abnormal glucose metabolism ( agm ) is a type of endocrine and metabolic disease that is clinically manifested with high levels of blood sugar maintained for a prolonged period of time . it is currently established that agm comprises distinct forms of disorders , ranging from impaired glucose regulation ( igr ) to diabetes mellitus ( dm ) . epidemiological data revealed an alarming the number of individuals with agm , which is expected to increase from the present 190 million to 366 million by 2030 worldwide . in addition , a higher rate of disease occurrence is observed in asian populations , strongly suggesting the emerging potential of agm becoming epidemic in developing countries . it is generally believed that the major risk factors for developing agm lie in the complex interactions between genetic , psychological , and social environments . the primary symptoms of agm are urination frequency , polydipsia , and polyphagia , which are often accompanied by other clinical complications [ 810 ] . previous studies have demonstrated that agm preventable through a variety of strategies , including performing sufficient physical exercise and adopting a healthy diet . bone mineral density ( bmd ) is medically defined as the amount of mineral matter per square centimeter of bones , which also acts as an indirect indicator for the risk of developing osteoporosis and fracture in clinical medicine . bmd is clinically featured by its painlessness and non - invasiveness , which involves low radiation exposure frequently performed in nuclear medicine or radiology departments in clinics or hospitals . various risk factors have been identified to be indicative of low bmd , including older age , vertebral abnormalities , primary hyperparathyroidism , history of eating disorders , and other additional factors . as a lifelong process , bone metabolism is characterized by generation and substitution of new bone tissues for mature bone tissues within the skeleton . it also controls bone regeneration and replacement following injuries , such as fractures and micro - damage that occur during normal activities . bone metabolism is maintained at a balanced rate through a complex crosstalk between growth and differentiation that heavily depends upon various regulatory signaling pathways , which includes hormones , cytokines , bone marrow - derived membrane , and growth factors [ 1921 ] . agm is a disease that includes inflammation ( a factor associated with reduced bmd ) and obesity ( a factor related to increased bmd ) . study reported that the systemic inflammation associated with the metabolic syndrome , such as agm , may activate bone resorption and further result in reduced bmd . in contrast , mitsuyo found higher bmd among subjects with agm , in which obesity appeared to be the main component increasing bmd . however , a definitive role for agm in bmd and bone metabolism remains to be fully elucidated , as several recent independent studies have reported discordant and seemingly conflicting results [ 2528 ] . higher bmd was protective in obese individuals with agm ; however , fracture risk was increased in more advanced diabetes , which may change bone quality with bmd remaining unchanged . weight loss is advocated in agm patients to reduce their cardiovascular risk , but it may also reduce bmd and increase bone turnover . agm has some detrimental impacts on bone metabolism , and it has significant outcomes for patients with diabetes with regard to decreased bmd and increased risk of fractures . therefore , we performed a meta - analysis to evaluate the correlation of agm with bmd and bone metabolism . research articles that addressed the correlation of agm with bmd and bone metabolism published before september 1 , 2014 were obtained by searching multiple independent computerized databases ( pubmed , china biomedicine ( cbm ) , embase , web of science , china national knowledge infrastructure ( cnki ) and cochrane library ) , utilizing selected keywords (  glucose tolerance test  or  glucose metabolism  ) and (  osteoporosis  ,  op  ,  bone metabolism  ,  bone density  ,  bone mineral density  or  bmd  ) . the bibliographies within the papers were further examined manually to identify additional relevant papers . in order to be enrolled in our meta - analysis , published papers must meet the following selection criteria : ( 1 ) designed as clinical cohort studies regarding the correlation between agm and bmd or bone metabolism ; ( 2 ) studied patients with agm in comparison with controls that had normal glucose metabolism ; ( 3 ) had complete data available ; and ( 4 ) written in chinese or english . exclusion criteria were : ( 1 ) lack of integrity for the literature data , ( 2 ) baseline characteristics being considerably different for the subjects between the observation and control group , and ( 3 ) repetition of published documents . relevant information from selected articles was extracted by 2 independent investigators and recorded on a predefined form . specifically , the following data were obtained : first author , time of publication , language , disease , diagnostic criterion , age , gender , study type , country , ethnicity , study design , sample size , and intervention measures . the newcastle - ottawa scale ( nos ) criteria were utilized to assess the studies independently . the nos criteria are scored as : ( 1 ) group selection : whether the exposed group has adequate or pool representation ( nos01 ) ; whether the unexposed group and exposed group come from the same population ( nos02 ) ; whether the included studies have reliably recorded and structured interviews ( nos03 ) ; whether observational outcomes were described at the beginning of the selected studies(nos04 ) ; ( 2 ) group comparability : whether the study selected the most important factors with the controls being appropriately analyzed ( nos05 ) ; whether the study controls other important confounding factors ( nos06 ) ; ( 3 ) group results : whether the study depended upon a blinded method ( nos07 ) ; whether the follow - up time was sufficient for the results to be valid ( nos08 ) ; whether there are a small number of missing subjects during the follow - up assessment despite no introduced deviation ( nos09 ) ; whether the non - response rate is the same in 2 groups ( nos10 ) . discrepancies for the nos scores of the included articles were further addressed by a third reviewer by group discussion and consulting . our meta - analysis was carried out with comprehensive meta - analysis 2.0 ( biostat inc . , the standard mean difference ( smd ) with its 95% confidence interval ( 95% ci ) was utilized for evaluating the differences between the observation and control group . the cochran s q - statistic was used for evaluating the heterogeneity across the enrolled studies , which was further measured by i test ( 0% , no heterogeneity ; 100% , maximal heterogeneity ) . a random - effects model was employed when heterogeneity was detected among studies , whereas a fixed - effects model was implemented in the presence of acceptable homogeneity . sensitivity analysis was conducted to assess if the results were affected after exclusion of any single selected study . the funnel plots together with the egger s linear regression test were constructed to determine if a publication bias was present . research articles that addressed the correlation of agm with bmd and bone metabolism published before september 1 , 2014 were obtained by searching multiple independent computerized databases ( pubmed , china biomedicine ( cbm ) , embase , web of science , china national knowledge infrastructure ( cnki ) and cochrane library ) , utilizing selected keywords (  glucose tolerance test  or  glucose metabolism  ) and (  osteoporosis  ,  op  ,  bone metabolism  ,  bone density  ,  bone mineral density  or  bmd  ) . in order to be enrolled in our meta - analysis , published papers must meet the following selection criteria : ( 1 ) designed as clinical cohort studies regarding the correlation between agm and bmd or bone metabolism ; ( 2 ) studied patients with agm in comparison with controls that had normal glucose metabolism ; ( 3 ) had complete data available ; and ( 4 ) written in chinese or english . exclusion criteria were : ( 1 ) lack of integrity for the literature data , ( 2 ) baseline characteristics being considerably different for the subjects between the observation and control group , and ( 3 ) repetition of published documents . relevant information from selected articles was extracted by 2 independent investigators and recorded on a predefined form . specifically , the following data were obtained : first author , time of publication , language , disease , diagnostic criterion , age , gender , study type , country , ethnicity , study design , sample size , and intervention measures . the newcastle - ottawa scale ( nos ) criteria were utilized to assess the studies independently . the nos criteria are scored as : ( 1 ) group selection : whether the exposed group has adequate or pool representation ( nos01 ) ; whether the unexposed group and exposed group come from the same population ( nos02 ) ; whether the included studies have reliably recorded and structured interviews ( nos03 ) ; whether observational outcomes were described at the beginning of the selected studies(nos04 ) ; ( 2 ) group comparability : whether the study selected the most important factors with the controls being appropriately analyzed ( nos05 ) ; whether the study controls other important confounding factors ( nos06 ) ; ( 3 ) group results : whether the study depended upon a blinded method ( nos07 ) ; whether the follow - up time was sufficient for the results to be valid ( nos08 ) ; whether there are a small number of missing subjects during the follow - up assessment despite no introduced deviation ( nos09 ) ; whether the non - response rate is the same in 2 groups ( nos10 ) . discrepancies for the nos scores of the included articles were further addressed by a third reviewer by group discussion and consulting . our meta - analysis was carried out with comprehensive meta - analysis 2.0 ( biostat inc . , englewood , new jersey , usa ) . the standard mean difference ( smd ) with its 95% confidence interval ( 95% ci ) was utilized for evaluating the differences between the observation and control group . the cochran s q - statistic was used for evaluating the heterogeneity across the enrolled studies , which was further measured by i test ( 0% , no heterogeneity ; 100% , maximal heterogeneity ) . a random - effects model was employed when heterogeneity was detected among studies , whereas a fixed - effects model was implemented in the presence of acceptable homogeneity . sensitivity analysis was conducted to assess if the results were affected after exclusion of any single selected study . the funnel plots together with the egger s linear regression test were constructed to determine if a publication bias was present . figure 1 presented the procedure that led to the identification and inclusion of eligible studies for our analysis . we initially retrieved a total of 844 studies after searching the electronic database combined with manual search . there were 123 duplicates , 16 non - human studies , 7 letters , reviews or meta - analysis , and 563 non - related articles that were considered ineligible and thus excluded . the remaining 135 studies were further reviewed , among which 124 were also excluded because 24 were non - cohort studies , 48 irrelevant to glucose metabolism and 52 irrelevant to bone metabolism or bmd . since there were 4 papers among the remaining ones that lacked sufficient information , this eventually led to 7 studies being enrolled for the analysis . these ultimately selected cohort studies , published between 2005 and 2014 , evaluated the correlation of agm with bmd and bone metabolism in asian and caucasian populations ( each in 3 studies ) with a total of 1123 subjects ( 560 patients with agm and 563 healthy controls ) [ 4046 ] . among these 7 articles , 2 were performed in the usa , 2 in greece , 2 in china , and 1 in israel . table 1 and figure 2 illustrate the baseline characteristics in detail , as well as the nos quality evaluation for the ultimately selected 7 studies . the differences with respect to body mass index ( bmi ) , insulin , and insulin resistance ( ir ) between patients with agm and healthy controls with normal glucose metabolism were reported in 6 , 3 , and 2 studies , respectively . considering the heterogeneity ( i > 50% , p<0.05 ) detected in our analysis , a random - effects model was applied to pool the data concerning these 3 indexes . the results demonstrated that bmi , insulin , and ir for patients with agm were significantly higher than for the control population with normal glucose metabolism ( bmi : smd=1.658 , 95% ci=0 . 001 ; insulin : smd=0.544 , 95% ci=0.030~1.058 , p=0.038 ; ir : smd=8.767 , 95% ci=4.178~13.356 , p<0.001 ) ( figure 3a3c ) . on the other hand , the differences with respect to osteocalcin ( oc ) and bmd between patients with agm and the population with normal glucose metabolism were reported in 2 and 5 studies , respectively . accordingly , a random - effects model was also applied to pool the data of these 2 indexes given the detected heterogeneity ( i2 > 50% , p < 0.05 ) . however , the results revealed no significant difference concerning the oc and bmd in patients with agm and the control subjects with normal glucose metabolism ( oc : smd=0.293 , 95% ci=0.023~0.609 , p=0.069 ; bmd : smd=0.805 , 95% ci=0 . 121 ) ( figure 3d , 3e ) . using the sensitivity analysis in our investigation , we revealed that removal of any single included study had a negligible impact on our findings , indicating the stability of our analysis . results from the sensitivity analysis suggested that all included studies had no detected effect on the merging effect value smd of the correlation between agm and bmd or bone metabolism ( figure 4a4e ) . the symmetrical funnel plots for all 7 studies did not support the presence of a publication bias . this was further corroborated by the egger linear regression analysis ( all p>0.05 ) ( figure 5a5c ) . figure 1 presented the procedure that led to the identification and inclusion of eligible studies for our analysis . we initially retrieved a total of 844 studies after searching the electronic database combined with manual search . there were 123 duplicates , 16 non - human studies , 7 letters , reviews or meta - analysis , and 563 non - related articles that were considered ineligible and thus excluded . the remaining 135 studies were further reviewed , among which 124 were also excluded because 24 were non - cohort studies , 48 irrelevant to glucose metabolism and 52 irrelevant to bone metabolism or bmd . since there were 4 papers among the remaining ones that lacked sufficient information , this eventually led to 7 studies being enrolled for the analysis . these ultimately selected cohort studies , published between 2005 and 2014 , evaluated the correlation of agm with bmd and bone metabolism in asian and caucasian populations ( each in 3 studies ) with a total of 1123 subjects ( 560 patients with agm and 563 healthy controls ) [ 4046 ] . among these 7 articles , 2 were performed in the usa , 2 in greece , 2 in china , and 1 in israel . table 1 and figure 2 illustrate the baseline characteristics in detail , as well as the nos quality evaluation for the ultimately selected 7 studies . the differences with respect to body mass index ( bmi ) , insulin , and insulin resistance ( ir ) between patients with agm and healthy controls with normal glucose metabolism were reported in 6 , 3 , and 2 studies , respectively . considering the heterogeneity ( i > 50% , p<0.05 ) detected in our analysis , a random - effects model was applied to pool the data concerning these 3 indexes . the results demonstrated that bmi , insulin , and ir for patients with agm were significantly higher than for the control population with normal glucose metabolism ( bmi : smd=1.658 , 95% ci=0 . 001 ; insulin : smd=0.544 , 95% ci=0.030~1.058 , p=0.038 ; ir : smd=8.767 , 95% ci=4.178~13.356 , p<0.001 ) ( figure 3a3c ) . on the other hand , the differences with respect to osteocalcin ( oc ) and bmd between patients with agm and the population with normal glucose metabolism were reported in 2 and 5 studies , respectively . accordingly , a random - effects model was also applied to pool the data of these 2 indexes given the detected heterogeneity ( i2 > 50% , p < 0.05 ) . however , the results revealed no significant difference concerning the oc and bmd in patients with agm and the control subjects with normal glucose metabolism ( oc : smd=0.293 , 95% ci=0.023~0.609 , p=0.069 ; bmd : smd=0.805 , 95% ci=0 . using the sensitivity analysis in our investigation , we revealed that removal of any single included study had a negligible impact on our findings , indicating the stability of our analysis . results from the sensitivity analysis suggested that all included studies had no detected effect on the merging effect value smd of the correlation between agm and bmd or bone metabolism ( figure 4a4e ) . the symmetrical funnel plots for all 7 studies did not support the presence of a publication bias . this was further corroborated by the egger linear regression analysis ( all p>0.05 ) ( figure 5a5c ) . to definitively explore the correlation of agm with bmd and bone metabolism , a systematical meta - analysis was performed . based on the experimental data obtained from previous studies , our meta - analysis revealed that bmi , insulin , and ir for patients with agm were significantly higher than for healthy individuals with normal glucose metabolism , implying that agm might lead to increased bmi , insulin , and ir . bmi is frequently utilized as a technically straightforward and easily interpreted method to assess the extent to which an individual s height - corrected body weight deviates from normal . according to the who criteria , bmi less than 18.5 is considered as underweight , which indicates potential health problems such as possible malnutrition and eating disorders ; in contrast , bmi greater than 25 is considered as overweight , especially for those who may be obese with bmi above 30 . as a peptide hormone secreted by the beta cells in the pancreas , insulin plays an indispensible role in regulating the metabolism of carbohydrates and fats . mechanistically , insulin exerts it physiological functions by facilitating the absorption of glucose from blood to fat tissues and skeletal muscles and simultaneously promoting fat deposition with suppressed energy consumption . insulin induces a variety of increased ( glycogen synthesis , lipid synthesis , amino acid and potassium uptake and esterification of fatty acids ) and decreased ( proteolysis , lipolysis , gluconeogenesis and autophagy ) cellular activities . however , there are aberrant conditions when cells are unable to biologically respond to insulin , resulting in metabolic syndromes and dm , which is medically defined as ir . for example , ir in muscle and fat cells compromises glucose uptake , whereas ir in liver cells diminishes synthesis and storage of glycogens and causes failed suppression of production and release of glucose into the blood . in line with this , our meta - analysis postulated that increased bmi , insulin , and ir are closely associated with agm . to further explore the correlation between agm and other indexes , interestingly , the stratified analysis indicated that oc was not significantly different between patients with agm and healthy controls with normal glucose metabolism . meanwhile , bmd was also not significantly different between patients with agm and healthy individuals with normal glucose metabolism . taken together , our findings are in line with previous studies that consistently showed no detectable correlation of agm with oc and bmd . similar to other published meta - analysis , we also acknowledged several limitations in the current meta - analysis . firstly , our analysis was severely limited by the number of the included studies , which might not accurately and strictly represent a suitable dataset for the statistical analysis . secondly , the sample size in the enrolled studies was relatively small , which might not provide sufficiently valid data for our results . a third limitation lies in the potential language bias in our selection procedure , since only those studies published in english and chinese were included . notably , we identified only 2 eligible studies published in chinese from those 7 studies . last but not least , our analysis was restricted by the selection procedure for controls , which was only population - based and might not represent the entire general population . in summary , our meta - analysis indicates that gm might lead to increased bmi , insulin , and ir .
backgroundthe aim of this meta - analysis was to explore the correlations of abnormal glucose metabolism ( agm ) with bone mineral density ( bmd ) and bone metabolism.material/methodsrelevant studies were identified using computerized and manual search strategies . 
 the included studies were in strict accordance with inclusion and exclusion criteria . 
 statistical analyses were conducted with the comprehensive meta - analysis 2.0 ( biostat inc . , 
 englewood , nj , usa).resultsour present meta - analysis initially searched 844 studies , and 7 studies were eventually incorporated in the present meta - analysis . 
 these 7 cohort studies included 1123 subjects altogether ( 560 patients with agm and 563 healthy controls ) . 
 the results showed that bone mass index ( bmi ) , insulin , and insulin resistance ( ir ) of patients with agm were significantly higher than that of the population with normal glucose metabolism ( bmi : smd=1.658 , 95% ci=0.663~2.654 , p=0.001 ; insulin : smd=0.544 , 95% ci=0.030~1.058 , p=0.038 ; ir : smd=8.767 , 95% ci=4.178~13.356 , p<0.001 ) . 
 however , the results also indicated there was no obvious difference in osteocalcin ( oc ) and bmd in patients with agm and the population with normal glucose metabolism ( oc : smd=0.293 , 95% ci=0.023~0.609 , p=0.069 ; bmd : smd=0.805 , 95% ci=0 . 
 212~1.821 , p=0.121).conclusionsour meta - analysis results suggest that agm might lead to increased bmi , insulin , and ir , while it has no significant correlation with bmd or bone metabolism .