23 Paget's Disease of Bone

Paget’s Disease of Bone 381 23 Paget’s Disease of Bone Richard Williams Whitehouse and A. Mark Davies CONTENTS Paget’s disease of bone has been considered a common disorder affecting approximately 3%– 23.1 Introduction 381 4% of the population over 40 years of age. Conse- 23.2 Aetiology 381 23.3 Epidemiology 382 quently it is the second commonest bone pathology 23.4 Imaging Appearances 382 of “metabolic” origin, after osteoporosis. However, 23.5 Complications 385 the prevalence of Paget’s disease varies considerably 23.5.1 Fracture and Deformity 385 around the world, being rare in the Far East and 23.5.2 Arthritis 386 commonest in the north west of England. Since the 23.5.3 Demineralisation 387 23.5.4 Tumour (Primary and Secondary) 387 1980’s, studies and reports from around the world 23.6 Treatment 389 have suggested a marked reduction in the incidence 23.6.1 Medical 389 of new cases of Paget’s disease of bone. In addition 23.6.2 Surgical 389 the age at first presentation appears to be increasing 23.7 Differential Diagnosis 390 whilst both the severity and extent of bone involve- 23.8 Conclusions 390 References 390 ment in new cases is decreasing. If substantiated and continued, these trends will result in the condition becoming rare. There has not, as yet been any report of a reduction in the incidence of the serious complications of Paget’s disease, in particular the develop- 23.1 ment of bone sarcoma. Introduction Paget’s disease of bone, named after the nineteenth century British surgeon Sir James Paget, remains a 23.2 condition of disputed aetiology, with virus infec- Aetiology tion and genetic susceptibility both implicated. Although sporadic and seemingly random in the Paget’s disease remains of uncertain and disputed sites and extent of bone involvement in individuals, aetiology. The two main theories are of “slow” virus because markedly altered bone turnover and cel- infection and genetic abnormality. Ownership of lular activity are histologically and biochemically dogs not vaccinated against canine distemper virus characteristic of the condition, it is often placed with appears to increase the risk of developing Paget’s metabolic bone diseases. disease, but so does ownership of cats or birds The pelvis, sacral and lumbar spine and femora (Khan et al. 1996) or a history of measles (Renier are the commonest locations for this condition, with et al. 1996b). Contact with cattle, ingestion of meat the pelvis (including the sacrum) involved in about from sick livestock and frequent ingestion of brains two thirds of cases. or bovid viscera during youth are also risk factors (López et al. 1997). There are regional variations in the significance of these risk factors. These observa- tions support one or more transmissible agents as R. W. Whitehouse, MD aetiological in Paget’s disease. Department of Clinical Radiology, Manchester Royal Inﬁ r- On electron microscopy, the nuclei of osteoclasts mary, Oxford Road, Manchester, M13 9WL, UK A. M. Davies, MD from pagetic bone contain lesions similar to “viral Consultant Radiologist, The MRI Centre, Royal Orthopaedic inclusion bodies” seen in other virally mediated con- Hospital, Birmingham, B31 2AP, UK ditions. In some centres, in-situ hybridisation tech- 382 R. W. Whitehouse and A. M. Davies niques have demonstrated messenger RNA (mRNA) ciated with osteoprotegerin deficiency caused by transcripts derived from various paramyxoviruses homozygous deletion of the gene encoding osteo- in bone cells from pagetic lesions, with measles and protegerin (TNFRSF11B) (Whyte et al. 2002). canine distemper virus being the most often found. Other environmental causes for Paget’s disease The findings of these studies have proved difficult have been suggested, for example calcium arsenate to replicate in other centres (Helfrich et al. 2000; (Lever 2002), a pesticide used in the cotton industry Ooi et al. 2000). Recently, in one study using an in- has been suggested as a possible cause of the marked situ reverse transcriptase polymerase chain reac- variation in prevalence of Paget’s disease in Lanca- tion technique, canine distemper virus mRNA has shire. Oral bacterial flora have also been suggested been found in 100% of material from pagetic bone as causative agents (Dickinson 1999). Evidence for (Mee et al. 1998). It has however been claimed that these hypotheses is extremely limited. measles virus is only found in laboratories that support a measles virus aetiology and canine distemper virus in laboratories that support the latter virus as the causative agent (Ralston and Helfrich 1999). 23.3 Osteoclast precursors transduced with measles Epidemiology virus genes can produce osteoclast like cells with features similar to Pagetic osteoclasts (Kurihara Paget’s disease varies widely in prevalence both et al. 2000; Reddy et al. 2001). An infectious virus within and between countries (Armas et al. 2002). has never been isolated from pagetic bone but a It has been historically commonest in the North full length viral gene has now been sequenced from West of England, rare in the Far East (Yip et al. pagetic bone (Friedrichs et al. 2002). Difficulties 1996) and commoner in other countries with high of contamination and reproducibility of these tests proportions of Caucasians, particularly of Western have dogged interpretation of the results of these European origin. A high prevalence of the disease viral gene studies. is found in Buenos Aires, for example, where 95% of Genetic studies have also been inconsistent patients were of European descent, particularly Ital- (Good et al. 2001; Nance et al. 2000). Paget’s disease ian and Russian (Gómez and Mautalen 2001). An is commoner than expected in first degree relatives archaeological study of 2770 skeletons from Humber of patients with the condition. However, there are in England dating from 900 to 1850 AD showed a both familial and sporadic forms of Paget’s disease prevalence of 2.1% in those aged over 40 years, with different genetic abnormalities. At least six with a non-significant increase from 1.7% to 3.1% mutations in the ubiquitin-associated domain of the pre- and post-1500 AD (Rogers et al. 2002). More SQSTM1 (p62-sequestosome 1) gene have been iden- recently, comparative surveys of pelvic radiographs tified in patients with familial Paget’s disease and and biochemical tests from many studies around the a proportion, but not all of sporadic cases (Hock- world have suggested a marked reduction in inci- ing et al. 2002; Eekhoff et al. 2004; Johnson et al. dence of new cases of Paget’s disease (Cundy et al. 2003). Familial Paget’s disease has an earlier age of 1997, 1999; Cooper et al. 1999; Doyle et al. 2002), onset and greater fracture rate than sporadic forms. reduced severity and number of sites involved in In an American study, familial cases were less likely new cases (Morales et al. 2002)and an older age to record the US or Canada as their grandparents’ at presentation over the last 25 years (Rapado et al. birthplace, strengthening a case for genetic rather 1999; Cundy et al. 1997), typically finding a halv- than local environmental factors in the developing of incidence over this period (van Staa et al. ment of the disease (Seton et al. 2003). Mutations in 2002). The condition is slightly commoner in men the TNFRSF11A gene causing early onset Paget like and is also slightly commoner in the right side of disease have also been described (Nakatsuka et al. the body. 2003). Differences in the genetic polymorphism of the oestrogen receptor-alpha gene and the calcium sensing receptor gene between pagetic and non- pagetic patients have also been detected, which may 23.4 contribute to genetic susceptibility to the disease Imaging Appearances (Donáth et al. 2004). Hyperphosphatasemia (Juvenile Paget’s disease) Both the incidental demonstration of Paget’s dis- is genetically distinct from Paget’s disease and asso- ease and its diagnosis is most often accomplished by Paget’s Disease of Bone 383 radiography. Biochemically, Paget’s disease may be suspected, or activity of known disease monitored by measurement of urinary hydroxyproline and serum total alkaline phosphatase (Fraser 1997). Further evaluation of biochemically suspected Paget’s disease and the identification of extent and severity of disease is usually by radiographs and bone scintig- raphy. The imaging appearances of Paget’s disease are consequently primarily by reference to those modalities (Hoffman 1998). Paget’s disease is described as passing through three phases, as demonstrated on conventional radiography. An initial lytic phase, a mixed phase and a sclerotic phase. The lytic phase is infrequently seen, being most often identified in the skull (because it may persist in this location, known as osteoporosis circumscripta) and in long bones. It is usually Fig. 23.1. AP radiograph showing mixed lytic and sclerotic of short duration, rapidly progressing to the mixed Paget’s disease involving the entire pelvis, both femora and lower lumbar spine phase. In this second phase abnormally coarsened and disorganised new bone is formed, resulting in thickening and heterogeneous density of the bone cortex and coarsening of the trabecular bone. These changes in both the cortex and medullary bone results in loss of definition of the margin between cortical and trabecular bone. The affected bone enlarges and distorts as if softened and has a spongy textural appearance on imaging (Fig. 23.1). His- tologically, haversian systems in cortical bone are destroyed and the new bone formed to replace them is in irregular plates creating a mosaic appearance. The final, sclerotic phase represents reduction in the previously overactive osteoclastic bone resorp- tion present in the first two phases, whilst osteoblast activity continues, resulting in increasing bone density and “filling in” of previously lytic areas, with a resultant more amorphous appearance to the bone Smith 2002 Fig.

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