EndocrinologyTier 2Disease (DEADMAN)

Bone metabolism disorders - Paget disease

Description

Focal disorder of grossly accelerated, disorganised bone remodelling
*Focal, not systemic - disease does not spread from bone to bone*, and no new sites appear after diagnosis
- So a bone scan at diagnosis defines the disease for life

Phases

1. Osteolytic - intense osteoclastic resorption. Advancing "blade of grass" or "flame" lucency in a long bone; osteoporosis circumscripta in the skull
2. Mixed - resorption + frenzied compensatory formation
3. Osteosclerotic/burnt-out - dense, expanded, coarsely trabeculated bone

Net result: bigger, denser, but structurally disorganised and mechanically weak bone
- Woven rather than lamellar; hypervascular
- High BMD on DEXA does not mean strong bone here

Distribution

Pelvis > femur > lumbar spine > skull > tibia
Monostotic ~1/3, polyostotic ~2/3
*~70% are asymptomatic* - found on an incidental X-ray or an isolated raised ALP

Rare under 55; prevalence rises with age - ~1-3% over 55 in Anglo-Celtic populations
M>F ~3:2
Highest prevalence: UK, Australia, New Zealand, Western Europe (Anglo-Celtic migration pattern)
- Incidence and severity have fallen markedly over the last 30 years - unexplained; supports an environmental trigger
15-40% have an affected first-degree relative

Primary abnormality is the osteoclast: giant, multinucleated (up to 100 nuclei), hyperactive, with viral-like nuclear inclusions
-> massively increased resorption
-> compensatory, disorganised osteoblastic new bone formation (hence the very high ALP)
-> woven bone, marrow fibrosis, hypervascularity

Contributors

Genetic
- SQSTM1 (p62) mutations in 10-50% of familial and ~5-10% of sporadic disease - impaired NF-kB signalling regulation -> osteoclast hyperactivity
- Autosomal dominant with incomplete penetrance; also TNFRSF11A (RANK), OPTN, CSF1
Environmental - long-suspected slow paramyxovirus (measles, canine distemper) infection; never proven, and the falling incidence is the strongest argument for some environmental factor

Biochemistry

Total ALP is the workhorse - reflects the number and activity of affected bones
- Can be normal in limited monostotic disease
- Confirm bone origin with bone-specific ALP or GGT (normal GGT excludes a hepatic source)
Calcium, phosphate and PTH are normal - hypercalcaemia only with immobilisation or coexisting primary hyperparathyroidism
P1NP and CTX as alternative turnover markers
Always exclude coexisting vitamin D deficiency before treating - it causes hypocalcaemia after a bisphosphonate

Imaging

Plain X-ray of the symptomatic site is the diagnostic test
- Cortical thickening, coarse trabeculation, bone expansion, mixed lysis and sclerosis
- Skull: osteoporosis circumscripta then "cotton wool" sclerosis, diploic widening
- Spine: "picture frame" vertebra, ivory vertebra
- Pelvis: thickened iliopectineal line, protrusio acetabuli
- Long bones: anterior tibial bowing ("sabre tibia"), lateral femoral bowing, transverse "banana" fissure fractures on the convexity
Radionuclide bone scan defines the extent - intensely avid; do this once, at diagnosis
- More sensitive than X-ray for extent, but less specific - correlate any hot spot with a radiograph
CT/MRI only for suspected cord compression, basilar invagination, or sarcoma

Examination

Enlarging skull (increasing hat size), frontal bossing, skull bruit
Deafness - conductive (ossicular involvement) and sensorineural (cochlear capsule involvement, VIII compression)
Other cranial neuropathies from foraminal narrowing or basilar invagination
Bowing deformity, limb length inequality, secondary OA of adjacent joints
Local warmth over the affected bone (hypervascularity)
*New or worsening pain, a soft tissue mass, or rapidly increasing warmth -> think sarcoma*

Who to treat

*Bone pain arising from a pagetic site is the primary indication*
- Classically deep, boring, worse at rest and at night - contrast mechanical/arthritic pain
Also treat for:
- Skull/petrous temporal involvement - hearing preservation
- Nerve root or spinal cord compression
- Involvement of a critical site - cervical spine, weight-bearing long bone, adjacent to a major joint
- Progressive deformity or long bone bowing
- High-output cardiac failure (rare, extensive disease)
- Hypercalcaemia of immobilisation
- Before elective surgery at a pagetic site - reduces the intense intra-operative bleeding
*A raised ALP alone in an asymptomatic patient is NOT an indication*
- PRISM/PRISM-EZ: intensive ALP-targeted bisphosphonate therapy did not reduce fracture, surgery or quality-of-life outcomes

Drug therapy

Zoledronic acid 5 mg IV as a single infusion is first line
- Faster, deeper and far more durable biochemical remission than oral bisphosphonates - often ~5 years or longer from a single dose
- Requires normal renal function (eGFR >35) and vitamin D repletion; warn about the acute phase reaction
Oral risedronate or alendronate if IV is unsuitable
Calcitonin is now a fallback only - weak, short-lived, tachyphylaxis
Calcium and vitamin D repletion before and after any bisphosphonate

Monitoring and retreatment

ALP at 3-6 months, then 6-12 monthly
Retreat for recurrent pain or a rising ALP - and prefer IV zoledronic acid again
- Do not re-dose zoledronic acid within 12 months
Analgesia: paracetamol, NSAIDs; treat secondary OA on its own merits

Surgery

Joint replacement for secondary OA, fracture fixation, osteotomy for deformity, spinal decompression
Pre-treat with a bisphosphonate where possible - pagetic bone is intensely vascular and bleeds

Other

Secondary osteoarthritis of hip and knee - the commonest cause of pain, and often the real problem when pain persists after treatment
Deafness (skull disease), other cranial neuropathies, basilar invagination -> hydrocephalus, brainstem compression
Spinal stenosis and cord compression - from bone expansion and from a vascular steal phenomenon
Pathological and fissure fractures (transverse, on the convex surface of a bowed bone)
High-output cardiac failure - only with very extensive disease
Hypercalcaemia with immobilisation; hyperuricaemia and gout; nephrolithiasis
SQSTM1 - also mutated in inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD), and in ALS

Slowly progressive within already-affected bones; no new sites develop
Most patients remain asymptomatic and require no treatment
Bisphosphonate produces durable biochemical and symptomatic remission; relapse announced by rising ALP
Osteosarcoma - <1% but the feared complication
- New, unremitting pain, soft tissue mass, rapid ALP rise, lytic destruction on X-ray
- Pelvis, femur, humerus. *Prognosis dismal - 5-year survival <10%*
- Giant cell tumour and other sarcomas occur less often
Deformity and secondary arthritis are irreversible - treatment prevents progression, it does not remodel bone that has already deformed

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