Article Text

Original research
Time elapsed from definitive diagnosis to surgery for osteonecrosis of the femoral head: a nationwide observational study in Japan
  1. Junichi Nakamura1,
  2. Wakaba Fukushima2,
  3. Wataru Ando3,4,
  4. Shigeo Hagiwara1,
  5. Yuya Kawarai1,
  6. Yuki Shiko5,
  7. Yohei Kawasaki5,6,
  8. Takashi Sakai7,
  9. Kazuya Ito2,8,
  10. Yoshiya Arishima9,
  11. Etsuo Chosa10,
  12. Yusuke Fujimoto9,
  13. Kazuo Fujiwara11,
  14. Yukiharu Hasegawa12,
  15. Shinya Hayashi13,
  16. Takashi Imagama7,
  17. Yutaka Inaba14,
  18. Yasuyuki Ishibashi15,
  19. Yasuhiro Ishidou9,
  20. Hideya Ito16,
  21. Hiroshi Ito17,
  22. Juji Ito18,
  23. Tetsuya Jinno19,20,
  24. Tamon Kabata21,
  25. Nobuhiro Kaku22,
  26. Ayumi Kaneuji23,
  27. Shunji Kishida1,
  28. Seneki Kobayashi24,
  29. Setsuro Komiya9,
  30. Toshikazu Kubo25,
  31. Tokifumi Majima26,
  32. Naohiko Mashima27,
  33. Masaaki Mawatari28,
  34. Hidenobu Miki29,
  35. Kazumasa Miyatake19,
  36. Goro Motomura30,
  37. Satoshi Nagoya31,
  38. Hiroaki Nakamura32,
  39. Yoshihide Nakamura15,
  40. Ryosuke Nakanishi33,
  41. Yasuharu Nakashima30,
  42. Satoshi Nakasone34,
  43. Takashi Nishii3,35,
  44. Takayuki Nishiyama13,36,
  45. Yoichi Ohta32,
  46. Kenji Ohzono4,
  47. Makoto Osaki37,
  48. Kan Sasaki18,
  49. Taisuke Seki12,38,
  50. Takaaki Shishido39,
  51. Takeshi Shoji40,41,
  52. Akihiro Sudo42,
  53. Michiaki Takagi18,
  54. Daisuke Takahashi26,
  55. Masaki Takao3,27,
  56. Sakae Tanaka16,
  57. Takeyuki Tanaka16,
  58. Tomonori Tetsunaga11,
  59. Keiichiro Ueshima25,
  60. Kengo Yamamoto39,
  61. Takuaki Yamamoto30,43,
  62. Yuji Yamamoto15,
  63. Takuma Yamasaki40,
  64. Yuji Yasunaga40,
  65. Nobuhiko Sugano3
  1. 1Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
  2. 2Department of Public Health, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
  3. 3Department of Orthopaedic Medical Engineering, Osaka University Graduate School of Medicine, Osaka, Japan
  4. 4Department of Orthopaedic Surgery, Kansai Rosai Hospital, Amagasaki, Japan
  5. 5Biostatistics Section, Clinical Research Centre, Chiba University Hospital, Chiba, Japan
  6. 6Faculty of Nursing, Japanese Red Cross College of Nursing, Tokyo, Japan
  7. 7Department of Orthopaedic Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
  8. 8Graduate School of Nursing, Osaka Metropolitan University, Osaka, Japan
  9. 9Department of Orthopaedic Surgery, Kagoshima University, Kagoshima, Japan
  10. 10Department of Orthopaedic Surgery, University of Miyazaki, Miyazaki, Japan
  11. 11Department of Orthopaedic Surgery, Okayama University, Okayama, Japan
  12. 12Department of Orthopaedic Surgery, Nagoya University, Nagoya, Japan
  13. 13Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
  14. 14Department of Orthopaedic Surgery, Yokohama City University, Yokohama, Japan
  15. 15Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
  16. 16Department of Orthopaedic Surgery, The University of Tokyo, Tokyo, Japan
  17. 17Department of Orthopaedic Surgery, Asahikawa Medical University, Asahikawa, Japan
  18. 18Department of Orthopaedic Surgery, Yamagata University, Yamagata, Japan
  19. 19Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
  20. 20Department of Orthopaedic Surgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
  21. 21Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
  22. 22Department of Orthopaedic Surgery, Oita University, Yufu, Japan
  23. 23Department of Orthopaedic Surgery, Kanazawa Medical University, Kahoku-gun, Japan
  24. 24Department of Orthopaedic Surgery, Suwa Red Cross Hospital, Suwa, Japan
  25. 25Department of Orthopaedic Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
  26. 26Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
  27. 27Department of Orthopaedic Surgery, Ehime University, Toon, Japan
  28. 28Department of Orthopaedic Surgery, Saga University, Saga, Japan
  29. 29Department of Orthopaedic Surgery, Osaka National Hospital, Osaka, Japan
  30. 30Department of Orthopaedic Surgery, Kyushu University, Fukuoka, Japan
  31. 31Department of Orthopaedic Surgery, Sapporo Medical University, Sapporo, Japan
  32. 32Department of Orthopaedic Surgery, Osaka Metropolitan University, Osaka, Japan
  33. 33Department of Orthopaedic Surgery, Showa University Fujigaoka Hospital, Yokohama, Japan
  34. 34Department of Orthopedic Surgery, University of the Ryukyus, Nakagami-gun, Japan
  35. 35Department of Orthopaedic Surgery, Osaka General Medical Centre, Osaka, Japan
  36. 36Department of Orthopaedic Surgery, Kakogawa Central City Hospital, Kakogawa, Japan
  37. 37Department of Orthopaedic Surgery, Nagasaki University, Nagasaki, Japan
  38. 38Depatrment of Orthopedic Surgery, Aichi Medical University Medical Centre, Okazaki, Japan
  39. 39Department of Orthopaedic Surgery, Tokyo Medical University, Tokyo, Japan
  40. 40Department of Orthopaedic Surgery, Hiroshima University, Hiroshima, Japan
  41. 41Department of artificial joints and biomaterials, Graduate school of biomedical & health sciences, Hiroshima university, Hiroshima, Japan
  42. 42Department of Orthopaedic Surgery, Mie University, Tsu, Japan
  43. 43Department of Orthopaedic Surgery, Fukuoka University, Fukuoka, Japan
  1. Correspondence to Dr Junichi Nakamura; njonedr{at}chiba-u.jp

Abstract

Objectives This study documents the time elapsed from the diagnosis of osteonecrosis of the femoral head (ONFH) to surgery, exploring the factors that influence ONFH severity.

Design Retrospective observational study of a nationwide database.

Setting The Kaplan-Meier method with log-rank tests was applied to examine the period from definitive diagnosis of ONFH to surgery using any surgery as the end point. For bilateral cases, the date of the first surgery was the endpoint.

Participants This study included 2074 ONFH cases registered in 34 university hospitals and highly specialised hospitals of the multicentre sentinel monitoring system of the Japanese Investigation Committee between 1997 and 2018.

Main outcome measure The primary outcome was the time from diagnosis to surgery. The secondary outcome was the proportion of subjects remaining without surgery at 3, 6 and 9 months, and at 1, 2 and 5 years after diagnosis.

Results The median time to surgery was 9 months (IQR 4–22 months) after diagnosis of ONFH. The time to surgery was significantly shorter in the alcohol alone group and the combined corticosteroid and alcohol group than in the corticosteroid alone group (p=0.018 and p<0.001, respectively), in early stage ONFH with no or mild joint destruction (stages II and III, p<0.001), and with joint preserving surgery (p<0.001). The proportion without surgery was 75.8% at 3 months, 59.6% at 6 months, 48.2% at 9 months, 40.5% at 1 year, 22.2% at 2 years and 8.3% at 5 years.

Conclusion ONFH has been considered to be an intractable disease that often requires surgical treatment, but the fact that surgery was performed in more than half of the patients within 9 months from diagnosis suggests severe disease with a significant clinical impact.

Trial registration number Chiba University ID1049.

  • EPIDEMIOLOGY
  • Factor Analysis, Statistical
  • Hip
  • REGISTRIES
  • RHEUMATOLOGY

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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STRENGTHS AND LIMITATIONS OF THIS STUDY

  • A nationwide multicentre study with a large sample of osteonecrosis of the femoral head (ONFH) patients in Japan between 1997 and 2018.

  • The diagnosis of ONFH was reliable by experts, despite a selection bias that participating facilities were limited to highly specialised hospitals.

  • Less than half of operated patients were included in this study because of missing data.

  • Old ONFH classifications were applied so that the less recent cases could be used.

  • The influence of other factors such as dose dependence of corticosteroids or alcohol, underlying disease and smoking was not analysed.

Introduction

Osteonecrosis of the femoral head (ONFH) is a difficult-to-treat disease in which the femoral head becomes ischaemic, resulting in articular collapse.1 2 In Japan, the number of new patients per year was estimated to be 2200 in 20043 with an annual incidence of 2.51 cases per 100 000 persons between 1999 and 2008.4 Systemic lupus erythematosus (SLE) was the most commonly reported underlying disease among patients with a history of systemic corticosteroid administration5; the incidence of osteonecrosis in SLE is 6% in paediatric patients (<15 years old), rising to 49% in adolescent patients (15–20 years old) and as high as 41% in adult patients (>20 years old). ONFH occurs at young ages and collapse of the femoral head occurs in more than half of the patients, resulting in a low quality of life.6 Gait disturbance results in labour loss. Therefore, destruction of the hip joint requires surgical intervention.7–9 Indications for surgery were hip pain and walking disability. Joint preserving surgery such as curved intertrochanteric varus osteotomy10 and rotational osteotomy11 are preferred for young patients with early-stage ONFH, while joint replacement surgery such as hemiarthroplasty and total hip arthroplasty (THA) are acceptable for patients with late-stage ONFH or large necrotic lesions.12 13 For those treatments, it is necessary to predict in advance which surgery will be required at what time, and to make a treatment plan that considers a patient’s personal and work schedules. However, little is known about the time from a definitive diagnosis of ONFH to surgery.

The Japanese Ministry of Health, Labour and Welfare established the Investigation Committee (JIC) for ONFH in 1975, and a multicentre sentinel monitoring system started in 1997. In previous studies, between 2003 and 2017, the 15-year surgical trend for ONFH showed a decrease of young people aged 16–39 and an increase of older people aged 60 and over.14 An MRI-based prospective longitudinal study of 623 cases for corticosteroid-associated ONFH at a single institution showed that the incidence of ONFH was 31%, that articular collapse occurred in 38% of ONFH patients within 10 years after diagnosis, and that 78% of patients with collapsed ONFH underwent surgery within 10 years after the articular collapse.15 However, larger studies are needed to clarify the time from diagnosis to surgery. It is clinically significant to provide an indicator of the severity of ONFH in patients requiring early surgery. This fact implicates the impact of this disease and helps in developing clinical guidelines and treatment strategies.

This study documents the time elapsed from the initial definitive diagnosis to surgery for ONFH. It explores the factors influencing severity, such as joint preservation or joint replacement surgery, using the nationwide database of the multicentre sentinel monitoring system.

Methods

Neither patients nor the public were involved in the design, conduct, reporting or dissemination of this research.

The ONFH monitoring system consists of two kinds of registries, either for new patients or for surgery14 16; the latter was used in this study. The ONFH registry diagnostically is reliable14 16 and covers 34 highly specialised hospitals nationwide although it is not a national registry. The subjects included 4388 primary surgeries from the ONFH monitoring system from July 1997 to March 2018 in accordance with the 1996 criteria (the old classification)17 or the 2001 revised criteria (the new classification)18 19 for ONFH. Reasons for exclusion of 2314 patients are shown in online supplemental figure 1; data were missing for 10 by gender, 551 by age at ONFH diagnosis, 845 by associated factors, 390 by type classification, 307 by stage classification, 30 by surgical date and 181 by surgical procedure. If there was a history of systemic corticosteroid administration or habitual alcohol intake in the questionnaire, it was defined as an associated factor. Any case without corticosteroid and/or alcohol use was omitted because the sample was too small to allow for sufficient analysis. The remaining 2074 cases with complete data sets were analysed in this study. The patients’ demographics are shown in table 1.

Table 1

Patient demographics

In the old classification of type17 for osteonecrosis lesion size, type A lesions occupy the medial one-third or less of the weight-bearing portion; type B lesions occupy the medial two-thirds or less of the weight-bearing portion and type C lesions occupy more than the medial two-thirds of the weight-bearing portion. In the new classification of type,18 19 type C is divided into two subtypes: type C1 lesions are localised within the acetabulum, and type C2 lesions extend laterally to the acetabular edge. In the old classification of stage17 for the progress of joint destruction, stage I shows no specific findings of osteonecrosis on radiographs but does on MRI, bone scintigram or with histology; stage II shows demarcating sclerosis without collapse of the femoral head; stage III shows a collapse of the femoral head including the crescent sign without joint space narrowing and stage IV shows osteoarthritic changes. In the new classification of stage,18 stage III is divided into two subtypes: stage III A shows a collapse of the femoral head less than 3 mm, and stage III B shows a collapse of 3 mm or more.

Data collection and analysis

A structured form was used to collect patients’ information on demographic and clinical characteristics. The form included the following basic information: date of birth, gender, date of ONFH diagnosis, associated factors (systemic corticosteroid administration20 21 and habitual alcohol intake22), the type and stage of ONFH classification,17–19 date of surgery and the kind of surgical procedure (joint preserving or joint replacement surgery). Although the registration questionnaire was updated in 2006, the new classification using types C1 and C2 was combined with the old type C classification. The new classification stages IIIA and IIIB were combined with the old stage III classification. Joint preserving surgery included core decompression and various osteotomy types. Joint replacement surgery included hemiarthroplasty and THA.

The time from definitive diagnosis of ONFH to surgery was set as the end point using the Kaplan-Meier method with log-rank tests. In bilateral cases, the date of the first surgery was the endpoint. The proportions of subjects remaining without surgery at 3, 6 and 9 months, and at 1, 2 and 5 years were calculated. All analyses were performed by using SAS V.9.4 (SAS Institute) and a p<0.05 was considered significant.

Patient and public involvement

No patient involved.

Results

The median time to surgery was 9 months (minimum 0 to maximum 120 months, IQR 4–22 months) after diagnosis of ONFH. The time to surgery was significantly shorter in the alcohol alone group and the combined corticosteroid and alcohol group than in the corticosteroid alone group (p=0.0180 and p=0.0004, respectively, figure 1A). The time to surgery using the old classification of type was not significantly different among groups (p=0.3684, figure 1B). The time to surgery was significantly shorter in stage II and III groups than in the stage IV group (p<0.0001 figure 1C). The time to surgery was significantly shorter in joint preserving surgery than in joint replacement surgery (p<0.0001, figure 1D). The proportion of patients without surgery was 75.8% (95% CI 74.0% to 77.6%) at 3 months, 59.6% (95% CI 57.5% to 61.7%) at 6 months, 48.2% (95% CI 46.0% to 50.3%) at 9 months, 40.5% (95% CI 38.4% to 42.6%) at 1 year, 22.2% (95% CI 20.4% to 24.0%) at 2 years and 8.3% (95% CI 7.2% to 9.6%) at 5 years.

Figure 1

The proportion of subjects remaining without surgery from definitive ONFH diagnosis. (A) Associated factors; (B) old type classification; (C) old stage classification; (D) surgical procedures. ONFH, osteonecrosis of the femoral head.

Regarding surgical procedures and associated factors, the time to joint preserving surgery was not significantly different among groups (both vs alcohol alone, p=0.7764; both vs corticosteroid alone, p=0.1831, figure 2A). On the other hand, the time to joint replacement surgery was significantly shorter in the group using both corticosteroids and alcohol than in the alcohol alone and the corticosteroid alone groups (p=0.0056 and p=0.0011, respectively, figure 2B). Regarding surgical procedures using the old classification of stage, the time to joint preserving surgery was not significantly different (stage II vs stage IV, p=0.0708; stage III vs stage IV, p=0.4803; figure 2C), but the time to joint replacement surgery was significantly shorter in stage II and stage III groups than in the stage IV group (p=0.0019 and p=0.0001, respectively, figure 2D). Regarding surgical procedures using the old classification of type, the time to joint preserving surgery was not significantly different between groups (type B vs type C, p=0.5284; figure 3A), nor was the time to joint replacement surgery (type B vs type C, p=0.1083; figure 3B). In the type B group, there was no significant difference between the time to joint preserving surgery and the time to joint replacement surgery (p=0.1073, figure 3C), but in the type C group, the time to joint preserving surgery was significantly shorter than the time to joint replacement surgery (p=0.0001, figure 3D). In the stage II and IV groups, there were no significant differences between the time to joint preserving surgery and the time to joint replacement surgery (p=0.0613 and p=0.1220, respectively), but in the stage III group, the time to joint preserving surgery was significantly shorter than the time to joint replacement surgery (p=0.0260, figure 4). The details of the proportion of patients without surgery are shown in online supplemental tables S1 and S2. The new classifications of type and stage were not significantly different in those patients without surgery (data not shown).

Figure 2

The proportion of subjects remaining without surgery from definitive ONFH diagnosis (subanalysis 1). Associated factors for (A) joint preserving surgery and (B) joint replacement surgery. Old stage classification for (C) joint preserving surgery and (D) joint replacement surgery. ONFH, osteonecrosis of the femoral head.

Figure 3

The proportion of subjects remaining without surgery from definitive ONFH diagnosis (subanalysis 2). (A) Joint preserving surgery and old type classification; (B) joint replacement surgery and old type classification; (C) comparison of surgical procedures in type B ONFH; (D) comparison of surgical procedures in type C ONFH. ONFH, osteonecrosis of the femoral head.

Figure 4

The proportion of subjects remaining without surgery from definitive ONFH diagnosis (subanalysis 3). Comparison of surgical procedures in (A) stage II; (B) stage III; (C) stage IV. ONFH, osteonecrosis of the femoral head.

Discussion

To our knowledge, this is the largest study to document the time elapsed from the initial definitive diagnosis of ONFH to surgery.15 The median time to surgery was 9 months after the diagnosis of ONFH; more than half of the cases underwent surgery within a year. The subanalysis revealed that patients with the combined use of corticosteroids and alcohol, early stage ONFH (II or III), and joint preserving surgery were more likely to have a shorter time between diagnosis and surgery. It is interesting to consider the factors that influence the time from diagnosis to surgery. There are several possibilities why the proportion of patients who did not have surgery was highest in the corticosteroid alone group. Many patients with underlying diseases, such as collagen diseases, were using corticosteroids. Physical activity was low in these patients, or in some cases the control of the underlying diseases was poor, so surgery could not be performed immediately. However, caution is required in interpreting the results of this study. The proportion of patients without surgery in this study is lower than in previously reported prospective studies. Shigemura et al15 reported that the proportion without surgery in a prospective study of corticosteroid-associated ONFH was 43% at 5 years and 22% at 10 years. It also should be noted that a smaller proportion of patients classified as stage IV had surgery. This late stage was classified immediately before surgery, suggesting that the patient endured the disease over a long period of time as the deformity progressed. The shorter time to surgery for joint preserving surgery was not surprising because joint preserving surgery should be done as soon as possible before joint destruction progresses and the cartilage has degenerated.

The significance of this study, a large-scale nationwide study, was to clarify the epidemiology of ONFH surgical cases, which was previously unknown. Registering and monitoring surgical cases not only makes it possible to grasp the actual state of surgical treatment at that time but also makes it possible to compare situations that change over time. By knowing the trends, it becomes possible to solve problems and predict future outcomes. However, there are few reports of large studies of ONFH surgery. Surgeries for ONFH from 1992 to 2008 in the USA increased from 3570 to 6400 per year.23 In 1992, 75% of surgeries were THAs; this increased to 88% in 2008. Over the same period, the percentage of joint preserving surgeries decreased from 25% to 12%. Similar trends were observed in a Japanese study,14 which used data from the same registry as ours. Between 2003 and 2017, in the Japanese multicentre study of 3844 cases, the proportion of THAs increased from 46.8% to 78.7%, although the proportion of osteotomies decreased from 33.5% to 15.1%, and the proportion of hemiarthroplasties decreased from 16.7% to 5.8%.14 Osteotomies and hemiarthroplasties decreased in patients aged 60 years or older, with type C ONFH in stages III and IV, but THAs increased in these groups. In another nationwide multicentre registry study of hip arthroplasties for ONFH in Japan from 1996 to 2015 that included the primary THAs of 3973 patients (4995 joints) with ONFH, postoperative dislocation occurred in 4.3% and reoperation in 3.9% with an average follow-up period of 5.6 years.24

There were several limitations to this study. First, less than half of the operated patients were included in this study because of missing data. Second, there might be selection bias because participating facilities were limited to highly specialised hospitals. However, the reliability of ONFH diagnosis was a strength. Third, the old JIC type and stage classifications were adopted so that the older cases before revision of the database could be used. The JIC classification of ONFH was changed during the study period. Recently, Association Research Circulation Osseous (ARCO) has proposed a new international classification that partially modifies the JIC classification and divides stage classifications IIIA and IIIB by 2 mm.25 In the 2021 revised ARCO type classification,26 type 1 is a small lesion confined to the region medial to the apex of the femoral head. Type 2 is a medium-sized lesion in which the lateral margin of the necrotic portion is between the apex of the femoral head and the lateral edge of the acetabulum. Type 3 is a large lesion that extends laterally to the lateral acetabular edge. In other words, type 1 of the ARCO classification is a combination of JIC’s type A and the smaller half of type B; type 2 is a combination of the larger half of type B and type C1; and type 3 is type C2. Fourth, this study did not investigate how corticosteroid dosage influenced surgery for ONFH. Fifth, the influence of other factors such as underlying disease27 28 and smoking29 30 could not be analysed because about half of the cases were excluded due to missing values. We would like to verify the proportion of patients who do not have surgery by artificial intelligence analysis using big data in the future.

In conclusion, ONFH has been considered to be an intractable disease that often requires surgical treatment, but the fact that surgery was performed in more than half of this ONFH sample within 9 months from diagnosis implicates the severe disease with a significant clinical impact.

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

Ethics statements

Patient consent for publication

Ethics approval

This was a retrospective observational study, and all procedures involving human participants were performed under the ethical standards of the institutional research committee in each participating hospital (Chiba University, ID1049) and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Acknowledgments

We thank all participants and all the former members of the Sentinel Monitoring Study Group of the Japanese Investigation Committee (JIC) for Osteonecrosis of the Femoral Head for their role in the data Safety and monitoring board. Former members were shown in alphabetical order of family name (affiliations where the work was carried out at that time) provided and cared for study patients: Dr Atsumi Takashi (Showa university Fujigaoka hospital); Dr Endo Naoto (Niigata University); Dr Fujioka Mikihiro (Kyoto Prefectural University of Medicine); Dr Higuchi Fujio (Kurume University Medical Centre); Dr Hotokebuchi Takao (Saga University); Dr Itoman Moritoshi (Kitasato University); Dr Iwamoto Yukihide (Kyushu University); Dr Kodaira Hiroyuki (Shinshu University School of Medicine); Dr Matsumoto Tadami (Kanazawa Medical University); Dr Matsuno Takeo (Asahikawa Medical University); Dr Okawa Takahiro (Kurume University Medical Centre); Dr Ninomiya Setsuo (Saitama Medical University); Dr Takaoka Kunio (Osaka Metropolitan University) and Taneda Hitoshi (Saitama Medical University).

References

Supplementary materials

Footnotes

  • Contributors JN, WF, WA, SHagiwara, YKawarai, YS, YKawasaki, TSakai, KI and NS conceived and designed the study. JN, WA, SHagiwara, YKawarai, TSakai, YA, EC, YF, KF, YH, SHayashi, TI, YInaba, IY, YIshidou, HidI, HirI, JI, TJ, TKabata, NK, AK, SKishida, SKobayashi, SKomiya, TKubo, TM, NM, MM, HM, KM, GM, SNagoya, HN, YNakamura, RN, YNakashima, SNakasone, TNishii, TNishiyama, YO, KO, MO, KS, TSeki, TShishido, TShoji, AS, MTakagi, DT, MTakao, ST, TTanaka, TTetsunaga, KU, KY, TYamamoto, YYamamoto, TYamasaki, YYasunaga and NS contributed to acquisition of data. JN, WF, YS, YKawasaki and KI analysed the data. JN, WF, WA, SHagiwara, YKawarai, TSakai, KI and NS contributed to the analytical strategy. JN, WF, WA, TSakai and KI drafted the manuscript. All authors participated in the revision of the manuscript. JN is responsible for the overall content as the guarantor.

  • Funding This study was supported by a research grant from the Health Labour Sciences Research Grant, the Ministry of Health Labour and Welfare, Japan (20FC1010 and 23FC1045). Correspondig author JN was supported by JSPS KAKENHI (23K08647).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.