pagets disease does not cause any noticeable symptoms, and it is only diagnosed during tests for an unrelated medical condition or when an affected bone is fractured. See the Health A-Z page on symptoms of Pagets disease for more information. There is no cure for the condition but the symptoms can be controlled by painkillers and a range of medications that help regulate bone growth. Following treatment for Pagets disease many people will have long periods of remission (where symptoms disappear) provided that the disease is picked up at an early stage. If the disease has progressed to an advanced stage by the time it is discovered, treatment is much less effective. Complications of Pagets disease are uncommon, but they can be potentially serious. They include:

fractured bones deformed bones deafness bone cancer

How common is Paget's disease?

After osteoporosis (brittle bones), Pagets disease is the second most common type of bone disease. Pagets disease occurs among people of white British descent, possibly due to genetic factors. It is very rare among other ethnic groups, such as Asians and Africans. Pagets disease is most widespread in Britain and it is also relatively widespread in countries where there have been high levels of migration from Britain, such as Australia, New Zealand and South Africa, and to a lesser extent the USA. There is also a marked variation in the number of cases of Pagets disease in different regions of Britain. For example, the condition is less common in the south of the country, where an estimated 1 in 100 people over the age of 55 is affected, and it is more widespread in the north, particularly in the county of Lancashire where 1 in 50 people of this age may be affected.

Who is affected by Pagets disease?

Pagets disease is an age-related condition. It is estimated that 1-2% of white adults aged over 55 have the condition. This figure increases to about 7% for white people who are over 80 years old.

Symptoms of Paget's disease

Pagets disease usually affects the bones of the pelvis or spine. Other areas of the body that can also be affected include the skull, the shoulders and the long bones in the arms and legs particularly the thigh bone.

Bone pain
Bone pain is the most common symptom of Pagets disease. The pain has been described as a dull, constant, "boring" sensation deep within the affected part of the body. The pain is usually worse at night when you are lying down. As Pagets disease progresses, you may experience deformities in the affected bones, such as twisted or misshaped limbs or scoliosis (curvature of the spine). Affected bones can sometimes fracture (break), particularly the longer bones in your arms and legs. Symptoms of fractured bones include:

pain and swelling in the affected area bruising or discoloured skin around the bone or joint the limb or body part being bent at an unusual angle (angulation)

Other symptoms
Pagets disease can cause a range of other symptoms depending on which bones are affected by the condition. These are described below.
The skull

If Pagets disease develops inside the bones of your skull it can cause the following symptoms:

hearing loss which can be total or partial vertigo feeling very dizzy or the sensation that you are moving when standing still headaches tinnitus a constant buzzing or ringing noise in your ears

The joints

Abnormal bone growth can cause damage to nearby cartilage. Cartilage is the thick, spongy tissue that cushions your joints. Cartilage damage can lead to progressive joint damage, which is known as osteoarthritis.

Symptoms of osteoarthritis include:

pain stiffness which is worse when you wake up in the morning, but usually improves within about 30 minutes of starting to move difficulty moving your affected joints

The nerves

Many of the major nerves in your body run through, or alongside, your bones. Abnormal bone growth can result in a bone compressing (squeezing), "pinching" or damaging a nerve. Depending on where the affected nerve is and its main purpose, this can lead to a wide range of symptoms. Possible symptoms affecting the nerves (neurological symptoms) include:

pain that travels from the base of your spine down into your legs (sciatica) pain that travels from your neck into your arms and chest (cervical radiculopathy) numbness or tingling in the affected limbs partial loss of movement in your limbs loss of balance bowel incontinence or urinary incontinence (the loss of bowel or bladder control)

When to seek medical advice

You should always visit your GP if you:

have persistent bone pain notice deformities in any of your bones experience any neurological symptoms, such as numbness or tingling

Causes of Paget's disease

Bone remodelling
To get a better understanding of how Pagets disease affects your bones, it is useful to understand how they are kept healthy throughout life. It is often assumed that once a persons bones reach adult size, they do not change, but this is not the case. In a similar way to skin, bone cells undergo a continuous cycle of regeneration, where old bone is removed and is replaced by new bone. This cycle is known as bone remodelling. Bone is made up of a protein called collagen and a mineral called hydroxyapatite. Two specialised cells are responsible for bone renewal and repair. These are known as:

osteoclasts cells that absorb old bones osteoblasts cells that lay down new bone

In Pagets disease, something goes wrong with the osteoclast cells and they begin to absorb collagen at a much faster rate than normal. The osteoblasts attempt to compensate for this by producing new bone, but because they have to work at a faster speed than normal, the bone that they produce becomes weak and unstable. Over time, this disruption to the bone remodelling process can lead to bones becoming bigger and weaker than normal.

Possible causes of Pagets disease

The exact cause of Pagets disease is unknown, but it is likely that the condition develops as result of a combination of genetic and environmental factors. These are described below.
Genetic factors

People who inherit certain mutated genes from their parents could go on to develop Paget's disease. The most important of these is a gene called SQSTM1. People with a mutation in this gene have a greatly increased risk of developing Pagets disease in later life. Seven other genes have now been identified which also increase the risk of Pagets disease substantially. In about 15% of cases, Pagets disease runs in families. If you have a close relative with Pagets disease, such as a parent, brother or sister, you are seven to eight times more likely to develop the condition.
Environmental factors

The evidence that environmental factors may play a role in Pagets disease is based on the fact that the number of people who are affected by the condition has fallen sharply over the last 50 years in Britain and New Zealand. In contrast, the number of people affected in some other countries, such as Italy, has remained static. The severity of symptoms also seems to be decreasing, as up to 60 years ago it was not uncommon for people to experience very severe symptoms in multiple bones. However, this is no longer the case. The reasons for these differences are unclear. In Britain, a possible reason for the decrease in the number of people who are affected by Pagets disease might be the significant changes that have been seen in the ethnic mix of the population over the past 50 years. An influx of people from Asia and Africa, where Pagets disease is rare, could account in part for the decreasing frequency of the disease. Another theory is that Pagets disease might be caused by a slow virus infection. Viruses that have been suggested as possible triggers for Pagets disease include:

measles virus a common childhood infection

canine distemper virus a virus that is responsible for distemper which is a type of viral infection that affects animals, mainly dogs respiratory syncitial virus which causes respiratory infections during childhood

Due to vaccines, both measles and distemper are now uncommon infections. This could account for the decrease in cases of Paget's disease. Another theory is that people with rural lifestyles, who regularly come into contact with farmyard animals, and who in the past had high levels of physical activity, may be at increased risk of developing Pagets disease. As the number of people living this type of lifestyle is much less common than it was, it could offer an alternative explanation for the fall in cases of Pagets disease. Improvements in nutrition and a reduction in the occurrence of rickets (a bone disorder caused by a vitamin deficiency) over the past 50 to 100 years have also been suggested as possibly accounting for the decreasing severity of Pagets disease.

Diagnosing Paget's disease

It is sometimes possible to diagnose Pagets disease in its early stages, leading to early treatment. However, it is not yet known whether this is effective in preventing the most serious complications, such as hearing loss and bone deformity.

Serum alkaline phosphatase (SAP)

In many cases, Pagets disease is first diagnosed during a blood test for another, unrelated condition. This occurs because the abnormal pattern of bone remodelling caused by Pagets disease leads to a rise in levels of a chemical called serum alkaline phosphatise (SAP) in your blood. The high levels of SAP can be detected with a blood test.

X-rays and bone scans

Pagets disease can often be confirmed by taking X-rays of the affected bones. This can help to determine whether the bones have become enlarged due to Pagets disease. As well as having an X-ray, a bone scan may also be recommended. This involves having a small amount of a harmless radioactive substance injected into your blood. This substance collects in the areas of bone where there is the most activity, such as where there is abnormal bone remodelling. A special camera, known as a gamma camera, is used to highlight where the radiation has collected. A bone scan is a useful way of pinpointing exactly where abnormal bone remodelling is taking place.

Further testing
Further testing is usually only required if:

You develop abnormalities that affect one or more joints. You are experiencing neurological symptoms (symptoms that affect your nerves, such as pain, numbness or tingling). A diagnosis of bone cancer is suspected.

In these circumstances, tests that can be used are:

A bone biopsy where a sample of bone is taken under local or general anaesthetic. A computer tomography (CT) scan where a series of X-rays of the affected bone are taken to show a detailed three-dimensional image. A magnetic resonance imaging (MRI) scan another type of scan that uses a strong magnetic field and radio waves to build up an image of the inside of the affected bone.

Treating Paget's disease

Dietary supplements
If you have Pagets disease, your GP may recommend that you take regular vitamin D and calcium supplements. Both of these help to strengthen your bones. Some bisphosphonates (see right) can also reduce the levels of calcium in your body, so you may need to "top up" your levels by taking supplements. If a blood test reveals that you have Pagets disease but you are not experiencing any symptoms, a policy of "watchful waiting" is likely to be recommended. This means that you will not receive treatment immediately, but your progress will be carefully monitored using regular blood tests. Treatment is usually recommended if you have symptoms that are associated with Pagets disease, such as bone pain or neurological symptoms (those that affect the nerves, causing symptoms such as pain, numbness and tingling). The short-term aim of treatment for Pagets disease is to relieve symptoms. The long-term aim is to prevent the condition from getting worse and to reduce the risk of complications developing. Treatment options for Pagets disease include:

medication to help regulate bone remodelling medication to relieve pain surgery

Regulating bone remodelling

There are a number of different medications that can be used to help regulate bone growth in cases of Pagets disease. These are outlined below.

Bisphosphonates

Bisphosphonates are the first choice medications that are used to regulate bone growth. These medicines work by suppressing (controlling) the actions of the osteoclasts cells, which means that the bone remodelling process should return to normal. A type of bisphosphonate called risedronate is usually recommended because it has proved to be effective in treating Pagets disease. Risedronate is available in tablet form and most people are advised to take one tablet a day over the course of a two-month period. It is usually recommended that risedronate is taken first thing in the morning, 30 minutes before eating or drinking anything (other than plain water). Take your risedronate tablet while you are standing or sitting up and avoid lying down for at least 30 minutes after taking it. This will help prevent heartburn (burning chest pain and discomfort). Side effects of risedronate include:

feeling sick stomach cramps or discomfort constipation bloating diarrhoea pain in your bones, muscles or joints headaches

If you are unable to take risedronate because you are unable to stay upright for 30 minutes, there are alternative bisphosphonates, such as pamidronate, that can be used. Pamidronate is given by injection, usually once a week over the course of six weeks. The most common side effects of pamidronate include:

mild, flu-like symptoms, such as high temperature joint pain headaches chills

However, these side effects usually pass within 48 hours of receiving an injection.
Zoledronic acid

Zoledronic acid is a new type of bisphosphonate that is increasingly being used as an alternative to risedronate or pamidronate. Zoledronic acid is a long-acting medication so you will only need to be given one injection a year. Flu-like symptoms, such as chills, fever and joint pain are common after receiving your first injection, although these side effects should pass within three to four days.

Calcitonin

If you have low levels of calcium in your blood (hypocalcemia), you will probably be unable to use bisphosphonates safely. This is because bisphosphonates can lower your calcium levels further which could be potentially dangerous. In such circumstances, an alternative medication called calcitonin may be recommended. Calcitonin is a synthetic (man-made) version of a hormone that is known to prevent bone loss. It is given by injection once a day. The recommended course will depend on how well you respond to treatment. If you require a relatively long course of treatment, training can be given so that you can administer the injections yourself. Common side effects of calcitonin include:

headaches changes in how things taste nausea abdominal pain vomiting diarrhoea fatigue dizziness

If you experience feelings of dizziness when taking calcitonin, avoid driving or operating machinery.

Painkillers
In most cases, painkillers that are available over the counter, such as paracetamol or ibuprofen, should be effective in relieving the symptoms of bone pain. If your symptoms continue, your GP can prescribe more powerful painkillers.

Physiotherapy
Some people with Pagets disease find that they benefit from having physiotherapy, particularly those who have had fractures or other types of damage in the bones of their legs or spine. A physiotherapist will be able to advise you about the use of equipment that is designed to reduce the weight placed on affected bones. This should help to reduce pain and make everyday physical activities easier. Examples include:

walking devices such as a cane or walking frame orthoses insoles that are made out of plastic and fit inside your shoe to hep support your feet spine braces designed to support the spine in the correct position

Some physiotherapists also provide energy-based therapy which uses different types of energy, such as electric currents or impulses to stimulate the nervous system. The electric impulses are thought to be effective in easing pain and promoting healing in some people. The physiotherapist will also be able to teach you a number of exercises that can:

improve your muscle strength maintain the range of movement and flexibility in your joints increase your physical stamina

See the Health A-Z topic about physiotherapy for more information and advice.

Surgery
If you develop a fracture in a bone, surgery may be required to realign the bones so that the affected bone is able to heal properly. See the Health A-Z page about treating broken bones for more information. If you experience severe osteoarthritis (joint inflammation and damage), surgery may be required to repair or replace a damaged joint. Surgical options for osteoarthritis include:

an arthroplasty where the damaged joint is removed and replaced with an artificial joint; the most commonly performed arthoplasties are hip replacements and knee replacements arthrodesis where the joint is fused into a in a permanent position

Complications of Paget's disease

Hypercalcaemia
The abnormally rapid process of bone remodelling that is associated with Pagets disease can sometimes lead to a build-up of calcium in the blood. The medical term for this is hypercalcaemia. Hypercalcaemia only occurs in people with Pagets disease who have been confined to bed after having an operation or following a fracture. However, even in these circumstances, hypercalcaemia is quite a rare complication. Symptoms of hypercalcaemia include:

extreme tiredness depression drowsiness constipation bone pain (or worsening bone pain if already present)

It is also relatively common for people with hypercalcaemia to develop kidney stones. Hypercalcaemia can be treated using a combination of medication to lower blood calcium levels and bisphosphonates to slow down bone remodelling.

Heart failure
In severe cases of Pagets disease, the blood vessels inside the bones can become damaged. This means that the heart has to work harder to pump blood around the body. In rare cases, the heart may no longer be able to pump enough blood around the body to meet demand. This is known as heart failure and it is a very rare complication of Pagets disease. Symptoms of heart failure include:

breathlessness (dyspnoea) when you are more active than normal or sometimes when you are resting extreme tiredness and weakness oedema swelling in the legs, ankles and feet

Heart failure can be treated using a combination of medications designed to reduce strain on the heart while also helping it to work more efficiently. In some cases, surgery may be recommended to repair or replace a damaged heart valve. See the Health A-Z topic about Heart failure for more information.

Sarcoma
Sarcoma is a type of cancer that starts in the bone cells. Very rarely it can occur as a complication of Pagets disease. It is estimated that less than 1 in 1,000 people with Pagets disease will go on to develop sarcoma later in life, usually many years after Pagets disease was first diagnosed. Symptoms of sarcoma include:

bone pain which is very similar to the pain that is associated with Pagets disease itself; it is a dull ache that is usually worse at night swelling around the affected bone a noticeable lump in the affected bone

Sarcoma is usually a very aggressive type of cancer and it is often necessary to remove the affected bone to prevent the cancer spreading to other parts of the body. See the Health A-Z topics about sarcoma and amputation for more information.

2. http://orthopedics.about.com/cs/pagets/a/pagets.htm

What is Pagets disease of Bone? Pagets disease is known as a bone remodeling disorder. Bone may seem like a very inactive tissue, but this is not the case. Bone is constantly undergoing turnover or replacement. New bone is formed, and old bone is absorbed. This process is known as bone remodeling. In most people this remodeling process occurs without problems. However, the process can go awry and create abnormalities of the bone. In Pagets disease, the bone remodeling

process is disregulated. New bone is placed where it is not needed, and old bone is removed where it is needed. This disregulation can distort the normal skeletal architecture. What causes Pagets disease? The cause of Pagets disease is not entirely known, but it is thought to be caused in part from a childhood virus. A virus particle, known as a paramyxovirus nucleocapsid, has been identified within the bone cells of individuals with Pagets disease. This virus particle is not found in normal bone. While this relationship has been identified, a clear connection between the virus and the cause of Pagets disease is not known. Pagets disease is more common in certain geographical locations, specifically England, Western Europe, and the United States. It is very uncommon in Scandinavia, China, and India. Pagets disease is most commonly diagnosed in the sixth decade, and increases in prevalence as age increases. Paget's disease is very uncommon in individuals under 40 years of age. In most cases, Pagets disease is a mild disease that does not cause any problems or complications. In fact, about 80% of individuals are diagnosed with Paget's disease following an x-ray performed for an unrelated reason. What are the symptoms of Pagets disease? In individuals who do experience symptoms from Pagets disease, the most common complaints relate to bone or joint pain. Other common symptoms include swelling of joints, tenderness or redness over the affected areas, and occasionally individuals will not know of Pagets disease until experiencing a fracture through a weakened area of bone. The most common bones affected by Pagets disease are the pelvis, femur (thigh bone), spine, skull, and tibia (shin bone). Diagnosis of Paget's disease is made by physical examination, x-rays, and laboratory studies. The physical examination may show abnormalities of the skeletal shape or bone deformities. X-rays commonly show abnormalities of bone turnover, including areas of increased and areas of decreased bone deposition. Laboratory studies will invariably show an increased level of alkaline phosphatase, a byproduct of bone formation. Calcium levels within the body are usually normal. What are the possible complications of Paget's disease? In addition to fractures through weak bone, there are important complications to Pagets disease of bone. Because of the high rate of bone turnover, the demands on the heart are increased, and patients with Pagets disease tend to have more heart problems. Bony deformities can cause problems such as arthritis and spinal stenosis. Finally, certain types of Pagets disease have a risk of developing cancer of the bone. The risk is low (less than 1%), but must be observed. What are the treatments for Paget's disease? Treatment for Pagets diseases consists of medications that alter the rate of bone turnover. The two most common treatment medications are bisphosphonates and calcitonin. These are the same treatment medications used in individuals with osteoporosis. The bisphosphonates bind to the bone to stop is from being reabsorbed. Calcitonin inhibits the cells that absorb the bone. Both these Paget's disease treatment medications prevent the weak parts of bone that cause deformity and are at high risk for being fractured.

Sometimes surgery is needed if there is a significant bone deformity or if there is a break in the bone. Fractures are most common in the femur (thigh bone) and tibia (shin bone), and are usually treated with an intramedullary rod, a rod that is inserted within the marrow cavity in the center of the bone. Unfortunately, fractures often take a long time to heal in patients with Pagets disease because of the abnormalities in bone turnover. Another common surgery in patients with Pagets disease is called an osteotomy. In this procedure a wedge of bone is removed to correct a malalignment. This procedure is often necessary when the bones of the legs become misshapen in the later stages of this disease.
3. http://emedicine.medscape.com/article/334607-overview

Background
Paget disease is a localized disorder of bone remodeling that typically begins with excessive bone resorption followed by an increase in bone formation. This osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. The English surgeon Sir James Paget first described chronic inflammation of bone as osteitis deformans in 1877.[1] Paget disease, as the condition came to be known, is the second most common bone disorder (after osteoporosis) in elderly persons. Approximately 70-90% of persons with Paget disease are asymptomatic; however, a minority of affected individuals experience various symptoms, including the following:

Bone pain (the most common symptom) Secondary osteoarthritis (when Paget disease occurs around a joint) Bony deformity (most commonly bowing of an extremity) Excessive warmth (due to hypervascularity) Neurologic complications (caused by the compression of neural tissues)

Paget disease may involve a single bone but is more frequently multifocal. It has a predilection for the axial skeleton (ie, spine, pelvis, femur, sacrum, and skull, in descending order of frequency), but any bone may be affected. After onset, Paget disease does not spread from bone to bone, but it may become progressively worse at preexisting sites. Sarcomatous degeneration of pagetic bone is an uncommon but often deadly complication. Pagetic sarcoma is malignant, and the course usually is rapid and fatal Although the etiology of Paget disease is unknown, both genetic and environmental contributors have been suggested. Ethnic and geographic clustering of Paget disease is well described. Paget disease is common in Europe (particularly Lancashire, England), North America, Australia, and New Zealand. It is rare in Asia and Africa. In the United States, most, although not all, individuals with Paget disease are white. (See Epidemiology.) A familial link for Paget disease was first reported by Pick in 1883, who described a fatherdaughter pair with Paget disease. This was followed shortly thereafter with a sibling case of Paget disease described by Lunn in 1885. Approximately 40% of persons with Paget disease

report a family history of the disease, although the true prevalence of the disease is likely higher. Some studies suggest a genetic linkage for Paget disease located on chromosome arm 18q. This has not been demonstrated in most families with Paget disease, however, which suggests genetic heterogeneity. An environmental trigger for Paget disease has long been considered but never proven. Bone biopsies in patients with Paget disease have demonstrated antigens from several different Paramyxoviridae viruses, including measles virus and respiratory syncytial virus, located within osteoclasts. However, the putative antigen or antigens remain unknown. Measurement of serum alkaline phosphatasein some cases, bone-specific alkaline phosphatase (BSAP)along with several urinary markers, can be useful in the diagnosis of Paget disease. Plain radiographs and bone scanning should be performed upon initial diagnosis. (See Workup.) Medical therapy is principally with bisphosphonates; surgical therapy may be indicated. (See Treatment.)

Pathophysiology
Three phases of Paget disease have been described: lytic, mixed lytic and blastic, and sclerotic. In an individual patient, different skeletal lesions may progress at different rates. Thus, at any one time, multiple stages of the disease may be demonstrated in different skeletal regions. Paget disease begins with the lytic phase, in which normal bone is resorbed by osteoclasts that are more numerous, are larger, and have many more nuclei (up to 100) than normal osteoclasts (5-10 nuclei). Bone turnover rates increase to as much as 20 times normal. The second phase, the mixed phase, is characterized by rapid increases in bone formation from numerous osteoblasts. Although increased in number, the osteoblasts remain morphologically normal. The newly made bone is abnormal, however, with collagen fibers deposited in a haphazard fashion rather than linearly, as with normal bone formation. As the osteoclastic and osteoblastic activities of bone destruction and formation repeat, a high degree of bone turnover occurs. In the final phase of Paget disease, the sclerotic phase, bone formation dominates and the bone that is formed has a disorganized pattern (woven bone) and is weaker than normal adult bone. This woven bone pattern allows the bone marrow to be infiltrated by excessive fibrous connective tissue and blood vessels, leading to a hypervascular bone state. After a variable amount of time, osteoclastic activity may decrease, but abnormal bone formation continues. Some pockets of normal-appearing lamellar bone may replace immature woven bone. Eventually, osteoblastic activity also declines, and the condition becomes quiescent. This is the sclerotic, or burned-out, phase. Continued bone resorption and formation are minimal or absent. Paget disease can affect every bone in the skeleton, but it has an affinity for the axial skeleton, long bones, and the skull. The skeletal sites primarily affected include the pelvis,

lumbar spine, femur, thoracic spine, sacrum, skull, tibia, and humerus. The hands and feet are very rarely involved. Complications of Paget disease depend on the site affected and the activity of the disease. When Paget disease occurs around a joint, secondary osteoarthritis may ensue. Skull involvement may lead to the following:

Deafness Vertigo Tinnitus Dental malocclusion Basilar invagination Cranial nerve disorders

Frequently, erythema is present over the affected bone area, which is due to the increased hypervascularity. In patients with Paget disease who have extensive bony involvement, this increased bone vascularity may cause high-output cardiac failure and an increased likelihood of bleeding complications following surgery. Vertebral involvement of Paget disease may be associated with serious complications, including nerve root compressions and cauda equina syndrome. Fractures, which are the most common complication of Paget disease, may occur and may have potentially devastating consequences. Rarely, pagetic bone may undergo a sarcomatous transformation. Standard serum chemistry values, including serum calcium, phosphorus, and parathyroid hormone levels, are normal in persons with Paget disease. However, hypercalcemia may complicate the course of Paget disease, most frequently in the setting of immobilization. Elevated levels of uric acid and an increased prevalence of gout have been reported in patients with Paget disease. levels of bone turnover markers (including markers of bone formation and resorption) are elevated in patients with active Paget disease and may be used to monitor the course of disease. The degree of elevation of these biomarkers helps identify the extent and severity of bone turnover. Markers of bone turnover that are useful to monitor in persons with Paget disease include the following:

Bone-specific alkaline phosphatase (marker of bone formation) Deoxypyridinoline (marker of bone resorption) N -Telopeptide of type I collagen (marker of bone resorption) Alpha-alpha type I C -telopeptide fragments

Alpha-alpha type I C-telopeptide fragments are sensitive markers of bone resorption for assessing disease activity and monitoring treatment efficacy in persons with Paget disease.[2] Serum osteocalcin, a marker of bone formation, is not a useful parameter to assess in persons with Paget disease. Upon successful treatment of Paget disease, the level of these bone markers is expected to decrease.

The juvenile form of Paget disease differs greatly from the adult version. Juvenile Paget disease is characterized by widespread skeletal involvement and has distinctly different histologic and radiologic features.

Etiology
The cause of Paget disease is unknown. Both genetic and environmental factors have been implicated.

Genetic predisposition
The geographic distribution of the disease may be explained by genetic transmission and dissemination by population migration. Studies have found a positive family history in 12.3% of 788 patients in the United States, 13.8% of 407 patients in Great Britain, and 22.8% of 658 patients in Australia. In the former 2 studies, a 7- to 10-fold increase in the incidence of Paget disease was observed in relatives of patients diagnosed with the condition, compared with control groups. In one study, 15-40% of affected patients had a first-degree relative with Paget disease. Numerous other studies have described families exhibiting autosomal dominant inheritance. Studies of potential genetic markers for Paget disease have found an association between human leukocyte antigenA (HLA-A), HLA-B, and HLA-C (class I) and clinical evidence of disease. Two studies reported an increased frequency of DQW1 and DR2 antigens (class II HLA). The studies on HLA have not been conclusive, however; variation among families tested suggests that genetic heterogeneity is likely.[3] Subsequent genome linkage studies identified several loci associated with Paget disease. Mutations in the sequestosome SQSTM1/p62 gene were identified in 30% of familial Paget cases. The SQSTM1/p62 protein is a selective activator of NFB (nuclear factor kappa-B) transcription factor, which is involved in osteoclast differentiation and activation in response to the cytokines interleukin-1 (IL-1) and RANKL (receptor activator of nuclear factor kappaB ligand). How germline DNA mutations can cause bone disease that is focal in nature remains unclear. Alterations in cytokine expression have been found in persons with Paget disease[4] : elevated interleukin-6 (IL-6) levels are found in bone marrow plasma and peripheral blood in patients with Paget disease but not in healthy controls. One hypothesis is that some unidentified viral infection up-regulates IL-6 and the IL-6 receptor genes; however, this has not been shown conclusively.[5, 6] Osteoclast precursors in patients with Paget disease also appear to be hyperresponsive to vitamin D (specifically, 1,25(OH)2 D3, the active form of vitamin D3[7] ) and calcitonin and have up-regulation of the c-fos proto-oncogene[8] and BC12, the antiapoptosis gene. Treatment efficacy of bisphosphonates in Paget disease may be due to suppression of RANKL-induced bone resorption, with decreases in RANKL and increased osteoprotegerin production. Macrophage-colony stimulating factor (M-CSF) may play a role in Paget disease. M-CSF is a growth factor produced by many cells, including osteoblasts and marrow fibroblasts.

Significantly high levels of M-CSF have been found in patients with untreated Paget disease; however, its exact role remains to be determined.

Environmental factors
Environmental factors also may contribute to the pathogenesis of Paget disease. Supporting observations include the variable penetrance of Paget disease within families with a genetic predisposition; the fact that the disease remains highly localized to a particular bone or bones rather than affecting the entire skeleton; and data that reveal a declining incidence and severity of the disease over the past 20-25 years. Viral infection The leading hypothesis for an infectious etiology in Paget disease is the slow virus theory. According to this hypothesis, bone marrow cells (the progenitors of osteoclasts) are infected by a virus, causing an abnormal increase in osteoclast formation. Clinical expression of these viral infections may take years, which may account for the advanced age of most people diagnosed with Paget disease. Familial and geographic clustering also may support the theory of a viral process. Suspected viruses are paramyxoviruses, such as measles or canine distemper viruses. Respiratory syncytial virus also is suspected; however, no virus has been cultured from pagetic tissue, and extracted ribonucleic acid (RNA) has not confirmed a viral presence. Some studies have found viral inclusion particles in pagetic osteoclasts.[9] Measles virus messenger RNA sequences have been found in osteoclasts and other mononuclear cells of pagetic bones. Canine distemper virus nucleocapsid antigens have also been found in osteoclasts from patients with Paget disease. However, the presence of these paramyxoviruslike nuclear inclusions does not prove that these are responsible for the development of pagetic lesions; rather, these inclusions may be markers of the disease itself.

Other suggested etiologies

The possibility of an inflammatory cause of Paget disease is supported by evidence of clinical improvement after treatment with anti-inflammatory medications. Elevated parathyroid hormone in Paget disease also has been observed, but no firm evidence links the 2 disorders, and one case of Paget disease was diagnosed in a patient with idiopathic hypoparathyroidism. An osteogenic mechanism also has been proposed. Autoimmune, connective tissue, and vascular disorders are proposed as other possible etiologies.

Epidemiology

United States statistics

Paget disease is estimated to affect 1 to 3 million people in the United States. Epidemiologic studies are inherently imprecise, however, because many individuals with Paget disease are asymptomatic.

According to a 2000 study by Altman et al, the prevalence of pelvic Paget disease in the United States was 0.71% 0.18%, based on data from the National Health and Nutrition Examination Survey I (NHANES I, 1971-1975). The male-to-female ratio was 1.2:1, and the prevalence of pelvic Paget disease was the same in white persons and black persons. The prevalence of pelvic Paget disease increases with age, with the highest prevalence in persons older than 65 years. A survey study suggested that the prevalence in the United States is 2.3% of the population between ages 65 and 74 years.[10] Paget disease is estimated to occur in 1-3% of individuals older than 45-55 years and in up to 10% of persons older than 80 years. Geographically, pelvic Paget disease was least common in the southern United States and most common in the northeastern United States.[10]

International statistics
The prevalence of Paget disease varies greatly in different areas of the world. The highest prevalence is in Europe (predominantly England, France, and Germany).[11] The United States, Australia, and New Zealand have high prevalence rates because of significant populations with northern European ancestry and a large population of British immigrants.[12] The disease is rare in Asian countries, especially China, India, and Malaysia, and in the Middle East and Africa. Prevalence may vary even within the same country.[13] A prevalence of 2% in certain British cities can be contrasted with rates in Lancaster, England, which had a prevalence of 8.3%.[14] In Europe, the prevalence rates of Paget disease appear to decrease from north to south, with the exception of Norway and Sweden, which both have very low rates (0.3%). The highest prevalence in Europe is found in England (4.6%) and France (2.4%) in hospitalized patients older than 55 years. Other European countries, such as Ireland, Spain, Germany, Italy, and Greece, report prevalence rates of Paget disease that range from 0.5% to approximately 2%. The prevalence rates of Paget disease in Australia and New Zealand range from 3-4%. The prevalence of Paget disease in sub-Saharan Africa is 0.01-0.02%. In Israel, Paget disease is predominantly found in Jews; however, cases have recently been reported in Israeli Arabs. In South America, the incidence of Paget disease is relatively high in Argentina (around Buenos Aires), which was settled by Spanish and Italian immigrants, and lower in Chile and Venezuela. Research from Europe and New Zealand indicates that the prevalence of Paget disease has decreased since the 1980s but that increased incidence with age has been maintained.[15] The estimated prevalence of Paget's disease in patients aged 55 years or older has decreased to approximately 2%.

Race-, sex-, and age-related differences in incidence

Paget disease is not known to demonstrate a predilection for any race. Nevertheless, unusual patterns of prevalence have been noted. Paget disease is more common in males than females. The male-to-female ratio is approximately 1.8:1.

Paget disease is distinctly rare in persons younger than 25 years and increases in frequency with increasing age. Paget disease is believed to develop in persons in the fifth decade of life and is most commonly diagnosed in the sixth decade. The incidence of Paget disease in persons older than 80 years is approximately 10%. There is a juvenile form of Paget disease, but it is very different from the adult form.

Prognosis
The general outlook for patients with Paget disease is good, especially if treatment is administered before major changes have occurred in the bones. Treatment does not cure Paget disease, but it can control it. Patients with severe polyostotic Paget disease have a less favorable prognosis than those with monostotic disease. Patients with polyostotic disease are at higher risk for complications. Morbidity from Paget disease can be extensive. The excessive remodeling of bone associated with Paget disease may result in pain, fractures, and bone deformities. Complications associated with fractures, such as articular and neurologic problems, may increase mortality in patients with Paget disease. The hypervascularity of bone that may result from Paget disease may cause excessive bleeding following fractures or surgery. The prognosis is extremely unfavorable if the patient has any type of sarcomatous degeneration, especially if there is multicentricity. The 5-year survival rate for a patient with Paget disease and sarcoma is 5-7.5%; however, it may be as high as 50% for those who undergo operative tumor ablation and chemotherapy before metastases occur. The 5-year survival rate for elderly patients with primary nonpagetic sarcoma is 37%. Higher doses of radiation may be delivered if the neoplasm is located on the limb. Consequently, a more central lesion carries a less favorable prognosis.

Patient Education
Patient education about the pathophysiology of Paget disease and its complications is essential. The patient needs to understand the importance of proper posture, body mechanics, and avoidance of trauma. Precautions against falling should be reinforced. At the same time, the hazards of immobility increase greatly with Paget disease. The patient should understand the necessity of staying active. Knowledge of the signs and symptoms of complications is important. For instance, increased local pain with soft tissue mass should be reported to a physician immediately, as this may represent a sarcoma. Understanding the potential side effects of medications is helpful and reassuring to the patient. For example, patients taking bisphosphonates should be aware of the potential for osteonecrosis of the jaw. Patient education about delayed bone healing and the long rehabilitation process is important in situations of fracture and postsurgery. Reinforcement about the importance of careful, prolonged, protected weight bearing is crucial because the pagetic bone is abnormal and weak. Nonunion and refracture rates are high among patients with Paget disease.

Family members should be informed of the increased incidence of Paget disease in families. Proper patient education on the nature of Paget disease is essential. The Paget Foundation for Paget's Disease of Bone and Related Disorders (telephone: 800-237-2438) can provide useful information for patients.

History
Paget disease is a localized disorder that may be monostotic (affecting only one bone) or polyostotic (affecting 2 or more bones). Monostotic disease accounts for 10-35% of cases. Paget disease has a predilection for the axial skeleton. The condition commonly affects the pelvis and spine, particularly the lumbar spine, with a frequency of 30-75%. The sacrum is involved in 30-60% of cases and the skull in 25-65% of cases. The proximal long bones, especially the femur, also are frequently affected (25-35% of cases). Involvement of the shoulder girdle and proximal humerus is not uncommon. Though any bone may be affected, the fibula, ribs, and bones in the hands and feet are involved infrequently. Paget disease does not spread from one bone to another, and new sites of involvement are rare after the initial diagnosis. Instead, lesions may continue to progress if left untreated. Most persons with Paget disease are asymptomatic. In these patients, the incidental finding of an elevated serum alkaline phosphatase level or characteristic radiographic abnormality may lead to detection of the disease. However, when symptoms do occur, bone pain is the most common complaint. The bone pain is dull, constant, boring, and deep below the soft tissues. It may persist or exacerbate during the night. Hip pain is most common when the acetabulum and proximal femur are involved, especially in the sclerotic stage. Bowing of the femur and long bones or protrusion of the acetabulum causes pain that becomes worse with weightbearing and is relieved with rest. Knee and shoulder pain may occur because of altered mechanical forces across the articular joints from deformed bones. Other patients with Paget disease present with a range of manifestations related to complications. These include musculoskeletal, neurologic, and cardiovascular problems. Pathologic fractures commonly result from weakened pagetic bone. Subtrochanteric femur fractures are the most common fractures affecting the lower limbs. Nonspecific headaches, impaired hearing, and tinnitus commonly result from skull involvement. The patient's hat size may increase (or, less commonly, decrease) as a result of skull enlargement or deformity. The most common cranial symptom is hearing loss, occurring in 30-50% of patients with skull involvement. The most common neurologic complication is deafness as a result of involvement of the petrous temporal bone. The hearing loss or deafness may be conductive (due to involvement of the middle-ear ossicles), sensorineural (due to auditory nerve compression/cochlear involvement), or mixed. Vertigo or tinnitus may occur with a frequency of 25% in patients who have Paget disease with cranial involvement.

Cranial nerve palsies can affect nerves other than the auditory nerve; however, this development is uncommon. Changes in vision may occur secondary to optic nerve involvement. Back and neck pain are common complaints, as Paget disease frequently affects the spine, especially the lumbar and sacral regions. Softened bone at the base of the skull may lead to platybasia, the descent of the cranium onto the cervical spine. Progressive pain, paresthesias, limb paresis, gait difficulties, or bowel and bladder incontinence may be caused by compression of the spinal cord or spinal nerve secondary to platybasia or vertebral fractures. Skull deformities may lead to hydrocephalus, basilar invagination, and cerebellar or brainstem compressive syndromes. These may manifest as nausea, dizziness, syncope, ataxia, incontinence, gait disturbances, or dementia. Involvement of the jaw and facial bone is uncommon in Paget disease, but it does occur. Facial disfigurement and malocclusion may be observed following enlargement of the maxilla or mandible. Tooth loss may occur with progressive root resorption. Absent periodontal membranes and lamina dura are associated with excessive cementum formation. Increased bone pain with an enlarging soft tissue mass and a lytic lesion is suggestive of a neoplasm (osteosarcoma), especially if a pathogenic fracture is present. This is an uncommon but potentially deadly complication.

Physical Examination
The physical examination findings may be normal in patients with Paget disease. In symptomatic cases, visual inspection may reveal bony deformities, such as an enlarged skull, spinal kyphosis, and bowing of the long bones of the extremities. Bone angulation and deformity may affect joints, with resulting pain and decreased range of motion. Because patients with Paget disease may also have gouty arthritis, they also should be evaluated for the presence of tophi. Localized pain and tenderness may be elicited with manual palpation. Superficial pressure reveals increased warmth of the skin at the affected site. Skin temperature may be correlated with metabolic activity of underlying bone and bone pain. Auscultation may reveal bruits of the tibia or skull. A soft tissue mass with increased pain may be caused by neoplasms, such as osteosarcoma. Paget disease of the skull may be asymptomatic; however, approximately one third of patients experience an increase in head size with or without deformity (frontal bossing, enlarged maxilla). The most common neurologic problem is hearing loss from compression of cranial nerve VIII and cochlear dysfunction. If the facial bones are affected, a patient may have facial deformity problems and, rarely, narrowing of the airway. Ataxia, gait disturbances, dementia, and neurologic compromise may result from hydrocephalus and cerebellar compression. With involvement of the lumbar spine, spinal stenosis or kyphosis may develop. If Paget disease affects the thoracic spine, the patient may have spinal cord compression, which can lead to neural function loss. Muscle weakness, paraparesis, and sensory loss compatible with spinal cord injury (SCI) may be present.

Fracture of a pagetic bone is an occasional and serious complication and may be either traumatic or spontaneous. The femur is the most common site of pagetic fracture. Most pagetic bone fractures heal normally.

Complications
Complications of Paget disease include the following:

Fractures Neoplasms Neuromuscular syndromes Joint disease Cardiovascular abnormalities

Angioid streaks of the retina have been found more commonly in patients with Paget disease and are quite frequent in pseudoxanthoma elasticum. Angioid streaks are linear disruptions of the Bruch membrane, with proliferative connective tissue emerging through the defects. Other complications of Paget disease include the following:

Hashimoto thyroiditis Dupuytren contracture Chondrocalcinosis Osteogenesis imperfecta Osteopetrosis

Fractures
Incomplete stress fractures frequently occur in Paget disease. Cortical stress fractures are common in the femur and tibia, with distinctive horizontal radiolucencies affecting the convex surface of the bone, whereas in osteomalacia, similar findings are seen on the concave aspects of the bone. Cartilaginous calluses, which do not mineralize fully in the fracture clefts, account for the relative radiolucency. Incomplete fissure fractures can extend into complete fractures. Mild injuries may cause acute true pathologic fractures in weakened pagetic bone. Pathologic fractures are more common in women than in men. The most frequent site of these fractures is the femur, but fractures commonly occur in the tibia, humerus, spine, and pelvis. Femur fractures are most common in the subtrochanteric region, followed by the upper third of the femoral shaft and then the neck. Nonunion and refracture at the same sites are much more common, as developing calluses may be affected by Paget disease. The rate of nonunion has been reported to be 40%.[16] Biopsies of pathologic fractures may be recommended to rule out sarcoma.

Neoplasm
Sarcomatous degeneration of pagetic bone is a deadly complication. Pagetic sarcoma is malignant, and the course usually is rapid and fatal. Sarcomatous degeneration may occur in

5-10% of patients with extensive pagetic skeletal involvement, but it may occur in less than 1% of patients with less widespread involvement. Men are affected with sarcomatous degeneration slightly more frequently than are women. Peak incidence is in the seventh and eighth decades of life. The femur is the most commonly affected site, followed by the proximal humerus; however, no bone is exempt, including sites of previously healed fractures. Sarcomas appear to originate from the fibrotic substrate of pagetic bone, and the predominance of certain cells determines the diagnosis. Osteosarcoma is the most common type of pagetic sarcoma (50-60%), followed by fibrosarcoma (20-25%), chondrosarcoma (10%), and sarcoma of myeloid and mesenchymal elements. Sarcomatous bone destruction or osteolysis is more characteristic of pagetic sarcoma than osteosclerosis. Other clinical and radiographic findings include the following:

Increased pain with a progressive lytic lesion An enlarging soft tissue mass Bony speculation Persistent fracture without healing Cortical destruction

In 33% of cases, the presentation involves a pathologic fracture of an affected long bone. Giant cell tumors are benign and may arise from pagetic bone. They usually involve the facial bones and mandible, although other sites, such as the pelvis, may be affected in rare cases. Giant cell tumors commonly affect elderly patients. They share some characteristics of sarcomas, as they typically affect patients with widespread polyostotic Paget disease and present as a soft tissue mass with a lytic lesion. The prognosis for patients with Paget disease who have giant cell tumors usually is good. High doses of steroids have been shown to reduce tumor mass. Radiation and surgery also have been used to treat symptomatic giant cell tumors. Lymphomas, multiple myelomas, Hodgkin lymphoma, leukemias, and metastatic disease all have been found in association with Paget disease. However, these neoplasms probably represent chance occurrences rather than true complications.

Neuromuscular Syndromes
Acute spinal cord compression may occur from pathologic fractures, such as vertebral body compression fractures. Enlargement of the pedicle, lamina, or vertebral body from the pagetic process also may cause spinal cord injury. Likewise, nerve root or spinal nerve compromise may occur. Spinal cord compression is most frequent in the upper thoracic spine because of the small vertebral canal. Spastic quadriplegia can result from platybasia. Basilar invagination or compression of posterior fossa structures may lead to cerebellar or brainstem compressive syndromes. The vertebrobasilar blood supply also may be compromised by kinking of the blood vessels.

Extradural fat ossification has been observed to be a cause of cauda equina syndrome. Hydrocephalus can be a complication, albeit a rare one. Entrapment of cranial nerves by pagetic bone may result in the expected cranial nerve palsies. The most common of these is injury to the eighth cranial nerve (the vestibulocochlear nerve), with resultant impaired hearing and deafness. The hearing loss may be sensorineural, conductive, or mixed and may be caused by compression from pagetic bone involvement of the temporal bone and labyrinth. Structural abnormalities of the ossicles of the middle ear and toxic effects to the inner ear have been observed. The optic nerve may be the second most commonly affected cranial nerve. Sciatic nerve compression between an enlarged ischium and lesser trochanter of the femur in external rotation or between the ilium and the piriformis muscle in internal rotation also has been described.

Joint Disease
Degenerative joint disease is associated with Paget disease. The most commonly reported site of articular abnormality is the hip. The knee also is commonly affected. The glenohumeral joint also may be affected, impairing rotator cuff function. Degenerative joint disease of the hip associated with Paget disease differs in appearance from primary degenerative joint disease. Osteophyte formation is not prominent. The frequency of joint-space narrowing of the hip in patients with Paget disease varies in several studies from 50-96%.[17] Joint space loss at the superior aspect of the hip articulation is the most common pattern, with a frequency of 80-85%. Acetabular involvement may cause either medial or axial joint space narrowing, especially if the femoral head also is affected. Acetabular protrusion may occur, causing hip pain that is aggravated by ambulation. The pathophysiology of arthritic changes associated with Paget disease is unknown. Enlargement of joints and altered biomechanics may cause abnormal stress across joints, giving rise to degenerative changes. Abnormal endochondral ossification that may compromise articular cartilage has been reported. For cases that require surgery, successful outcomes of total hip and knee arthroplasties have been reported. Conditions that have been found to coexist with Paget disease, but that have no proven relationship with Paget disease, include the following:

Rheumatoid arthritis Psoriatic arthritis Ankylosing spondylitis Diffuse idiopathic skeletal hyperostosis Pseudogout Peyronie disease Pigmented villonodular synovitis

Hyperuricemia may cause clinical gout in some patients.

Cardiovascular Abnormalities
Increased cardiac output has been observed in patients with Paget disease involving at least 15% of the skeleton. Left ventricular hypertrophy is an associated finding. Increased soft tissue and pagetic bone vascularity has been implicated as a contributing factor. High-output congestive heart failure may occur, but it is rare. The condition has been reported only in patients with severe, widespread Paget disease. Calcific aortic stenosis is 4 times more common in patients with Paget disease, especially those with severe disease, than in individuals without Paget disease. Calcifications may be produced by the turbulent blood flow across cardiac valves caused by increased cardiac output. Calcifications have been found in the interventricular septum, which may cause heart block and conduction abnormalities.

Diagnostic Considerations
The differential diagnosis of Paget disease includes osteomalacia, which may be part of the spectrum of osseous abnormalities accompanying chronic renal insufficiency. Patients with mild osteomalacia may present with nonspecific bone pain and tenderness. Elevated levels of bone-specific alkaline phosphatase may occur in osteomalacia or in Paget disease. Both disorders may result in fractures. However, in Paget disease, distinctive horizontal radiolucencies are visible on the convex surface of the bone, whereas in osteomalacia they are visible on the concave aspects of the bone. In patients with malignancy, bone pain may indicate skeletal metastasis.

Differentials

Osteoarthritis Osteoporosis

3. http://www.paget.org/index.php/healthcare-professionals/pagets-disease-of-bone/127-a-nursesguide-to-the-management-of-pagets-disease.html

A Nurse's Guide to the Management of Paget's Disease

Introduction
Although Pagets disease is the second most common bone disease in the US, it often goes unrecognized and untreated until its course has advanced. Nurses, radiologists and other health care professionals who work in hospital emergency rooms, nursing homes and family clinics should be aware of Pagets disease and its symptoms, in order to identify patients as early as possible and utilize the effective treatments that are available to manage the disease.

In one typical diagnostic scenario, an elderly person suffers a broken bone in an accident and a radiologist recognizes Pagets lesions in the x-rays. Other patients, assuming that they have arthritis, treat Paget-related bone pain with increasing amounts of over-the-counter medications. They do not learn that the source of the pain is Pagets disease until they receive a proper diagnosis, sometimes years after the pain began. Nurses, on the front-line of health care, need to know what to look for and what questions to ask in order to find Pagets disease early in the diseases progression. The earlier a diagnosis is made, the more effective the treatment, and the less devastating the impact on the individual patient.

What is Pagets Disease of Bone?

First described by the eminent British surgeon Sir James Paget in 1877, Pagets disease of bone is a disorder of bone remodeling in which there is excessive bone resorption followed by excessive bone formation that results in bone that is architecturally unsound. The disease occurs in both males and females, affecting 1.5 to 8% of the population over 50 years of age in many countries. It is much less common in people of Asian, Indian and Scandinavian ancestry. Pagets disease may be found in multiple family members. In some families mutations in the sequestosome 1 gene appear to increase the susceptibility of affected individuals to develop the disorder. There is also evidence of measles virus in the bone lesions of Pagets disease. An animal model of Pagets disease has been developed by inserting a measles virus protein into the bone cells of mice. There is ongoing research to determine how the gene-measles virus interaction might produce Pagets disease.

Clinical Presentation
Pagets disease may cause the enlargement and deformity of a single bone or multiple bones. As a result, bone pain, arthritis, noticeable skeletal deformities and fractures can occur. While any bone can be affected, the most common sites are the femur, tibia, pelvis, vertebrae and skull. Long bones in the leg tend to bow, and the skin over the Pagetic lesion is frequently warm due to the increased blood flow to the site. The skull can become enlarged and lead to headaches or hearing loss when the disease affects the temporal bone. The spine may develop curvature in advanced cases. In the spine, the increased bone volume may compress the spinal cord or nerve roots, causing severe pain and impaired neurological functioning. Hip pain is a common complaint when the pelvis or thighbone is involved. Clinical signs and symptoms will vary from one patient to the next, depending on the number and location of affected skeletal sites, as well as on the rapidity of the abnormal bone turnover. Long-term observation of Pagets disease patients indicates that the disease does not spread from one bone to another. The most devastating complication of Pagets disease is a transformation of the bone that becomes cancerous. Fortunately, osteosarcoma or other types of sarcoma occur in less than 1 percent of patients with Pagets disease, but this is a significantly higher rate than in nonaffected individuals. In patients with Pagets disease, osteosarcoma is often fatal.

Pathology of Pagets Disease

The initial abnormality in Pagets disease is a dramatic increase in the rate of bone resorption in one or more areas of the skeleton. Pagetic osteoclasts are abnormal approximately five times larger than normal containing an average number of 20 nuclei per cell compared with three to four nuclei in normal adult osteoclasts. However, the osteoblasts, though numerous, are not abnormal. Because bone resorption triggers bone formation, the rate of bone resorption is matched by a rapid rate of bone formation over time. The new bone is structurally disorganized, however, resulting in an overall decrease in bone strength and an increase in susceptibility to bowing and fractures. In addition, a high level of vascularity and an excess of fibrous connective tissue in the marrow mark the abnormal bone.

Guidelines for Assessment

It is likely that many patients have the disorder for a long period before any diagnosis is made, especially because Pagets disease is often asyptomatic and the diagnosis may be an incidental finding. Pagets disease can be diagnosed in patients through radiology, radionuclide bone scanning, biochemical testing of bone resorption parameters, or biochemical testing of bone formation parameters. At least one measurement of bone metabolic activity and x-rays of affected bones are the minimum recommended level of evaluation to track and monitor the progression of treatment in a patient with Pagets disease.

Biochemical Tests
Elevated levels of the enzyme serum alkaline phosphatase (SAP) detected in routine serum chemistry profiles can be the first indication that an individual has Pagets disease and not arthritis or another disorder. Alkaline phosphatase, an enzyme produced by bone cells and a marker for bone formation, is over-produced by Pagetic bones. A mild over-production might indicate a healing fracture, but a SAP level two or more times higher than normal strongly suggests Pagets disease, provided there is no evidence of liver disease or renal failure. Less frequently, biochemical tests of bone resorption are used to assess disease activity. These include serum and urinary N-telopeptide or C-telopeptide and the less specific tests: urinary hydroxyproline, pyridinoline or deoxypyridinoline.

Radiographic Testing
Bones affected by Pagets disease have a characteristic appearance on x-rays. These characteristic changes include the presence of osteolytic lesions and enlarged bones with a chaotic sclerotic appearance. A decrease in joint space is an indication of degenerative arthritis, a common disorder in people with Pagets disease.

Radionuclide Bone Scan

A radionuclide bone scan is the most sensitive means of detecting Pagets disease in the skeleton. A radiolabeled bisphosphonate is injected intravenously and circulates through the blood stream. This substance then localizes in Pagetic areas of bone where there is increased blood flow and high levels of bone formation. This test is used primarily to establish the full extent of Pagets activity. It is not generally used to monitor the effects of treatment.

Medical History
The diagnosis of Pagets disease for patients in clinical settings begins with obtaining a careful medical history. This history includes documentation of family members who have been diagnosed with the disease. Specific symptoms related to Pagets disease should be sought including pain (onset, location, severity), deformity and increased warmth over an extremity. General history taking includes documentation of current and previous medical conditions, fractures, surgeries, medications, height (maximum and current) and weight. Patients who come for a second opinion regarding a previous diagnosis of Pagets disease should be queried regarding the following: Date of diagnosis How the diagnosis was made Skeletal site/s affected Date of diagnostic test (bone scan, x-ray, lab test) Serum alkaline phosphatase level Current/previous Pagets medications Symptoms Previous fractures Physical function limitations a. Activities of daily living b. Mobility c. Balance d. Hearing. A compete medical history, physical examination and interpretation of laboratory test results contribute to making an accurate diagnosis and identifying the appropriate management strategy.

Objectives for Management of Pagets Disease

The three major objectives for the management of patients with Pagets disease are: 1. Minimize symptoms 2. Improve the patients physical function 3. Help slow the disease process, limit disability and prevent complications. The nurse plays a major role in helping the patient accomplish each of these objectives by providing the patient and family members with education and professional support and by encouraging the patient's adherence to therapy.

Indications for Treatment

Treatment for Pagets disease is based on antiresorptive therapy. There are four general indications for treatment of Pagets disease: 1. Symptoms due to metabolically active Pagets disease warrant treatment, including bone pain related to a pagetic site or fatigue fracture, headache resulting from an affected skull, back pain from affected pagetic vertebrae or other neurological syndromes associated with Pagetic changes.

2. Treatment is warranted in a patient planning to undergo elective surgery on a pagetic site, such as hip replacement, in an attempt to minimize the operative blood loss due to hypervascularity present in active Pagetic bone. 3. Treatment is indicated in the management of hypercalcemia, a rare occurrence when a patient with multiple bones affected by Pagets disease and a highly elevated serum alkaline phosphatase level undergoes prolonged immobilization. 4. Many Pagets disease specialists believe that treatment is indicated as an attempt to decrease local progression and reduce the risk of future complications even in asymptomatic patients whose sites of disease and degree of metabolic activity place them at risk of progression and complications. This group of patients includes individuals who may be at risk for: a. Bowing deformities in their long bones b. Hearing loss because of skull enlargement c. Neurological complications due to Pagetic changes in their vertebrae d. Secondary arthritis as a complication of Pagets disease located next to major joints. Though there is no direct evidence that aggressive treatment of Pagets disease is associated with prevention of progression or reduction in risk of future complications, investigators have looked to indirect evidence to suggest this possibility. This indirect evidence includes the assumptions that: 1. Failure to treat Pagets disease is associated with the further extension of the osteolytic lesions in a bone and the progression of bone deformities. 2. Successful treatment of Pagets disease is associated with restoration of normal patterns of new bone deposition. 3. Improvement of facial and skull deformities may be observed after successful treatment. (Shown in one study.) Therefore, specialists conclude that it is good clinical practice to treat both symptomatic patients whose symptoms may improve after a reduction in abnormal bone turnover and asymptomatic patients who have active Pagets disease in areas of the skeleton that might be expected to produce future complications of clinical significance.

Adherence to Therapy
Be aware of the emotional impact of the words Pagets disease. Increasing concern about skeletal health, risk of complications and safety of drug therapy are major concerns that can produce stress and anxiety in individuals who have been diagnosed with Pagets disease. Counseling patients can promote implementation of new behaviors to optimize skeletal health, reduce further consequences and enhance quality of life. The targets of such counseling are:

a. Behaviors related to adherence to medical therapy b. Injury prevention c. Physical therapy when indicated. Continuous collaboration between nurses and patients can help improve adherence. Factors that may negatively influence adherence include the patients unfulfilled expectations and/or inadequate explanation of the disease to the patient. The nurses approach to each patient should be specific, individualized, consistent and nonjudgmental. It is important for the nurse to understand the following patient issues to help the patient make appropriate changes in health behaviors: 1. Individual health beliefs 2. Motivation to change and level of commitment 3. Presence or absence of denial of risk or severity of disease. Counseling techniques to promote and maintain new health behaviors include: 1. Provide specific individual information regarding diagnosis risks, cost and benefits of medical therapy, including side effects, duration of treatment and cost. 2. Set mutual goals 3. Provide patient with flowsheet to document diagnostic test dates, laboratory results, medication (doses, start & stop dates, side effects). See example enclosed. 4. Provide feedback regarding response to therapy 5. Encourage long-term follow-up. 6. Dispel fears and misperceptions.

Therapy Options
Four main methods of treatment exist for a patient with Pagets disease: 1. Pharmacological therapy using either bisphosphonates or calcitonin 2. Pain management using analgesics 3. Surgery 4. Non-pharmacological therapy (focusing mainly on physical therapy as a means of improving muscle strength to help control some types of pain). Pharmacological Treatment Bisphosphonates Bisphosphonates suppress or reduce bone resorption by osteoclasts. They do this both directly by hindering the recruitment and function of osteoclasts and perhaps indirectly by stimulating osteoblasts to produce an inhibitor of osteoclast formation. There is now a reasonable understanding of how these drugs work, and the differences between the various types of bisphosphonates are better understood. Currently, six bisphosphonates are approved by the US Food and Drug Administration (FDA) for the treatment of Pagets disease. These include zoledronic acid and pamidronate, which are given intravenously, and etidronate, tiludronate, alendronate and risedronate, which are taken orally.

Mild to severe forms of Pagets disease can be suppressed with one 5 mg infusion of zoledronic acid for up to two years. A mild form of Pagets disease can be suppressed with one or two 60mg infusions of pamidronate, while a more severe manifestation of the disease may require several infusions of 60-90 mg of pamidronate on a weekly or twice-weekly basis. Serum alkaline phosphatase testing should occur approximately two to three months after the appropriate number of infusions is administered. Oral calcium and vitamin D supplementation (preferably vitamin D3) are recommended for patients using bisphosphonates to lessen hypocalcemia. Both alendronate and risedronate have been shown to reduce the biochemical indices of bone turnover, often into the normal range, in patients with mild to moderate-to-severe Pagets disease. Alendronate is taken as a daily 40mg tablet for six months; risedronate is taken as a daily 30mg tablet for two to three months. These drugs are generally taken at least 30 minutes before breakfast with water only. Etidronate and tiludronate are less potent than alendronate and risedronate. They are both taken as daily 400 mg tablets. Etidronate the original bisphosphonate used to treat Pagets disease is taken for six months, while tiludronate is taken for three months. With both of these bisphosphonates, calcium supplements and food and beverages should not be taken for several hours before or following taking the drugs. Investigators have recognized that secondary resistance to individual bisphosphonates (etidronate and pamidronate) can occur. Therefore, it may be necessary for a patient to switch from one bisphosphonate to another in long-term treatment. Due to the generally poor absorption of the bisphosphonates, it is vital that patients take oral bisphosphonates in the prescribed manner to avoid incomplete absorption of the drugs. Oral bisphosphonates are generally well tolerated. The main problem can be irritation of the esophagus. Calcitonin Subcutaneous injection of salmon calcitonin was the first widely utilized therapy for Pagets disease. Salmon calcitonin has been shown to reduce elevated indices of bone turnover by 50%, decrease symptoms of bone pain, reduce warmth over affected bones, improve some neurological complications and promote healing of lytic lesions. Today, the use of calcitonin is limited mostly to patients who do not tolerate bisphosphonates. In the case of secondary resistance to salmon calcitonin, a switch to bisphosphonate therapy is necessary. The therapies most widely recommended by Pagets disease medical specialists are the four more potent bisphosphonates: zoledronic acid, pamidronate, alendronate and risedronate. Pain Management: Analgesics Pain directly attributable to Pagets disease is generally relieved through anti-osteoclast treatment as described above. Some pain may be the result of muscle spasm associated with either bone deformity or arthritic or neurological complications. In this case, acetaminophen,

nonsteroidal anti-inflammatory drugs (NSAIDS) or the cox-2 inhibitors may be helpful for the management of nonskeletal pain in addition to the main pagetic therapy chosen. Surgery Different orthopedic interventions that may be necessary in pagetic patients include: 1. Fixing a complete fracture through Pagetic bone; 2. Realigning the knee through tibial osteotomy to decrease mechanical pain, particularly if medical therapy is unsuccessful in managing severe pain symptoms; and/or 3. Replacing the hip and/or knee through total joint arthroplasty for patients unresponsive to anti-osteoclast treatment and therapy for the osteoarthritis. When repairing a pagetic fracture, total immobilization of that site should be avoided if possible. In all cases of surgical intervention, pre-treatment with a potent bisphosphonate is very important. Since hypervascularity is a feature of active Pagets disease, this may lead to serious bleeding during an operation. Pre-treatment with a bisphosphonate will reduce the hypervascularity and reduce the risk of greater-than-normal operative blood loss.

THE COST OF THESE DRUGS VARIES IN DIFFERENT AREAS AND ACCORDING TO A PATIENTS INSURANCE COVERAGE. Bisphosphonates Approved for Paget's disease of bone
(Listed in order of most recent FDA Approval)

I.Bisphosphonates Administration and Dosage

Zoledronic Acid Trade Name: Reclast (Novartis) FDA approval: 2007 Intravenous Approval regimen is 5 mg intravenous infusion over 15 minutes. The drug should not be administered if creatinine clearance is less than 35 ml/min. To reduce the risk of hypocalcemia patients should receive 1500 mg calcium and 800 units of vitamin D (preferably D3) over 2 weeks. For patients with hypocalcemia, Pagets disease should not be treated until the hypocalcemic condition has been corrected and vitamin D deficiency has been treated. Suppression of disease activity can last up to 2 years. Tablet 30 mg once daily for 2 months Must be taken on an empty stomach, with 6-8 ounces of water in the morning. Patients should wait at least 30 minutes after taking Actonel before eating any food, drinking anything other than water, or taking any medication.

Risedronate Trade Name: Actonel (Procter & Gamble/Aventis) FDA approval: 1998

 Patients should not lie down for at least 30 minutes after taking Actonel. (Patient may sit.)

Tiludronate Trade Name: Skelid (Sanofi-Synthelabo, Inc.) FDA approval: 1997 Alendronate (Fosamax) FDA approval: 1995

Tablet 400 mg (two 200 mg tablets) once daily for 3 months Must be taken on an empty stomach with 6-8 ounces of water. Skelid may be taken any time of day, as long as there is a period of 2 hours before and after consuming food, beverages, and medications. Tablet 40 mg once daily for 6 months Must be taken on an empty stomach, with 6-8 ounces of water, in the morning. Patients should wait at least 30 minutes after taking Fosamax before eating any food, drinking anything other than tap water, or taking any medication. Patients should not lie down for at least 30 minutes after taking Fosamax. (Patient may sit.) Fosamax 40 mg (Alendronate Sodium) tablets are available in generic form at retail pharmacies with the name Alendronate Sodium Tablets. A prescription is required.

Pamidronate Trade Name: Aredia (Novartis) FDA approval: 1994

Intravenous Approved regimen is 30 mg intravenous infusion over 4 hours on 3 consecutive days A more commonly used regimen is a 60 mg or 90 mg intravenous infusion over 2-4 hours and repeated as clinically indicated. A single infusion is sometimes effective in mild disease; 2-3 or more infusions may be required in more severe disease. A course of Aredia may be readministered at intervals as needed. Tablet 200 to 400 mg once daily for 6 months 200-400 mg dose is approved; 400 mg dose is preferred Must be taken with 6-8 ounces of water on an empty stomach (no food, beverages, or medications for 2 hours before and after dose). Course of Didronel should not exceed 6 months. Repeat courses can be given after rest periods of 3-6 months duration.

Etidronate Trade Name: Didronel (Procter & Gamble) FDA approval: 1977

Three of the above bisphosphonates, Reclast, Actonel and Fosamax are also approved to treat osteoporosis. The dose for Reclast for both diseases is a single 5mg infusion once a year. The osteoporosis doses for Actonel and Fosamax vary depending on which formulation of the drugs are used.

II. Calcitonin
Trade Name:

Administration and Dosage

Injection

Miacalcin (Novartis) Approved by FDA 1990

50 to 100 units daily or 3 times per week for 6-18 months Miacalcin is also approved to treat osteoporosis. Miacalcin nasal spray is approved for treating osteoporosis, but is not approved or recommended for treating Pagets disease.

Osteonecrosis of the Jaw

Beginning in 2003 reports began to appear concerning osteonecrosis of the jaw (ONJ) in patients treated with bisphosphonates. ONJ is a very uncommon condition which is usually found after a tooth is pulled or after other surgical procedures in the oral cavity. ONJ is characterized by dissolution of the gum over the affected area, leaving the bone exposed. The bone shows evidence of cell death and pain may be severe. Healing of the bone may occur after antibiotic therapy, but in some patients the abnormal bone is removed. Bone removal does not always produce a satisfactory result. There is very poor understanding of the exact cause of ONJ and the incidence of the problem in the general population has never been determined. ONJ can be a complication of radiation therapy to the face and is often associated with oral infections. About 95 % of cases of ONJ have occurred in patients with advanced cancer, particularly breast cancer and multiple myeloma. Many of these patients were treated with intravenous bisphosphonates on a monthly basis for than one year to protect against the complications produced by cancers which invade the skeleton. It is hypothesized that the bisphosphonate drugs pamidronate and/or zoledronic acid reduce blood flow to the bone and suppress bone cell activity, thus causing ONJ. Since many of these cancer patients also receive cancer chemotherapy and steroid hormones the exact cause of ONJ has not been established. Millions of patients with osteoporosis and a smaller number of patients with Pagets disease of bone have been treated with oral bisphosphonates, but only a small percentage of these patients have developed ONJ during bisphosphonate therapy. The much lower dose of the bisphosphonate drugs used to treat osteoporosis and Pagets disease could account for the very low incidence of ONJ in these patients. Despite the extremely small chance that a patient with Pagets disease would develop ONJ while taking a bisphosphonate drug, it would be helpful to stress the importance of good dental hygiene and a regular dental examination, particularly before starting bisphosphonate therapy. If dental surgery is needed, the patient should be encouraged to delay the beginning of the bisphosphonate treatment until the surgery healing is complete. If dental surgery is needed while the patient is taking the bisphosphonate therapy, the dentist should be informed about the treatment and the least invasive dental procedure by considered. If surgery is needed, there appears to be no advantage to stopping the bisphosphonate treatment because of the long-term storage of the bisphosphonate drugs in the skeleton. The above advice may be modified as new research findings about ONJ are known.

Vitamin D and Calcium

Considering the growing amount of information indicating that a high percentage of elderly individuals have inadequate intake of vitamin D it is important to provide guidance to Pagets disease patients about vitamin D and calcium intake. This is particularly important to those who will receive bisphosphonate therapy since a patient who has severe vitamin D deficiency can develop symptomatic and even prolonged hypocalcemia if the vitamin D deficiency is not corrected before the bisphosphonate treatment is initiated. Vitamin D deficiency is usually caused by inadequate exposure of the skin to the ultraviolet light of the sun, by sun screen use and/or by inadequate intake of vitamin D. The diagnosis is made by measurement of serum 25OH vitamin D. This is a liver metabolite of vitamin D which is subsequently converted to 1,25(OH)2vitamin D in the kidney. 1,25(OH)2vitamin D is the main form of the vitamin which regulates calcium and phosphorus absorption in the intestine. Studies suggest that a serum 25OHD level of 30ng/ml is the minimum required level for maximal absorption of calcium and that the majority of elderly Americans have levels below this. There are two forms of vitamin D which have identical actions, vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Vitamin D3 is synthesized in the skin of humans and numerous species. Vitamin D2 is made by yeast and fungi. Vitamin supplements contain either of the forms as indicated on the product label. Vitamin D3 is the preferred form of vitamin D because evidence shows that D3 disappears from the blood much more slowly than D2. The recommended amount of vitamin D for older adults is 1000 units daily. A daily calcium intake of 1200-1500mg is recommended. If there is a suspicion of a vitamin D deficiency in a Pagets disease patient, this can be confirmed by measuring serum 25OHD. If the deficiency is confirmed, higher doses of vitamin D3 or D2 given for several months can correct the deficiency before beginning the bisphosphonate treatment.

4. http://orthopedics.ygoy.com/pagets-disease-occurence-causes-and-symptoms-of-pagets-disease/

Pagets disease Occurence, Causes and Symptoms of Pagets disease

The chronic disease causing deformed and enlarged bones is termed as Pagets disease. The Pagets disease has several other names like the osteitis deformans or osteodystrophia deformans. This medical condition was named after a British surgeon, Sir James Paget. He described the osteitis deformans for the first time in the year 1877. The excessive formation and breakdown of the bone tissues can result in weakened bones, leading to pain in the bones, fractures, arthritis or deformations of the bones. Occurrence of Pagets disease

The Pagets disease is diagnosed in people after their 40s, but is rarely identified in people below 40 years of age. This disease is more prevalent in men compared to women. The osteodystrophia deformans is found prevalent among 1.5 8.0% of population based on the country of residence and age of the patients. This disease is found in about 10-40% of people among familial persons; i.e. it runs among family affecting more than one people in each family. Children of an osteitis deformans patient need to undergo an alkaline phosphatase blood test every 2-3 years after their 40s. This is because they are more susceptible. This is also applicable in siblings of the patient. If the level of the alkaline phosphatase is observed to be above normal, other tests are required to be done like a bone-specific alkaline phosphatase test, an X-ray or a bone scan.

Causes of Pagets disease Two basic causes have been identified causing the Pagets disease. These are

Viral causes Genetic causes

Viral causes of Pagets disease The osteitis deformans may have been caused by slow infection of a virus (paramyxoviruses). These viruses reside inside the human body for a long time (many years) before the appearance of the symptoms. Along with these viruses, even the following infections have been found associated with the occurrence of the osteodystrophia deformans. But no scientific evidences have been proved yet. Several studies have suggested that the following contamination may have resulted in the onset of the osteodystrophia deformans.

Measles Canine distemper virus Respiratory syncytial virus

Genetic causes of Pagets disease The occurrence of the osteodystrophia deformans has been found hereditary in several cases. Symptoms of Pagets disease Several mild cases of the osteodystrophia deformans have no symptoms, making the patient unaware of the occurrence of the disease. Sometimes, the symptoms might be confused with other bone disorders. The following symptoms are observed in patients with osteodystrophia deformans

Bone pain pain is felt in bone(s) affected by the disease, and gets localized to areas near the joint. This is the most common symptom. Headache, pressure on nerves and loss of hearing these are the signs of affected skull bones due to the disease. Pressure on the nerves is also felt when the spine is affected.

Vascular steal syndrome of the skull this may also occur in the patient suffering from osteodystrophia deformans. It would cause drowsiness or somnolence. If Vascular steal syndrome of the vertebrae occurs, it results in paralysis. In advanced cases, the head size might increase, the spine may get curved or the limb might get bowed. Pain in the hip this occurs when the pelvis or thighbone is affected. Arthritis when osteodystrophia deformans damages the joint cartilages, arthritis is caused. Spreading of the teeth intraorally, caused due to the placing of the intraoral force of the labial tissues (muscles) on the anterior teeth. Chalkstick fractures Hypercementosis in teeth Mosaic bone pattern

Comparison of Bone Pathology Condition Calcium Phosphate Alkaline Parathyroid Comments phosphatase hormone No effect Variable No effect Bone mass levels decreased No effect No effect No effect Presence of thick, dense bones (called Marble bones) Decreased Variable Increased Soft bones level levels level Decreased Increased Increased Brown level level level tumors No effect Increased levels No effect Bone architecture is affected

Osteoporosis No effect Osteopetrosis No effect

Osteomalacia Decreased and Rickets level Osteitis Increased fibrosa level cystica Pagets No effect disease

Pagets Disease Diagnosis and Prognosis of Pagets Disease

The Pagets disease was also referred as Osteitis deformans. But now this term is considered technically incorrect and is given another name, the osteodystrophia deformans. A British surgeon, Sir James Paget documented the disease for the first time. According to him, the Pagets disease was caused due to some inflammatory process. This was later found to be the action of paramyxovirus. But till date, no virus has been isolated claiming to have caused the disease. Some evidences also suggest that Pagets disease is caused due to an intrinsic hyperresponsive reaction caused to vitamin D and ligand RANK. But these require further confirmatory experimentation.

Diagnosis of Pagets disease Many a times, the symptoms of the Pagets disease are confused with those of the Arthritis and other bone diseases. This often makes the diagnosis complicated. This requires accurate diagnosis using one or more tests mentioned below

X-ray test A Pagetic bone is easily visible on an X-ray film. Alkaline phosphatase blodd test If the level of alkaline phosphatase is found higher than the normal, this suggests the onset of the Pagets disease. Bone scans Bone scans can be used to determine the extent of the condition. This requires further X-ray test for confirmation.The disease occurs is three different stages inside a human body. o Osteoclastic activity o Mixed osteoclastic-osteoblastic activity o Exhaustive (burnt out) stage

Prognosis of Pagets disease

If appropriate treatment of the disease is done, then the outlook has been found good. But the treatment must be done before any major changes have occurred in the affected bone. The disease can affect any bone(s). The spine, pelvis, lower legs, thighs and skull are the common sites of occurrence. Normal bones are generally not affected by affected bones. The symptoms show a very slow progress. The aim of treating Pagets disease is not to cure the disease but to lessen the severity of the symptoms. The major complication called Osteogenic sarcoma is seen rarely in people with osteodystrophia deformans. This occurrence is as rare as about 1% or less in patients. Other associated medical complications include o Arthritis o Cardiovascular disease o Development of angioid streaks o Formation of malignant tumor of bone o Headache o Loss of hearing o Loss of vision o Loosening of facial bones o Problems in the nervous system o Stone formation in kidney

Pagets Disease Complications of Pagets Disease

Pagets disease is characterized by abnormally deformed and unusually enlarged bones in the patient. This is a chronic disease. The following complications have been observed in patients with Pagets disease. Increase in the level of alkaline phosphatase in the blood is the diagnostic characteristic of the disease.

Arthritis

In Pagets disease, the long bones in the leg can get bowed. Undesired bowing of the leg bone can distort the bone alignment and increase pressure on the nearby joints. o The Pagetic bone might get enlarged causing wearing of the joint surfaces. o These results in arthritic pain and Osteoarthritis resulted from Pagets disease. Affected skull o When the skull and the bones surrounding the inner ear are affected, hearing loss may be experienced. o The hearing ability can even be lost. o Patients may require hearing aids. o Some researchers believe that Pagets disease might be associated with Beethovens deafness. o The eye nerves may also be affected causing loss of vision in the patient. But this is a rare occurrence. Cardiovascular disease o Severe cases of this disease can result in cardiovascular disease. This is the case where more than 15% of the skeletal system is involved. o Due to the formation of the AV connections in the bone, the heart is forced to pump more blood and work harder. This is done to ensure that the oxygen supplies to the body tissues are not disturbed. Adequate amount of oxygen reaches everywhere. o Such conditions lead to elevated cardiac output which causes calcification of the aortic valve. This results in aortic stenosis leading to left ventricular hypertrophy and eventually leading to high-output congestive failure. Kidney stones o It has been observed that Pagetic patients are more prone to experience kidney stones. Problems in the nervous system o Pressure on brains, pressure on nerves or spinal cord is a few common but major complications in Pagetic patients. Pagetic bones can also restrict the blood flow to the spinal cord and brain. o Such conditions can result in severe problems in the nervous system. Development of Sarcoma o Pagets disease is rarely found associated with the development of malignant tumor in the bone (sarcoma). o The common symptoms of sarcoma include sudden onset of pain or worsening of pain in the bone. Loosening of facial bones o When the disease affects the facial bones, the teeth gets loosened. This can cause severe disturbances with chewing and talking. Angioid streaks o Sometimes, some kind of pathological deposition or calcification of collagen can result in development of Angioid streaks. o Angioid streaks are small breaks observed in the Bruchs membrane. o The Bruchs membrane is formed of an elastic tissue in the retina. o In case of angioid streaks, the Bruchs membrane is calcified and gets cracked. This is how the visibility is challenged.
o

Pagets Disease Treatment of Pagets Disease

Endocrinologists, otolaryngologists, orthopedic surgeons, rheumatologists, neurologists all kinds of specialized physicians are involved in treating the Pagets disease. They evaluate the specific symptoms, diagnose and prescribe the appropriate method of treatment for the patient. The approach of treatment of Pagets disease is based on the extent of the condition and activity of the medical ailment. The following kinds of treatments are prescribed to the Pagetic patients 1. Drug therapyThe prime goal of treatment here is not to cure the disease but to relive the severity of the symptoms. The progress of the disease is also restricted by proper method of treatment. The following drugs are approved by the U.S. Food and Drug Administration to treat Pagets disease o Bisphosphonates Currently, five different bisphosphonates are available. The ones which are most commoly prescribed include Actonel (risedronic acid) Aredia (pamidronic acid) Didronel (Etidronic acid ) Fosamax (alendronic acid) Prescription : These tablets must be taken along with 6-8 oz of water (water should not be taken from any source with high mineral contents in it). The tablets must be taken in empty stomach. People with severe kidney disease must not use these drugs. The use of the above bisphosphonates depends on the patient and the severity of the disease. A few drugs are mentioned below that are prescribed commonly to most patients Aredia (pamidronate disodium): This drug is used in its intravenous form. 30 mg of the drug is infused over 4 hours for 3 consecutive days and is then taken. More often, 60 mg of the drug is infused for 24 hours for 2 or more consecutive days (sometimes non-consecutive). Didronel (etidronate disodium): This drug is taken in the tablet form of 200400 mg doses. It is usually taken once daily for over a 6 months period. In general, 400 mg (higher dose) is used. No food, medication or beverages are allowed 2 hours prior to and after the intake of the tablets. The course cannot be stretched beyond 6 months. If required, it can be started again after a short rest period of 3-6 months. Fosamax (alendronate sodium): The above tablet is consumed daily for over 6 months.

Each tablet is of 40 mg. The patient is not allowed to eat, drink or take any medication 30 minutes before and after taking this tablet. The patient must not lie down after taking this medicine. He is advised to sit. Drinking only tap water is allowed. Skelid (tiludronate disodium): 2 tablets (each of 200 mg) are taken daily for 3 months. These can be taken anytime but a gap period of 2 hours must be maintained after and before taking these tablets. Actonel (risedronate sodium): One tablet contains about 30 mg of the Bisphosphonates. It must be taken daily once for about 2 months. The patient is needed to wait for at least 30 minutes before and after taking the tablet. He is not allowed to take either food, medication or drink anything else than tap water. The patient must sit and not lie down. Reclast (Aclasta or zoledronic acid): The above medicine is an infusion taken over 2 years. 1 single dose of the above medicine contains 5 mg of Bisphosphonate infused over 15 min.

Calcitonin The Miacalcin is administered by injection. Either 50 100 units are administered daily or thrice in a week for 6 18 months. The course is repeated with small rest periods. This medicine is seldom used and is appropriate only in case of a few patients. But the nasal spray is not approved to treat Pagets disease. 2. Surgery o Medical therapy is advised before surgery to reduce the complications and more often the bleeding in the patient. o It is advised that the patient must have a clear discussion with the physician before deciding over any surgery. o The major complications which require surgery for treatment are mentioned below Fractures surgeries might place and hold the fractures at better positions for faster healing. Severe degenerative arthritis when medication and physical therapy are no longer fruitful and the disability has increased in severity, then such cases demand surgeries. These commonly include the joint replacement surgeries of the knees and hips. Bone deformity the painful weight bearing joints might require cutting and realignment of the affected bones. This is commonly performed at the knee and is called osteotomy.
o

Enlargement of the spine or skull is always dangerous. Such cases can claim our nervous system. Such kind of neurologic symptoms require medication for treatment and not surgery. 3. Diet and Exercise o A Pagetian patient is advised to receive 1000-1500 mg of calcium daily along with 400 units of Vitamin D (from adequate sunshine). o Patients under treatment with bisphosphonates require the above significantly. o If a patient in taking oral bisphosphonates, he/she must not take calcium or calcium supplements at least 2 hours before and after the tablet. This is to avoid the inhibition of bisphosphonate absorption. o Those with kidney ailments (like stones) must enquire with their respective physician about their calcium ad Vitamin D intake. o Regular exercises are highly recommended to maintain our overall bone health (skeletal health). o Exercises will prevent gain in weight and trigger joint mobility. o But it is advised that the patient must discuss his/her exercise plans with his/her respective physician.
5. http://www.mja.com.au/public/issues/181_05_060904/wal10268_fm.html#CHDECIFJ

Pagets disease of bone John P Walsh MJA 2004; 181 (5): 262-265

Introduction Epidemiology and pathogenesis of Pagets disease Diagnosis Clinical features Diagnostic imaging Biochemistry

Treatment Conclusion Acknowledgement Competing interests References Author details

Abstract

Pagets disease of bone is common, affecting up to 4% of Australians over the age of 55 years. The incidence of the disease and the severity of newly diagnosed cases appear to be falling, for unknown reasons. The cause of Pagets disease is unknown, but there is a strong genetic influence. Recently, mutations in the sequestosome 1/p62 gene have been identified as a cause of familial Pagets disease and of some apparently sporadic cases of the disease. The disease is often asymptomatic, but can cause bone pain, deformity, fracture and other complications. Pagets disease is eminently treatable. Potent bisphosphonates such as pamidronate, alendronate and risedronate relieve symptoms and may reduce the risk of complications. The Pharmaceutical Benefits Scheme subsidises treatment only for patients with symptomatic disease. A strong case be made for also treating asymptomatic patients with involvement of long bones, vertebrae or base of skull, patients with significant osteolytic lesions, and perhaps all younger patients.

Pagets disease of bone is a chronic disorder, characterised by focal areas of excessive osteoclastic bone resorption accompanied by a secondary increase in osteoblastic bone formation. The classic description of the disease was by Sir James Paget in 1877 in a paper describing the clinical features of a disorder he called osteitis deformans.1 The disease results in bone expansion and structural weakness, which can cause pain, deformity, and a range of complications. Here, I review recent advances in understanding of the disease, as well as practical management. For more detailed reviews, see two recently published sets of consensus management guidelines.2,3

Epidemiology and pathogenesis of Pagets disease Pagets disease predominantly affects the elderly. It is uncommon in people under the age of 55 years and is more common in males than females, with a sex ratio of 1.8 : 1. There are marked geographical differences in prevalence. The disease is most common in the United Kingdom (particularly Lancashire), followed by Australia, New Zealand and North America, in part reflecting the large number of British migrants to those countries.4 By contrast, the disease is uncommon in Scandinavia, Africa and Asia. A radiographic study carried out in Western Australia in 1978 reported a prevalence of 4% in people aged over 55 years.5 Recent studies from the United Kingdom and New Zealand suggest that the incidence of Pagets disease is falling, perhaps by as much as 50% over the past 20 years, and that the severity of newly diagnosed cases is falling.6,7 The reason for this is unknown. There are no recent prevalence studies from Australia. The cause of Pagets disease is unknown. There is a strong genetic component, and 15% 20% of those affected have a first-degree relative with the disease.8,9 Genome linkage scans have identified several loci associated with familial Pagets disease. Recently, mutations in the sequestosome 1/p62 gene have been identified in about a third of affected kindreds, and in 5%15% of patients with no family history of the disorder.10-12 The SQSTM1/p62 protein is a selective activator of the transcription factor NFB, which plays an important role in osteoclast differentiation and activation in response to the cytokines RANK-ligand and interleukin-1.13,14 Mutations in the SQSTM1/p62 gene are therefore a plausible cause of Pagets disease, but it is unclear how germline DNA mutations (present in every osteoclast) cause bone disease that is focal in nature. Environmental factors may also play a role. Several studies have postulated that viruses, particularly paramyxoviruses such as canine distemper or measles virus, play a role in pathogenesis, but definitive evidence for this is lacking.15 Presumably, the declining incidence of Pagets disease reflects a decline in one or more as yet unidentified environmental influences. Diagnosis Clinical features Pagets disease presents clinically in a variety of ways (Box 1), depending in part on the bones affected. Most commonly, the disease involves the pelvis, lumbosacral spine, skull, femur or tibia, but any bone may be affected, and the disease may be localised to one or a few bones or widespread throughout the skeleton. Not infrequently, the disease is asymptomatic, and is detected as an incidental finding at radiography or because of an increase in serum alkaline phosphatase activity. Pagetic bone pain occurs in a minority of patients. Sometimes this has distinct characteristics, being constant (day and night), present at rest and poorly localised, with a dull, boring character. Other patients have more localised pain, worse on weight-bearing and sometimes self-limiting, which may arise from microfractures or localised lytic lesions. Pagets disease adjacent to a joint can cause secondary arthropathy with the clinical features of osteoarthritis. Deformity, such as bowing of the femur or tibia, may be asymptomatic or associated with mechanical pain in the affected limb or on the contralateral side, arising from secondary gait problems. Cortical fissure fractures arise from abnormal mechanical forces on weakened

bone. They may be asymptomatic or painful. They often remain unchanged over time with no response to treatment, but can progress to complete fracture (Box 2). The most common neurological complication is deafness arising from involvement of the petrous temporal bone. It may be conductive in nature (from involvement of the middle-ear ossicles), sensorineural (from auditory nerve compression or cochlear involvement) or mixed. Other neurological syndromes are uncommon, but include vertigo, spinal cord compression, local compression syndromes, such as cranial nerve palsies, and, rarely, hydrocephalus or brainstem compression from basilar invagination. Malignant transformation of pagetic bone to osteosarcoma is rare (lifetime risk, < 1%). Diagnostic imaging Pagets disease is diagnosed primarily by radiological examination. Early in the course of the disease, lytic activity predominates, causing focal osteolytic lesions (osteoporosis circumscripta) or flame-shaped, advancing lytic wedges in the long bones (Box 2A). Subsequently, areas of sclerosis develop, leading to the characteristic appearances of mixed lytic and sclerotic areas, thickened trabeculae, bone expansion, cortical thickening and deformity. The radiological appearances are usually characteristic, but occasionally a differential diagnosis of sclerotic or lytic metastases needs to be considered. An isotope bone scan is recommended in all patients as part of the initial diagnostic assessment to determine the distribution of the disease, in particular the involvement of sites with the potential for complications, such as base of skull, spine and long bones (Box 3). Computed tomography scanning is helpful to assess skull-base involvement (including patients with deafness), spinal stenosis or other neurological complication. Biochemistry Plasma total alkaline phosphatase level is the most clinically useful marker of disease activity. In patients with monostotic or limited disease, the level may be in the upper reference range: thus, a normal alkaline phosphatase level does not exclude the disorder. Liver function tests should be performed, in particular measurement of glutamyltranspeptidase level, as liver disease can also result in elevated alkaline phosphatase activity, causing diagnostic confusion (Box 1). If there is doubt as to the tissue origin of elevated levels of plasma alkaline phosphatase, assessment of alkaline phosphatase isoenzymes should be requested. In patients whose total alkaline phosphatase level is not elevated, and in those with liver disease, measurement of bone-specific alkaline phosphatase level (where available) or urine markers of bone resorption is helpful. Biochemical assessment should also include measurement of 25-hydroxyvitamin D for two reasons: osteomalacia can present with bone pain and a raised alkaline phosphatase level, and vitamin D deficiency should be corrected before prescribing bisphosphonate therapy. Treatment Pagets disease is treatable, but not all patients require treatment (see Box 4). Bone pain at pagetic sites is an indication for treatment, as there is good evidence that this responds to bisphosphonate therapy.3 In individual patients, it can be difficult to determine whether pain is arising from Pagets disease or from coexisting conditions such as osteoarthritis. In such cases, a therapeutic trial of bisphosphonate therapy is reasonable if the pain localises to an area of pagetic involvement. Patients with neurological complications should receive

treatment, particularly those with spinal stenosis or cord compression, as symptoms may improve with medical therapy.3 Currently, only patients with symptomatic Pagets disease are eligible for Pharmaceutical Benefits Scheme (PBS) subsidies for their treatment. A strong case can also be made for treating asymptomatic patients in whom the location of the disease puts them at risk of future complications. This includes those with involvement of the long bones such as femur, tibia or humerus, particularly if significant lytic lesions are present, and those with vertebral involvement, because of the risk of fracture or spinal stenosis. Many authorities regard involvement of the base of the skull as an indication for treatment, because of the risk of pagetic deafness, which, once present, rarely responds to medical or surgical therapy. It may also be reasonable to treat younger patients with asymptomatic involvement of joint surfaces, such as the acetabulum, in the hope of preventing secondary arthritis. Evidence that treatment prevents pagetic complications is limited, and unlikely ever to be available from randomised controlled trials. In addition, preoperative medical treatment is recommended for patients undergoing elective surgery (such as joint replacement) to bones with metabolically active Pagets disease. The rationale for this is that bisphosphonate treatment reduces skeletal blood flow in Pagets disease,16 and therefore may reduce intraoperative blood loss. Direct evidence for reduced blood loss is, however, lacking.2 Potent second- and third-generation bisphosphonates are the treatment of choice for Pagets disease, and have superseded other treatments (such as calcitonin and the first-generation bisphosphonate etidronate). In Australia, the most widely used drugs are pamidronate, alendronate and risedronate (Box 4).

Pamidronate is administered by slow intravenous infusion over 24 hours. A variety of treatment regimens have been used.2,3 A single dose of 60 mg is adequate for some patients with mild disease,2,17 whereas two to four doses (and occasionally more), administered days or weeks apart, are required for more severe disease. Alendronate is conventionally prescribed as a 6-month treatment course,2,3,18,19 but recent data suggest that 3 months treatment is adequate for many patients.17,20 Risedronate is prescribed as a 2-month course of treatment.

All three drugs are generally well tolerated. The most common side effects of pamidronate are a transient flu-like syndrome of fever, myalgia and arthralgia. Serious side effects are rare, but uveitis and acute renal failure have been reported. With alendronate and risedronate, the most common side effects are upper gastrointestinal symptoms. Preliminary data suggest that another intravenous bisphosphonate, zoledronic acid, is also effective for Pagets disease, and the results of randomised controlled trials are awaited. Vitamin D deficiency should be corrected with ergocalciferol or cholecalciferol before starting bisphosphonate treatment, and calcium supplementation is advisable to minimise bisphosphonate-induced hypocalcaemia and secondary hyperparathyroidism.21 The aims of treatment are to achieve clinical remission (relief of symptoms), biochemical remission (return of plasma alkaline phosphatase level to the reference range) and radiological remission (filling-in of osteolytic lesions). Disease activity is readily monitored by measuring plasma alkaline phosphatase level every 3 months after starting treatment, and treatment can be stopped when the level returns to the reference range, or when there has been no further reduction on successive measurements. In patients whose alkaline

phosphatase level is not elevated at baseline and in patients with liver disease, treatment response can be monitored by observing changes in alkaline phosphatase level within the reference range, measurement of bone-specific alkaline phosphatase or urine markers of bone resorption, or repeat isotope bone scans. After remission of Pagets disease has been achieved, patients no longer receiving treatment should be followed up periodically, for example by annual clinical review, with measurement of alkaline phosphatase level. For patients with osteolytic lesions at baseline, repeat radiography should also be performed. Repeat isotope bone scanning is rarely required, as the distribution of affected bones does not change over time, and disease activity can be assessed by simpler means. Relapse inevitably occurs, often several years after the initial treatment course, and patients should then be offered further therapy. Relapse is usually apparent from an increase in alkaline phosphatase activity, but in some patients clinical relapse (recurrent pain) and radiological relapse (progression of osteolytic lesions) precede biochemical relapse. In this case further treatment should be given, even when the alkaline phosphatase level is normal. With repeated courses of treatment the disease can become resistant to individual bisphosphonates. This was first described with etidronate,22 and, more recently, with pamidronate.17,23,24 In such cases, the disease still responds to other potent bisphosphonates; for example, patients whose disease has become resistant to pamidronate can be effectively treated with alendronate or risedronate.17,23 Non-pharmacological treatments should not be neglected. For example, patients with deformity resulting in leg shortening may benefit from shoe raises or orthotics to assist with pain relief and gait difficulties. Conclusion Pagets disease is a common, treatable disorder affecting older Australians. Further research into the genetics of this disease will lead to a better understanding of its pathogenesis, and potentially to new treatments. 1 Clinical presentation and investigation of Pagets disease Clinical presentation

Investigation

Incidental finding on radiology or biochemistry Bone pain Arthropathy Deformity Fracture Deafness Neurological complications Osteosarcoma

Alkaline phosphatase level Liver function tests Vitamin D level Isotope bone scan Radiography of affected bones

2 Radiographic features of Pagets disease

A. Pagets disease of the tibia, with a flame-shaped lytic wedge (arrowhead) and a pathological fracture (arrow). B. Longstanding Pagets disease of the femur, with bone expansion, trabecular thickening, mixed lytic and sclerotic areas, and fissure fractures (arrows). C. Active Pagets disease of the skull, with marked cortical thickening and an area of osteoporosis circumscripta (arrows). D. The same patient some years later (after bisphosphonate treatment), with the lytic lesion largely replaced by sclerotic bone. 3 Isotope bone scanning in Pagets disease

A patient with polyostotic Pagets disease, showing involvement of the skull, left scapula, thoracic vertebrae (T7, T9 and T11), left femur and right calcaneum. 4 Indications for bisphosphonate therapy and the drugs recommended

Indications

Pain in pagetic bones or joints Neurological complications Significant osteolytic lesions with fracture risk Involvement of long bones, vertebrae or base of skull Patients undergoing surgery to pagetic bones Asymptomatic joint involvement

Recommended drugs

Pamidronate 60 mg, given intravenously, 14 doses, days or weeks apart Alendronate 40 mg/d, given orally for 36 months Risedronate 30 mg/d, given orally for 2 months