Diagnosis and Management of Pagets Disease of Bone[1]

Diagnosis and Management of Paget’s Disease of Bone An educational program provided by The Paget Foundation 120 Wall Street #1602 New York, NY 10005 Tel: 212-509-5335 Fax: 212-509-8492 E-mail: Pagetfdn@aol.com Website: www.paget.org Sir James Paget History of Paget’s Disease • Sir James Paget named disease osteitis deformans in 1876, suspecting basic inflammatory process1,2 referred to as Paget’s disease of bone1 • Today predominantly Epidemiology: Prevalence of Paget’s Disease in the US • • Second most common bone disease after osteoporosis1 Roughly estimated at approximately 2% of the US population over age 55 years1 – Prevalence increases markedly with age, uncommon before age 401,2 15% to 30% of patients have positive family histories 1 Most common in people of Northern European descent1 • • 1. Siris ES, Roodman GD. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, DC: ASBMR; 2006:320-330. 2. Altman RD, et al. J Bone Miner Res. 2000;15:461-465. Genetic Abnormalities in Familial Paget’s Disease & Related Disorders • Classical Paget’s disease • Autosomal dominant • Mutations of sequestosome 1/p62 gene (5q 35qter) • Linkage to 5q 31, 18q 21-22, 18q 23, 2q 36, 10p 13 Paget’s disease ,hereditary inclusion body myopathy and dementia • Autosomal dominant • Mutations of valosin containing protein Familial expansile osteolysis • Autosomal Dominant • Mutation of signal peptide of rank (18q) • • Paget’s Disease: Description • Chronic, progressive skeletal disorder • Increased size and number of osteoclasts • Localized areas of excessive bone resorption and formation – – May have only one affected bone or have pagetic lesions in multiple bones New lesions rarely develop in previously unaffected bone after diagnosis Paget’s Disease: An Osteoclast-Mediated Disorder Histology of Pagetic Bone Osteoclasts Multinucleated osteoclast Multinucleated osteoclast Courtesy of Pierre Delmas, MD. Osteoclast Nucleus Containing Measles-like Nucleocapsid Structure X 32,000 Pagetic Bone and Normal Bone Normal Pagetic Siris ES, Roodman GD. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, DC: ASBMR; 2006:320-330. Paget’s Disease: Clinical Presentation • Usually mild or asymptomatic1 • Diagnosis is often based on incidental findings1 – Elevated total or bone specific serum alkaline • phosphatase – Radiological findings Patients may present with symptoms that are nonspecific or suggestive of other conditions1 – Pain – Fracture – Deformity – Osteoarthritis – Hearing loss 1Siris ES, Roodman GD. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, DC: ASBMR; 2006:320-330. Paget’s Disease: Common Sites of Involvement • Paget’s disease can occur in any bone, but most commonly: – Skull – Vertebrae – Pelvis – Femur – Tibia Diagnosing Paget’s Disease: Tests • Laboratory tests1,2 – Alkaline phosphatase, a marker of bone formation – Any level above normal, especially in the absence of elevated liver enzymes – Bone-specific alkaline phosphatase may be more reliable. Elevated markers of bone resorption (serum βC-telopeptide of type 1 collagen [CTX], urine N-telopeptide of type I collagen [NTX]) Radiographs1,2 – Characteristic appearance usually confirms diagnosis Bone scan to assess extent of disease1 • • 1. Lyles KW, et al. J Bone Miner Res. 2001;16:1379-1387. 2. Selby PL, et al. Bone. 2002;31:366-373. Early-Stage (Lytic) Paget’s Disease: Tibia V-shaped ―blade of grass‖ lesion characteristic of lytic phase of Paget’s disease Courtesy of Pierre Delmas, MD. Advanced Paget’s Disease in the Tibia: Sclerotic and Lytic Lesions Secondary osteolytic front Primarily sclerotic changes, with enlargement and thickening of long bones Courtesy of Pierre Delmas, MD. Paget’s Disease: Progression Over 15 Years in Untreated Patient Bowing Cortical thickening Courtesy of Pierre Delmas, MD. 1976 1991 Early-Stage (Lytic) Paget’s Disease in the Skull: Known as “Osteoporosis Circumscripta” Lytic border Courtesy of Pierre Delmas, MD. Advanced (Sclerotic) Paget’s Disease: “Cotton Wool” Skull Diffuse sclerotic changes Lytic lesion Courtesy of Pierre Delmas, MD. Advanced Paget’s Disease in the Pelvis Diffuse sclerotic changes Bony enlargement Courtesy of Nuria Guañabens, MD. Paget’s Disease in the Femur Accentuation of trabecular pattern Cortical thickening Curved deformity of the femur Courtesy of Nuria Guañabens, MD. Paget’s Disease of Femur X-Ray Courtesy of R. Bockman, MD, PhD Bone Scan Pathology Paget’s Disease: “Picture Frame” Vertebral Body Lytic lesion Cortical thickening Courtesy of Pierre Delmas, MD. A Bone Scan Showing Polyostotic Disease Bilateral Thermogram of a Tibia Bone region with increased metabolic activity Ring EFJ, et al. In: Kanis, JA, ed. Bone Disease and Calcitonin. Eastbourne, England: Armour Pharmaceutical Co, 1977: 39-48 Paget’s Disease: Physical Examination1 • Physical examination may reveal – Skeletal deformity – Abnormal gait – Elevated temperature, erythema, or tenderness over affected bone – Hearing loss – Dilated scalp veins – High-output cardiac failure – Neurological findings 1. Siris ES, Roodman GD. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, DC: ASBMR; 2006:320-330. Paget’s Disease in the Skull Skull enlargement Dilated scalp veins Courtesy of Pierre Delmas, MD. Skeletal Deformities: Bowing of Long Bones Bowing of humerus Courtesy of Jacques Brown, MD. Skeletal Deformities: Bowing of Lower Limbs Bowed femurs Bowed tibias Courtesy of Pierre Delmas, MD. Other Complications of Paget’s Disease • Osteoarthritis adjacent to affected bones, particularly in the hips • Fracture (complete, fissure, vertebral compression) • Neurologic • Cardiac • Neoplastic (Rare) Osteosarcoma Rare finding (<1%) Giant Cell tumors (benign) Lyles KW, et al. J Bone Miner Res. 2001;16:1379-1387. Complications of Paget’s Disease: Fissure Fracture in the Tibia Fissure fracture Complications of Paget’s Disease: Complete (Chalk-Stick) Fracture in a Femur Courtesy of Pierre Delmas, MD. Complications of Paget’s Disease: Neurologic Disorders • • • • • • • • • Hearing deficit Cranial nerve deficits Mottled retinal degeneration;angioid streaks Basilar impression Hydrocephalus Myelopathy Radicular neuropathies Spinal stenosis Spinal vascular steal syndrome Complications of Paget’s Disease: Hearing Loss Audiogram • Occurs with temporal • • • • bone involvement High-frequency sensory loss Low-frequency conductive loss Bilateral Progressive Complications of Paget’s Disease: Angioid Streak Crack in Bruch’s membrane, termed “angioid streak” Complications of Paget’s Disease: Cardiovascular • Increased cardiac output • Congestive heart failure • Generalized atherosclerosis • Aortic valve calcification • Endocardial calcification Complications of Paget’s Disease: Neoplastic • Sarcoma (osteosarcoma, • chondrosarcoma, fibrosarcoma) Benign giant cell tumor Complications of Paget’s Disease: Osteosarcoma in Pagetic Femur Sarcomatous degeneration Reproduced with permission from: N. Kelepouris. Clinical manifestations and diagnosis of Paget's disease of bone. In: Rose, BD (Ed), UpToDate (version 13.3), Waltham, MA 2006. Copyright © 2006 UpToDate, Inc. Complications of Paget’s Disease: Giant Cell Tumor of Scapula Courtesy of F. Singer, MD Histology of Giant Cell Tumor Courtesy of F. Singer, MD The Personal Impact of Paget’s Disease • Self-report survey of 958 persons with Paget’s disease revealed: – Frequent comorbidities – Arthritis/arthrosis (64%) – Hypertension (32%) – Heart problems (28%) – Nearly half of patients (47%) reported depression – 44% reported their health as ―fair‖ or ―poor‖ – Only 21% reported their quality of life was ―very good‖ or ―excellent‖ Gold DT, et al. J Bone Miner Res. 1996;11:1897-1904. Managing Paget’s Disease: Bisphosphonates and Other Treatment Strategies • • • • Bisphosphonates (gold standard of antipagetic therapy)1-3 Subcutaneous calcitonin (rarely used)1,2 Pain management – NSAIDs, COX-2 inhibitors, analgesics, opioids1,2 Surgery1,2 – Fractures, bone deformities, osteoarthritis Indications for Treatment of Paget’s Disease • • • • • Bone pain Preparation for orthopedic surgery Fracture of pagetic bone Hypercalcemia and/or hypercalciuria Neurologic deficit associated with cranial or vertebral disease Presence of high-output congestive heart failure Prevention of future complications • • FDA-Approved Therapies and Dosing Regimens for Paget’s Disease* Agent Oral agents Didronel® (etidronate) Dose Duration of Therapy 6 mo 3 mo 3 mo 6 mo 2 mo 4 h on 3 cons. days Single, 15 min. infusion 5 -10 mg/kg/d or 11-20 mg/kg/d Skelid® (tiludronate) 400 mg/d Fosamax® (alendronate) 40 mg/d Actonel® (risedronate) 30 mg/d IV agents Aredia® (pamidronate) 30 mg/d Reclast® 5 mg (zoledronic acid) Effect of Etidronate on Alkaline Phosphatase Activity and Urinary Hydroxyproline Excretion Percent of Pretreatment Value Effect of Intravenous Pamidronate on Alkaline Phosphatase Activity and Urinary Hydroxyproline Excretion Effect on Serum Alkaline Phosphatase of Alendronate 40 mg/day Vs. Placebo or Etidronate 400mg/day Effect of Tiludronate Therapy on Serum Alkaline Phosphatase Activity Biochemical Remission Induced by Risedronate Treatment Risedronate 30 mg/day x 2 mos. Etidronate 400 mg/day x 6 mos. Zoledronic Acid Lowers Alkaline Phosphatase Levels More Than Risedronate Mean ( SE) Total Alkaline Phosphatase by Visit Total Alkaline Phosphatase (U/L) Zoledronic Acid 5mg IV, 15 min (n=121) 500 P < .001 Risedronate 30mg/d x 60d (n=80) P < .001 P < .001 400 300 200 100 0 0 10 Normal alkaline phosphatase range P < .001 P < .001 28 63 91 182 Days Reid IR, et al. N Engl J Med. 2005;353:898-908. Copyright © 2003 Massachusetts Medical Society. All right reserved. Adapted with permission, 2007. During Study Extension, Zoledronic Acid Maintained Mean Serum ALP Better Than Risedronate 200 Start of extended observation period Zoledronic Acid 5mg IV, 15 min (n=121) Risedronate 30mg/d x 60d (n=80) Total AlP reference range Serum ALP (U/L) 150 100 50 0 6 12 18 24 Mean (± SE) of the absolute value and reference ranges are presented. Adapted from Hosking D, et al. J Bone Miner Res. 2007;22:142-148. With permission of the American Society for Bone and Mineral Research. Time From Initiation of Therapy (months) Adverse Events With Zoledronic Acid Comparable to Risedronate After Day 3 Zoledronic Acid (n = 177) Adverse Events† Total with any AE Pain in arm or leg Arthralgia Dizziness Nasopharyngitis Diarrhea Headache Back pain Risedronate (n = 172) P Value .16 .99 .05 .41 .29 .81 .46 .04 Patients, n (%) 117 (66.1) 13 (7.3) 9 (5.1) 9 (5.1) 9 (5.1) 8 (4.5) 7 (4.0) 4 (2.3) 126 (73.3) 12 (7.0) 19 (11.0) 5 (2.9) 14 (8.1) 9 (5.2) 10 (5.8) 12 (7.0) Synthetic Salmon Calcitonin Dose • 50 to 100 units (0.25-50 ml)/day for 6-18 months or longer, with repeat course as needed • Subcutaneous or intramuscular injection Side Effects • Nausea (~10%) • Local irritation at injection site (10%) • Flushed ears and face (10-20%) • Bronchospasm (rare) • Uriticaria (rare) • Anaphylaxis (rare) Drug Resistance • Primary (uncommon) • Secondary: >50% of patients treated >6 months develop calcitonin antibodies, high titers usually produce resistance (10-20%) • Bisphosphonates Adverse effects • UGI intolerance, diarrhea (oral) • Acute phase reaction • Musculoskeletal/bone pain • Hypocalcemia • Renal failure reported with high dose intravenous bisphosphonates (obtain serum creatinine level before each dose of intravenous bisphosphonate) • Ocular inflammation (rare) • Osteonecrosis of jaw (ONJ) -rare Contraindications • Hypocalcemia • Vitamin D deficiency • Hypoparathyroidism • Severe renal insufficiency • Bisphosphonates, Vitamin D and Calcium • Correct vitamin D deficiency before • administering a bisphosphonate Instruct patients to take 1500 mg of calcium and 800 units of vitamin D (preferably vitamin D3) daily during the 10 days after an infusion of zoledronic acid • Incidence of ONJ – Rare Occurrence with Oral or infrequent IV use as in Paget’s – Reported in patients not taking bisphosphonates1–3 Osteonecrosis of Jaw (ONJ) and Bisphosphonates • ONJ was added to the ―Precautions‖ section of the Prescribing Information for ALL IV and oral bisphosphonates. occurred in cancer patients receiving IV bisphosphonates4-7 • Bisphosphonate-associated ONJ has predominantly 1. Peters E et al. Oral Surg Oral Med Oral Pathol. 1993;75:739–743. 2. Erdogan O et al. J Diabetes Complications. 2005;19:364–367. 3. Lenz JH et al. J Craniomaxillofac Surg. 2005;33:395–403. 4. NIH Osteoporosis and Related Bone Diseases—National Resource Center. Revised November 2005; Available at: www.niams.nih.gov/bone/hi/oralhealth_bone.pdf. 5. Ruggiero S et al. J Oral Maxillofac Surg. 2004;62:527–534. 6. Bamias A et al. J Clin Oncol. 2005;23:8580–8587. 7. Woo SB et al. Ann Intern Med. 2006;144:753–761. Management Strategies for Osteonecrosis of Jaw • • Patients who develop ONJ during bisphosphonate therapy should receive care by an oral surgeon. Management of patients with chronic bone exposure has reportedly included1: • Local irrigation with povidone-iodine and 0.12% chlorhexidine mouthwash • Oral antibiotics and anti-inflammatory drugs (other pain medications as needed to control symptoms) • Conservative debridement for necrotic tissue Aggressive surgical intervention (such as bone resection) appears counterproductive and may produce further exposed bone. 2 For patients requiring dental procedures (such as surgery), there are no data available to suggest that discontinuation of bisphosphonate treatment reduces the risk for ONJ. Current data are not adequate to support that stopping the administration of bisphosphonates is beneficial for improving the outcome of ONJ.1,3 • • • 1. Ficarra G et al. J Clin Periodontol. 2005;32:1123–1128. 2. Marx RE et al. J Oral Maxillofac Surg. 2005;63:1567–1575. 3. Migliorati CA et al. J Am Dent Assoc. 2005;136:1658–1668. Orthopaedic Management Corrective Osteotomy for Deformity Deformity Malalignment • mechanical overload • limitation of motion • pain • dysmorphic appearance Courtesy of J. Parvizi, M.A. Frankle, F.H. Sim Post-Op Hip Arthroplasty in Paget’s • • Complex technical challenges Gross deformities - Coxa vara - Femoral bowing - Acetabular protrusio Stress fracture of proximal femur Subcapital fracture or nonunion • • Courtesy of J. Parvizi, M.A. Frankle, F.H. Sim Degenerative Arthritis of the Hip: Preoperative Hip Replacement in Paget’s Disease Patient Follow-Up Untreated Patients • Annual serum total or bone specific alkaline phosphatase measurement • Periodic x-rays of osteolytic lesions Treated Patients • Serum total or bone specific alkaline phosphatase measurement every 3-6 months • Bone resorption markers are optional • Periodic x-rays of osteolytic lesions For More Information About Paget’s Disease Please Visit: www.paget.org