1. Presentation by: Dr. Louis Ricca Clinical Associate Professor of Medicine University of South Florida Diagnosis and Management of Paget’s Disease of Bone Sir James Paget 1814-1899

2. History of Paget’s Disease Sir James Paget named disease osteitis deformans in 1876, suspecting basic inflammatory process 1,2 Today predominantly referred to as Paget’s disease of bone 1

4. What is Paget’s Disease?

7. 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

8. Epidemiology: Prevalence of Paget’s Disease in the US 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. Second most common bone disease after osteoporosis 1 Roughly estimated at approximately 2% of the US population over age 55 years 1 – Prevalence increases markedly with age, uncommon before age 40 1,2 15% to 30% of patients have positive family histories 1 Most common in people of Northern European descent 1

12. Histology of Pagetic Bone Paget’s Disease: An Osteoclast-Mediated Disorder Osteoclasts Multinucleated osteoclast Courtesy of Pierre Delmas, MD. Multinucleated osteoclast

16. 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. Pagetic Bone and Normal Bone NormalPagetic

17. Osteoclast Nucleus Containing Measles-like Nucleocapsid Structure Osteoclast Nucleus Containing Measles-like Nucleocapsid Structure X 32,000

18. Paget’s Disease: Clinical Presentation Usually mild or asymptomatic 1 Diagnosis is often based on incidental findings 1 – Elevated total or bone specific serum alkaline phosphatase – Radiological findings Patients may present with symptoms that are nonspecific or suggestive of other conditions 1 – 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.

19. Paget’s Disease: Common Sites of Involvement Paget’s disease can occur in any bone, but most commonly: – Skull – Vertebrae – Pelvis – Femur – Tibia

20. Diagnosing Paget’s Disease: Tests Laboratory tests 1,2 – 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]) Radiographs 1,2 – Characteristic appearance usually confirms diagnosis Bone scan to assess extent of disease 1 1.Lyles KW, et al. J Bone Miner Res. 2001;16:1379-1387. 2.Selby PL, et al. Bone. 2002;31:366-373.

22. 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

23. Lyles KW, et al. J Bone Miner Res. 2001;16:1379-1387. 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)

24. Paget’s Disease in the Skull Courtesy of Pierre Delmas, MD. Skull enlargement Dilated scalp veins

26. Courtesy of Pierre Delmas, MD. Early-Stage (Lytic) Paget’s Disease in the Skull: Known as “Osteoporosis Circumscripta” Lytic border

27. Advanced (Sclerotic) Paget’s Disease: “Cotton Wool” Skull Lytic lesion Diffuse sclerotic changes Courtesy of Pierre Delmas, MD.

29. Complications of Paget’s Disease: Angioid Streak Crack in Bruch’s membrane, termed “angioid streak”

30. Paget’s Disease: “Picture Frame” Vertebral Body Courtesy of Pierre Delmas, MD. Lytic lesion Cortical thickening

32. Courtesy of Pierre Delmas, MD. Early-Stage (Lytic) Paget’s Disease: Tibia V-shaped “blade of grass” lesion characteristic of lytic phase of Paget’s disease

35. Courtesy of Pierre Delmas, MD. Advanced Paget’s Disease in the Tibia: Sclerotic and Lytic Lesions Primarily sclerotic changes, with enlargement and thickening of long bones Secondary osteolytic front

36. 1976 Paget’s Disease: Progression Over 15 Years in Untreated Patient Courtesy of Pierre Delmas, MD. 1991 Bowing Cortical thickening

37. Complications of Paget’s Disease: Neoplastic Sarcoma (osteosarcoma, chondrosarcoma, fibrosarcoma) Benign giant cell tumor

38. Complications of Paget’s Disease: Osteosarcoma in Pagetic Femur 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. Sarcomatous degeneration

40. Complications of Paget’s Disease: Fissure Fracture in the Tibia Fissure fracture

42. Complications of Paget’s Disease: Complete (Chalk-Stick) Fracture in a Femur Courtesy of Pierre Delmas, MD.

44. Courtesy of Nuria Guañabens, MD. Advanced Paget’s Disease in the Pelvis Bony enlargement Diffuse sclerotic changes

46. Courtesy of Nuria Guañabens, MD. Paget’s Disease in the Femur Curved deformity of the femur Cortical thickening Accentuation of trabecular pattern

47. Paget’s Disease of Femur Courtesy of R. Bockman, MD, PhD X-RayBone ScanPathology

48. Courtesy of Jacques Brown, MD. Skeletal Deformities: Bowing of Long Bones Bowing of humerus

49. Skeletal Deformities: Bowing of Lower Limbs Courtesy of Pierre Delmas, MD. Bowed femurs Bowed tibias

50. A Bone Scan Showing Polyostotic Disease

53. 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.

54. 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, opioids 1,2 Surgery 1,2 – Fractures, bone deformities, osteoarthritis

55. 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

56. FDA-Approved Therapies and Dosing Regimens for Paget’s Disease* Didronel ® (etidronate)5 -10 mg/kg/d or6 mo 11-20 mg/kg/d3 mo Skelid ® (tiludronate)400 mg/d Fosamax ® (alendronate)40 mg/d6 mo Actonel ® (risedronate)30 mg/d2 mo Oral agents Aredia ® (pamidronate)30 mg/d4 h on 3 cons. days IV agents AgentDoseDuration of Therapy Reclast ® (zoledronic acid) 5 mgSingle, 15 min. infusion

57. Effect of Intravenous Pamidronate on Alkaline Phosphatase Activity and Urinary Hydroxyproline Excretion

58. Effect on Serum Alkaline Phosphatase of Alendronate 40 mg/day Vs. Placebo or Etidronate 400mg/day

59. Biochemical Remission Induced by Risedronate Treatment Risedronate 30 mg/day x 2 mos. Etidronate 400 mg/day x 6 mos.

60. Zoledronic Acid Lowers Alkaline Phosphatase Levels More Than Risedronate P <.001 010286391182 Days 0 100 200 300 400 500 Total Alkaline Phosphatase (U/L) Mean (  SE) Total Alkaline Phosphatase by Visit P <.001 Reid IR, et al. N Engl J Med. 2005;353:898-908. Copyright © 2003 Massachusetts Medical Society. All right reserved. Adapted with permission, 2007. Risedronate 30mg/d x 60d (n=80) Zoledronic Acid 5mg IV, 15 min (n=121) Normal alkaline phosphatase range

61. 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. During Study Extension, Zoledronic Acid Maintained Mean Serum ALP Better Than Risedronate Time From Initiation of Therapy (months) Serum ALP (U/L) 6121824 0 50 100 150 200 Start of extended observation period Risedronate 30mg/d x 60d (n=80) Zoledronic Acid 5mg IV, 15 min (n=121) Total AlP reference range

62. Adverse Events With Zoledronic Acid Comparable to Risedronate After Day 3 Zoledronic Acid (n = 177) Risedronate (n = 172) Adverse Events † Patients, n (%)P Value Total with any AE117 (66.1)126 (73.3).16 Pain in arm or leg13 (7.3) 12 (7.0).99 Arthralgia9 (5.1)19 (11.0).05 Dizziness9 (5.1) 5 (2.9).41 Nasopharyngitis9 (5.1)14 (8.1).29 Diarrhea8 (4.5) 9 (5.2).81 Headache7 (4.0)10 (5.8).46 Back pain4 (2.3)12 (7.0).04

63. 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%)

64. 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

65. 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 D 3 ) daily during the 10 days after an infusion of zoledronic acid

66. Osteonecrosis of Jaw (ONJ) and Bisphosphonates Incidence of ONJ – Rare Occurrence with Oral or infrequent IV use as in Paget’s – Reported in patients not taking bisphosphonates 1–3 ONJ was added to the “Precautions” section of the Prescribing Information for ALL IV and oral bisphosphonates. Bisphosphonate-associated ONJ has predominantly occurred in cancer patients receiving IV bisphosphonates 4-7 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.

67. 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 included 1 : 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.