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

This program was supported by an

educational grant from the Alliance
Tel: 212-509-5335 for Better Bone Health: Procter &
Fax: 212-509-8492 Gamble Pharmaceuticals and
E-mail: Pagetfdn@aol.com Aventis Pharmaceuticals
Website: www.paget.org
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
Dose (Miacalcin®)
• 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%)
 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