Abstract
ABSTRACTAn evidence‐based clinical guideline for the diagnosis and management of Paget's disease of bone (PDB) was developed using GRADE methodology, by a Guideline Development Group (GDG) led by the Paget's Association (UK). A systematic review of diagnostic tests and pharmacological and nonpharmacological treatment options was conducted that sought to address several key questions of clinical relevance. Twelve recommendations and five conditional recommendations were made, but there was insufficient evidence to address eight of the questions posed. The following recommendations were identified as the most important: 1) Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of metabolically active disease in patients with PDB. 2) Serum total alkaline phosphatase (ALP) is recommended as a first‐line biochemical screening test in combination with liver function tests in screening for the presence of metabolically active PDB. 3) Bisphosphonates are recommended for the treatment of bone pain associated with PDB. Zoledronic acid is recommended as the bisphosphonate most likely to give a favorable pain response. 4) Treatment aimed at improving symptoms is recommended over a treat‐to‐target strategy aimed at normalizing total ALP in PDB. 5) Total hip or knee replacements are recommended for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate. There is insufficient information to recommend one type of surgical approach over another. The guideline was endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone Research Society (UK), and the British Geriatric Society. The GDG noted that there had been a lack of research on patient‐focused clinical outcomes in PDB and identified several areas where further research was needed. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Highlights
Paget’s disease of the bone is a nonmalignant skeletal disorder characterized by focal abnormalities in bone remodeling at one or more skeletal sites
This guideline differs from previous guidelines published on this subject[58,59,60] in that we considered both pharmacological and nonpharmacological treatment options; in that we had patient representation on the guideline development group and sought feedback from patients in the peerreview process; and in that we have provided information on the key questions used to develop the guideline, as well as details of the search strategy and numbers of publications that were reviewed for each key question
Specific anti-Pagetic treatment involves the use osteoclast inhibitors to reduce the elevations in bone turnover that are characteristic of active disease, whereas other treatments such as analgesics, nonsteroidal antiinflammatory drugs, and anti-neuropathic agents are used for symptom control.[54,84] We have mainly focused on the use of bisphosphonates, which are currently considered to be the treatment of choice for PDB and which are the only agents that have been evaluated in randomized controlled trials.[66]
Summary
Paget’s disease of the bone is a nonmalignant skeletal disorder characterized by focal abnormalities in bone remodeling at one (monostotic) or more (polyostotic) skeletal sites. Many affected individuals have a family history,(6,7) and an autosomal dominant pattern of inheritance with incomplete penetrance may be observed.[8,9,10] The most important susceptibility gene for PDB is SQSTM1,(11,12) which encodes p62, a protein involved in the nuclear factor kappa B (NF-kB) signaling pathway.[13] Mutations in SQSMT1 have been identified in 40% to 50% of familial cases and in 5% to 10% of patients who do not report having a family history.[9,14,15] Most of the causal mutations impair the ability of p62 to bind ubiquitin, and this leads to activation of receptor activator of nuclear kappa B ligand (RANKL)-induced NF-kB signaling with increased osteoclast activity.[16] Rarely, familial PDB or PDB-like disorders may occur in association with mutations in other genes.[17,18,19] In some of these syndromes, PDB is part of a multisystem disorder accompanied by myopathy and neurodegeneration.[20,21] Several other common risk alleles have been identified through genomewide association that increase susceptibility to PDB but that in themselves are not causal.[22]
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