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There are occasional marked discordances in BMD T-scores at the lumbar spine (LS) and femoral neck (FN). We investigated whether such discordances could contribute independently to fracture prediction using FRAX. We studied 21,158 women, average age 63 years, from 10 prospective cohorts with baseline FRAX variables as well as FN and LS BMD. Incident fractures were collected by self-report and/or radiographic reports. Extended Poisson regression examined the relationship between differences in LS and FN T-scores (ΔLS-FN) and fracture risk, adjusted for age, time since baseline and other factors including FRAX 10-year probability for major osteoporotic fracture calculated using FN BMD. To examine the effect of an adjustment for ΔLS-FN on reclassification, women were separated into risk categories by their FRAX major fracture probability. High risk was classified using two approaches: being above the National Osteoporosis Guideline Group intervention threshold or, separately, being in the highest third of each cohort. The absolute ΔLS-FN was greater than 2 SD for 2.5% of women and between 1 and 2 SD for 21%. ΔLS-FN was associated with a significant risk of fracture adjusted for baseline FRAX (HR per SD change = 1.09; 95% CI = 1.04-1.15). In reclassification analyses, only 2.3-3.2% of the women moved to a higher or lower risk category when using FRAX with ΔLS-FN compared with FN-derived FRAX alone. Adjustment of estimated fracture risk for a large LS/FN discrepancy (>2SD) impacts to a large extent on only a relatively small number of individuals. More moderate (1-2SD) discordances in FN and LS T-scores have a small impact on FRAX probabilities. This might still improve clinical decision-making, particularly in women with probabilities close to an intervention threshold.

Diabetes increases fracture and falls risks. We evaluated the performance of the Garvan fracture risk calculator (FRC) in individuals with versus without diabetes. Using the population-based Manitoba bone mineral density (BMD) registry, we identified individuals aged 50-95 years undergoing baseline BMD assessment from 1 September 2012, onwards with diabetes and self-reported falls in the prior 12 months. Five-year Garvan FRC predictions were generated from clinical risk factors, with and without femoral neck BMD. We identified non-traumatic osteoporotic fractures (OF) and hip fractures (HF) from population-based data to 31 March 2018. Fracture risk stratification was assessed from area under the receiver operating characteristic curves (AUROC). Cox regression analysis was performed to examine the effect of diabetes on fractures, adjusted for Garvan FRC predictions. The study population consisted of 2618 women with and 14,064 without diabetes, and 636 and 2201 men with and without the same, respectively. The Garvan FRC provided significant OF and HF risk stratification in women with diabetes, similar to those without diabetes. Analyses of OF in men were limited by smaller numbers; no significant difference was evident by diabetes status. Cox regression showed that OF risk was 23% greater in women with diabetes adjusted for Garvan FRC including BMD (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.01-1.49), suggesting it slightly underestimated risk; a non-significant increase in diabetes-related HF risk was noted (HR 1.37, 95% CI 0.88-2.15). Garvan FRC shows similar fracture risk stratification in individuals with versus without diabetes, but may underestimate this risk., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Quantitative ultrasound measurement (QUS) and bone mineral density (BMD) have each been shown to predict fracture risk in women. The present study examined whether a combination of QUS and BMD could improve the predictive accuracy of fracture risk. This is a population-based prospective study which involved 454 women and 445 men aged 62-89 years. Femoral neck BMD (FNBMD) was measured by DXA and calcaneal QUS was measured as broadband ultrasound attenuation (BUA) by a CUBA sonometer. Fragility fracture was ascertained by X-ray reports during the follow-up period, which took place between mid-1989 and 2009. During the follow-up period (median 13 years, range 11-15), 75 men and 154 women sustained a fragility fracture. In women, the model with FNBMD and BUA had a higher AUC compared to that without BUA (0.73 vs. 0.71 for any fracture, 0.81 vs. 0.77 for hip fracture, and 0.72 vs. 0.70 for vertebral fracture). Reclassification analysis yielded a total net reclassification improvement of 7.3%, 11.1%, and 5.2% for any, hip, and vertebral fractures, respectively. For men, the addition of BUA to FNBMD did not improve the predictive power for any, hip, or vertebral fracture. These results suggest that calcaneal QUS is an independent predictor of fracture risk and that a combination of QUS and BMD measurement could improve the predictive accuracy of fracture risk in elderly women.

An important objective of genetic research in osteoporosis is to translate genotype data into the prognosis of fracture. The present study sought to develop a prognostic model for predicting osteoporotic fracture by using information from a genetic marker and clinical risk factors. It was designed as a prospective epidemiological study which involved 894 women of Caucasian background aged 60+ years who had been followed for a median of 9 years (from 1989 and 2008, range 0.2-18 years). During the follow-up period, fragility fracture was ascertained by X-ray reports for all women. Bone mineral density (BMD) at the femoral neck was measured by dual-energy X-ray absorptiometry. Genotypes of the Sp1 binding site in the first intron of the collagen I alpha 1 (COLIA1) gene polymorphism were determined by polymerase chain reaction, digestion with BalI restriction enzyme, and agarose gel electrophoresis. The relationship between COL1A1 genotype and fracture was assessed by the Cox proportional hazards model, from which nomograms were developed for individualizing the risk of fracture. The distribution of COL1A1 genotypes was consistent with the Hardy-Weinberg equilibrium law: GG (63.8%), GT (32.6%), and TT (3.6%). During the follow-up period, there were 322 fractures, including 77 hip and 127 vertebral fractures. There was an overrepresentation of the TT genotype in the fracture group (6.2%) compared with the nonfracture group (2.3%). Compared with carriers of GT and GG, women carrying the TT genotype had increased risk of any fracture (relative risk [RR] = 1.91, 95% CI 1.21-3.00), hip fracture (RR = 3.67, 95% CI 1.69-8.00), and vertebral fracture (RR = 3.36, 95% CI 1.81-6.24). The incorporation of COL1A1 genotypes improved the risk reclassification by 2% for any fragility fracture, 4% for hip fracture, and 5% for vertebral fracture, beyond age, BMD, prior fracture, and fall. Three nomograms were constructed for predicting fracture risk in an individual woman based on age, BMD, and COLIA1 genotypes. These data suggest that the COLIA1 Sp1 polymorphism is associated with the risk of fragility fracture in Caucasian women and that the polymorphism could enhance the predictive accuracy of fracture prognosis. The nonograms presented here can be useful for individualizing the short- and intermediate-term prognosis of fracture risk and help identify high-risk individuals for intervention for appropriate management of osteoporosis.

Increased cross-sectional area and strength of long bones has been observed in transgenic mice with 2-fold (OSV9) and 3-fold (OSV3) elevation of osteoblast vitamin D receptor (VDR) levels. In the present study, mineralization density distributions, including typical calcium content (Ca(Peak)) and homogeneity of mineralization (Ca(Width)) of femoral bone and growth plate cartilage, were determined by quantitative backscattered electron imaging (qBEI). Fourier-transform infrared (FTIR) microspectroscopy was used to examine mineral content, collagen and crystal maturation, and scanning small angle X-ray scattering (scanning-SAXS) for studying mineral particle thickness and alignment. In addition, X-ray diffraction (XRD) of distal tibiae revealed mineral particle c-axis size. In trabecular bone, the increase in Ca(Peak) was significant for both OSV9 (+ 3.14%, P = 0.03) and OSV3 (+ 3.43%, P = 0.02) versus controls with 23.61 +/- 0.45 S.D. wt% Ca baseline values. In cortical bone, Ca(Peak) was enhanced for the OSV3 mice (+ 1.84%, P = 0.02) versus controls with 26.61 +/- 0.28 S.D. wt% Ca, and OSV9 having intermediate values. Additionally, there was significantly increased homogeneity of mineralization as denoted by a reduction of Ca(Width) (-8.4%, P = 0.01) in primary spongiosa. FTIR microspectroscopy, with the exception of an increased collagen maturity in OSV3 trabecular bone (+ 9.9%, P = 0.02), XRD, and scanning-SAXS indicated no alterations in the nanostructure of transgenic bone. These findings indicate that elevation of osteoblastic vitamin D response led to formation of normal bone with higher calcium content. These material properties, together with indications of decreased bone resorption in secondary spongiosa and increased cortical periosteal bone formation, appear to contribute to the improved mechanical properties of their long bones and suggest an important physiological role of the vitamin D-endocrine system in normal bone mineralization.