PAGET’S DISEASE Ronen Gurfinkel PGY4 December 21, 2011.

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


Bone formation dominates Bone continues to be formed in a

disorganized pattern

Pathophysiology

Lamellar bone

Pathophysiology

“Mosaic” or “woven” bone

Pathophysiology


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


Two main manifestations Pain Deformity

Other manifestations Fractures Bone tumours Neurologic disease Cardiac disease Calcium and phosphate abnormalities


Two main manifestations Pain

Directly related to pagetic lesion Degenerative arthritis Nerve impingement Osteosarcoma

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


Other manifestations Fractures

Commonest complication of Paget disease Commonest sites are femur and tibia

Bone tumours Neurologic disease Cardiac disease Calcium and phosphate abnormalities


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


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


Other manifestations Fractures Bone tumours Neurologic disease Cardiac disease

Heart failure Aortic stenosis Conduction abnormalities

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


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.


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

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

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?

PAGET’S DISEASE Ronen Gurfinkel PGY4 December 21, 2011.

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