Paget's disease of bone

ABSTRACT

Approximately 1 to 3 million Americans suffer from Paget's disease of the bone. This chronic disease often results in pain, deformity, and mobility impairments, and can dramatically impair a patient's quality of life. The primary care provider plays a pivotal role in diagnosing and managing the patient with Paget's disease. This article discusses Paget's disease diagnosis, management, pharmacologic therapy, referral, and follow-up.

Paget's disease of the bone (PD), or osteitis deformans, affects 1.2 % to 4% of Americans over age 50;1 approximately 1 to 3 million Americans are afflicted with this chronic disease.2 The pain, deformity, and mobility impairments often associated with PD can dramatically impair a patient's quality of life. The primary care provider plays a pivotal role in the timely diagnosis and management of the patient with PD.

Epidemiology

Following osteoporosis, Paget's disease is the second most prevalent bone remodeling disease.3 Paget's disease occurs in 1.2% to 4% of people over age 50, with the frequency increasing up to 15 % by age 90.1 Disease onset is rare prior to age 40, and it affects men slightly more often than women.1 The disorder is mostly seen in whites in the United States, Germany, France, and the United Kingdom and is relatively rare in the Scandinavian countries, China, Japan, and Africa.4

Pathogenesis

Paget's disease is a chronic, localized disorder of bone remodeling.5 Pagetic bone formation is characterized by focal areas of abnormally rapid osteoclast-mediated resorption.6 These osteoclasts are larger and more plentiful and contain more nuclei than those found in normal bone.1

Subsequent bone formation by osteoblasts is too rapid, leading to new bone composition that is structurally inferior to normal bone.3 Pagetic bone is less compact, more vascular, and especially prone to deformity and fractures.7 The disease can affect any bone in the body and can be either monostotic (affecting one area) or polyostotic.8 Approximately 68% of cases occur in the pelvis.9 Other areas of occurrence include the femur (SS%), spine (49%), and skull (44%).9 The disease usually evolves slowly and rarely moves from one site to another.

Etiology

The etiology of PD is uncertain. Viral particles (particularly respiratory syncytial viruses, measles, canine distemper, or paramyxoviruses) have been found in the osteoclasts of pagetic bone.1 Such viral inclusions may trigger the abnormal remodeling process.7 Genetic and hereditary factors have also been indicated in PD,10 and this has been especially evident in patients diagnosed at young ages or in patients with an especially deforming disease progression.7

Clinical Manifestations and Complications

An array of clinical manifestations can occur in PD depending on the involvement site and the number of bones affected.4 However, most PD cases are asymptomatic and are diagnosed from abnormal X-ray findings and serum alkaline phosphatase levels obtained for unrelated problems.11 Pain is the most frequently reported presenting symptom.12 In one study, 34 of 56 PD patients listed pain as the main reason they sought medical attention.13

Pain may result from the pagetic bone itself or from the altered mechanics of neighboring bones and joints.13 Pain is frequently described as aching and deep, occurring most frequently at night;9 however, it may also be sharp, especially when long weight-bearing bones are affected.7 Bone pain is frequently accompanied by muscle spasms.9

The pain from PD can result from subsequent osteoarthritis of adjacent joints.13 It can even result from radiculopathy associated with nerve compression or spinal stenosis.1 Sudden or increasing pain despite treatment should alert the clinician to a possible fracture or to the relatively rare complication of osteosarcoma at the pagetic bone site.7

Bone deformity is another clinical manifestation of PD.7 Such deformity is readily evident in the patient who develops a bowed tibia or femur.4 The deformed mechanics of dependent long bones and the ofteninvolved pain can lead to significant gait impairment.13 In a study involving patients with Paget's disease of the tibia and femur, impairments in both cadence and gait velocity were identified.14 A subsequent study demonstrated that patients with long-standing PD of the tibia, femur, and acetabular portion of the ilium also showed significant mobility impairments.5 Such mobility impairments may be initial presenting symptoms.13

Paget's disease in other areas of the skeleton may lead to bone deformity and complications. For example, PD of the skull can be particularly disfiguring.15 Bony enlargement of the cranium may result in headaches, tinnitus, and vertigo.16 Dental, auditory, and visual complications may result from craniofacial involvement.8 In rare circumstances, PD of the skull may result in basilar invagination and impairment of cerebrospinal fluid flow, resulting in hydrocephalus.1

Metabolic complications of PD are rarely observed;1 serum calcium and phosphorus levels are usually normal;9 however, hypercalcemia may be seen in immobilized patients with severe PD.1 Accelerated bone activity may result in hyperuricemia, thereby predisposing the patient to gout and kidney stones.6 Mild hyperparathyroidism has been seen, but its association is unclear.1

Other manifestations of PD are related to the vascular nature of pagetic bone itself. On physical examination, skin overlying pagetic bone is warm to the touch.15 When large amounts of the skeleton are affected, it is possible for the vascularity of pagetic bone to result in a compensatory high-output heart failure, especially in a patient with underlying heart disease.15

Circulatory "steal" conditions in which blood is shunted to diseased bone may leave neighboring parts of the body deprived.13 This has been postulated in the cognitive decline occasionally seen in patients who have extensive PD of the skull.13 Similar reports of neurologic sequelae progressing to severe radiculopathy and paraparesis have also been cited in instances where the spine is affected.1

The most feared complication of PD is the development of malignant degeneration.4 Sarcoma is rare, occurring in less than 1% of PD cases,10 and about 5% to 10% of severe polyostotic cases.4 When the various sarcomas do occur, they develop mostly in the pelvis, long bones, spine, and skull.4 Currently, data do not exist to suggest that treatment of Paget's disease reduces the frequency of malignant transformation. Treatment for these sarcomas is usually difficult, and the prognosis is grim.1 Benign lesions such as hematopoietic masses, giant cell tumors, and granulomas may also occur.4

Diagnosis

X-rays and laboratory studies are instrumental in establishing the diagnosis of PD when combined with clinical signs and symptoms.1,9 The radiologic findings of cortical thickening, osteolytic lesions, and irregular areas of calcification frequently serve as justification for the diagnosis.4 X-rays may also identify the condition of neighboring joints and aid in the diagnosis of any concomitant fissure fractures.7 This information may be useful in evaluating symptoms and in offering prognostic information.7

Bone scans are particularly useful in the diagnosis of PD and are more sensitive than simple X-rays in the detection of pagetic lesions.1 Areas of intense bone activity have an affinity for the radioisotope tracer.9 Increased blood flow, as seen in PD, influences the amount of tracer that accumulates in the bone.1 Consequently intense radioisotope uptake by pagetic bone is characteristic of PD (see Figure 1).9 Repeated bone scans are generally not indicated in the routine monitoring of disease activity.9 Instead, biochemical tests provide an easier and more cost-effective screening tool.1

Other radiologic tests used in PD are helpful in determining the extent of complications associated with the disease.1 Magnetic resonance imaging (MRI) and computed tomography are useful in identifying the degree of problems associated with arthritis and spinal stenosis.1 Computed tomography and MRI studies are also obtained if a malignant tumor is suspected.9 However, a needle biopsy or open biopsy is the standard for identifying malignant degeneration.9

The serum alkaline phosphatase level is the biochemical test used most often for PD detection.6 The level, which correlates with the extent of pagetic involvement and bone formation by osteoblasts, is used with the characteristic X-ray findings to diagnose PD.1,6 Serum alkaline phosphatase levels also correlate well with bone scan findings and disease progression.7 Specific serum bone alkaline phosphatase measurements have recently been developed and are especially useful in the monitoring of monostotic disease.12

Urinary excretion of hydroxyproline and pyridinoline are correlated with osteoclast activity.10 These markers of bone resorption must be collected from urine over 2 to 24 hours. These tests are used infrequently because of the expense and inconvenience.1

Management

Many patients with PD do not require treatment with antipagetic drugs.6 Mild joint and bone pain may be managed with aspirin or other nonsteroidal antiinflammatory drugs. Adequate analgesia should be stressed because pain is the most frequently reported disease symptom.12 Opioid analgesics should be avoided when possible, particularly in the older adult population, who often tolerate opioids poorly.1

Prosthetic devices such as canes and shoe lifts may assist ambulation,7 and physical therapy may assist mobility impairments.1 The home environment should be arranged to prevent falls that could result in pathologic fractures.1 Dental, auditory, and mental status evaluations may be indicated in patients with PD of the skull.8

Sources vary on indications for specific antipagetic drugs, but most agree on significant bone pain, bone deformity, neurologic complications, involvement of long weight-bearing bones, involvement of the spine or base of the skull, and preparation for orthopedic surgery.12

Patient Education

The potential causes, manifestations, and treatment of PD must be thoroughly discussed with patients and family members (see Patient Education). Medication administration should be discussed, including the purpose, dose, route, and adverse effects. Instructions on subcutaneous (S.C.) injection should be provided to patients or family members who will need to administer calcitonin injections.6

Patients should understand that there is no cure for the disease and that treatment goals focus on pain relief, restoration of function, and prevention of complications. Patients will require emotional support to assist with the psychological and social impact of having this chronic disease.

Pharmacologic Therapy

Several pharmacologic therapies are approved by the Food and Drug Administration (FDA) for the treatment of PD: human and salmon calcitonin administered in S.C. form and the five bisphosphonates: etidronate, pamidronate, alendronate, tiludronate, and risedronate (see Table 1).3,17-19 These drugs work by inhibiting osteoclast-mediated bone resorption.3,17-19 Bone resorption inhibition leads to a secondary decrease in bone formation by osteoblasts.20 Thus, these drugs, which reduce pain and slow the progression of the disease20 work to inhibit the pathogenesis of PD.

Evidence suggests that these drugs may prevent or reverse the progressive deformities of PD.20 Such findings have led many clinicians to adopt an aggressive, long-term approach to management, treating asymptomatic disease in any bone that could progress to complications at a later date.7 Currently, most clinicians treating PD believe that the bisphosphonates are the first choice of therapy.

Etidronate was the first bisphosphonate available in the treatment of PD.9 Similar to all bisphosphonates, this medication binds to crystals in the bone and remains for prolonged periods.12 The long half-life enables it to work even after therapy is discontinued.1 The recommended daily dose is 5 mg/kg/day orally for 6 months.11 Etidronate should be taken on an empty stomach because of its variable absorption from the gastrointestinal tract.21 Adverse effects are infrequent.

Etidronate may provide remission for years after the 6 months of therapy but should be used for no longer because of its propensity to cause mineralization defects with overuse.7 Repeated 6-month therapy courses can be instituted after 6 months off the medication.7 Resistance is common after several courses of treatment.1

Pamidronate, a second-generation bisphosphonate, does not impair bone mineralization.10 A typical dosing regimen is 30 mg/day diluted in 250 to 500 ml 5% dextrose or 0.9% sodium chloride solution given intravenously (I.V) and slowly (over 3 to 4 hours) for 3 days.1 This can be repeated if needed.1 Disadvantages of pamidronate use include its I.V administration and its tendency to cause flulike symptoms in approximately 20% of patients.7,22 Some patients will also become hypocalcemic during treatment; therefore, calcium supplementation (1,000 mg/day) is recommended.7

Similar to pamidronate, alendronate is a secondgeneration bisphosphonate used for PD treatment that does not impair bone mineralization. The drug is administered daily in a 40-mg tablet for 6 months.12 Adverse effects are typically mild. Patients should avoid lying down for at least 30 minutes after taking the medication to avoid esophagitis. They should also be instructed to always drink 8 ounces of water with the medication.21

Alendronate has received much attention because of its trial results in the treatment of osteoporosis. Several clinical trials have supported the effectiveness of this drug in the treatment of PD. One such trial consisted of a randomized, double-blind comparison between 40 mg/day of oral alendronate versus placebo over 6 months in 55 patients with PD.23 A 73% reduction in serum alkaline phosphatase measurement was found in the alendronate-treated group, whereas placebo group levels remained unchanged.23Additionally, 48% of the alendronate group revealed significant radiologic improvement in affected bones with no evidence of abnormal mineralization.23

Tiludronate is yet another bisphosphonate approved for the treatment of PD.24 It has been successful in normalizing bone turnover without impairing mineralization.24 The recommended daily dose is 400 mg over a 3-month period.17 The manufacturer advises taking the medication with a full 8-ounce glass of water either 1 hour before or 2 hours after eating.

Risedronate is the newest drug available for the treatment of PD.18,19 This drug has been found to be effective in reducing serum alkaline phosphatase readings, and it does not impair bone mineralization at recommended dosages.19,25 Early trials revealed a 50% reduction in biochemical markers in over 90% of patients treated with the drug.18 Risedronate is a potent bisphosphonate and may prove to be helpful in patients with severe PD who have not responded well to other drugs.15 The recommended daily dose is 30 mg once daily for 60 days.18,19 Like alendronate, risedronate must be taken with 8 ounces of water and the patient should refrain from lying down for at least 30 minutes after taking the medication.18

Calcitonin has been found to relieve bone pain in approximately 80% of patients treated.9 Long-term use has also been found to reverse certain neurologic deficits, stabilize hearing loss, reduce increased cardiac output, and heal osteolytic lesions.1 Older patients should be closely monitored for anorexia and weight loss.9

The initial starting dose for PD is 0.25 mg of human calcitonin or 25 to 50 international units of salmon calcitonin given S.C. every night, the dose increasing every 1 to 2 weeks until the usual maintenance dose of 100 international units of salmon calcitonin or 0.50 mg of human calcitonin is reached.lI Once evidence of a response exists (fracture healing or reduction in serum alkaline phosphatase), the dose is gradually reduced to 50 to 100 international units three times a week.7

Calcitonin use results in a 50% to 70% reduction in both urinary hydroxyproline and serum alkaline phosphatase levels.9 However, not all patients develop normal biologic indexes with this drug.9 Some patients may develop a resistance to the drug, and increasing the dose does not result in an increased therapeutic response.7 When resistance occurs, the calcitonin should be stopped and a bisphosphonate should be added.

Plicamycin, formerly mithramycin, was previously used in the treatment of PD, but its adverse effect profile and the availability of newer and more potent bisphosphonates now limit its use.7 Gallium, the antiresorptive drug currently approved for use in the hypercalcemia of malignancy, may prove helpful in the treatment of PD; however, limited clinical results are available.12 Several other bisphosphonates that may prove useful in the treatment of PD are currently under development.12

Referral

Clinicians who are knowledgeable about PD and its treatment can provide the necessary care to the PD patient. Specialists may be consulted to assist with particular problems. Neurosurgical referral may be indicated in cases of spinal cord or nerve compression syndromes.6 Similarly, orthopedic referral is indicated when a fracture occurs or when a patient is limited by pagetic degenerative arthritis of the knee or hip.1 A rheumatology or endocrinology referral may be warranted to assist with antipagetic drug initiation or disease mangement problems refractory to standard treatment.6

Surgery

Surgery is not a primary treatment of PD; however, sereral sequelae of PD may require surgical intervention. Medical management of fractures in pagetic bone is associated with a risk of delayed union.9 Therefore, open reduction with internal fixation is advised.9 Patients with PD and severe osteoarthritis of the knee or hip may benefit from total joint replacement.I Osteotomy is rarely required to correct the bowing deformity in a long bone.1 Spinal decompression surgery may be necessary in cases of spinal involvement.1 Pagetic bone is vascular and bleeds easily;12 consequently, treatment with calcitonin or a bisphosphonate is indicated before surgical therapy is instituted.1

Follow-up

Follow-up frequency depends on disease severity and treatment response.12 For example, the asymptomatic patient should return at least yearly for a complete skeletal and neurologic examination and a serum alkaline phosphatase measurement.1 If the patient has PD of the skull, yearly eye and audiometry examinations should also be performed.9

The symptomatic patient should be monitored every 2 to 6 months, depending on the treatment response.11 Alkaline phosphatase readings are also useful at these visits. Repeat X-rays and bone scanning are generally not indicated;6 however, some researchers recommend repeat X-rays of the skull and weight-bearing bones every 6 to 12 months.12

PD in Practice

Patients with PD suffer from pain, deformity, and mobility impairments. Although many patients do not require treatment with antipagetic drugs,6 several pharmacologic therapies are FDA-approved for the treatment of PD. Pain relief, function restoration, and prevention of complications are the treatment goals for the patient with PD. Patients will also require emotional support to assist with the psychological impact of having this chronic disease.

ACKNOWLEDGMENTS

The authors thank Charlene Waldman, Executive Director of the Paget's Foundation, for information provided in this manuscript. Parts of this work were supported by grants from the Veterans Administration (VA) Medical Research Service, HD 30442, from National Institute on Child Health and Human Development, and AG11268 from National Institute on Aging, 2031AH94004 from the Bureau of Health Professions, and by grant PR-30 from the Division of Research Resources, General Clinical Research Program, National Institutes of Health.

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ABOUT THE AUTHORS

Tammy Lewis, RN, GNP, MSN, is a nurse practitioner at Greensboro Medical Associates in Greensboro, N.C.

Anita S. Tesh, RN,C, MSN, EdD, is an associate professor at the University of North Carolina at Greensboro, Greensboro, N.C. Kenneth W. Lyles, MD, is an associate professor at Duke University Medical Center and the Geriatric Research Education Clinical Center, VA Medical Center, and Director of the Sarah W. Stedman Center for Nutritional Studies in Durham, N.C.

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