Paget’s
Disease of Bone (Osteitis Deformans)
1.
Cause and Etiology
Paget's disease of bone (PDB) is a chronic, focal disorder
of bone remodeling characterized by excessive and disorganized bone turnover.
The etiology of PDB remains partially elucidated, with evidence supporting both
genetic and environmental contributions.
1.1 Genetic Factors
Paget’s disease exhibits a strong familial aggregation,
with an autosomal dominant inheritance pattern seen in some families. Up to 40%
of affected individuals have a first-degree relative with the disease. Several
genes have been implicated:
·
SQSTM1 (Sequestosome 1): Mutations in this gene, especially affecting the
ubiquitin-associated (UBA) domain, are the most well-established genetic cause.
SQSTM1 encodes p62, a scaffold protein involved in NF-κB signaling, which
regulates osteoclastogenesis and survival. Mutations lead to enhanced NF-κB
activity and increased osteoclast activity.
·
TNFRSF11A and TNFRSF11B: Mutations affecting the RANK/RANKL/OPG signaling axis, critical in
osteoclast differentiation and activation, have also been associated with
familial PDB and PDB-like syndromes.
·
Other Genetic Loci:
Genome-wide association studies (GWAS) have identified loci such as 1p13,
10p13, 14q32, and 15q24 associated with susceptibility.
1.2 Environmental Factors
Several environmental triggers have been proposed, though
none have been definitively proven.
·
Viral Hypothesis:
Paramyxoviral nucleocapsid-like inclusions have been observed in osteoclasts
from affected bone, with measles virus, canine distemper virus, and respiratory
syncytial virus being the most commonly implicated. However, attempts to
confirm viral presence via PCR and other molecular techniques have yielded
inconsistent results.
·
Geographic and Temporal Clustering: There has been a noted decline in the prevalence and severity of
PDB over recent decades in Western countries, suggestive of a diminishing
environmental trigger, possibly a viral pathogen that is now better controlled.
·
Occupational Exposures: Some studies have suggested that exposure to environmental toxins
such as lead and arsenic may be associated with increased risk, though evidence
is weak.
2.
Pathophysiology
Paget's disease is primarily a disease of bone remodeling,
involving an uncoupling of the resorption and formation phases. It progresses
through three histologically and functionally distinct stages:
2.1 Lytic Phase
(Osteoclastic Phase)
This is the initial phase characterized by aggressive bone
resorption.
·
Osteoclasts in PDB are numerous, enlarged, and
hypernucleated (sometimes containing up to 100 nuclei per
cell).
·
These cells exhibit high
resorptive capacity and are often abnormal in function and morphology.
·
The excessive bone resorption
leads to the release of cytokines and growth factors that stimulate
osteoblastic recruitment.
2.2 Mixed Phase
Bone resorption continues, but there is a simultaneous, exaggerated osteoblastic
response, leading to the formation of new bone matrix.
·
The bone laid down is disorganized and architecturally
abnormal, forming a mosaic or “jigsaw puzzle” pattern of
lamellar bone due to haphazard cement lines.
·
The marrow is often replaced by
fibrovascular
tissue.
2.3 Sclerotic Phase
The bone becomes sclerotic, thickened, and enlarged, but
structurally weaker
due to poor mineralization and disorganized architecture.
·
The abnormal bone is highly vascular,
prone to fracture, deformity, and expansion.
·
Bone pain is partly due to
microfractures and increased intraosseous pressure and
vascularity.
3.
Epidemiology
3.1 Prevalence
·
Varies significantly by
geographic region. The highest prevalence is found in Western Europe,
particularly the UK, where up to 5% of individuals over 55 years may be
affected.
·
In contrast, it is rare in
Scandinavia, Asia, and Africa.
3.2 Age and Gender
·
Most commonly diagnosed in
individuals over
50 years of age.
·
There is a slight male predominance
(M:F = 1.4:1).
3.3 Temporal Trends
·
A significant decline in prevalence and
severity has been reported in recent decades.
·
This decline suggests either
environmental changes or improved public health measures, such as widespread
vaccination.
3.4 Familial Patterns
·
Up to 30–40% of cases in
high-prevalence countries report a family history.
·
In familial cases, disease
tends to present earlier and is often more severe and polyostotic.
4.
Clinical Presentation
Paget’s disease is often asymptomatic and incidentally
discovered on radiographs or due to elevated alkaline phosphatase (ALP) levels.
Symptomatic disease presents variably depending on the bones involved.
4.1 Bone Pain
·
Most common symptom.
·
Often deep, dull, and present
at rest.
·
May be due to microfractures, vascular congestion,
or periosteal
stretching.
4.2 Skeletal Deformities
·
Bowing of long bones
(especially tibia and femur).
·
Skull enlargement (increased
hat size) and frontal bossing.
·
Kyphosis due to vertebral
involvement.
4.3 Pathologic Fractures
·
Occur in weight-bearing bones
such as the femur and tibia.
·
Fractures are typically transverse
and occur in areas of abnormal bone.
4.4 Neurologic Complications
·
Cranial nerve compression from
skull involvement (hearing loss, tinnitus, vertigo).
·
Spinal stenosis from vertebral
expansion.
·
Hydrocephalus (rare) from
basilar invagination.
4.5 Vascular Manifestations
·
High-output cardiac failure in
severe, extensive disease due to increased vascularity.
·
Steal syndromes may cause
distal ischemia.
4.6 Other Complications
·
Osteoarthritis:
Common at joints adjacent to the affected bone.
·
Giant cell tumor of bone: A Rare, benign but aggressive tumor in Pagetic bone.
·
Malignant transformation: 1% risk of sarcomatous degeneration, usually osteosarcoma.
5.
Imaging Features
5.1 Radiographs
·
Most important first-line
diagnostic tool.
Lytic
Phase:
·
Well-demarcated osteolytic lesions
(“blade of grass” or “flame-shaped” lucencies).
Mixed
Phase:
·
Coarsened trabecular pattern.
·
Cortical thickening.
·
Bone enlargement.
Sclerotic
Phase:
·
Homogeneously sclerotic and
expanded bone.
·
“Cotton wool” appearance in the
skull.
·
Vertebral bodies may show the
“picture frame” appearance.
5.2 Bone Scintigraphy
·
Technetium-99m bone scan is
highly sensitive.
·
Shows increased uptake
in affected areas.
5.3 CT and MRI
·
CT provides detail on cortical
integrity and fractures.
·
MRI is useful in assessing soft
tissue involvement or malignant transformation.
5.4 Laboratory
·
Elevated total alkaline phosphatase (ALP)
is the most consistent lab abnormality.
·
Normal calcium and phosphate
(unless complicated by immobilization or fracture).
·
Bone turnover markers like PINP, CTX may be
elevated.
·
Urinary hydroxyproline or NTx
may be monitored for treatment response.
6.
Treatment
Treatment is aimed at suppressing bone turnover,
relieving symptoms, and preventing complications.
6.1 Indications for
Treatment
·
Symptomatic disease (pain,
deformity).
·
Asymptomatic disease with:
o
Lesions at risk for
complications (e.g., weight-bearing bones, skull, spine).
o
Preoperative planning for
orthopedic surgery in an affected area.
o
Elevated ALP indicates active
disease.
6.2 Bisphosphonates
Mainstay of therapy; inhibits osteoclast-mediated bone
resorption.
First-line
Agent: Zoledronic Acid
·
5 mg IV infusion once.
·
May normalize ALP and provide years of remission.
·
Preferred due to potency and
long duration.
Other
Options:
·
Risedronate: 30 mg orally daily
for 2 months.
·
Alendronate: 40 mg orally daily
for 6 months.
·
Pamidronate: 60–90 mg IV over
2–4 hours.
Monitoring:
·
ALP levels every 3–6 months.
·
Re-treatment if ALP rises
again.
6.3 Calcitonin
·
Less effective, reserved for
patients who cannot tolerate bisphosphonates.
·
Administered subcutaneously or
intranasally.
6.4 Pain Management
·
NSAIDs, acetaminophen.
·
Physical therapy.
6.5 Orthopedic Intervention
·
Joint replacement for secondary
osteoarthritis.
·
Internal fixation for
fractures.
·
Decompressive surgery for
neural compression.
7.
Prognosis
·
With effective treatment, most patients live a normal
lifespan.
·
Zoledronic acid induces biochemical and radiographic
remission in over 90% of cases.
·
Risk of sarcomatous transformation
is low (<1%), but prognosis is poor if it occurs.
·
Hearing loss and deformities
are often irreversible,
hence the importance of early diagnosis and treatment.
Prognostic Factors
·
Extent and distribution of bone
involvement.
·
Baseline ALP level.
·
Presence of complications
(e.g., fractures, osteoarthritis, neurologic impairment).
·
Response to bisphosphonate
therapy.
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