Osteitis deformans or Paget’s disease is a focal disorder of bone remodelling. The initial event of excessive resorption is followed by a compensatory increase in new bone formation, increased local bone blood flow and fibrous tissue in adjacent bone marrow. Ultimately, formation exceeds resorption but the new bone is structurally abnormal.
Epidemiological studies are difficult because most affected individuals are asymptomatic. Paget’s disease is most often seen in Europe and particularly in northern England. It affects men and women (2 : 3) over the age of 40 years. The incidence
approximately doubles per decade thereafter, with up to 10% of individuals radiologically affected by the age of 90. A positive family history is noted in about 14%.
Aetiology and pathogenesis
A number of genes have been implicated in Paget’s disease, including nuclear factor kappa B (NF-κB), sequestrosome p62 (which results in activation of NF-κB), osteoprotegerin and 6Cl2 (an anti-apoptotic gene). Intracellular inclusions in the
osteoclasts in pagetic lesions are believed to be paramyxovirus nucleocapsid (e.g. canine distemper virus, measles or respiratory syncytial virus). However, similar microfilaments are seen in other bone disorders, and theories of a viral aetiology
in Paget’s remain contentious. Altered expression of c-fos (an oncogene) is one suggested mechanism linking viral infection with the pathogenic changes in osteoclasts, which are
more numerous and contain an increased number of nuclei (up to 100). Increased osteoclastic bone resorption is followed by formation of woven bone, which is weaker than normal bone, which leads to deformity and increased fracture risk. Unaffected
bone remains normal throughout the disease course (i.e. Paget’s disease does not spread, but can become symptomatic at previously silent sites).
Most (60–80%) people with radiologically identified Paget’s disease are asymptomatic. Diagnosis often follows the finding of an asymptomatic elevation of serum alkaline phosphatase, or a plain X-ray performed for other indications. The disease
may involve one bone (monostotic, in 15%) or many (polyostotic). The most common sites in order of frequency are pelvis, lumbar spine, femur, thoracic spine, sacrum, skull and tibia. Small bones of the feet and hands are rarely involved.
Symptoms include the following:
- Bone pain, most often in the spine or the pelvis
- Joint pain when an involved bone is close to a joint, leading to cartilage damage and osteoarthritis
- Deformities, in particular bowed tibia and skull changes
- Neurological complications: nerve compression (deafness from VIIIth cranial nerve involvement; also cranial nerves II, V, VII may be involved); spinal stenosis;
hydrocephalus due to blockage of the aqueduct of Sylvius
- High-output cardiac failure and myocardial hypertrophy
due to increased bone blood flow
- Pathological fractures
- Osteogenic sarcoma in pagetic bone (fewer than 1% of cases, but a 30-fold increased risk compared with non-pagetic patients).
- X-ray features vary from predominantly lytic lesions (osteoporosis circumscripta in the skull is characteristic), through a mixed phase, to a mainly sclerotic phase of bone expansion, thickening of trabeculae and loss of distinction between cortex and trabeculae (de-differentiation).
- Isotope bone scans show the extent of skeletal involvement, but are unable to distinguish between Paget’s disease and sclerotic metastatic carcinoma
(especially breast and prostate).
- Increased serum alkaline phosphatase with normal serum calcium and phosphate reflects increased bone turnover. Levels may be normal with limited or
monostotic Paget’s. Levels are reduced with treatment and increase during relapse. Mild hypercalcaemia follows immobilization only when there is extensive
- Urinary hydroxyproline excretion is increased and may
also be used as a marker of disease activity.
Bisphosphonates are the mainstay of treatment. New boneformed after treatment is lamellar, not woven (reflecting normalization of bone turnover rather than a direct effect on osteoblasts). Treatment is interrupted and repeat courses are guided by symptoms and by recurrence in elevation of alkaline phosphatase or urinary hydroxyproline. In addition to treating symptomatic patients, treatment of asymptomatic
lesions is appropriate if there is a significant risk of potential complications, e.g. fracture in weight-bearing long bones or the spine, nerve entrapment or deafness with skull involvement, and before orthopaedic procedures in involved bone
(to reduce vascularity).
- Intravenous bisphosphonates
Zoledronate is the most commonly used agent for Paget’s disease, administered as a single infusion over 15 min.
Pamidronate is an alternative but takes longer to infuse, is less potent and some patients develop drug resistance for unknown reasons. Both drugs can be associated with a firstdose reaction characterized by ‘flu-like’ symptoms, including transient pyrexia over 24–48 hours, which can be ameliorated with paracetamol.
Oral bisphosphonates are typically used at doses higher than those for osteoporosis. They are less effective than zoledronate but at least as effective as pamidronate. Alendronate is given at a dose of 40 mg daily for 6 months, repeated after a further 6 months if necessary. Risedronate is given at a dose of 30 mg daily for 2 months, repeated after a further 2 months if necessary.
Joint replacement or osteotomy is sometimes necessary to correct deformity or pain due to associated degenerative joint disease (osteoarthrosis). Intra-articular injection of lidocaine can be useful to differentiate joint or bone disease. Neurosurgery may be required where there is spinal disease. Osteosarcoma usually requires amputation, though wide excision and limb-salvage can be successful at distal sites.