Ronen Gurfinkel PGY4 December 21, 2011 Paget’s Disease Ronen 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 Mixed lytic and blastic Sclerotic 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 Sclerotic 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 Urine hydroxyproline 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 Bone scan 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 Pain management with analgesics Surgery 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 Surgery 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 Alendronate 100 Pamidronate 100-1,000 Risedronate Third 1,000-10,000 Ibandronate 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 patients Reid 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 Retreatment 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?