this study is part of the ongoing finnish diabetic nephropathy ( finndiane ) study , with the aim to identify genetic , clinical , and environmental risk factors for diabetic nephropathy in patients with t1d . the study was initiated in 1997 , and follow - up data have been collected since 2004 either by re - examination of the patients or review of the medical files . detailed description of the follow - up protocol has been described previously ( 11 ) . t1d was defined as an onset of diabetes before the age of 40 years and permanent insulin treatment initiated within 1 year of diagnosis . for this study , outcomes were ascertained in patients in the finndiane prospective cohort recruited between 1997 and 2004 , in whom serum opg was estimated on baseline samples ( n = 1,939 ) . furthermore , patients with end - stage renal disease ( esrd ; dialysis or transplantation ) at baseline were excluded from analysis , as risk factors for adverse outcomes are clearly different in these patients . written informed consent was obtained from each patient , and the study was performed in accordance with the declaration of helsinki as revised in the year 2000 . at baseline , all patients also underwent a thorough clinical investigation in connection with a regular patient visit to their attending physician . data on medication and diabetes complications were registered with the use of a standardized questionnaire , which was completed by the physician based upon medical files . blood pressure was measured twice in the sitting position after a 10-min rest , and the average of these two measurements was used in the analysis . height , weight , and waist - to - hip ratio were recorded , and blood was drawn for the measurements of hba1c , lipids , and creatinine . hba1c and creatinine were determined by standardized assays at each center and glomerular filtration rate ( gfr ) estimated using the chronic kidney disease epidemiology collaboration formula ( 12,13 ) . serum lipid and lipoprotein concentrations were analyzed centrally by automated enzymatic methods ( hoffmann - la roche , basel , switzerland ) . urinary albumin was determined in one sample using an immunoturbidimetric method ( hitachi 911 analyzer ; roche diagnostics , basel , switzerland ) . in addition , serum opg was measured by a sandwich time - resolved immunofluorometric assay using commercially available antibodies ( r&d systems , minneapolis , mn ) , as previously described ( 14 ) . renal status was defined based on the urinary albumin excretion rate ( aer ) in three overnight or 24-h urine collections . normal aer was defined as < 20 g / min or < 30 mg/24 h , microalbuminuria as 20 g / min  aer < 200 g / min or 30 mg/24 h  aer < 300 mg/24 h , and macroalbuminuria as aer 200 g / min or 300 mg/24 h. esrd was defined as patients undergoing dialysis or having received a kidney transplant . identification of the cvd until the end of 2010 was obtained by linking the finndiane data with the hospital discharge register ( hdr ) and the finnish cause of death registry . the hdr lists all discharged hospital patients , each patient s unique personal identifier ( assigned to every resident of finland ) , dates of admission and discharge , and up to four diagnoses with the icd and procedure codes that are based on the nordic classification of surgical procedures . completeness and accuracy of the hdr concerning vascular disease has been shown to be very high ( 15 ) . cvd was defined as a history of myocardial infarction , a coronary artery procedure ( bypass surgery or angioplasty ) , stroke , or a peripheral artery procedure ( bypass surgery or angioplasty ) , which was verified on the basis of icd discharge codes specifying cv events . limb amputations were further ascertained on the basis of icd discharge codes specifying amputation , regardless of the presence or absence of documented peripheral vascular disease ( pvd ) . deaths from any cause through to 17 march 2010 were identified via a search of the finnish national death registry and center databases . vitality status was verified from the finnish national death registry and cause of death classified on the basis of death certificates . the causes of death in this cohort were cv death ( 49% ) , cancer - related death ( 8% ) , infection - related death ( 9% ) , and other causes ( 34% ) . pairwise multiple comparisons were made with the student - newman - keuls post hoc analysis to detect significant differences between groups . a p value < 0.05 was considered statistically significant . to evaluate the independent predictors of all - cause mortality , cv , coronary , stroke , and amputation events , we used multivariate cox proportional hazards models . model selection from candidate variables was accomplished by minimization of the akaike and bayesian information criteria ( 16 ) . overall , cox model fit was assessed by : 1 ) approximation of cumulative cox - snell residuals to ( -log ) kaplan - meier estimates , residual plots , and specific testing of the proportional hazards assumption ( 17 ) and 2 ) harrell s c statistic ( 18 ) and added - variable goodness - of - fit tests ( 19 ) . cox model performance was adjudged by the explained variation using 5,000 bootstrap repetitions of the whole data set , adjusting for covariates ( 20 ) . the potential for multiple colinearity was tested using the variance inflation factor and condition number , in which a variance inflation factor < 10 and condition number < 30 are desirable ( 21 ) . this study is part of the ongoing finnish diabetic nephropathy ( finndiane ) study , with the aim to identify genetic , clinical , and environmental risk factors for diabetic nephropathy in patients with t1d . the study was initiated in 1997 , and follow - up data have been collected since 2004 either by re - examination of the patients or review of the medical files . detailed description of the follow - up protocol has been described previously ( 11 ) . t1d was defined as an onset of diabetes before the age of 40 years and permanent insulin treatment initiated within 1 year of diagnosis . for this study , outcomes were ascertained in patients in the finndiane prospective cohort recruited between 1997 and 2004 , in whom serum opg was estimated on baseline samples ( n = 1,939 ) . furthermore , patients with end - stage renal disease ( esrd ; dialysis or transplantation ) at baseline were excluded from analysis , as risk factors for adverse outcomes are clearly different in these patients . written informed consent was obtained from each patient , and the study was performed in accordance with the declaration of helsinki as revised in the year 2000 . at baseline , all patients also underwent a thorough clinical investigation in connection with a regular patient visit to their attending physician . data on medication and diabetes complications were registered with the use of a standardized questionnaire , which was completed by the physician based upon medical files . blood pressure was measured twice in the sitting position after a 10-min rest , and the average of these two measurements was used in the analysis . height , weight , and waist - to - hip ratio were recorded , and blood was drawn for the measurements of hba1c , lipids , and creatinine . hba1c and creatinine were determined by standardized assays at each center and glomerular filtration rate ( gfr ) estimated using the chronic kidney disease epidemiology collaboration formula ( 12,13 ) . serum lipid and lipoprotein concentrations were analyzed centrally by automated enzymatic methods ( hoffmann - la roche , basel , switzerland ) . urinary albumin was determined in one sample using an immunoturbidimetric method ( hitachi 911 analyzer ; roche diagnostics , basel , switzerland ) . in addition , serum opg was measured by a sandwich time - resolved immunofluorometric assay using commercially available antibodies ( r&d systems , minneapolis , mn ) , as previously described ( 14 ) . renal status was defined based on the urinary albumin excretion rate ( aer ) in three overnight or 24-h urine collections . normal aer was defined as < 20 g / min or < 30 mg/24 h , microalbuminuria as 20 g / min  aer < 200 g / min or 30 mg/24 h  aer < 300 mg/24 h , and macroalbuminuria as aer 200 g / min or 300 mg/24 h. esrd was defined as patients undergoing dialysis or having received a kidney transplant . identification of the cvd until the end of 2010 was obtained by linking the finndiane data with the hospital discharge register ( hdr ) and the finnish cause of death registry . the hdr lists all discharged hospital patients , each patient s unique personal identifier ( assigned to every resident of finland ) , dates of admission and discharge , and up to four diagnoses with the icd and procedure codes that are based on the nordic classification of surgical procedures . completeness and accuracy of the hdr concerning vascular disease has been shown to be very high ( 15 ) . cvd was defined as a history of myocardial infarction , a coronary artery procedure ( bypass surgery or angioplasty ) , stroke , or a peripheral artery procedure ( bypass surgery or angioplasty ) , which was verified on the basis of icd discharge codes specifying cv events . limb amputations were further ascertained on the basis of icd discharge codes specifying amputation , regardless of the presence or absence of documented peripheral vascular disease ( pvd ) . deaths from any cause through to 17 march 2010 were identified via a search of the finnish national death registry and center databases . vitality status was verified from the finnish national death registry and cause of death classified on the basis of death certificates . the causes of death in this cohort were cv death ( 49% ) , cancer - related death ( 8% ) , infection - related death ( 9% ) , and other causes ( 34% ) . pairwise multiple comparisons were made with the student - newman - keuls post hoc analysis to detect significant differences between groups . a p value < 0.05 was considered statistically significant . to evaluate the independent predictors of all - cause mortality , cv , coronary , stroke , and amputation events , we used multivariate cox proportional hazards models . model selection from candidate variables was accomplished by minimization of the akaike and bayesian information criteria ( 16 ) . overall , cox model fit was assessed by : 1 ) approximation of cumulative cox - snell residuals to ( -log ) kaplan - meier estimates , residual plots , and specific testing of the proportional hazards assumption ( 17 ) and 2 ) harrell s c statistic ( 18 ) and added - variable goodness - of - fit tests ( 19 ) . cox model performance was adjudged by the explained variation using 5,000 bootstrap repetitions of the whole data set , adjusting for covariates ( 20 ) . the potential for multiple colinearity was tested using the variance inflation factor and condition number , in which a variance inflation factor < 10 and condition number < 30 are desirable ( 21 ) . the finndiane cohort in whom serum opg was estimated comprised 1,939 adult patients with t1d without esrd . the cohort characteristics at baseline have been previously described in detail ( 11 ) and are summarized in table 1 . the mean age of the participants was 39 years , with a median duration of diabetes of 20 years . forty - seven percent of patients had hypertension ( defined by the use of antihypertensive agents and/or a blood pressure > 140/90 mmhg ) . at baseline , 17% had a urinary aer in the microalbuminuric range , 13% had a urinary aer in the macroalbuminuric range , and 65% had a urinary aer in the normoalbuminuric range . a further 5% of study participants were unclassified because of an inadequate number of urine collections , and 12% of patients had an estimated gfr ( egfr ) < 60 ml / min/1.73 m , most of whom also had macroalbuminuria . demographic and biochemical characteristics of the study subjects serum opg concentrations did not differ between patients with t1d and normoalbuminuria or microalbuminuria ( table 1 ) . however , patients with macroalbuminuria had higher opg concentrations than those with microalbuminuria or normal aer . patients with moderate to severe renal impairment ( egfr < 60 ml / min/1.73 m ) also had higher opg concentrations that those without renal impairment ( 1.9  0.1 vs. 1.4  0.1 g / ml ; p < 0.05 ) . in addition , after adjusting for renal function , opg remained independently correlated with high - sensitivity c - reactive protein , a marker of systemic inflammation ( p < 0.01 ) , and hba1c , a marker of chronic glycemic control ( p < 0.05 ; data not shown ) . notably age , sex , body mass , blood pressure , and lipid concentrations were not associated with opg after adjusting for renal function . patients with established cvd had higher opg concentrations than those without macrovascular disease ( 2.0  0.1 vs. 1.7  0.1 mg / l ; p < 0.001 ) . however , the observed difference in serum opg in patients with t1d with or without cvd was attributable to an excess of patients with ckd and eliminated after adjusting for renal function . furthermore , patients with retinopathy requiring laser treatment had higher opg concentrations than those without severe retinal disease ( 1.9  0.1 vs. 1.6  0.1 mg / l ; p < 0.001 ) . a total of 166 patients ( 9% , 0.8 per hundred person - years ) died during follow - up ( mean of 10.2 years ) . serum opg concentrations at baseline were higher in patients who died due to an all - cause mortality ( 2.0  0.1 vs. 1.6  0.1 mg / l ; p = 0.006 ) . however , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with all - cause mortality , opg was no longer associated with all - cause mortality on multivariate cox regression analysis ( p not significant ; table 2 ) . cox regression analysis for the predictive value of serum opg for all - cause mortality , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event during the follow - up period ( mean of 10.5 years ) , 190 patients experienced their first cv event ever ( of 1,844 patients without prior cvd ; 1.0 per hundred patient - years ) . again , serum opg concentrations at baseline were higher in patients who had an incident cvd event ( 2.2  0.1 vs. 1.6  0.1 mg / l ; p < 0.001 ) . after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with cvd , opg remained significantly associated with incident cvd on multivariate cox regression analysis ( p = 0.03 ; table 3 , fig . cox regression analysis for the predictive value of serum opg for incident cvd , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event the relationship of serum opg concentrations ( above and below the mean ) with new - onset cvd ( a ) and amputation / leg revascularization ( b ) , stratified according to the stage of albuminuria , and adjusted for other risk factors . , patients with microalbuminuria and opg concentrations below median ; + , patients with microalbuminuria and opg concentrations above median ; m , patients with macroalbuminuria and opg concentrations below median ; m+ , patients with macroalbuminuria and opg concentrations above median ; n , patients with normal aer and opg concentrations below median ; n+ , patients with normal aer and opg concentrations above median . during the follow - up period ( mean of 10.5 years ) , 152 patients experienced their first coronary event ( of 1,868 patients without prior coronary heart disease [ chd ] ; 0.8 per hundred patient - years ) . furthermore , serum opg concentrations at baseline were increased in patients who had an incident cvd event ( 2.2  0.1 vs. 1.3  0.1 mg / l ; p = 0.002 ) . after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with chd , the association of opg with incident chd was of borderline significance on multivariate cox regression analysis ( p = 0.07 ; table 4 ) . cox regression analysis for the predictive value of serum opg for incident chd , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event during a mean of 10.3 years of follow - up , 71 patients experienced their first stroke event ( of 1,903 patients without a prior stroke ; 0.3 per hundred patient - years ) . again , serum opg concentrations at baseline were higher in patients who had an incident stroke ( 2.2  0.1 vs. 1.6  0.1 mg / l ; p = 0.02 ) . after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with stroke , opg was not associated with stroke on multivariate cox regression analysis ( p = 0.7 ; table 5 ) . cox regression analysis for the predictive value of serum opg for incident stroke , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event during a mean of 10.2 years of follow - up , 80 patients had a leg revascularization procedure or an amputation ( any cause ) as their first cv event ( of 1,922 patients without prior cvd ; 0.4% per hundred patient - years ) . serum opg concentrations at baseline were higher in patients who had an incident leg revascularization procedure or amputation ( 2.0  0.1 vs. 1.6  0.1 mg / l ; p < 0.001 ) . after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with pvd events , opg was independently associated with leg revascularization procedure or an amputation on multivariate cox regression analysis ( p = 0.004 ; table 6 , fig . cox regression analysis for the predictive value of serum opg for incident amputation or peripheral revascularization , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event the finndiane cohort in whom serum opg was estimated comprised 1,939 adult patients with t1d without esrd . the cohort characteristics at baseline have been previously described in detail ( 11 ) and are summarized in table 1 . the mean age of the participants was 39 years , with a median duration of diabetes of 20 years . forty - seven percent of patients had hypertension ( defined by the use of antihypertensive agents and/or a blood pressure > 140/90 mmhg ) . at baseline , 17% had a urinary aer in the microalbuminuric range , 13% had a urinary aer in the macroalbuminuric range , and 65% had a urinary aer in the normoalbuminuric range . a further 5% of study participants were unclassified because of an inadequate number of urine collections , and 12% of patients had an estimated gfr ( egfr ) < 60 ml / min/1.73 m , most of whom also had macroalbuminuria . serum opg concentrations did not differ between patients with t1d and normoalbuminuria or microalbuminuria ( table 1 ) . however , patients with macroalbuminuria had higher opg concentrations than those with microalbuminuria or normal aer . patients with moderate to severe renal impairment ( egfr < 60 ml / min/1.73 m ) also had higher opg concentrations that those without renal impairment ( 1.9  0.1 vs. 1.4  0.1 g / ml ; p < 0.05 ) . in addition , after adjusting for renal function , opg remained independently correlated with high - sensitivity c - reactive protein , a marker of systemic inflammation ( p < 0.01 ) , and hba1c , a marker of chronic glycemic control ( p < 0.05 ; data not shown ) . notably age , sex , body mass , blood pressure , and lipid concentrations were not associated with opg after adjusting for renal function . patients with established cvd had higher opg concentrations than those without macrovascular disease ( 2.0  0.1 vs. 1.7  0.1 mg / l ; p < 0.001 ) . however , the observed difference in serum opg in patients with t1d with or without cvd was attributable to an excess of patients with ckd and eliminated after adjusting for renal function . furthermore , patients with retinopathy requiring laser treatment had higher opg concentrations than those without severe retinal disease ( 1.9  0.1 vs. 1.6  0.1 mg / l ; p < 0.001 ) . a total of 166 patients ( 9% , 0.8 per hundred person - years ) died during follow - up ( mean of 10.2 years ) . serum opg concentrations at baseline were higher in patients who died due to an all - cause mortality ( 2.0  0.1 vs. 1.6  0.1 mg / l ; p = 0.006 ) . however , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with all - cause mortality , opg was no longer associated with all - cause mortality on multivariate cox regression analysis ( p not significant ; table 2 ) . cox regression analysis for the predictive value of serum opg for all - cause mortality , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event during the follow - up period ( mean of 10.5 years ) , 190 patients experienced their first cv event ever ( of 1,844 patients without prior cvd ; 1.0 per hundred patient - years ) . again , serum opg concentrations at baseline were higher in patients who had an incident cvd event ( 2.2  0.1 vs. 1.6  0.1 mg / l ; p < 0.001 ) . after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with cvd , opg remained significantly associated with incident cvd on multivariate cox regression analysis ( p = 0.03 ; table 3 , fig . cox regression analysis for the predictive value of serum opg for incident cvd , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event the relationship of serum opg concentrations ( above and below the mean ) with new - onset cvd ( a ) and amputation / leg revascularization ( b ) , stratified according to the stage of albuminuria , and adjusted for other risk factors . , patients with microalbuminuria and opg concentrations below median ; + , patients with microalbuminuria and opg concentrations above median ; m , patients with macroalbuminuria and opg concentrations below median ; m+ , patients with macroalbuminuria and opg concentrations above median ; n , patients with normal aer and opg concentrations below median ; n+ , patients with normal aer and opg concentrations above median . during the follow - up period ( mean of 10.5 years ) , 152 patients experienced their first coronary event ( of 1,868 patients without prior coronary heart disease [ chd ] ; 0.8 per hundred patient - years ) . furthermore , serum opg concentrations at baseline were increased in patients who had an incident cvd event ( 2.2  0.1 vs. 1.3  0.1 mg / l ; p = 0.002 ) . after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with chd , the association of opg with incident chd was of borderline significance on multivariate cox regression analysis ( p = 0.07 ; table 4 ) . cox regression analysis for the predictive value of serum opg for incident chd , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event during a mean of 10.3 years of follow - up , 71 patients experienced their first stroke event ( of 1,903 patients without a prior stroke ; 0.3 per hundred patient - years ) . again , serum opg concentrations at baseline were higher in patients who had an incident stroke ( 2.2  0.1 vs. 1.6  0.1 mg / l ; p = 0.02 ) . after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with stroke , opg was not associated with stroke on multivariate cox regression analysis ( p = 0.7 ; table 5 ) . cox regression analysis for the predictive value of serum opg for incident stroke , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event during a mean of 10.2 years of follow - up , 80 patients had a leg revascularization procedure or an amputation ( any cause ) as their first cv event ( of 1,922 patients without prior cvd ; 0.4% per hundred patient - years ) . serum opg concentrations at baseline were higher in patients who had an incident leg revascularization procedure or amputation ( 2.0  0.1 vs. 1.6  0.1 mg / l ; p < 0.001 ) . after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with pvd events , opg was independently associated with leg revascularization procedure or an amputation on multivariate cox regression analysis ( p = 0.004 ; table 6 , fig . cox regression analysis for the predictive value of serum opg for incident amputation or peripheral revascularization , after adjusting for factors associated with serum opg concentrations , as well as other factors independently associated with the studied event opg concentrations are positively correlated with coronary calcification ( 6 ) , vascular stiffness ( 7 ) , and the presence of unstable plaque ( 8) as well as all - cause and cv mortality in elderly women ( 22 ) , as well as men with coronary artery disease ( 23 ) . previous studies have suggested that opg concentrations are also associated with cv mortality in patients with diabetes ( 9,10,24 ) . the current study extends these findings to show that opg predicted not only incident cvd and pvd events but was also associated with the risk of all - cause mortality in patients with t1d . although it has been suggested in small studies that children with t1d have increased opg concentrations compared with nondiabetic individuals ( 25 ) , in our large adult cohort , opg concentrations were not directly elevated by t1d . elevation of the opg concentration was only observed in those with overt nephropathy or established macrovascular disease . the mechanisms by which opg concentrations are increased in these settings are unclear ( 26 ) . the retention of peptides like opg and cystatin c associated with renal impairment provides part of the answer . in our study , opg levels were certainly higher in patients with moderate to severe renal impairment ( egfr < 60 ml / min/1.73 m ) . however , after adjusting for renal function and albuminuria , opg levels remained a significant predictor of adverse outcomes . indeed , some of the risk attributable to renal disease may be medicated through accelerated vascular calcification . this may be one reason why egfr was eliminated as an independent predictor of adverse outcomes in this cohort . the independent association of opg with high - sensitivity c - reactive protein , a marker of systemic inflammation ( p < 0.01 ) , may also have contributed to elevated opg levels in patients with overt complications , as inflammation is also elevated in patients with complications and inflammation may also drive the expression of opg . it acts as a receptor for the receptor activator of nuclear factor-b ligand ( rankl ) and interferes in its binding to cell - surface rank ( 27 ) . opg has been shown to block the differentiation of osteoclasts , the bone - resorbing cell type . opg also has an important regulatory role in endocrine function and the immune system ( 4 ) . opg is present in blood vessels ( 4,28 ) and especially in the smooth muscle cells of the vascular media ( 29,30 ) , which are thought to be the major source of opg in the arterial wall . consequently , the elevation of circulating opg concentrations in proatherogenic settings has been thought to represent a compensatory phenomenon to limit further vascular damage . however , by inhibiting the regulatory pathways signaled through the rank receptor , and particularly those of the atheroprotective ligand tumor necrosis factor-related apoptosis - inducing ligand ( trail ) ( 33 ) , elevated opg concentrations may also have direct actions on vascular function , as well as the development and progression of vascular disease . indeed , it has been previously shown that human full - length opg induces the proliferation of rodent vascular smooth muscle cells and augments atherogenesis in diabetic apolipoprotein e knockout mice ( 34 ) . in addition , it has been demonstrated that opg is able to initiate transforming growth factor-dependent changes in vascular smooth muscle cells , stimulating proliferation , inflammation , and fibrogenesis . such data suggest that the increases in adverse vascular outcomes associated with elevated opg concentration in our patients with t1d may be causally linked . vascular calcification is strongly associated with pvd in patients with diabetes , including the risk for amputation . vascular calcification score on plain radiographs of the feet is a predictor of peripheral arterial disease in patients with ckd . however , our study is the first to show an independent link between opg and peripheral vascular events ( amputation or revascularization ) . although amputation may have multiple etiologies , we chose to use this more pragmatic outcome as it is often difficult to determine the relative contribution of infection , neuropathy , or vascular insufficiency as the cause of a foot ulcer or subsequent need for amputation . while opg was higher in those participants with severe retinal disease in our much larger patient cohort , after adjusting for the confounding effects of renal impairment , this difference was eliminated . similarly , no association between opg and diabetic retinopathy was reported in a cohort of 200 patients with t1d ( 35 ) . by contrast , opg has previously been associated with maculopathy in patients with type 2 diabetes ( t2d ) ( 24 ) . the reasons for this difference between t1d and t2d is unclear , although it may be due to confounding effects of renal impairment in older patients with t2d . in conclusion , we demonstrate that serum opg is independently associated with cv complications and mortality in adults with t1d . blocking the actions of opg consequently may therefore offer one potential intervention to slow the development and progression of vascular disease in diabetes . indeed , complete blockade of opg in mice causes early onset osteoporosis and arterial calcification ( 32 ) . this suggests that a better target for the prevention of vascular disease may be to augment its ligands , trail and rankl . for example , studies using trail in apolipoprotein e knockout mice with t1d have shown promising reductions in atherogenesis ( 33 ) , possibly by overcoming the inhibitory effects of its decoy - receptor opg .