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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  

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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 

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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

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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 

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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 

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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

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Subcutaneous calcitonin (rarely used)1,2

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Pain management – NSAIDs, COX-2 inhibitors, analgesics, opioids1,2

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Surgery1,2 – Fractures, bone deformities, osteoarthritis

Indications for Treatment of Paget’s Disease     

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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 

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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

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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

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ONJ was added to the “Precautions” section of the Prescribing Information for ALL IV and oral bisphosphonates.

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Bisphosphonate-associated ONJ has predominantly occurred in cancer patients receiving IV bisphosphonates4-7

Management Strategies for Osteonecrosis of Jaw  

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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  

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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

For More Information About Pagetâ&#x20AC;&#x2122;s Disease Please Visit: www.paget.org