Diagnosis and Management of Paget’s Disease of Bone
E.F. Weltevreden MD PhD Gelre Hospitals Apeldoorn, The Netherlands Modified from: www.paget.org
Sir James Paget
History of Paget’s Disease – Sir James Paget named disease osteitis deformans in 1876, suspecting basic inflammatory process – Today predominantly referred to as Paget’s disease of bone
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 histories1 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; 2006:320330. 2. Altman RD, et al. J Bone Miner Res. 2000;15:461-465.
Causes and effects of Paget’s Disease on Bone
Causes and effects of Paget’s Disease on Bone
Molecular window
Genetic Abnormalities in Familial Paget’s Disease & Related Disorders
Classical Paget’s disease – Autosomal dominant – Mutations of sequestosome 1/p62 gene (5q 35-qter) – 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
Multinucleated osteoclast
Paget’s Disease: An Osteoclast-Mediated Disorder Histology of Pagetic Bone
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 findings 1 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
Advanced Paget’s Disease in the Tibia: Sclerotic and Lytic Lesions
Secondary osteolytic front Primarily sclerotic changes, with enlargement and thickening of long bones
Paget’s Disease: progression over 15 Years in Untreated Patient Bowing
Cortical thickening
1976
1991
Early-Stage (Lytic) Paget’s Disease in the Skull: Known as “Osteoporosis Circumscripta”
Lytic border
Advanced (Sclerotic) Paget’s Disease: “Cotton Wool” Skull Diffuse sclerotic changes
Lytic lesion
Paget’s Disease in the Skull
Eindhoven, The Netherlands
Egil's Bones An Icelandic saga tells of a Viking who had unusual, menacing features, including a skull that could resist blows from an ax. He probably suffered from an ailment called Paget's disease Â
Paget’s Disease in the Femur
Curved deformity of the femur
Accentuation of trabecular pattern Cortical thickening
Paget’s Disease of Femur
X-Ray
Bone Scan
Pathology
Paget’s Disease: “Picture Frame” Vertebral Body Lytic lesion
Cortical thickening
Active phase, osteoclastic. DD hyperparathyreoidism Early Osteoblastic phase.
Early Osteoblastic phase; + woven bone, mosaic pattern
Late phase. Mosaic pattern less evident. Polarized light !
Even in cancelous / trabecular bone! Suggest M.Paget.
A Bone Scan Showing Polyostotic Disease
Bilateral Thermogram of a Tibia
Bone region with increased metabolic activity
Paget’s Disease: physical Examination 1 – 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
Skeletal Deformities: bowing of Long Bones Bowing of humerus
Skeletal Deformities: Bowing of Lower Limbs Bowed femurs
Bowed tibias
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)
Complications of Pagetâ&#x20AC;&#x2122;s Disease: Fissure Fracture in the Tibia
Fissure fracture
Complications of Pagetâ&#x20AC;&#x2122;s Disease: Complete (Chalk-Stick) Fracture in a Femur
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 Pagetâ&#x20AC;&#x2122;s Disease: Osteosarcoma in Pagetic Femur Sarcomatous degeneration
Histology of Pagetâ&#x20AC;&#x2122;s sarcoma
Complications of Pagetâ&#x20AC;&#x2122;s Disease: Giant Cell Tumor of Scapula
Histology of Giant Cell Tumor
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”
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
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 ď Ž
ď Ž
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
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 bisphosphonates1–3
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 bisphosphonates4-7
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
Orthopaedic Management Corrective Osteotomy for Deformity Deformity
Malalignment • mechanical overload • limitation of motion • pain • dysmorphic appearance
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
Degenerative Arthritis of the Hip: Preoperative
Hip Replacement in Pagetâ&#x20AC;&#x2122;s Disease Post-Op
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
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