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

 

Introduction

Although Paget’s 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 Paget’s 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 Paget’s 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 Paget’s 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 Paget’s disease early in the disease’s progression. The earlier a diagnosis is made, the more effective the treatment, and the less devastating the impact on the individual patient.

What is Paget’s Disease of Bone?

First described by the eminent British surgeon Sir James Paget in 1877, Paget’s 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.

Paget’s 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 Paget’s disease. An animal model of Paget’s 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 Paget’s disease.

Clinical Presentation

Paget’s 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 Paget’s disease patients indicates that the disease does not spread from one bone to another.

The most devastating complication of Paget’s 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 Paget’s disease, but this is a significantly higher rate than in non-affected individuals. In patients with Paget’s disease, osteosarcoma is often fatal.

Pathology of Paget’s Disease

The initial abnormality in Paget’s 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 Paget’s disease is often asyptomatic and the diagnosis may be an incidental finding. Paget’s 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 Paget’s 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 Paget’s 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 Paget’s 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 Paget’s 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 Paget’s disease.

Radionuclide Bone Scan

A radionuclide bone scan is the most sensitive means of detecting Paget’s 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 Paget’s activity. It is not generally used to monitor the effects of treatment.

Medical History

The diagnosis of Paget’s 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 Paget’s 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 Paget’s 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 Paget’s 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 Paget’s Disease

The three major objectives for the management of patients with Paget’s disease are:
    1. Minimize symptoms
    2. Improve the patient’s 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 Paget’s disease is based on antiresorptive therapy. There are four general indications for treatment of Paget’s disease:

1. Symptoms due to metabolically active Paget’s 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 Paget’s disease and a highly elevated serum alkaline phosphatase level undergoes prolonged immobilization.

4. Many Paget’s 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 Paget’s disease located next to major joints.

Though there is no direct evidence that aggressive treatment of Paget’s 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 Paget’s disease is associated with the further extension of the osteolytic lesions in a bone and the progression of bone deformities.

2. Successful treatment of Paget’s 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 Paget’s 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 “Paget’s 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 Paget’s 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 patient’s unfulfilled expectations and/or inadequate explanation of the disease to the patient. The nurse’s 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 Paget’s 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 Paget’s 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 Paget’s disease can be suppressed with one 5 mg infusion of zoledronic acid for up to two years. A mild form of Paget’s 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 Paget’s 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 Paget’s 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 Paget’s 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 Paget’s disease medical specialists are the four more potent bisphosphonates: zoledronic acid, pamidronate, alendronate and risedronate.

Pain Management: Analgesics

Pain directly attributable to Paget’s 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 Paget’s 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 PATIENT’S 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, Paget’s 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.
Risedronate
Trade Name:
Actonel®
(Procter & Gamble/Aventis)
FDA approval: 1998
 • 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.
 • 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

 • 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.

Alendronate
(Fosamax®)
FDA approval: 1995

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

Administration and Dosage

Trade Name:
Miacalcin®
(Novartis)
Approved by FDA 1990

 • Injection
 • 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 Paget’s 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 Paget’s 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 Paget’s disease could account for the very low incidence of ONJ in these patients.

Despite the extremely small chance that a patient with Paget’s 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 Paget’s 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 Paget’s 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.

 

 

 

Paget's Disease - Information for Healthcare Providers

info_button_64These resources are for healthcare professionals involved in treating Paget's disease of bone.

 

A Physician's Guide to The Management of Paget's Disease of Bone
A Nurse's Guide to the Management of Paget's Disease
Educational Slide Program - Diagnosis and Management of Paget’s Disease of Bone