Paget's disease of bone — epidemiology, aetiology, pathophysiology, clinical manifestations and management

Definition. Paget's disease of bone (osteitis deformans) is a focal disorder of bone remodelling in which greatly increased and disorganised osteoclastic bone resorption is followed by vigorous but disorganised compensatory osteoblastic new bone formation. The result is expanded, thickened, hypervascular but structurally weak woven bone with a characteristic mosaic pattern of irregular cement lines. It may be monostotic or polyostotic, and — a key examination point — once established, it does not spread to previously uninvolved bones; the extent at diagnosis is the lifelong extent.

Epidemiology. A disease of later life — rare below 40 years, with prevalence rising steadily with age to about 1– 2% of those over 55 in the United Kingdom. Male predominance, roughly 3:2. There is striking geographic clustering: highest rates in the United Kingdom (classically Lancashire), Western Europe, Australia, New Zealand and North America; it is rare in Scandinavia, Asia and Africa and uncommon in India. The incidence, prevalence and severity have all fallen substantially over the past three decades, which is strong indirect evidence for an environmental cause.

Aetiology — genetic factors. 15–40% have a positive family history, with autosomal dominant inheritance and incomplete penetrance. Mutations in SQSTM1, which encodes the protein p62 in the RANK–NF-κB signalling pathway, are the commonest — found in about 40–50% of familial and 5–10% of sporadic cases, the P392L mutation being most frequent. Other susceptibility loci involve TNFRSF11A (RANK), TNFRSF11B (osteoprotegerin), CSF1, OPTN and TM7SF4/DC-STAMP — all genes governing osteoclast formation and function.

Aetiology — environmental factors. The longest-standing hypothesis is chronic paramyxovirus infection of osteoclasts (measles, canine distemper or respiratory syncytial virus), supported by nuclear inclusion bodies resembling paramyxovirus nucleocapsids in pagetic osteoclasts — but this remains unproven and controversial. Other proposed factors: low dietary calcium and vitamin D in youth, repetitive mechanical loading of the skeleton, cattle and rural exposure, and environmental toxins. The falling incidence in the absence of any genetic change points firmly to an environmental contribution.

Pathophysiology — the three phases.

Osteolytic (lytic) Greatly increased number and size of osteoclasts Osteoporosis circumscripta in the skull; "blade of with abnormally numerous nuclei; intense grass" or "flame-shaped" advancing lytic front in a resorption long bone

Mixed Vigorous compensatory osteoblastic bone Mixed lysis and sclerosis; cortical thickening begins formation with marrow fibrosis and marked hypervascularity; alkaline phosphatase rises sharply

Sclerotic (burnt-out) Dense, disorganised woven bone with a mosaic Bone expansion, thickened cortex, coarse of irregular cement lines; turnover falls trabeculae; "cotton wool" skull, "picture frame" vertebra The consequences flow directly from this biology: the bone is bigger but weaker (deformity and fracture), hypervascular (warmth, bleeding at surgery, arteriovenous shunting), and distorts adjacent structures (nerve compression, secondary osteoarthritis).

Distribution. Involvement is asymmetric and axially predominant. In descending order of frequency: pelvis (commonest), lumbar spine, femur, skull, tibia, humerus and sacrum. Skull and long-bone involvement account for most of the clinically important complications.

Clinical manifestations — general. 70–80% of patients are asymptomatic and are detected incidentally on a radiograph taken for another reason, or through an isolated raised alkaline phosphatase. Kane's specifically notes that mild asymptomatic elevations of alkaline phosphatase are common in the elderly, but liver disease and Paget's disease should be considered if the elevation is moderate. When symptomatic, the features are: bone pain — deep, boring, worse at rest and at night and not relieved by rest (unlike osteoarthritis); bone deformity — anterolateral bowing of the tibia ("sabre tibia"), femoral bowing, increasing skull size so that the hat no longer fits, frontal bossing, kyphosis and loss of height; and increased warmth over the affected bone from hypervascularity. Kane's also lists Paget's disease among the medical illnesses that may present with or be accompanied by depression.

Skeletal complications. Pathological fracture — characteristically transverse "chalk-stick" fractures of a bowed long bone. Secondary osteoarthritis of the hip and knee — in practice the commonest cause of pain in a patient with Paget's disease. Protrusio acetabuli, spinal stenosis and vertebral collapse. Rarely, osteosarcoma in under 1% — heralded by a sudden increase in pain, a new soft-tissue mass and a further rise in alkaline phosphatase, and carrying a very poor prognosis.

Neurological, otological and cardiac complications. Deafness is the classic complication of skull disease and is mixed — conductive from ossicular and cochlear capsule involvement, and sensorineural from cochlear involvement and eighth nerve compression. Kane's lists Paget's disease among the causes of hearing loss in older adults and states that it "may lead to both kinds of hearing loss and should be evaluated radiologically and by an alkaline phosphatase determination". Skull base disease causes platybasia and basilar invagination with brainstem compression and hydrocephalus; spinal disease causes cord and nerve root compression, sometimes by a vascular steal mechanism. Extensive polyostotic disease involving more than roughly 15–20% of the skeleton can cause high-output cardiac failure through arteriovenous shunting. Also seen: hypercalcaemia of immobilisation and hyperuricaemia with gout.

Investigations and management. Biochemistry — serum total alkaline phosphatase is the key screening and monitoring test; Kane's metabolic bone table gives the diagnostic pattern for Paget's disease as normal or high calcium, normal or high phosphate, HIGH alkaline phosphatase and NORMAL parathyroid hormone. Use bone-specific ALP or P1NP if there is coexisting liver disease. Radiology — plain radiographs of the relevant regions confirm the diagnosis; a radionuclide bone scan is then done to map the extent of disease (more sensitive but less specific). Biopsy only if malignancy is suspected. Indications to treat — symptomatic bone pain due to active disease, and to prevent or limit complications: before elective surgery on pagetic bone (reduces operative bleeding), neurological compression, hypercalcaemia of immobilisation, high-output cardiac failure, and active disease at critical sites (skull, spine, weight-bearing long bones, bone adjacent to a major joint). Drug of choice — a single 5 mg intravenous infusion of zoledronic acid, which produces a more rapid, more complete and more sustained response than oral bisphosphonates, with biochemical remission in about 90% of patients, often lasting many years. Alternatives: risedronate 30 mg daily for 2 months, alendronate 40 mg daily for 6 months, or intravenous pamidronate; calcitonin only if bisphosphonates are contraindicated. Correct vitamin D deficiency and hypocalcaemia before infusion; caution if eGFR is below about 35 mL/min; warn about the acute-phase reaction after the first dose. Monitor total alkaline phosphatase at 3–6 months and then 6–12 monthly, and retreat no sooner than 12 months after zoledronate if pain recurs or ALP rises. Adjunctive care — analgesia (paracetamol; NSAIDs only with great caution in older adults), physiotherapy, walking aids, a shoe raise or orthosis for leg-length discrepancy, hearing aids and audiological review, joint replacement for secondary osteoarthritis, and surgical decompression for cord or nerve compression.

PRISM and PRISM-EZ have overturned the "treat to normalise alkaline phosphatase" doctrine. The PRISM trial randomised 1324 patients to intensive bisphosphonate therapy aimed at normalising bone turnover versus symptomatic treatment; its extension, PRISM-EZ, continued 502 patients with zoledronic acid as the first-choice agent in the intensive arm, giving a total follow-up of about 7.3 years. Intensive therapy produced no reduction in fractures, orthopaedic procedures, progression of deafness, bone pain or quality of life; indeed the intensive arm showed a signal of more fractures and more orthopaedic surgery. The authors concluded that in established Paget's disease, bisphosphonate therapy should focus on the control of symptoms rather than on the suppression of bone turnover.

Guidelines and the genetics of prevention. The Endocrine Society clinical practice guideline and the UK Paget's Association guideline (JBMR 2019) agree on the substantial fall in incidence, on a similar approach to evaluation (plain radiographs to confirm, then a bone scan to define extent), and both name a single 5 mg intravenous dose of zoledronate as the treatment of choice where there is no contraindication. The ZiPP randomised controlled trial of prophylactic zoledronic acid in asymptomatic carriers of SQSTM1 mutations showed that treatment can prevent or modify the development of new bone lesions but did not alter clinical outcomes over the trial period — so genetic screening with pre-emptive treatment is not routine practice.