The incidene of postoperative heterotopic ossication in cervical disc arthroplasty--A systematic review and meta-analysis

Background: Heterotopic ossication has become a common disease after CDA, which has attracted much attention. Understanding the law of its occurrence and development can provide theoretical basis for the formulation of HO prevention strategies. To acquire the objective data and the change rule of HO incidence, a meta-analysis of all available evidence was performed. Methods: A search of the literature was conducted on Pubmed/MEDLINE, EMBASE, and Web of Science. Relevant studies including incidence-relative data of HO were selected according to eligibility criteria. Results: 52 studies were eligible and nally included and the quality assessment showed a relative high score of them. The results of the analysis reminded us that the incidence of HO increased with the extension of follow-up time, both based on the number of cases and the number of segments, and the increase mainly occurred after 6 years. Grade III-IV HO showed us a positive correlation with follow-up time (R2=0.218), while Grade I-II HO did not change a lot in different follow-up time points. Conclusions: The follow-up time after CDA should be long enough, so as to ensure the true clinical results. HO occurs all the postoperative time and Grade I-II HO will gradually develop into Grade III-IV, while continuous new HO keeps the number of Grade I-II in a dynamic balance. Through this study, we can preliminarily dene the relatively objective incidence and change rule of HO, which provides data basis and theoretical basis for the future research of HO prevention strategy.


Abstract
Background: Heterotopic ossi cation has become a common disease after CDA, which has attracted much attention. Understanding the law of its occurrence and development can provide theoretical basis for the formulation of HO prevention strategies. To acquire the objective data and the change rule of HO incidence, a meta-analysis of all available evidence was performed. Methods: A search of the literature was conducted on Pubmed/MEDLINE, EMBASE, and Web of Science. Relevant studies including incidence-relative data of HO were selected according to eligibility criteria. Results: 52 studies were eligible and nally included and the quality assessment showed a relative high score of them. The results of the analysis reminded us that the incidence of HO increased with the extension of follow-up time, both based on the number of cases and the number of segments, and the increase mainly occurred after 6 years. Grade III-IV HO showed us a positive correlation with follow-up time (R2=0.218), while Grade I-II HO did not change a lot in different follow-up time points. Conclusions: The follow-up time after CDA should be long enough, so as to ensure the true clinical results. HO occurs all the postoperative time and Grade I-II HO will gradually develop into Grade III-IV, while continuous new HO keeps the number of Grade I-II in a dynamic balance. Through this study, we can preliminarily de ne the relatively objective incidence and change rule of HO, which provides data basis and theoretical basis for the future research of HO prevention strategy.

Background
At present, cervical disc degenerative disease (CDDD) has become the important cause of endangering health and affecting quality of life among middle-aged and elderly people [1][2][3]. Along with the development of the society and the acceleration of work pace, more and more young people are suffering from it. Late stage or severe CDDD will progress to herniated disc and cervical spinal stenosis, requiring operation with heavy nancial burden.
Decades ago, anterior cervical decompression and fusion (ACDF) became the gold standard for treating CDDD. With the continuous development of clinical surgery technology, new generations of fusion devices keep appearing, the fusion rate keeps increasing, and postoperative complications are becoming less and less. And as the technology reaches its zenith, its own shortcomings are gradually being highlighted. The loss of cervical mobility after fusion, especially in multi-segment surgery, leads to a decrease in patients' quality of life. On the other hand, the adjacent segment disease (ASD) caused by the increase of compensatory activity also attracts the attention of spine surgeons.
In this medical background, the concept of non-fusion is particularly valuable. At rst, clinical scholars tried to apply arti cial disc and arti cial nucleus pulposus in the treatment of lumbar disc degeneration, but the clinical effect was not signi cantly different from that of fusion surgery [4]. Considering the signi cant impact of cervical mobility on quality of life, more research was devoted to the study of arti cial cervical disc or cervical dynamic stabilization device. Starting with Bryan disc of Medtronic, a series of bionic arti cial prosthesis are coming into the market one by one, and all of them have achieved good clinical effects. Because the arti cial disc can maintain the range of motion of the surgical segment, it can prevent the occurrence of ASD to some extent [5].
However, with the deepening of research and clinical follow-up, the heterotopic ossi cation (HO) after cervical disc arthroplasty (CDA) compromised the clinical value of this emerging operation greatly. HO is de ned as the process by which trabecular bone forms outside of the normal skeletal structure, occupying space in soft tissue where it shouldn't exist, which was rstly reported in the total hip arthroplasty-related postoperative complication [6,7]. Presently, the mechanism of HO is not clear, and there is no well-accepted effective prevention strategy. We must rst understand the occurrence of HO, which is also a theoretical premise to prevent the complication. In this paper, the incidence of HO was meta-analyzed and relevant conclusions were drawn.

Methods
The study is a systematic review and meta-analysis, and the ethics statement is not necessary.

Searching Strategy
We have searched Medline, Web of Science, and Embase for the articles published from the inception to March, 2019. The searching strategy was built with the following terms: (((cervical disc replacement[Title/Abstract]) OR cervical disc arthroplasty[Title/Abstract])) AND ((heterotopic ossi cation) OR HO). The references of all publications were also retrieved to obtain possible studies.

Inclusion and exclusion criteria
Studies were included if they met the following inclusion criteria: (1). Study design was randomized cohort study or controlled trials.
(3). The HO incidence of one or several time points were reported.
(4). The HO in the studies was graded by McAfee's classi cation system. (5). Articles were written with English or Chinese.
Publications were excluded if they were with following characteristics: (1). Review articles, meta-analysis, cases reports, animal/cadaver studies, editorials, or letters.
(2). The type of prosthesis was inappropriate, for example, the Dynamic Cervical Implant (DCI).
(3). Article was not formally published, only with an "accepted" status.

Data extraction
For each study included, the following data and information were collected: rst author, year of publication, type of prosthesis, study design, follow-up period, sample size, HO incidence. The data were independently extracted by 2 professors, and any disagreements were resolved by discussion and consensus.

Quality assessment
Here we used the methodological scoring system reported by Loney et al[8] to to evaluate the included studies. The evaluation system has a maximum score of 8 points as listed in Table-1. The quality of included studies was evaluated independently by 2 authors.

Statistical analysis
We calculated the overall incidence of HO with 95% con dence intervals (CIs), and obtained corresponding forest plots. The I 2 statistic and Q tests were used to evaluate the heterogeneity. If I2 value was bigger than 50%, we considered that signi cant heterogeneity was existing. In this meta-analysis, random-effects model was used. We use the following transformation to merge and analyze the two-category data: While the x and (n-x) are both bigger than 5: While one of the x or (n-x) is equal to or smaller than 5: All of the analyses were performed with RevMan 5.3.

Searching results
The initial database search identi ed a total of 327 records and duplicate-check removed 123 of them. After the titles and abstracts were reviewed, 14 of them were eliminated. A full-text review was evaluated in the 190 records maintained, and 138 of them were excluded because of they didn't meet the inclusion criteria. Finally, 52 articles, meeting the inclusion criteria, were included in the present meta-analysis. Figure-1 shows the selection process and the characteristics of included studies were listed in Table-2.

Annual incidence of HO
According to the follow-up period, we classi ed the included data with the interval of 12 months. When we based our assessment on the number of cases, as shown in Figure-2A and Figure-2B, the total incidence of HO, without limitation of follow-up period, was 39% (95% CI: 32%-47%), and with the extension of follow-up period, the incidence increased year by year. Similarly, based on the number of levels, as shown in Figure-3A and Figure-3B, the total incidence of HO was 39% (95% CI: 33%-45%), and with the extension of follow-up period, the incidence also increased year by year. The two statistical methods ended up with similar results. Actually, within 6 years, the HO incidence did not obviously change, while after 6 years, the incidence, no matter case-based or level-based, signi cantly increased.

Annual incidence of low-grade (Grade I-II) and high-grade (Grade III-IV) HO
According to the McAfee's grading system, as listed in Table-3

Analysis of publication bias
As shown in Figure-6, the characteristics of the four parts are similar. The distribution of included data is relatively discrete and symmetrical, reminding us that the publication bias were found insigni cant, while the data varied widely from one study to another.

Discussion
CDA have already been the classical surgical procedure in anterior cervical approach, whose effect of treatment is the same as that of traditional ACDF. What's more, the ROM of index level could also be remained and the living quality of patients was improved. But unfortunately, the superiority of CDA has been seriously compromised by the occurrence of HO.
In large joints replacement, for example the total hip arthroplasty (THA), HO is a frequent complication and the exact mechanism of it remains unknown [59,60]. Several in ammatory processes including a series of mediators and growth factors are possibly involved in the formation of HO, which leads to the recruitment of mesenchymal stem cells and the formation of bone. In recent years, with the gradual development of CDA, more and more clinicians have realized the signi cance of HO after cervical spine surgery. The mechanism of HO is still unclear, and many studies have suggested that it may be related to soft tissue injury, improper prosthesis size, and other factors. Accordingly, many clinicians have put forward corresponding prevention strategies, such as thorough irrigation of the surgical eld, postoperative use of NSAIDs drugs, etc., but with little effect, and there is no well-accepted prophylaxis.
In different reports, the incidence rate of HO varies greatly, which may be due to the different degree of understanding and diagnostic method of HO by different authors [61]. Through meta-analysis of existing data, this study attempted to obtain a relatively objective incidence of HO and explore its variation rule during follow-up period.
The results of the analysis showed that the incidence of HO increased with the extension of follow-up time, both based on the number of cases and the number of segments, and the increase mainly occurred after 6 years. This result suggests that the follow-up time after CDA should be long enough, especially for young patients, so as to ensure the true clinical results. On the other hand, based on the McAfee's grading system, we analyzed Grade I-II and Grade III-IV respectively, and found that the incidence of HO in Grade I-II did not increase signi cantly with the extension of follow-up time. On the contrary, the incidence of Grade III-IV HO increased with the extension of follow-up time. The results were veri ed in the Linear-regression analysis. This indicates that HO occurs all the postoperative time and Grade I-II HO will gradually develop into Grade III-IV, while continuous new HO keeps the number of Grade I-II in a dynamic balance.
The de ciency of this study mainly lies in that, in order to observe the principle of "prefer less to more", we added the entry of "exclude polycentric study" in the exclusion criteria, which is to prevent possible data duplication. However, this standard also makes the amount of data available reduce greatly. In some follow-up points, only 1-2 articles are included, so the data obtained are not objective enough.
Through this study, we can preliminarily de ne the relatively objective incidence and change rule of HO, which provides data basis and theoretical basis for the future research of HO prevention strategy.

Conclusion
With the extension of follow-up time, the incidence of HO increased year by year, both in case-and level-based analyses, to which the Grade III-IV HO contributed a lot. HO would happen in anytime of follow-up period and the existing HO, on the other hand, would develop into the more severe grades.

Declarations
Consent for Publication: Not applicable.
Acknowledgements: The authors wish to extend their gratitude to Hong Ying (Operation Center, West China Hospital of Sichuan University) for designing and executing the database searches.
Funding: This study was supported by the National Natural Science Foundation of China (grant no. 81702156 to Y Meng).
Availability of data and materials: All relevant data has been provided in gures, tables and supplements.
Authros' contributions: Guo YJ and Liu H conceived of the study and developed its design and protocol. Chen JL organized the search and selection process; i.e. the electronic database search, removal of duplicates, coordinated the contributions of the other authors and drafted the manuscript. Eligibility and quality assessments were done by the following pairs of authors: Meng Y/Ding C and Wang BY/Rong X. Reference hand search was done by Guo YJ. Data-extraction in preparation for meta-analysis was done by Guo YJ and Chen JL. Figures and tables were prepared by Guo YJ. Guo YJ conducted the statistical pooling of data in Revman and helped to draft the rst manuscript. All authors have read and approved the nal manuscript.
Con icts of interests: There's no con icts of interests among all of the authors.     a Forest plots of annual incidence of HO based on levels number b Annual incidence of HO based on levels number Annual incidence of HO based on levels number showed us an increasing trend along with the follow-up period.  5A Forest plots of annual incidence of Grade III-IV HO 5B Annual incidence of Grade III-IV HO There's a slightly increasing trend in the annual incidence of Grade III-IV HO. 5C Linear-regression analysis of Grade III-IV HO incidence and Follow-up Period The linear-regression analysis of Grade III-IV HO incidence and follow-up period showed a slight correlation (R2=0.218).