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 Paget1814-1899

History of Paget’s Disease

• Sir James Paget named disease osteitis deformans in 1876, suspecting basic inflammatory process1,2

• Today predominantly referred to as Paget’s disease of bone1

What is Paget’s Disease?

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

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 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

Histology of Pagetic Bone

Paget’s Disease: An Osteoclast-Mediated Disorder

Osteoclasts

Multinucleated osteoclast

Courtesy of Pierre Delmas, MD.

Multinucleatedosteoclast

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

Normal Pagetic

Osteoclast Nucleus Osteoclast Nucleus Containing Measles-like Containing Measles-like Nucleocapsid StructureNucleocapsid Structure

X 32,000X 32,000

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.

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

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)

Paget’s Disease in the Skull

Courtesy of Pierre Delmas, MD.

Skullenlargement

Dilatedscalpveins

Courtesy of Pierre Delmas, MD.

Early-Stage (Lytic) Paget’s Disease in the Skull:

Known as “Osteoporosis Circumscripta”

Lytic border

Advanced (Sclerotic) Paget’s Disease: “Cotton Wool” Skull

Lyticlesion

Diffuse sclerotic changes

Courtesy of Pierre Delmas, MD.

Complications of Paget’s Disease: Angioid Streak

Crack in Bruch’s membrane, termed “angioid streak”

Paget’s Disease: “Picture Frame” Vertebral Body

Courtesy of Pierre Delmas, MD.

Lytic lesion

Corticalthickening

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

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

1976

Paget’s Disease: Progression Over 15 Years in Untreated Patient

Courtesy of Pierre Delmas, MD.1991

Bowing

Cortical thickening

Complications of Paget’s Disease: Neoplastic

• Sarcoma (osteosarcoma, chondrosarcoma, fibrosarcoma)

• Benign giant cell tumor

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

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

Fissurefracture

Complications of Paget’s Disease: Complete (Chalk-Stick) Fracture in a Femur

Courtesy of Pierre Delmas, MD.

Courtesy of Nuria Guañabens, MD.

Advanced Paget’s Disease in the Pelvis

Bony enlargement

Diffuse sclerotic changes

Courtesy of Nuria Guañabens, MD.

Paget’s Disease in the Femur

Curved deformity of the femur Cortical

thickening

Accentuation of trabecular pattern

Paget’s Disease of Femur

Courtesy of R. Bockman, MD, PhD

X-Ray Bone Scan Pathology

Courtesy of Jacques Brown, MD.

Skeletal Deformities: Bowing of Long Bones

Bowing of humerus

Skeletal Deformities: Bowing of Lower Limbs

Courtesy of Pierre Delmas, MD.

Bowedfemurs

Bowedtibias

A Bone Scan Showing Polyostotic Disease

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*

Didronel® (etidronate) 5 -10 mg/kg/d or 6 mo

11-20 mg/kg/d 3 mo

3 moSkelid® (tiludronate) 400 mg/d

Fosamax® (alendronate) 40 mg/d 6 mo

Actonel® (risedronate) 30 mg/d 2 mo

Oral agents

Aredia® (pamidronate) 30 mg/d 4 h on 3 cons. days

IV agents

Agent Dose Duration of Therapy

Reclast® (zoledronic acid)

5 mg Single, 15 min.infusion

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

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

P < .001

0 10 28 63 91 182Days

0

100

200

300

400

500

To

tal

Alk

alin

e P

ho

sph

atas

e (U

/L)

Mean ( SE) Total Alkaline Phosphatase by Visit

P < .001

P < .001

P < .001 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 alkalinephosphatase range

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)

Ser

um

AL

P (

U/L

)

6 12 18 240

50

100

150

200Start of extendedobservation period

Risedronate 30mg/d x 60d (n=80)

Zoledronic Acid 5mg IV, 15 min (n=121)

Total AlP reference range

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 AE 117 (66.1) 126 (73.3) .16

Pain in arm or leg 13 (7.3) 12 (7.0) .99

Arthralgia 9 (5.1) 19 (11.0) .05

Dizziness 9 (5.1) 5 (2.9) .41

Nasopharyngitis 9 (5.1) 14 (8.1) .29

Diarrhea 8 (4.5) 9 (5.2) .81

Headache 7 (4.0) 10 (5.8) .46

Back pain 4 (2.3) 12 (7.0) .04

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 injectionSide 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

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

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.