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1 Supplemental tables: Abbreviations: Osteoprotegerin (OPG), Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL), fibroblast growth factor-23 (FGF-23), C-terminal cross-linked telopeptide of type-i collagen (CTX), Procollagen type 1 amino terminal propeptide (P1NP), Charlson Comorbidity Index (CCI)
2 Table 1. Description and overview of ICD codes used. Description ICD 8 koder ICD 10 koder Fracture , , ,816.19, , , , , , , S02.0 S02.9, S07.0 S07.9, S12.0 S12.9, S22.0 S22.9, S32.0 S32.8, S42.0 S42.9, S52.0 S52.9, S62.0 S62.9, S72.0 S72.9, S82.0 S82.9, S92.0 S , , , , Falls W Hypoglycemia E160, E161, E , Alcohol related diagnosis 303 F10 Hypo thyroidism 244 E02, E03 Hyper thyroidism 242 E05 Neuropathy , E10.4, E11.4 Nefropathy , E10.2, E11.2 Retinopathy , E10.3, E11.3 Malignants tumor C00 C75 Aids B21 B24 Metastasis ; 199 C76 C80 Mild liver disease 571; ; B18; K70.0 K70.3; K70.9; K71; K73; K74; K76.0 Moderate or severe liversygdom ; ; ; ; ; ; B15.0; B16.0; B16.2; B19.0; K70.4; K72; K76.6; I85 Hemiplegia 344 G81; G82 Leukemia C91 C95 Lymphoma ; C81 C85; C88; C90; C96 Moderate eller severe renal disease 403; 404; ; 584; ; ; ; 792 I12; I13; N00 N05; N07; N11; N14; N17 N19; Q61 Myocardial infarction 410 I21; I22; I23 Heart failure ; ; ; ; I50; I11.0; I13.0; I ; Dementia ; F00 F03; F05.1; G30 Peripheral vascular disease 440; 441; 442; 443; 444; 445 I70; I71; I72; I73; I74; I77 Cerebrovascular disease 430; 431; 432; 433; 434; 435; I60 I69; G45; G46 436; 437; 438 Chronic lung disease ; J40 J47; J60 J67; J68.4; J70.1; J70.3; J84.1; J92.0; J96.1; J98.2; J98.3 Connective tissue disease 712; 716; 734; 446; M05; M06; M08; M09; M30; M31; M32; M33; M34; M35; M36; D86 Ulcer ; ; K22.1; K25 K28
3 Table 2 Simple linear regression of density parameters in type 1 diabetes Variable Hip T-score Spine T-score vbmd tibia (mg HA/cm 3 ) Characteristics Age (years) ( ; ( ; ) ) BMI (kg/m 2 ) ( ; ( ; 0.154) 0.144) Diabetes duration ( ( ; (years) ; 0.174) ) CCI ( ; ( ; ) 495) Femur T-score (0.697 ; 0.918) Spine T-score (0.327 ; 0.582) vbmdradius ( ; ( ; vbmd tibia ) ( ; ) vbmd radius (mg HA/cm 3 ) (-4.58 ; -1.33) (-21.6 ; ) 3.94 (0.242 ; 7.64) 1.54 ( ; 3.48) (-1.08 ; 1.20) ( ; 0.436) 3.09 (-26.2 ; 32.4) (-18.0 ; 12.3) (0.523 ; 0.929) 20.7 (8.68 ; 32.8) 21.5 (6.26 ; 36.8) ) ( ; ) Biochemical parameters (0.503 ; 0.792) CTX (ng/ml) (-4.79 ; ( ; (-252 ; 99.1) (-280 ; 152) 0.371) ) Osteocalcin(ng/ml) ( ; (-7.31 ; -1.81) (-6.31 ; -1.06) (-7.33 ; ) ) P1NP (ng/ml) ( ; (-2.20 ; ) (-2.71 ; ) ) Sclerostin (pmol/l) ( ; ( ; ( ; ) ) 0.501) OPG (pmol/l) ( ; ( ; (-8.40 ; 4.54) (-12.4 ; 3.26) ) ) Female vs. male (-1.04 ; ( ; 0.308) (-52.7 ; 6.17) (-46.5 ; 27.5) gender* 1.62) No microvascular complication vs. micovascular ( ; (-1.35 ; ) 4.56 (-25.1 ; 34.2) 7.58 (-29.0 ; 44.2) complication* 0.359) Non smoker vs. smoker* (0.270 ; 1.36) ( ; 1.14) 2.23 (-36.9 ; 41.4) (-65.6 ; 29.6) Bold indicates statistical significance. Regressions have also been performed by alcohol consumption, creatinine, vitamin 25, HbA1c, RANKL, and FGF-23 with no significant associations.
4 Table 3 Simple linear regression of density parameters in type 2 diabetes Variables Hip T-score Spine T-score vbmd tibia (mg HA/cm 3 ) Characteristics Age (years) ( ; ( ; ) ) BMI (kg/m 2 ) ( ; ( ; 0.128) 0.151) Diabetes duration ( ; ( ; (years) ) ) CCI ( ; ( ; ) 0.248) Femur T-score (0.663 ; 0.881) Spine T-score (0.393 ; 0.589) vbmdradius ( ; ( ; vbmd tibia ) ( ; ) vbmd radius (mg HA/cm 3 ) (-2.61 ; 0.441) (-2.84 ; 0.942) 1.09 (-1.63 ; 3.81) (-6.17 ; 0.230) (-1.27 ; 1.82) (-2.01 ; 1.70) (-13.8 ; ) (-17.6 ; -1.49) (0.579 ; 1.04) 17.5 (9.53 ; 25.5) 13.9 (3.26 ; 24.5) ) ( ; ) Biochemical parameters (0.385 ; 0.717) CTX (ng/ml) (-5.65 ; -1.38) (-7.96 ; -1.86) -137 (-240 ; -32.8) (-192 ; 70.3) Osteocalcin(ng/ml) ( ; ( ; (-3.47 ; 0.421) (-3.14 ; 1.68) ) ) P1NP (ng/ml) ( ; ( ; (-1.66 ; ) (-1.41 ; 0.533) ) ) Sclerostin (pmol/l) ( ; ) ( ; ) ( ; 0.672) ( ; 0.802) Creatinine (mmol/l) ( ; ) ( ; ) ( ; 0.624) ( ; 0.924) Female vs. male ( ; (-1.44 ; (-51.4 ; -4.29) (-39.6 ; 18.9) gender* ) ± 0.222) ± No microvascular complication vs ( ; ( ; (-27.7 ; 22.5) (-29.0 ; 29.6) micovascular complication* 0.528) 0.750) Non smoker vs. smoker* ( ; 0.790) ( ; 1.20) 4.23 (-21.5 ; 30.0) 9.31 (-20.9 ; 39.5) Bold indicates statistical significance. Regressions have also been performed by alcohol consumption, vitamin 25, HbA1c, RANKL, and FGF-23 with no significant associations.
5 Table 4. Multiple linear regression for bone density parameters Variable Hip T-score Spine T-score Age (years) ( ; ) ( ; ) BMI (kg/m 2 ) ( ; ) ( ; ) Male vs. female gender ( ; 0.527) ( ; 0.338) Type 2 vs. type 1 diabetes (0.144 ; 0.862) ( ; 0.901) Microvascular complication ( ; 0.528) Smoker vs. non smoker ( ; ) CCI ( ; )- CTX (ng/ml) -2.22(-3.67 ; ) (-6.06 ; -1.91) Sclerostin (pmol/l) ( ; ) ( ; ) Creatinine (mmol/l) (-6.06 ; 1.91) Bold indicates statistical significance. OR: Odds ratio. Adjusted by other factors in the table.
6 Table 5 Simple linear regression of cortical porosity and bone tissue stiffness in type 2 diabetes Variables Porosity Tibia (%) Porosity Radius (%) Tibia (kn/mm) Radius (kn/mm) Characteristics Age (years) (-3.32 ; 1.17) (-1.39 ; 0.357) ( ; 0.183) ( ; ) BMI (kg/m 2 ) (-3.34 ; 4.62) (-1.30 ; 1.74) ( ; ) ( ; ) Diabetes duration (years) (-1.63 ; 2.86) ( ; 0.791) ( ; ) ( ; ) CCI (-18.5 ; 1.65) (-6.87 ; 0.778) ( ; 0.498) ( ; 0.267) Alcohol consumption (units/week) 2.73 (0.300 ; 5.16) 1.06 ( ; 2.09) ( ; ) ( ; ) Hip T-score 29.4 (16.1 ; 42.6) 12.1 (7.35 ; 16.9) ( ; 0.327) ( ; ) Femur T-score 23.9 (11.7 ; 36.1) 9.38 (4.90 ; 13.9) ( ; 0.215) ( ; 0.399) Spine T-score 19.3 (10.4 ; 28.1) 7.54 (4.32 ; 10.8) ( ; 0.232) ( ; 0.218) vbmdradius (0.228 ; 0.817) (0.119 ; 0.322) ( ; ) ( ; ) vbmd tibia (0.399 ; 1.03) (0.176 ; 0.412) ( ; ) ( ; ) Biochemical parameters CTX (ng/ml) -192 (-344 ; -39.5) (-127 ; -9.17) 2.37 (-2.49 ; 7.24) (-2.70 ; 3.07) P1NP (ng/ml) -1.27(-2.40 ; ) (-1.05 ; ) ( ; ) ( ; ) Osteocalcin(ng/ml) (-4.50 ; 0.679) (-2.36 ; 0.216) ( ; ) ( ; ) FGF-23 (RU/ml) ( ; ) ( ; ) ( ; ) ( ; ) Sclerostin (pmol/l) ( ; 1.09) (0.112 ; 0.580) ( ; ) ( ; ) OPG (pmol/l) (-14.5 ; 1.47) (-6.37 ; ) ( ; 0.315) ( ; 0.179) Creatinine (mmol/l) (-88.8 ; 1.86) (0.184 ; 0.877) ( ; ) ( ; ) Female vs. male gender* (-102 ; -40.1) (-48.7 ; -30.0) ± (-1.70 ; 0.481) ( ; 0.360) No microvascular complication vs (-45.8 ; 27.2) (-24.0 ; 2.65) (-1.69 ; 0.542) (-1.18 ; ) micovascular complication* Non smoker vs. smoker* 11.3 (-26.2 ; 48.7) 3.02 (-11.0 ; 17.0) (-1.53 ; 0.777) ( ; 0.616) Bold indicates statistical significance. Regressions have also been performed by HbA1c and RANKL with no significant associations.
7 Table 6 Simple linear regression of cortical porosity and bone tissue stiffness in type 1 diabetes Variables Porosity Tibia (%) Porosity Radius (%) Tibia (kn/mm) Radius (kn/mm) Characteristics Age (years) (-5.53 ; -1.41) (-21.6 ; ) (0.101 ; 0.249) ( ; ) BMI (kg/m 2 ) 2.22 (-2.58 ; 7.02) 1.54 ( ; 3.48) ( ; ) ( ; ) Diabetes duration (years) (-2.10 ; 0.724) ( ; 0.436) ( ; ) ( ; ) CCI (-83.4 ; -15.5) (-18.0 ; 12.3) ( ; ) ( ; 0.470) Hip T-score 40.7 (27.5 ; 53.9) 15.5 (9.70 ; 21.3) (-1.30 ; 0.029) ( ; 0.347) Femur T-score 36.7 (23.6 ; 49.9) 12.7 (6.82 ; 18.6) ( ; 0.503) ( ; 0.433) Spine T-score 15.4 (4.69 ; 26.1) 4.68 (0.104 ; 9.27) ( ; ) ( ; 0.344) vbmdradius (0.116 ; 0.657) (0.120 ; 0.326) ( ; ) ( ; ) vbmd tibia (0.344 ; 0.952) (0.134 ; 0.389) ( ; ) ( ; ) Biochemical parameters Osteocalcin(ng/ml) (-8.59 ; -2.23) (-3.09 ; ) (-8.59 ; -2.23) (-3.09 ; ) FGF-23 (RU/ml) ( ; 0.194) ( ; ) ( ; ) ( ; ) OPG (pmol/l) (-11.0 ; 5.13) (-4.73 ; 1.93) (0.113 ; 0.704) ( ; 0.355) Creatinine (mmol/l) 1.22 ( ; 2.54) (0.207 ; 1.25) ( ; ) ( ; ) 25 OHD vitamin (nmol/l) ( ; 0.403) ( ; ) ( ; ) ( ; ) Female vs. male (-97.2 ; (-50.0 ; -28.2) (-1.12 ; 2.16) ± ( ; 3.20) gender* 38.9) ± No microvascular complication vs (-61.1 ; 11.9) (-21.5 ; 9.25) (-1.79 ; 1.23) ± (-1.04 ; ) micovascular complication* Non smoker vs. smoker* 17.6 (-17.3 ;52.4) ± 7.02 (-13.1 ; 27.1) (-1.39 ; 2.42) (-1.24 ; 0.379) Bold indicates statistical significance. Regressions have also been performed by alcohol consumption, HbA1c, CTX, P1NP, RANKL, and sclerostin with no significant associations.
8 Table 7 Multiple linear regression of bone tissue stiffness in diabetes patients Variable Tibia (kn/mm) Radius (kn/mm) Age (years) (-2.96 ; ) ( ; ) BMI (kg/m 2 ) (-1.99 ; 3.17) ( ; 1.25) Male vs. female gender 68.3 (45.9 ; 90.7) 35.2 (27.7 ; 42.6) Type 2 vs. type 1 diabetes 29.4 (2.87 ; 55.9) 7.38 (-1.04 ; 15.8) Alcohol consumption (units/week) (-2.26 ; 0.657) ( ; 0.593) CCI (-15.8 ; 0.779) - FGF-23 (RU/ml) ( ; ) Bold indicates statistical significance. Adjusted by covariates in the table
9 Table 8 Multiple linear regression of volumetric bone mineral density in diabetes patients Variable vbmd tibia(mg HA/cm 3 ) (n = 117) vbmd radius (mg HA/cm 3 ) (n = 115) Age (years) (-2.13 ; ) (-2.71 ; ) BMI (kg/m 2 ) (-1.13 ; 2.69) (-3.90 ; 1.23) Male vs. female gender 10.9 (-5.46 ; 27.3) (-28.8 ; 15.2) Type 2 vs. type 1 diabetes 2.80 (-16.3 ; 21.9) 12.3 (-13.2 ; 37.9) CCI (-9.56 ; 2.38) (-13.6 ; 2.40) Osteocalcin (ng/ml) (-1.48 ; 1.54) (-2.22 ; 1.89) Hip T-score 20.0 (12.2 ; 27.8) 21.1 (10.7 ; 31.6) Bold indicates statistical significance. Adjusted by covariates in the table
10 Table 9 Multiple linear regression of cortical porosity in diabetes patients Variable Porosity Tibia (%) Porosity Radius (%) Age (years) ( ; 0.190) ( ; ) BMI (kg/m 2 ) ( ; ) ( ; ) Male vs. female gender ( ; 1.36) ( ; 0.789) Type 2 vs. type 1 diabetes (-1.80 ; 0.177) ; ; 0.571) Diabetes duration (years) ; ; ) ( ; ) Osteocalcin (ng/ml) ( ; ) ( ; ) FGF-23 (RU/ml) ( ; ) ( ; ) vbmd tibia ( ; ) vbmd radius (mg HA/cm 3 ) ( ; ) 25 OHD vitamin (nmol/l) ( ; ) Bold indicates statistical significance. Adjusted by covariates in the table.
11 Table 10 Unadjusted odds ratio for composite fracture endpoint (incident fracture and vertebral fracture) in type 1 and type 2 diabetes Type 1 diabetes Type 2 diabetes Variable OR 95 % CI OR 95 % CI Age (years) Male vs. female gender BMI (kg/m 2 ) Diabetes duration (years) Previous fracture Previous major osteoporotic fracture Previous hypoglycemic events Charlson Comorbidity Index Microvascular complication Current smoker Former smoker Alcohol use (units/week) FGF-23 (RU/ml) Sclerostin (pmol/l) Sclerostin in tertiles RANKL (pmol/l) 1.05 < < OPG (pmol/l) Creatinin (mmol/l) OHD vitamin (nmol/l) HbA1c (mmol/mol) Hip T-score Femur T-score Spine T-score Total forearm BMD < < Bold indicates statistical significance. OR: Odds ratio.
(n=6279). Continuous variables are reported as mean with 95% confidence interval and T1 T2 T3. Number of subjects
Table 1. Distribution of baseline characteristics across tertiles of OPG adjusted for age and sex (n=6279). Continuous variables are reported as mean with 95% confidence interval and categorical values
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