Diagnosis and Management of Pagets Disease of Bone

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Diagnosis and Management of Pagets Disease of
Bone

• An educational program provided by

The Paget Foundation
120 Wall Street 1602 New York, NY 10005
This program was supported by an educational
grant from the Alliance for Better Bone Health
Procter Gamble Pharmaceuticals and Aventis
Pharmaceuticals
Tel [phone] Fax [phone] E-mail
Pagetfdn_at_aol.com Website www.paget.org
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Portrait of Sir James Paget
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Pagets First Patient
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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

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Bone Showing Active Lesion of Pagets Disease
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Composite Sections of Normal and Pagetic Bone
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Section of Osteoclast Nucleus Containing
Measleslike Nucleocapsid
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Radiograph of a Skull Demonstrates Osteoporosis
Circumscripta
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Radiograph of a Femur
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Radiograph of a Tibia Demonstrate Severe
Osteolytic Activity
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Radiograph of a Skull Shows Late-Stage Disease
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Magnetic Resonance Image of a Skull
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Computed Tomography of a Vetebra
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Radiograph of a Thoracic Spine
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A Bone Scan Showing Widespread Disease
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Bilateral Thermogram of a Tibia
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Biochemical Findings in Pagets 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

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Metabolic Complications of Pagets Disease

• Hypercalciuria
• Hypercalcemia with immobilization
• Hyperparathyroidism (controversial)
• Gouty diathesis

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Musculoskeletal Complications of Pagets Disease

• Skeletal pain
• Skeletal deformities
• Fractures
• Secondary osteoarthritis

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Musculoskeletal Complications Pelvic Involvement
and Degenerative Arthritis
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Musculoskeletal Complications Lower Extremities
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Musculoskeletal Complications Fissure Fracture
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Musculoskeletal Complications Chalk-Stick
Fracture
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Neurologic Complications of Pagets Disease

• Hearing deficit
• Cranial nerve deficits
• Mottled retinal degenerationangioid streaks
• Basilar impression
• Hydrocephalus
• Myelopathy
• Radicular neuropathies
• Spinal stenosis
• Spinal vascular steal syndrome

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Ocular Complications Fundus of the Eye
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Cardiovascular Complications of Pagets Disease

• Increased cardiac output
• Congestive heart failure
• Generalized atherosclerosis
• Aortic valve calcification
• Endocardial calcification

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Neoplastic Complications of Pagets Disease

• Sarcoma (osteosarcoma, chondrosarcoma,
  fibrosarcoma)
• Metastatic carcinoma
• Hematologic malignancies
• Giant-cell tumor

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Neoplastic Complications of Pagets Disease
Related Osteogenic Sarcoma
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Indications for Treatment of Pagets 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

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Specific Therapies for Pagets 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)

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Bisphosphonates Approved for Other Indications or
Under Study for Pagets Disease

• Clodronate
• Olpadronate
• Ibandronate
• Zoledronate
• Neridronate

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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 (10-20)

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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

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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

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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

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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

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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

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Nonspecific and Experimental Therapies for
Pagets Disease of Bone

• Analgesics
• NSAIDS
• Plicamycin
• Gallium nitrate

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Hierarchy of Pagets 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

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Hip Replacement for Pagets Disease and
Degenerative Arthritis
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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