Paget s disease of bone Dr Sanjeev Patel Consultant

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Pagets disease of bone

• Dr Sanjeev Patel
• Consultant Physician Senior Lecturer in
  Rheumatology
• Epsom St Helier University Hospitals
• St Georges, University of London

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Objectives

• Pathology
• Clinical presentation
• Investigations
• Treatment

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Characteristics of Pagets disease

• Disease of osteoclasts
• Osteoclasts show abnormal morphology and are
  increased in number
• Focal areas of increased and disorganised bone
  turnover
• Focal bone involvement is common

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Osteoclast
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Bone remodelling
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Osteoclasts in Pagets disease

• Morphology
• Up to 100 nuclei (normal 3 to 20)
• Presence of nuclear inclusions

• Physiology
• Hypersensitive to osteoclastogenic factors such
  as 1,25D and RANKL

Roodman Windle JCI 2005115200-208
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Lamellar bone
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Mosaic pattern
Irregular bone formation. Many reversal lines
indicate zones of previous resorption against
which new bone has been deposited. This imparts
to the bone the typical to "mosaic" pattern.
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Current understanding of preosteoblastic/stromal
cell regulation of osteoclastogenesis
Khosla Endocrinology, Volume 142(12).December
2001.5050-5055
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Aetiology of Pagets disease

• Inflammatory Paget 1877
• Vascular Cone 1922
• Viral Rebel et al 1974 Mills Singer 1976
• Neoplastic Rasmusen Bordier 1974
• Lead Toxicity Spencer et al 1992
• Genetic McKusick 1972Siris 1996

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Current theory for the aetiology of Pagets
disease of bone

• Genetic factors
• Enhance basal osteoclastogenesis and create a
  permissive environment for its development
• Non-genetic (environmental) factors
• Viral infections

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Genetics

• 7 potential susceptibility loci have been
  identified
• SQSTM1 most important for adult PDB

Daroszewska Ralston 2005109257-263
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Genetics

• 15 to 40 of patients with Pagets have at least
  one affected first-degree relative
• 25-50 of familial Pagets diseases patients and
  5 to 15 of sporadic patients have mutations
  present in exons 7 or 8 of sequestosome 1 gene
  (SQSTM1)
• SQSTM1 gene involved in the activation of RANK

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SQSTM1 gene
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Non-genetic factors

• Several reasons why environment important
• Variable penetrance
• Localised disease rather than all of the skeleton
• Incidence and severity changing
• Viral infection
• Paramyxovirus (controversial)
• Measles virus nuclear protein found in OC nuclei
• Canine distemper virus also found
• Others

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Pathogenesis of Pagets disease
Enhanced basal osteoclastogenesis
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Pathogenesis of Pagets disease
Enhanced basal osteoclastogenesis
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Pathogenesis of Pagets disease
Enhanced basal osteoclastogenesis
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Pathogenesis of Pagets disease
Enhanced basal osteoclastogenesis
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Pathogenesis of Pagets disease
Enhanced basal osteoclastogenesis
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Epidemiology

• Affects about 1 to 5 of those above 50 yrs
• Increases with age (rare lt 40 years)
• Mainly caucasians of European descent
• Only about 5 are symptomatic

Selby et al Bone 200231366-373
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The Rotterdam Study

• Population based study using blood tests and
  radiographs
• Mean age 71 yrs
• 20.5 of subjects with elevated AlkP had Pagets
• 86 of patients with Pagets had normal AlkP
• (whereas in outpatient clinics 85 have raised
  AP)

Eekhoff et al JBMR 200419566-570
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UK
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Clinical features

• Pain
• Deformity
• Osteoarthritis
• Fracture
• Neurological symptoms
• Sarcomatous transformation
• Cardiac failure

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Monostotic Pagets disease

• Pagets disease affecting one bone
• 5 to 40 of patients presenting with pain
• Common sites are the ilium, tibia and femur

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Investigations

• Markers of bone turnover
• X-rays
• Isotope bone scans
• Bone biopsy (rarely needed)

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Biochemical markers of bone remodelling
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Differential diagnosis

• Raised alkaline phosphatase
• Metastatic bone disease
• Osteomalacia
• Hyperparathyroidism
• Liver disease
• Similar radiographic appearance
• Metastatic disease
• Lymphoma
• Fribrous dysplasia
• Chronic osteomyelitis

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Plain x-rays

• Help define stage of disease
• Lytic or sclerotic
• Presence of
• fracture (stress)
• Osteoarthritis

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Plain x-rays
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Isotope bone scans

• Visualises whole of skeleton
• Defines extent and distribution of disease
• Ideally all patients should undergo isotope bone
  scanning and X-rays of affected areas

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Isotope bone scans
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Monostotic Pagets uptake index
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Treatment of Pagets disease

• Drugs
• Bisphosphonates
• Risedronate, Zoledronate, Etidronate, Tiludronate
• Calcitonin
• Mithramycin (historical)
• Guidelines
• Selby et al Bone 200231366-373

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Drug Treatment

• Bisphosphonates
• Drugs which promote osteoclast apoptosis
• Reduce bone turnover
• Reduce woven bone formation
• Increase lamellar bone formation
• Filling in of lytic areas
• Improves bone strength

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Bisphosphonates

• Etidronate
• Tiludronate
• Clodronate
• Pamidronate
• Risedronate
• Zoledronate

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Comparison of a Single Infusion of Zoledronic
Acid with Risedronate for Paget's Disease
Zoledronate 5mg i.v. Risedronate 30mg/day for 60
days
Reid et al NEJM 2005353898-901
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Comparison of a Single Infusion of Zoledronic
Acid with Risedronate for Paget's Disease
Zoledronate 5mg i.v. Risedronate 30mg/day for 60
days
Reid et al NEJM 2005353898-901
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Guidelines for treatment - UK

• Indications for treatment
• Symptom control
• Reduce long term complications
• Fracture, Osteoarthritis, Others
• No evidence for reducing long term complications
  by intensive treatment of Pagets disease
• Ralston et al PRISM Study Endocrine Abstracts
  (2006) 12 OC15

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Monitoring treatment

• Symptom improvement
• Biochemistry (aim to reduce AP into normal range)
• X-rays (for weight bearing lytic areas)
• Isotope bone scanning (for monostotic disease)

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Summary

• Common
• Most patients asymptomatic
• Common cause for raised AlkP particularly if
  gamma GT is normal
• Easily treated with modern bisphosphonates
• Pain can be improved
• Long term complications reduced?