Paget's Disease of Bone

Paget's disease of bone is a chronic disorder of excessive and disorganised bone remodelling, and the second most common metabolic bone disease after osteoporosis. Most patients have no symptoms: in 70-80% the disease is an incidental finding on a radiograph or in the blood tests.

Who. Prevalence is 3-4% over the age of 55, with a male predominance (M:F 3:2). The disease is common in the UK, Australia and New Zealand, in people of Anglo-Saxon descent, and rare in Asia and Africa. It clusters in families, and 15-30% of patients have an affected relative.

Why it matters to the surgeon. Pagetic bone fractures and deforms, the joints beside it develop secondary arthritis, and at operation it bleeds more and makes implant fixation harder.

The cell at fault. The disease is driven by abnormal osteoclast activity. Pagetic osteoclasts are abnormally large and multinucleated, with up to 100 nuclei against the normal 3-5.

Three phases. The lesion moves from resorption to formation, and each phase has its own radiographic signature:

• Lytic (osteoclastic). The initial phase. Excessive osteoclast activity resorbs bone faster than it is replaced, and radiographs show an advancing lytic front.
• Mixed (active remodelling). Osteoblasts attempt repair but lay down disorganised woven bone instead of lamellar bone, giving a mosaic pattern on histology. Most symptomatic disease occurs in this phase, and most lesions show this mixed pattern.
• Sclerotic (burnt-out). The late phase. Osteoblasts predominate and turnover falls, leaving dense sclerotic bone with a cotton-wool appearance on radiographs. The bone remains structurally abnormal and may still cause complications.

The histology. Woven bone replaces lamellar bone, marked by mosaic cement lines that record multiple resorption-formation cycles, with the giant osteoclasts described above.

Why the bone fails. Woven bone is structurally weaker than normal lamellar bone. Pagetic bone is therefore mechanically weak despite its increased mass and despite looking denser on imaging, and it is susceptible to stress fractures and pathological fractures with minimal trauma.

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Aetiology. Multifactorial, and not settled. Genetic contributors include SQSTM1 gene mutations, found in 15-30% of familial cases, and chromosome 18q abnormalities. The paramyxovirus (measles) "slow virus" hypothesis remains unproven and contested. Geographic clustering and declining incidence suggest an environmental trigger; with the SQSTM1 genetics, they point to a gene-environment interaction whose trigger is still unidentified.

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History. When the disease does declare itself, the complaints are skeletal:

• Bone pain - deep, aching, worse at night
• Deformity - bowing of long bones, skull enlargement
• Fracture - after minimal trauma, or a stress fracture
• Arthritis pain - in the hip or knee next to pagetic bone

Systemic features are rare and are developed below: high-output cardiac failure with extensive disease, hearing loss and cranial nerve involvement from the skull base, spinal stenosis, and hypercalcaemia during immobilisation.

Examination. Look for the enlarged bone: an increased skull circumference, a bowed tibia or femur, and a gait disturbed by leg length discrepancy or joint deformity. Active lesions are tender, the skin over pagetic bone is warm from its hypervascularity, and secondary arthritis brings a joint effusion. Examine the cranial nerves when the skull base is involved, and look for spinal cord signs when vertebral disease brings stenosis.

An elevated ALP with a sclerotic or expanded bone has several mimics. The discriminators are serum calcium, PTH, the pattern of bone change, and whether multiple bones are involved.

Bisphosphonates. First-line treatment. They inhibit osteoclast activity, reduce bone turnover, normalise the ALP and reduce bone pain. A single 5mg infusion of zoledronic acid is the standard of care, and its remission lasts 2 years or more.

Who to treat. Symptomatic disease is treated: bone pain attributable to Paget's, neurological complications from nerve compression, and the rare high-output cardiac failure. Treatment is also given before planned surgery on pagetic bone, and for high-risk lesions even when they are asymptomatic, although whether the last group needs treatment is unresolved (see Controversies):

• Weight-bearing long bones - risk of fracture and deformity
• Skull base - risk of cranial nerve compression
• Spine - risk of stenosis
• Juxta-articular disease - risk of secondary arthritis

Calcium and vitamin D. Ensure adequate calcium and vitamin D before treatment, and always co-administer calcium 1000-1200mg and vitamin D 800-1000 IU daily. They prevent hypocalcaemia after bisphosphonate treatment and optimise bone health.

Monitoring. Check the ALP at 3, 6 and 12 months. Normalisation or a 75% reduction marks a response, and a rising ALP means reactivation; bone turnover markers (NTX, CTX) are more sensitive. Normalising the ALP is a marker of response, not in itself a treatment goal worth chasing (see Controversies).

Indications. Surgery deals with the mechanical consequences of the disease:

• Pathological fractures - fixation often required
• Stress fractures - prophylactic fixation if high-risk (femoral neck)
• Nonunion - may require bone graft and revision fixation
• Secondary arthritis - joint arthroplasty, the hip most commonly
• Severe deformity affecting function - corrective osteotomy
• Spinal stenosis or nerve root compression - decompression

Preoperative optimisation. Give a bisphosphonate 3-6 months before elective surgery. It reduces bone vascularity, normalises turnover and improves fixation quality, and the reduction in operative blood loss is quoted at 40-50%, or up to 50%. Pagetic bone is highly vascular, so cross-match and have blood products available for significant intraoperative bleeding.

At operation. Fractures need long implants that bypass the pagetic bone, and deformity correction is complicated by the altered anatomy. Each of the recurring problems has its answer:

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Total hip arthroplasty. Femoral anatomy is altered by bowing and coxa vara, and acetabular protrusion is common. Classic teaching is a cemented long-stem femoral component for better fixation in soft bone, with a cementless acetabular component and screw fixation considered. Heterotopic ossification occurs at a higher rate, so consider prophylaxis with indomethacin or radiation.

Cemented or not. The cemented long stem is classic teaching, yet modern registry data (Di Martino 2021) show good survival with various fixation types. In that data the dominant problems are bleeding and heterotopic ossification, not fixation failure.

The four figures below show a pagetic proximal tibia at knee arthroplasty, after fracture, and after fixation.

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Why output rises. Actively remodelling pagetic bone is intensely hypervascular. Dilated marrow sinusoids and increased blood flow through the affected bone and overlying skin behave functionally like a low-resistance arteriovenous shunt, felt clinically as warmth over the bone. Where a large fraction of the skeleton is involved, the summed increase in resting blood flow raises cardiac output and preload.

Who decompensates. True high-output failure is rare and generally requires extensive polyostotic disease; monostotic or limited disease does not cause it. The increased demand most often decompensates pre-existing cardiac disease (ischaemic or valvular) in an elderly population rather than causing failure in a healthy heart. Warmth and bounding pulses over pagetic limbs are supportive signs.

The valve. Paget's is associated with an excess of calcific aortic valve disease and generalised vascular calcification, which compounds cardiac risk and can coexist with the high-output physiology.

Treatment. Suppressing bone turnover with a bisphosphonate reduces pagetic bone vascularity and blood flow, and can improve the high-output state. The same hypervascularity that drives the cardiac load is what makes preoperative bisphosphonate reduce surgical bleeding.

Hearing loss is the commonest neurological complication, and is typically mixed sensorineural and conductive. The dominant contributor is thought to be pagetic remodelling and demineralisation of the cochlear (otic) capsule and cochlear structures, rather than simple compression of the eighth nerve at the internal auditory meatus; a conductive component can arise from involvement of the ossicles and temporal bone. Established hearing loss responds poorly, so treatment aims to slow progression.

Basilar invagination. Softening of the pagetic skull base allows the odontoid to migrate upward into the foramen magnum (basilar invagination, platybasia). The result can be brainstem and upper cervical cord compression, vertebrobasilar symptoms, and obstructive hydrocephalus from aqueduct or outflow compromise. It is a serious, though uncommon, complication of extensive calvarial disease.

Spinal stenosis. Vertebral Paget's with bony expansion narrows the canal and neural foramina, causing spinal stenosis, myelopathy, radiculopathy or cauda equina syndrome. In pagetic spinal syndrome some of the deficit is due not only to mechanical compression but to a vascular steal, with blood diverted from the spinal cord into the adjacent hypervascular bone.

Global epidemiology: Strong geographic and ethnic gradient. Highest prevalence in populations of Anglo-Celtic / Western European descent (UK, Australia, New Zealand, North America, and emigrant communities), where it affects roughly 1-4% over age 55. Rare in Scandinavia, much of Asia and sub-Saharan Africa. Incidence and severity have declined markedly over recent decades across high-prevalence regions, supporting an environmental contribution alongside SQSTM1-related genetic susceptibility.

Side-by-Side Guideline Comparison

Related pages: Paget's Sarcoma for the staging, histology and reconstruction of the transformation summarised here, and Osteosarcoma for the disease it becomes - noting that pagetic sarcoma behaves nothing like the adolescent tumour and is not managed by the same neoadjuvant protocol; Osteomalacia for the mirror-image cortical lucency, whose Looser zones sit on the compression side while pagetic fissures sit on the tension side; Renal Osteodystrophy and Hyperparathyroidism for the other causes of a raised alkaline phosphatase with abnormal bone turnover, separated here by the normal calcium and phosphate; Fibrous Dysplasia for the other expansile disorder that deforms and bows long bones in an older skeleton; Bisphosphonates for the drug class whose Paget's dosing is unlike its osteoporosis dosing - a single 5mg zoledronate infusion, not an annual course; Osteoclasts and Bone Resorption for the RANKL-driven cell that starts the pagetic lesion, and Bone Remodeling for the coupled cycle that is disordered here; Total Hip Arthroplasty Indications and Heterotopic Ossification for the arthroplasty considerations the Di Martino data above informs; and Osteoporosis for the disease most often confused with this one on a report of "abnormal bone density".

Treating to an ALP target. The PRISM-EZ RCT found that intensively suppressing bone turnover to normalise ALP gave no improvement in pain, quality of life or fractures over symptomatic treatment, and a non-significant trend to more fractures.

Treating asymptomatic disease. Guidelines suggest treating active disease "at risk of complications", but robust evidence that bisphosphonates prevent fracture, deformity, deafness or arthritis is lacking (Cochrane). Whether asymptomatic high-risk sites still warrant treatment remains unresolved, and practice varies from treat-all-active to treat-symptoms-only.