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PAGET’S DISEASERonen Gurfinkel PGY4
December 21, 2011
Objectives
To review the background, epidemiology, and clinical presentation of Paget's disease
To review the current treatment options for Paget’s disease
Case 1
An old woman, painted in 1513 by Flemish artist Quinten Massys
Skull, facial, collar bone and hand deformities
Case 1 – “The Ugly Duchess”
Case 2
46 year old man with bilateral thigh and leg pain
Pain was worse after exercise PMH: nil Meds: nil Family history: Sister had breast cancer
Case 2
1 year later, patient noted left shin was misshapen
Over next 3 years Left tibia had become larger and developed an
anterior curve Developed enlargement and arching of left
femur and widening of left pelvis Enlargement of right skull Functional status minimally affected Patient tried various medicines that were of no
benefit
Case 2
Over next 17 years Slow and uniform progression of all
abnormalities Right leg became similarly involved Range of motion in knees decreased
bilaterally Hat size increased from 22 ½ inches to 27
¼ inches Became kyphotic
Case 2
Case 2
At age 64, patient developed difficulty hearing
At age 68, patient noted pain in the left forearm and elbow, associated with increasing swelling
Patient died 2 months later
Background
1876 – Sir James Paget described 5 cases of “chronic inflammation of bones” that he termed osteitis deformans
Background
Paget’s disease Localized disorder of bone remodeling Typically begins with excessive bone
resorption Followed by an increase in bone formation
Pathophysiology
Lamellar bone
Pathophysiology
Paget’s disease is associated with an abnormal histologic pattern of lamellar bone
This abnormal bone structure results from a sequence of 3 phases
Typically, all 3 phases are seen simultaneously at multiple sites
Pathophysiology
Three phases Lytic Mixed lytic and blastic Sclerotic
Pathophysiology
Three phases Lytic
Normal bone is resorbed by osteoclasts that are more numerous, are larger, and have more nuclei (up to 100)
Bone turnover rates up to 20 times faster than normal
Mixed lytic and blastic Sclerotic
Pathophysiology
Pathophysiology
Three phases Lytic Mixed lytic and blastic
Rapid increase in bone formation from numerous (morphologically normal) osteoblasts
Newly made bone is abnormal Collagen fibers are deposited in a
haphazard manner High bone turnover rate continues
Sclerotic
Pathophysiology
Three phases Lytic Mixed lytic and blastic Sclerotic
Bone formation dominates Bone continues to be formed in a
disorganized pattern
Pathophysiology
Lamellar bone
Pathophysiology
“Mosaic” or “woven” bone
Pathophysiology
Three phases Lytic Mixed lytic and blastic Sclerotic
Bone formation dominates Bone continues to be formed in a
disorganized pattern Infiltration of marrow by excessive
fibrous connective tissue and blood vessels
Hypervascular bone state
Epidemiology
Second most common bone disorder in elderly persons
Affects 1 to 3 million people in the United States, but prevalence difficult to estimate Based on 1971-1975 NHANES I data, US
prevalence was 0.7% Prevalence increases with age
Very rare in individuals age < 25 1-3% of individuals age > 40 > 10% of individuals age > 80
Altman RD, Bloch DA, Hochberg MC, Murphy WA. Prevalence of pelvic Paget's disease of bone in the United States. J Bone Miner Res. Mar 2000;15(3):461-5.
Epidemiology
Prevalence of Paget’s disease varies by location Highest prevalence in Europe
Mainly in England, France, and Germany High prevalence in North America Rare in Asia, Middle East, and Africa
Prevalence 0.01% in sub-Saharan Africa Higher rates are seen in men
Male:Female ratio 1.2-1.8:1
Etiology
Etiology of Paget’s disease is unknown Studies suggest that genetic factors and/or viral
infection play a role Genetic factors
14-25% of family members of patients with Paget’s disease eventually develop Paget’s disease
First-degree relatives of patients with Paget’s disease have a 7-10x increased risk of developing Paget’s disease
Several loci have been found on chromosomes 5, 6, and 18 in fmailies with autosomal dominant inheritance of Paget’s disease
Viral Infection
Etiology
Etiology of Paget’s disease is unknown Studies suggest that genetic factors and/or viral
infection play a role Genetic factors Viral Infection
Nuclei and cytoplasm of osteoclasts appear to contain uncharacterized viral particles
Virus may be a member of the Paramyxoviridae family Infection by members of this viral family promotes the fusion of
infected cells, with the subsequent formation of multinucleated giant cells
Other viruses have also been implicated in the pathogenesis of Paget disease
Canine distemper virus (3x risk in owners of unvaccinated dogs) Measles virus (identified in osteoclasts)
Clinical Manifestations
Most patients are asymptomatic Signs and symptoms are variable
Location and extent of bone involved Relation of pagetic bone to adjacent structures
Monostotic disease in about 1/3 of patients Most commonly affected sites
Pelvis Spine Skull Long bones
Clinical Manifestations
Two main manifestations Pain Deformity
Other manifestations Fractures Bone tumours Neurologic disease Cardiac disease Calcium and phosphate abnormalities
Clinical Manifestations
Two main manifestations Pain Deformity
Clinical Manifestations
Two main manifestations Pain
Directly related to pagetic lesion Degenerative arthritis Nerve impingement Osteosarcoma
Deformity
Clinical Manifestations
Two main manifestations Pain Deformity
Long bones – Bowing Tibia – sabre shin Femur – shepherd’s crook
Skull Enlargement in frontal and occipital areas with
“cotton wool” appearance
Sabre Shin
Shepherd’s Crook
a
“Cotton Wool” Apperance
Clinical Manifestations
Other manifestations Fractures Bone tumours Neurologic disease Cardiac disease Calcium and phosphate abnormalities
Clinical Manifestations
Other manifestations Fractures
Commonest complication of Paget disease Commonest sites are femur and tibia
Bone tumours Neurologic disease Cardiac disease Calcium and phosphate abnormalities
Clinical Manifestations
Other manifestations Fractures Bone tumours
Higher incidence in Paget’s disease Develop in 1% of patients Osteosarcoma is the commonest type Giant cell tumours also occur (benign)
Neurologic disease Cardiac disease Calcium and phosphate abnormalities
Clinical Manifestations
Other manifestations Fractures Bone tumours Neurologic disease
Skull involvement can lead to hearing loss (CN 8) CN 2, 3, and 7 palsies also seen Skull base involvement can lead to hydrocephalus Spine involvement can cause nerve impingement and
ischemic myelitis Sciatic compression
Cardiac disease Calcium and phosphate abnormalities
Clinical Manifestations
Other manifestations Fractures Bone tumours Neurologic disease Cardiac disease
Heart failure Aortic stenosis Conduction abnormalities
Calcium and phosphate abnormalities
Clinical Manifestations
Other manifestations Fractures Bone tumours Neurologic disease Cardiac disease Calcium and phosphate abnormalities
Hypercalcemia and hypercalciuria Secondary hyperparathyroidism
Investigations
Serum ALP Urine hydroxyproline C-telopeptide collagen cross-links 25-hydroxy vitamin D
Investigations
Serum ALP Most commonly used Marker of bone formation (increased osteoblastic activity) In untreated Paget’s disease, level is correlated with
degree of disease activity Can measure total ALP or bone-specific ALP
Total ALP and bone-specific ALP have sensitivities of 74% and 84%, respectively
Bone-specifc ALP can be measured if liver function is abnormal Total ALP may be normal in monostotic or local disease
Urine hydroxyproline C-telopeptide collagen cross-links 25-hydroxy vitamin D
Alvarez L, Guañabens N, Peris P, Monegal A, Bedini JL, Deulofeu R, et al. Discriminative value of biochemical markers of bone turnover in assessing the activity of Paget's disease. J Bone Miner Res. Mar 1995;10(3):458-65
Investigations
Serum ALP Urine hydroxyproline
Product of collagen breakdown and marker of bone resorption
20-30% of total levels are from bone resorption Levels correlate with disease extent and activity Levels may be increased by dietary collagen
and skin diseases C-telopeptide collagen cross-links 25-hydroxy vitamin D
Investigations
Serum ALP Urine hydroxyproline C-telopeptide
Cross-linked C-terminal telopeptides are fragments of type 1 collagen released during bone resorption
Highly sensitive to detect bone resorption 25-hydroxy vitamin D
Investigations
Serum ALP Urine hydroxyproline C-telopeptide collagen cross-links 25-hydroxy vitamin D
Exclude osteomalcia
Investigations
Plain radiographs Bone scan
Investigations
Plain radiographs Lytics lesions
Appear as radiolucencies Can have wedge-shaped appearance in long bones
(“blade of grass”) Osteoporosis circumscripta
Areas of bone formation Enlarged bone with Increased density Coarsened trabecula “Picture frame” appearance of vertebral body “Ivory vertebra”
Bone scan
Investigations
Osteoporosis Circumscripta
Investigations
Investigations
Plain radiographs Bone scan
Most sensitive test, but less specific than plain radiography
Lesions appear as “hotspots” Used pre-treatment to document extent of
disease Can be repeated to rule out neoplasms if
there is increase in pain or ALP after successful treatment
Investigations
Treatment
Objectives of treatment Reduce symptoms Improve function Slow disease process and prevent
complications No direct evidence to support this, however:
Untreated Paget’s disease is associated with extension of osteolytic lesions and progression of deformities
Normal pattern of new bone deposition seen with treated Paget’s disease
Treatment can lead to improvement in facial and skull deformities
Treatment
Non-pharmacological Pain management with analgesics Surgery Anti-resorptive therapies
Treatment
Non-pharmacological Mainly physiotherapy
Increase muscle strength to help control some pain
Accupuncture Hydrotherapy Transcutaneous electrical nerve stimulation
Pain management with analgesics Surgery Anti-resorptive therapies
Treatment
Non-pharmacological Pain management with analgesics
Useful for muscle spasm or arthritis pain Acetaminophen NSAIDs
Surgery Anti-resorptive therapies
Treatment
Non-pharmacological Pain management with analgesics Surgery
Repair of fractures Hip and knee arthroplasty
Anti-resorptive therapies
Treatment
Non-pharmacological Pain management with analgesics Surgery Anti-resorptive therapies
Bisphosphonates Calcitonin
Treatment
Indications for treatment Symptomatic disease Asymptomatic disease, but active disease
ALP 2-4x upper limit of normal Active disease at sites where complications can
occur (elevated ALP or positive bone scan) Hypercalcemia secondary to immobilization Preoperatively for planned surgery at active
site
Treatment
Contraindications to treatment Elderly asymptomatic patients whose life
span would limit the chance of future complications
Metabolically inactive lesions No osteolytic lesions on radiographs No increased uptake on bone scan
Calcitonin
32-amino acid polypeptide hormone, discovered in 1962 Salmon calcitonin used in 1970’s, was the first effective
therapy for Paget’s disease Only the subcutaneous route is approved for Paget’s disease
Inhibits osteoclasts via the calcitonin receptor Limitations
Reduces bone turnover markers by 40-50% Acquired resistance due to antibodies in 26% Rapid relapse seen after discontinuation Side effects include nausea, vomiting, and flushing
Useful when bisphophonates are not tolerated or contraindicated
Bisphosphonates
Synthetic analogues of inorganic pyrophosphate Simple Nitrogen-containing
Bind hydroxyapatite crystals of bone
Bisphosphonates
Bisphosphonates
Bone resorption suppressed within days to weeks Decreased C-telopeptide and
hydroxyproline Bone formation suppressed within weeks
to months Decreased ALP
First line in treatment of Paget’s disease
Simple Bisphosphonates
Inhibit bone resoprtion by generating toxic analog of adenosine triphosphate Bisphosphonate is metabolized by osteoclasts
to metabolites that exchange with the terminal pyrophosphate moiety of ATP
Results in an ATP that cannot be used as a source of energy
The osteoclasts then undergo apoptosis Produce rapid decrease in bone turnover Response related to total dose
Simple Bisphosphonates
Etidronate First bisphosphonate to be studied in humans in early 1970’s Approved by FDA in 1978 for the treatment of Paget’s disease,
and is still approved by Health Canada for Paget’s disease The least potent of currently available bisphosphonate drugs Treatment associated with osteomalacia
Clodronate and tiludronate Intermediate potency bisphosphonates Clodronate was first bisphosphonate to be used IV in high doses They are not associated with osteomalacia Studies with these agents showed that a more prolonged
remission is achieved if ALP nadir was in the lower half of normal range
Are not approved by Health Canada for Paget’s disease
Nitrogen-containing Bisphosphonates
Newer and more potent Inhibit the farnesyl pyrophosphate synthase
enzyme in osteoclasts, which leads to suppression of protein prenylation, a process essential for bone resorption and cell survival Create cytoskeletal abnormalities in the
osteoclast Promotes detachment of the osteoclast from the
bone perimeter Leads to reduced bone resorption
Bisphosphonates
Nitrogen-containing Bisphosphonates
First study in Paget’s disease published in 1979 Oral pamidronate used in 18 patients Bone resorption normalized in most within
a week Return to normal bone formation in 3-6
months IV pamidronate shown to heal lytic
lesions
Frijlink WB et al. Treatment of Paget's disease with (3-amino-1-hydoxypropylidene)-1,1-bisphosphonate (APD). Lancet 1979: 799–803.
Nitrogen-containing Bisphosphonates
Sustained suppression of bone turnover at doses that do not impair mineralization
Agents approved by Health Canada Oral: alendronate, risedronate IV: pamidronate, zoledronate
Bisphosphonates
Relative Resorptive Potency of Bisphosphonates
Drug Generation Relative Potency
Etidronate First 1
Clodronate 10
Tiludronate Second 10
Alendronate 100
Pamidronate 100-1,000
Risedronate Third 1,000-10,000
Ibandronate 1,000-10,000
Zoledronate 10,000+
Bisphosphonates
Poorly absorbed when taken orally Must be taken with plain water, first thing
in the morning and at least 30 minutes before the first food, beverage, or other oral medications
Patients should not lie down during this period to prevent gastroesophageal reflux and possible esophageal irritation
Bisphosphonates
Normal serum levels of calcium, phosphorus and 25-hydroxy vitamin D should be present when initiating bisphosphonate therapy and throughout the ensuing year Patients should be given supplemental vitamin
D (800 IU daily) and calcium (1200 mg of elemental calcium/day in divided doses) to avoid hypocalcemia
Additional vitamin D supplementation (50,000 IU weekly) should be given for eight weeks prior to initiating therapy in patients whose 25-hydroxy vitamin D level is less than 50 nmol/L
Bisphosphonates
Alendronate Efficacy in Paget’s shown in 2 studies in 1996
Placebo controlled trial 55 patients ALP decreased by 73%, and normalized in 48% of
patients Radiologic improvement in 48% of patients
Compared to etidronate 89 patients ALP decreased in 79% in aledronate group vs 44% in
etidronate group ALP normalized in 63% of aledronate vs 17% of
etidronate patientsReid IR et al. Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate — a randomized, placebo-controlled trial. Am J Med 1996;101:341–8.Siris E et al. Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone. J Clin Endocrinol Metab 1996;81:961–7.
Bisphosphonates
Risedronate Efficacy demonstrated in 3 open-label
studies in 1998 Largest of these had 162 patients ALP decreased by 66% and normalized in
54% of patients Relieved bone pain in 26% of patients with
pain at study start
Siris ES et al. Risedronate in the treatment of Pagets-disease of bone — an open label, multicenter study. J Bone Miner Res 1998;13:1032–8.
Bisphosphonates
Bisphosphonates
Risedronate Compared to etidronate in a 1999
randomized double-blind study 123 patients ALP normalized in 73% of risedronate vs 15% of
etidronate patients Median time to ALP normalization 91 days in
risedronate group Significant decrease in pain only seen in
risedronate group
Miller PD et al. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Am J Med 1999;106:513–20.
Bisphosphonates
Zoledronate Most potent bisphosphonate with highest in vitro affinity
to hydroxyapatite NEJM 2005, 2 randomized double-blind studies of 357
patients Single zoledronate 5 mg infusion vs risedronate 30 mg po daily
for 6 months Primary endpoint: normalization of ALP or 75% reduction of
excess ALP at 6 months Primary endpoint reached in 96% of zoledronate vs 74% of
risedronate patients Zoledronate showed superior effects on quality of life
measures, including pain relief Lower frequency of loss of response in post-trial follow-up for a
median of 190 days (1% vs 27%)
Reid IR et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N Engl J Med 2005;353:898–908.
Bisphosphonates
Bisphosphonates
Bisphosphonates
Zoledronate JMBR 2011, open follow-up of responders from
2005 study 152 patients treated with zoledronate, 115 treated
with risedronate Followed up to 6.5 years without further treatment Endpoints: time to relapse, loss of response Relapse rates of 0.7% in zolendronate group vs 20%
in risedronate group Loss of response 12.5% in zoledronate group vs 62%
in risedronate group Better quality-of-life scores in zolendronate group
Bisphosphonates
Bisphosphonates
Bisphosphonates
Zoledronate Flu-like illness develops in 1/3 of patients
during the first infusion
Bisphosphonates
Michou and Brown. Emerging strategies and therapies for treatment of Paget’s disease of bone. Drug Des Devel Ther. 2011; 5: 225–239.
Treatment
Monitoring ALP most commonly used, every 3 months
x 2, then every 6 months thereafter Bone scan or radiographs at 6 months can
be used in those with normal pre-treatment ALP
Retreatment Persistent symptoms ALP did not normalize with initial treatment Relapse (eg ALP increase 25% above nadir)
Questions?