- Email: [email protected]
Diagnosis & Management of Paget Disease of the Bone
Diagnosis & Management of Paget Disease of the Bone Angella Sherwood
ABSTRACT Paget disease of bone causes excessive osteoblastic and osteoclastic activity resulting in bone that is structurally inferior to normal bone. Paget disease of bone is the second most common bone disorder in the United States, yet it often goes unrecognized. It is often asymptomatic; therefore, treatment is often delayed until the disease is in the late stages. In the late stages of the disease, the most common presentation is bone pain. Paget disease of bone may also cause fractures, bone deformity, neurologic symptoms, and cardiovascular complications. It is diagnosed by radiographs and laboratory panels, and is treated with bisphosphonates. Keywords: Bisphosphonates, bone pain, paget disease of bone
54
The Journal for Nurse Practitioners - JNP
January 2008
AGET DISEASE OF BONE (PDB) is the second most common bone disorder after osteoporosis in the United States,1,2 but it often goes undetected because of the high prevalence of asymptomatic patients. PDB is characterized by excessive osteoclastic bone resorption followed by excessive bone formation from osteoblasts, resulting in bone that is architecturally unsound.This can lead to bone pain, bone deformity, and skeletal fragility.2 Nurse practitioners should be aware of PDB and be able to recognize the signs and symptoms associated with the disease. Early detection can optimize timely treatment and therefore possibly prevent the complications associated with the disease course. PDB is a chronic, progressive bone disease that can affect one bone (monostoic) or several bones (polystotic).3-5 If patients are symptomatic, they may seek treatment of bone pain, fractures, neurologic symptoms, bony deformities, and cardiovascular complications.6,7 PDB is defined by The Paget Foundation as a disease of the osteoclast and is the most exaggerated example of disordered bone remodeling. It is a focal disorder of accelerated skeletal remodeling that can involve a single or multiple bones.2 Bone pain is the hallmark sign of PDB, although it is often overlooked by many health care providers.The purpose of this article is to inform primary care nurse practitioners of the disease itself, explain the signs and symptoms of PDB, and describe treatment methods that are available to reduce associated complications of the disease.
P
Epidemiology The global prevalence of PDB is 2%,6 and it is more common in countries with large Anglo-Saxon populations such as the North America, Great Brittan,Australia, New Zealand, and Western Europe.8 It is rare in Africa and Asia.9 In the United States, the prevalence is estimated to be 3% in white persons older than 50 years9 and in as many as 10% of persons older than 80 years. It occurs equally in men and women.10 PDB has been found to be familial with 15% to 40% of persons having a positive family history of the disease.5 The cause is uncertain,3,4 but evidence suggests that it may have genetic and environmental influences.8 Viral infections such as paramyxovirus nuclocapsids, measles virus, canine distemper virus, and respiratory syncytial virus are also indicated as a cause.11,12 www.npjournal.org
Disease Course PDB is characterized by three distinct radiographic phases: the osteolytic phase, the mixed phase, and the osteosclerotic phase.The increased bone resorption and remodeling that occurs in the disease process leads to characteristics found on radiographs that usually allow establishment of diagnosis through the combination of three straightforward signs: hypertrophy of the affected bones, irregular condensation with a fibrillar or mottled appearance, and loss of the clear-cut delineation between cortical and trabecular bone.6 The initial osteolytic phase is most common in the skull and long bones and is characterized by prominent bone resorption and obvious hypervascularization. On radiograph, this stage is apparent by circumscribed osteolytic skull lesions called osteoporosis circumscripta, which gives the appearance of cotton-wool.These lesions are mostly seen in the frontal and occipital regions, and they may cause headache, hearing loss, or hydrocephalus.6,13 In long bones, the osteolytic stage is characterized by an advancing lytic wedge, also called a “blade of grass” lesion. The mixed phase is depicted by aggressive bone formation and resorption that replaces normal lamellar bone with a mosaic woven bone pattern.This mosaic woven pattern of bone is structurally inferior and may cause bowing or fracture of long bones, spinal stenosis with secondary nerve root compression, and bone pain. In this same phase, fibrous connective tissue may replace normal bone marrow.The osteosclerotic phase is characterized by bone resorption slowing, leading to hard, dense, and less vascular bone. Radiographs show dense, cortical and trabecular bone deposition, causing boney hypertrophy.All stages may be present at one time at different bony sites.14 Clinical Presentation PDB is typically asymptomatic; however, bone pain is the hallmark symptom. PDB can affect any bone, but the most common sites are the pelvis and sacrum (⬎60%), followed by the spine (50%), skull and femurs (40%), tibias, humeri, and clavicles (20%).6 The symptomatic patient may have pain in one or more bones or joints that increases on weight bearing.The pain may intensify as the day goes on and is unrelated to activity.A sudden onset of pain may indicate that a fracture has occurred (Table 1). The practitioner may find increased skin temperature over a pagetic lesion because of the increased vascularity of affected bone if the disease is active.5 Softening of long The Journal for Nurse Practitioners - JNP
55
Table 1. Clinical Presentation15 Symptom
Cause Usually results from osteoarthritis in joints adjacent to pagetic bones
Differential Diagnosis
Bone deformities
Can be a result of rapid formation of poor-quality bone
Paget’s disease of bone
Fractures
Bone in pagetic lesions is weaker than normal and can develop characteristic “chalk-stick” fractures
Radiographs may show “blade of grass” lesion, dense sclerosis, and boney overgrowth, or blastic burntout phase.20
Osteosarcoma
May also have pain, fever, mass near joint, and leukocytosis. Radiographs will show permeated lytic destruction of metaphyseal bone, with eventual cortical breakthrough into the subperiosteal space; a typical sunburst pattern of chaotic neoplastic bone may be seen outside the involved bone.20
Osteomalacia
Serum calcium levels may be low or normal; may have hypophosphatemia, aminoaciduria, acidosis, glucosuris, and hypouricemia. Radiographs may show thinning of cortical bone, stress fractures, or pathologic fractures; they may look identical to osteoporosis.20
Bone pain
Hearing loss
Temporal bone involvement
Nerve root compression
Impingement of nerve root by increased bone formation
Headache
Skull affected by PDB
Hydrocephalus
Skull affected by PDB
bones from pagetic lesions, such as the femur, may occur and cause deformities and gait disturbance.7 Skull enlargement, although rare, may also occur, causing headaches and hearing loss if the temporal bone is involved. If spine involvement is present, the patient may have radiculopathies and impaired neurologic function because of compression of the spinal cord or spinal nerves.2 Cardiovascular complications, such as congestive heart failure, may occur because of increased blood flow in pagetic bone.7 Other cardiac complications include arterial and cardiac valvular calcification.7 Patients with PDB have significantly an increased risk of developing osteoarthritis in the knees and hips if the pagetic lesion forms near a weight-bearing joint.16 Osteosarcoma, although rare, may occur in approximately 1% of patients with the disease.17 Diagnosis PDB may be an incidental finding during the work-up of other condtions.18 Most often patients are asymptomatic. It is estimated that only 5% of patients with PDB will be symptomatic.18 PDB in asymptomatic patients may be diagnosed by plain radiographs that are incidentally taken for a suspected fracture or other reasons and by abnormal laboratory findings. The diagnosis of PDB may be suspected by finding an elevated level of serum alkaline phosphatase (ALP) on a complete metabolic or liver panel.The elevation will reflect both the extent and the activity of the disease.3,4 Normal ALP range for adults is 38 to 126 U/L.8 ALP is an enzyme that originates primarily in the bone, liver, and placenta, with some activity in the intestines and kidney.This enzyme is mainly used for the assessment of hepatobiliary and bone diseases. In bone disease, the ALP level rises in proportion to 56
Table 2. Differential Diagnoses for Elevated ALP Levels with Bone Pain
The Journal for Nurse Practitioners - JNP
Findings
new bone cell production that results from osteoblastic activity and the deposit of calcium in the bones.19 However, ALP levels may be in the normal range when the extent of the disease is small or after successful medical treatment.8 An elevated serum ALP level may be present in bone disease such as PDB, metastatic bone disease, osteogenic sarcoma, and osteomalacia (Table 2).19 To distinguish bone disease from hepatobiliary disease, a ␥-glutamyl transpeptidase (GGT) enzyme may be drawn, which will be elevated in hepatobiliary disease but not in bone disease. Bone-specific ALP, although it is less readily available and does not exhibit more benefit than total ALP, may also be drawn to differentiate the source of elevated ALP levels and may be used to assess treatment of PDB.18 Although additional biochemical tests that reflect osteoclast activity and resultant bone collagen resorption are available, they are not typically used.These tests include measurements of urinary hydroxyproline/creatinine and measurements of urinary and serum deoxypyridinoline, N-telopeptide, and C-telopeptide.21 The diagnosis of PDB is primarily made through plain radiograph. Bone scintigraphy may be used to show the extent of disease and is the most efficient means of detecting Paget disease in the skeleton, but it is not recommended as a diagnostic tool.18 Bone scintigraphy is a January 2008
Table 3. Recommended Indications for Antiresorptive Treatment8 • Symptoms resulting from active bone lesions such as bone pain, headache with skull involvement, back pain because of pagetic radiculopathy or arthropathy, other neurologic syndromes, and fissure fractures • Prophylaxis, even in asymptomatic patients, when affected site and their metabolic hyperactivity suggest risk because of progression and complications, such as fracture in weight-bearing long bones or nerve • Elective surgery for a pagetic site (eg, total joint arthroplasty) • Hypercalcemia resulting from immobilization
radionuclide bone scan that uses a radio-labeled bisphosphonate.The bisphosphonate is injected intravenously and is concentrated in areas of increased blood flow and high levels of bone formation, both common characteristics of Paget disease.This test is used primarily to establish the full extent of skeletal involvement for a patient.21 Treatment Treatment is directed toward controlling symptoms and preventing long-term complications in asymptomatic patients. Indications for pharmacologic therapy are as follows: to control symptoms such as bone pain, fracture, headache, pain from pagetic radiculopathy or arthropathy, or neurologic complications; to decrease local blood flow and minimize complications related to blood loss for patients undergoing surgery on an active pagetic site; to prevent acceleration of disease activity that has been reported after surgery or fractures; to reduce hypercalcemia associated with immobilization; to decrease progression and reduce the risk of future complications in asymptomatic patients such as bowing of long bones, hearing loss because of skull enlargement; and for secondary osteoarthritis as a complication of Paget disease located next to major joints (Table 3).2,14 The key indicator of efficacy is improvement in symptoms such as pain and decrease in symptoms of nerve compression.22 In addition, markers of bone turnover such as ALP levels should decrease.22 Improvements in appearance of radiographs or bone scintigraphy should also occur, but bowed extremities will not improve and deafness is unlikely to improve.23 Pharmacologic Management of PDB Bisphosphonates are the current mainstay treatment for PDB and work by suppressing bone resorption by osteowww.npjournal.org
clasts. Calcitonin works in the same way, but it is usually reserved for patients who cannot tolerate bisphosphonate therapy. Currently, five bisphosphonates and calcitonin are approved by the Food and Drug Administration (FDA) to treat PDB in the United States (Table 4). Salmon calcitonin was the first osteoclast inhibitor to be used in the treatment of PDB.5 Calcitonin has the benefits of suppressing bone turnover and reducing bone pain, but it is less effective and can be expensive compared with bisphosphonates.24 Calcitonin can have side effects of flushing, skin rash, nausea, and vomiting, and patients can also develop a resistance to calcitonin after repeated use.The usual starting dose is 100 units subcutaneously at bedtime. Some benefits will be apparent in 2 to 6 weeks, with reductions in serum ALP levels up to 50% and im-provement in lytic lesions by 3 to 6 months.25 The dose should be reduced 50 to 100 units subcutaneously every other day after initial improvements in ALP levels and when lytic lesions are seen.The appropriate treatment duration has not been established. Intermittent therapy may be tried, and in some cases indefinite treatment may be required.26 On occasion, it may be beneficial to use calcitonin in combination with a bisphosphonate to get optimal therapeutic results. Studies have shown that alendronate and risedronate have superior results compared with tiludronate and etidronate in terms of normalizing bone turnover and pain relief. Etidronate may also cause osteomalacia and is rarely used now.22,27 In patients with moderate-to-severe disease, alendronate normalizes ALP levels in more than 67% of patients, with an overall fall in ALP levels of 79% compared with 44% with etidronate.14 Alendronate is administered at 400 mg/day for 6 months. Risedronate was shown to reduce serum ALP levels by 80% and to normalize indexes of bone turnover in 73% of patients with moderately active disease compared with 15% of patients receiving etidronate.14 Risedronate is administered at 30 mg/day for 2 months. A comparative double-blind study compared tiludronate and etidronate and found tiludronate to be more effective.28 Tiludronate is administered at 400 mg for 3 months, and etidronate is administered at 400 mg/day for 6 months. Etidronate was found to have similar effects of efficacy compared with calcitonin. Pamidronate is also more potent than etidronate and is given in a single 60-mg dose intravenously for patients with mild disease and in infusions of 20 to 60 mg over 4 to 24 hours intermittently every 3 to 18 months in The Journal for Nurse Practitioners - JNP
57
Table 4. Pharmacologic Agents Approved by the FDA for the Treatment of Paget Disease2,14 Drug Name Zoledronic Acid
Dose 5 mg intravenously. Infusion over 15 mins.
Administration 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 D3 over 2 weeks. Correct any hypocalcemia and vitamin D deficiencies before treatment. Suppression of disease activity can last up to 2 years.
Tiludronate (Skelid)
400 mg/d for 3 mo
Must be taken on empty stomach with 6-8 oz of water 2 h before or after a meal.
Pamidronate (Aredia)
30 mg intravenously over 3 consecutive days or 60-90 mg intravenously at various intervals determined by disease
Infusion must be given over 2-4 hours. A course may be readministered at intervals at needed. Serum creatinine should be tested before each treatment.
Alendronate (Fosamax)
40 mg/d for 6 mo
Must be taken on empty stomach with 6-8 oz of water in morning. Wait 45 min before eating or drinking anything except water and before lying down.
Risedronate (Actonel)
30 mg/d for 2 mo
Must be taken on empty stomach with 6-8 oz of water in morning. Wait 45 min before eating or drinking anything except water and before lying down.
Calcitonin (Miacalcin)
50-100 units subcutaneously daily or 3 times/wk for 6-18 mo
Given as an injection.
patients with more severe disease.Total doses of 240 to 480 mg may be needed in some patients.22 Side effects include flulike symptoms in the first few days after administration in approximately 20% of patients; these symptoms can be reduced by diluting 60 mg of pamidronate in at least 1000 mL of fluid.29 Hypocalcemia may occur when pamidronate is given in high doses, but it can be improved by giving 1000 mg of calcium daily for 1 to 2 weeks after treatment.30 Zoledronic acid was recently approved for the treatment of PDB. One study has shown an 80% decrease in ALP levels at 6 months with normalization in 89% of subjects with a single infusion of 5 mg.31 Supportive Therapy Problems arising from bowing of the extremities, gait disturbances, or spinal stenosis may be improved by shoe lifts, canes, orthotics, and physical therapy.3,4,32 Pain unresolved by bisphosphonates is likely to respond to nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen.8 Referral for surgery may be required in some cases of unremitting pain or if fractures occur (Table 5).8 58
The Journal for Nurse Practitioners - JNP
Table 5. Indications for Referral33 • Rheumatologist referral is indicated if disease is unresponsive to usual treatment. • Orthopedic referral is indicated for fractures and unremitting pain that could be treated with total joint arthroplasty. • Neurosurgery referral is indicated if spinal stenosis causes unremitting pain or loss of function, or if hydrocephalus occurs.
Tibial osteotomy may be performed to realign the knee and relieve pain.Total joint arthroplasty may be indicated in cases of severe secondary osteoarthritis, and spinal stenosis may be relived by surgical spinal decompression.8 Case Report A 59-year-old white man comes to a primary care office as a new patient with a chief complaint of right knee and thigh pain for the past year.The pain increases on weight bearing and intensifies as the day goes on.The pain is not related to activity and has increased in intensity during the January 2008
Table 6. Resources for Patient Education Organization
Phone Number
NIH Osteoporosis and Related Bone Disorders, National Resource Center
(800) 624-2663
www.health.gov/nhic/Scripts/Entry.cfm?HRCode5HR2459
(301) 495-4484 or (877) 22-NIAMS
www.niams.nih.gov www.niams.nih.gov/bone/hi/paget/paget_newpatient.htm
National Institute of Arthritis and Musculoskeletal and Skin Diseases
URL
National Library of Medicine
(800) 272-4787
www.nlm.nih.gov
Paget Foundation for Paget’s Disease of Bone and Related Disorders
(800) 237-2438
www.paget.org
past month. He had been treated for osteoarthritis with NSAIDs in the past by another primary care physician with unsatisfactory results. He has a history of hyperlipidemia and is currently taking a statin with no symptoms of myalgias. He has not had a complete physical examination in several years, although he did have regular liver function tests and lipid panels by his former practitioner.The patient has not had any previous radiographs taken of the knee.A complete physical examination by the nurse practitioner was performed.The physical examination revealed a warm, tender right mid femur. Full range of motion and minimal crepitus of the knee were noted.A slight varus deformity of the right femur caused an antalgic gait. Conductive hearing loss of the left ear was also noted on examination. A radiograph of the right femur and knee were ordered and laboratory work that included a complete blood count complete metabolic panel, prostate-specific antigen, lipid panel, and liver function test.All laboratory work was within normal limits with the exception of an elevated serum ALP of 369 U/L (normal range for adults, 38-126 U/L8). Differential diagnoses included liver disease,ALP elevations because of statin or NSAID use, and bone diseases such as PDB, osteosarcoma, and osteomalacia. Because no other laboratory tests were abnormal, liver disease and elevations because of statin and NSAID use were excluded. Once the radiograph report was received, the cause of elevated ALP levels was apparent.The radiographs showed a “blade of grass” lesion, consistent with the osteolytic phase of PDB of the right femur and secondary osteoarthritis of the right knee. The patient was then sent for bone scintigraphy to reveal the extent of the disease.The results showed “hot spots” or increased uptake in the right femur and left temporal bone indicative of active PDB in the right femur and left temporal bone.This would explain the pain and deformity of the right leg and the hearing loss www.npjournal.org
in the left ear.The patient was started on risedronate 30 mg/day and will be continued for 2 months.The patient will be evaluated for treatment response by monitoring the ALP level every 3 months and by yearly follow-up radiographs.The patient was also instructed to start calcium and vitamin D and to start a regular exercise program to maintain bone health. PDB can easily be disregarded as osteoarthritis because of its presentation and patient population, but it can easily by recognized by routine laboratory panels and radiographs.This case of PDB may have been missed because of PDB being in a stage too early to recognize, or it may have been disregarded as typical pain of osteoarthritis by the former practitioner.Although it is true that many patients with PBD have secondary osteoarthritis, it is still essential to rule out PDB. Often practitioners diagnose osteoarthritis by presentation alone and never consider other diagnoses. Early recognition is essential so that therapy may be initiated for optimal outcomes. Patient Education Counseling is a critical component of the management plan about preventing falls and fractures, including avoiding heavy lifting for patients with vertebral involvement and weight control in obese patients to reduce pain related to weight bearing. Maintaining good bone health is also important to prevent fractures.This can be done by following the recommended daily allowances for the appropriate age and sex of the patient. Patients should be en-couraged to stay physically active. If the tibia or proximal femur is involved, heavy weight-bearing exercise should be avoided until the disease is in remission.33 Low or non– weight-bearing exercises such as swimming, bicycling, and Tai Chi are excellent for patients with painful arthro-pathy.33 Although rare, complete immobilization may precipitate hypercalcemia, and it should be avoided. The Journal for Nurse Practitioners - JNP
59
Patient adherence to medication regimens is imperative to improve outcomes and prevent disease complications.Teaching the patient how to take bisphosphonates is important to maintain compliance. Because bisphosphonates have a high propensity to cause gastrointestinal disturbances, instructions should be closely followed to prevent adverse effects that can cause noncompliance. Bisphosphonates should be taken in the morning on an empty stomach with a full glass of water.The patient should not lie down or eat for at least 30 minutes. Patients should be advised to report any worsening symptoms that could be a sign of disease worsening, fracture, or sarcomatous development. Patients with skull involvement need to understand neuropathic symptoms and should report these symptoms promptly.33 Family members should inform their health care providers of a family history of PDB and report any bone pain or neurologic problems promptly.33 Several Web sites are available to provide current information on the management of PDB (Table 6). Nurse practitioners can direct patients and families to the various resources to enhance knowledge of PDB. Conclusions Paget disease of the bone is the second most common bone disorder in the United States. It affects approximately 2% of the population older than 50 years and 10% of the population older than 80 years. Its cause may be familial, so family members should be aware of the disease in the family history. It is a slow but progressive disease. It is usually asymptomatic, but when symptomatic it can be painful and debilitating. Bone pain is the hallmark sign, and PDB must be included in the differential diagnosis, especially in patients older than 50 years. It can easily be detected by simple metabolic or liver chemistry panels and radiographs. If caught early, disease progression may be halted by pharmacologic therapy that may enable patients to live a healthy active life. References 1. van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C. Incidence and natural history of Paget’s disease of bone in England and Wales. J Bone Miner Res. 2002;17(3):465-471. 2. The Paget Foundation. A health professional’s guide to the management of Paget’s disease of bone. Available at: www.paget.org/Information/FactSheet/mgmt_of_pdisbone.html. Accessed January 25, 2007. 3. Kanis J. Pathophysiology and Treatment of Paget’s Disease of Bone. 2nd ed. London, United Kingdom: Martin Duntz; 1998. 4. Altman R. Disorders of Bone and Mineral Metabolism. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. 5. Langston AL, Ralston SH. Management of Paget’s disease of bone. Rheumatology. 2004;43(8):955-959. 6. Rousiere M, Michou L, Cornelis F, Orcel P. Paget’s disease of bone. Best Pract Res Clin Rheumatol. 2003;17(6):1019-1041.
60
The Journal for Nurse Practitioners - JNP
7. Pratt H, Sampson M. Paget’s disease of bone presenting as chest pain and shoulder immobility. Clin Radiol. 2005;60(3):407-409. 8. Whyte MP. Paget’s disease of bone. N Engl J Med. 2006;355(6):593-600. 9. Ankrom MA, Shapiro JR. Paget’s disease of bone (osteitis deformans). J Am Geriatr Soc. 1998;46(8):1025-1033. 10. Delmas PD, Meunier PJ. The management of Paget’s disease of bone. N Engl J Med. 1997;336(8):558-566. 11. Basle MF, Fournier JG, Rozenblatt S, Rebel A, Bouteille M. Measles virus RNA detected in Paget’s disease bone tissue by in situ hybridization. J Gen Virol. 1986;67(Pt 5):907-913. 12. Gordon M, Mee AP, Anderson DC, Sharpe PT. Canine distemper virus transcripts sequenced from pagetic bone. Bone Miner. 1992;19(2):159-174. 13. Rozin A, Bar-Shalom R, Ish-Shalom S. Paget’s disease of bone or osteopetrosis? Clin Rheumatol. 2006;25(4):544-547. 14. Kasper DL, Braunwald E, , Hauser S, Longo D, Jameson JL, Fauci AS. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGrawHill Co. Inc.; 2005. 15. Roodman GD, Windle JJ. Paget disease of bone. J Clin Invest. 2005;115(2):200-208. 16. Helliwell PS, Porter G. Controlled study of the prevalence of radiological osteoarthritis in clinically unrecognised juxta-articular Paget’s disease. Ann Rheum Dis. 1999;58(12):762-765. 17. Grimer RJ, Cannon SR, Taminiau AM, et al. Osteosarcoma over the age of forty. Eur J Cancer. 2003;39(2):157-163. 18. Selby PL, Davie MW, Ralston SH, Stone MD. Guidelines on the management of Paget’s disease of bone. Bone. 2002;31(3):366-373. 19. Fischbach F. A Manual of Laboratory & Diagnostic Tests. 4th ed. Philadelphia. PA: Lippincott; 1992. 20. Skinner H. Current Diagnosis & Treatment in Orthopedics. 2nd ed. New York, NY: McGraw-Hill; 1995. 21. The Paget Foundation. A health professional’s guide to the management of Paget’s disease of bone. Available at: www.paget.org/Information/FactSheet/mgmt_of_pdisbone.html. Accessed January 25, 2007. 22. Kelepouris N. Treatment of Paget’s disease of bone. 2006. Available at: www.utdol.com/utd/content/topic.do?topicKey=othrheum. Accessed December 26, 2006. 23. Donath J, Krasznai M, Fornet B, Gergeley P Jr, Poor G. Effect of bisphosphonate treatment in patients with Paget’s disease of the skull. Rheumatology (Oxford). 2004;43(1):89-94. 24. Martin T. Actions of calcitonin and mithramycin. Arthritis Rheum. 1980;23(10):1131-1138. 25. Singer FR. Clinical efficacy of salmon calcitonin in Paget’s disease of bone. Calcif Tissue Int. 1991;49(suppl 2):S7-S8. 26. Avramides A, Flores A, DeRose J, Wallach S. Paget’s disease of the bone: observations after cessation of long-term synthetic salmon calcitonin treatment. J Clin Endocrinol Metab. 1976;42(3):459-463. 27. MacGowan JR, Pringle J, Morris VH, Stamp TC. Gross vertebral collapse associated with long-term disodium etidronate treatment for pelvic Paget’s disease. Skeletal Radiol. 2000;29(5):279-282. 28. Roux C, Gennari C, Farrerons J, et al. Comparative prospective, doubleblind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget’s disease of bone. Arthritis Rheum. 1995;38(6):851-858. 29. Rosen HN, Moses AC, Gundberg C, et al. Therapy with parenteral pamidronate prevents thyroid hormone-induced bone turnover in humans. J Clin Endocrinol Metab. 1993;77(3):664-669. 30. Fraser WD, Logue FC, Gallacher SJ, et al. Direct and indirect assessment of the parathyroid response to pamidronate therapy in Paget’s disease of bone and hypercalcemia of malignancy. Bone Miner. 1991;12(2):113-121. 31. Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med. 2005;353(9):898-908. 32. Hadjipavlou AG, Gaitanis IN, Kontakis GM. Paget’s disease of the bone and its management. J Bone Joint Surg Br. 2002;84-B(2):160-169. 33. Buttaro T, Trybulski J, Bailey P, Sandberg-Cook J. Primary Care a Collaborative Practice. 2nd ed. St. Louis, MO: Mosby; 2003.
Angella Sherwood,ARNP, is an employee of Lee Memorial Health System, Department of Neurological Surgery, in Fort Myers, FL. She may be reached at angiesherwood@ hotmail.com. She reports that she has no relationships with business or industry that would represent a conflict of interest. 1555-4155/08/$ see front matter © 2008 American College of Nurse Practitioners doi:10.1016/j.nurpra.2007.06.002
January 2008
ABSTRACT Paget disease of bone causes excessive osteoblastic and osteoclastic activity resulting in bone that is structurally inferior to normal bone. Paget disease of bone is the second most common bone disorder in the United States, yet it often goes unrecognized. It is often asymptomatic; therefore, treatment is often delayed until the disease is in the late stages. In the late stages of the disease, the most common presentation is bone pain. Paget disease of bone may also cause fractures, bone deformity, neurologic symptoms, and cardiovascular complications. It is diagnosed by radiographs and laboratory panels, and is treated with bisphosphonates. Keywords: Bisphosphonates, bone pain, paget disease of bone
54
The Journal for Nurse Practitioners - JNP
January 2008
AGET DISEASE OF BONE (PDB) is the second most common bone disorder after osteoporosis in the United States,1,2 but it often goes undetected because of the high prevalence of asymptomatic patients. PDB is characterized by excessive osteoclastic bone resorption followed by excessive bone formation from osteoblasts, resulting in bone that is architecturally unsound.This can lead to bone pain, bone deformity, and skeletal fragility.2 Nurse practitioners should be aware of PDB and be able to recognize the signs and symptoms associated with the disease. Early detection can optimize timely treatment and therefore possibly prevent the complications associated with the disease course. PDB is a chronic, progressive bone disease that can affect one bone (monostoic) or several bones (polystotic).3-5 If patients are symptomatic, they may seek treatment of bone pain, fractures, neurologic symptoms, bony deformities, and cardiovascular complications.6,7 PDB is defined by The Paget Foundation as a disease of the osteoclast and is the most exaggerated example of disordered bone remodeling. It is a focal disorder of accelerated skeletal remodeling that can involve a single or multiple bones.2 Bone pain is the hallmark sign of PDB, although it is often overlooked by many health care providers.The purpose of this article is to inform primary care nurse practitioners of the disease itself, explain the signs and symptoms of PDB, and describe treatment methods that are available to reduce associated complications of the disease.
P
Epidemiology The global prevalence of PDB is 2%,6 and it is more common in countries with large Anglo-Saxon populations such as the North America, Great Brittan,Australia, New Zealand, and Western Europe.8 It is rare in Africa and Asia.9 In the United States, the prevalence is estimated to be 3% in white persons older than 50 years9 and in as many as 10% of persons older than 80 years. It occurs equally in men and women.10 PDB has been found to be familial with 15% to 40% of persons having a positive family history of the disease.5 The cause is uncertain,3,4 but evidence suggests that it may have genetic and environmental influences.8 Viral infections such as paramyxovirus nuclocapsids, measles virus, canine distemper virus, and respiratory syncytial virus are also indicated as a cause.11,12 www.npjournal.org
Disease Course PDB is characterized by three distinct radiographic phases: the osteolytic phase, the mixed phase, and the osteosclerotic phase.The increased bone resorption and remodeling that occurs in the disease process leads to characteristics found on radiographs that usually allow establishment of diagnosis through the combination of three straightforward signs: hypertrophy of the affected bones, irregular condensation with a fibrillar or mottled appearance, and loss of the clear-cut delineation between cortical and trabecular bone.6 The initial osteolytic phase is most common in the skull and long bones and is characterized by prominent bone resorption and obvious hypervascularization. On radiograph, this stage is apparent by circumscribed osteolytic skull lesions called osteoporosis circumscripta, which gives the appearance of cotton-wool.These lesions are mostly seen in the frontal and occipital regions, and they may cause headache, hearing loss, or hydrocephalus.6,13 In long bones, the osteolytic stage is characterized by an advancing lytic wedge, also called a “blade of grass” lesion. The mixed phase is depicted by aggressive bone formation and resorption that replaces normal lamellar bone with a mosaic woven bone pattern.This mosaic woven pattern of bone is structurally inferior and may cause bowing or fracture of long bones, spinal stenosis with secondary nerve root compression, and bone pain. In this same phase, fibrous connective tissue may replace normal bone marrow.The osteosclerotic phase is characterized by bone resorption slowing, leading to hard, dense, and less vascular bone. Radiographs show dense, cortical and trabecular bone deposition, causing boney hypertrophy.All stages may be present at one time at different bony sites.14 Clinical Presentation PDB is typically asymptomatic; however, bone pain is the hallmark symptom. PDB can affect any bone, but the most common sites are the pelvis and sacrum (⬎60%), followed by the spine (50%), skull and femurs (40%), tibias, humeri, and clavicles (20%).6 The symptomatic patient may have pain in one or more bones or joints that increases on weight bearing.The pain may intensify as the day goes on and is unrelated to activity.A sudden onset of pain may indicate that a fracture has occurred (Table 1). The practitioner may find increased skin temperature over a pagetic lesion because of the increased vascularity of affected bone if the disease is active.5 Softening of long The Journal for Nurse Practitioners - JNP
55
Table 1. Clinical Presentation15 Symptom
Cause Usually results from osteoarthritis in joints adjacent to pagetic bones
Differential Diagnosis
Bone deformities
Can be a result of rapid formation of poor-quality bone
Paget’s disease of bone
Fractures
Bone in pagetic lesions is weaker than normal and can develop characteristic “chalk-stick” fractures
Radiographs may show “blade of grass” lesion, dense sclerosis, and boney overgrowth, or blastic burntout phase.20
Osteosarcoma
May also have pain, fever, mass near joint, and leukocytosis. Radiographs will show permeated lytic destruction of metaphyseal bone, with eventual cortical breakthrough into the subperiosteal space; a typical sunburst pattern of chaotic neoplastic bone may be seen outside the involved bone.20
Osteomalacia
Serum calcium levels may be low or normal; may have hypophosphatemia, aminoaciduria, acidosis, glucosuris, and hypouricemia. Radiographs may show thinning of cortical bone, stress fractures, or pathologic fractures; they may look identical to osteoporosis.20
Bone pain
Hearing loss
Temporal bone involvement
Nerve root compression
Impingement of nerve root by increased bone formation
Headache
Skull affected by PDB
Hydrocephalus
Skull affected by PDB
bones from pagetic lesions, such as the femur, may occur and cause deformities and gait disturbance.7 Skull enlargement, although rare, may also occur, causing headaches and hearing loss if the temporal bone is involved. If spine involvement is present, the patient may have radiculopathies and impaired neurologic function because of compression of the spinal cord or spinal nerves.2 Cardiovascular complications, such as congestive heart failure, may occur because of increased blood flow in pagetic bone.7 Other cardiac complications include arterial and cardiac valvular calcification.7 Patients with PDB have significantly an increased risk of developing osteoarthritis in the knees and hips if the pagetic lesion forms near a weight-bearing joint.16 Osteosarcoma, although rare, may occur in approximately 1% of patients with the disease.17 Diagnosis PDB may be an incidental finding during the work-up of other condtions.18 Most often patients are asymptomatic. It is estimated that only 5% of patients with PDB will be symptomatic.18 PDB in asymptomatic patients may be diagnosed by plain radiographs that are incidentally taken for a suspected fracture or other reasons and by abnormal laboratory findings. The diagnosis of PDB may be suspected by finding an elevated level of serum alkaline phosphatase (ALP) on a complete metabolic or liver panel.The elevation will reflect both the extent and the activity of the disease.3,4 Normal ALP range for adults is 38 to 126 U/L.8 ALP is an enzyme that originates primarily in the bone, liver, and placenta, with some activity in the intestines and kidney.This enzyme is mainly used for the assessment of hepatobiliary and bone diseases. In bone disease, the ALP level rises in proportion to 56
Table 2. Differential Diagnoses for Elevated ALP Levels with Bone Pain
The Journal for Nurse Practitioners - JNP
Findings
new bone cell production that results from osteoblastic activity and the deposit of calcium in the bones.19 However, ALP levels may be in the normal range when the extent of the disease is small or after successful medical treatment.8 An elevated serum ALP level may be present in bone disease such as PDB, metastatic bone disease, osteogenic sarcoma, and osteomalacia (Table 2).19 To distinguish bone disease from hepatobiliary disease, a ␥-glutamyl transpeptidase (GGT) enzyme may be drawn, which will be elevated in hepatobiliary disease but not in bone disease. Bone-specific ALP, although it is less readily available and does not exhibit more benefit than total ALP, may also be drawn to differentiate the source of elevated ALP levels and may be used to assess treatment of PDB.18 Although additional biochemical tests that reflect osteoclast activity and resultant bone collagen resorption are available, they are not typically used.These tests include measurements of urinary hydroxyproline/creatinine and measurements of urinary and serum deoxypyridinoline, N-telopeptide, and C-telopeptide.21 The diagnosis of PDB is primarily made through plain radiograph. Bone scintigraphy may be used to show the extent of disease and is the most efficient means of detecting Paget disease in the skeleton, but it is not recommended as a diagnostic tool.18 Bone scintigraphy is a January 2008
Table 3. Recommended Indications for Antiresorptive Treatment8 • Symptoms resulting from active bone lesions such as bone pain, headache with skull involvement, back pain because of pagetic radiculopathy or arthropathy, other neurologic syndromes, and fissure fractures • Prophylaxis, even in asymptomatic patients, when affected site and their metabolic hyperactivity suggest risk because of progression and complications, such as fracture in weight-bearing long bones or nerve • Elective surgery for a pagetic site (eg, total joint arthroplasty) • Hypercalcemia resulting from immobilization
radionuclide bone scan that uses a radio-labeled bisphosphonate.The bisphosphonate is injected intravenously and is concentrated in areas of increased blood flow and high levels of bone formation, both common characteristics of Paget disease.This test is used primarily to establish the full extent of skeletal involvement for a patient.21 Treatment Treatment is directed toward controlling symptoms and preventing long-term complications in asymptomatic patients. Indications for pharmacologic therapy are as follows: to control symptoms such as bone pain, fracture, headache, pain from pagetic radiculopathy or arthropathy, or neurologic complications; to decrease local blood flow and minimize complications related to blood loss for patients undergoing surgery on an active pagetic site; to prevent acceleration of disease activity that has been reported after surgery or fractures; to reduce hypercalcemia associated with immobilization; to decrease progression and reduce the risk of future complications in asymptomatic patients such as bowing of long bones, hearing loss because of skull enlargement; and for secondary osteoarthritis as a complication of Paget disease located next to major joints (Table 3).2,14 The key indicator of efficacy is improvement in symptoms such as pain and decrease in symptoms of nerve compression.22 In addition, markers of bone turnover such as ALP levels should decrease.22 Improvements in appearance of radiographs or bone scintigraphy should also occur, but bowed extremities will not improve and deafness is unlikely to improve.23 Pharmacologic Management of PDB Bisphosphonates are the current mainstay treatment for PDB and work by suppressing bone resorption by osteowww.npjournal.org
clasts. Calcitonin works in the same way, but it is usually reserved for patients who cannot tolerate bisphosphonate therapy. Currently, five bisphosphonates and calcitonin are approved by the Food and Drug Administration (FDA) to treat PDB in the United States (Table 4). Salmon calcitonin was the first osteoclast inhibitor to be used in the treatment of PDB.5 Calcitonin has the benefits of suppressing bone turnover and reducing bone pain, but it is less effective and can be expensive compared with bisphosphonates.24 Calcitonin can have side effects of flushing, skin rash, nausea, and vomiting, and patients can also develop a resistance to calcitonin after repeated use.The usual starting dose is 100 units subcutaneously at bedtime. Some benefits will be apparent in 2 to 6 weeks, with reductions in serum ALP levels up to 50% and im-provement in lytic lesions by 3 to 6 months.25 The dose should be reduced 50 to 100 units subcutaneously every other day after initial improvements in ALP levels and when lytic lesions are seen.The appropriate treatment duration has not been established. Intermittent therapy may be tried, and in some cases indefinite treatment may be required.26 On occasion, it may be beneficial to use calcitonin in combination with a bisphosphonate to get optimal therapeutic results. Studies have shown that alendronate and risedronate have superior results compared with tiludronate and etidronate in terms of normalizing bone turnover and pain relief. Etidronate may also cause osteomalacia and is rarely used now.22,27 In patients with moderate-to-severe disease, alendronate normalizes ALP levels in more than 67% of patients, with an overall fall in ALP levels of 79% compared with 44% with etidronate.14 Alendronate is administered at 400 mg/day for 6 months. Risedronate was shown to reduce serum ALP levels by 80% and to normalize indexes of bone turnover in 73% of patients with moderately active disease compared with 15% of patients receiving etidronate.14 Risedronate is administered at 30 mg/day for 2 months. A comparative double-blind study compared tiludronate and etidronate and found tiludronate to be more effective.28 Tiludronate is administered at 400 mg for 3 months, and etidronate is administered at 400 mg/day for 6 months. Etidronate was found to have similar effects of efficacy compared with calcitonin. Pamidronate is also more potent than etidronate and is given in a single 60-mg dose intravenously for patients with mild disease and in infusions of 20 to 60 mg over 4 to 24 hours intermittently every 3 to 18 months in The Journal for Nurse Practitioners - JNP
57
Table 4. Pharmacologic Agents Approved by the FDA for the Treatment of Paget Disease2,14 Drug Name Zoledronic Acid
Dose 5 mg intravenously. Infusion over 15 mins.
Administration 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 D3 over 2 weeks. Correct any hypocalcemia and vitamin D deficiencies before treatment. Suppression of disease activity can last up to 2 years.
Tiludronate (Skelid)
400 mg/d for 3 mo
Must be taken on empty stomach with 6-8 oz of water 2 h before or after a meal.
Pamidronate (Aredia)
30 mg intravenously over 3 consecutive days or 60-90 mg intravenously at various intervals determined by disease
Infusion must be given over 2-4 hours. A course may be readministered at intervals at needed. Serum creatinine should be tested before each treatment.
Alendronate (Fosamax)
40 mg/d for 6 mo
Must be taken on empty stomach with 6-8 oz of water in morning. Wait 45 min before eating or drinking anything except water and before lying down.
Risedronate (Actonel)
30 mg/d for 2 mo
Must be taken on empty stomach with 6-8 oz of water in morning. Wait 45 min before eating or drinking anything except water and before lying down.
Calcitonin (Miacalcin)
50-100 units subcutaneously daily or 3 times/wk for 6-18 mo
Given as an injection.
patients with more severe disease.Total doses of 240 to 480 mg may be needed in some patients.22 Side effects include flulike symptoms in the first few days after administration in approximately 20% of patients; these symptoms can be reduced by diluting 60 mg of pamidronate in at least 1000 mL of fluid.29 Hypocalcemia may occur when pamidronate is given in high doses, but it can be improved by giving 1000 mg of calcium daily for 1 to 2 weeks after treatment.30 Zoledronic acid was recently approved for the treatment of PDB. One study has shown an 80% decrease in ALP levels at 6 months with normalization in 89% of subjects with a single infusion of 5 mg.31 Supportive Therapy Problems arising from bowing of the extremities, gait disturbances, or spinal stenosis may be improved by shoe lifts, canes, orthotics, and physical therapy.3,4,32 Pain unresolved by bisphosphonates is likely to respond to nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen.8 Referral for surgery may be required in some cases of unremitting pain or if fractures occur (Table 5).8 58
The Journal for Nurse Practitioners - JNP
Table 5. Indications for Referral33 • Rheumatologist referral is indicated if disease is unresponsive to usual treatment. • Orthopedic referral is indicated for fractures and unremitting pain that could be treated with total joint arthroplasty. • Neurosurgery referral is indicated if spinal stenosis causes unremitting pain or loss of function, or if hydrocephalus occurs.
Tibial osteotomy may be performed to realign the knee and relieve pain.Total joint arthroplasty may be indicated in cases of severe secondary osteoarthritis, and spinal stenosis may be relived by surgical spinal decompression.8 Case Report A 59-year-old white man comes to a primary care office as a new patient with a chief complaint of right knee and thigh pain for the past year.The pain increases on weight bearing and intensifies as the day goes on.The pain is not related to activity and has increased in intensity during the January 2008
Table 6. Resources for Patient Education Organization
Phone Number
NIH Osteoporosis and Related Bone Disorders, National Resource Center
(800) 624-2663
www.health.gov/nhic/Scripts/Entry.cfm?HRCode5HR2459
(301) 495-4484 or (877) 22-NIAMS
www.niams.nih.gov www.niams.nih.gov/bone/hi/paget/paget_newpatient.htm
National Institute of Arthritis and Musculoskeletal and Skin Diseases
URL
National Library of Medicine
(800) 272-4787
www.nlm.nih.gov
Paget Foundation for Paget’s Disease of Bone and Related Disorders
(800) 237-2438
www.paget.org
past month. He had been treated for osteoarthritis with NSAIDs in the past by another primary care physician with unsatisfactory results. He has a history of hyperlipidemia and is currently taking a statin with no symptoms of myalgias. He has not had a complete physical examination in several years, although he did have regular liver function tests and lipid panels by his former practitioner.The patient has not had any previous radiographs taken of the knee.A complete physical examination by the nurse practitioner was performed.The physical examination revealed a warm, tender right mid femur. Full range of motion and minimal crepitus of the knee were noted.A slight varus deformity of the right femur caused an antalgic gait. Conductive hearing loss of the left ear was also noted on examination. A radiograph of the right femur and knee were ordered and laboratory work that included a complete blood count complete metabolic panel, prostate-specific antigen, lipid panel, and liver function test.All laboratory work was within normal limits with the exception of an elevated serum ALP of 369 U/L (normal range for adults, 38-126 U/L8). Differential diagnoses included liver disease,ALP elevations because of statin or NSAID use, and bone diseases such as PDB, osteosarcoma, and osteomalacia. Because no other laboratory tests were abnormal, liver disease and elevations because of statin and NSAID use were excluded. Once the radiograph report was received, the cause of elevated ALP levels was apparent.The radiographs showed a “blade of grass” lesion, consistent with the osteolytic phase of PDB of the right femur and secondary osteoarthritis of the right knee. The patient was then sent for bone scintigraphy to reveal the extent of the disease.The results showed “hot spots” or increased uptake in the right femur and left temporal bone indicative of active PDB in the right femur and left temporal bone.This would explain the pain and deformity of the right leg and the hearing loss www.npjournal.org
in the left ear.The patient was started on risedronate 30 mg/day and will be continued for 2 months.The patient will be evaluated for treatment response by monitoring the ALP level every 3 months and by yearly follow-up radiographs.The patient was also instructed to start calcium and vitamin D and to start a regular exercise program to maintain bone health. PDB can easily be disregarded as osteoarthritis because of its presentation and patient population, but it can easily by recognized by routine laboratory panels and radiographs.This case of PDB may have been missed because of PDB being in a stage too early to recognize, or it may have been disregarded as typical pain of osteoarthritis by the former practitioner.Although it is true that many patients with PBD have secondary osteoarthritis, it is still essential to rule out PDB. Often practitioners diagnose osteoarthritis by presentation alone and never consider other diagnoses. Early recognition is essential so that therapy may be initiated for optimal outcomes. Patient Education Counseling is a critical component of the management plan about preventing falls and fractures, including avoiding heavy lifting for patients with vertebral involvement and weight control in obese patients to reduce pain related to weight bearing. Maintaining good bone health is also important to prevent fractures.This can be done by following the recommended daily allowances for the appropriate age and sex of the patient. Patients should be en-couraged to stay physically active. If the tibia or proximal femur is involved, heavy weight-bearing exercise should be avoided until the disease is in remission.33 Low or non– weight-bearing exercises such as swimming, bicycling, and Tai Chi are excellent for patients with painful arthro-pathy.33 Although rare, complete immobilization may precipitate hypercalcemia, and it should be avoided. The Journal for Nurse Practitioners - JNP
59
Patient adherence to medication regimens is imperative to improve outcomes and prevent disease complications.Teaching the patient how to take bisphosphonates is important to maintain compliance. Because bisphosphonates have a high propensity to cause gastrointestinal disturbances, instructions should be closely followed to prevent adverse effects that can cause noncompliance. Bisphosphonates should be taken in the morning on an empty stomach with a full glass of water.The patient should not lie down or eat for at least 30 minutes. Patients should be advised to report any worsening symptoms that could be a sign of disease worsening, fracture, or sarcomatous development. Patients with skull involvement need to understand neuropathic symptoms and should report these symptoms promptly.33 Family members should inform their health care providers of a family history of PDB and report any bone pain or neurologic problems promptly.33 Several Web sites are available to provide current information on the management of PDB (Table 6). Nurse practitioners can direct patients and families to the various resources to enhance knowledge of PDB. Conclusions Paget disease of the bone is the second most common bone disorder in the United States. It affects approximately 2% of the population older than 50 years and 10% of the population older than 80 years. Its cause may be familial, so family members should be aware of the disease in the family history. It is a slow but progressive disease. It is usually asymptomatic, but when symptomatic it can be painful and debilitating. Bone pain is the hallmark sign, and PDB must be included in the differential diagnosis, especially in patients older than 50 years. It can easily be detected by simple metabolic or liver chemistry panels and radiographs. If caught early, disease progression may be halted by pharmacologic therapy that may enable patients to live a healthy active life. References 1. van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C. Incidence and natural history of Paget’s disease of bone in England and Wales. J Bone Miner Res. 2002;17(3):465-471. 2. The Paget Foundation. A health professional’s guide to the management of Paget’s disease of bone. Available at: www.paget.org/Information/FactSheet/mgmt_of_pdisbone.html. Accessed January 25, 2007. 3. Kanis J. Pathophysiology and Treatment of Paget’s Disease of Bone. 2nd ed. London, United Kingdom: Martin Duntz; 1998. 4. Altman R. Disorders of Bone and Mineral Metabolism. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. 5. Langston AL, Ralston SH. Management of Paget’s disease of bone. Rheumatology. 2004;43(8):955-959. 6. Rousiere M, Michou L, Cornelis F, Orcel P. Paget’s disease of bone. Best Pract Res Clin Rheumatol. 2003;17(6):1019-1041.
60
The Journal for Nurse Practitioners - JNP
7. Pratt H, Sampson M. Paget’s disease of bone presenting as chest pain and shoulder immobility. Clin Radiol. 2005;60(3):407-409. 8. Whyte MP. Paget’s disease of bone. N Engl J Med. 2006;355(6):593-600. 9. Ankrom MA, Shapiro JR. Paget’s disease of bone (osteitis deformans). J Am Geriatr Soc. 1998;46(8):1025-1033. 10. Delmas PD, Meunier PJ. The management of Paget’s disease of bone. N Engl J Med. 1997;336(8):558-566. 11. Basle MF, Fournier JG, Rozenblatt S, Rebel A, Bouteille M. Measles virus RNA detected in Paget’s disease bone tissue by in situ hybridization. J Gen Virol. 1986;67(Pt 5):907-913. 12. Gordon M, Mee AP, Anderson DC, Sharpe PT. Canine distemper virus transcripts sequenced from pagetic bone. Bone Miner. 1992;19(2):159-174. 13. Rozin A, Bar-Shalom R, Ish-Shalom S. Paget’s disease of bone or osteopetrosis? Clin Rheumatol. 2006;25(4):544-547. 14. Kasper DL, Braunwald E, , Hauser S, Longo D, Jameson JL, Fauci AS. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGrawHill Co. Inc.; 2005. 15. Roodman GD, Windle JJ. Paget disease of bone. J Clin Invest. 2005;115(2):200-208. 16. Helliwell PS, Porter G. Controlled study of the prevalence of radiological osteoarthritis in clinically unrecognised juxta-articular Paget’s disease. Ann Rheum Dis. 1999;58(12):762-765. 17. Grimer RJ, Cannon SR, Taminiau AM, et al. Osteosarcoma over the age of forty. Eur J Cancer. 2003;39(2):157-163. 18. Selby PL, Davie MW, Ralston SH, Stone MD. Guidelines on the management of Paget’s disease of bone. Bone. 2002;31(3):366-373. 19. Fischbach F. A Manual of Laboratory & Diagnostic Tests. 4th ed. Philadelphia. PA: Lippincott; 1992. 20. Skinner H. Current Diagnosis & Treatment in Orthopedics. 2nd ed. New York, NY: McGraw-Hill; 1995. 21. The Paget Foundation. A health professional’s guide to the management of Paget’s disease of bone. Available at: www.paget.org/Information/FactSheet/mgmt_of_pdisbone.html. Accessed January 25, 2007. 22. Kelepouris N. Treatment of Paget’s disease of bone. 2006. Available at: www.utdol.com/utd/content/topic.do?topicKey=othrheum. Accessed December 26, 2006. 23. Donath J, Krasznai M, Fornet B, Gergeley P Jr, Poor G. Effect of bisphosphonate treatment in patients with Paget’s disease of the skull. Rheumatology (Oxford). 2004;43(1):89-94. 24. Martin T. Actions of calcitonin and mithramycin. Arthritis Rheum. 1980;23(10):1131-1138. 25. Singer FR. Clinical efficacy of salmon calcitonin in Paget’s disease of bone. Calcif Tissue Int. 1991;49(suppl 2):S7-S8. 26. Avramides A, Flores A, DeRose J, Wallach S. Paget’s disease of the bone: observations after cessation of long-term synthetic salmon calcitonin treatment. J Clin Endocrinol Metab. 1976;42(3):459-463. 27. MacGowan JR, Pringle J, Morris VH, Stamp TC. Gross vertebral collapse associated with long-term disodium etidronate treatment for pelvic Paget’s disease. Skeletal Radiol. 2000;29(5):279-282. 28. Roux C, Gennari C, Farrerons J, et al. Comparative prospective, doubleblind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget’s disease of bone. Arthritis Rheum. 1995;38(6):851-858. 29. Rosen HN, Moses AC, Gundberg C, et al. Therapy with parenteral pamidronate prevents thyroid hormone-induced bone turnover in humans. J Clin Endocrinol Metab. 1993;77(3):664-669. 30. Fraser WD, Logue FC, Gallacher SJ, et al. Direct and indirect assessment of the parathyroid response to pamidronate therapy in Paget’s disease of bone and hypercalcemia of malignancy. Bone Miner. 1991;12(2):113-121. 31. Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med. 2005;353(9):898-908. 32. Hadjipavlou AG, Gaitanis IN, Kontakis GM. Paget’s disease of the bone and its management. J Bone Joint Surg Br. 2002;84-B(2):160-169. 33. Buttaro T, Trybulski J, Bailey P, Sandberg-Cook J. Primary Care a Collaborative Practice. 2nd ed. St. Louis, MO: Mosby; 2003.
Angella Sherwood,ARNP, is an employee of Lee Memorial Health System, Department of Neurological Surgery, in Fort Myers, FL. She may be reached at angiesherwood@ hotmail.com. She reports that she has no relationships with business or industry that would represent a conflict of interest. 1555-4155/08/$ see front matter © 2008 American College of Nurse Practitioners doi:10.1016/j.nurpra.2007.06.002
January 2008