Paget’s Disease of Bone

Paget’s disease of bone (osteitis deformans) is a focal disorder of greatly accelerated and disorganised bone remodelling, affecting one bone (monostotic) or several (polyostotic) — but never the entire skeleton, which distinguishes it from metabolic bone disease.

It is rare before the age of 40 and its prevalence rises steeply with age (about 1–3% of people over 55 in the UK), with a male predominance.

Geographically it is common in the United Kingdom, Western Europe, Australia and North America and distinctly rare in India, Asia, Scandinavia and Africa — but it does occur in Indians and should not be dismissed.

Both prevalence and severity have fallen worldwide over recent decades, which strongly suggests a waning environmental trigger.

Genetic: mutations in SQSTM1 (p62), particularly P392L, are found in 40–50% of familial and 5–10% of sporadic cases, inherited in an autosomal dominant pattern with incomplete penetrance. Other genes include OPTN, TNFRSF11A and VCP.

Environmental: paramyxovirus (measles, canine distemper, respiratory syncytial virus) nuclear inclusions have been described in pagetic osteoclasts but remain unproven. Other proposed factors are low dietary calcium in youth, repetitive mechanical loading, and environmental toxins.

The primary abnormality is in the osteoclast — pagetic osteoclasts are large, multinucleated, hyperactive and hypersensitive to vitamin D and RANKL, producing intense focal resorption.

This is followed by frantic, disorganised osteoblastic repair, laying down structurally abnormal woven bone with a “mosaic” pattern of irregular cement lines, marked hypervascularity and marrow fibrosis. The bone is bigger and denser but mechanically weak.

Three phases: (i) osteolytic — resorption predominates; (ii) mixed osteolytic–osteoblastic; (iii) osteosclerotic or “burnt-out” — dense sclerotic bone with low turnover.

Up to 70–80% are asymptomatic, detected incidentally through an unexplained isolated rise in alkaline phosphatase or an X-ray performed for another reason.

Commonest sites in descending order: pelvis > lumbar spine > femur > thoracic spine > sacrum > skull > tibia > humerus.

Bone pain is the commonest symptom — deep, boring, worse at rest and at night, unlike mechanical pain; the overlying skin may be warm because of hypervascularity.

Deformity: anterolateral bowing of the tibia (“sabre tibia”) and femur, kyphosis, frontal bossing with increasing hat size, and secondary osteoarthritis of the hip and knee from altered joint mechanics — often the actual cause of pain.

Skull involvement: deafness (both conductive from ossicular involvement and sensorineural from cochlear capsule and VIIIth nerve compression) — Paget’s disease is a listed cause of hearing loss in the elderly and should be evaluated radiologically and with alkaline phosphatase. Also tinnitus, headache, platybasia and basilar invagination leading to hydrocephalus and brainstem compression.

Spinal involvement: back pain, spinal stenosis, radiculopathy, and rarely cord ischaemia from a vascular “steal” phenomenon.

Complications: pathological and fissure fractures, high-output cardiac failure (extensive disease, now rare), hypercalcaemia of immobilisation, hypercalciuria and renal stones, and osteosarcoma in under 1% — suspect this if there is new severe pain, a soft-tissue mass, or a sudden further rise in ALP; the prognosis is dismal.

Serum total alkaline phosphatase is the key screening and monitoring test, raised roughly in proportion to disease activity and extent. Calcium, phosphate and PTH are characteristically normal.

Biochemical differentiation of metabolic bone disease: Disease Calcium Phosphate Alkaline phosphatase PTH Paget’s disease Normal / high Normal / high High Normal Osteoporosis Normal Normal Normal Normal / high Osteomalacia Low / normal Low High / normal High Primary High Low / normal High / normal High hyperparathyroidism Hyperthyroidism High High High / normal Low

If ALP is normal or liver disease coexists, use bone-specific ALP or P1NP; urinary NTX/CTX reflect resorption. Any older person with a borderline low calcium and a raised ALP should also be assessed for vitamin D deficiency.

Plain radiography is diagnostic — cortical thickening, coarse trabeculae, bone expansion, and mixed lysis with sclerosis. Classic signs: “osteoporosis circumscripta” of the skull, “cotton-wool” skull, the “blade of grass” or “flame-shaped” lytic front advancing along a long bone, “picture-frame” vertebra, “ivory” vertebra, and pseudofractures on the convex (tension) surface.

Radionuclide bone scan (Tc-99m MDP) is the best test to map the full extent of disease — intense uniform uptake in affected bones. It is more sensitive but less specific than X-ray, so every hot spot needs radiographic confirmation.

CT and MRI are reserved for suspected complications — spinal stenosis, basilar invagination, or sarcomatous transformation.

Asymptomatic patients with limited disease at low-risk sites may simply be observed with periodic alkaline phosphatase measurement.

Indications for bisphosphonate therapy: bone pain, before elective surgery at a pagetic site (to reduce hypervascularity and blood loss), hypercalcaemia of immobilisation, and disease at high-risk sites — skull, spine, weight-bearing long bones and bone adjacent to major joints.

Zoledronic acid 5 mg as a single intravenous infusion is the treatment of choice. It normalises ALP in most patients and produces remission lasting several years, and is more effective than pamidronate or risedronate at normalising ALP.

Alternatives: risedronate 30 mg daily for 2 months, alendronate 40 mg daily for 6 months, or IV pamidronate. Give calcium and vitamin D before and after to prevent hypocalcaemia, and warn about the transient flu-like acute-phase reaction (about 40% after the first infusion, much milder subsequently).

Calcitonin is now second-line, reserved for patients in whom bisphosphonates are contraindicated. Denosumab has been used off-label in selected refractory cases.

Adjunctive measures: analgesics and NSAIDs for pain, walking aids and shoe raises for deformity and leg-length discrepancy, hearing aids and audiological rehabilitation, physiotherapy, and falls prevention.

Surgery for fracture fixation, joint replacement in secondary osteoarthritis, osteotomy for deformity, and decompression for spinal stenosis or basilar invagination. Pre-treat with a bisphosphonate to reduce operative bleeding.

Monitoring: ALP at 3–6 months, then 6–12 monthly. Retreat if pain recurs or ALP rises, but not within 12 months of neridronate or zoledronate.