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Monostotic Paget's disease of the femur: A diagnostic challenge and an overlooked risk
Bone 57 (2013) 517–521
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Bone journal homepage: www.elsevier.com/locate/bone
Original Full Length Article
Monostotic Paget's disease of the femur: A diagnostic challenge and an overlooked risk J. Bachiller-Corral a, C. Díaz-Miguel a, A. Morales-Piga b,⁎ a b
Department of Rheumatology, Ramón y Cajal Hospital, Madrid, Spain Rare Disease Research Institute (Instituto de Investigación de Enfermedades Raras — IIER), Carlos III Institute of Health (Instituto de Salud Carlos III — ISCIII), Madrid, Spain
a r t i c l e
i n f o
Article history: Received 29 June 2013 Revised 22 August 2013 Accepted 23 August 2013 Available online 1 September 2013 Edited by: Peter Ebeling Keywords: Paget's disease Osteitis deformans Monostotic Femoral involvement Radiological diagnosis
a b s t r a c t Background: Although radiological diagnosis of Paget's disease of bone (PD) is usually straightforward, monostotic cases may potentially raise specific problems which lead to performing invasive procedures. Therefore, the purpose of this study is to ascertain whether or not monostotic femoral Paget's disease (MFPD) presentation poses particular diagnostic difficulties which prompt excessive use of excisional biopsies. Methods: We retrospectively reviewed the medical records of 24 MFPD patients identified from a series of 412 patients; their clinical features were compared with those of the remaining 164 monostotic cases and the radiological images were systematically assessed. Results: When compared with the remaining monostotic cases, MFPD patients were more prone to having normal alkaline phosphatase levels (31.8% vs. 16.4%; 0.08) and a significantly higher percentage of patients have PD symptoms (75% vs. 51%; 0.02) and complain of bone pain (73.9% vs. 40.8%; 0.003). Six (25%) MFPD patients evidenced a fracture over the pagetic lesion. This incidence is higher than that of the monostotic cases of other locations (8.4%; p = 0.02). The existence of PD lesion was not recognised initially in 10 cases and an excisional bone biopsy was performed in 7 (29%). One patient subsequently experienced a fracture through the biopsy site and another two experienced worsening of their previous bone pain. Conclusion: The femur is a relatively common monostotic PD location which often causes diagnostic confusion, prompting a bone biopsy in many cases. Careful assessment of this lesion by X-ray examination may help attain an early appropriate diagnosis and avoidance of unnecessary surgical morbidity. © 2013 Elsevier Inc. All rights reserved.
Introduction Paget's disease of bone (PD) is a fairly common medical condition in many European countries, the United States, and other populations of British ancestry [1,2]. For instance, the estimated prevalence in a radiological study undertaken in the United Kingdom in the 1970s in people over 55 ranged between 2% and 5% [3]. Although more recent studies conducted with similar methods in the same geographical area [4] and in other countries [5–7] suggest that the prevalence could be decreasing, PD is still considered to be an important cause of morbidity in this fast-growing age group, despite the fact that a high proportion of patients remain asymptomatic throughout their evolution [8]. One of the consequences of this high prevalence is the frequent finding of a PD bone lesion in current clinical practise. Taking into account the large variety of radiological appearances [2,9–12] – sometimes mimicking those of other significant morbid disorders (i.e.: bone tumours and metastasis) – , PD should always be considered in differential diagnosis of osteoesclerotic as well as osteolytic skeletal lesions [2]. Nevertheless, the ⁎ Corresponding author. E-mail addresses: [email protected] (J. Bachiller-Corral), [email protected] (C. Díaz-Miguel), [email protected] (A. Morales-Piga). 8756-3282/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bone.2013.08.023
most common radiologic appearance of the disease, usually present in its “mixed” and “blastic” phases, is distinctive [12]. In fact, the combination of patchy areas of bone sclerosis or lysis with coarsening of the trabecular pattern, together with local enlargement, mostly at the expense of cortical subperiosteal thickening, is virtually diagnostic of PD [2,9–11]. Therefore, in cases with more than one lesion (“polyostotic PD”), the diagnosis is almost always straightforward because at least one of the locations will show the aforementioned typical features. On the contrary, in monostotic cases, whose frequency has been reported as ranging from 10–20% [2] to close to 50% [13], the diagnosis may be far more difficult and confusion with other conditions may arise [12,14–16]. The issue could be greater in certain skeletal areas where PD's radiological features tend to be less characteristic and, particularly, when the early osteolytic form of the disease is present [17]. In these instances, the need to rule out life-threatening conditions, such as primary bone tumours or skeletal metastasis, prompts the performance of some invasive techniques which are associated with a certain degree of morbidity. The main goal of this study is to address whether monostotic femoral Paget's disease presentation raises specific diagnostic problems and subsequently causes an excessive number of excisional bone biopsies. In addition, we seek to identify any eventual clinical or radiological feature that may help avoid unnecessary harmful procedures.
518
J. Bachiller-Corral et al. / Bone 57 (2013) 517–521
Table 1 Comparison of numerical (mean ± SD) and categorical (%) characteristics between cases with monostotic PD of the femur and monostotic PD cases of other locations.
Age at diagnosis Sex Female Male Extent of skeletal lesionsa Alkaline phosphataseb (U/L) Alkaline phosphatase/ extent of bone lesions Normal alkaline phosphatase Urinary hydroxyprolinec (mg/24 h) Urinary hydroxyproline/ extent of bone lesions Asymptomatic case Bone pain Bone deformity Fracture Diagnostic biopsy Antiresorptive therapy a b c
Monostotic femur involvement [n = 24]
Other monostotic cases [n = 164]
p
64.6 ± 11.5
64.8 ± 11.4
0.92
13 (54.1) 11 (45.8) 3.2 ± 0.9 199.3 ± 109.3 61.6 ± 26.5
83 (50.6) 81 (49.3) 4.1 ± 1.6 290.0 ± 205.3 86.9 ± 106.3
0.74 0.008 0.04 0.27
7 (31.8) 42.2 ± 18.7
26 (16.4) 50.8 ± 30.2
0.08 0.25
13.4 ± 5.6
6.8 ± 25.5
0.58
6 (25.0) 17 (73.9) 11 (45.8%) 6 (25.0) 7 (29.1) 17 (70.8)
78 (49.0) 58 (35.3) 28 (19.4) 13 (8.4) 10 (6.6) 100 (61.7)
0.02 0.003 0.03 0.011 0.001 0.15
Evaluated by using Coutris' index [20]. Normal range 40–128 U/l. Normal range 18–40 mg/24 h.
Patients and methods From a series of 412 PD patients reviewed in our Unit from 1992 to the present, we retrospectively reviewed the medical records of the 24 (5.8%) in whom the disease was only present as a lesion in the femur. Characteristics of these monostotic femoral Paget disease (MFPD) patients were then compared with those of the 164 monostotic cases from other locations seen during the same period of time. All patients were recorded at diagnosis, and clinical, radiological, and biochemical evaluations were at baseline. Throughout the period of the study, the diagnosis was based on the same roentgenographic criteria [18].
Clinical evaluation Clinical evaluation included primary bone pain assessment as differentiated from non-specific musculoskeletal pain. Other features, such as typical bone deformity, (anterior and lateral bowing), localised skin hyperthermia, secondary neighbourhood (hip or knee) osteoarthritis, fractures (either complete or cortical fissures), and sarcomatous degeneration were recorded using a computerised purpose-designed codified questionnaire. According to the presence or absence of any of these PD symptoms, patients were classified as symptomatic or asymptomatic. Image evaluation Plain radiograph images of PD femoral lesions were available in medical charts in all cases. In addition, “ad hoc” frontal and lateral views of the whole femur were made for this study. Radiological evaluation was made following a structured protocol including the most relevant common PD features: trabecular pattern, cortical thickening and local bone enlargement. According to previous reports, the evolutionary phases of PD lesions were defined as: “lytic”, “mixed” or “blastic” [9]. In addition, several radiological traits associated with femoral involvement like coxa vara (neck shaft angle ≤ 115°), anterior and lateral bowing, protrusio acetabuli, and secondary arthropathy (from either hip or knee) were evaluated. The presence or absence of Monckeberg-type vascular calcifications [19] was also recorded. Radiographs were jointly assessed by two expert rheumatologists (A. M-P. and J. B-C.) and consensus was achieved in all cases. Bone scans performed with 99mTc-EHDP was available for all patients. The skeletal extent of the disease, based on bone scan uptake, was determined by using the index proposed by Coutris [20]. This index represents the sum of the coefficients conventionally assigned to each lesion according to the amount of bone affected. Biochemical assessment Serum and urine samples were obtained after an overnight fasting. Serum total alkaline phosphatase activity (normal range: 40–128 U/l) was assayed by an automated method using a p-nitrophenyl phosphate substrate following the International Federation of Clinical Chemistry
Fig. 1. Complete fracture of Paget's disease femoral lesion after biopsy. A. Pagetic lesion in distal femur. B. Lesion after bone biopsy. C. Fracture over the intervened area.
J. Bachiller-Corral et al. / Bone 57 (2013) 517–521
guidelines. After a 24-hour period of consuming a gelatin-free diet, a 24-hour urine specimen was collected and an appropriate sample was analysed for calcium, phosphate, hydroxyproline (radioimmunoassay) and creatinine determination. Statistical methods Significant differences (p b 0.05) were determined using the twotailed Student's t test (or non-parametric test when appropriate) and the chi-square test with Yates' correction. Results We did not observe statistically significant differences between 24 MFPD patients and 164 monostotic cases of other locations in terms of
Fig. 2. Femoral fracture on Paget's disease lesion with sarcomatous degeneration.
519
age (mean ± SD): 64.6 ± 11.5 vs. 64.8 ± 11.4, or gender (femaleto-male ratio: 13/11 vs. 83/81; p = 0.74) [Table 1]. The percentage of monostotic femoral patients (31.8%) who presented with normal alkaline phosphatase values at diagnosis is almost double that of other monostotic cases (16.4%), the difference being near the level of significance (p = 0.08). The difference in the percentage of cases who presented with any pagetic symptom (75.0% vs. 51%) attained statistical significance (p = 0.02). Of the MFPD, 17 out of 24 (73.9%) complained of primary bone pain at the femoral site, in 3 of them being of severe intensity. This figure is higher than that of the remaining monostotic cases (35.3%; p = 0.003). Of the 24 MFPD, 11 (45.8%) showed some degree of bone deformity on the affected limb at clinical examination (accompanied by warmth of overlying skin in 3) whereas this feature was observed in 28 (19.4%) other monostotic patients (p = 0.03). Six (25%) MFPD cases experienced a fracture over the pagetic lesion. One was an impacted fracture, one a complete fracture after a minor fall, another a complete fracture after biopsy (Fig. 1), two were fissure-fractures, and the remaining one was a pathological fracture (Fig. 2). Overall incidence is higher than the correspondent of the monostotic cases in other locations (13 of 164; 8.4%), the difference being statistically significant (p = 0.02). One of the 24 MFPD patients suffers a malignant transformation (osteogenic sarcoma) of bone lesion versus 3 in the remaining 388 throughout our entire series. The radiological pattern of the 24 PD lesions was considered “mixed” in 17, predominantly “blastic” in 6, and purely “lytic” in one. X-ray examination confirmed clinically detected bone deformity in all 11 (45.8%) cases, showing the typical appearance (anterior and lateral bowing) in 5 of them (Fig. 3). There was bone enlargement in 23 (96%) cases, which was very marked in 10 cases, and moderate in 13 cases. Of the 19 cases with a lesion located at the femoral neck, 8 had coxa vara. In addition, 10 had protrusio acetabuli and 8 showed a certain degree of secondary arthropathy. Three showed Monckeberg-type vascular calcifications on plain X-rays. The lesion was located in the left leg in 14 of the 24 MFPD patients, while 10 had it in the right. In 17 instances the lesion was located at the proximal femur, 5 were confined to the distal part of the bone, and the remaining 2 presented a lesion virtually spanning the femur as a whole (Table 2). The characteristics of these two do not differ from the more prevailing proximal subset. On the contrary, lesions located on the distal femur tend to be more atypical with a relatively higher proportion of cases having a “blastic” appearance (instead of “mixed”) and less markedly, both coarsening trabecular pattern and
Fig. 3. Monostotic lesion on proximal left femur, with typical Paget's disease radiological pattern, cortical thickening, coxa vara, and lateral bowing.
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Table 2 Disclosure of X-ray characteristic PD signs and associated traits, in the three types of monostotic femoral pagetic lesion according to topographical location. X-ray sign
Characteristic PD signs
Location (# cases)
Appearance/phase
Coarsened trabecular pattern
Cortical thickening
Protrusio acetabuli
Coxa vara
Secondary osteoarthritis
“Monckeberg-type” vascular calcifications
Proximal (n = 17)
Lytic 1 Blastic 4 Mixed 12 Lytic 0 Blastic 2 Mixed 3 Lytic 0 Blastic 0 Mixed 2
Yes 15 No 2
No 0 Moderate 9 Intense 8 No 1 Moderate 3 Intense 1 No 0 Moderate 1 Intense 1
Yes 7 No 10
Yes 6 No 11
Yes 5 No 12
Yes 1 No 16
Yes 1 No 4
Yes 1 No 5
Yes 3 No 2
Yes 1 No 4
Yes 2 No 0
Yes 1 No 1
Yes 1 No 0
Yes 1 No 1
Distal (n = 5) Whole femur (n = 2)
Associated traits
Yes 3 No 2 Yes 2 No 0
cortical thickening (Fig. 4). There were no significant differences in clinical manifestations and alkaline phosphatase levels between groups with proximal and distal involvement. Likewise, no differences were observed in the same variables when comparing groups with different femoral extension (above and below mean Coutris' index). Of the 5 patients whose lesion is located at the distal end of the femoral bone, 3 (60%) underwent diagnostic biopsy, while 4 (23.5%) patients among those 17 who had a proximal lesion (p = 0.27) were biopsied. Fourteen (58.3%) of the MFPD cases were originally considered by doctors as having a typical PD radiological pattern. In another 6 (25%), the diagnosis could be established with an acceptable degree of certainty and in the remaining 4 (16.7%) the radiological picture was deemed unclear and other possibilities were considered, notably bone malignancy. As a consequence, an excisional bone biopsy was performed in 7 cases (29.1%) in 3 instances before the patient was admitted to our Unit. When comparing this figure with the frequency among the
Fig. 4. Atypical lesion of PD in distal femur: absence of typical features such as cortical thickening and coarsened trabecular pattern.
other 164 monostotic cases – 10 (6.6%) of 164 cases – the risk [OR (IC 95%)] of undergoing this invasive procedure among MFPD patients rises to 6.34 (1.95–17.25; p = 0.001). A few months after the biopsy, a patient had a fracture just over the intervened area without noticeable trauma (Fig. 1). Two additional cases developed an intensification of their prior bone pain in the months following the surgical procedure. Discussion In the vast majority of PD cases, the presence of patchy areas of bone sclerosis or lysis with distortion of the trabecular architecture in combination with cortical thickening and focal bone enlargement is virtually diagnostic of the disease [2,9–11]. However, depending on the number and location of skeletal areas involved, as well as evolutionary factors (i.e. the phase in which lesions are found), this distinctive appearance could be somewhat elusive. Therefore, at an early stage, PD could present radiologic problems [21] before the lesion reaches its mature appearance. Furthermore, there are monostotic lesions which represent a bigger diagnostic challenge; in polyostotic cases there will likely be at least one image depicting the disease's typical features. Therefore, the main problem may happen in younger patients whose isolated lesion is located on skeletal areas where the radiological picture may be less characteristic [17] or requires more time to develop the typical PD roentgenographic changes [14,15]. Under these circumstances, monostotic PD lesions can give rise to confusion with primary [17] or metastatic bone tumours [22], chronic infection, and fibrous dysplasia, among other disorders [2,10–12]. This may lead to performing unnecessary diagnostic procedures which are potentially harmful or undergoing inappropriate therapeutic measures [2,8,22]. Despite this concern, there have been few reports addressing such issues and, to our knowledge, there are no previous reports which focus on monostotic PD of the femur. One of the limitations of this study is the fact that we were only able to research a relatively low number of patients. The comparison with the remaining monostotic cases allows us to more accurately describe the features of this subgroup, thus disclosing a possible peculiarity of this presentation. However, there was no appropriate comparison group available to help understand our work's main purpose more deeply. Only by comparing a similar population with isolated femoral lesions of another significance (particularly of a neoplastic nature) would it be possible to analyse all the relevant clinical and radiological features that may have discriminatory power in order to establish a predictive value. In the absence of such a comparison, the results offered here should be regarded with caution. In our series, the femur is the second most common monostotic location after the pelvis. When compared with the other 164 monostotic cases, the 24 MFPD patients were prone to having normal alkaline phosphatase serum activity (31.8% vs. 16.4%; 0.08). Since previous work has demonstrated a significant positive linear correlation between the extent of bone affected and biochemical values [23], such a difference could be
J. Bachiller-Corral et al. / Bone 57 (2013) 517–521
better explained on the basis of a lesser amount of bone affected in MFPD in comparison with other skeletal areas. In fact, the difference is blurred when activity rates are adjusted for the amount of affected bone. On the contrary, the higher and significant percentage of MFPD cases that suffer any PD symptom (75% vs. 51%; 0.02), complain of bone pain (73.9 vs. 40.8%; 0.003), evidence bone deformity (45.8% vs. 19.4%; p = 0.03) or develop a fracture (25 vs. 8.4%; p = 0.02), may have a true biological meaning. Overall, these findings (which seem logically interconnected) imply that isolated femoral presentation causes substantially more morbidity than other monostotic PD lesions. This greater aggressiveness together with the diagnostic difficulty raised by some MFPD cases lacking the characteristic PD radiological features may explain why 7 of these 24 patients underwent an excisional biopsy. This figure is remarkably higher than that of other monostotic cases (OR = 6.34; 1.95–17.25). In one of them, the biopsy site was spontaneously fractured a few months after the biopsy. Two additional cases experienced intensified bone pain after the surgical procedure. Our data shows that the majority of PDFP cases arise on the proximal region of the femur. We have also observed that when this area is involved, the characteristic radiological signs of PD are nearly always present (Table 2) and, hence, the diagnosis is usually straightforward. On the contrary, in cases where there is distal involvement, radiological signs characteristic of the PD lesion occur with lesser frequency or are less marked, so that differentiation with other issues – particularly neoplastic disorders – could be harder to carry out. As a consequence, distal cases suffer an excisional bone biopsy with a higher significant frequency than other PDFP cases and the incidence of complications derived from this invasive procedure is concentrated in this subset of cases. In these more elusive lesions, the finding of associated clinical or radiographic signs like bone deformity (especially when warmth of overlying skin is also present) and Monckeberg-type vascular calcifications may help in performing an accurate diagnosis. In the same manner, it is worth noting that the presence of coxa vara deformity and “protrusio acetabuli”, together with the peculiar degenerative joint changes associated with PD, have come to be considered as virtually specific to the disease [24]. While sometimes it may be difficult to differentiate from pseudo-protrusio (increase in acetabular wall width), true protrusio acetabuli has been reported in as many as 25% of PD cases with hip joint involvement [25]. Structural weakness of pagetic bone in combination with bone enlargement and coxa vara deformity, the latter leading to an alteration in mechanical force across the hip joint, may account for this high number [2,25]. We have observed protrusio acetabuli not only in cases located in the proximal femur, but also in one case located in distal areas. The histological evidence of an increased turnover commonly observed even in unaffected bone [26] might help to explain the presence of this complication, even when distal lesions occur. On the other hand, osteoarthritis related to PD is a common cause of symptoms in people with PD and it has been frequently reported in the hip (30%) and knee (11%) of such patients [27]. As in several of our cases, the presence of this secondary osteoarthritis, which in the case of the “Pagetic coxopathy” that typically shows a narrowing of the medial (rather than superior) joint space [25,28], may help to differentiate PD from other more aggressive issues. In conclusion, the finding of an isolated PD femoral lesion is occasionally seen in medical practise. Certain clinical and radiological peculiarities present in some of these cases along with an unusually high percentage of normal alkaline phosphatase values observed in
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the entire MFPD patient population, imply some diagnostic difficulty. Patients with proximal MFPD, which nearly always show the characteristic X-ray pattern, should not and need not be biopsied for diagnostic confirmation. On the contrary, the subset in which the lesion is confined to the distal region of the femur's radiological appearance could be misleading. These cases account for the bulk of the observed excess risk when undergoing a bone biopsy is needed. The recognition and correct assessment of some associated clinical and radiological traits may help to avoid diagnostic procedures which result in an increased risk of fracture. References [1] Singer FR, Krane SM. Paget's disease of bone. In: Avioli LV, Krane SM, editors. Metabolic bone disease. San Diego: Academic Press; 1998. p. 545–605. [2] Kanis JA. Pathophysiology and treatment of Paget's disease of bone. London: Martin Dunitz; 1998. [3] Barker DJP. The epidemiology of Paget's disease of bone. Br Med Bull 1984;40:396–400. [4] Cooper C, Schafheutle K, Dennison E, Kellingray S, Guyer P, Barker D. The epidemiology of Paget's disease in Britain: is the prevalence decreasing? J Bone Miner Res 1999;14:192–7. [5] Cundy T, McAnulty K, Wattie D, Gamble G, Rutland M, Ibbertson HK. Evidence for secular change in Paget's disease. Bone 1997;20:69–71. [6] Morales-Piga AA, Bachiller-Corral FJ, Abraira V, Beltrán J, Rapado A. Is clinical expressiveness of Paget's disease of bone decreasing? Bone 2002;30:399–403. [7] Poor G, Donath J, Fornet B, Cooper C. Epidemiology of Paget's disease in Europe: the prevalence is decreasing. J Bone Miner Res 2006;21:1545–9. [8] Selby PL, Davie MWJ, Ralston SH, Stone MD. Guidelines on the management of Paget's disease of bone. Bone 2002;31:366–73. [9] Milgram JW. Radiographical and pathological assessment of the activity of Paget's disease of bone. Clin Orthop 1977;127:43–54. [10] Resnick D, Niwayama G. Paget's disease. In: Resnick D, Niwayama G, editors. Diagnosis of bone and joint disorders. 2nd ed. Philadelphia: Saunders; 1987. p. 2127–70. [11] Smith SE, Murphey MD, Motamedi K, Mulligan ME, Resnik CS, Gannon FH. Radiologic spectrum of Paget's disease of bone and its complications with pathologic correlation. Radiographics 2002;22:1191–216. [12] Wellman HN, Schauwecker D, Robb JA, Khairi MR, Johnston CC. Skeletal scintimaging and radiography in the diagnosis and management of Paget's disease. Clin Orthop Relat Res 1977;127:55–62. [13] Varenna M, Zucchi F, Galli L, Manara M, De Marco G, Sinigaglia L. Demographic and clinical features related to a symptomatic onset of Paget's disease of bone. J Rheumatol 2010;37:155–60. [14] Schreiber MH, Richardson GA. Paget's disease confined to one lumbar vertebra. Am J Roentgenol 1963;90:1271–6. [15] Perrot S, Mortier E, Renoux M, Job-Deslandre C, Menkes CJ. Monostotic Paget's disease involving the calcaneus. Diagnostic and therapeutic problems. Rev Rhum 1995;62:45–57. [16] Amr R, Choudry Q. Monostotic Paget's disease of the patella. Bone 2006:1382–4. [17] Eisman JA, Martin JM. Osteolytic Paget's disease. J Bone Joint Surg 1986;68-A:112–7. [18] Murray RO, Jacobson HG. Miscellaneous disorders of unknown origin. In: Murray RO, editor. The radiology of skeletal disorders, vol. II; 1979 [Edinburgh]. [19] Acar J, Delbarre F, Waynberger M. Les complications cardio-vasculaires de la maladie osseuse de Paget. Arch Mal Coeur 1968;6:849–68. [20] Coutris G. Analyse des perturbations des voies principales du métabolisme calcique dans la maladie de Paget. Rev Rhum Mal Osteoartic 1975;42:759–67. [21] Doyle FH, Banks LM, Pennock JM. Radiologic observations on bone resorption in Paget's disease. Arthritis Rheum 1980;23:1185–92. [22] Katapuram SV, Phillips WC. Paget's disease of bone mimicking metastases. J Can Assoc Radiol 1982;33:239–45. [23] Meunier PJ, Salson C, Mathieu L, Delmas P, Alexandre C, Charhon S. Skeletal distribution and biochemical parameters of Paget's disease of bone. Clin Orthop 1987;217:37–44. [24] Guyer PB, Dewbury KC. The hip joint in Paget's disease of bone (Paget's “coxopathy”). Br J Radiol 1978;51:574–8. [25] Graham J, Harris WH. Paget's disease involving the hip joint. J Bone Joint Surg 1971;53B:650–9. [26] Meunier PJ, Coindre J, Edouard CM, Arlot ME. Bone histomorphometry in Paget's disease. Quantitative and dynamic analysis of Paget’s disease and nonpagetic bone tissue. Arthritis Rheum 1980;23:1095–103. [27] Altman RD, Collins B. Musculoskeletal manifestations of Paget's disease of bone. Arthritis Rheum 1980;23:1121–7. [28] Winfield J, Stamp TCB. Bone and joint symptoms in Paget's disease. Ann Rheum Dis 1984;43:769–73.
Contents lists available at ScienceDirect
Bone journal homepage: www.elsevier.com/locate/bone
Original Full Length Article
Monostotic Paget's disease of the femur: A diagnostic challenge and an overlooked risk J. Bachiller-Corral a, C. Díaz-Miguel a, A. Morales-Piga b,⁎ a b
Department of Rheumatology, Ramón y Cajal Hospital, Madrid, Spain Rare Disease Research Institute (Instituto de Investigación de Enfermedades Raras — IIER), Carlos III Institute of Health (Instituto de Salud Carlos III — ISCIII), Madrid, Spain
a r t i c l e
i n f o
Article history: Received 29 June 2013 Revised 22 August 2013 Accepted 23 August 2013 Available online 1 September 2013 Edited by: Peter Ebeling Keywords: Paget's disease Osteitis deformans Monostotic Femoral involvement Radiological diagnosis
a b s t r a c t Background: Although radiological diagnosis of Paget's disease of bone (PD) is usually straightforward, monostotic cases may potentially raise specific problems which lead to performing invasive procedures. Therefore, the purpose of this study is to ascertain whether or not monostotic femoral Paget's disease (MFPD) presentation poses particular diagnostic difficulties which prompt excessive use of excisional biopsies. Methods: We retrospectively reviewed the medical records of 24 MFPD patients identified from a series of 412 patients; their clinical features were compared with those of the remaining 164 monostotic cases and the radiological images were systematically assessed. Results: When compared with the remaining monostotic cases, MFPD patients were more prone to having normal alkaline phosphatase levels (31.8% vs. 16.4%; 0.08) and a significantly higher percentage of patients have PD symptoms (75% vs. 51%; 0.02) and complain of bone pain (73.9% vs. 40.8%; 0.003). Six (25%) MFPD patients evidenced a fracture over the pagetic lesion. This incidence is higher than that of the monostotic cases of other locations (8.4%; p = 0.02). The existence of PD lesion was not recognised initially in 10 cases and an excisional bone biopsy was performed in 7 (29%). One patient subsequently experienced a fracture through the biopsy site and another two experienced worsening of their previous bone pain. Conclusion: The femur is a relatively common monostotic PD location which often causes diagnostic confusion, prompting a bone biopsy in many cases. Careful assessment of this lesion by X-ray examination may help attain an early appropriate diagnosis and avoidance of unnecessary surgical morbidity. © 2013 Elsevier Inc. All rights reserved.
Introduction Paget's disease of bone (PD) is a fairly common medical condition in many European countries, the United States, and other populations of British ancestry [1,2]. For instance, the estimated prevalence in a radiological study undertaken in the United Kingdom in the 1970s in people over 55 ranged between 2% and 5% [3]. Although more recent studies conducted with similar methods in the same geographical area [4] and in other countries [5–7] suggest that the prevalence could be decreasing, PD is still considered to be an important cause of morbidity in this fast-growing age group, despite the fact that a high proportion of patients remain asymptomatic throughout their evolution [8]. One of the consequences of this high prevalence is the frequent finding of a PD bone lesion in current clinical practise. Taking into account the large variety of radiological appearances [2,9–12] – sometimes mimicking those of other significant morbid disorders (i.e.: bone tumours and metastasis) – , PD should always be considered in differential diagnosis of osteoesclerotic as well as osteolytic skeletal lesions [2]. Nevertheless, the ⁎ Corresponding author. E-mail addresses: [email protected] (J. Bachiller-Corral), [email protected] (C. Díaz-Miguel), [email protected] (A. Morales-Piga). 8756-3282/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bone.2013.08.023
most common radiologic appearance of the disease, usually present in its “mixed” and “blastic” phases, is distinctive [12]. In fact, the combination of patchy areas of bone sclerosis or lysis with coarsening of the trabecular pattern, together with local enlargement, mostly at the expense of cortical subperiosteal thickening, is virtually diagnostic of PD [2,9–11]. Therefore, in cases with more than one lesion (“polyostotic PD”), the diagnosis is almost always straightforward because at least one of the locations will show the aforementioned typical features. On the contrary, in monostotic cases, whose frequency has been reported as ranging from 10–20% [2] to close to 50% [13], the diagnosis may be far more difficult and confusion with other conditions may arise [12,14–16]. The issue could be greater in certain skeletal areas where PD's radiological features tend to be less characteristic and, particularly, when the early osteolytic form of the disease is present [17]. In these instances, the need to rule out life-threatening conditions, such as primary bone tumours or skeletal metastasis, prompts the performance of some invasive techniques which are associated with a certain degree of morbidity. The main goal of this study is to address whether monostotic femoral Paget's disease presentation raises specific diagnostic problems and subsequently causes an excessive number of excisional bone biopsies. In addition, we seek to identify any eventual clinical or radiological feature that may help avoid unnecessary harmful procedures.
518
J. Bachiller-Corral et al. / Bone 57 (2013) 517–521
Table 1 Comparison of numerical (mean ± SD) and categorical (%) characteristics between cases with monostotic PD of the femur and monostotic PD cases of other locations.
Age at diagnosis Sex Female Male Extent of skeletal lesionsa Alkaline phosphataseb (U/L) Alkaline phosphatase/ extent of bone lesions Normal alkaline phosphatase Urinary hydroxyprolinec (mg/24 h) Urinary hydroxyproline/ extent of bone lesions Asymptomatic case Bone pain Bone deformity Fracture Diagnostic biopsy Antiresorptive therapy a b c
Monostotic femur involvement [n = 24]
Other monostotic cases [n = 164]
p
64.6 ± 11.5
64.8 ± 11.4
0.92
13 (54.1) 11 (45.8) 3.2 ± 0.9 199.3 ± 109.3 61.6 ± 26.5
83 (50.6) 81 (49.3) 4.1 ± 1.6 290.0 ± 205.3 86.9 ± 106.3
0.74 0.008 0.04 0.27
7 (31.8) 42.2 ± 18.7
26 (16.4) 50.8 ± 30.2
0.08 0.25
13.4 ± 5.6
6.8 ± 25.5
0.58
6 (25.0) 17 (73.9) 11 (45.8%) 6 (25.0) 7 (29.1) 17 (70.8)
78 (49.0) 58 (35.3) 28 (19.4) 13 (8.4) 10 (6.6) 100 (61.7)
0.02 0.003 0.03 0.011 0.001 0.15
Evaluated by using Coutris' index [20]. Normal range 40–128 U/l. Normal range 18–40 mg/24 h.
Patients and methods From a series of 412 PD patients reviewed in our Unit from 1992 to the present, we retrospectively reviewed the medical records of the 24 (5.8%) in whom the disease was only present as a lesion in the femur. Characteristics of these monostotic femoral Paget disease (MFPD) patients were then compared with those of the 164 monostotic cases from other locations seen during the same period of time. All patients were recorded at diagnosis, and clinical, radiological, and biochemical evaluations were at baseline. Throughout the period of the study, the diagnosis was based on the same roentgenographic criteria [18].
Clinical evaluation Clinical evaluation included primary bone pain assessment as differentiated from non-specific musculoskeletal pain. Other features, such as typical bone deformity, (anterior and lateral bowing), localised skin hyperthermia, secondary neighbourhood (hip or knee) osteoarthritis, fractures (either complete or cortical fissures), and sarcomatous degeneration were recorded using a computerised purpose-designed codified questionnaire. According to the presence or absence of any of these PD symptoms, patients were classified as symptomatic or asymptomatic. Image evaluation Plain radiograph images of PD femoral lesions were available in medical charts in all cases. In addition, “ad hoc” frontal and lateral views of the whole femur were made for this study. Radiological evaluation was made following a structured protocol including the most relevant common PD features: trabecular pattern, cortical thickening and local bone enlargement. According to previous reports, the evolutionary phases of PD lesions were defined as: “lytic”, “mixed” or “blastic” [9]. In addition, several radiological traits associated with femoral involvement like coxa vara (neck shaft angle ≤ 115°), anterior and lateral bowing, protrusio acetabuli, and secondary arthropathy (from either hip or knee) were evaluated. The presence or absence of Monckeberg-type vascular calcifications [19] was also recorded. Radiographs were jointly assessed by two expert rheumatologists (A. M-P. and J. B-C.) and consensus was achieved in all cases. Bone scans performed with 99mTc-EHDP was available for all patients. The skeletal extent of the disease, based on bone scan uptake, was determined by using the index proposed by Coutris [20]. This index represents the sum of the coefficients conventionally assigned to each lesion according to the amount of bone affected. Biochemical assessment Serum and urine samples were obtained after an overnight fasting. Serum total alkaline phosphatase activity (normal range: 40–128 U/l) was assayed by an automated method using a p-nitrophenyl phosphate substrate following the International Federation of Clinical Chemistry
Fig. 1. Complete fracture of Paget's disease femoral lesion after biopsy. A. Pagetic lesion in distal femur. B. Lesion after bone biopsy. C. Fracture over the intervened area.
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guidelines. After a 24-hour period of consuming a gelatin-free diet, a 24-hour urine specimen was collected and an appropriate sample was analysed for calcium, phosphate, hydroxyproline (radioimmunoassay) and creatinine determination. Statistical methods Significant differences (p b 0.05) were determined using the twotailed Student's t test (or non-parametric test when appropriate) and the chi-square test with Yates' correction. Results We did not observe statistically significant differences between 24 MFPD patients and 164 monostotic cases of other locations in terms of
Fig. 2. Femoral fracture on Paget's disease lesion with sarcomatous degeneration.
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age (mean ± SD): 64.6 ± 11.5 vs. 64.8 ± 11.4, or gender (femaleto-male ratio: 13/11 vs. 83/81; p = 0.74) [Table 1]. The percentage of monostotic femoral patients (31.8%) who presented with normal alkaline phosphatase values at diagnosis is almost double that of other monostotic cases (16.4%), the difference being near the level of significance (p = 0.08). The difference in the percentage of cases who presented with any pagetic symptom (75.0% vs. 51%) attained statistical significance (p = 0.02). Of the MFPD, 17 out of 24 (73.9%) complained of primary bone pain at the femoral site, in 3 of them being of severe intensity. This figure is higher than that of the remaining monostotic cases (35.3%; p = 0.003). Of the 24 MFPD, 11 (45.8%) showed some degree of bone deformity on the affected limb at clinical examination (accompanied by warmth of overlying skin in 3) whereas this feature was observed in 28 (19.4%) other monostotic patients (p = 0.03). Six (25%) MFPD cases experienced a fracture over the pagetic lesion. One was an impacted fracture, one a complete fracture after a minor fall, another a complete fracture after biopsy (Fig. 1), two were fissure-fractures, and the remaining one was a pathological fracture (Fig. 2). Overall incidence is higher than the correspondent of the monostotic cases in other locations (13 of 164; 8.4%), the difference being statistically significant (p = 0.02). One of the 24 MFPD patients suffers a malignant transformation (osteogenic sarcoma) of bone lesion versus 3 in the remaining 388 throughout our entire series. The radiological pattern of the 24 PD lesions was considered “mixed” in 17, predominantly “blastic” in 6, and purely “lytic” in one. X-ray examination confirmed clinically detected bone deformity in all 11 (45.8%) cases, showing the typical appearance (anterior and lateral bowing) in 5 of them (Fig. 3). There was bone enlargement in 23 (96%) cases, which was very marked in 10 cases, and moderate in 13 cases. Of the 19 cases with a lesion located at the femoral neck, 8 had coxa vara. In addition, 10 had protrusio acetabuli and 8 showed a certain degree of secondary arthropathy. Three showed Monckeberg-type vascular calcifications on plain X-rays. The lesion was located in the left leg in 14 of the 24 MFPD patients, while 10 had it in the right. In 17 instances the lesion was located at the proximal femur, 5 were confined to the distal part of the bone, and the remaining 2 presented a lesion virtually spanning the femur as a whole (Table 2). The characteristics of these two do not differ from the more prevailing proximal subset. On the contrary, lesions located on the distal femur tend to be more atypical with a relatively higher proportion of cases having a “blastic” appearance (instead of “mixed”) and less markedly, both coarsening trabecular pattern and
Fig. 3. Monostotic lesion on proximal left femur, with typical Paget's disease radiological pattern, cortical thickening, coxa vara, and lateral bowing.
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Table 2 Disclosure of X-ray characteristic PD signs and associated traits, in the three types of monostotic femoral pagetic lesion according to topographical location. X-ray sign
Characteristic PD signs
Location (# cases)
Appearance/phase
Coarsened trabecular pattern
Cortical thickening
Protrusio acetabuli
Coxa vara
Secondary osteoarthritis
“Monckeberg-type” vascular calcifications
Proximal (n = 17)
Lytic 1 Blastic 4 Mixed 12 Lytic 0 Blastic 2 Mixed 3 Lytic 0 Blastic 0 Mixed 2
Yes 15 No 2
No 0 Moderate 9 Intense 8 No 1 Moderate 3 Intense 1 No 0 Moderate 1 Intense 1
Yes 7 No 10
Yes 6 No 11
Yes 5 No 12
Yes 1 No 16
Yes 1 No 4
Yes 1 No 5
Yes 3 No 2
Yes 1 No 4
Yes 2 No 0
Yes 1 No 1
Yes 1 No 0
Yes 1 No 1
Distal (n = 5) Whole femur (n = 2)
Associated traits
Yes 3 No 2 Yes 2 No 0
cortical thickening (Fig. 4). There were no significant differences in clinical manifestations and alkaline phosphatase levels between groups with proximal and distal involvement. Likewise, no differences were observed in the same variables when comparing groups with different femoral extension (above and below mean Coutris' index). Of the 5 patients whose lesion is located at the distal end of the femoral bone, 3 (60%) underwent diagnostic biopsy, while 4 (23.5%) patients among those 17 who had a proximal lesion (p = 0.27) were biopsied. Fourteen (58.3%) of the MFPD cases were originally considered by doctors as having a typical PD radiological pattern. In another 6 (25%), the diagnosis could be established with an acceptable degree of certainty and in the remaining 4 (16.7%) the radiological picture was deemed unclear and other possibilities were considered, notably bone malignancy. As a consequence, an excisional bone biopsy was performed in 7 cases (29.1%) in 3 instances before the patient was admitted to our Unit. When comparing this figure with the frequency among the
Fig. 4. Atypical lesion of PD in distal femur: absence of typical features such as cortical thickening and coarsened trabecular pattern.
other 164 monostotic cases – 10 (6.6%) of 164 cases – the risk [OR (IC 95%)] of undergoing this invasive procedure among MFPD patients rises to 6.34 (1.95–17.25; p = 0.001). A few months after the biopsy, a patient had a fracture just over the intervened area without noticeable trauma (Fig. 1). Two additional cases developed an intensification of their prior bone pain in the months following the surgical procedure. Discussion In the vast majority of PD cases, the presence of patchy areas of bone sclerosis or lysis with distortion of the trabecular architecture in combination with cortical thickening and focal bone enlargement is virtually diagnostic of the disease [2,9–11]. However, depending on the number and location of skeletal areas involved, as well as evolutionary factors (i.e. the phase in which lesions are found), this distinctive appearance could be somewhat elusive. Therefore, at an early stage, PD could present radiologic problems [21] before the lesion reaches its mature appearance. Furthermore, there are monostotic lesions which represent a bigger diagnostic challenge; in polyostotic cases there will likely be at least one image depicting the disease's typical features. Therefore, the main problem may happen in younger patients whose isolated lesion is located on skeletal areas where the radiological picture may be less characteristic [17] or requires more time to develop the typical PD roentgenographic changes [14,15]. Under these circumstances, monostotic PD lesions can give rise to confusion with primary [17] or metastatic bone tumours [22], chronic infection, and fibrous dysplasia, among other disorders [2,10–12]. This may lead to performing unnecessary diagnostic procedures which are potentially harmful or undergoing inappropriate therapeutic measures [2,8,22]. Despite this concern, there have been few reports addressing such issues and, to our knowledge, there are no previous reports which focus on monostotic PD of the femur. One of the limitations of this study is the fact that we were only able to research a relatively low number of patients. The comparison with the remaining monostotic cases allows us to more accurately describe the features of this subgroup, thus disclosing a possible peculiarity of this presentation. However, there was no appropriate comparison group available to help understand our work's main purpose more deeply. Only by comparing a similar population with isolated femoral lesions of another significance (particularly of a neoplastic nature) would it be possible to analyse all the relevant clinical and radiological features that may have discriminatory power in order to establish a predictive value. In the absence of such a comparison, the results offered here should be regarded with caution. In our series, the femur is the second most common monostotic location after the pelvis. When compared with the other 164 monostotic cases, the 24 MFPD patients were prone to having normal alkaline phosphatase serum activity (31.8% vs. 16.4%; 0.08). Since previous work has demonstrated a significant positive linear correlation between the extent of bone affected and biochemical values [23], such a difference could be
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better explained on the basis of a lesser amount of bone affected in MFPD in comparison with other skeletal areas. In fact, the difference is blurred when activity rates are adjusted for the amount of affected bone. On the contrary, the higher and significant percentage of MFPD cases that suffer any PD symptom (75% vs. 51%; 0.02), complain of bone pain (73.9 vs. 40.8%; 0.003), evidence bone deformity (45.8% vs. 19.4%; p = 0.03) or develop a fracture (25 vs. 8.4%; p = 0.02), may have a true biological meaning. Overall, these findings (which seem logically interconnected) imply that isolated femoral presentation causes substantially more morbidity than other monostotic PD lesions. This greater aggressiveness together with the diagnostic difficulty raised by some MFPD cases lacking the characteristic PD radiological features may explain why 7 of these 24 patients underwent an excisional biopsy. This figure is remarkably higher than that of other monostotic cases (OR = 6.34; 1.95–17.25). In one of them, the biopsy site was spontaneously fractured a few months after the biopsy. Two additional cases experienced intensified bone pain after the surgical procedure. Our data shows that the majority of PDFP cases arise on the proximal region of the femur. We have also observed that when this area is involved, the characteristic radiological signs of PD are nearly always present (Table 2) and, hence, the diagnosis is usually straightforward. On the contrary, in cases where there is distal involvement, radiological signs characteristic of the PD lesion occur with lesser frequency or are less marked, so that differentiation with other issues – particularly neoplastic disorders – could be harder to carry out. As a consequence, distal cases suffer an excisional bone biopsy with a higher significant frequency than other PDFP cases and the incidence of complications derived from this invasive procedure is concentrated in this subset of cases. In these more elusive lesions, the finding of associated clinical or radiographic signs like bone deformity (especially when warmth of overlying skin is also present) and Monckeberg-type vascular calcifications may help in performing an accurate diagnosis. In the same manner, it is worth noting that the presence of coxa vara deformity and “protrusio acetabuli”, together with the peculiar degenerative joint changes associated with PD, have come to be considered as virtually specific to the disease [24]. While sometimes it may be difficult to differentiate from pseudo-protrusio (increase in acetabular wall width), true protrusio acetabuli has been reported in as many as 25% of PD cases with hip joint involvement [25]. Structural weakness of pagetic bone in combination with bone enlargement and coxa vara deformity, the latter leading to an alteration in mechanical force across the hip joint, may account for this high number [2,25]. We have observed protrusio acetabuli not only in cases located in the proximal femur, but also in one case located in distal areas. The histological evidence of an increased turnover commonly observed even in unaffected bone [26] might help to explain the presence of this complication, even when distal lesions occur. On the other hand, osteoarthritis related to PD is a common cause of symptoms in people with PD and it has been frequently reported in the hip (30%) and knee (11%) of such patients [27]. As in several of our cases, the presence of this secondary osteoarthritis, which in the case of the “Pagetic coxopathy” that typically shows a narrowing of the medial (rather than superior) joint space [25,28], may help to differentiate PD from other more aggressive issues. In conclusion, the finding of an isolated PD femoral lesion is occasionally seen in medical practise. Certain clinical and radiological peculiarities present in some of these cases along with an unusually high percentage of normal alkaline phosphatase values observed in
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the entire MFPD patient population, imply some diagnostic difficulty. Patients with proximal MFPD, which nearly always show the characteristic X-ray pattern, should not and need not be biopsied for diagnostic confirmation. On the contrary, the subset in which the lesion is confined to the distal region of the femur's radiological appearance could be misleading. These cases account for the bulk of the observed excess risk when undergoing a bone biopsy is needed. The recognition and correct assessment of some associated clinical and radiological traits may help to avoid diagnostic procedures which result in an increased risk of fracture. References [1] Singer FR, Krane SM. Paget's disease of bone. In: Avioli LV, Krane SM, editors. Metabolic bone disease. San Diego: Academic Press; 1998. p. 545–605. [2] Kanis JA. Pathophysiology and treatment of Paget's disease of bone. London: Martin Dunitz; 1998. [3] Barker DJP. The epidemiology of Paget's disease of bone. Br Med Bull 1984;40:396–400. [4] Cooper C, Schafheutle K, Dennison E, Kellingray S, Guyer P, Barker D. The epidemiology of Paget's disease in Britain: is the prevalence decreasing? J Bone Miner Res 1999;14:192–7. [5] Cundy T, McAnulty K, Wattie D, Gamble G, Rutland M, Ibbertson HK. Evidence for secular change in Paget's disease. Bone 1997;20:69–71. [6] Morales-Piga AA, Bachiller-Corral FJ, Abraira V, Beltrán J, Rapado A. Is clinical expressiveness of Paget's disease of bone decreasing? Bone 2002;30:399–403. [7] Poor G, Donath J, Fornet B, Cooper C. Epidemiology of Paget's disease in Europe: the prevalence is decreasing. J Bone Miner Res 2006;21:1545–9. [8] Selby PL, Davie MWJ, Ralston SH, Stone MD. Guidelines on the management of Paget's disease of bone. Bone 2002;31:366–73. [9] Milgram JW. Radiographical and pathological assessment of the activity of Paget's disease of bone. Clin Orthop 1977;127:43–54. [10] Resnick D, Niwayama G. Paget's disease. In: Resnick D, Niwayama G, editors. Diagnosis of bone and joint disorders. 2nd ed. Philadelphia: Saunders; 1987. p. 2127–70. [11] Smith SE, Murphey MD, Motamedi K, Mulligan ME, Resnik CS, Gannon FH. Radiologic spectrum of Paget's disease of bone and its complications with pathologic correlation. Radiographics 2002;22:1191–216. [12] Wellman HN, Schauwecker D, Robb JA, Khairi MR, Johnston CC. Skeletal scintimaging and radiography in the diagnosis and management of Paget's disease. Clin Orthop Relat Res 1977;127:55–62. [13] Varenna M, Zucchi F, Galli L, Manara M, De Marco G, Sinigaglia L. Demographic and clinical features related to a symptomatic onset of Paget's disease of bone. J Rheumatol 2010;37:155–60. [14] Schreiber MH, Richardson GA. Paget's disease confined to one lumbar vertebra. Am J Roentgenol 1963;90:1271–6. [15] Perrot S, Mortier E, Renoux M, Job-Deslandre C, Menkes CJ. Monostotic Paget's disease involving the calcaneus. Diagnostic and therapeutic problems. Rev Rhum 1995;62:45–57. [16] Amr R, Choudry Q. Monostotic Paget's disease of the patella. Bone 2006:1382–4. [17] Eisman JA, Martin JM. Osteolytic Paget's disease. J Bone Joint Surg 1986;68-A:112–7. [18] Murray RO, Jacobson HG. Miscellaneous disorders of unknown origin. In: Murray RO, editor. The radiology of skeletal disorders, vol. II; 1979 [Edinburgh]. [19] Acar J, Delbarre F, Waynberger M. Les complications cardio-vasculaires de la maladie osseuse de Paget. Arch Mal Coeur 1968;6:849–68. [20] Coutris G. Analyse des perturbations des voies principales du métabolisme calcique dans la maladie de Paget. Rev Rhum Mal Osteoartic 1975;42:759–67. [21] Doyle FH, Banks LM, Pennock JM. Radiologic observations on bone resorption in Paget's disease. Arthritis Rheum 1980;23:1185–92. [22] Katapuram SV, Phillips WC. Paget's disease of bone mimicking metastases. J Can Assoc Radiol 1982;33:239–45. [23] Meunier PJ, Salson C, Mathieu L, Delmas P, Alexandre C, Charhon S. Skeletal distribution and biochemical parameters of Paget's disease of bone. Clin Orthop 1987;217:37–44. [24] Guyer PB, Dewbury KC. The hip joint in Paget's disease of bone (Paget's “coxopathy”). Br J Radiol 1978;51:574–8. [25] Graham J, Harris WH. Paget's disease involving the hip joint. J Bone Joint Surg 1971;53B:650–9. [26] Meunier PJ, Coindre J, Edouard CM, Arlot ME. Bone histomorphometry in Paget's disease. Quantitative and dynamic analysis of Paget’s disease and nonpagetic bone tissue. Arthritis Rheum 1980;23:1095–103. [27] Altman RD, Collins B. Musculoskeletal manifestations of Paget's disease of bone. Arthritis Rheum 1980;23:1121–7. [28] Winfield J, Stamp TCB. Bone and joint symptoms in Paget's disease. Ann Rheum Dis 1984;43:769–73.