Paget's Disease of Bone

Abstract

Sir James Paget described the disease as follows: It begins in middle age or later, is very slow in progress, may continue for many years without influence on the general health, and may give no other trouble than those which are due to the changes of shape, size, and direction of the diseased bones (Paget 1877). Paget's disease is a focal disorder of bone remodeling that occurs in an aging skeleton. Aberrant osteoclast activation is the critical lesion leading to the disease phenotype. Paget's disease leads to impaired structural integrity and distortion of bone, the consequences of which include localized bone pain, deformity, fracture, and early arthritis. Neurological sequelae such as hearing loss, spinal stenosis, and neuropathies can occur, depending on the sites of affected bones. Osteosarcomas arise in pagetic bone in a small number of cases (Seton 2008; Hansen et al. 2006) Both familial and sporadic cases of Paget's disease are caused often by a mutation in SQSTM1. This mutation results in a C→ T transition mutation (P392L) that in turn results in aberrant osteoclast activation (Laurin et al. 2002). However, not all cases are associated with this disease mutation (Kurihara et al. 2007; Morissette et al. 2006). The serum alkaline phosphatase, a marker of osteo-blastic activity, is a good indicator of skeletal extent and activity of Paget's disease. Spot urine assays for N-telopeptide levels have replaced 24-h urine collections for hydroxyproline as a measure of antiresorptive activity. The goal of treating Paget's disease with antiresorptive agents such as the bisphosphonates and calcitonin is to normalize the serum alkaline phosphatase and urine N-telopeptide levels. Bisphosphonates are the treatment of choice. However, calcitonin has a role in the elderly patient with renal insufficiency in whom relief of pain rather than remission is a reasonable outcome. Resistance to the effects of one bisphosphonate does not predict resistance to another.