Paget's Disease of the Bone

Question 1

Paget’s disease of the bone (PDB) is ______ in 1 or more bones due to abnormally large and overactive __ causing focal areas of excessive __, with compensatory __ at pagetic sites resulting in ______

Common symptoms (4)

Alternative name: __

Answer 1

Abnormal bone remodeling
Overactive osteoclast - excessive bone resorption
Compensatory bone formation by osteoblasts
Disorganised, enlarged, structurally weak bone

Symptoms:
- Bone pain
- Skeletal deformities
- Pseudofractures
- Osteoarthritis

Alternative name: osteitis deformans

Question 2

Causes of PDB is unknon, but postulated:
- Genetic mutations in __ - encodes protein in osteoclast function
- __ infection - EM noted osteoclast intranuclear structures resembling nuclecaspids, though no virus cultured

Answer 2

SQSTM1 gene
Paramyxovirus

Question 3

Epidemiology and clinical presentation of PDB

Answer 3

Middle age > 40 years old, increasing with age
Men > women
European > African and Asian
(US: 2-3% of population > 55 years)

1. Asymptomatic, incidental findings
   - Elevated ALP, abnormal XR of bones
2. Bone pain or osteoarthritis
   - Deep aching, at rest or activity, worse at night
3. Skeletal deformities
   - Enlarged skull (lion facies)
   - Long bone deformity, tibial anterior bowing, femoral anterolateral bowing
   - Subtle increased warmth (increased blood flow)
   - Surgical scars for previous long bone fractures
4. Complications
   - Hearing loss and use of hearing aid
   - High output failure and hyperdynamic circulation (collapsing pulse)
   - Cranial nerve compression (CN8, CN2, CN5, CN7)
   - Spinal disease and vascular steal syndrome

Question 4

Differential diagnosis of PDB

Answer 4

1. Chronic osteomyelitis
2. Fibrous dysplasia
3. Metastatic disease to the bones
4. Metaphyseal dysplasia (Engelmann’s disease)
5. Hyperostosis frontalis interna
6. Familial expansile osteolysis
7. Osteosarcoma
8. ALP elevation in liver or biliary disease
9. Osteomalacia
10. Hyperparathyroidism
11. Multiple myeloma

Question 5

What bones are involved in PDB?

Answer 5

Mono-ostotic or poly-ostotic
Predilection for axial skeleton, but can affect any bone
Number of skeletal sits involved stable over time, rarely developing new lesions after diagnosis

Commonest
1. Pelvis - 70%
2. Femur - 55%
3. Lumbar spine - 53%
4. Skull - 42%
5. Tibia - 32%

Question 6

Triphasic progression of pagetic bone lesion

Answer 6

1. Lytic phase - focal bone resorption
   - Increased osteoclast activity - enlarged, multinucleated
   - Bone loss ,wedge shaped resorption in long bones or circumscribed lytic lesions in skull
2. Intermediate phase - osteoblast and accelerated bone formation
   - Disorgansied bone architecture (mosaic or woven) with mixed lytic/sclerotic phase
   - Impaired bone strength, risk of fracture
   - Bone appears enlarged, sclerotic, with bowing deformities, linear radiolucencies (pseudofracture), calvarium and cortical thickening, coarse trabeculae
3. Cold phase - reduced bone cell activity
   - Persistent abnormal bone architecture, woven bone converted to dense lamellar bone

Question 7

Investigations for PDB

Answer 7

Elevated ALP in normal vitamin D (excludes osteomalacia)
Isotopic bone scan

Biochemical
1. ALP - normal in osteolytic phase, raised in osteoblastic
(To send bone specific ALP)
2. Calcium and albumin
3. Liver function test
4. Vitamin D

Imaging
5. Plain XR
6. Radionucleide bone scan

Question 8

Management and treatment goals of PDB

Answer 8

1. Adequate calcium and vitamin D levels
2. Analgesia for pain control
3. Biphosphonates if indicated (see separate card)
   - IV zoledronate 5mg: achieves ALP normalisation 96% (75% reduction in ALP)
4. Calcitonin - less effective
5. Denosumab - off label use with significant fractur risk and BMD on stopping

Treatment goals
1. ALP reduction, reaching nadir by 3-6 months
(Alternative markers: C-telopeptides, N-telopeptides, P1NP, BSALP)
- No data to support normalisation reduces long term complication risks

Question 9

What are the indications for biphosphonate treatment in PDB?

Answer 9

1. Symptomatic active PDB
2. High risk of complications - fracture in weight bearing bones, nerve compression
3. Before elective surgery - reduces hypervascularity and perioperative blood loss
4. Hypercalcaemia with immobility

Question 10

What are the side effects of biphosphonates?

Answer 10

1. Osteonecrosis of jaw
2. Atypical femoral fractures (subtrochanteric)
3. Nephrotoxicity, esp if eGFR < 35
4. Hypocalcaemia, worse in vit D deficiency
5. Oesophagitis and dyspepsia

Question 11

Complications of PDB

Answer 11

1. Osteoarthritis
2. Bone deformity
3. Fracture and pseudofracture
4. Hearing loss
   - Ossicle ankylosis and narrowing of IAM
   - Cochlear damage from bony overgrowth
5. Cranial nerve compression
6. Spinal stenosis and radiculopathy
7. Obstructive hydrocephalus - base of skull compression
8. High output cardiac failure
9. Hypercalcaemia
10. Giant cell tumour or osteosarcoma

Question 12

Risk of osteosarcoma in PDB

Answer 12

< 1% of all patients
Suspect in PDB with:
- Increasing bone pain and swelling, worse at night
- New mass
- New fracture at pagetic site

Investigations: MRI of specific site

Prognosis: poor (5 year survival 10%)

Question 13

What are causes of tibial bowing?

Answer 13

1. Paget’s disease of the bone
2. Neurofibromatosis (pseudoarthrosis of tibia)
3. Rickets
4. Fibrous dysplasia
5. Fibular hemimelia
6. Trauma
7. Congenital