Fractures in children and adolescents with diabetes mellitus during 2001-2020

doi:10.21203/rs.3.rs-4949270/v1

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Fractures in children and adolescents with diabetes mellitus during 2001-2020

https://doi.org/10.21203/rs.3.rs-4949270/v1

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Purpose: To compare fracture risk among paediatric patients, between those with diabetes mellitus (DM) and a matched comparison group.

Methods: In this registry-based cohort study, individuals who were diagnosed with DM during 2001-2020, at age 1-17 years, were matched in a 1:5 ratio to a comparison group. Clinical, laboratory and demographic data were obtained from the electronic database of Meuhedet Health Services.

Results: The DM and comparison groups included 1049 and 5245 individuals, respectively. The median age at DM diagnosis was 10.9 years. The median follow-up period of both groups was 5.5 years (IQR 3.6-8.2). We did not find a statistically significant risk for fractures among children with DM (adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.93-1.31, p=0.25). In a subgroup analysis of boys aged >11 years at DM diagnosis, the adjusted HR for fractures was 1.47 (95%CI 1.06-2.04, p=0.02) relative to the comparison group. In a multivariate analysis, male gender (adjusted HR 1.99, 95%CI 1.46-2.73, p<0.001) and recurrent hospitalizations (adjusted HR 1.53 95%CI 1.02-2.30, p=0.04) were associated with increased risks for fractures among children with DM.

Conclusions: We found increased fracture risk among boys aged >11 years at diagnosis of DM compared to a matched comparison group.

diabetes

fractures

children

adolescents

While several studies showed impaired bone health and increased fracture risk among adults with diabetes mellitus (DM), data regarding children is still sparse.

What is new:

We found that among boys aged >11 years at DM diagnosis, the adjusted HR for fractures was 1.47 relative to the comparison group.
Male gender and recurrent hospitalization were associated with increased risks for fractures among the DM group.
Recognition of the risk factors of fractures in this population may promote developing guidance for prevention and treatment.

Several studies have shown reduced bone mineral content and reduced bone mineral density (BMD), both in children and adults with type 1 diabetes (T1D) [1, 2]. Deficits in BMD are defined as mild to moderate [3]. Other contributors to bone fragility in T1D are impaired bone microarchitecture, geometry and strength [4]. In T1D, accumulation of excessive advanced glycation end products in the bone leads to the formation of abnormal cross-links between type 1 collagen fibers, resulting in reduced bone strength [5]. Moreover, several studies have shown low concentrations of both bone formation and bone resorption markers in individuals with T1D, suggesting a state of low bone turnover [6]. Indeed, this emerging complication was the focus of the 2022 clinical practice consensus guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) [7].

Impaired bone quality and quantity may translate to a higher fracture risk across the life span [8, 9]. A meta-analysis of six studies, including 39,925 adults with T1D aged 18–50 years old, verified increased fracture risk in young and middle-aged adults.[10] A 1.9-fold increased risk of any fracture and a 4.4-fold increased risk of hip fracture were reported among individuals with T1D compared to individuals without. In other studies among adult populations, reported risks of hip fracture were 3–12 fold increased in individuals with T1D [3].

Only a few studies have explored risks of fractures among children and adolescents with TID. A large population-based cohort study used data from The Health Improvement Network (THIN) in the U.K., in which 30,394 individuals aged 0–89 years with T1D were compared with 303,872 age-, sex-, and practice-matched individuals without T1D [8]. Among those with T1D, aged 0–19 years, the adjusted hazard ratios (HRs) for any fracture were 1.14 in males and 1.35 in females. Two other studies that explored the impact of glycemic control on fracture risk among the paediatric population with T1D did not include healthy comparison groups [11, 12].

Bone fragility has been identified as a complication also of type 2 diabetes (T2D) [13]. T2D face has been reported to pose an increased risk of fracture, albeit less than that of T1D [14]. A meta-analysis of 21 studies revealed a relative risk for hip fracture of 5.67 in T1D (95% CI 3.66–9.07) and 1.34 in T2D (95% CI 1.19–1.51) [15]. Contrasting with T1D, individuals with T2D show preserved or even increased BMD compared to healthy controls [13]. Mechanisms underlying bone fragility in T2D include impaired bone quality, decreased bone turnover and reduced bone strength. In recent years, the prevalence of T2D in adolescents has rapidly increased [16, 17]. Young-onset T2D may have a more severe phenotype than T2D occurring at an older age [14].

The aim of our study was to compare the fracture risk during childhood and adolescence, between individuals with DM and a large matched population without DM, and to identify factors that contribute to the risk.

Study design and data source

For the purpose of this historical cohort study, we extracted information from the electronic database of Meuhedet, a health maintenance organization that provides complete healthcare services to 1.3 million people of all ages and ethnicities in Israel, across all regions of the country. A comprehensive data warehouse maintains patient information, including demographic data, laboratory tests, referrals to outpatient clinics, and diagnoses given at ambulatory medical encounters and hospital discharge letters.

Study population and diagnosis of DM

The study inclusion criteria were the diagnosis of DM during 2001–2020, at the age of 1–17 years, and insurance with Meuhedet at least two years before the diagnosis. The end of the follow-up period was defined as the earliest of the following three dates: age 18 years, the study census date (August 31, 2023), or the end of insurance by Meuhedet Health Services. DM was identified according to the International Classification of Diseases, Ninth Revision (ICD-9) code 250, and included both T1D and T2D. The incidence rate of T1D in Israel in 2015 was 13.8/100,000 [17]. The incidence of youth-onset T2D in Israel was 0.6/100,000 in 2008 and 3.4/100,000 in 2019 [17]. Among children and adolescents with diabetes in Israel in 2015, 92.5% had TID, 5.1% T2D and 2.4% another DM type [18]. Accordingly, we assume that during the study period (2001–2020), about 95% of our patients with DM had T1D.

The DM group was matched in a 1:5 ratio to individuals from the general population who were insured by Meuhedet Health Services and not diagnosed with DM. As various factors have been reported to affect the incidence of fractures [19], we matched the comparison group by age (year and month of birth), sex, resident socioeconomic status (SES) and population sector, as detailed below. We marked the date of DM diagnosis as the index date for both groups.

The exclusion criteria of both groups were any chronic disease that may affect bone health according to the (ICD)-9 codes: malignant neoplasm (ICD9 codes 140–208), parathyroid disorder (ICD9 252, 275), disorders of the pituitary gland (ICD9 253), adrenal disease (ICD9 255), ovarian and testicular hypofunction (ICD9 256–258), neuromuscular disorders (ICD9 330, 342, 343, 344, 348.1), inflammatory bowel disease (ICD9 555, 556), chronic kidney disease (ICD9 582, 585, 586), rheumatic diseases (ICD9 710, 714, 715, 720), eating disorders (ICD9 307.1, 307.5, 783) and primary bone disease (ICD9 733.0, 733.2, 733.3, 733.9, 733.92). Celiac disease (ICD9 579.3) and thyroid disorder (ICD9 240, 242–245) were not excluded, since they are common among individuals with TID, and we aimed to explore associations of these comorbidities on fracture risk.

Clinical and demographic data

For each child, we obtained age, sex, population sector, SES, anthropometric measurements, laboratory test results, fractures and hospitalizations. We defined recurrent hospitalization as two or more hospitalizations since DM diagnosis.

The three main population sectors recorded in the Meuhedet Health Service’s database are the general Jewish population (41%), ultra-orthodox Jews (43%) and Arabs (16%). These sectors differ in paediatric fracture incidence [19].

The SES index (Points Location Intelligence, Israel), an integral part of the electronic database of Meuhedet Health Service, is based on residency address, according to classification by the Israel Central Bureau of Statistics. The index is rated on a scale of 1–10, with 1 as the lowest. For this study, we classified three levels: low (1–3), medium (4–6) and high (7–10).

Laboratory results

Data of HbA1C and 25-hydroxy vitamin D (25-OH-vitD) were extracted at DM diagnosis (± 90 days, the nearest to the index date); and during the entire follow-up period. Data of 25-OH-vitD test results were available from 2015.

Diagnosis of fracture

All the fracture events that occurred between the index date and the end of the study period were included in the analysis. The fractures were identified by coded diagnoses from an ambulatory clinic or a hospital emergency room. Fracture type was classified according to ICD-9 codes 800–829.

To differentiate between a single fracture event that was recorded at repetitive visits, and two distinct fracture events, we defined a period within all the fracture diagnoses that were related to the same fracture. Accordingly, we extracted all the fracture diagnoses of the first 200 children who experienced a fracture during 2019, as we previously described [19]. We then manually reviewed the patients’ electronic medical records, and used the results as a guideline. An interval of 90 days from the previous fracture diagnosis was considered the cut-off for defining a new fracture. The sensitivities and specificities to identify two distinct fracture events were 88%, and 95%, respectively. When the same fracture event was reported more than once using different ICD-9 codes, the more specific code was used.

Statistical analysis

We described categorical variables as numbers and percentages, and the χ2 test to compare between proportions. Continuous variables were evaluated for normal distributions using histograms, and reported as means and standard deviations, or as medians and interquartile ranges (IQRs), as appropriate. We used the T-test to compare normally distributed variables and the Mann–Whitney test for non-normally distributed variables.

We calculated incidence rate ratios using negative binomial regression models. We compared the risk for fractures between the two groups and within the DM group using Cox proportional hazard regression analyses for crude and adjusted hazard (HRs). We used Kaplan–Meier curves to illustrate the first fracture event for each child since the index date. In subgroup analyses according to sex and age at DM diagnosis, we used the typical age of entering puberty as the cut-off point. Accordingly, the boys were divided into two subgroups, ≤ 11 or > 11 years; and the girls, ≤ 10 years or > 10 years.

All the statistical tests were two-sided, and p < 0.05 was considered statistically significant. Statistical analysis was performed with R version 4.3.0 (R Foundation for Statistical Computing).

Ethical Considerations

The Institutional Review Board of Meuhedet Health Services (number 01-10.06.20) approved the study protocol. Informed consent was waived due to de-identification of the data.

Study population

A total of 1049 children diagnosed with DM met the study criteria. The comparison group included 5245 matched children who were not diagnosed with DM before or during the follow-up period. Sociodemographic characteristics and clinical data of the two groups are presented in Table 1. The median age at DM diagnosis was 11.4 years (IQR 7.8–13.8) in males and 10.3 years (IQR 7.4–13.0) in females. The median follow-up period was 5.48 years (IQR 3.55–8.17). The mean 25-OH-vitD values were 18.5 ± 7.2 ng/ml (n = 565) and 18.3 ± 8.0 ng/ml (n = 1,408), for the DM and comparison groups, respectively (p = 0.7).

Table 1

Characteristics of children with diabetes mellitus and a matched comparison group
	Diabetes group (n = 1,049)	Comparison group (n = 5,245)	p-value
Sex			1
Female	500 (47.7%)	2500 (47.7%)
Male	549 (52.3%)	2745 (52.3%)
Socioeconomic status			1
Low	222 (22.7%)	1110 (22.7%)
Medium	523 (53.5%)	2615 (53.5%)
High	232 (23.7%)	1160 (23.7%)
Sector			1
Jewish general population	589 (56.1%)	2945 (56.1%)
Ultra-orthodox Jews	277 (26.4%)	1385 (26.4%)
Arabs	183 (17.4%)	915 (17.4%)
Age at diabetes diagnosis, y	10.9 (7.5–13.4)
HbA1c at diagnosis, mg%	9.7 (8.1–11.7)
HbA1c during the follow up, mg%	8.3 ± 1.6
Celiac disease	126 (12.0%)	112 (2.1%)	< 0.001
Thyroid disorder	108 (10.3%)	144 (2.7%)	< 0.001
Median length of follow-up, years	5.48 (3.5–8.2)	5.48 (3.5–8.2)	1
Total follow up, patient-years	6,342	31,710
Continuous data are presented as medians (interquartile ranges) or means ± standard deviations. Categorical data are presented as numbers and percentages of the groups.

Fracture incidence rates

In the DM group, 178 (17%) had at least one fracture, as did 792 (15%) in the comparison group (p = 0.14). In the respective groups, 249 and 1019 fractures occurred. The respective overall fracture incidence rates were 393 and 321 per 10,000 patient-years (PY). This difference was not statistically significant (incidence rate ratio 1.09 95%CI = 0.94–1.25, p = 0.24).

In a Cox regression analysis that controlled for patient sex, population sector, age at the index date, and a comorbidity with celiac or thyroid disease, the adjusted HR for fractures among children with DM compared to those without DM was 1.1 (95%CI 0.93–1.31, p = 0.25). Figure 1 presents in both groups, the cumulative incidence curves of the incidence of fractures from the index date.

Fracture risk according to sex and age at diagnosis

Figure 2 presents the results of subgroup analyses for boys according to age at diagnosis of DM. Compared to their matched counterparts, boys diagnosed at age ≤ 11 years had the same risk of fracture (adjusted HR = 1.03, 95%CI 0.79–1.34, p = 0.84); while boys diagnosed at > 11 years had a higher risk (adjusted HR = 1.48, 95%CI 1.09–2.02, p = 0.01). Among the girls, we did not find a significantly increased fracture risk for either age group examined (≤ 10 and > 10 years). the adjusted HRs were 1.32, 95%CI 0.96–1.82 (p = 0.09) among those aged ≤ 10 years at diagnosis and 0.59, 95%CI 0.32–1.07 (p = 0.08) among those aged > 10 years.

Comorbidity with celiac disease

A total of 126 (12%) children were diagnosed with both DM and celiac disease. We did not find an increased fracture risk among these children compared to children without either of these diseases (HR-1.37, 95%CI 0.95–1.99, p = 0.10).

Fracture site

Table 2 presents the sites of first fractures for children with DM and the comparison group. The most common site was the upper limb in both groups (66.3% and 67.9% of the fractures, respectively). We did not find significant differences between the groups regarding fracture sites.

Table 2

First facture sites of children with diabetes mellitus and a matched comparison group
	Diabetes group (n = 178)	Comparison group (n = 792)
Upper limb
carpal	9 (5.1)	31 (3.9)
metacarpal	11 (6.2)	28 (3.5)
phalanges	37 (20.8)	163 (20.6)
radius/ulna	52 (29.2)	256 (32.3)
humerus	6 (3.4)	42 (5.3)
upper limb NOS	3 (1.7)	19 (2.4)
Lower limb
tarsal/metatarsal	20 (11.2)	48 (6.1)
phalanges	8 (4.5)	34 (4.3)
tibia/fibula	14 (7.9)	69 (8.7)
femur	1 (0.6)	5 (0.6)
patella	1 (0.6)	2 (0.2)
lower limb NOS	0 (0.0)	1 (0.1)
Face and skull
face bone	2 (1.1)	31 (3.9)
skull	0 (0.0)	0 (0.0)
Trunk
clavicle	1 (0.6)	14 (1.8)
pelvis	0 (0.0)	1 (0.1)
rib	0 (0.0)	1 (0.1)
scapula	1 (0.6)	1 (0.1)
vertebra	0 (0.0)	3 (0.4)
Other NOS	12 (6.7)	43 (5.4)
The data are presented as numbers (percentages of the total group).
n, number of first fractures; NOS, not otherwise specified

Variables associated with fractures in the DM group

In the multivariable analysis of the DM group (Table 3), we adjusted for the following variables: patient sex, population sector, age at the index date, recurrent hospitalization and comorbidity with celiac or thyroid disease. Male gender (adjusted HR = 1.99, 95% CI 1.46–2.73, p < 0.001) and recurrent hospitalizations (adjusted HR = 1.53, 95% CI 1.02–2.30, p = 0.04) were associated with increased risks for fractures. We did not find an association of HbA1C levels or of 25OH-vitD with fractures; however, data regarding these parameters were incomplete.

Table 3

Crude and adjusted hazard ratios, obtained from univariate and multivariable analyses, respectively, of parameters associated with fractures in children diagnosed with diabetes mellitus
	Crude HR (95%CI)	p	Adjusted HR (95%CI)	p
Age at diagnosis (for each additional year)	0.99 (0.95–1.04)	0.74	1.00 (0.96–1.05)	0.97
Sex: Female	Ref		Ref
Male	2.06 (1.51–2.81)	< 0.001	1.99 (1.46–2.73)	< 0.001
Sector: General Jewish	Ref		Ref
Ultra-orthodox Jews	1.01 (0.71–1.43)	0.96	0.96 (0.68–1.37)	0.83
Arabs	1.04 (0.69–1.57)	0.86	1.01 (0.66–1.53)	0.98
Celiac disease	1.23 (0.82–1.83)	0.32	1.20 (0.80–1.80)	0.38
Thyroid disease	0.52 (0.28–0.96)	0.04	0.63 (0.34–1.17)	0.14
Recurrent hospitalizations	1.54 (1.03–2.29)	0.03	1.53 (1.02–2.30)	0.04
All the variables were included in the multivariable analysis. HR-hazard ratio, CI-confidence interval

Among paediatric patients with DM followed for 5.5 years after the diagnosis of DM, we did not find a statistically significant risk of fractures compared to a large comparison group. However, among the boys diagnosed with DM during pubertal years, the risk was 1.5-fold greater than that of a matched group.

We report an adjusted HR for fractures among children with DM of 1.1 (95% CI 0.93–1.31). Though this result was not statistically significant, the trend was similar to the finding of the THIN study, which included 5,195 patients with T1D aged 0–19 years, and a comparison group in a ratio of 1:10. The adjusted HR for any fracture during childhood was 1.14 in males with T1D compared to the matched group, and 1.35 in females [8]. This finding and the finding of our study differ considerably from reports of a 2-6-fold increased fracture risk in adults with T1D [3, 10]. One line of explanation may be that most fractures during childhood occur during physical activity, especially in high-risk sports like snowboarding or soccer [20, 21]. Notably, children with T1D were reported to perform less vigorous physical activity that increases the risk of trauma and fractures than their healthy peers [22]. Moreover, in adults, fracture risk reflects a combination of increased bone fragility and increased risk of falls. The latter may be related to microvascular complications: peripheral and autonomous neuropathy, retinopathy and orthostatic hypotension [12]. Obviously, significant microvascular complications that may affect the risk of falls are less common during childhood.

Interestingly, we found a 1.5-fold increased fracture risk among boys who were diagnosed with DM during pubertal years compared to the matched group. This novel finding may reflect an effect of diagnosing DM during adolescence, which is a vulnerable period for fractures, especially in boys [23, 24]. The unique characteristics of the rapid growth of the long bones in adolescents pose a risk for fractures, as demonstrated in our previous study [19]. In individuals with T1D, deficits in BMD may develop early in the disease course [25]. In a prospective study, Weber et al. described deficits in BMD at the time of T1D diagnosis, suggestive that the negative effect on bone health begins in the pre-diabetes stage of the disease [25]. The authors also reported low bone accrual during the first year following diagnosis among those with poor glycemic control [25]. The combination of bone fragility during the pubertal spurt and the findings of the study by Weber et al. may explain our finding of increased fracture risk among boys diagnosed with DM during puberty. Among girls with DM, we did not find an increased fracture risk for either age group examined (≤ 10 and > 10 years).

We report similar fracture sites in the DM and the comparison groups; the most common site was the upper limb (about two thirds of the fractures). This corroborates another study that evaluated bone fractures in children [11].

For the DM group of our cohort, we found that male gender and recurrent hospitalizations were associated with increased risks of fractures. Several studies tried to identify risk factors for fractures among individuals with TID, with inconsistent results. Poor glycemic control [8, 12, 26, 27], the presence of diabetes-related complications [8] and hypoglycemia [28] were identified in some, but not all, studies as contributing to fracture risk. In the THIN study [8], each 1% increase in the average HbA1c level was associated with a 5% greater risk of fracture in males and an 11% greater risk in females. Diabetic neuropathy was a significant risk factor in males (HR 1.33, 95% CI 1.03–1.72) and females (HR 1.52, 95% CI 1.19–1.92). Diabetic retinopathy was significant only in males (HR 1.13, 95% CI 1.01–1.28) [8].

We found a trend of increased fracture risk among children with comorbidity of both DM and celiac disease. Celiac disease is known to increase bone fragility [29]; however, the risk of the comorbidity of T1D and celiac is still controversial. In a population-based study that included 4598 individuals with T1D and 958 with T1D and celiac disease, having celiac disease did not affect the fracture risk [30]. By contrast, Eckert et al showed an increased fracture risk among children and young adults with T1D and celiac disease, especially among prepubertal children. In the THIN study, the comorbidity of celiac disease was a significant risk factor in females (HR 1.80, 95% CI 1.18–2.76), but not in males [8].

Strengths and limitations

The main strengths of this study were the sole focus on the age group of the paediatric population and the inclusion of a matched comparison group without diabetes. The DM and the comparison groups were matched by several factors that may affect the incidence of fractures. To the best of our knowledge, a similar study design was not previously reported. Last, the database afforded including the majority of fractures, as its comprehensive medical data comprise primary care visits, community-based emergency services and hospitalizations.

The limitations of the study include the mixed population of various types of diabetes. However, as detailed above, about 95% of the cohort likely had T1D [17, 18]. As a smaller risk of fractures has been reported for T2D than T1D, the inclusion of only patients with T1D would probably strengthen the results. Another limitation is the relatively small cohort, which limited the power of this study. Lastly, our database did not include complete laboratory results and data regarding medications provided along the entire 20 years of the study period.

In conclusion, our study showed an increased fracture risk among boys who were diagnosed with diabetes during their pubertal years. Further research is needed to support our results, calculate the risk in larger cohorts, elucidate the mechanism of bone fragility and identify risk factors for fractures in the paediatric DM population. This may promote developing guidance for prevention and treatment of fragility fractures in this population.

BMD-bone mineral density, CI-confidence interval, DM-diabetes mellitus, HR-hazard ratio, ICD-9-International Classification of Diseases, Ninth Revision, IQR-interquartile range, PY-patient-year, SES-socioeconomic status, T1D-type 1 diabetes, T2D-type 2 diabetes.

Author Contributions: GZ, HG and YLS: conception and design of the study, acquisition of data. GZ and YLS: analysis and interpretation of data and drafting the initial manuscript and editing it. All the authors reviewed the manuscript, revised it and approvedthe final manuscript as submitted.

Funding: No specific fund supports the current study.

Competing Interests: The authors have no competing interests to disclose.

Data Availability Statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Meuhedet Health Services (number 01-10.06.20). Because there was no identification of subjects for whom data were retrieved, informed consent was waived.

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No competing interests reported.

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Fractures in children and adolescents with diabetes mellitus during 2001-2020

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Abstract

Figures

What is known

Introduction

Methods

Study design and data source

Study population and diagnosis of DM

Clinical and demographic data

Laboratory results

Diagnosis of fracture

Statistical analysis

Ethical Considerations

Results

Study population

Fracture incidence rates

Fracture risk according to sex and age at diagnosis

Comorbidity with celiac disease

Fracture site

Variables associated with fractures in the DM group

Discussion

Strengths and limitations

Abbreviations

Declarations

References

Additional Declarations

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