1 Introduction

Paget’s disease of bone (PDB), also called osteitis deformans or scleromalacia, is a progressive monostotic or polyostotic metabolic bone disease characterized by focal abnormal bone remodeling [1]. It was first discovered in 1876 by the British pathologist, Sir James Paget, and named after him [2]. However, the etiology of PDB remains unclear. A previous study reported that in about 14% of patients with a positive family history, the risk of PDB in first-degree relatives of patients was 7–10 higher times than that in general population [3,4,5]. Mutations in sequestosome1 gene (SQSTM1) are likely to be associated with the development of this disease [6]. Other triggers include certain environmental factors, such as deficiency of vitamin D and calcium during childhood [7, 8], zoonotic infection [9], toxic exposure [10], and virus infection [11].

After osteoporosis, PDB is the second most common metabolic bone disease in western countries, with the highest incidence rate in the UK (5.4%), followed by Australia and New Zealand [12,13,14], and the lowest being in Japan (0.00028%) [15]. An epidemiological investigation related to PDB in Japan revealed that the sex ratio (male to female) was 0.86:1, and ostealgia and bone malformation were the most common symptoms [16]. Another study in Hong Kong, including 7 patients with PDB [17], showed that only 1 patient was diagnosed based on clinical manifestations, while the others were diagnosed based on abnormal total alkaline phosphatase (TALP) levels or incidentally by X-ray.

In 2012, a case study of 160 patients with PDB was conducted in China. A sex ratio (male: female) of 3:2 was reported. Bone malformation was found to be the most common clinical manifestation, followed by ostealgia, fracture, and deafness. The most frequently affected bones included the femur, pelvis, skull, vertebra, and tibia [18]. However, this study had certain limitations. First, statistical data of onset age, clinical features, and affected bones were lacking. Second, the status of PDB diagnosis and treatment in China was not systematically reviewed. Third, the correlation between onset age and gender, and the correlation of TALP with gender and ostealgia were not analyzed.

In this review, we summarized the clinical characteristics and the status of diagnosis and treatment of PDB in mainland China over the last 60 years, with an aim to improve the clinician’s understanding of this disease. Furthermore, we statistically analyzed the relationship between age of onset and gender, as well as the correlation of TALP with gender and ostealgia. Clinical department records and comparison of clinical manifestations of PDB between mainland China and western countries and Japan were also included.

2 Materials and methods

2.1 Inclusion criteria

Eligible studies included those in which PDB was diagnosed based on: (1) typical X-ray or Computed Tomography (CT) images, (2) increased TALP levels, (3) abnormal values of radionuclide bone scan (RBS), and (4) pathological alterations. Patients who conform to the first three criteria and/or the last one can be diagnosed as PDB. In addition, case reports, case series, and original articles were also included.

2.2 Exclusion criteria

Studies on Paget’s disease of breast or other parts of the body as well as those including other racial and ethnic groups were excluded. We also excluded narrative reviews, foreign language studies, publications that failed to provide the required statistics, and studies that are not available in full text. For studies published more than once, the most recent one was included.

2.3 Literature search

A comprehensive search of several databases was performed from each database’s earliest inception to May 2018. The databases included China National Knowledge Infrastructure (CNKI), China Biology Medicine disc (CBM), PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Wanfang Data Knowledge Service Platform (WANFANG), and Weipu Chinese Science and Technology Journal Database (VIP).The following terms were used to conduct the search: Chinese terms for “Paget’s disease of bone, Paget’s disease, deformation osteitis”, English terms for “osteitis deformans (Mesh), Paget’s disease of bone, or Paget disease of bone”, and “China or Chinese (Affiliation)”. Besides database search, we also performed a manual search for the included studies, related comments, and reference lists of systematic reviews.

2.4 Literature selection and data extraction

Two researchers independently imported all relevant articles into the Endnote software and assessed all included studies as described in the inclusion and exclusion criteria. Following de-duplication, titles were independently screened for eligibility, followed by screening of abstracts and then the full-text.

Researchers independently extracted data from the included articles. The following data were abstracted: publication year, province, sex, age, clinical manifestations, commonly involved bones, TALP expression, pathologic findings, diagnostic techniques, treatment options, and medical departments.

2.5 Assessment of study quality

Included studies were all case reports, original articles, and retrospective studies, with a follow-up period ranging from 2 months to 25 years.

2.6 Statistical analysis

Differences between the two independent researchers were settled by consensus. If consensus was not reached, the assessment of a third researcher was decisive. All statistical analyses were performed using SPSS 22.0 software (Statistical Product and Service Solutions, USA).

3 Results

3.1 Study selection

The database search yielded 752 articles, of which 118 studies [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135] including a total of 332 cases were ultimately selected for this systematic review (Fig. 1),among them, two studies with 10 cases were familial [135, 136].

Fig. 1
figure 1

Flow chart of the literature retrieval and screening process. CNKI, China National Knowledge Infrastructure; CBM, China Biology Medicine disc; EMBASE, Excerpta Medica Database; VIP, Weipu Chinese Science and Technology Journal Database; WANFANG, Wanfang Data Knowledge Service Platform

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3.2 PDB-related articles published over the last 60 years in mainland China

An analysis of all statistical results showed that the number of PDB cases increased over the years. 1961–1969: 5 cases, 1980–1989: 17 cases, 1990–1999: 43 cases, 2000–2009: 107 cases, 2010–2018: 160 cases, 1970–1979: no cases reported (Fig. 2).

Fig. 2
figure 2

Number of PDB cases in studies published over the last 60 years in mainland China

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3.3 Age and gender ratio of PDB

We analyzed 156 patients whose age could be obtained. Among them, the minimum age was 2 months, the maximum age was 86 years, the mean age was 55.1 ± 7.2 years, and the peak age was 46–60 years. Cases of patients below 30 years of age were rare. Patients in the age groups of 0–15 and 16–30 were not analyzed due to insufficient case numbers. Data of patients in the age groups of 31–45, 46–60, 61–75, and > 75 were compared with chi-square test. No statistical differences between males and females in each age group were observed (p > 0.05; Fig. 3).

Fig. 3
figure 3

Age distribution of 156 PDB patients whose age could be obtained. There was no significant difference in the number of PDB cases between males and females in each age group (p > 0.05)

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3.4 Basic clinical features of patients with PDB

This study included 256 clinically affected patients, of which 226 patients (around 88.3%) displayed clinical symptoms of PDB and 30 patients (around 11.7%) visited the hospital due to increased TALP levels or abnormal X-ray scans. No significant difference in clinical manifestations between different genders was reported (p > 0.05; Fig. 4a). From a total of 147 patients with affected bones, 80 were monostotic and 67 were polyostotic cases. The most commonly affected bones in the monostotic cases included the skull, pelvis, tibia, and centrum. The TALP levels of 46 patients were analyzed, and those of 3 patients were in the normal range, while those of 43 patients were increased. The mean TALP level was 1200.8 ± 172.9 U/L. The TALP level in majority of the patients was 10 times higher than the normal upper limit. Related complications, including osteosarcoma, spinal stenosis, and giant-cell tumor were rare (Table 1).

Fig. 4
figure 4

Statistical analysis of the relationship between onset age and gender, and the correlation of TALP with gender and ostealgia. (a) There was no significant difference in clinical manifestations between different genders, as indicated by chi-square test (p = 0.144). (b) There was no significant correlation between TALP level and ostealgia, as indicated by chi-square test (p = 0.288). (c) There was no significant difference in TALP level between males and females, as indicated by chi-square test (p = 0.883). TALP, total alkaline phosphatase

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Table 1 Basic clinical features of 332 patients with PDB
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There was an increase in the TALP level of 113 (89.7%) out of 126 patients, whose TALP levels could be obtained. Chi-square test results showed that there was no statistically significant correlation between TALP level and ostealgia (p = 0.288; Fig. 4b). In addition, we also analyzed differences in TALP level between males and females using chi-square test, and results indicated that there were no significant differences (p = 0.883; Fig. 4c).

3.5 Common clinical symptoms of PDB

The most common clinical symptom of PDB included ostealgia, followed by bone malformation. Hearing loss was the least frequently reported symptom. A total of 19 patients suffered fractures (Table 2).

Table 2 Clinical manifestations of 167 patients with symptomatic PDB
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3.6 Distribution of clinical departments

Our study also recorded the clinical departments at which patients with PDB were first diagnosed. Analysis revealed that the most common department was endocrinology, followed by orthopedics, followed by nuclear medicine, and occasionally the emergency department. No department records of 219 cases were obtained (Fig. 5).

Fig. 5
figure 5

Clinical departments at which patients with PDB were first diagnosed. Endo, endocrinology department; Ortho, orthopedic department; NS, neurosurgery department; Stoma, stomatology department; Rheu, rheumatology department; Hema, hematology department; Neuro, neurology department; Neph, nephrology department; NM, nuclear medicine department; EM, emergency department

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3.7 Diagnostic methods used for patients with PDB

X-ray scans and evaluation of TALP levels were most commonly applied for diagnosis, and 40.7% of patients were diagnosed by clinical pathology. In addition, CT scan, RBS, and MRI were also used for diagnosis in a fraction of patients (Table 3).

Table 3 The diagnostic methods used for 172 patientsa with PDB
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3.8 Treatment methods for patients with PDB

The most frequently used drugs included calcitonin and bisphosphonates. Around 36.4 and 30.6% of patients were found to be administered calcium and vitamin D, respectively, and 27.3% of patients underwent surgery for bone malformation or fractures (Table 4).

Table 4 Treatment methods used for 121 patientsa with PDB
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In this review, we also analyzed the status of PDB treatment in mainland China over different time periods. Data indicated that etidronate disodium was used as the principal drug before 2000, pamidronate disodium and calcitonin were used from 2000 to 2009, and zoledronate gradually started being used after 2010 (Table 5).

Table 5 Treatment status of PDB in mainland China at different time points
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3.9 Clinical manifestations of PDB in different countries

Data on onset age were gathered for middle-aged and elderly PDB patients in various countries. The incidence of the disease among males was higher than that among females in mainland China, the UK and the USA, Japan inversely. The number of monostotic cases was slightly higher in other countries, except the USA, where polyostotic cases were more commonly reported. The commonly involved bones and clinical manifestations were different between countries. The treatments mainly included bisphosphonates and calcitonin. Familial aggregation was rarely reported in mainland China and Japan; however, no data were obtained for the other two countries. The gender ratio of PDB patients was compared between mainland China and Japan using chi-square test, and a significant difference in morbidity between males and females was reported (p < 0.05). However, no significant difference in gender ratio was observed between mainland China and the USA (Table 6).

Table 6 Comparison of clinical manifestations of PDB among various countries
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4 Discussion

This systematic review aimed to identify the clinical features of PDB in mainland China. Here, we analyzed 118 articles, including a total of 332 patients with PDB, in which 10 cases were familial. Family aggregation was not distinct in mainland China. In Japan, where PDB-related morbidity is low, familial incidence was around 6.3%, which was lesser than that in the USA (12.3%) [3] and the UK (13.8%) [4]. We found that the number of PDB cases significantly increased after 2000. However, whether this was due to increased morbidity or improved diagnosis and treatment remains to be confirmed by more epidemiological data. Our data indicated that PDB incidence is associated with regional disparity in mainland China, which is in accordance with a previous study that reported the prevalence rate of PDB in 17 towns in the UK [13].

The age of patients included in this study ranged from 2 months to 86 years, the peak age being 46–60 years. The rate of incidence appeared to decrease with age, however, it remarkably increased in Japan and other countries with high PDB prevalence. The prevalence rate of PDB in males was found to be slightly higher than that in females in mainland China, which is similar to that in the USA and UK, but not Japan. A statistically significant difference in morbidity between sexes was observed between mainland China and Japan, but not between mainland China and the USA. Meanwhile, no significant differences between sexes in each age group were observed.

Based on the frequency of occurrence, PDB clinical symptoms were roughly similar between mainland China and Japan, USA, and UK. The numbers of monostotic cases were more than those of polyostotic cases in mainland China, and similar results were reported in Japan, but not the USA. In addition, the commonly involved bones were different among various countries. The femur was reported to be the most commonly affected bone in this study, which is consistent with previous studies in Japan [16] and the UK [137]. These data indicate that clinicians should be wary of the possibility of PDB when patients present with fractures at common parts without an apparent cause. Since studies on the occurrence of related complications have seldom been reported, the exact incidence rate of PDB complications remains unknown. In mainland China, PBD has rarely been complicated with osteosarcoma (0.9%), compared with that in Japan (1.8%) [16], as well as spinal stenosis (0.6%) and giant-cell tumor (0.3%),but the occurrence of malignant bone tumors was similar to some regions in the UK [138].

American researchers conducted a systematic review and a meta-analysis of PDB in 2015 [139], and reported that procollagen type 1 amino-terminal propeptide (P1NP) was a valuable indicator for PDB detection and to monitor TALP and bone alkaline phosphatase levels, and urine N-terminal telopeptide was also an essential marker for monitoring disease activity. PDB failed to be diagnosed using bone turnover markers, which are regarded as preferred indexes in primary screening and post-treatment re-examinations. A previous literature study [140] showed that approximately 95% of untreated patients displayed increased TALP levels, which is consistent with our findings. Moreover, two foreign studies [141, 142] showed that most patients with increased TALP presented with ostealgia. In our study, 85 out of 113 (75.2%) PDB patients with elevated TALP levels had ostealgia, indicating an association between the metabolic activity of PDB and ostealgia. Nevertheless, we analyzed the correlation between TALP level and ostealgia as well as TALP levels between males and females, and results showed no significant correlation and differences, respectively.

In mainland China, most PDB patients were diagnosed at the endocrinology and orthopedics department, indicating that this disease may not be well understood by physicians of other departments where PDB patients were diagnosed rarely, which may lead to a missed or delayed diagnosis. Therefore, improving PDB recognition by these physicians is of great importance.

In this study, PDB was diagnosed based on X-ray scans and TALP levels. Additionally, RBS, CT, MRI, and bone pathology tests were also used for diagnosis in a fraction of cases. However, CT and MRI are not recommended as routine examinations in western countries based on their clinical guidelines, in which bone pathology is not put forward, as they may result in wastage of medical resources and increase of financial burden and medical risk in patients. Our findings indicated that in China when considering the diagnosis of PDB, X-ray scans combining with TALP levels should be also preferred as the first-line diagnostic methods. Thus, this may contribute to improving PDB diagnosis efficiency and treatment in terms of saving medical resources and expense of patients.

PDB is a chronic disease, and its development can be controlled by early diagnosis and treatment. Clinical guidelines in western countries [143,144,145] recommend bisphosphonate as the primary drug, with zoledronate being the most effective. In 2017, a cohort study [146] of 107 patients administered zoledronate was conducted, including a 10 year-follow up. P1NP levels were monitored, and low recurrence rates and lasting effects were observed. Moreover, randomized, placebo-controlled clinical trials have demonstrated that bisphosphonates can effectively reduce bone turnover [141, 147, 148], improve ostealgia [147, 149], and promote healing of osteolytic lesions [141] and recovery of bone tissues [141]. Another study showed that bisphosphonates could be used to prevent related complications of PDB [150]; however, this requires further validation [151]. In case of patients presenting with fractures, surgery is a common treatment choice. The percentage of surgeries were found to high according to our study (27.3%), which may be due to lack of knowledge of PDB among Chinese clinicians, leading to non-systematic early diagnosis and medical therapy.

This study had certain limitations. Since PDB is a rare disease, resulting in the lack of extensive epidemiological data, our study included a small sample size. Missing data in the included articles and the quality of literature together may have contributed to possible bias to the interpretation of the clinical features of PDB. However, this is the most detailed systematic analysis and evaluation of the clinical characteristics and the status of diagnosis and treatment of PDB in mainland China among other studies that have been reported so far.

In conclusion, this study revealed that familial aggregation in PDB was not obvious among patients in mainland China, and sporadic cases were higher. The clinical manifestations of PDB mainly included ostealgia, bone malformation, hearing loss, and fracture, and bisphosphonate was the primary drug used for treatment. These findings were similar to those reported in Japan, UK, and USA.