BON-10717; No. of pages: 5; 4C: Bone xxx (2015) xxx–xxx
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Original Full Length Article
Bone status of Indian children and adolescents with type 1 diabetes mellitus Lavanya S. Parthasarathy a, Vaman V. Khadilkar a, Shashi A. Chiplonkar a, M. Zulf Mughal b, Anuradha V. Khadilkar a,⁎ a b
Growth and Endocrine Unit, Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, India Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK
a r t i c l e
i n f o
Article history: Received 20 February 2015 Revised 20 April 2015 Accepted 29 April 2015 Available online xxxx Keywords: Bone density IGF1 Type 1 diabetes Children
a b s t r a c t Objective: Low bone mineral density has been reported in children and adolescents with type 1 diabetes (T1DM). The aims of this cross-sectional study were to study growth, serum IGF1 concentrations and bone health parameters assessed by Dual Energy X-ray Absorptiometry (DXA). Methods: Height was measured and converted to Z scores (HAZ). Serum IGF1 concentrations were measured (ELISA) in a subset. Bone mineral content for total body (less head) (TBBMC) and lumbar spine was measured (n = 170, 77 boys, 6–16 years old) and converted to Z scores using local normative data. Result: Mean age was 11.1 ± 3.8 years, disease duration was 2.2 ± 2.5 years and HbA1C was 10.1 ± 1.8%. Diabetic children were shorter than reference population (HAZ −0.6 ± 1.1); Z scores for height and total body bone area (TBBA) for height were b−2SD in 12% & 6% respectively. Serum IGF1 Z scores were lower amongst group with longer disease duration (−1.58 ± 1.3 vs −2.63 ± 0.7; P = 0.037). Disease duration (β = −0.180, P = 0.000) and metabolic control (HbA1C; β = −0.096, P = 0.042) were negative predictors of HAZ and TBBA for height Z in younger children. Using the Molgaard approach, children with longer disease duration had lower HAZ (− 0.31 ± 0.92 vs − 1.28 ± 1.11; P = 0.000; “short bones”) and TBBA for height Z scores (0.12 ± 1.62 vs −0.53 ± 0.94; P = 0.044; “slender bones”). Older children (tanner stages 4 and 5) had lower BMC and BA as compared to reference population possibly due to delayed growth spurt. Conclusion: Longer duration of diabetes was associated with shorter and slender but appropriately mineralized bones. Small and slender bones in diabetic children may increase risk of fragility fractures in the future. This article is part of a Special Issue entitled “Bone and diabetes”. © 2015 Published by Elsevier Inc.
Introduction A number of studies have shown that the bone mineral density (BMD) as measured by dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) is impaired in children with diabetes [1–3]. However, longitudinal studies performed using a pQCT indicate that there is an improvement in bone mineralization over time [4]. The changes in the bone mineral density in diabetes are caused by a number of factors such as hypoinsulinemia, deteriorating renal function, increased production of advanced glycation end products, low peak bone mass and increased production of inflammatory cytokines [5]. The increased urinary calcium excretion linked to
⁎ Corresponding author at: Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, 32 Sassoon Road, Pune 411 001, India. Fax: +91 20 26141340. E-mail addresses: [email protected] (L.S. Parthasarathy), [email protected] (V.V. Khadilkar), [email protected] (S.A. Chiplonkar), [email protected] (M. Zulf Mughal), [email protected] (A.V. Khadilkar).
hyperglycemia leads to a negative calcium balance [6], alterations in vitamin D metabolism [7], and low insulin like growth factors [8], which lead to impaired growth of bone. Amongst other osteoporotic factors in T1DM is the absence of amylin (a 37 amino acid peptide), that is co-secreted by pancreatic cells [9]. Administration of amylin in a previous study to streptozotocin induced diabetic rats has helped in maintaining bone mass, inhibiting biochemical markers of bone resorption, and elevation of biochemical markers of bone formation [10]. Impaired growth and mineralization in the long run may increase the risk of fractures. There are a number of studies which have reported increased risk of hip fractures in adults with type 1 diabetes [11–14]. Intensive insulin treatment regimens and monitoring of the disease with multiple daily blood sugar testing is prohibitively expensive for many families in India [15,16]. Hence, optimum control of diabetes is often difficult to achieve in these patients. Lettgen et al. and Heilman et al. have reported a relationship between low bone mineral density and higher HBA1C concentrations in diabetic children and adolescents [3,17]. Disease duration is another important factor discussed in previous studies affecting bone status in children with diabetes [17]. As we
http://dx.doi.org/10.1016/j.bone.2015.04.050 8756-3282/© 2015 Published by Elsevier Inc.
Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
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have previously reported, disease duration also negatively affects growth amongst diabetic children. For children diagnosed with diabetes at less than 5 years of age, a greater loss of height is seen during puberty. Chronic disease affecting bone mineralization often affects body and bone size as well. Reduced height for age and reduced bone area for height will result in short and narrow bones as assessed by dual energy X-ray absorptiometry (DXA) using the method of Molgaard et al. [18]. Taken together, poor metabolic control and disease duration may have a detrimental effect on bone growth and mineralization in children and adolescents with diabetes. The growth hormone (GH)/IGF axis is a major determinant of bone mass acquisition. Circulating IGF-1 is produced by the liver, is structurally similar to insulin and helps to mediate the skeletal growth promoting actions of GH [8]. Reports suggest that poor metabolic control may alter the GH/IGF-1 axis, and lead to alterations in bone size and density in patients with T1DM. Thus, our aims were to cross-sectionally study growth, serum IGF1 concentrations and bone health parameters as assessed by DXA in 6–16 year old Indian children and adolescents with type 1 diabetes mellitus attending a specialty out-patient tertiary care clinic in Pune, India. We hypothesized that height and DXA measured bone size and bone mineral density parameters would be impaired in children with type 1 diabetes, when compared with contemporary reference population. Methods Parents and children with diabetes aged 6 to 16 years attending the diabetes clinic at a tertiary care hospital in Pune, India were approached to take part in this cross sectional study. Out of 192 patients approached, 170 agreed to take part in the study. The study was approved by the institutional ethics Committee. Parents provided written informed consent and children gave assent for the study. For illiterate parents the information was read out to them either in Marathi or Hindi. If they agreed to take part in the study, then their signature or thumbprint was witnessed by an independent witness, usually one of the senior staff unrelated to the study, from the hospital. This study was conducted between Nov 2011 and March 2014. Patients on any other medication but insulin for blood glucose control, with known comorbidities such as celiac disease, untreated hypothyroidism and eating disorders or with any other chronic disorder were excluded from the study. In total 3 children were excluded; 2 with celiac disease and one with polyendocrinopathy. Tanner staging for sexual maturity was performed by a pediatric endocrinologist [19,20]. Data on duration of diabetes, current medications, family and personal medical history, history of fractures, age at onset of diabetes, duration of diabetes and insulin regimen were collected using standardized questionnaires. History of fractures including age at fracture, site, and cause was cross checked from patient records. Medical history provided by parents was verified from hospital medical records. Anthropometry Standing height was measured to the nearest millimeter using a portable stadiometer (Leicester Height Meter, Child Growth Foundation, UK), and weight was measured using an electronic scale to the nearest 100 g. Body mass index (BMI) was calculated by the formula weight/ height in meter square. The height, weight and BMI were converted to Z scores [21]. Biochemical measurements Control of blood sugar was evaluated by measuring glycosylated hemoglobin (HbA1C). A fasting blood sample (5 ml) was collected between 7 and 9 am by a trained pediatric nurse. HbA1C was measured by HPLC (BIO-RAD, Germany). Serum IGF1 concentrations were
measured in a subset of children (n = 54) by Enzyme Linked Immunosorbent Assay (Thermo Scientific Multiskan EX reader). The serum IGF1 concentrations were then converted to Z scores using available Asian reference data [22]. DXA measurements The GE-Lunar DPX Pro (GE Healthcare, Wisconsin, USA) Pencil Beam DXA scanner (software version encore 2005, 9.30.044) was used to measure bone mineral content (BMC [g]), bone area (BA [cm2]) for total body (less head) and lumbar spine in 170 children with T1DM. While measuring the lumbar spine, the child was supine, and the physiological lumbar lordosis was flattened by elevation of the knees. For body composition variables, technique precision was 12.5 g for TBBMC (0.98% cv), 13.8 cm2 for TBBA (1.13% cv) and 166.8 g for lean body mass (0.74% cv). For LSBMC, technique precision was 0.50 g (2.04% cv) while for LSBA it was 0.80 cm2 (2.74% cv). Z scores for TBBMC for bone area (TBBA), TBBA for height, lean body mass (LBM) for height, TBBMC for LBM and lumbar spine bone mineral apparent density (LSBMAD) were computed using ethnic specific reference data [23]. Statistical analysis All statistical analyses were carried out using the SPSS for Windows software program, version 12 (SPSS, Chicago, IL, USA). All outcome variables were tested for normality before performing statistical analyses. Differences in means were tested using Student's t test. One way ANOVA with post hoc Tukey's test was used to compare the means between groups according to disease duration. Linear regression was used to identify factors affecting HAZ and TBBA for height Z scores. A p value of b0.05 was considered significant. In order to interrogate the effect of diabetes on bone size (whether it was caused by both short and or slender bones) and mineralization we used the method of Molgaard et al. [18]. In order to look at the effect of diabetes on LBM and whether this affected the bone mineralization we used the method of Crabtree et al. [24]. Results Mean age of the study group was 11.1 ± 3.8 years. There were no significant differences in the anthropometric parameters or Z scores calculated for height, weight and BMI between the genders except for height (Table 1). However, diabetic children were shorter and lighter as compared to the reference population (HAZ − 0.6 ± 1.1, WAZ −0.6 ± 1.0). The mean HbA1C was 10.1 ± 1.8% indicating suboptimal metabolic control. Bone and body composition parameters are illustrated in Table 2; both boys and girls had mean values within the reference range. Boys had significantly higher TBBMC for TBBA Z scores as compared to girls (0.2 ± 1.1 vs −0.2 ± 1.0, p b 0.05). Twelve percent children had their HAZ scores less than − 2 and 22% had scores less than − 1. For TBBA for height Z scores 6% children had scores less than −2 and 18% children had scores less than −1. Using linear regression, predictors for both these parameters were assessed. Disease
Table 1 Anthropometric characteristics in boys and girls. Parameters
Boys (77)
Girls (93)
P value
Age (year) Height (cm)a Weight (kg) BMI (kg/m2) Height Z score Weight Z score BMI Z score HbA1C (%)
11.4 ± 3.6 140.4 ± 20.0 34.9 ± 14.5 16.7 ± 3.1 −0.6 ± 1.2 −0.6 ± 1.0 −0.4 ± 0.9 10.3 ± 2.5
10.8 ± 3.9 133.8 ± 18.0 31.7 ± 13.1 16.5 ± 3.6 −0.6 ± 1.0 −0.5 ± 1.0 −0.3 ± 0.9 10.1 ± 1.8
0.314 0.026 0.130 0.740 0.963 0.538 0.477 0.717
a
Mean significantly different between genders, P b 0.05.
Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
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Table 2 Body composition and bone parameters in boys and girls.
Parameters Lean mass (g)a Bone mineral content (g)a Fat %a LSBMAD Z scores Assessment of bone health using the Molgaard et al. method Height Z score (Do these patients have short bones?) TBBA for height Z scores (Do these patients have slender bones?) TBBMC for TBBA Z scoresa (Do these patients have under mineralized bones or light bones?) Assessment of bone health using the Crabtree et al. method LBM for height Z scores TBBMC for LBM Z scores a
Table 3 Bone parameters according to disease duration tertiles (n = 54).
Height Z score TBBA_FOR_HEIGHT TBBMC_FOR_TBBA TBBMC_FOR_LBM LBM_FOR_HEIGHT LSBMAD b
Girls
P value
25285 ± 9154 1250.0 ± 519.1 19.3 ± 8.4 0.0 ± 1.1
20540 ± 6490 1091.5 ± 497.2 26.9 ± 10.5 0.0 ± 1.0
0.0001 0.049 0.000 0.926
−0.6 ± 1.2
−0.6 ± 1.0
0.963
−0.2 ± 1.2
−0.2 ± 1.3
0.650
0.2 ± 1.1
−0.2 ± 1.0
0.010
0.1 ± 1.1 −0.2 ± 1.1
0.1 ± 1.2 −0.5 ± 1.0
0.997 0.165
Mean significantly different between genders, P b 0.05.
duration (β = −0.180, P = 0.000) and metabolic control (β = −0.096, P = 0.042) were identified as significant negative predictors of HAZ. Also for TBBA for height Z scores, disease duration (β = −0.146, P = 0.028) and metabolic control (β = −0.150, P = 0.048) were identified as significant negative predictors in younger children (tanner stages 1, 2 and 3). Only 5 children had suffered fractures; two occurred before the diagnosis of diabetes. Those who reported fractures had suffered falls or injuries while playing sports and all three were forearm fractures. To further analyze the effect of disease duration on bone status, the group was divided according to tertiles of disease duration; duration b6 months, duration between 6 months and 2.5 years and duration N2.5 years (Table 3/Fig. 1). Using the Molgaard et al. approach [18], children with longer duration of diabetes had significantly lower height for age Z scores (− 0.31 ± 0.92 vs − 1.28 ± 1.11; P = 0.000, short bones) and bone area for height Z scores (0.12 ± 1.62 vs − 0.53 ± 0.94; P = 0.044, slender bones). However, the TBBMC for TBBA Z scores were not significantly affected by duration of diabetes (−0.12 ± 1.17 vs 0.21 ± 1.32; P N 0.05). The serum IGF1 Z scores were also the least amongst the group with the longest disease duration (− 1.6 ± 1.3 vs − 2.6 ± 0.7; P b 0.05) (Fig. 2). Thus, disease duration was associated with shorter and slender bones but not light or under mineralized bones. Furthermore, using the Crabtree et al. model [24] we did not observe a relationship between disease duration and LBM for height (0.17 ± 1.32 vs 0.07 ± 0.90, P = 0.865) or TBBMC for LBM (− 0.22 ± 1.15 vs − 0.42 ± 1.16, P = 0.633). Taken together our results suggest that disease duration seems to affect skeletal growth parameters but not lean body mass or skeletal mineralization. To study the effect of puberty on TBBMC and TBBA, comparisons between diabetic children and reference data were made across different pubertal stages. Both parameters for the first 3 tanner stages in boys and girls were comparable to the reference population but there was a dip seen in tanner stages 4 and 5 possibly due to delayed growth spurt. In
a
Boys
Duration b6 months
Duration 6 months– 2.5 years
−0.31 ± 0.92a 0.12 ± 1.62a −0.12 ± 1.17 −0.22 ± 1.16 0.17 ± 1.33 0.08 ± 1.01
−0.54 ± 0.97b −0.44 ± 1.07 0 ± 0.87 −0.44 ± 0.94 0.04 ± 1.16 −0.02 ± 1.05
advanced stages of puberty when TBBMC and TBBA were compared to reference population, we observed that the increment in bone size seemed to deviate from the reference population but the BMC contained within the BA was within the reference range (Figs. 3, 4). Discussion Our cross sectional data show that Indian children and adolescents with type 1 diabetes are shorter as compared to reference population and have short and narrow bones with increasing duration of diabetes, particularly in younger children. During later stages of puberty, bone area was lower than that of the reference population; however, bones were adequately mineralized. Lean body mass (surrogate measure of muscle mass) for height and TBBMC for LBM were not affected. However, bone mineralization appears to be normal for the bone size. There is a gender difference seen in TBBMC for TBBA Z scores which cannot be explained by factors such as age, metabolic control or disease duration. Delayed puberty in children with diabetes has been debated and reports suggest that though the chronological age at onset of puberty and the duration of the pubertal growth spurt are not significantly different between diabetic and healthy adolescents, diabetic adolescents have a blunted pubertal growth spurt which seems to be associated with a reduced peak height velocity [25]. Though we do not have data on the growth spurt, it is likely that the lower bone area seen in diabetic children in later tanner stages was as a result of a delayed spurt. Besides bone mineral density, the size of a bone is an important factor determining its strength, especially in tubular bones. Thus, shorter and slender bones of younger children with longer diabetes duration may be associated with reduced bone strength. Our data are in keeping with findings of Kawashima et al., [26] who have reported that in mice, during childhood and adolescence, hyperglycemia leads to slender adult bones, resulting in reduced bone strength and reduced fracture resistance. Further support for our findings comes from the study by Bechtold et al., who used a peripheral quantitative computed Duration< 6 months
Duration 6mo-2.5 yrs
Duration > 2.5 yrs
0.4
Duration N2.5 years −1.28 ± 1.11 −0.53 ± 0.94 0.21 ± 1.32 −0.42 ± 1.16 0.08 ± 0.91 −0.35 ± 1.1
Significant difference between b6 months and N2.5 years (P b 0.05). Significant difference between 6 months–2.5 years and N2.5 years (P b 0.05).
0.2 0 -0.2 -0.4 -0.6 -0.8 -1 -1.2 -1.4
Fig. 1. Bone parameters according to disease duration (n = 54).
Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
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IGF1 Z Scores
0 -0.5
Duration< 6 months Duration 6mo-2.5 yrs
It is well established that the development of a functional musculoskeletal system requires muscle forces. The loading regulates the shape and density of developing bones, as well as the size [28]. Since muscle and bone are closely functionally linked, it is recommended that the diagnostic evaluation of bone parameters should always include an assessment of the musculature. Thus we analyzed the lean mass in our diabetic children [29]. However, the lean body mass measured by DXA is a surrogate for the muscle mass. Using the Crabtree et al. [24] model we have demonstrated that the lean body mass was not affected in these children. The LBM for the given height seems to be normal, but there is a decrease in height itself. Hence, studying the muscle cross section area using pQCT studies is important. In a study by Bechtold et al. in Germany, authors report that prepubertal children with early manifestation of disease had a lower muscle cross sectional area at the diaphyseal site [1]. Though children in our study seem to have normal LBM, this may be due to different measurement techniques. The results of our study need to be confirmed using a pQCT. The effect of IGF1 on bone and growth has been described previously by Moyer-Mileur et al. [8]. They have reported that poor metabolic control predicted alterations in the GH/IGF-1 axis. In their study, lower IGF-1 and greater IGFBP-1 and -5 relative to IGF-1 levels were predicted by poor metabolic control, whereas, a higher IGFBP-1/IGF-1 ratio was predictive of smaller, less mineralized bones. We did not measure the IGF binding proteins in our children but with increasing duration of diabetes, lower IGF1 Z scores were recorded. As reported by our previous study and studies conducted by others, Indian children with diabetes are shorter as compared to their peers [16]. Also, in a longitudinal study conducted by us previously, we have reported that duration of diabetes negatively affects height velocity amongst diabetic children [30]. In children who have been diagnosed with diabetes at less than 5 years of age, a greater loss of height is seen during puberty. This supports our results of narrowing of bones in children with longer disease duration due to loss of height. Hence, there are changes in children and adolescents with diabetes from childhood that may increase the propensity of fractures in adulthood. As seen in our study the changes are related to diabetes affecting the growth amongst these children which in turn has led to shorter and slender bones. The neck of the femur being a tubular bone is at a higher risk of fracture if the bones remain short and slender. The increased risk of fractures in adults seems to be associated with the changes in bone size and geometry due to reduced growth during childhood rather than bone density. Data on final height or onset of puberty were not available as our data are cross sectional and hence the effect of delayed pubertal growth spurt on bone parameters could not be assessed. Further, normalization of bone parameters with age has been reported by Bechtold et al. [4], we need well designed longitudinal studies to confirm our results. Studies previously done have reported that the total CSA, cortical CSA, and muscle CSA are significantly reduced amongst diabetic children as compared to reference population. Hence, studies done using the peripheral
Duration > 2.5 yrs
-1 -1.5 -2 -2.5 -3
Fig. 2. Serum IGF1 (according to disease duration tertiles, n = 54).
tomography scanner to study the bone size and mineralization parameters at the radius in children with type 1 diabetes mellitus. These investigators reported that the total cross sectional area, cortical cross sectional area and muscle cross sectional area at the radius were significantly lower in diabetic children with early manifestation of the disease [1]. The muscle cross sectional area is a surrogate measure of muscle mass on pQCT scanner, thus, the results of Bechtold et al. may differ from our DXA measured changes i.e., the LBM for height Z scores was not different in children with different disease durations. The metabolic control in our children was less optimal than in their study, but papers reporting poor metabolic control as ours and bone parameters, are, to the best of our knowledge, not available. Hence, comparisons have been made with the available data. If our and other's finding of ‘slender bones’ persist then it is possible that children with longer diabetes duration and sub-optimal metabolic control may have increased propensity to long bone fractures. There is a very high incidence of hip fractures reported in various cohorts of adults with type 1 diabetes. These studies have reported a 3 to 12% increase in risk amongst older diabetics for hip fractures [11–14]. The IOWA study with the largest cohort of postmenopausal women has reported that women with type 1 diabetes were 12 times more likely to report an incident of hip fracture than women without diabetes [11]. Another large population based study from Sweden has reported that the incidence of hip fractures before age 30 amongst diabetics was almost negligible but increased quickly thereafter and that as many as 1 in 15 patients with type 1 diabetes may sustain a hip fracture before the age of 65 [12]. The nurses' health study and a study from Scotland have also demonstrated a similar increase in risk of hip fractures amongst type 1 diabetics [13,14]. Children from our study have not reported fractures but the literature reports a high incidence of hip fractures amongst adults. A study recently conducted in Belarus amongst type 1 diabetic patients between 20–55 years of age has also reported higher vertebral fractures independent of BMD [27]. The LSBMAD scores of our children as a group were normal, however, when looked at across disease duration there is a trend seen across the disease duration groups. Thus, with increasing duration of diabetes, the group may show a decline in the BMAD scores and put them at risk of vertebral fractures too.
Reference Data
DM
Reference Data
DM
2000
2000
BMC (gm)
BMC (gm)
2500
1500 1000 500
1500
1000
500 1
2
3 Tanner Stage
3.1 Boys
4
5
1
2
3 Tanner stage
4
5
3.2 Girls
Fig. 3. Comparison of total body bone mineral content according to pubertal stages in diabetic children and Indian reference data.
Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
L.S. Parthasarathy et al. / Bone xxx (2015) xxx–xxx
Reference Data
DM
5
Reference Data
DM
2000
2500
BA (cm 2)
BA (cm2 )
2000 1500
1500
1000
1000 500
500 1
2
3
Tanner Stage
4
4.1 Boys
5
1
2
3
4
5
Tanner Stage 4.2 Girls
Fig. 4. Comparison of total body bone area according to pubertal stages in diabetic children as compared to Indian reference data.
quantitative computer tomography (pQCT) are required to study the changes in bone geometry amongst diabetic children [4]. The effects we observed on the bone size are derived from Molgaard et al. method and should be ideally studied using a pQCT. In conclusion, we did not find an effect of diabetes on bone size or mineralization for the whole group, however, longer duration of diabetes was associated with shorter and slender bones, especially in younger children. Children and adolescents in later stages of puberty also had slender bones possibly as a result of a delayed growth spurt. This may have long term implications of increased propensity to fractures. A follow-up study including pQCT for measurement of bone parameters for diaphyseal sites is required to confirm these findings. Author contribution statement Study design was planned by all authors. LP, AK and VK carried out the data collection. SC carried out the statistical analyses. All the authors contributed to the drafts of the manuscript. Disclosure statement The authors have nothing to disclose. Conflict of interest None. Acknowledgments Our sincere thanks to Mr. Pancharatnam for funding this project. The authors also acknowledge funding from the University Grants Commission (UGC), Government of India (UGC-Ref. No.: 1486/(NETDEC. 2010)), to the first author. References [1] Bechtold S, Dirlenbach I, Raile K, Noelle V, Bonfig W, Schwarz HP. Early manifestation of type 1 diabetes in children is a risk factor for changed bone geometry: data using peripheral quantitative computed tomography. Pediatrics 2006 Sep;118:627–34. [2] Moyer-Mileur LJ, Dixon SB, Quick JL, Askew EW, Murray MA. Bone mineral acquisition in adolescents with type 1 diabetes. J Pediatr 2004 Nov;145:662–9. [3] Heilman K, Zilmer M, Zilmer K, Tillmann V. Lower bone mineral density in children with type 1 diabetes is associated with poor glycemic control and higher serum ICAM-1 and urinary isoprostane levels. J Bone Miner Metab 2009;27:598–604. [4] Bechtold S, Putzker S, Bonfig W, Fuchs O, Dirlenbach I, Schwarz HP. Bone size normalizes with age in children and adolescents with type 1 diabetes. Diabetes Care 2007;30:2046–50. [5] Botushanov NP, Orbetzova MM. Bone mineral density and fracture risk in patients with type 1 and type 2 diabetes mellitus. Folia Med (Plovdiv) Oct–Dec 2009; 51(4):12–7. [6] Zeiton AAH, El-Ela AA. Calcium homeostasis in children with type I diabetes mellitus. Suez Canal Univ Med J 1999;2:47–59.
[7] Thrailkill KM, Jo CH, Cockrell GE, Moreau CS, Fowlkes JL. Enhanced excretion of vitamin D binding protein in type 1 diabetes: a role in vitamin D deficiency? J Clin Endocrinol Metab 2011;96:142–9. [8] Moyer-Mileur LJ, Slater H, Jordan KC, Murray MA. IGF-1 and IGF-binding proteins and bone mass, geometry, and strength: relation to metabolic control in adolescent girls with type 1 diabetes. J Bone Miner Res 2008;23:1884–91. [9] Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabetes mellitus. J Bone Miner Res 2007 Sep;22(9):1317–28. [10] Horcajada-Molteni MN, Chanteranne B, Lebecque P, Davicco MJ, Coxam V, Young A, et al. Amylin and bone metabolism in streptozotocin-induced diabetic rats. J Bone Miner Res 2001 May;16(5):958–65. [11] Nicodemus KK, Folsom AR. Iowa Women's Health Study. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 2001;24: 1192–7. [12] Miao J, Brismar K, Nyrén O, Ugarph-Morawski A, Ye W. Elevated hip fracture risk in type 1 diabetic patients: a population-based cohort study in Sweden. Diabetes Care 2005;28:2850–5. [13] Janghorbani M, Feskanich D, Willett WC, Hu F. Prospective study of diabetes and risk of hip fracture: the Nurses' Health Study. Diabetes Care 2006;29:1573–8. [14] Hothersall EJ, Livingstone SJ, Looker HC, Ahmed SF, Cleland S, Leese GP, et al. Contemporary risk of hip fracture in type 1 and type 2 diabetes: a national registry study from Scotland. J Bone Miner Res 2014;29:1054–60. [15] Bhatia E, Aggarwal A. Insulin therapy for patients with type 1 diabetes. J Assoc Physicians India 2007;55(Suppl.:29–34):39–40. [16] Khadilkar VV, Parthasarathy LS, Mallade BB, Khadilkar AV, Chiplonkar SA, Borade AB. Growth status of children and adolescents with type 1 diabetes mellitus. Indian J Endocrinol Metab 2013;17:1057–60. [17] Lettgen B, Hauffa B, Möhlmann C, Jeken C, Reiners C. Bone mineral density in children and adolescents with juvenile diabetes: selective measurement of bone mineral density of trabecular and cortical bone using peripheral quantitative computed tomography. Horm Res 1995;43:173–5. [18] Mølgaard C, Thomsen BL, Prentice A, Cole TJ, Michaelsen KF. Whole body bone mineral content in healthy children and adolescents. Arch Dis Child 1997;76:9–15. [19] Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44:291–303. [20] Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13–23. [21] Khadilkar VV, Khadilkar AV, Cole TJ, Sayyad MG. Crosssectional growth curves for height, weight and body mass index for affluent Indian children, 2007. Indian Pediatr 2009;46:477–89. [22] Xu S, Gu X, Pan H, Zhu H, Gong F, Li Y, et al. Reference ranges for serum IGF-1 and IGFBP-3 levels in Chinese children during childhood and adolescence. Endocr J 2010;57:221–8. [23] Khadilkar AV, Sanwalka NJ, Chiplonkar SA, Khadilkar VV, Mughal MZ. Normative data and percentile curves for dual energy X-ray absorptiometry in healthy Indian girls and boys aged 5–17 years. Bone 2011;48:810–9. [24] Crabtree NJ, Kibirige MS, Fordham JN, Banks LM, Muntoni F, Chinn D, et al. The relationship between lean body mass and bone mineral content in paediatric health and disease. Bone 2004;35:965–72. [25] Chiarelli F, Giannini C, Mohn A. Growth, growth factors and diabetes. Eur J Endocrinol Nov 2004;151(Suppl. 3):U109–17. [26] Kawashima Y, Fritton JC, Yakar S, Epstein S, Schaffler MB, Jepsen KJ, et al. Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis. Bone Apr 2009;44(4):648–55. [27] Zhukouskaya VV, Eller-Vainicher C, Vadzianava VV, Shepelkevich AP, Zhurava IV, Korolenko GG, et al. Prevalence of morphometric vertebral fractures in patients with type 1 diabetes. Diabetes Care 2013;36:1635–40. [28] Tatara AM, Lipner JH, Das R, et al. The role of muscle loading on bone (re)modeling at the developing enthesis. In: Heymann D, editor. PLoS ONE, 9(5); 2014. p. e97375. [29] Schönau Eckhard, Fricke Oliver. Muskel und Knochen–eine funktionelle Einheit. Dtsch Arztebl 2006;103(50):3414–9. [30] Khadilkar VV, Khadilkar AV, Parthasarathy LS, Chiplonkar SA, Gupte-Phanse S. Reduced longitudinal growth in Indian children and adolescents with type 1 diabetes. 16th International Congress of Endocrinology. Chicago: Bioscientifica; June 21–24 2014. p. 361.
Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
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Original Full Length Article
Bone status of Indian children and adolescents with type 1 diabetes mellitus Lavanya S. Parthasarathy a, Vaman V. Khadilkar a, Shashi A. Chiplonkar a, M. Zulf Mughal b, Anuradha V. Khadilkar a,⁎ a b
Growth and Endocrine Unit, Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, India Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK
a r t i c l e
i n f o
Article history: Received 20 February 2015 Revised 20 April 2015 Accepted 29 April 2015 Available online xxxx Keywords: Bone density IGF1 Type 1 diabetes Children
a b s t r a c t Objective: Low bone mineral density has been reported in children and adolescents with type 1 diabetes (T1DM). The aims of this cross-sectional study were to study growth, serum IGF1 concentrations and bone health parameters assessed by Dual Energy X-ray Absorptiometry (DXA). Methods: Height was measured and converted to Z scores (HAZ). Serum IGF1 concentrations were measured (ELISA) in a subset. Bone mineral content for total body (less head) (TBBMC) and lumbar spine was measured (n = 170, 77 boys, 6–16 years old) and converted to Z scores using local normative data. Result: Mean age was 11.1 ± 3.8 years, disease duration was 2.2 ± 2.5 years and HbA1C was 10.1 ± 1.8%. Diabetic children were shorter than reference population (HAZ −0.6 ± 1.1); Z scores for height and total body bone area (TBBA) for height were b−2SD in 12% & 6% respectively. Serum IGF1 Z scores were lower amongst group with longer disease duration (−1.58 ± 1.3 vs −2.63 ± 0.7; P = 0.037). Disease duration (β = −0.180, P = 0.000) and metabolic control (HbA1C; β = −0.096, P = 0.042) were negative predictors of HAZ and TBBA for height Z in younger children. Using the Molgaard approach, children with longer disease duration had lower HAZ (− 0.31 ± 0.92 vs − 1.28 ± 1.11; P = 0.000; “short bones”) and TBBA for height Z scores (0.12 ± 1.62 vs −0.53 ± 0.94; P = 0.044; “slender bones”). Older children (tanner stages 4 and 5) had lower BMC and BA as compared to reference population possibly due to delayed growth spurt. Conclusion: Longer duration of diabetes was associated with shorter and slender but appropriately mineralized bones. Small and slender bones in diabetic children may increase risk of fragility fractures in the future. This article is part of a Special Issue entitled “Bone and diabetes”. © 2015 Published by Elsevier Inc.
Introduction A number of studies have shown that the bone mineral density (BMD) as measured by dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) is impaired in children with diabetes [1–3]. However, longitudinal studies performed using a pQCT indicate that there is an improvement in bone mineralization over time [4]. The changes in the bone mineral density in diabetes are caused by a number of factors such as hypoinsulinemia, deteriorating renal function, increased production of advanced glycation end products, low peak bone mass and increased production of inflammatory cytokines [5]. The increased urinary calcium excretion linked to
⁎ Corresponding author at: Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, 32 Sassoon Road, Pune 411 001, India. Fax: +91 20 26141340. E-mail addresses: [email protected] (L.S. Parthasarathy), [email protected] (V.V. Khadilkar), [email protected] (S.A. Chiplonkar), [email protected] (M. Zulf Mughal), [email protected] (A.V. Khadilkar).
hyperglycemia leads to a negative calcium balance [6], alterations in vitamin D metabolism [7], and low insulin like growth factors [8], which lead to impaired growth of bone. Amongst other osteoporotic factors in T1DM is the absence of amylin (a 37 amino acid peptide), that is co-secreted by pancreatic cells [9]. Administration of amylin in a previous study to streptozotocin induced diabetic rats has helped in maintaining bone mass, inhibiting biochemical markers of bone resorption, and elevation of biochemical markers of bone formation [10]. Impaired growth and mineralization in the long run may increase the risk of fractures. There are a number of studies which have reported increased risk of hip fractures in adults with type 1 diabetes [11–14]. Intensive insulin treatment regimens and monitoring of the disease with multiple daily blood sugar testing is prohibitively expensive for many families in India [15,16]. Hence, optimum control of diabetes is often difficult to achieve in these patients. Lettgen et al. and Heilman et al. have reported a relationship between low bone mineral density and higher HBA1C concentrations in diabetic children and adolescents [3,17]. Disease duration is another important factor discussed in previous studies affecting bone status in children with diabetes [17]. As we
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Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
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have previously reported, disease duration also negatively affects growth amongst diabetic children. For children diagnosed with diabetes at less than 5 years of age, a greater loss of height is seen during puberty. Chronic disease affecting bone mineralization often affects body and bone size as well. Reduced height for age and reduced bone area for height will result in short and narrow bones as assessed by dual energy X-ray absorptiometry (DXA) using the method of Molgaard et al. [18]. Taken together, poor metabolic control and disease duration may have a detrimental effect on bone growth and mineralization in children and adolescents with diabetes. The growth hormone (GH)/IGF axis is a major determinant of bone mass acquisition. Circulating IGF-1 is produced by the liver, is structurally similar to insulin and helps to mediate the skeletal growth promoting actions of GH [8]. Reports suggest that poor metabolic control may alter the GH/IGF-1 axis, and lead to alterations in bone size and density in patients with T1DM. Thus, our aims were to cross-sectionally study growth, serum IGF1 concentrations and bone health parameters as assessed by DXA in 6–16 year old Indian children and adolescents with type 1 diabetes mellitus attending a specialty out-patient tertiary care clinic in Pune, India. We hypothesized that height and DXA measured bone size and bone mineral density parameters would be impaired in children with type 1 diabetes, when compared with contemporary reference population. Methods Parents and children with diabetes aged 6 to 16 years attending the diabetes clinic at a tertiary care hospital in Pune, India were approached to take part in this cross sectional study. Out of 192 patients approached, 170 agreed to take part in the study. The study was approved by the institutional ethics Committee. Parents provided written informed consent and children gave assent for the study. For illiterate parents the information was read out to them either in Marathi or Hindi. If they agreed to take part in the study, then their signature or thumbprint was witnessed by an independent witness, usually one of the senior staff unrelated to the study, from the hospital. This study was conducted between Nov 2011 and March 2014. Patients on any other medication but insulin for blood glucose control, with known comorbidities such as celiac disease, untreated hypothyroidism and eating disorders or with any other chronic disorder were excluded from the study. In total 3 children were excluded; 2 with celiac disease and one with polyendocrinopathy. Tanner staging for sexual maturity was performed by a pediatric endocrinologist [19,20]. Data on duration of diabetes, current medications, family and personal medical history, history of fractures, age at onset of diabetes, duration of diabetes and insulin regimen were collected using standardized questionnaires. History of fractures including age at fracture, site, and cause was cross checked from patient records. Medical history provided by parents was verified from hospital medical records. Anthropometry Standing height was measured to the nearest millimeter using a portable stadiometer (Leicester Height Meter, Child Growth Foundation, UK), and weight was measured using an electronic scale to the nearest 100 g. Body mass index (BMI) was calculated by the formula weight/ height in meter square. The height, weight and BMI were converted to Z scores [21]. Biochemical measurements Control of blood sugar was evaluated by measuring glycosylated hemoglobin (HbA1C). A fasting blood sample (5 ml) was collected between 7 and 9 am by a trained pediatric nurse. HbA1C was measured by HPLC (BIO-RAD, Germany). Serum IGF1 concentrations were
measured in a subset of children (n = 54) by Enzyme Linked Immunosorbent Assay (Thermo Scientific Multiskan EX reader). The serum IGF1 concentrations were then converted to Z scores using available Asian reference data [22]. DXA measurements The GE-Lunar DPX Pro (GE Healthcare, Wisconsin, USA) Pencil Beam DXA scanner (software version encore 2005, 9.30.044) was used to measure bone mineral content (BMC [g]), bone area (BA [cm2]) for total body (less head) and lumbar spine in 170 children with T1DM. While measuring the lumbar spine, the child was supine, and the physiological lumbar lordosis was flattened by elevation of the knees. For body composition variables, technique precision was 12.5 g for TBBMC (0.98% cv), 13.8 cm2 for TBBA (1.13% cv) and 166.8 g for lean body mass (0.74% cv). For LSBMC, technique precision was 0.50 g (2.04% cv) while for LSBA it was 0.80 cm2 (2.74% cv). Z scores for TBBMC for bone area (TBBA), TBBA for height, lean body mass (LBM) for height, TBBMC for LBM and lumbar spine bone mineral apparent density (LSBMAD) were computed using ethnic specific reference data [23]. Statistical analysis All statistical analyses were carried out using the SPSS for Windows software program, version 12 (SPSS, Chicago, IL, USA). All outcome variables were tested for normality before performing statistical analyses. Differences in means were tested using Student's t test. One way ANOVA with post hoc Tukey's test was used to compare the means between groups according to disease duration. Linear regression was used to identify factors affecting HAZ and TBBA for height Z scores. A p value of b0.05 was considered significant. In order to interrogate the effect of diabetes on bone size (whether it was caused by both short and or slender bones) and mineralization we used the method of Molgaard et al. [18]. In order to look at the effect of diabetes on LBM and whether this affected the bone mineralization we used the method of Crabtree et al. [24]. Results Mean age of the study group was 11.1 ± 3.8 years. There were no significant differences in the anthropometric parameters or Z scores calculated for height, weight and BMI between the genders except for height (Table 1). However, diabetic children were shorter and lighter as compared to the reference population (HAZ − 0.6 ± 1.1, WAZ −0.6 ± 1.0). The mean HbA1C was 10.1 ± 1.8% indicating suboptimal metabolic control. Bone and body composition parameters are illustrated in Table 2; both boys and girls had mean values within the reference range. Boys had significantly higher TBBMC for TBBA Z scores as compared to girls (0.2 ± 1.1 vs −0.2 ± 1.0, p b 0.05). Twelve percent children had their HAZ scores less than − 2 and 22% had scores less than − 1. For TBBA for height Z scores 6% children had scores less than −2 and 18% children had scores less than −1. Using linear regression, predictors for both these parameters were assessed. Disease
Table 1 Anthropometric characteristics in boys and girls. Parameters
Boys (77)
Girls (93)
P value
Age (year) Height (cm)a Weight (kg) BMI (kg/m2) Height Z score Weight Z score BMI Z score HbA1C (%)
11.4 ± 3.6 140.4 ± 20.0 34.9 ± 14.5 16.7 ± 3.1 −0.6 ± 1.2 −0.6 ± 1.0 −0.4 ± 0.9 10.3 ± 2.5
10.8 ± 3.9 133.8 ± 18.0 31.7 ± 13.1 16.5 ± 3.6 −0.6 ± 1.0 −0.5 ± 1.0 −0.3 ± 0.9 10.1 ± 1.8
0.314 0.026 0.130 0.740 0.963 0.538 0.477 0.717
a
Mean significantly different between genders, P b 0.05.
Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
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Table 2 Body composition and bone parameters in boys and girls.
Parameters Lean mass (g)a Bone mineral content (g)a Fat %a LSBMAD Z scores Assessment of bone health using the Molgaard et al. method Height Z score (Do these patients have short bones?) TBBA for height Z scores (Do these patients have slender bones?) TBBMC for TBBA Z scoresa (Do these patients have under mineralized bones or light bones?) Assessment of bone health using the Crabtree et al. method LBM for height Z scores TBBMC for LBM Z scores a
Table 3 Bone parameters according to disease duration tertiles (n = 54).
Height Z score TBBA_FOR_HEIGHT TBBMC_FOR_TBBA TBBMC_FOR_LBM LBM_FOR_HEIGHT LSBMAD b
Girls
P value
25285 ± 9154 1250.0 ± 519.1 19.3 ± 8.4 0.0 ± 1.1
20540 ± 6490 1091.5 ± 497.2 26.9 ± 10.5 0.0 ± 1.0
0.0001 0.049 0.000 0.926
−0.6 ± 1.2
−0.6 ± 1.0
0.963
−0.2 ± 1.2
−0.2 ± 1.3
0.650
0.2 ± 1.1
−0.2 ± 1.0
0.010
0.1 ± 1.1 −0.2 ± 1.1
0.1 ± 1.2 −0.5 ± 1.0
0.997 0.165
Mean significantly different between genders, P b 0.05.
duration (β = −0.180, P = 0.000) and metabolic control (β = −0.096, P = 0.042) were identified as significant negative predictors of HAZ. Also for TBBA for height Z scores, disease duration (β = −0.146, P = 0.028) and metabolic control (β = −0.150, P = 0.048) were identified as significant negative predictors in younger children (tanner stages 1, 2 and 3). Only 5 children had suffered fractures; two occurred before the diagnosis of diabetes. Those who reported fractures had suffered falls or injuries while playing sports and all three were forearm fractures. To further analyze the effect of disease duration on bone status, the group was divided according to tertiles of disease duration; duration b6 months, duration between 6 months and 2.5 years and duration N2.5 years (Table 3/Fig. 1). Using the Molgaard et al. approach [18], children with longer duration of diabetes had significantly lower height for age Z scores (− 0.31 ± 0.92 vs − 1.28 ± 1.11; P = 0.000, short bones) and bone area for height Z scores (0.12 ± 1.62 vs − 0.53 ± 0.94; P = 0.044, slender bones). However, the TBBMC for TBBA Z scores were not significantly affected by duration of diabetes (−0.12 ± 1.17 vs 0.21 ± 1.32; P N 0.05). The serum IGF1 Z scores were also the least amongst the group with the longest disease duration (− 1.6 ± 1.3 vs − 2.6 ± 0.7; P b 0.05) (Fig. 2). Thus, disease duration was associated with shorter and slender bones but not light or under mineralized bones. Furthermore, using the Crabtree et al. model [24] we did not observe a relationship between disease duration and LBM for height (0.17 ± 1.32 vs 0.07 ± 0.90, P = 0.865) or TBBMC for LBM (− 0.22 ± 1.15 vs − 0.42 ± 1.16, P = 0.633). Taken together our results suggest that disease duration seems to affect skeletal growth parameters but not lean body mass or skeletal mineralization. To study the effect of puberty on TBBMC and TBBA, comparisons between diabetic children and reference data were made across different pubertal stages. Both parameters for the first 3 tanner stages in boys and girls were comparable to the reference population but there was a dip seen in tanner stages 4 and 5 possibly due to delayed growth spurt. In
a
Boys
Duration b6 months
Duration 6 months– 2.5 years
−0.31 ± 0.92a 0.12 ± 1.62a −0.12 ± 1.17 −0.22 ± 1.16 0.17 ± 1.33 0.08 ± 1.01
−0.54 ± 0.97b −0.44 ± 1.07 0 ± 0.87 −0.44 ± 0.94 0.04 ± 1.16 −0.02 ± 1.05
advanced stages of puberty when TBBMC and TBBA were compared to reference population, we observed that the increment in bone size seemed to deviate from the reference population but the BMC contained within the BA was within the reference range (Figs. 3, 4). Discussion Our cross sectional data show that Indian children and adolescents with type 1 diabetes are shorter as compared to reference population and have short and narrow bones with increasing duration of diabetes, particularly in younger children. During later stages of puberty, bone area was lower than that of the reference population; however, bones were adequately mineralized. Lean body mass (surrogate measure of muscle mass) for height and TBBMC for LBM were not affected. However, bone mineralization appears to be normal for the bone size. There is a gender difference seen in TBBMC for TBBA Z scores which cannot be explained by factors such as age, metabolic control or disease duration. Delayed puberty in children with diabetes has been debated and reports suggest that though the chronological age at onset of puberty and the duration of the pubertal growth spurt are not significantly different between diabetic and healthy adolescents, diabetic adolescents have a blunted pubertal growth spurt which seems to be associated with a reduced peak height velocity [25]. Though we do not have data on the growth spurt, it is likely that the lower bone area seen in diabetic children in later tanner stages was as a result of a delayed spurt. Besides bone mineral density, the size of a bone is an important factor determining its strength, especially in tubular bones. Thus, shorter and slender bones of younger children with longer diabetes duration may be associated with reduced bone strength. Our data are in keeping with findings of Kawashima et al., [26] who have reported that in mice, during childhood and adolescence, hyperglycemia leads to slender adult bones, resulting in reduced bone strength and reduced fracture resistance. Further support for our findings comes from the study by Bechtold et al., who used a peripheral quantitative computed Duration< 6 months
Duration 6mo-2.5 yrs
Duration > 2.5 yrs
0.4
Duration N2.5 years −1.28 ± 1.11 −0.53 ± 0.94 0.21 ± 1.32 −0.42 ± 1.16 0.08 ± 0.91 −0.35 ± 1.1
Significant difference between b6 months and N2.5 years (P b 0.05). Significant difference between 6 months–2.5 years and N2.5 years (P b 0.05).
0.2 0 -0.2 -0.4 -0.6 -0.8 -1 -1.2 -1.4
Fig. 1. Bone parameters according to disease duration (n = 54).
Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
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IGF1 Z Scores
0 -0.5
Duration< 6 months Duration 6mo-2.5 yrs
It is well established that the development of a functional musculoskeletal system requires muscle forces. The loading regulates the shape and density of developing bones, as well as the size [28]. Since muscle and bone are closely functionally linked, it is recommended that the diagnostic evaluation of bone parameters should always include an assessment of the musculature. Thus we analyzed the lean mass in our diabetic children [29]. However, the lean body mass measured by DXA is a surrogate for the muscle mass. Using the Crabtree et al. [24] model we have demonstrated that the lean body mass was not affected in these children. The LBM for the given height seems to be normal, but there is a decrease in height itself. Hence, studying the muscle cross section area using pQCT studies is important. In a study by Bechtold et al. in Germany, authors report that prepubertal children with early manifestation of disease had a lower muscle cross sectional area at the diaphyseal site [1]. Though children in our study seem to have normal LBM, this may be due to different measurement techniques. The results of our study need to be confirmed using a pQCT. The effect of IGF1 on bone and growth has been described previously by Moyer-Mileur et al. [8]. They have reported that poor metabolic control predicted alterations in the GH/IGF-1 axis. In their study, lower IGF-1 and greater IGFBP-1 and -5 relative to IGF-1 levels were predicted by poor metabolic control, whereas, a higher IGFBP-1/IGF-1 ratio was predictive of smaller, less mineralized bones. We did not measure the IGF binding proteins in our children but with increasing duration of diabetes, lower IGF1 Z scores were recorded. As reported by our previous study and studies conducted by others, Indian children with diabetes are shorter as compared to their peers [16]. Also, in a longitudinal study conducted by us previously, we have reported that duration of diabetes negatively affects height velocity amongst diabetic children [30]. In children who have been diagnosed with diabetes at less than 5 years of age, a greater loss of height is seen during puberty. This supports our results of narrowing of bones in children with longer disease duration due to loss of height. Hence, there are changes in children and adolescents with diabetes from childhood that may increase the propensity of fractures in adulthood. As seen in our study the changes are related to diabetes affecting the growth amongst these children which in turn has led to shorter and slender bones. The neck of the femur being a tubular bone is at a higher risk of fracture if the bones remain short and slender. The increased risk of fractures in adults seems to be associated with the changes in bone size and geometry due to reduced growth during childhood rather than bone density. Data on final height or onset of puberty were not available as our data are cross sectional and hence the effect of delayed pubertal growth spurt on bone parameters could not be assessed. Further, normalization of bone parameters with age has been reported by Bechtold et al. [4], we need well designed longitudinal studies to confirm our results. Studies previously done have reported that the total CSA, cortical CSA, and muscle CSA are significantly reduced amongst diabetic children as compared to reference population. Hence, studies done using the peripheral
Duration > 2.5 yrs
-1 -1.5 -2 -2.5 -3
Fig. 2. Serum IGF1 (according to disease duration tertiles, n = 54).
tomography scanner to study the bone size and mineralization parameters at the radius in children with type 1 diabetes mellitus. These investigators reported that the total cross sectional area, cortical cross sectional area and muscle cross sectional area at the radius were significantly lower in diabetic children with early manifestation of the disease [1]. The muscle cross sectional area is a surrogate measure of muscle mass on pQCT scanner, thus, the results of Bechtold et al. may differ from our DXA measured changes i.e., the LBM for height Z scores was not different in children with different disease durations. The metabolic control in our children was less optimal than in their study, but papers reporting poor metabolic control as ours and bone parameters, are, to the best of our knowledge, not available. Hence, comparisons have been made with the available data. If our and other's finding of ‘slender bones’ persist then it is possible that children with longer diabetes duration and sub-optimal metabolic control may have increased propensity to long bone fractures. There is a very high incidence of hip fractures reported in various cohorts of adults with type 1 diabetes. These studies have reported a 3 to 12% increase in risk amongst older diabetics for hip fractures [11–14]. The IOWA study with the largest cohort of postmenopausal women has reported that women with type 1 diabetes were 12 times more likely to report an incident of hip fracture than women without diabetes [11]. Another large population based study from Sweden has reported that the incidence of hip fractures before age 30 amongst diabetics was almost negligible but increased quickly thereafter and that as many as 1 in 15 patients with type 1 diabetes may sustain a hip fracture before the age of 65 [12]. The nurses' health study and a study from Scotland have also demonstrated a similar increase in risk of hip fractures amongst type 1 diabetics [13,14]. Children from our study have not reported fractures but the literature reports a high incidence of hip fractures amongst adults. A study recently conducted in Belarus amongst type 1 diabetic patients between 20–55 years of age has also reported higher vertebral fractures independent of BMD [27]. The LSBMAD scores of our children as a group were normal, however, when looked at across disease duration there is a trend seen across the disease duration groups. Thus, with increasing duration of diabetes, the group may show a decline in the BMAD scores and put them at risk of vertebral fractures too.
Reference Data
DM
Reference Data
DM
2000
2000
BMC (gm)
BMC (gm)
2500
1500 1000 500
1500
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500 1
2
3 Tanner Stage
3.1 Boys
4
5
1
2
3 Tanner stage
4
5
3.2 Girls
Fig. 3. Comparison of total body bone mineral content according to pubertal stages in diabetic children and Indian reference data.
Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
L.S. Parthasarathy et al. / Bone xxx (2015) xxx–xxx
Reference Data
DM
5
Reference Data
DM
2000
2500
BA (cm 2)
BA (cm2 )
2000 1500
1500
1000
1000 500
500 1
2
3
Tanner Stage
4
4.1 Boys
5
1
2
3
4
5
Tanner Stage 4.2 Girls
Fig. 4. Comparison of total body bone area according to pubertal stages in diabetic children as compared to Indian reference data.
quantitative computer tomography (pQCT) are required to study the changes in bone geometry amongst diabetic children [4]. The effects we observed on the bone size are derived from Molgaard et al. method and should be ideally studied using a pQCT. In conclusion, we did not find an effect of diabetes on bone size or mineralization for the whole group, however, longer duration of diabetes was associated with shorter and slender bones, especially in younger children. Children and adolescents in later stages of puberty also had slender bones possibly as a result of a delayed growth spurt. This may have long term implications of increased propensity to fractures. A follow-up study including pQCT for measurement of bone parameters for diaphyseal sites is required to confirm these findings. Author contribution statement Study design was planned by all authors. LP, AK and VK carried out the data collection. SC carried out the statistical analyses. All the authors contributed to the drafts of the manuscript. Disclosure statement The authors have nothing to disclose. Conflict of interest None. Acknowledgments Our sincere thanks to Mr. Pancharatnam for funding this project. The authors also acknowledge funding from the University Grants Commission (UGC), Government of India (UGC-Ref. No.: 1486/(NETDEC. 2010)), to the first author. References [1] Bechtold S, Dirlenbach I, Raile K, Noelle V, Bonfig W, Schwarz HP. Early manifestation of type 1 diabetes in children is a risk factor for changed bone geometry: data using peripheral quantitative computed tomography. Pediatrics 2006 Sep;118:627–34. [2] Moyer-Mileur LJ, Dixon SB, Quick JL, Askew EW, Murray MA. Bone mineral acquisition in adolescents with type 1 diabetes. J Pediatr 2004 Nov;145:662–9. [3] Heilman K, Zilmer M, Zilmer K, Tillmann V. Lower bone mineral density in children with type 1 diabetes is associated with poor glycemic control and higher serum ICAM-1 and urinary isoprostane levels. J Bone Miner Metab 2009;27:598–604. [4] Bechtold S, Putzker S, Bonfig W, Fuchs O, Dirlenbach I, Schwarz HP. Bone size normalizes with age in children and adolescents with type 1 diabetes. Diabetes Care 2007;30:2046–50. [5] Botushanov NP, Orbetzova MM. Bone mineral density and fracture risk in patients with type 1 and type 2 diabetes mellitus. Folia Med (Plovdiv) Oct–Dec 2009; 51(4):12–7. [6] Zeiton AAH, El-Ela AA. Calcium homeostasis in children with type I diabetes mellitus. Suez Canal Univ Med J 1999;2:47–59.
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Please cite this article as: Parthasarathy LS, et al, Bone status of Indian children and adolescents with type 1 diabetes mellitus, Bone (2015), http:// dx.doi.org/10.1016/j.bone.2015.04.050
