Diagnosis and Management of Pagets Disease of Bone

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 This program was supported by an educational grant from the Alliance for Better Bone Health: Procter & Gamble Pharmaceuticals and Aventis Pharmaceuticals Portrait of Sir James Paget Paget’s First Patient Epidemiology Prevalence • High: United Kingdom, United States, Australia, New Zealand, Western Europe • Low: Scandinavia, China, Japan, India Prevalence in men and women nearly equal Family History: positive in as many as 40% of patients Bone Showing Active Lesion of Paget’s Disease Composite Sections of Normal and Pagetic Bone Section of Osteoclast Nucleus Containing Measleslike Nucleocapsid Radiograph of a Skull Demonstrates Osteoporosis Circumscripta Radiograph of a Femur Radiograph of a Tibia Demonstrate Severe Osteolytic Activity Radiograph of a Skull Shows Late-Stage Disease Magnetic Resonance Image of a Skull Computed Tomography of a Vetebra Radiograph of a Thoracic Spine A Bone Scan Showing Widespread Disease Bilateral Thermogram of a Tibia Biochemical Findings in Paget’s Disease Indices of bone resorption • Urinary hydroxyproline • Urinary collagen crosslinks • Urinary calcium/creatinine (fasting) Indices of bone formation • Serum total or bone-specific alkaline phosphatase • Serum osteocalcin Metabolic Complications of Paget’s Disease • • • • Hypercalciuria Hypercalcemia with immobilization Hyperparathyroidism (controversial) Gouty diathesis Musculoskeletal Complications of Paget’s Disease • Skeletal pain • Skeletal deformities • Fractures • Secondary osteoarthritis Musculoskeletal Complications: Pelvic Involvement and Degenerative Arthritis Musculoskeletal Complications: Lower Extremities Musculoskeletal Complications: Fissure Fracture Musculoskeletal Complications: Chalk-Stick Fracture Neurologic Complications of Paget’s Disease • • • • • • • • • Hearing deficit Cranial nerve deficits Mottled retinal degeneration;angioid streaks Basilar impression Hydrocephalus Myelopathy Radicular neuropathies Spinal stenosis Spinal vascular steal syndrome Ocular Complications: Fundus of the Eye Cardiovascular Complications of Paget’s Disease • • • • • Increased cardiac output Congestive heart failure Generalized atherosclerosis Aortic valve calcification Endocardial calcification Neoplastic Complications of Paget’s Disease • Sarcoma (osteosarcoma, chondrosarcoma, fibrosarcoma) • Metastatic carcinoma • Hematologic malignancies • Giant-cell tumor Neoplastic Complications of Paget’s Disease Related Osteogenic Sarcoma 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 Specific Therapies for Paget’s Disease of Bone in U.S. Calcitonin • Salmon calcitonin (By injection Miacalcin®) Bisphosphonates • Etidronate disodium (Didronel®) • Pamidronate disodium (Aredia®) • Alendronate sodium (Fosamax®) • Tiludronate disodium (Skelid®) • Risedronate sodium (Actonel®) Bisphosphonates Approved for Other Indications or Under Study for Paget’s Disease • • • • • Clodronate Olpadronate Ibandronate Zoledronate Neridronate Synthetic Salmon Calcitonin (Miacalcin®) 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 (1020%) Etidronate Disodium (Didronel®) Dose • 5 mg/kg/day po 2 hours before or after meals for 6 months • Repeat only after drug-free period of at least 3 months Side Effects • Increased or recurrent bone pain at pagetic sites • Onset of bone pain at previously asymptomatic sites • Diarrhea • Nausea Drug Resistance • Primary: Uncertain, probably 5-10% • Secondary: 15-24% Pamidronate Disodium (Aredia®) Dose • 30 mg intravenous infusion over 4 hours on 3 consecutive days is approved regimen but seldom used • 60 mg or 90 mg intravenous infusions over 2-4 hours are commonly used in mild disease a single infusion is effective, 2-3 or more infusions may be required in more severe disease • Depending upon the response to the initial treatment, the drug may be re-administered at irregular intervals Side Effects • About 1/3 of patients have an acute phase reaction within 24 hours, including fever, myalgia and slight leucopenia. Seldom occurs afters initial infusion • Inflammation of the eye occurs rarely Drug Resistance • Primary: rare • Secondary: may occur, but incidence is unknown Alendronate Sodium (Fosamax®) Dose • 40 mg tablet taken with 6-8 oz of tap water at least 30 minutes before breakfast daily for 6 months • Retreatment may be considered after a 6-month post treatment evaluation and in patients whose serum alkaline phosphatase activity did not reach the normal range Side Effects • Esophagitis may occur but can be prevented in most patients by instructing the patient to swallow the tablet with a large glass of water and not lie down for at least 30 minutes • Musculoskeletal pain may occur in 6% of patients Drug Resistance • Not reported Tiludronate Disodium (Skelid®) Dose • Two 200 mg tablets (400 mg) taken daily with 6-8 oz of tap water for 3 months. No food, calcium or indomethacin should be taken within 2 hours before or after • Assess patients 3 months after treatment is finished. Retreatment data are limited but suggest similar responsiveness as with initial treatment Side Effects • Nausea and diarrhea are uncommon • Seldom discontinued because of poor tolerance Drug Resistance • Not reported Risedronate Sodium (Actonel®) Dose • 30 mg tablet taken with 6-8 oz of tap water at least 30 minutes before breakfast for 2 months. Patients should remain upright at least 30 minutes after taking the medication • Retreatment may be considered following observation for at least 2 months if the initial course of treatment did not normalize serum alkaline phosphatase activity or if a biochemical relapse occurs. A second 2-month course of 30 mg daily is recommended Side Effects • Diarrhea, arthralgia and headache were the most frequent adverse events with the majority of cases being mild in severity Drug Resistance • Not reported Nonspecific and Experimental Therapies for Paget’s Disease of Bone • • • • Analgesics NSAIDS Plicamycin Gallium nitrate Hierarchy of Paget’s Disease Treatments Mild Disease Activity (up to 2-3 fold increase of alkaline phosphatase) • Salmon calcitonin or any bisphosphonate may normalize biochemistry Moderate Disease Activity (3-6 fold increase of alkaline phosphatase) • Pamidronate, alendronate or risedronate are most likely to normalize biochemistry Severe Disease Activity (>6 fold increase of alkaline phosphatase) • More than one course of pamidronate, alendronate or risedronate may be needed to normalize disease activity • Not all patients may have complete suppression of disease activity Hip Replacement for Paget’s Disease and Degenerative Arthritis Patient Follow-Up Untreated Patients • Annual serum alkaline phosphatase measurement • Annual x-rays of osteolytic lesions Treated Patients • Serum alkaline phosphatase measurement every 3-4 months • Urinary hydroxyproline or collagen crosslinks are optional • Annual x-rays of osteolytic lesions