Updated: 4/2/2019

Paget's Disease

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Introduction
  • A condition of abnormal bone remodeling
    • original osseous tissue is reconstructed through active interplay between excessive bone resorption and abnormal new bone formation  
  • Pathophysiology
    • increased osteoclastic bone resorption is the primary cellular abnormality 
    • cause is thought to be a slow virus infection (intra-nuclear nucleocapsid-like structure)
      • paramyxovirus
      • respiratory syncytial virus
  • Epidemiology
    • peak incidence in the 5th decade of life
    • common in Caucasians (northern European / Anglo-Saxon descent)
    • males = females
    • location
      • may be monostotic or polyostotic
      • common sites include femur > pelvis > tibia > skull > spine
  • Genetics
    • inheritance
      • most cases are spontaneous
      • hereditary
        • familial clusters have been described with ~40% autosomal dominant transmission
    • genetics 
      • most important is 5q35 QTER (ubiquitine binding protein sequestosome 1) SQSTM1 (p62/Sequestosome)
        • tend to have severe Paget disease
      • also insertion mutation in TNFRSF11A for gene encoding RANK
  • Orthopaedic manifestations
    • bone pain
    • long bone bowing
    • fractures, due to brittle bone and tend to be transverse
    • large joint osteoarthritis
      • excessive bleeding during THA
      • malalignment during TKA
    • secondary sarcoma
  • Associated conditions
    • high output heart failure
  • Prognosis & malignancy
    • Paget's sarcoma
      • less than 1% will develop malignant Paget's sarcoma (secondary sarcoma)
      • osteosarcoma > fibrosarcoma and chondrosarcoma  
      • most common in pelvis, femur, and humerus
      • poor prognosis
        • 5-year survival for metastatic Paget's sarcoma < 10% 
        • treatment includes chemotherapy and wide surgical resection 
Classification
  • Phases
    • lytic phase
      • intense osteoclastic resorption
    • mixed phase
      • resorption and compensatory bone formation
    • sclerotic phase
      • osteoblastic bone formation predominates
    • all three phases may co-exist in the same bone
Presentation
  • Symptoms
    • asymptomatic
      • frequently asymptomatic and found incidentally
    • pain
      • pain may be the presenting symptom due to
        • stress fractures
        • increased vascularity and warmth
      • new intense pain and swelling
        • suspicious for Paget's sarcoma in a patient with history of Paget's + new intense pain and swelling
    • cardiac symptoms
      • can present with high-output cardiac failure particularly if large/multiple lesions & pre-existing diminished cardiac function
Imaging
  • Radiographs
    • coarsened trabeculae which give the bone a blastic appearance
      • both increased and decreased density may exist depending on phase of disease
        • lytic phase
          • lucent areas with expansion and thinned, intact cortices
          • 'blade of grass' or 'flame-shaped' lucent advancing edge
        • mixed phase
          • combination of lysis + sclerosis with coarsened trabeculae
        • sclerotic phase
          • bone enlargement with cortical thickening, sclerotic and lucent areas image  
    • remodeled cortices
      • loss of distinction between cortices and medullary cavity
    • long bone bowing
      • bowing of femur or tibia image
    • fractures 
    • hip and knee osteoarthritis
    • osteitis circumscripta
      • (cotton wool exudates) in skull image
    • Paget's secondary sarcoma
      • shows cortical bone destruction
      • soft tissue mass
  • MRI
    • may show lumbar spinal stenosis
  • Bone scan image
    • accurately marks site of disease
    • intensely hot in lytic and mixed phase
    • less hot in sclerotic phase
  • CT scan
    • cortical thickening and coarsened trabeculae
Evaluation
  • Laboratory findings 
    • elevated serum ALP
    • elevated urinary collagen cross-links
    • elevated urinary hydroxyproline (collagen breakdown marker)
    • increased urinary N-telopeptide, alpha-C-telopeptide, and deoxypyridinoline
    • normal calcium levels
Histology
  • Characteristic histology post
    • woven bone and irregular broad trabeculae with disorganized cement lines in a mosaic pattern    
    • profound bone resorption - numerous large osteoclasts with multiple nuclei per cell 
      • virus-like inclusion bodies in osteoclasts  
      • Paget's osteoclasts larger, more nuclei than typical osteoclasts
    • fibrous vascular tissue interspersed between trabeculae
Treatment
  • Nonoperative
    • observation and supportive therapy  
      • treatment for asymptomatic Paget's disease
        • physiotherapy, NSAIDS, oral analgesics
    • medical therapy aimed at osteoclast inhibition  
      • bisphosphonates are 1st line treatment for symptomatic Pagets
        • oral
          • alendronate and risedronate
          • etidronate disodium (Didronel) 
            • older generation medication
            • inhibits osteoclasts and osteoblasts
            • cannot be used for more than 6 months at a time
        • intravenous
          • pamidronate, zoledronic acid (Zometa)
            • newer generation medications that only inhibit osteoclasts
            • disadvantageous in that they only come in IV form
      • calcitonin are 2nd line (after bisphosphonates)
        • causes osteoclasts to shrink in size and decreases their bone resorptive activity within minutes
        • administered subcutaneously or intramuscularly
      • teriparatide is contraindicated in Paget's disease due to risk of secondary osteosarcoma 
  • Operative
    • THA / TKA
      • indications
        • affected patients with degenerative joint disease
      • technique
        • treat Paget's with pharmacologic agents prior to arthroplasty to reduce bleeding
      • outcomes
        • greater incidence of suboptimal alignment secondary to pagetoid bone
        • the most common complications include
          • malalignment with knee arthroplasty 
          • bleeding with hip arthroplasty
    • metaphyseal osteotomy and plate fixation  
      • indications
        • fractures through pathologic bowing of long bones
        • impending pathologic fracture of long bone with bowing
Differentials & Groups
 
 
Benign lesion in older patient (40-80)
 
Multiple lesions in the older patient
 
Treatment is Observation only(assuming no imp. path. fx.)
 
Benefits from Bisphosphonate therapy
Paget's Disease
 
 
 
Enchondroma
     
   
Bone island
     
 
   
Bone infarct
 
 
 
   
Hyperparathyroidism
 
 
 
 
   
Metastatic bone disease    
       
Myeloma    
 
 
 
Lymphoma    
       
NOF        
   
Osteochondroma
 
 
 
 
   
Eosinophillic granuloma        
   
Fibrous dysplasia
 
 
 
     




 
IBank
 
Location
Age
Xray
Xray
CT
B. Scan
MRI
MRI
Histo(1)
Case A fibula
10 yrs.
   
   
(1) - histology does not always correspond to clinical case 

 

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Questions (23)
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(OBQ12.81) A 78-year-old female presents with mild right hip pain following a twisting injury. She denies fever, weight-loss, and night sweats. She has a positive family history for breast cancer. Laboratory studies show a WBC of 8.9 k/uL (range 4-11,000) and an ESR of 12 mm/hr (range 0-22). A radiograph is obtained and shown in Figure A. A CT scan of the chest, abdomen, and pelvis is performed and shows no evidence of metastatic lesions. A biopsy is performed and shown in Figures B and C. What is the most appropriate next step in treatment? Review Topic

QID: 4441
FIGURES:
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1

Wide resection with perioperative chemotherapy

14%

(605/4359)

2

Wide resection with perioperative radiation

8%

(356/4359)

3

Wide resection alone

8%

(363/4359)

4

Radiation alone

5%

(227/4359)

5

Observation with evaluation for bisphonate therapy

64%

(2769/4359)

L 3

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(SBQ11PA.83) A 67-year-old male patient is scheduled for left total hip arthroplasty. A pre-operative examination reveals elevated serum alkaline phosphatase and urine hydroxyproline. A radiograph of his hip/pelvis is seen in Figure A. Taking into context the clinical and radiographic presentation, what would you expect to be the most common complication with this procedure? Review Topic

QID: 4108
FIGURES:
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1

Implant malalignment

8%

(292/3887)

2

Increased blood loss

59%

(2288/3887)

3

Peri-prosthetic fracture

30%

(1160/3887)

4

Sciatic nerve palsy

2%

(72/3887)

5

Deep vein thrombosis

1%

(46/3887)

L 4

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(OBQ11.194) A 55-year-old male presents with left hip pain and stiffness. Radiographs are shown in Figures A and B. A biopsy of the left femur is performed and shown in Figure C. Which of the following medications is contraindicated in this patient? Review Topic

QID: 3617
FIGURES:
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1

Teriparatide

68%

(1222/1805)

2

Alendronate

10%

(188/1805)

3

Ergocalciferol

4%

(71/1805)

4

Zoledronic acid

3%

(53/1805)

5

Calcitonin

15%

(263/1805)

L 3

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(OBQ11.11) Paget's disease may predispose a patient to the development of which of the following malignant neoplasms? Review Topic

QID: 3434
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1

Chondrosarcoma

4%

(101/2574)

2

Osteosarcoma

53%

(1365/2574)

3

Spindle cell sarcoma of bone

3%

(71/2574)

4

All of the above

35%

(909/2574)

5

None of the above

5%

(122/2574)

L 5

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(OBQ10.78) Which of the following conditions can be characterized by excessive bone resorption and disordered bone formation as characterized by the radiograph in Figure A? Review Topic

QID: 3166
FIGURES:
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1

Osteopetrosis

4%

(70/1623)

2

Paget's disease of bone

90%

(1466/1623)

3

Osteogenesis imperfecta

3%

(48/1623)

4

Rickets

2%

(29/1623)

5

Legg-Calve-Perthes disease

1%

(9/1623)

L 1

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(OBQ10.104) The disease shown in the radiograph and biopsy specimen, Figures A and B, is best characterized by which of the following laboratory findings Review Topic

QID: 3198
FIGURES:
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1

Decreased urinary N-telopeptide and increased urinary alpha-C-telopeptide

4%

(83/2326)

2

Low serum vitamin D levels

10%

(231/2326)

3

Increased urinary N-telopeptide and decreased urinary alpha-C-telopeptide

18%

(408/2326)

4

Increased urinary N-telopeptide and alpha-C-telopeptide

59%

(1382/2326)

5

Increased urinary N-telopeptide and decreased urinary excretion of pyridinium crosslinks

9%

(202/2326)

L 3

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(OBQ09.59) A 55-year-old male has a several month history of hip pain. He is diagnosed with Paget's disease based on his radiographs and positive bone scan indicating a lytic phase. What cell demonstrated by the red arrow in the Figures below is most commonly associated with the etiology Paget's disease? Review Topic

QID: 2872
FIGURES:
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1

Figure A

2%

(36/2096)

2

Figure B

15%

(324/2096)

3

Figure C

72%

(1513/2096)

4

Figure D

5%

(95/2096)

5

Figure E

5%

(111/2096)

L 2

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(OBQ08.129) A 65-year-old man complains of deformity of the right leg. He denies pain at rest but does complain of ankle and lower leg pain when walking more than a half mile. A radiograph is shown in Figure A. Following 6 months of orthotic and brace treatment, he continues to struggle with pain. Which of the following is the best treatment option? Review Topic

QID: 515
FIGURES:
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1

Continued orthotic and brace treatment

8%

(54/692)

2

Corrective osteotomy and plate fixation

45%

(310/692)

3

Intramedullary fixation

29%

(204/692)

4

Amputation

13%

(89/692)

5

Corrective osteotomy, knee arthrodesis, and plate fixation

4%

(27/692)

L 5

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(OBQ06.137) All of the following statements regarding Paget's sarcoma are correct EXCEPT? Review Topic

QID: 323
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1

The 5-year survival for metastatic Paget's sarcoma is less than 10%

12%

(120/981)

2

Less than 1% of patients with Paget's disease develop secondary Paget's sarcoma

6%

(58/981)

3

While osteosarcoma is the most common histologic sub-type of Paget's sarcoma, fibrosarcoma and chondrosarcoma sub-types also occur

4%

(42/981)

4

Paget's sarcoma typically occurs in patients over 50 years of age

2%

(19/981)

5

Treatment of Paget's sarcoma is via surgery alone

75%

(737/981)

L 2

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(OBQ05.111) A 62-year-old female sustained the injury seen in Figure A after a fall at home. Her past medical history is significant for mild hypertension only. She is not currently taking any medications. Her pre-operative assessment revealed elevated serum alkaline phosphatase. Serum calcium and phosphate were normal. What is the most likely underlying diagnosis? Review Topic

QID: 997
FIGURES:
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1

Paget's bone disease

86%

(1984/2307)

2

Osteoporosis

9%

(214/2307)

3

Osteomyelitis

0%

(3/2307)

4

Renal osteomalacia

4%

(90/2307)

5

Aneurysmal bone cyst

0%

(6/2307)

L 1

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(SBQ05PA.19) A 70-year-old man presents with intermittent right lower extremity pain over several years. He denies any history of trauma. Physical examination reveals mild tenderness over the proximal third of right tibia with slight tibial bowing. A routine blood test shows an elevated serum alkaline phosphatase. Radiographs of the right tibia are shown in Figures A and B. A total body bone scan is shown in Figure C. What malignant transformation is most commonly associated with this patients underlying condition? Review Topic

QID: 2004
FIGURES:
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1

Osteosarcoma

77%

(2092/2711)

2

Fibrosarcoma

9%

(233/2711)

3

Multiple myeloma

12%

(321/2711)

4

Giant cell tumor

1%

(29/2711)

5

Osteoid Osteoma

1%

(23/2711)

L 2

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(SBQ05PA.85) A 52-year-old male farmer presents with right hip pain for the past 4 months. On physical examination there is pain with internal rotation of his right hip. Laboratory studies show elevated serum alkaline phosphatase. Serum calcium is normal. Urinary studies show elevated urinary N-telopeptide, alpha-C-telopeptide, and deoxypyridinoline markers. A radiograph of the pelvis is shown in Figures A. What would be the most appropriate treatment for this patient? Review Topic

QID: 2070
FIGURES:
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1

Antibiotics

0%

(16/3284)

2

Bisphosphonates

83%

(2736/3284)

3

Monoclonal-B antibodies

4%

(136/3284)

4

Chemotherapy

8%

(257/3284)

5

Wide resection and radiotherapy

4%

(116/3284)

L 2

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(SBQ05PA.54) Which of the following would be the most appropriate treatment for a patient with asymptomatic Paget's disease? Review Topic

QID: 2039
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1

Supportive therapy

50%

(1410/2832)

2

Calcitonin

4%

(122/2832)

3

Vitamin D and Calcium

6%

(174/2832)

4

Bisphosphonates

38%

(1086/2832)

5

Monoclonal-B antibody

1%

(22/2832)

L 4

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(SBQ05PA.100) A 78 year-old male has been having progressive pain in his left thigh and hip when walking. He is otherwise healthy and takes no medications. Laboratory evaluation reveals normal ESR and CRP, but elevated urinary hydroxyproline and increased urinary N- and alpha-C-telopeptides. Which of the following radiographs is most consistent with his clinical picture? Review Topic

QID: 2085
FIGURES:
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1

Figure A

3%

(11/361)

2

Figure B

20%

(71/361)

3

Figure C

9%

(31/361)

4

Figure D

4%

(14/361)

5

Figure E

64%

(230/361)

L 3

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(OBQ04.169) A 65-year-old male presents with increasing shoulder pain over the past 9 months. He is otherwise healthy and has no other complaints. Radiograph of his shoulder is shown in Figure A. Whole body bone scan and biopsy photograph are shown in Figures B and C. What is the most appropriate treatment for this patient? Review Topic

QID: 1274
FIGURES:
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1

Referral to endocrinology

20%

(299/1501)

2

Radiation therapy and chemotherapy

28%

(419/1501)

3

Wide resection and reconstruction

8%

(126/1501)

4

Radiation therapy, wide resection, and reconstruction

7%

(111/1501)

5

Chemotherapy, wide resection, and reconstruction

36%

(538/1501)

L 4

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