A Physician's Guide to The Management of Paget's Disease of Bone

What is Paget's Disease ?

First diagnosed by Sir James Paget in 1877, Paget's disease of bone, or osteitis deformans, is a disease of the osteoclast. It is a focal disorder characterized by excessive osteoclastic bone resorption followed by excessive bone formation, resulting in bone that is architecturally unsound. This can lead to bone pain, bone deformity and skeletal fragility.

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 of 20 nuclei per cell compared with three to four nuclei in normal adult osteoclasts. The osteoblasts, though numerous, are not abnormal. As bone resorption is coupled to 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.

Etiology

Past studies of the etiology of Paget's disease have implicated paramyxoviruses and genetic factors in the pathogenesis of the disorder. Structures in the nuclei of osteoclasts of all patients with Paget's disease strongly resemble the nucleocapsids of viruses of the Paramyxoviridae family which includes measles virus and respiratory syncytial virus. Immunochemical staining and molecular studies have supported this impression although not all studies have been positive. Recently an animal model of Paget's disease has been developed by placing the measles virus nucleocapsid protein into osteoclast precursor cells of transgenic mice. The bone lesions which developed were very similar to the pathology of Paget's disease.

About 20% of patients fall into the category of familial Paget's disease in which there appears to be autosomal dominant transmission with incomplete penetrance. Approximately 20-30% of families have a mutation in the sequestosome 1 gene. The protein produced by this gene is important in the interleukin-6, tumor necrosis factor and rank ligand signaling pathways which help regulate osteoclast function. When a mutated sequestosome 1 gene is placed into the osteoclast precursors of transgenic mice a generalized increase in osteoclast-mediated bone resorption is produced, but the pathology of Paget's disease is not found.

A second gene mutation has been found in the valosine containing protein of a very rare type of familial Paget's disease in which muscle dysfunction and dementia are prominent features.

It appears that the gene mutations thus far demonstrated in familial Paget's disease are not sufficient to produce the bone lesions, but probably increase the susceptibility of affected family members to develop the disorder. The interaction of the paramyxovirus and genetic factors is under present study.

Clinical Presentation of Paget's Disease

While Paget's disease may affect any bone, the most commonly involved bones are the pelvis, vertebrae, skull, femur and tibia. Prevalent signs and symptoms of Paget's disease are skeletal deformity and bone pain. Pain usually results from the rheumatologic and neurologic complications of the disease rather than from the abnormal bone. When bone pain does occur among patients, its onset is frequently late in the disease process and is usually unrelated to physical activity. Pain from a pagetic lesion in the femur or tibia, however, may increase with weight bearing. A sudden onset of pain usually indicates that a fracture has occurred.

Skeletal deformities that occur as a result of Paget's disease are most often noted in the lower extremities and the skull. Long bones tend to exhibit bowing, while the skull can become enlarged and alter its shape.

Skull involvement is often associated with headaches or hearing loss when the disease affects the temporal bone.

When present in the spine, the increased bone volume may cause compression of the spinal cord or nerve roots and may result in severe pain and impaired neurological function. Frequently, the skin over the pagetic lesions is warm due to the increased blood flow to the bone and overlying soft tissue.

A number of complications may result from Paget's disease. Of these, the most devastating is a malignant transformation of the involved bone that becomes cancerous. Osteosarcoma or other types of sarcoma occurs in less than 1 percent of patients with Paget's disease, but at a significantly higher rate than in non-affected individuals. Osteosarcoma is often fatal in patients with Paget's disease, possibly because of delayed diagnosis.

Diagnostic Evaluation and Recommendations

Paget's disease can be diagnosed in patients through radiology, radionuclide bone scanning, biochemical testing of bone resorption and formation parameters. When tested through roentgenographic or radiographic means, Paget's disease displays three distinctive stages. In the earliest stage of the disease, an osteolytic lesion may be observed in the affected long bone. In the second stage of the disease, x-rays reveal both osteolytic and sclerotic changes in the same bone. In the last stage of the disease, the sclerotic lesion dominates the bone and there may be an increase in the dimensions of the bone itself.

A radionuclide bone scan using a radiolabeled bisphosphonate is an efficient means of detecting the extent of Paget's disease in the skeleton; however, it is not a disease specific test. The radionuclide bisphosphonate is injected intravenously and is concentrated in areas of increased blood flow and high levels of bone formation, both common characteristics of Paget's disease.

Biochemical tests reflecting osteoclast activity and resultant bone collagen resorption include measurements of urinary hydroxyproline/creatinine as well as measurements of urinary and serum deoxypyridinoline, N-telopeptide and C-telopeptide. The latter two tests are more specific. As a marker of osteoblast activity, the measurement of serum total alkaline phosphatase activity provides a general indication of bone turnover and disease activity in Paget's disease. Serum bone specific alkaline phosphatase activity is often helpful in distinguishing patients who have liver disease from those with Paget's disease of bone.

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. For most patients, a decrease in the total serum alkaline phosphatase activity is sufficient to indicate and determine changes in overall disease activity. Since the total serum alkaline phosphatase level is a reflection of both the total bone surface affected by Paget's disease as well as the total activity of the disease at those sites, serum alkaline phosphatase can be normal in patients with a small focus of symptomatic Paget's disease. Serial radiographs should be performed on those patients with lytic lesions in weight-bearing long bones in order to document healing. A bone scan is valuable in defining the full extent of the disease and identifying asymptomatic lesions located in "at risk" areas.

Indications for Treatment

Treatment for Paget's disease is based upon antiresorptive therapy. There are four general indications for treatment of Paget's disease:

1. Symptoms due to metabolically active Paget's disease warrant treatment. This includes 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. Postoperative treatmentmay be helpful in preventing acceleration of disease activity which has been reported after surgery or fractures.

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 investigators 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 hyperactivity place them at risk of progression and complications. This group includes individuals who may be at risk for bowing deformities in their long bones, for hearing loss, optic nerve impingement, skull enlargement; neurological complications due to pagetic changes in their vertebrae; or for secondary arthritis as a complication of Paget's disease adjacent to major joints.

There is no direct evidence that aggressive treatment of Paget's disease is associated with prevention of progression or reduction in risk for future complications. Investigators have looked to indirect evidence, however, to suggest this possibility. This evidence includes:

• Failure to treat Paget's disease associated with the further destruction of the bone and the progression of bone deformities;
• Successful treatment of Paget's disease associated with restoration of normal patterns of new bone deposition; and
• One study has shown that facial and skull deformities improved after successful treatment.

Some investigators conclude, therefore, that it is good clinical practice to treat both symptomatic patients whose symptoms may respond to a reduction in abnormal bone turnover as well as asymptomatic patients with active Paget's disease that is likely to cause future problems.

Therapy Options

Four main methods of treatment exist for a patient with Paget's disease: non-pharmacological therapy (focusing mainly on physical therapy as a means of improving muscle strength and mobility to help control some types of pain); pharmacological therapy using either bisphosphonates or calcitonins; pain management using analgesics; or surgery.

Pharmacological Treatment

Bisphosphonates

Bisphosphonates are the most widely used drugs for the management of Paget's disease. The potent oral bisphosphonates, alendronate and risedronate, both reduce the biochemical indices for bone turnover into the normal range in many patients with a moderate to severe form of Paget's disease.

Alendronate is taken as a daily 40 mg tablet for six months; risedronate is taken as a daily 30 mg tablet for two months. Etidronate and tiludronate are less potent than alendronate and risedronate. The dose of both drugs is a 400 mg tablet; etidronate is taken daily for six months and tiludronate for three months. All oral bisphosphonates are poorly absorbed and need to be taken with water only 30-120 minutes before breakfast.

The intravenous bisphosphonates, pamidronate and zoledronic acid, have the advantage of infrequent administration. A 60-90 mg infusion of pamidronate given over 2-4 hours can produce a remission of a year in patients with mild to moderate Paget's disease. More severe disease may require multiple infusions. A single 5 mg infusion of zoledronic acid produces a normal alkaline phosphatase in nearly 90% of all patients, including those with very elevated indices of bone turnover. The remission lasts at least two years in the great majority of the patients.

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 extraction or after other surgical procedures in the oral cavity. ONJ is characterized by dissolution of the gum, 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 must be removed.

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 had been treated with intravenous bisphosphonates on a monthly basis for more than one year to protect against the complications produced by cancers which invade the skeleton. It is hypothesized that the extensive use of intravenous bisphosphonate drugs such as 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 received cancer chemotherapy and steroid hormones and were immunocompromised, 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 and gum 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 be considered. If surgery is needed, there is no clinical evidence that stopping the bisphosphonate is protective.

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 25OHD. This is a liver metabolite of vitamin D which is subsequently converted to 1, 25(OH)2D in the kidney, intestine and select peripheral tissues. 1, 25(OH)2D is the most active 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 suppression of PTH secretion. Unfortunately, the majority of elderly Americans have levels below this.

There are two forms of vitamin D, 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.

Calcitonins                                                                                                                

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 percent, decrease symptoms of bone pain, reduce warmth over affected bones, improve some neurological complications and promote healing of lytic lesions. Its use today 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.

Drugs 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.

THE COST OF THESE DRUGS VARIES IN DIFFERENT AREAS AND ACCORDING TO A PATIENT'S INSURANCE COVERGE.

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 bone deformity or arthritic or neurological complications. In this case, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), or cox-2 inhibitors may be helpful for the management of pagetic pain in addition to the main pagetic therapy chosen.

Surgery

Different orthopedic interventions may be necessary in pagetic patients:

• Fixing a complete fracture through pagetic bone;
• Realigning the knee through tibial osteotomy to decrease mechanical pain, particularly if medical therapy is unsuccessful in managing severe pain symptoms; and/or
• Replacing the hip and/or knee through total joint arthroplasty for patients unresponsive to anti-osteoclast treatment and therapy for the osteoarthritis.
• Relieving compression produced by pagetic vertebrae on the spinal cord or nerve roots.

When repairing a pagetic fracture, total immobilization of that site should be avoided if possible. Pre-treatment with a bisphosphonate will reduce the hypervascularity and reduce the risk of greater-than-normal operative blood loss. Post-operative treatment may prevent acceleration of disease activity that has been reported after surgery or fractures.

Neurosurgery is rarely required to decompress the posterior fossa in patients with marked skull enlargement.

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