Target Values and Daytime Variation of Bone Turnover Markers in Monitoring Osteoporosis Treatment After Fractures

The serum bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type 1 collagen (CTX) are recommended for monitoring adherence and response of antiresorptive drugs (ARD). BTM are elevated about 1 year after fracture and therefore BTM target values are most convenient in ARD treatment follow-up of fracture patients. In this prospective cohort study, we explored the cut-off values of P1NP and CTX showing the best discriminating ability with respect to adherence and treatment effects, reflected in bone mineral density (BMD) changes. Furthermore, we explored the ability of BTM to predict subsequent fractures and BTM variation during daytime in patients using ARD or not. After a fragility fracture, 228 consenting patients (82.2% women) were evaluated for ARD indication and followed for a mean of 4.6 years (SD 0.5 years). BMD was measured at baseline and after 2 years. Serum BTM were measured after 1 or 2 years. The largest area under the curve (AUC) for discrimination of patients taking ARD or not was shown for P1NP 2% gain in BMD (lumbar spine and total hip) was largest at cut-off values for P1NP <30 μg/L and CTX <0.25 μg/L. Higher P1NP was associated with increased fracture risk in patients using ARD (hazard ratio [HR]logP1NP = 15.0; 95% confidence interval [CI] 2.7–83.3), p = 0.002. P1NP and CTX were stable during daytime, except in those patients not taking ARD, where CTX decreased by 21% per hour during daytime. In conclusion, P1NP <30 μg/L and CTX <0.25 μg/L yield the best discrimination between patients taking and not taking ARD and the best prediction of BMD gains after 2 years. Furthermore, higher P1NP is associated with increased fracture risk in patients on ARD. BTM can be measured at any time during the day in patients on ARD.publishedVersio

Estimated Glomerular Filtration Rate (eGFR) based on cystatin C was associated with increased risk of hip and proximal humerus fractures in women and decreased risk of hip fracture in men, whereas eGFR based on creatinine was not associated with fracture risk in both sexes: The Tromsø Study

Purpose - Patients with end-stage kidney disease have an increased fracture risk. Whether mild to moderate reductions in kidney function is associated with increased fracture risk is uncertain. Results from previous studies may be confounded by muscle mass because of the use of creatinine-based estimates of the glomerular filtration rate (eGFRcre). We tested the hypothesis that lower eGFR within the normal range of kidney function based on serum cystatin C (eGFRcys) or both cystatin C and creatinine (eGFRcrecys) predict fractures better than eGFR based on creatinine (eGFRcre). Methods - In the Tromsø Study 1994–95, a cohort of 3016 women and 2836 men aged 50–84 years had eGFRcre, eGFRcys and eGFRcrecys estimated using the Chronic Kidney Disease Epidemiology Collaboration equations. Hazard ratios (HRs) (95% confidence intervals) for fracture were calculated in Cox's proportional hazards models and adjusted for age, height, body mass index, bone mineral density, diastolic blood pressure, smoking, physical activity, previous fracture, diabetes and cardiovascular disease. Results - During a median of 14.6 years follow-up, 232, 135 and 394 women and 118, 35 and 65 men suffered incident hip, proximal humerus and wrist fractures. In women, lower eGFRcre did not predict fracture, but the risk for hip and proximal humerus fracture increased per standard deviation (SD) lower eGFRcys (HRs 1.36 (1.16–1.60) and 1.33 (1.08–1.63)) and per SD lower eGFRcrecys (HRs 1.25 (1.08–1.45) and 1.30 (1.07–1.57)). In men, none of the eGFR estimates were related to increased fracture risk. In contrast, eGFRcys and eGFRcrecys were inversely associated with hip fracture risk (HRs 0.85 (0.73–0.99) and 0.82 (0.68–0.98)). Conclusions - In women, each SD lower eGFRcys and eGFRcrecys increased the risk of hip and proximal humerus fracture by 25–36%, whereas eGFRcre did not. In men, none of the estimates of eGFR were related to increased fracture risk, and each SD lower eGFRcys and eGFRcrecys decreased the risk of hip fracture by 15–18%. The findings particularly apply to a cohort of generally healthy individuals with a normal kidney function. In future studies, the association of measured GFR using the gold standard method of iohexol clearance with fractures risk should be examined for causal inference. More clinical research is needed before robust clinical inferences can be made

Trabecular bone score and vertebral fracture assessment in patients with fragility fractures

Background Trabecular bone score (TBS), vertebral fracture assessment (VFA) and bone mineral density (BMD) affords information of bone strength and fracture risk. Further understanding of the contribution of each of them in post-fracture risk assessment is of interest to improve identification of individuals at high risk of subsequent fractures and to set screening strategies for fracture patients. In patients with recent fragility fractures, we studied risk factors for fracture, TBS, prevalence of semiquantitatively assessed vertebral fractures (SQ1-SQ3 fractures) using VFA and assessed BMD using dual energy x-ray absorptiometry. The objectives were to explore i) the clinical characteristics, prevalence of low TBS and SQ1-SQ3 fractures in patients with fractures, ii) the differences between the sexes and between patients with and without vertebral fractures, iii) the risk factors for fractures including TBS, proportion of SQ1-SQ3 fractures and BMD in patients with different types of fragility fractures, iv) the differences between patients with central and peripheral fractures and v) the determinants of TBS and SQ1-SQ3 fractures and the interaction between these. Methods This cross-sectional study included a total of 839 women and men above 50 years of age who recently had sustained a fragility fracture. A total of 771 had TBS calculated, 679 had VFA performed, 804 had BMD of the total hip, femoral neck and/or spine, and 696 had responded to a questionnaire about risk factors for fracture. Paper I included all these patients. Of these, 495 women and 119 men who all had valid measurement of TBS, VFA and BMD of the femoral neck, total hip and lumbar spine were included in paper II. Paper III included 496 women who all had responded to a questionnaire about risk factors for fracture, had valid measurements of TBS and BMD of femoral neck and/or lumbar spine and 423 had VFA performed. Results Paper I: The mean age of the patients was 65.8 years and 80.5% were women. The prevalence of low TBS (≤ 1.23) was 34.0% and 34.8% had SQ1-SQ3 fractures. The proportion of patients with osteoporosis (BMD T-score ≤ -2.5) at the femoral neck was 13.8% and the skeletal site with lowest BMD T-score 27.4%. Women exhibited lower mean TBS and lower BMD at all sites than men. Patients with SQ1-SQ3 fractures were older, had lower TBS and lower BMD at all sites than those without SQ1-SQ3 fractures (all p < 0.05). Paper II: Patients with centrally sited fractures exhibited lower mean TBS and a higher proportion of both SQ1-SQ3 fractures, SQ2-SQ3 fractures and SQ3 fractures and lower BMD of the femoral neck, total hip and lumbar spine than patients with peripherally sited fractures (all p < 0.05). Paper III: Higher age, a history of parental hip fracture and daily alcohol intake were associated with lower TBS. Higher BMD of the femoral neck and lumbar spine were associated with higher TBS. Age and prior fragility fractures were positively associated with SQ1-SQ3 fractures, while lumbar spine BMD was negatively associated with SQ1-SQ3 fractures. No association between TBS and SQ1-SQ3 fractures was found. Conclusions More than half of the patients with fragility fractures had SQ1-SQ3 fractures, low TBS or both. Patients with central fragility fractures exhibited lower TBS, a higher prevalence of SQ1-SQ3 fractures and lower femoral neck BMD than patients with peripheral fractures. This suggests that patients with central fragility fractures have a higher risk of subsequent fractures and should get the highest priority in secondary fracture prevention. No association between TBS and SQ1-SQ3 fractures was found; hence they may act as independent risk factors, justifying the use of both in post-fracture risk assessment

Increased cortical porosity and reduced cortical thickness of the proximal femur are associated with nonvertebral fracture independent of Fracture Risk Assessment Tool and Garvan estimates in postmenopausal women

The Fracture Risk Assessment Tool (FRAX) and Garvan Calculator have improved the individual prediction of fracture risk. However, additional bone measurements that might enhance the predictive ability of these tools are the subject of research. There is increasing interest in cortical parameters, especially cortical porosity. Neither FRAX nor Garvan include measurements of cortical architecture, important for bone strength, and providing independent information beyond the conventional approaches. We tested the hypothesis that cortical parameters are associated with fracture risk, independent of FRAX and Garvan estimates. This nested case-control study included 211 postmenopausal women aged 54–94 years with nonvertebral fractures, and 232 controls from the Tromsø Study in Norway. We assessed FRAX and Garvan 10-year risk estimates for fragility fracture, and quantified femoral subtrochanteric cortical porosity, thickness, and area from computed tomography images using StrAx1.0 software. Per standard deviation higher cortical porosity, thinner cortices, and smaller cortical area, the odds ratio (95% confidence interval) for fracture was 1.71 (1.38–2.11), 1.79 (1.44–2.23), and 1.52 (1.19–1.95), respectively. Cortical porosity and thickness, but not area, remained associated with fracture when adjusted for FRAX and Garvan estimates. Adding cortical porosity and thickness to FRAX or Garvan resulted in greater area under the receiver operating characteristic curves. When using cortical porosity (>80th percentile) or cortical thickness (20%), 45.5% and 42.7% of fracture cases were identified, respectively. Using the same cutoffs for cortical porosity or thickness combined with Garvan (threshold >25%), 51.2% and 48.3% were identified, respectively. Specificity for all combinations ranged from 81.0–83.6%. Measurement of cortical porosity or thickness identified 20.4% and 17.5% additional fracture cases that, were unidentified using FRAX alone, and 16.6% and 13.7% fracture cases unidentified using Garvan alone. In conclusion, cortical parameters may help to improve identification of women at risk for fracture

Cortical bone structure of the proximal femur and incident fractures

Purpose: Fracture risk is most frequently assessed using Dual X-ray absorptiometry to measure areal bone mineral density (aBMD) and using the Fracture Risk Assessment Tool (FRAX). However, these approaches have limitations and additional bone measurements may enhance the predictive ability of these existing tools. Increased cortical porosity has been associated with incident fracture in some studies, but not in others. In this prospective study, we examined whether cortical bone structure of the proximal femur predicts incident fractures independent of aBMD and FRAX score. Methods: We pooled 211 postmenopausal women with fractures aged 54–94 years at baseline and 232 fracturefree age-matched controls based on a prior nested case-control study from the Tromsø Study in Norway. We assessed baseline femoral neck (FN) aBMD, calculated FRAX 10-year probability of major osteoporotic fracture (MOF), and quantified femoral subtrochanteric cortical parameters: porosity, area, thickness, and volumetric BMD (vBMD) from CT images using the StrAx1.0 software. Associations between bone parameters and any incident fracture, MOF and hip fracture were determined using Cox's proportional hazard models to calculate hazard ratio (HR) with 95% confidence interval. Results: During a median follow-up of 7.2 years, 114 (25.7%) of 443 women suffered one or more incident fracture. Cortical bone structure did not predict any incident fracture or MOF after adjustment for age, BMI, and previous fracture. Each SD higher total cortical porosity, thinner cortices, and lower cortical vBMD predicted hip fracture with increased risk of 46–62% (HRs ranging from 1.46 (1.01–2.11) to 1.62 (1.02–2.57)). After adjustment for FN aBMD or FRAX score no association remained significant. Both lower FN aBMD and higher FRAX score predicted any incident fracture, MOF and hip fractures with HRs ranging from 1.45–2.56. Conclusions: This study showed that cortical bone measurements using clinical CT did not add substantial insight into fracture risk beyond FN aBMD and FRAX. We infer from these results that fracture risk related to the deteriorated bone structure seems to be largely captured by a measurement of FN aBMD and the FRAX tool

Target Values and Daytime Variation of Bone Turnover Markers in Monitoring Osteoporosis Treatment After Fractures

The serum bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type 1 collagen (CTX) are recommended for monitoring adherence and response of antiresorptive drugs (ARD). BTM are elevated about 1 year after fracture and therefore BTM target values are most convenient in ARD treatment follow-up of fracture patients. In this prospective cohort study, we explored the cut-off values of P1NP and CTX showing the best discriminating ability with respect to adherence and treatment effects, reflected in bone mineral density (BMD) changes. Furthermore, we explored the ability of BTM to predict subsequent fractures and BTM variation during daytime in patients using ARD or not. After a fragility fracture, 228 consenting patients (82.2% women) were evaluated for ARD indication and followed for a mean of 4.6 years (SD 0.5 years). BMD was measured at baseline and after 2 years. Serum BTM were measured after 1 or 2 years. The largest area under the curve (AUC) for discrimination of patients taking ARD or not was shown for P1NP 2% gain in BMD (lumbar spine and total hip) was largest at cut-off values for P1NP <30 μg/L and CTX <0.25 μg/L. Higher P1NP was associated with increased fracture risk in patients using ARD (hazard ratio [HR]logP1NP = 15.0; 95% confidence interval [CI] 2.7–83.3), p = 0.002. P1NP and CTX were stable during daytime, except in those patients not taking ARD, where CTX decreased by 21% per hour during daytime. In conclusion, P1NP <30 μg/L and CTX <0.25 μg/L yield the best discrimination between patients taking and not taking ARD and the best prediction of BMD gains after 2 years. Furthermore, higher P1NP is associated with increased fracture risk in patients on ARD. BTM can be measured at any time during the day in patients on ARD

Serum parathyroid hormone is associated with increased cortical porosity of the inner transitional zone at the proximal femur in postmenopausal women: the Tromsø Study

Summary: Serum parathyroid hormone (PTH) was associated with increased bone turnover markers and cortical porosity of the inner transitional zone at the proximal femur. These results suggest that PTH through increased intracortical bone turnover leads to trabecularisation of inner cortical bone in postmenopausal women. Introduction: Vitamin D deficiency leads to secondary hyperparathyroidism and increased risk for fractures, whereas its association with cortical porosity is less clear. We tested (i) whether serum 25-hydroxyvitamin D (25(OH)D) and PTH were associated with cortical porosity and (ii) whether the associations of 25(OH)D) and PTH with fracture risk are dependent on cortical porosity. Methods: This case-control study included 211 postmenopausal women, 54–94 years old, with prevalent fractures and 232 controls from the Tromsø Study. Serum 25(OH)D, PTH, and bone turnover markers (procollagen type I N-terminal propeptide [PINP] and C-terminal cross-linking telopeptide of type I collagen [CTX]) were measured. Femoral subtrochanteric cortical and trabecular parameters were quantified using computed tomography, and femoral neck areal bone mineral density (FN aBMD) was quantified using dual-energy X-ray absorptiometry. Results: Compared with controls, fracture cases exhibited reduced serum 25(OH)D and increased PTH, PINP, and CTX, increased femoral subtrochanteric cortical porosity, and reduced cortical thickness and FN aBMD (all, p  0.10). PTH was associated with increased PINP, CTX, and cortical porosity of the inner transitional zone and reduced trabecular bone volume/tissue volume and FN aBMD (p ranging from 0.003 to 0.054). Decreasing 25(OH)D and increasing PTH were associated with increased odds for fractures, independent of age, height, weight, calcium supplementation, serum calcium, cortical porosity, and thickness. Conclusions: These data suggest that serum PTH, not 25(OH)D, is associated with increased intracortical bone turnover resulting in trabecularisation of the inner cortical bone; nevertheless, decreasing 25(OH)D) and increasing PTH are associated with fracture risk, independent of cortical porosity and thickness

Women with type 2 diabetes mellitus have lower cortical porosity of the proximal femoral shaft using low-resolution CT than nondiabetic women, and increasing glucose is associated with reduced cortical porosity

Increased cortical porosity has been suggested as a possible factor increasing fracture propensity in patients with type 2 diabetes mellitus (T2DM). This is a paradox because cortical porosity is generally associated with high bone turnover, while bone turnover is reduced in patients with T2DM. We therefore wanted to test the hypothesis that women with T2DM have lower bone turnover markers (BTM) and lower cortical porosity than those without diabetes, and that higher serum glucose and body mass index (BMI) are associated with lower BTM, and with lower cortical porosity. This cross-sectional study is based on a prior nested case-control study including 443 postmenopausal women aged 54–94 years from the Tromsø Study, 211 with non-vertebral fracture and 232 fracture-free controls. Of those 443 participants, 22 women exhibited T2DM and 421 women did not have diabetes. All had fasting blood samples assayed for procollagen type I N-terminal propeptide (PINP), C-terminal cross-linking telopeptide of type I collagen (CTX) and glucose, and femoral subtrochanteric architecture was quantified using low-resolution clinical CT and StrAx1.0 software. Women with T2DM had higher serum glucose (7.2 vs. 5.3 mmol/L), BMI (29.0 vs. 26.4 kg/m2), and higher femoral subtrochanteric total volumetric bone mineral density (vBMD) (783 vs. 715 mg HA/cm3), but lower cortical porosity (40.9 vs. 42.8%) than nondiabetic women (all p Increasing glucose and BMI were associated with lower bone turnover suggesting that reduced intracortical and endocortical remodeling leads to reduced porosity and thicker cortices. Using low-resolution clinical CT, cortical porosity was lower in women with T2DM compared to women without diabetes. This indicates that other changes in bone qualities, not increased cortical porosity, are likely to explain the increased fracture propensity in patients with T2DM

Determinants of trabecular bone score and prevalent vertebral fractures in women with fragility fractures: a cross-sectional sub-study of NoFRACT

Summary: Determinants of trabecular bone score (TBS) and vertebral fractures assessed semiquantitatively (SQ1–SQ3) were studied in 496 women with fragility fractures. TBS was associated with age, parental hip fracture, alcohol intake and BMD, not SQ1–SQ3 fractures. SQ1–SQ3 fractures were associated with age, prior fractures, and lumbar spine BMD, but not TBS. Introduction: Trabecular bone score (TBS) and vertebral fractures assessed by semiquantitative method (SQ1–SQ3) seem to reflect different aspects of bone strength. We therefore sought to explore the determinants of and the associations between TBS and SQ1–SQ3 fractures. Methods: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative included 496 women aged ≥ 50 years with fragility fractures. All responded to a questionnaire about risk factors for fracture, had bone mineral density (BMD) of femoral neck and/or lumbar spine assessed, TBS calculated, and 423 had SQ1–SQ3 fracture assessed. Results: Mean (SD) age was 65.6 years (8.6), mean TBS 1.27 (0.10), and 33.3% exhibited SQ1–SQ3 fractures. In multiple variable analysis, higher age (βper SD = − 0.26, 95% CI: − 0.36,− 0.15), parental hip fracture (β = − 0.29, 95% CI: − 0.54,− 0.05), and daily alcohol intake (β = − 0.43, 95% CI − 0.79, − 0.08) were associated with lower TBS. Higher BMD of femoral neck (βper SD = 0.34, 95% CI 0.25–0.43) and lumbar spine (βper SD = 0.40, 95% CI 0.31–0.48) were associated with higher TBS. In multivariable logistic regression analyses, age (ORper SD = 1.94, 95% CI 1.51–2.46) and prior fragility fractures (OR = 1.71, 95% CI 1.09–2.71) were positively associated with SQ1–SQ3 fractures, while lumbar spine BMD (ORper SD = 0.75 95% CI 0.60–0.95) was negatively associated with SQ1–SQ3 fractures. No association between TBS and SQ1–SQ3 fractures was found. Conclusion: Since TBS and SQ1–SQ3 fractures were not associated, they may act as independent risk factors, justifying the use of both in post-fracture risk assessment

Determinants of trabecular bone score and prevalent vertebral fractures in women with fragility fractures: a cross-sectional sub-study of NoFRACT

Summary - Determinants of trabecular bone score (TBS) and vertebral fractures assessed semiquantitatively (SQ1–SQ3) were studied in 496 women with fragility fractures. TBS was associated with age, parental hip fracture, alcohol intake and BMD, not SQ1–SQ3 fractures. SQ1–SQ3 fractures were associated with age, prior fractures, and lumbar spine BMD, but not TBS. Introduction - Trabecular bone score (TBS) and vertebral fractures assessed by semiquantitative method (SQ1–SQ3) seem to reflect different aspects of bone strength. We therefore sought to explore the determinants of and the associations between TBS and SQ1–SQ3 fractures. Methods - This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative included 496 women aged ≥ 50 years with fragility fractures. All responded to a questionnaire about risk factors for fracture, had bone mineral density (BMD) of femoral neck and/or lumbar spine assessed, TBS calculated, and 423 had SQ1–SQ3 fracture assessed. Results - Mean (SD) age was 65.6 years (8.6), mean TBS 1.27 (0.10), and 33.3% exhibited SQ1–SQ3 fractures. In multiple variable analysis, higher age (βper SD = − 0.26, 95% CI: − 0.36,− 0.15), parental hip fracture (β = − 0.29, 95% CI: − 0.54,− 0.05), and daily alcohol intake (β = − 0.43, 95% CI − 0.79, − 0.08) were associated with lower TBS. Higher BMD of femoral neck (βper SD = 0.34, 95% CI 0.25–0.43) and lumbar spine (βper SD = 0.40, 95% CI 0.31–0.48) were associated with higher TBS. In multivariable logistic regression analyses, age (ORper SD = 1.94, 95% CI 1.51–2.46) and prior fragility fractures (OR = 1.71, 95% CI 1.09–2.71) were positively associated with SQ1–SQ3 fractures, while lumbar spine BMD (ORper SD = 0.75 95% CI 0.60–0.95) was negatively associated with SQ1–SQ3 fractures. No association between TBS and SQ1–SQ3 fractures was found. Conclusion - Since TBS and SQ1–SQ3 fractures were not associated, they may act as independent risk factors, justifying the use of both in post-fracture risk assessment