Effect of bisphosphonates on local recurrence of giant cell tumor of bone: a meta-analysis

Figures & data

Table 1 Characteristics of the included studies

Study	Sample size, I/C	Intervention	Control	Similarities	Surgical procedures (BP group)	Surgical procedures (control group)	Average follow- up after surgery (months)	Outcome measures
Tse et al (2008)^Citation23	44 (24/20)	Seven received pamidronate 90 mg, and 17 received zoledronic acid 4 mg twice before surgery and three times after surgery	No placebo	Not mentioned	IC: 21 WR: 3	IC: 15 WR: 4	115.4 (control group) 48 (BP group)	Local recurrence rate, local BMD
Zheng et al (2009)^Citation24	39 (19/20)	Zoledronic acid 4 mg or incadronate disodium 10 mg twice before surgery and three times after surgery	No placebo	Not mentioned	IC: 16 WR: 3	IC: 15 WR: 5	43.6	Local recurrence rate, pain VAS, swelling relief
Fan (2013)^Citation25	55 (29/26)	Zoledronic acid 4 mg three times after surgery	No placebo	Calcium	IC: 17 WR: 12	IC: 15 WR: 11	45	Local recurrence rate, Enneking postoperative functional score, local BMD
Xu et al (2014)^Citation26	85 (32/53)	Zoledronic acid 4 mg once before surgery and monthly after surgery for 2 years	No placebo	Postoperative adjuvant radiotherapy	Not mentioned	Not mentioned	54.7	Local recurrence rate
Ding et al (2016)^Citation27	37 (22/15)	Zoledronic acid 4 mg one to three times before surgery and once every 6 months after surgery for 2 years	No placebo	Not mentioned	IC: 15 WR: 7	IC: 10 WR: 5	24	Local recurrence rate, pain VAS
Xu et al (2017)^Citation28	35 (19/16)	Seven received zoledronic acid 4 mg, and 12 received incadronate disodium 10 mg once before surgery and monthly after surgery for 2 years	No placebo	Postoperative adjuvant radiotherapy	Not mentioned	Not mentioned	47.2	Local recurrence rate, nerve function
Kundu et al (2018)^Citation29	37 (18/19)	Zoledronic acid 4 mg three times 2 weeks before surgery	No placebo	Not mentioned	IC: 18 WR: 0	IC: 19 WR: 0	32	Local recurrence rate, functional scores

Abbreviations: BMD, bone mineral density; BPs, bisphosphonates; I/C, intervention/control groups; IC, intralesional curettage; WR, wide resection.

Figure 1 Flowchart of the selection strategy and inclusion/exclusion criteria for the present meta-analysis.

Table 2 Newcastle–Ottawa scale assessment of the quality of the studies

Study	Selection				Comparability based on design or analysis	Exposure			Total scores	Qualitya
	Case definition adequate	Representativeness of the cases	Selection of controls	Definition of controls		Ascertainment of exposure	Same method of ascertainment for cases and controls	Nonresponse rate
Tse et al (2008)^Citation23	⋆b	⋆	⋆	⋆	⋆	⋆	⋆	✰	7	High
Zheng et al (2009)^Citation24	⋆	⋆	⋆	⋆	⋆⋆	✰	✰	✰	6	Medium
Fan (2013)^Citation25	⋆	⋆	⋆	⋆	⋆⋆	⋆	⋆	✰	8	High
Xu et al (2014)^Citation26	⋆	⋆	⋆	✰	⋆	⋆	⋆	✰	5	Medium
Ding et al (2016)^Citation27	⋆	⋆	⋆	✰	⋆⋆	⋆	✰	✰	6	Medium
Xu et al (2017)^Citation28	⋆	⋆	⋆	✰	⋆⋆	⋆	⋆	✰	7	High
Kundu et al (2018)^Citation29	⋆	⋆	✰	✰	⋆⋆	⋆	⋆	✰	6	Medium

Notes:

a The quality is assessed by the score as follows: ≥7, high quality; ≥5 to <7, medium quality; <5, low quality.

b Cells with a star indicate that the corresponding item is addressed satisfactorily in the publication in question.

Figure 2 Forest plots for the effect of BPs on total postoperative recurrence in patients with GCTB.

Abbreviations: BPs, bisphosphonates; GCTB, giant cell tumor of bone.

Figure 3 Forest plots for subgroup analysis for the effect of BPs on postoperative recurrence in patients with GCTB with different tumor grades.

Notes: (A) For patients with stage I–II GCTB, a significant difference in local recurrence rate was found between the BP group and the control group (P<0.05). (B) For patients with stage III GCTB, a significant difference in local recurrence rate was found between the BP group and the control group.

Abbreviations: BPs, bisphosphonates; GCTB, giant cell tumor of bone.

Figure 4 Forest plots for subgroup analysis for the effect of BPs on postoperative recurrence in patients with GCTB with different surgical procedures.

Notes: (A) For patients who underwent intralesional curettage, a significant difference in local recurrence rate was found between the BP group and the control group (P<0.01). (B) For patients who underwent wide resection, there was no significant difference in local recurrence rate between the BP group and the control group (P=0.16).

Abbreviations: BPs, bisphosphonates; GCTB, giant cell tumor of bone.

Figure S1 The funnel plots asymmetry for the outcome showed the evidence of publication bias on the meta-analyses for (A) total postoperative recurrence, (B) subgroup of stage I–II GCTB, (C) subgroup of stage III GCTB, (D) subgroup of intralesional curettage, and (E) subgroup of wide resection.

Abbreviation: GCTB, giant cell tumor of bone.

Table S1 PRISMA 2009 checklist

Section/topic	#	Checklist item	Reported on page #
TITLE
Title	1	Identify the report as a systematic review, meta-analysis, or both.	1
ABSTRACT
Structured summary	2	Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.	3
INTRODUCTION
Rationale	3	Describe the rationale for the review in the context of what is already known.	4
Objectives	4	Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).	4
METHODS
Protocol and registration	5	Indicate if a review protocol exists, if and where it can be accessed (eg, Web address) and, if available, provide registration information including registration number.	5
Eligibility criteria	6	Specify study characteristics (eg, PICOS, length of follow-up) and report characteristics (eg, years considered, language, publication status) used as criteria for eligibility, giving rationale.	5
Information sources	7	Describe all information sources (eg, databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.	5
Search	8	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.	5
Study selection	9	State the process for selecting studies (ie, screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).	5
Data collection process	10	Describe method of data extraction from reports (eg, piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.	5
Data items	11	List and define all variables for which data were sought (eg, PICOS, funding sources) and any assumptions and simplifications made.	5
Risk of bias in individual studies	12	Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.	6
Summary measures	13	State the principal summary measures (eg, risk ratio, difference in means).	6
Synthesis of results	14	Describe the methods of handling data and combining results of studies, if done, including measures of consistency (eg, I^2) for each meta-analysis.	6
Risk of bias across studies	15	Specify any assessment of risk of bias that may affect the cumulative evidence (eg, publication bias, selective reporting within studies).	6
Additional analyses	16	Describe methods of additional analyses (eg, sensitivity or subgroup analyses, meta-regression), if done, indicating which were prespecified.	6
RESULTS
Study selection	17	Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.	6
Study characteristics	18	For each study, present characteristics for which data were extracted (eg, study size, PICOS, follow-up period) and provide the citations.	7
Risk of bias within studies	19	Present data on risk of bias of each study and, if available, any outcome level assessment (see Item 12).	7
Results of individual studies	20	For all outcomes considered (benefits or harms), present, for each study: a) simple summary data for each intervention group, b) effect estimates and confidence intervals, ideally with a forest plot.	7
Synthesis of results	21	Present results of each meta-analysis done, including CIs and measures of consistency.	7
Risk of bias across studies	22	Present results of any assessment of risk of bias across studies (see Item 15).	8
Additional analysis	23	Give results of additional analyses, if done (eg, sensitivity or subgroup analyses, meta-regression [see Item 16]).	8
DISCUSSION
Summary of evidence	24	Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (eg, health care providers, users, and policy makers).	8–10
Limitations	25	Discuss limitations at study and outcome level (eg, risk of bias) and at review-level (eg, incomplete retrieval of identified research, reporting bias).	10
Conclusions	26	Provide a general interpretation of the results in the context of other evidence and implications for future research.	11
FUNDING
Funding	27	Describe sources of funding for the systematic review and other support (eg, supply of data); role of funders for the systematic review.	11

Table S2 GRADE evidence profile for effect of BPs on recurrence giant cell tumor of bone

Summary of findings			Quality assessment
	n (I/C)	OR (95% CI)	Limitationsa	Inconsistency	Indirectness	Imprecision	Others	Quality
Total	6 (145/150)	0.20 (0.10–0.38)	No serious	No serious	No serious	No serious	Strong associationb	High
Stage I–II	6 (72/65)	0.29 (0.11–0.76)	No serious	No serious	No serious	No serious	Strong association	High
Stage III	6 (73/85)	0.16 (0.07–0.39)	No serious	No serious	No serious	No serious	Strong association	High
Intralesional curettage	4 (69/55)	0.19 (0.07–0.52)	No serious	No serious	No serious	Seriousc	Strong association	Moderate
Wide resection	4 (25/26)	0.35 (0.08–0.51)	No serious	Seriousd	No serious	Serious	Strong association	Moderate

Notes:

a The inadequate case definition and substantial loss follow-up in some studies may raise the risk of bias.

b Effect size >0.05 is considered to be large and strengthen the evidence.

c The number of included patients <150 is considered to be small and may cause imprecision.

d Inconsistent report of outcomes may raise the risk of bias.

Abbreviations: GRADE, Grading of Recommendations Assessment, Development and Evaluation; I/C: intervention/control groups.

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