Systematic review and meta-analysis of incidence and outcomes of hip and vertebral fractures hip fracture in patients with end-stage kidney disease

Last update: June 24 2022.

Authors: Yoshinosuke Shimamura MD, MPH^{1, 2}; Yasutaka Kuniyoshi MD, PhD^2,3; Hiroshi Ueta MD, PhD^2,4; Takamasa Miyauchi MD, PhD^2,5; Mari Yamamoto MD^2,6; Yasushi Tsujimoto MD, MPH^{2, 7}.

¹Department of Nephrology, Teine Keijinkai Medical Center, Sapporo, Hokkaido, Japan.

²Scientific Review WorkshopS Peer Support Group (SRWS-PSG), Osaka, Japan.

³Department of Pediatrics, Tsugaru Hoken Kensei Hospital, Hirosaki, Aomori, Japan.

⁴Department of Anesthesiology and Critical Care, Kobe City Hospital Organization, Kobe City Medical Center General Hospital, Kobe, Japan.

⁵Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Kawasaki, Japan.

⁶Department of Rheumatology and Nephrology, Chubu Rosai Hospital, Nagoya, Japan.

⁷Department of Nephrology and Dialysis, Kyoritsu Hospital, Kawanishi, Hyogo, Japan.

Corresponding author: Yoshinosuke Shimamura MD, MPH

Address: Department of Nephrology, Teine Keijinkai Medical Center, 1-40, 12 chome, 1 jyou, Maeda, Teine, Sapporo, Hokkaido, 0068555, Japan.

E-mail: yshimamura.tkh@gmail.com

Author contributions:

YS is the guarantor. YS, YK, HU, TM, MY, and YT drafted the manuscript.

All authors contributed to the development of the selection criteria, the risk of bias assessment strategy, and data extraction criteria. YS, YK, and YT developed the search strategy. YK and YT provided statistical expertise. All authors read, provided feedback, and approved the final manuscript.

Hip fracture is one of the major health problems in patients with end-stage kidney disease (ESKD) requiring renal replacement therapy, including hemodialysis, peritoneal dialysis, or kidney transplantation, because they have a higher risk for hip fracture than the general population ¹²³. In addition, several studies have demonstrated that hip fracture had a high burden of morbidity and mortality, and costs in patients with ESKD ⁴⁵⁶. Along with the aging of the dialysis population, the increased risk of fractures may be explained by changes in phosphorus handling, vitamin D metabolism, and alternations in parathyroid hormone production and secretion associated with exacerbation of renal impairment ⁷.

Although prior studies have reported mortality rates after hip fracture in those with ESKD ⁷⁸⁹, the reported mortality rates vary across studies. Besides, a comprehensive and quantitative analysis of each finding in these studies has not been conducted.

Therefore, we aim to conduct a systematic review and meta-analysis to systematically and quantitatively evaluate the mortality rate and time-period mortality after hip fracture and spinal fracture in patients with ESKD treated with hemodialysis, peritoneal dialysis, or kidney transplantation.

What are the mortality rate, 1-year mortality, and 5-year mortality after hip fracture and spinal fracture in patients with ESKD treated with hemodialysis or peritoneal dialysis, or kidney transplant?

We followed the Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 ¹⁰ for preparing this protocol.

Inclusion criteria of articles for the review

4.1.1. Types of included studies

We will include prospective and retrospective cohort studies, including cohorts from controlled trials, that describe outcomes after hip or spinal fracture in patients with ESKD treated with hemodialysis or peritoneal dialysis or kidney transplant. We will also include original reports such as case series in which all participants had mortality outcomes or cohort studies. We will not restrict publication date and status (full publication, conference abstract, and unpublished data).

We will exclude case reports with three cases or less, animal and laboratory studies, and literature reviews. We will also exclude not yet recruiting, recruiting, or withdrawn studies in Clinical.Trial.gov.

4.1.2. Study participants

Inclusion criteria:

We will include patients with ESKD treated with hemodialysis or peritoneal dialysis or kidney transplant, regardless of the etiology of chronic kidney disease, follow-up duration, and country of origin. We will include patients of any age, sex, and race.

Exclusion criteria:

None.

4.1.3. Intervention(s) or exposure(s)

Not applicable.

4.1.4. Comparator(s) or control(s)

Not applicable.

Meta-analysis

We will use a single-arm analysis. For categorical variables, the percentage, mean, and standard deviation were calculated. We will calculate pooled incidence rate and incident proportion of death in patients with ESKD after hip fracture as well as in those with ESKD after spinal fracture. The random-effects model (DerSimonian and Laired method) will be used for pooled estimates to consider the variance between and among the studies. We will conduct statistical analyses using the R software (R Development Core Team 2019), with packages meta version 4.15-0 and metaphor version 2.4-0.

Subgroup analysis

To evaluate the clinical heterogeneity of study participants, we will perform subgroup analyses for primary outcomes with sex (men versus. women), race (Black versus. non-Blacks), presence or absence of cardiovascular diseases [hypertension, coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease], presence or absence of diabetes mellitus, types of renal replacement therapy (hemodialysis, peritoneal dialysis, or kidney transplant, and participants’ age category (Age ≥75 versus. Age <75), if possible.

Sensitivity analysis

We will perform a sensitivity analysis limited to population-based cohort studies that describe outcomes after hip or spinal fracture in patients with ESKD treated with hemodialysis or peritoneal dialysis or kidney transplant. We will also perform a sensitivity analysis excluding the outcome data other than 1-year and 5-year mortality to confirm the robustness of the main results.

Type of outcomes

4.2.1. Primary outcomes

1. Mortality rate, 1-year mortality, and 5-year mortality after hip fracture.
2. Mortality rate, 1-year mortality, and 5-year mortality after spinal fracture.

Search methods

4.3.1. Electronic search

We will search Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, and EMBASE via ProQuest Dialog. See Appendix 1, 2, and 3 for the search strategies.

4.3.2. Other sources

For ongoing or unpublished trials, we will also search World Health Organization International Clinical Trials Platform Search Portal (ICTRP) and ClinicalTrials.gov, as shown in Appendix 4 and 5. We will also confirm paper references including the extracted studies. We will ask the authors of original studies for unpublished or additional data.

Data collection and analysis

4.4.1. Selection of the studies

Two independent authors will screen the titles and abstracts of studies identified using the search strategy against the inclusion and exclusion criteria. The full text of the potentially eligible studies will be obtained and independently assessed for eligibility by two authors. If we are not sure whether the studies meet the inclusion criteria because of the abstract only, we will contact the original authors of these studies. Any disagreements will be resolved by discussion, and if this fails, a third reviewer will act as an arbiter.

4.4.2. Data extraction and management

Two review authors will perform data extraction for the studies independently. The 1-year and 5-year mortality will be extracted, but the mortality less than 1 year will not be extracted. We will extract the data if studies report the mortality of more than 1 year and less than 5 years (e.g., 2-year mortality), but do not report either 1-year or 5-year mortality. In that case, the outcome data for less than 3 years will be included as 1-year mortality, and the data for 3 to 5 years will be included as 5-year mortality. We will perform a sensitivity analysis excluding the outcome data other than 1-year and 5-year mortality to confirm the robustness of the main results. Any disagreements will be resolved by discussion, and if this fails, a third reviewer will act as an arbiter. We will contact the original authors if necessary. We will use data extraction which was checked beforehand for 10 randomly selected studies.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias for each study using the Joanna Briggs Institute Prevalence Critical Appraisal Tool ¹¹¹². We will assess the following domains:

1. Was the sample frame appropriate to address the target population?
2. Were study participants sampled in an appropriate way?
3. Was the sample size adequate?
4. Were the study subjects and the setting described in detail?
5. Was the data analysis conducted with sufficient coverage of the identified sample?
6. Were valid methods used for the identification of the condition?
7. Was the condition measured in a standard, reliable way for all participants?
8. Was there appropriate statistical analysis?
9. Was the response rate adequate, and if not, was the low response rate managed appropriately? Any disagreements will be resolved by discussion, and if this fails, a third reviewer will act as an arbiter. In this study, the overall risk of bias will be calculated as the number of “Yes” responses for each domain divided by the total number of domains and expressed as a percentage. The overall risk of bias will be defined based on the calculated percentage as follows: <50%: high risk of bias; 50% to 80%: moderate risk of bias; >80%: low risk of bias).

Measures of treatment effects

Incidence rate and risk (incidence proportion) with 95% confidence intervals (CIs) and 95% prediction intervals. Incidence rate will be measured as the number of incident cases per measure of exposure and incidence proportion will be measured as the number of incident cases over a specified time frame. The statistical heterogeneity will be assessed using τ² statistics, which provide a logit scale measure of between-study variance, represented in a more readily interpretable way by the 95% prediction intervals.

Handling of missing data

We will not complement the missing values.

Assessment of heterogeneity

We will evaluate the statistical heterogeneity by visual inspection of the forest plots and calculating the I² statistic (I² values of 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity). If heterogeneity is detected (I²>50%), we will verify the possible causes. Cochrane Chi-square test (Q-test) will be performed to calculate I²statistic, and P value less than 0.10 will be defined as statistically significant.

Assessment of reporting bias

We will search the clinical trial registry system (ClinicalTrial.gov and ICTRP) to identify completed but unpublished studies. We will assess the potential publication bias by visual inspection of the funnel plot. Egger test will also be performed. Funnel plots are likely to be inaccurate in meta-analyses of prevalence studies with low proportions of outcomes ¹⁴, we will not conduct the test and visual inspection if we find less than 20 studies ¹⁵¹⁶or studies that have similar sample sizes.

None.

A	B
#1	[mh “Kidney Diseases”]
#2	[mh “Renal Replacement Therapy”]
#3	[mh “Renal Dialysis”]
#4	[mh “Peritoneal Dialysis”]
#5	[mh “Hemodiafiltration”]
#6	[mh “Hemodialysis, Home”]
#7	#1 OR #2 OR #3 OR #4 OR #5 OR #6
#8	ESRD:ti,ab
#9	“end stage renal disease”:ti,ab
#10	ESKD:ti,ab
#11	“end stage kidney disease”:ti,ab
#12	ESKF:ti,ab
#13	“end stage kidney failure”:ti,ab
#14	ESRF:ti,ab
#15	“end stage renal failure”:ti,ab
#16	CKD:ti,ab
#17	“chronic kidney disease”:ti,ab
#18	“chronic kidney failure”:ti,ab
#19	“renal transplantation”:ti,ab
#20	CAPD:ti,ab
#21	CCPD;ti,ab
#22	APD;ti,ab
#23	“hemodialysis”:ti,ab
#24	“haemodialysis”ti,ab
#25	“hemodiafiltration”:ti,ab
#26	“haemodiafiltration”:ti,ab
#27	#8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26
#28	#7 OR #27
#29	[mh “Femoral Fractures”]
#30	“femoral fracture”:ti,ab
#31	“femoral neck fracture”:ti,ab
#32	“hip fracture”:ti,ab
#33	#30 OR #31 OR #32
#34	#29 OR #33
#35	[mh “Spinal Fractures”]
#36	“vertebral fracture”:ti,ab
#37	“spine fracture”:ti,ab
#38	#36 OR #37
#39	#35 OR #38
#40	#34 OR #39
#41	"incidence [MeSH: noexp]" OR [mh mortality] OR "follow up studies [MeSH: noexp]" OR prognos*:ti,ab,kw OR predict*:ti,ab,kw OR course*:ti,ab,kw
#42	#28 AND #40 AND #41
#43	[mh “Animals”] NOT [mh “Humans”]
#44	#42 NOT #43

Appendix 1: CENTRAL search strategy

A	B
#1	Kidney Diseases [mh]
#2	Renal Replacement Therapy [mh]
#3	Renal Dialysis [mh]
#4	Peritoneal Dialysis [mh]
#5	Hemodiafiltration [mh]
#6	Hemodialysis, Home [mh]
#7	#1 OR #2 OR #3 OR #4 OR #5 OR #6
#8	ESRD [tiab]
#9	“End Stage Renal Disease” [tiab]
#10	ESKD [tiab]
#11	“End Stage Kidney Disease” [tiab]
#12	ESKF [tiab]
#13	“End Stage Kidney Failure” [tiab]
#14	ESRF [tiab]
#15	“End Stage Renal Failure” [tiab]
#16	CKD [tiab]
#17	“Chronic Kidney Disease” [tiab]
#18	“Chronic Kidney Failure” [tiab]
#19	“Renal Transplantation” [tiab]
#20	CAPD [tiab]
#21	CCPD [tiab]
#22	APD [tiab]
#23	“Hemodialysis” [tiab]
#24	“Haemodialysis” [tiab]
#25	“Hemodiafiltration” [tiab]
#26	“Haemodiafiltration” [tiab]
#27	#8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26
#28	#7 OR #27
#29	Femoral Fractures [mh]
#30	“Femoral Fracture” [tiab]
#31	“Femoral Neck Fracture” [tiab]
#32	“Fracture, Hip” [tiab]
#33	#30 OR #31 OR #32
#34	#29 OR #33
#35	Spinal Fractures [mh]
#36	“Vertebral Fracture” [tiab]
#37	#35 OR #36
#38	#34 OR #37
#39	Mortality [mh]
#40	“Mortalty” [tiab]
#41	#39 OR #40
#42	Death [mh]
#43	“Death” [tiab]
#44	#42 OR #43
#45	Survival [mh]
#46	“Survival” [tiab]
#47	#45 OR #46
#48	Prognosis [mh]
#49	“Prognosis” [tiab]
#50	#48 OR #49
#51	#41 OR #44 OR #47 OR #50
#52	#28 AND #38 AND #51

Appendix 2: MEDLINE (via PubMed) search strategy

A	B
S1	EMB.EXACT.EXPLODE(“kidney diseases”)
S2	EMB.EXACT.EXPLODE(“renal replacement therapy”)
S3	EMB.EXACT.EXPLODE (“hemodialysis”)
S4	EMB.EXACT.EXPLODE (“peritoneal dialysis”)
S5	EMB.EXACT.EXPLODE (“hemodiafiltration”)
S6	EMB.EXACT.EXPLODE (“home dialysis”)
S7	#1 OR #2 OR #3 OR #4 OR #5 OR #6
S8	ab(ESRD) OR ti(ESRD)
S9	ab(end stage renal disease) OR ti(end stage renal disease)
S10	ab(ESKD) OR ti(ESKD)
S11	ab(end stage kidney disease) OR ti(end stage kidney disease)
S12	ab(ESKF) OR ti(ESKF)
S13	ab(end stage kidney failure) OR ti(end stage kidney failure)
S14	ab(ESRF) OR ti(ESRF)
S15	ab(end stage renal failure) OR ti(end stage renal failure)
S16	ab(CKD) OR ti(CKD)
S17	ab(chronic kidney disease) OR ti(chronic kidney disease)
S18	ab(chronic kidney failure) OR ti(chronic kidney failure)
S19	ab(renal transplantation) OR ti(renal transplantation)
S20	ab(CAPD) OR ti(CAPD)
S21	ab(CCPD) OR ti(CCPD)
S22	ab(APD) OR ti(APD)
S23	ab(hemodialysis) OR ti(hemodialysis)
S24	ab(haemodialysis) OR ti(haemodialysis)
S25	ab(hemofiltration) OR ti(hemofiltration)
S26	ab(haemodiafiltration) OR ti(haemodiafiltration)
S27	S8 OR s9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26
S28	S7 OR S27
S29	EMB.EXACT.EXPLODE (“femur fractures”)
S30	ab(femoral fracture) OR ti(femoral fracture)
S31	ab(femoral neck fracture) OR ti(femoral neck fracture)
S32	ab(hip fracture) OR ti(hip fracture)
S33	S30 OR S31 OR S32
S34	S29 OR S33
S35	EMB.EXACT.EXPLODE (“spine fractures”)
S36	ab(vertebral fracture) OR ti(vertebral fracture)
S37	ab(spinal fracture) OR ti(spinal fracture)
S38	S36 OR S37
S39	S35 OR S38
S40	S34 OR S39
S41	EMB.EXACT.EXPLODE (“mortality”)
S42	EMB.EXACT.EXPLODE (“survival”)
S43	EMB.EXACT.EXPLODE (“prognosis”)
S44	S41 OR S42 OR S43
S45	ab(mortality) OR ti(mortality)
S46	ab(survival) OR ti(survival)
S47	ab(prognosis) OR ti(prognosis)
S48	S45 OR S46 OR S47
S49	S44 OR S48
S50	S28 AND S40 AND S49
S51	EMB.EXACT (animal experiment) NOT (EMB.EXACT (human experiment) OR EMB.EXACT (human))
S52	S50 NOT S51

Appendix 3: EMBASE search strategy (ProQuest Dialog)

A
Conditions: “Kidney Diseases” OR “Renal Replacement Therapy” OR “Renal Dialysis” OR “Peritoneal Dialysis” OR “Hemodiafiltration”
Intervention: “Femoral Fractures” OR “Spinal Fractures”
Recruitment status is ALL.

Appendix 4: ICTRP search strategy

A
Condition or disease: (Kidney Diseases OR Renal Replacement Therapy OR Renal Dialysis OR Peritoneal Dialysis OR Hemodiafiltration) AND (Femoral Fractures OR Spinal Fractures)
Intervention: Not applicable
Other terms: Mortality OR Death OR Survival OR Prognosis

Appendix 5: ClinicalTrial.gov search strategy