What is Paget's Disease of Bone?

Paget’s disease affects the normal repair and renewal process of bone. Throughout life, bone is renewed and repaired through a process called bone remodelling. Paget’s disease is characterised by abnormalities in this process. The affected bone is renewed and repaired at an increased rate, adversely affecting the bone’s structure. Bone affected by Paget's disease may be enlarged and misshapen. 

Paget’s disease can occur in any bone, often causes no symptoms and may be found by chance. For those with symptoms, these may include pain, deformity and fracture. Either single or multiple bones may be affected with common sites being the spine, skull, pelvis and thigh (femur).

The risk of developing Paget’s disease increases with age and it is most commonly diagnosed in those over 50 years. Paget’s disease is the second most common metabolic bone disease after osteoporosis. Approximately 1% of people in the UK, over the age of 55 years, are thought to be affected. The condition is also common in other European countries such as France, Spain and Italy and in people of European descent who have emigrated to other regions of the world, such as Australia, New Zealand, the United States of America and Canada. 

You may be interested in our Paget's Jargon Buster, which can be found by following this link.

How Does Paget's Disease Affect Bone?

Bone is an active living tissue that is constantly being renewed through a process known as remodelling. Cells called osteoclasts break down old, damaged bone to make way for new bone laid down by cells called osteoblasts. Over time, this bone is mineralised, forming a hard and strong skeleton.

Under normal circumstances, the amount of bone removed is balanced by the amount of bone laid down. In Paget’s disease, the processes of bone resorption and bone formation are markedly increased. The osteoclasts are larger than normal and break down bone faster than normal. The osteoblasts respond to this by depositing new bone at an increased rate. This dysregulation of bone turnover in Paget’s disease results in abnormalities of the bone structure, weakening of the bone and enlargement or deformity of the affected bones. Pagetic bone often appears misshapen and enlarged. 

You can learn more from our booklets (available in the Member's area of this website, or from our office) or by watching the video below. Details regarding membership and its benefits can be found by following this link.

In the following video, Dr Anna Daroszewska discusses what Paget’s Disease of Bone is, and the effects of treatment with a bisphosphonate. Anna is based in Liverpool and is a Trustee of the UK charity, The Paget's Association and this video is ​part of a series of videos looking at The Treatment Story for International Paget's Awareness Day 2021.

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What Causes Paget's Disease?

There are still some uncertainties about the causes of Paget’s disease, but it is generally believed to be due to a combination of genetic and environmental influences.

Genetic factors play a key role in predisposing to Paget's disease. It is thought that people who develop Paget’s disease inherit variations in one or more genes that regulate osteoclast activity, causing bone resorption to be increased. This is thought to be responsible for the increased bone remodelling that is typical of the disease. The most important predisposing gene for Paget’s is called Sequestosome 1 (SQSTM1). Abnormalities of SQSTM1 have been identified in 40% to 50% of people with a family history of Paget's disease and also in 5% to 10% of people who have no family history. The children of people with Paget’s disease are about seven times more likely to develop Paget’s disease than people who don’t have a family history.

Environmental factors also play a role in Paget’s disease, as evidenced by the fact, that over the last few decades, the frequency and severity of the disease have declined in many countries, and is most marked in regions that previously had a high prevalence, such as the UK. Various environmental triggers have been suggested, including dietary calcium or vitamin D deficiency, exposure to environmental toxins, repetitive mechanical stress on the bone, skeletal trauma and slow viral infections. Despite this, researchers have yet to discover which environmental factors influence the development of Paget’s disease.

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The Symptoms of Paget’s 

Many people who have Paget’s disease do not have symptoms and never develop complications. In many cases, individuals are unaware that they have the condition. It may be discovered by chance on x-ray or if a blood test is performed for another reason.

Of those who present with symptoms, pain is the most common. Pain may arise from the affected bone itself, or from the altered biomechanics of limb deformity; for example, a bowed leg alters the way you walk and puts stress on the joints and soft tissues.

The blood flow to active areas of Paget’s disease increases and this can lead to a feeling of warmth over the affected bone. The affected bone may become enlarged and misshapen.

In many cases there may be no symptoms and individuals are unaware that they have Paget’s disease.

For more information see our Fact's Booklet and Magazines which are all available in the Members' Area of this website. Details regarding membership and its benefits can be found by following this link.

Complications of Paget's Disease

The potential for complications will depend on which bones are affected by Paget’s disease. Complications may require medical or surgical intervention.

Examples of complications arising from the involvement of specific bones:

• Skull. Paget's in the skull can cause headaches, hearing loss, ringing in the ears and a change in shape and/or size of the skull (i.e. enlarged head, wide forehead).
• Spine. Paget's in the spine can lead the affected vertebrae to become enlarged and deformed which can cause curvature of the spine, pain, and pressure on nerve roots with tingling, weakness and numbness in the legs.
• Femur. Paget's in the femur (thigh) can cause local pain at the site of the Paget's disease or related to osteoarthritis of the hip joint. Fissure (partial) fractures in the bone may lead to a complete fracture.
• Pelvis. Paget's in the pelvis may be painful and accelerate osteoarthritis in the hip joint.
• Shin. When the lower leg is affected the bone may feel warm, be painful and it may bow. Osteoarthritis may develop in the knee joint and fissure fractures may occur possibly leading to complete fracture.

Deformity: Paget’s disease can cause bone to become enlarged and misshapen. For example, if the skull is affected, the enlarged bone is sometimes first noticed when the individual becomes aware that their head is larger and their forehead may be wider than normal. Long-standing disease over many years may cause the weight-bearing bones of the leg to develop a bowing deformity.

Deafness: If the skull is involved, hearing loss can occur.

Fracture: There is an increased risk of fracture, particularly in the long bones of the arm and leg. Fractures may initially be incomplete, (stress fractures or fissure fractures), which are at high risk of complete fracture. Fissure fractures predominantly, but not exclusively, affect weight-bearing bones, such as the thigh bone (femur).

Osteoarthritis: Paget’s disease can predispose to the development of osteoarthritis at adjacent joints. You can read an article by Dr S. Tuck,"Paget's and Osteoarthritis"  in our Member's Area.

Neurological complications: Neurological complications can occur, often because of bony overgrowth leading to compression. For example, enlargement of vertebrae in the spine can produce pressure on nerves causing pain, leg weakness or sciatica.

Increased vascularity: Should the bone fracture or surgery be undertaken, active Paget’s disease has the potential to result in excessive blood loss. This is because blood flow increases to areas where Paget’s disease is active.

Heart disease: Paget’s disease does not directly affect the heart but if it is in many bones, is highly active and uncontrolled, the heart may have to work harder to pump extra blood to the affected bones. Whilst heart failure due to this increased blood flow has been reported, it is extremely rare.

Osteosarcoma: An unusual and very rare complication of Paget’s disease is a type of bone cancer, called osteosarcoma. This occurs in less than 1:1,000 people with the disease. Members of the Paget's Association can login to the members' area to read an article by experts in Norwich and read about Allan Reid who developed this rare condition.  The Bone Cancer Research trust also has information on their website.

Concerns?

Anyone who has concerns about any of the above, can contact our Nurse Helpline by following this link.

For more information see our Fact's Booklet and Magazines which are all available in the Members' Area of this website. Details regarding membership and its benefits can be found by following this link.

How is Paget's Diagnosed?

It has been estimated that less than 10% of patients with x-ray evidence of Paget’s disease come to medical attention. When Paget's disease is suspected, a full assessment by a hospital consultant is recommended to determine if treatment is required.

Paget's disease may be identified by an x-ray, blood test or bone scan.

In many cases, Paget’s disease is found by chance when tests are carried out for another reason.

1. Blood tests

   A common blood test in general practice is to measure liver function. Included in this test is an enzyme called alkaline phosphatase (ALP). This is present in many cells within the body, but particularly in liver and bone cells (osteoblasts). If there is overactivity of the osteoblasts due to Paget’s disease, alkaline phosphatase is released into the bloodstream and can be measured.

   When Paget’s disease is active, the ALP level will often, but not always, be raised. A raised ALP can stand out as being the only abnormal result. If there is co-existent liver disease, it may be necessary to perform further blood tests to identify the source of the elevated ALP.

   Read Professor Fraser's article on Blood tests in Paget’s Disease of Bone, which you will find under Information in the Members' Area of this website. 

2. X-ray

   When an x-ray is taken of a bone affected by Paget’s disease, characteristic features can often be seen.

   Research has shown that plain x-rays targeted to several sites, the abdomen, skull and facial bones, and both tibiae (shins), are likely to detect 93% of bones affected by Paget’s disease, compared with a single x-ray of the abdomen, which detected less (79%).

   A single x-ray cannot give any information about other bones which may be affected. A radionuclide bone scan, as described below, is the best way of fully evaluating the extent of Paget’s disease.

3.  Bone scan

   Radionuclide bone scans, also known as scintigrams, isotope bone scans or nuclear medicine bone scans, are the most helpful in Paget’s disease. A bone scan is recommended to determine which bones have Paget’s disease and how active the disease is. The radionuclide scan involves the use of a small amount of a radioactive tracer, which is injected into a vein in the arm. After some time, the tracer collects in the bones and pictures can be taken by a scanner (gamma camera). Information sheet (PDF): Isotope Bone Scans

4. Bone biopsy

   A bone biopsy is a procedure in which a small sample of bone is taken and examined under a microscope. This is seldom required but can be useful if there is uncertainty about the diagnosis.

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Assessment of Paget's Disease

When Paget’s disease is suspected, it is important that there is a detailed assessment process, ideally carried out by a hospital consultant who understands the condition. The consultant will consider symptoms, enquire about any family history of the condition, and ensure that appropriate investigations are carried out.

Many rheumatologists and endocrinologists have the expertise to treat patients with Paget’s disease and it is likely that most hospitals in the UK have a specialist who can deal with the condition. If there is no specialist locally, then referral to one of the Paget’s Association Centres of Excellence might be worthwhile.

In some cases Paget’s disease does not cause any symptoms and requires no treatment, however, a good assessment is still necessary.

• Treatment may be recommended if the affected bones are painful
• Sometimes treatment is given if Paget's disease affects a site that might be expected to cause complications

The website of your local hospital may list your local specialists. They are often (not always) found in the rheumatology or endocrinology department. In some areas, there may be a metabolic bone centre or clinic.

Centres of Excellence

The Paget's Association has awarded Centre of Excellence status to several hospital and university departments which demonstrate excellence in both the treatment of Paget’s disease and research into the condition. Details can be found by following this link.

Do you need more information?

For more information see our Fact's Booklet and Magazines, which are all available in the Members' Area of this website. Details regarding membership and its benefits can be found by following this link.

Treatment for Paget's Disease

Paget’s disease does not always cause any symptoms and not everyone needs treatment. The main reason for treatment is if the affected bones are painful. If the pain is directly from Paget’s disease, it often improves with treatment. Pain, however, can arise from complications.

Bisphosphonates

Bisphosphonates are drugs which work by inhibiting the bone remodelling process. These drugs reduce abnormal bone destruction by the osteoclasts, thereby restoring a more normal remodelling process.

For those who require treatment, the current first-line bisphosphonate, due to its potency and prolonged duration of action, is zoledronic acid. It is the bisphosphonate most likely to relieve pain from active Paget’s disease.

The main treatment goal is to control bone pain. The clinical benefit of giving bisphosphonates to patients who have a raised level of alkaline phosphatase in their blood, but do not have symptoms, is unknown.

Scroll down to see the individual tabs below for more information about treatment.

Paget's Guideline

A clinical Guideline, for the diagnosis and management of Paget’s Disease of Bone in adults, was commissioned by the Paget's Association. The full Guideline was published in the Journal of Bone and Mineral Research. It has been endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone Research Society (UK), and the British Geriatric Society.

You can read the clinical Guideline by following this link.

Facts Booklet. The Paget's Association updated its booklet,  'Paget's - The Facts', in line with the Guideline. This is available to download from the members' area of this website and also by contacting the Paget's Association.

Details regarding membership and its benefits can be found by following this link.

Zoledronate Infusion

For those who require treatment, the current first-line bisphosphonate, due to its potency and prolonged duration of action, is zoledronate (zoledronic acid). It is the bisphosphonate most likely to relieve pain from active Paget’s disease. It is usually given in a hospital, as an outpatient.

A single dose of 5mg is given through an infusion (a drip) directly into the bloodstream (intravenous), over 15 to 30 minutes.

Over the following months, this treatment often normalises the abnormal bone remodelling and one dose can be effective for many years.

Further Information

Booklets containing more detailed information are available to download in the Members' Area of this website. Alternatively, they can be posted to you. Please telephone 0161 799 4646 or use the contact form.

Details regarding membership and its benefits can be found by following this link.

Intravenous treatment with zoledronate (zoledronic acid) is usually the first consideration, as it acts quicker and lasts longer, however, alternatives can be found below.

Alternatives to Zoledronate for Paget's Disease

Risedronate (oral)

Bisphosphonates can also be given as tablets; these are slightly less effective than an infusion of zoledronic acid, at reducing bone remodelling, and the effect doesn’t last quite as long.

The most commonly used oral treatment is 30mg of risedronate sodium, taken daily, for two months. If necessary, the course can be repeated.
For risedronate to be effective, it is important that you do not take it with food, other medicines or drinks (other than plain water). If taken at the same time, medicines containing any of the following lessen the effect of risedronate: calcium, magnesium, aluminium (e.g. some indigestion mixtures) or iron. To ensure risedronate is absorbed properly, it should be taken with a full glass of water, on an empty stomach, first thing in the morning. These tablets can irritate your oesophagus (the tube that takes food into your stomach) therefore, sit upright or stand for at least 30 minutes after taking it. Wait at least 30 minutes before eating or drinking (other than water), and before taking other medication.

Pamidronate (infusion)

Pamidronate is an effective treatment but has largely been superseded by zoledronate, which lasts longer and is easier to administer. Pamidronate is given in several doses, intravenously (an infusion into the bloodstream), and repeated when necessary, dependant on symptoms. Doses can vary, but commonly 60mg is given by an infusion over a period of four hours and this is repeated on three consecutive days.

Calcitonin (injection)

In cases where bisphosphonates are not recommended, calcitonin injections may be considered to treat bone pain in Paget’s disease.

Booklets containing more detailed information are available to download in the Members' Area of this website. Alternatively, they can be posted to you. Please telephone 0161 799 4646 or use the contact form.

WHAT ABOUT SIDE EFFECTS OF BISPHOSPHONATES?

You should discuss your individual circumstances with your doctor, but if bisphosphonate treatment is required, the benefits often outweigh the risk of any potential side effects.

A comprehensive review on the effects of bisphosphonates in the treatment of Paget’s disease, published in 2017, concluded that serious side effects were rare and that the most common side effects experienced were a flu-like illness in people given bisphosphonates by infusion, and stomach upset in those given tablets. Severe side effects causing treatment discontinuation were rare.

The most common side effect with zoledronic acid is a flu-like reaction that lasts a day or two in most people who experience it. It is usually of mild or moderate severity, but more severe reactions can sometimes occur. Pamidronate can also cause a flu-like reaction but there is less information on the frequency with which this occurs or its severity. If a flu-like reaction does occur with either drug, it can usually be controlled with paracetamol or ibuprofen.

Both zoledronate and pamidronate (see below) may cause a decrease in calcium levels. The risk of this is reduced in people who have a good dietary calcium intake and those with normal levels of vitamin D. Sometimes vitamin D levels (25-hydroxy vitamin D) might be measured before treatment to determine if supplements are required. Depending on the results, calcium and vitamin D supplements may be given prior to treatment as a preventative measure.

The most common side effect of taking oral bisphosphonates (risedronate) is stomach upset. 

On rare occasions, bisphosphonates are associated with osteonecrosis of the jaw (ONJ). This is a condition which may present after dental surgery when exposed bone fails to heal. ONJ is rarely seen in those with Paget’s disease and the risk of ONJ is greater if bisphosphonates are given for cancer. As a precaution, however, if possible, complete any extensive dental treatment prior to bisphosphonate treatment. If you have to undergo extensive dental procedures, it is important to inform your dentist that you are having, or have had treatment with a bisphosphonate.

When should bisphosphonates be avoided?

The decision to give treatment may be modified if you have another medical problem which could be aggravated by bisphosphonates. As bisphosphonates are excreted by the kidneys they cannot be used if there is significant kidney disease. If you are being considered for bisphosphonate treatment the doctor will usually organise a blood test to check kidney function, to see if it is safe to go ahead. Although bisphosphonates are rarely given to younger people, they should be avoided during pregnancy as their effects on the foetus are unknown.

Booklets containing more detailed information are available to download in the Members' Area of this website. Alternatively, they can be posted to you. Please telephone 0161 799 4646 or use the contact form.

You may be interested in our Paget's Jargon Buster, which can be found by following this link.

Recommendations for Clinicians

A clinical Guideline, for the Diagnosis and Management of Paget’s Disease of Bone in Adults, was commissioned by the Paget's Association and published in 2019, in the Journal of Bone and Mineral Research. It has been endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone Research Society (UK), and the British Geriatric Society. 

These are the recommendations* highlighted by the Guideline Development Group as the most important:

• Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of the metabolically active disease in patients with Paget’s Disease of Bone.
• Serum total alkaline phosphatase (ALP) is recommended as a first-line biochemical screening test, in combination with liver function tests, in screening for the presence of metabolically active Paget’s Disease of Bone.
• Bisphosphonates are recommended for the treatment of bone pain associated with Paget’s disease. Zoledronic acid is recommended as the bisphosphonate most likely to give a favourable pain response.
• Treatment aimed at improving symptoms is recommended over a treat‑to target strategy aimed at normalising total ALP in Paget’s Disease of Bone.
• Total hip or knee replacements are recommended for patients with Paget’s Disease of Bone who develop osteoarthritis, for whom medical treatment is inadequate. There is insufficient information to recommend one type of surgical
• approach over another.

You can download a summary of the Guideline here.

*Reproduced from the following paper: Ralston, S. H., Corral-Gudino, L., Cooper, C., Francis, R. M., Fraser, W. D., Gennari, L., Guañabens, N., Javaid, M. K., Layfield, R., O’Neill, T. W., Russell, R. G., Stone, M. D., Simpson,
K., Wilkinson, D., Wills, R., Zillikens, M. C. and Tuck, S. P. (2019), Diagnosis and Management of Paget’s Disease of Bone in Adults: Journal of Bone Mineral Research. Vol. 34, p 579-604.