Management of Paget's disease of bone
A. L. Langston and
S. H. Ralston1
Health Services Research Unit and 1 Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Correspondence to: S. H. Ralston, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail: s.ralston{at}abdn.ac.uk
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Abstract
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Paget's disease of bone is a common condition with a strong genetic component, characterized by focal increases in bone turnover, affecting one or more bones throughout the skeleton. Paget's disease can be asymptomatic but is frequently associated with bone pain, bone deformity, pathological fracture, secondary osteoarthritis and deafness. Inhibitors of osteoclastic bone resorption, such as bisphosphonates and calcitonin, suppress bone turnover and improve bone pain in Paget's disease. Many patients also require therapy with analgesics and anti-inflammatory agents, since pain in Paget's disease can arise not only from increased bone turnover but also from complications such as osteoarthritis and nerve compression syndromes, which do not respond well to antiresorptive therapy. Comparative studies have shown that second- and third-generation bisphosphonates, such as tiludronate, alendronate and risedronate, are more effective than etidronate at inhibiting bone turnover in Paget's disease but they have not been found to be significantly more effective in controlling bone pain. Importantly, none of the treatments that are currently available for Paget's disease have been shown to prevent complications such as deafness, fracture or bone deformity, or to alter the natural history of the disease. More research is required to define the long-term effects of antiresorptive treatment on clinical outcomes in Paget's disease, so that clinicians and their patients can make better-informed choices about the risks and benefits of treatment.
KEY WORDS: Paget's disease, Bone, Management, Bisphosphonate, Calcitonin
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Introduction
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Paget's disease of bone (PDB) is a common metabolic bone disease, second in prevalence only to osteoporosis in patients of European descent. The disease is rare in those aged under 40 years, but the prevalence increases with age, and by the eighth decade 8% of British men and 5% of women are affected by PDB [1]. The overall prevalence in subjects above the age of 55 years in the UK is currently about 3.1%, which compares with a prevalence of about 5% some 25 years ago [2]. This indicates that the disease is becoming less common, which may be due to changes in either environmental exposure to causal agents or in the ethnic mix of the population.
PDB is characterized by increased bone turnover, which can affect a single bone (monostotic) or multiple bones (polyostotic). The axial skeleton is frequently involved and the bones most commonly affected include the pelvis (70%), femur (55%), lumbar spine (53%), skull (42%) and tibia (32%) [3]. There is a tendency for PDB to involve the dominant limbs and this has led to the suggestion that lesions may be targeted to bones that are subject to increased mechanical loading [3]. Evidence in support of this comes from the observation that Pagetic lesions tend to start at the sites of muscle insertions into bone and that patients who experience repetitive mechanical loading of specific bones can develop Paget's disease localized to these sites [4].
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Aetiology
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The aetiology of Paget's disease continues to be a subject of debate. There is evidence to suggest that PDB might be caused by a slow-virus infection of osteoclasts, but this remains controversial, with positive results in some studies and negative results in others [57]. Other environmental factors, such as dietary calcium intake and exposure to industrial toxins, have also been implicated in the aetiology of PDB [8, 9]. Genetic factors play an important role in Paget's disease and between 15 and 40% of individuals have a positive family history of the condition. Positional cloning studies have resulted in the identification of three genes that are mutated in familial Paget's disease and related syndromes, such as familial expansile osteolysis and idiopathic hyperphosphatasia. These are RANK, a member of the TNF receptor superfamily that regulates osteoclast activity; osteoprotegerin, a decoy receptor for RANK; and sequestosome 1, a protein involved in regulating NF
B signalling [10].
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Clinical presentation and diagnosis
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The most common presentation of Paget's disease is as an incidental finding in patients who are undergoing biochemical or radiological investigations for other conditions. Paget's disease patients can also present to the rheumatologist, orthopaedic surgeon or ENT specialist with symptoms specifically related to the disease, such as bone pain, bone deformity, fracture and deafness. Although many patients in the UK are seen by rheumatologists, there is no evidence to suggest that patients benefit from being treated within the remit of any particular medical or surgical subspeciality.
The diagnosis of PDB is based on finding an elevated serum alkaline phosphatase (sAP) level in a patient with typical X-ray features of osteosclerosis, osteolysis and bone expansion. Radionuclide bone scans are more sensitive than plain X-rays in detecting PDB, and many clinicians use bone scans to screen for PDB and evaluate skeletal involvement of the disease. The bone scan appearance in PDB is usually pathognomic, but it has been recommended that the diagnosis should also be confirmed by conventional radiography of at least one site [11].
Patients with PDB run a significantly increased risk of developing osteoarthritis [12] and epidemiological surveys have shown that the need for hip replacement because of osteoporosis is increased 3.1-fold in PDB patients compared with age-matched controls [1]. Osteosarcoma is a rare complication of PDB, with an incidence rate of 0.1% per 100 patient years [1], but virtually all osteosarcomas that occur in adults over the age of 60 years do so in patients with PDB [13]. Other complications of PDB include spinal stenosis, internal hydrocephalus, basilar impression, cranial nerve deficits and other nerve root compression syndromes [11]. Hypercalcaemia can occur as a complication of PDB in patients who are immobilized or dehydrated, but hypercalcaemia in an ambulant PDB patient suggests the presence of a coexisting disease, such as primary hyperparathyroidism. Vascular steal syndromes may occur in PDB due to the increased bone blood flow, and when this occurs in the thoracic spine, paraplegia can develop [14]. High-output cardiac failure is said to be a complication of PDB, but has not been encountered by one of the authors (S.H.R.) in over 25 years of practice. Pain is the most common symptom associated with PDB, although it is often difficult to be certain whether this is caused by the increase in bone turnover or by complications of the disease, such as osteoarthritis and nerve compression syndromes. Clinical examination in Paget's disease is often normal, but bone deformity may be observed in patients with advanced disease. An increase in skin temperature can often be detected over affected bones if the disease is active.
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Treatment of Paget's disease
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Many antiresorptive drugs have been used over the years for the treatment of PDB, including mithramycin (plicamycin), glucagon, actinomycin D and gallium nitrate. These agents are seldom, if ever, used nowadays since they have been superseded by more effective and better-tolerated treatments.
Calcitonin was the first osteoclast inhibitor to be used in treatment of PDB. Calcitonin is effective in suppressing bone turnover and improving bone pain in PDB [15], but is more expensive than bisphosphonates; is generally less effective in suppressing bone turnover; and has a short duration of action once treatment has stopped. Many patients develop side-effects such as nausea, vomiting and flushing, and resistance may also occur with repeated use, because of down-regulation of calcitonin receptors on the osteoclast or the development of antibodies [16]. Calcitonin has an advantage over the first-generation bisphosphonate etidronate, in that it does not inhibit bone mineralization and is more effective in healing lytic lesions [17]. Inhibition of bone mineralization is less of a problem with second-, third- and fourth-generation bisphosphonates and most clinicians view calcitonin as a second-line therapy to be used in PDB patients who are intolerant of bisphosphonates.
Bisphosphonates are the most widely used antiresorptive agents for the treatment of Paget's disease. They have in common a core structure of phosphorouscarbonphosphorous atoms, to which is attached various chemical side-chains. The nature of the side-chains has a profound effect on the antiresorptive potency of bisphosphonates and on the mechanism by which osteoclast inhibition occurs [18]. Simple bisphosphonates, such as etidronate, clodronate and tiludronate, are relatively weak antiresorptive agents, which work by incorporating into non-hydrolysable analogues of ATP, thereby depleting intracellular energy stores and promoting osteoclast apoptosis [19]. Bisphosphonates that contain a nitrogen atom in the side-chain (amino-bisphosphonates) are much more potent and act by inhibiting farnesyl pyrophosphate (FPP) synthase, an intermediate enzyme in the mevalonate pathway [20]. FPP synthase is essential for lipid modification (prenylation) of key signalling molecules in osteoclasts [21]. Amino-bisphosphonate-mediated inhibition of this enzyme therefore disrupts these signalling pathways, leading to failure of resorptive function and cell death. Bisphosphonates are thought to improve bone pain in Paget's disease by inhibiting bone turnover. However, there is evidence that some, but not all, bisphosphonates can have an analgesic effect in mice [22, 23] by mechanisms unrelated to the effect on bone. The relevance of this to the treatment of bone pain in clinical practice is currently unclear.
All bisphosphonates are poorly absorbed from the gastrointestinal tract [24], and absorption is further diminished when the drug is taken with food. In view of this, oral bisphosphonates must be taken on an empty stomach with water, allowing an interval of at least half an hour before the intake of food or drink. Amino-bisphosphonates can cause upper gastrointestinal side-effects, such as heartburn and dyspepsia, and several cases of oesophageal ulceration and stricture have been reported with alendronate, due to the tablet sticking in the oesophagus [25, 26]. Alendronate and other amino-bisphosphonates should therefore be used with caution in patients with dysphagia, symptomatic oesophageal disease, gastritis, duodenitis or ulcers, and these drugs are contraindicated when there are abnormalities of the oesophagus or other factors which delay oesophageal emptying [27]. The other major side-effect of amino-bisphosphonates is an acute febrile reaction. This is most prominent after the first exposure to an intravenously administered amino-bisphosphonate but can also occur in patients who are treated with oral amino-bisphosphonates. It has been stated that the acute-phase response is observed only after the first administration of an amino-bisphosphonate, but our experience is that febrile reactions can recur with repeated administration. Other side-effects with bisphosphonates are rare; they include uveitis, taste disturbance, hearing disturbances and skin rashes.
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Indications for antiresorptive treatment
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Antiresorptive treatment suppresses bone turnover in Paget's disease and improves the appearance of Pagetic lesions on isotope bone scan, but the clinical evidence base only supports the use of antiresorptive drugs for the treatment of bone pain. Bone pain in Paget's disease can be managed either with simple analgesics and non-steroidal anti-inflammatory drugs or with antiresorptive drugs such as calcitonin and bisphosphonates. The relative efficacy of symptomatic treatment versus antiresorptive treatment for controlling Pagetic bone pain has not been investigated, although randomized controlled trials have shown that etidronate and tiludronate are significantly more effective than placebo in controlling pain [2831]. Randomized, double-blind, controlled studies have compared the effects of tiludronate [32], alendronate [33] and risedronate [34] with those of etidronate in the treatment of PDB. Whilst the newer bisphosphonates were uniformly more effective than etidronate in reducing sAP values, they were not significantly more effective than etidronate in controlling pain. Pamidronate has been found to be effective at inhibiting bone turnover, improving scintigraphic appearances and improving bone pain in PDB, but has not been studied in the context of a randomized controlled trial [11].
Four bisphosphonates are currently licensed for treatment of PDB in the UK. These are etidronate, pamidronate, tiludronate and risedronate. Clodronate, alendronate and ibandronate have been used in the treatment of PDB, but they are not marketed for the treatment of Paget's disease within the UK. Zoledronate is currently under investigation as a treatment for PDB in the UK and other countries (Table 1). Many clinicians use amino-bisphosphonates in preference to less potent bisphosphonates, such as etidronate and tiludronate, in patients with extensive Paget's disease or those who have developed resistance to treatment, as they are more likely to restore sAP values to normal. The long-term effect of this strategy on clinical outcome in these patients remains unclear, however.
The dissociation between the response of sAP and the response of pain may be due to the fact that even modest suppression of bone turnover in PDB is enough to improve bone pain. Another reason is that pain in PDB can be multifactorial in origin, resulting not only from increased bone turnover but also from problems such as osteoarthritis, nerve compression syndromes, bone deformity and coexisting diseases, which do not respond well to osteoclast inhibitors. Other potential indications for antiresorptive treatment in PDB that have been put forward include: prophylactic treatment of younger patients to prevent bone deformity or progression of arthritis [35, 36]; preoperative treatment of patients who require orthopaedic surgery in an effort to reduce operative blood loss [11]; and prophylactic treatment of patients with deformed, weight-bearing bones to prevent fractures [35, 36]. Whilst potent antiresorptive drugs such as the amino-bisphosphonates have been shown to improve some aspects of bone architecture and to promote healing of lytic lesions in PDB [37, 38], there is no evidence to suggest that they prevent progression of bone deformity, deafness or osteoarthritis and there is no evidence that antiresorptive therapy prevents fracture or reduces operative blood loss. Deafness is one of the most serious complications of PDB and it has been suggested that asymptomatic patients with disease of the skull should be treated to prevent progression of deafness [11]. The evidence upon which this recommendation is based is of very poor quality, and is mostly in relation to calcitonin therapy [3942]. Whilst several authors have implied that there may be nothing to lose by treating these patients [11, 43], it should be borne in mind that hearing loss in PDB is positively correlated with bone mineral density (BMD) of the cochlear capsule [44] and that bisphosphonate treatment increases the BMD of affected bones (including the skull bones) [45]. In view of this, there is a theoretical concern that bisphosphonate treatment may worsen deafness.
Many patients also derive benefit from physical methods of pain management, including acupuncture, physiotherapy, hydrotherapy and transcutaneous electrical nerve stimulation, although their efficacy has not been specifically evaluated in PDB.
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Monitoring treatment
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It is usual to assess the response to antiresorptive treatment by measuring biochemical markers of bone turnover. Total sAP is the most commonly used marker, since it is inexpensive, widely available and has high reproducibility [11]. Total sAP is elevated in untreated PDB, is correlated with disease extent, and falls within about 710 days of starting antiresorptive therapy, reaching a nadir after 34 months. Other, more specific bone markers of bone turnover, such as bone-specific alkaline phosphatase, N-telopeptide collagen cross-links, C-telopeptide collagen cross-links, pyridium cross-links and urinary hydroxyproline, are also elevated in untreated PDB, and are reduced by antiresorptive treatment,, but offer no clear advantage over sAP in monitoring response. Some clinicians initiate further courses of antiresorptive treatment when sAP levels rise above the normal range, although there is no evidence that this gives a better outcome than waiting until symptoms recur.
In cases of monostotic PDB, symptoms attributable to increased bone turnover may be observed in patients who have normal sAP values. Clinical studies have shown that scintigrams (isotope bone scans) can demonstrate dramatic responses to bisphosphonate treatment in these circumstances [46]. It is unclear whether normalization of scintigraphic appearance correlates with clinical outcome in these patients or offers any advantage over assessing the treatment response by symptomatic criteria. In the absence of such evidence, it is difficult to justify the use of serial bone scans as a method of assessing the treatment response in view of the radiation dose involved [11].
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Future prospects
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Bisphosphonates have been used for the treatment of PDB for nearly 35 years, but there is virtually no information on the long-term effects of these or other antiresorptive drugs on the natural history of PDB or complications such as deafness, fracture and bone deformity. Meunier and Vignot [47] reported that deformity progressed and complications developed over a 12-year period in 62% of patients despite receiving bisphosphonate treatment. At that time, however, most patients were being treated with etidronate and normalization of sAP was achieved in only 29% of cases. Whilst the newer, highly potent amino-bisphosphonates can suppress bone turnover to near-normal levels in a high proportion of PDB patients, we do not know if this translates into a better long-term clinical outcome. Indeed, the information gained so far from comparative studies of bisphosphonates indicates that increased antiresorptive potency does not provide significantly better pain control, although it should be acknowledged that most studies have been underpowered to detect changes in pain and other aspects of quality of life. There is a prospect that early intervention with newer, more potent bisphosphonates could be undertaken in minimally symptomatic patients to prevent disease progression, but rigorously designed clinical studies will need to be undertaken to determine if they are effective for this indication. If such data were forthcoming they would have major implications for patients with familial PDB, since it is now possible to identify people within families who are genetically predisposed to developing the disease [4850].
Until recently, treatment studies of PDB were short-term and powered to detect changes in alkaline phosphatase rather than to address effects on symptoms, quality of life and complications of PDB, which are of concern to patients [51]. Recently, however, a large multicentre trial (PRISM) has been set up in the UK to address the effects of anti-Pagetic treatment on important clinical outcomes in PDB. It is hoped that information from this study will allow doctors to make a better-informed judgement as to what represents the optimal strategy for treatment for the individual patient.
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Acknowledgments
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We wish to acknowledge the Arthritis Research Campaign, the National Association for the Relief of Paget's Disease, Proctor & Gamble Pharmaceuticals and Aventis Pharma for grant support. The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Executive Department of Health. The views expressed are those of the authors and not necessarily those of the funding body.
S.H.R. acts as a consultant for Proctor & Gamble, Aventis Pharma and Novartis, which are pharmaceutical companies that manufacture drugs used in the treatment of Paget's disease. S.H.R. and A.L.L. have received funding from the Arthritis Research Campaign, the National Association for the Relief of Paget's Disease, Proctor & Gamble Pharmaceuticals and Aventis Pharma for the PRISM trial of treatment strategies in PDB.
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References
|
---|
- van Staa TP, Selby P, Leufkens HG, Lyles K, Sprafka JM, Cooper C. Incidence and natural history of Paget's disease of bone in England and Wales. J Bone Miner Res 2002;17:46571.[ISI][Medline]
- Barker DJ, Chamberlain AT, Guyer MJ. Paget's disease of bone: the Lancashire focus. Br Med J 1980;280:11057.[ISI][Medline]
- Kanis JA. Pathophysiology and treatment of Paget's disease of bone, 1st edn. London: Martin Dunitz, 1992.
- Solomon LR. Billiard-player's fingers: an unusual case of Paget's disease of bone. Br Med J 1979;1:931.
- Helfrich MH, Hobson RP, Grabowski PS et al. A negative search for a paramyxoviral etiology of Paget's disease of bone: molecular, immunological, and ultrastructural studies in U.K. patients. J Bone Miner Res 2000;15:231529.[ISI][Medline]
- Friedrichs WE, Reddy SV, Bruder JM et al. Sequence analysis of measles virus nucleocapsid transcripts in patients with Paget's disease. J Bone Miner Res 2002;17:14551.[ISI][Medline]
- Rima BK, Gassen U, Helfrich MH, Ralston SH. The pro and con of measles virus in Paget's disease: con [comment]. J Bone Miner Res 2002;17:22902.[ISI][Medline]
- Lever JH. Paget's disease of bone in Lancashire and arsenic pesticide in cotton mill wastewater: a speculative hypothesis. Bone 2002;31:4346.[CrossRef][ISI][Medline]
- Siris ES. Epidemiological aspects of Paget's disease: family history and relationship to other medical conditions. Semin Arthritis Rheum 1994;23:2225.[ISI][Medline]
- Janssens K, Van Hul, W. Molecular genetics of too much bone. Human Mol Genet 2002;11:238593.[Abstract/Free Full Text]
- Selby PL, Davie MWJ, Ralston SH, Stone MD. Guidelines on the management of Paget's disease of bone. Bone 2002;31:36673.[CrossRef][ISI][Medline]
- Helliwell PS. Osteoarthritis and Paget's disease. Br J Rheumatol 1995;34:10613.[ISI][Medline]
- Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: osteosarcoma and related tumors. [Review]. Cancer Genet Cytogenet 2003;145:130.[CrossRef][ISI][Medline]
- Douglas DL, Duckworth T, Russell RG et al. Effect of dichloromethylene diphosphonate in Paget's disease of bone and in hypercalcaemia due to primary hyperparathyroidism or malignant disease. Lancet 1980;1:10437.[CrossRef][Medline]
- Martin TJ. Actions of calcitonin and mithramycin. Arthritis Rheum 1980;23:11318.[ISI][Medline]
- Dube WJ, Goldsmith RS, Arnaud SB, Arnaud CD. Development of antibodies to porcine calcitonin during treatment of Paget's disease of bone. Mayo Clin Proc 1973;48:436.[ISI][Medline]
- Nagant de Deuxchaisnes C, Rombouts-Lindemans C, Huaux JP, Devogelaer JP, Malghem J, Maldague B. Calcitonin or diphosphonates for osteolytic Paget's disease? Lancet 1980;1:374.
- Rogers MJ, Gordon S, Benford HL et al. Cellular and molecular mechanisms of action of bisphosphonates. [Review]. Cancer 2000;88(12 Suppl.):296178.[CrossRef]
- Frith JC, Monkkonen J, Auriola S, Monkkonen H, Rogers MJ. The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 2001;44:220110.[CrossRef][ISI][Medline]
- Dunford JE, Thompson K, Coxon FP et al. Structureactivity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001;296:23542.[Abstract/Free Full Text]
- Coxon FP, Helfrich MH, Vant Hof R et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 2000;15:146776.[ISI][Medline]
- Bonabello A, Galmozzi MR, Bruzzese T, Zara GP. Analgesic effect of bisphosphonates in mice. Pain 2001;91:26975.[CrossRef][ISI][Medline]
- Goicoecha C, Porras E, Alfaro MJ, Martin MI. Alendronate induces antinociception in mice, not related with its effects in bone. Jpn J Pharmacol 1999;79:4337.[CrossRef][ISI][Medline]
- Fogelman I, Smith L, Mazess R et al. Absorption of oral diphosphonate in normal subjects. Clin Endocrinol 1986;24:5762.[ISI][Medline]
- Kelly R, Taggart H. Incidence of gastrointestinal side effects due to alendronate is high in clinical practice. Br Med J 1997;315:1235.[Free Full Text]
- de Groen PC, Lubbe DF, Hirsch LJ et al. Esophagitis associated with the use of alendronate [comment]. [Review]. N Engl J Med 1996;335:101621.[Abstract/Free Full Text]
- British National Formulary. Vol. 45, March. London: British Medical Association & Royal Pharmaceutical Society of Great Britain, 2003.
- Altman RD, Johnston CC, Khairi MR, Wellman H, Serafini AN, Sankey RR. Influence of disodium etidronate on clinical and laboratory manifestations of Paget's disease of bone (osteitis deformans). N Engl J Med 1973;289:137984.[ISI][Medline]
- Canfield R, Rosner W, Skinner J et al. Diphosphonate therapy of Paget's disease of bone. J Clin Endocrinol Metab 1977;44:96106.[Abstract]
- Ralston SH, Boyce BF, Cowan RA et al. The effect of 1 alpha-hydroxyvitamin D3 on the mineralization defect in disodium etidronate-treated Paget's diseasea double-blind randomized clinical study. J Bone Miner Res 1987;2:512.[ISI][Medline]
- Fraser WD, Stamp TC, Creek RA, Sawyer JP, Picot C. A double-blind, multicentre, placebo-controlled study of tiludronate in Paget's disease of bone. Postgrad Med J 1997;73:496502.[Abstract]
- Roux C, Gennari C, Farrerons J et al. Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget's disease of bone. Arthritis Rheum 1995;38:8518.[Medline]
- Siris E, Weinstein RS, Altman R et al. Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone. J Clin Endocrinol Metab 1996;81:9617.[Abstract]
- Miller PD, Brown JP, Siris ES, Hoseyni MS, Axelrod DW, Bekker PJ. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Am J Med 1999;106:51320.[CrossRef][ISI][Medline]
- Siris ES. Extensive personal experience: Paget's disease of bone. J Clin Endocrinol Metab 1995;80:3358.[CrossRef][ISI][Medline]
- Lyles KW, Siris ES, Singer FR, Meunier PJ. A clinical approach to diagnosis and management of Paget's disease of bone. [Review]. J Bone Miner Res 2001;16:137987.[ISI][Medline]
- Brown JP, Chines AA, Myers WR, Eusebio RA, Ritter-Hrncirik C, Hayes CW. Improvement of pagetic bone lesions with risedronate treatment: a radiologic study. Bone 2000;26:2637.[CrossRef][ISI][Medline]
- Reid IR, Nicholson GC, Weinstein RS et al. Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial. [comment] [erratum appears in Am J Med 1997;102:322]. Am J Med 1996;101:3418.[CrossRef][ISI][Medline]
- Menzies MA, Greenberg PB, Joplin GF. Otological studies in patients with deafness due to Paget's disease before and after treatment with synthetic human calcitonin. Acta Otolaryngol 1975;79:37883.[ISI][Medline]
- Lando M, Hoover LA, Finerman G. Stabilization of hearing loss in Paget's disease with calcitonin and etidronate. Arch Otolaryngol Head Neck Surg 1988;114:8914.[Abstract]
- Solomon LR, Evanson JM, Canty DP, Gill NW. Effect of calcitonin treatment on deafness due to Paget's disease of bone. Br Med J 1977;2:4857.[Medline]
- el Sammaa M, Linthicum FH Jr, House HP, House JW. Calcitonin as treatment for hearing loss in Paget's disease. Am J Otol 1986;7:2413.[ISI][Medline]
- Delmas PD, Meunier PJ. The management of Paget's disease of bone. [Review]. N Engl J Med 1997;336:55866.[Free Full Text]
- Monsell EM, Cody DD, Bone HG et al. Hearing loss in Paget's disease of bone: the relationship between pure-tone thresholds and mineral density of the cochlear capsule. Hear Res 1995;83:11420.[CrossRef][ISI][Medline]
- Patel S, Pearson D, Bhallah A, Maslanka W, White DA, Hosking DJ. Changes in bone mineral density in patients with Paget's disease treated with risedronate. Ann Rheum Dis 1997;56:4059.[Abstract/Free Full Text]
- Patel S, Pearson D, Hosking DJ. Quantitative bone scintigraphy in the management of monostotic Paget's disease of bone. Arthritis Rheum 1995;38:150612.[Medline]
- Meunier PJ, Vignot E. Therapeutic strategy in Paget's disease of bone. Bone 1995;17(5 Suppl.):489S491S.[CrossRef]
- Hughes AE, Ralston SH, Marken J et al. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 2000;24:458.[CrossRef][ISI][Medline]
- Laurin N, Brown JP, Morissette J, Raymond V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 2002;70:15828.[CrossRef][ISI][Medline]
- Hocking LJ, Lucas GJ, Daroszewska A et al. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum Mol Genet 2002;11:27359.[Abstract/Free Full Text]
- Gold DT, Boisture J, Shipp KM, Pieper CF, Lyles KW. Paget's disease of bone and quality of life. J Bone Miner Res 1996;11:1897904.[ISI][Medline]
Submitted 28 November 2003;
revised version accepted 29 April 2004.