Paget’s Disease of Bone

Paget`s disease of bone (osteitis deformans) is a focal disorder of bone remodelling characterised by excessive and disorganised osteoclastic bone resorption followed by a coupled but chaotic osteoblastic response. The result is bone that is enlarged, structurally weak, hypervascular, and deformed — a mosaic of woven and lamellar bone (the `mosaic pattern` on histology) that lacks the normal organised Haversian architecture. First described by Sir James Paget in 1877, it is the second most common metabolic bone disease after osteoporosis. Understanding Paget`s is essential for orthopaedic surgeons due to its multiple complications — pathological fracture, malignant transformation to osteosarcoma, neural compression, and arthroplasty challenges.

• Epidemiology: most common in people of Northern European (Anglo-Saxon) descent; prevalence 2–3% in adults over 55 in the UK; rare in Africa and Asia; male:female ratio approximately 1.5:1; primarily a disease of the elderly (rare under 40 years); the prevalence and severity appear to be declining in the UK (possibly reflecting changes in dietary habits or reduced paramyxovirus exposure — the leading aetiological hypothesis)
• Aetiology: the exact cause remains uncertain; leading hypothesis is a `slow virus` — measles or other paramyxovirus (canine distemper virus) that infects and activates osteoclasts in genetically susceptible individuals; genetic component: SQSTM1 gene mutations (sequestosome-1 — a scaffold protein involved in NF-κB signalling, a key regulator of osteoclast activity) are found in 30–40% of familial cases and 5–10% of sporadic cases; other candidate loci identified but no single causative gene; the RANK/RANKL/OPG pathway is centrally dysregulated in Paget`s osteoclasts
• Distribution: monostotic (single bone) in ~15% of cases; polyostotic (multiple bones) in ~85%; the most commonly affected bones (in order): lumbar spine, pelvis, femur, skull, tibia; the radius and humerus are less commonly affected; small bones of the hands and feet are rarely involved; any bone can be affected; the distribution is highly variable between patients

• Bone pain: the most common symptom; deep, aching, constant pain at rest and at night (unlike mechanical pain which is worse with activity and relieved by rest); the bone is warm and tender to palpation (hypervascularity); pain at night is particularly characteristic; the skull may cause headache if involved
• Deformity: bowing of weight-bearing bones (tibia — anterior bowing producing the classic `sabre tibia`; femur — lateral bowing producing a varus deformity); skull enlargement (increasing hat size — cranial enlargement due to skull Paget`s — a classic history); jaw involvement (leontiasis ossea); spinal Paget`s causing kyphosis
• Pathological fracture: the pagetic bone is enlarged but mechanically weak (woven bone has inferior mechanical properties to normal lamellar bone); fractures occur through pagetic bone with minimal trauma; the typical pattern is a transverse (`chalk stick`) fracture on the convex surface of a bowed long bone (tension side); the lateral femur and anterior tibia are the classic sites; these fractures can be very difficult to treat surgically — the bone is hypervascular (significant intraoperative blood loss), hard and drill-resistant, and standard implants may not fit the deformed bone
• Nerve compression: spinal Paget`s causes spinal canal stenosis from enlarged vertebrae (spinal claudication; paraparesis); skull base Paget`s causes cranial nerve compression — sensorineural hearing loss (CN VIII — most common cranial nerve complication; the cochlea is enclosed in the petrous temporal bone which is commonly affected); optic nerve compression (rare); trigeminal neuralgia (CN V)
• Osteosarcoma in Paget`s disease: the most feared complication; occurs in <1% of patients with Paget`s but represents approximately 15–30% of all osteosarcomas in patients over 50 years; secondary osteosarcoma arising in Paget`s is the most common cause of osteosarcoma in the elderly; presents as new or changed pain, rapidly increasing swelling, and radiological destruction of the previously stable pagetic bone; the prognosis is very poor (5-year survival <10%) — much worse than primary osteosarcoma in young patients; clinical warning: sudden worsening of pain in a known Paget`s patient = sarcomatous change until proven otherwise
• High-output cardiac failure: Paget`s bone is intensely hypervascular; in extensive polyostotic disease, the arteriovenous shunting within pagetic bone can significantly increase cardiac output; in patients with pre-existing cardiac disease, this may precipitate high-output heart failure; bisphosphonate treatment reduces hypervascularity and cardiac demand

• Alkaline phosphatase (ALP): the primary biochemical marker of disease activity; markedly elevated in active Paget`s (total ALP is predominantly bone-derived in this context); ALP reflects the degree of osteoblastic activity (coupled to osteoclastic resorption); can reach 10–20× the upper limit of normal in active disease; the total ALP may be misleadingly low if only one small bone is affected; bone-specific ALP (BALP) and P1NP (procollagen type 1 N-terminal propeptide) are more sensitive markers; ALP and P1NP are used to monitor response to treatment (should fall by >50% after effective bisphosphonate treatment)
• Bone scan (Tc-99m MDP): the most sensitive investigation for identifying the extent of Paget`s disease; the pagetic bones show markedly increased uptake (`hot spots`) on the bone scan — the entire affected bone lights up; a whole-body bone scan at diagnosis delineates the extent of disease (monostotic vs polyostotic); the characteristic pattern is that the ENTIRE bone is involved (unlike metastases which produce focal multifocal hot spots)
• Plain X-ray: shows the characteristic features (blade of grass, cotton wool, picture frame, sabre tibia, ivory vertebra); assesses for deformity, bowing, and fracture; the X-ray diagnosis is usually straightforward in established disease

• Bisphosphonate therapy — the cornerstone of treatment: intravenous zoledronate 5 mg single infusion is the most effective and now the preferred treatment for active Paget`s disease; a single infusion achieves normalisation of bone turnover markers (ALP) in 80–90% of patients and sustained remission for years; oral bisphosphonates (risedronate 30 mg/day for 2 months) are less effective but acceptable for mild disease; indications for treatment: symptomatic disease (bone pain); planned orthopaedic surgery on pagetic bone (pre-operative bisphosphonate treatment reduces hypervascularity and surgical blood loss); rapidly progressive disease; lytic disease threatening weight-bearing bone; asymptomatic disease — the evidence for treating asymptomatic Paget`s to prevent complications is NOT established; the PRISM trial (Reid et al., NEJM 2011) showed no difference in clinical outcomes between symptomatic-only treatment and intensive treatment
• Surgical management: (1) Pathological fracture — IMN preferred for femoral and tibial shaft fractures through pagetic bone; cortical thickening and bowing make standard nails difficult to introduce — special flexible nails or pre-bent nails may be needed; significant blood loss anticipated — pre-operative bisphosphonate treatment and embolisation for very vascular lesions; (2) Total joint arthroplasty — Paget`s patients are at high risk of heterotopic ossification after hip arthroplasty (prophylaxis with indomethacin or radiotherapy mandatory); standard cementless implants may not fit the altered anatomy; revision arthroplasty is more complex; (3) Spinal decompression for spinal stenosis from Paget`s — bisphosphonate treatment first (may be sufficient); laminectomy or decompression for refractory neurological deficit; (4) Osteotomy for severe deformity

• Paget`s distribution: lumbar spine, pelvis, femur, skull, tibia (in order of frequency); 85% polyostotic; `SQSTM1` gene mutation in familial cases; paramyxovirus (measles/canine distemper) leading aetiological hypothesis
• ALP: markedly elevated (10–20× ULN) in active Paget`s; monitor response to bisphosphonate (fall >50% = good response); bone-specific ALP and P1NP more sensitive markers; ALP is normal in osteoporosis (differentiation point)
• Radiological features: `blade of grass`/`flame front` (lytic phase, long bone); `osteoporosis circumscripta` (skull — large lytic area); `cotton wool skull` (mixed phase); `picture frame pelvis` (thickened outer cortex + coarsened trabeculae); `ivory vertebra` (sclerotic phase); `sabre tibia` (anterior bowing + cortical thickening)
• Chalk stick fracture: transverse fracture on the convex (tension) surface of a bowed pagetic long bone; lateral femur or anterior tibia; pathognomonic of Paget`s fracture pattern
• Sarcomatous change: <1% of Paget`s patients; 15–30% of osteosarcomas in adults >50; secondary osteosarcoma in Paget`s = very poor prognosis (<10% 5-year survival); sudden worsening of pain + soft tissue mass in known Paget`s = sarcoma until proven otherwise → urgent MRI + biopsy
• Hearing loss: most common cranial nerve complication; sensorineural hearing loss from CN VIII compression in petrous temporal bone Paget`s; cochlear involvement; audiometry screening in skull Paget`s
• Treatment: IV zoledronate 5 mg single infusion = most effective (80–90% ALP normalisation; years of remission); pre-operative bisphosphonate reduces blood loss for surgery on pagetic bone; PRISM trial — no benefit of intensive treatment over symptom-driven treatment in asymptomatic Paget`s
• Heterotopic ossification (HO) risk: very high after THA in Paget`s; mandatory prophylaxis with indomethacin 75 mg/day × 6 weeks or single-fraction radiotherapy (7–8 Gy) to the hip before arthroplasty; bisphosphonate treatment pre-operatively reduces vascularity