Pawel Szulc

Background: Data on the link between alcohol intake and prospectively assessed changes in areal bone mineral density (aBMD) are scarce. Our aim was to assess the association of alcohol intake with bone loss and microarchitectural decline prospectively assessed in older men. Methods: In 818 men aged 60 to 87 years, bone microarchitecture was assessed at the distal radius and distal tibia (XtremeCT; Scanco Medical). Areal aBMD was assessed by dual energy X-ray absorptiometry (Hologic Inc.). Both were assessed at baseline, then after 4 and 8 years. Linear mixed models were adjusted for age, body mass index, bioavailable 17β-estradiol, osteoprotegerin, parathyroid hormone, Creactive protein and for grip strength (radius) or for the lower limb physical function score (tibia). Results: At baseline, aBMD and bone microarchitecture measures did not differ across the classes of alcohol intake. During the follow-up, aBMD decrease did not vary differently across the classes of alcohol intake. Men drinking 16 to 112 g alcohol per week had the slowest bone microarchitecture decline (reference group). At the distal radius, trabecular BMD (Tb.BMD) and number (Tb.N) decreased faster in men consuming 224 g/week vs. the reference group. At the distal tibia, cortical thickness (Ct.Thd), cortical area (Ct.Ar), reaction force, and failure load decreased faster in men consuming 224 g/week versus the reference group. Conclusions: Moderate alcohol intake is associated with slower bone decline. Very low and higher alcohol intake were associated with faster bone microarchitecture deterioration in older men when assessed prospectively.

Summary The relationship between bone mineral density (BMD) at the forearm and fracture risk was determined in a meta-analysis of primary data from 11 cohort studies of 35,121 men and women. Low forearm BMD was a significant predictor of fracture risk, independently of FRAX®. Introduction The aim of this study was to quantify the relationship between forearm BMD, FRAX and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value on fracture risk. Methods We studied 35,121 men and women from 11 predominantly population-based cohorts followed for an average of 11.1 years and a total of 388,654 person-years. The association between forearm BMD, FRAX probabilities (calculated without femoral neck BMD), and the risk of fracture was examined using an extension of the Poisson regression model in each cohort by sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD difference in BMD). The different studies were merged using weighted coefficients. Results The GR of forearm BMD for major osteoporotic fracture was 1.41 (95% confidence interval [CI] 1.31–1.51) when adjusted for age and time since baseline and was similar in men and women (p > 0.20). GRs decreased significantly with age. When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, forearm BMD remained a significant, independent predictor for fracture (GR = 1.34, 95% CI 1.26–1.44). A similar GR was noted for hip fracture (GR = 1.48; 95% CI 1.35–1.62) that persisted after adjustment for FRAX (GR = 1.39; 95% CI 1.27–1.52). Adjustments to FRAX probabilities based on forearm BMD varied by age and Z-score. Conclusions Forearm BMD is a risk factor for MOF and hip fracture risk beyond the risk attributable to FRAX. Its validation on an international basis permits its use in case finding with FRAX.

Objective: In osteogenesis imperfecta (OI), phenotypic variability and the limited predictive value of genotype–phenotype correlations underscore the need for reliable predictive marker of disease severity. Periostin is a matricellular protein involved in bone formation, remodeling, and response to mechanical stress. It interacts with type I collagen and modulates osteoblast activity via Wnt/β-catenin and TGF-β signaling. Given its established role in other bone disorders, we hypothesized that circulating periostin may be a relevant biomarker in OI. Methods: We performed a matched case–control analysis of serum periostin levels in 61 adult patients with OI and 61 age-, sex-, and BMI-matched controls. Periostin was measured by ELISA. Associations between periostin levels and clinical variables were assessed using t-tests, Pearson correlations, and multivariable linear regression models. Results: Mean periostin levels were significantly higher in OI patients than in controls (796.5 ± 209 vs 713.6 ± 167 pmol/L, P = .017). Among OI patients, higher periostin level was associated with female sex (P = .01), presence of scoliosis (P = .01), and Sillence type III (P = .05). Positive correlations were observed between periostin and markers of axial skeletal severity as height–wingspan discrepancy (r = 0.30, P = .023). In multivariable analysis, the number of severe fractures (defined as femur/pelvis/humerus/vertebral fractures) was independently associated with higher periostin level (β = 25.6, P = .041), while smoking was negatively associated (β = −269.8, P = .012). Conclusion: This study is the first to report the elevated circulating level of periostin in adults with OI and its association with disease severity.

Summary The relationship between bone mineral density (BMD) at the femoral neck and fracture risk was determined in a meta-analysis of primary data of 307205 men and women from 53 cohort studies. Low BMD was an important predictor of fracture risk, particularly for hip fracture. Introduction This study aimed to quantify the relationship between DXA-measured femoral neck BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value on fracture risk, with a view to updating FRAX®. Methods We studied 307,205 men and women from within 53 predominately population-based cohorts followed up for an average of 8.7 years and a total of 2,683,185 person-years. The association of BMD and fracture risk was examined using a Poisson model in each cohort separately by sex. Results were expressed as a gradient of risk (GR, hazard ratio/standard deviation decrease in BMD). The different studies were then merged using weighted coefficients. Results Most hip fractures arose in men and women with low bone mass or osteoporosis at baseline (73% and 92%, respectively) as was also the case for MOF (65% and 85%, respectively). BMD at the femoral neck strongly predicted hip fractures both in men and women with a similar gradient of risk and absolute risk at any given T-score. At the age of 65 years, the GR was 2.73 (95% CI = 2.29–3.26) in men and 2.61 (95% CI = 2.34–2.92) in women. However, the magnitude of association was significantly dependent on age, with a higher gradient of risk at younger ages. For example, at age 50 years, the GR was 3.49 (95% CI 2.51–4.84) in men and decreased to 2.14 (1.96–2.34) at age 80 years. The change in GR with age was slightly less marked in women (3.23 [2.75–3.80] and 2.11 [1.99–2.44], respectively). The GR for major osteoporotic fracture (MOF) remained unchanged with age (p = 0.12 for women and p = 0.89 for men). A significant decrease in GR for hip fracture was observed with increasing duration of follow-up, but the magnitude of the effect was modest compared with the effect of age. For other fracture outcomes, including non-hip major osteoporotic fracture, the gradient of risk was lower than for hip fracture. Conclusions Femoral neck BMD is a risk factor for fracture of substantial importance, particularly for future hip fracture. The lower magnitude of association at older age is consistent with other non-skeletal factors contributing to hip fracture risk with advancing age. Its validation on an international basis supports its use in case finding strategies. Its use should, however, take account of the variations in predictive value of BMD with age, sex, length of follow-up, and BMD.

In this meta-analysis of international cohorts, current smoking is confirmed as a significant BMD-independent predictor of future fracture with a stronger relationship in men than in women. A causative and reversible effect of smoking on fracture risk is suggested by past smoking having a significantly lower risk than current smoking. In this meta-analysis of international cohorts, the aim was to examine the relationship of current and past smoking with fracture risk to provide an update for future iterations of the FRAX tool. The risk of fracture associated with current and past smoking was estimated using an extended Poisson model applied separately to each of 58 prospective international cohort studies. Covariates included current time since start of follow up, current age, and in an additional model, BMD at the femoral neck. The results of the different studies were merged by using inverse-variance weighted β-coefficients. This analysis included a total of 1,691,024 participants (61.2% women, overall mean age 58.8 years). Current smoking, documented in 12.1% of all participants (15.2% and 10.1% respectively in men and women), was associated with a significantly increased risk of any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and particularly hip fracture in both sexes. The hazard ratio (HR) for fracture was greater in men than in women for all fracture categories [e.g. hip fracture HR (95% confidence interval): 1.78 (1.58-2.00) vs. 1.64 (1.50-1.78)]. Low BMD explained about 19-54% of the increase in risk. When compared with never smoking, past smoking was associated with a significantly lower risk than current smoking [e.g. hip fractures for men, HR in past smokers: 1.08 (1.05-1.12) vs. 1.73, 95%CI (1.46-2.05) in current smokers]. Our results confirm the association between current smoking and increased fracture risk that is partly independent of BMD; these data will be used to inform future iterations of FRAX.

Background: Provision of vascular imaging results has been investigated to prompt changes towards healthy lifestyle behaviours, but effects on body composition and muscle health are unknown. Aim: This secondary analysis of a 12-week parallel-group randomised controlled trial (RCT) aims to explore body composition and muscle health effects of providing healthy lifestyle education (Ed) with and without abdominal aortic calcification (AAC) results. Methods: A total of 240 Australian community-dwelling older men and women (mean ± SD age 68 ± 5 years; 58% female; 57.1% with evidence of AAC) were randomised to AAC + Ed ( n = 121) or Control + Ed ( n = 119). Linear mixed models were used to compare between-group changes in body composition (dual-energy X-ray absorptiometry), grip strength, and subjective physical function. Results: In total, 226 (94%) participants completed the trial. Provision of AAC results with lifestyle education provided no benefits to body composition, grip strength or physical function, compared to education alone. Exploratory analyses within the AAC + Ed group showed that those with evidence of AAC at baseline had greater declines in fat mass (net difference in change [95% CI] -0.6 [-1.0, -0.1] kg, p = 0.016) and visceral adipose tissue (-31 [-61, -1] g, p = 0.044) compared to those without evidence of AAC. Conclusions: Providing AAC results with healthy lifestyle education did not improve body composition or muscle health in older adults, compared to education alone. Provision of AAC results to those with evidence of AAC at baseline did improve total and visceral fat mass compared to those without evidence of AAC, but these findings require further investigation. Trial registration: Australian New Zealand Clinical Trial Registry (anzctr.org.au); registration number ACTRN12618001087246; registered 28/06/2018.

CKD may be complicated by mineral and bone disorders (CKD-MBD). Data on the association between estimated glomerular filtration rate (eGFR) and bone microarchitecture are limited. We studied the link between eGFR and bone microarchitecture (baseline, changes) assessed by HR-pQCT in older men followed for 8 yr. In 826 men aged ≥60, eGFR was calculated using 3 equations based on creatinin and cystatin C: CKDEPI-2012, EKFC without race and sex, and CKDEPI-2021 without race. Bone microarchitecture was assessed at the distal radius and distal tibia by HR-pQCT at baseline, then after 4 and 8 yr. Reaction force and failure load were estimated by microfinite element analysis. Changes in bone measures across the eGFR classes were explored using linear mixed effect models. At baseline, distal radius bone microarchitecture did not differ across the eGFR groups (CKDEPI-2012), whereas distal tibia trabecular measures and failure load were higher in men with decreased eGFR. During the follow-up, lower eGFR was associated with a more rapid decrease in total BMD (Tt.BMD), cortical area (Ct.Ar) and BMD (Ct.BMD), trabecular BMD (Tb.BMD), and failure load at the distal radius. Low eGFR was also associated with a faster increase in trabecular area (Tb.Ar) and trabecular distribution heterogeneity (Tb.1/N.SD). At the distal tibia, low eGFR was associated with a more rapid decrease in Tt.BMD, Ct.Ar, Ct.BMD, Tb.1/N.SD, and failure load as well as with a faster increase in Tb.Ar. The patterns were similar for changes expressed as percentages. The patterns were similar for 2 other equations. Lower eGFR is associated with a faster decline in cortical bone microarchitecture and bone strength at the distal radius and tibia in older men. This phenomenon may contribute to the higher fracture risk in older adults with CKD.

Summary In the largest meta-analysis of international cohorts to date, a family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. Parental and sibling histories of fracture carry the same significance for future fracture, including the impact of family hip fracture on future hip fracture risk. Purpose We have undertaken a meta-analysis of international prospective cohorts to quantify the relationship between a family history of fracture and future fracture incidence. Methods The analysis dataset comprised 350,542 men and women from 42 cohorts in 29 countries followed for 2.8 million person-years. We investigated the relationship between family history of hip fracture or any fracture and the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture alone using an extended Poisson model in each cohort. Models were adjusted for current age, sex, BMD, and follow-up time. Results As no difference in influence of family history of fracture was seen between genders, results are presented for men and women combined. A parental history of hip fracture was associated with a higher risk of incident fracture across all fracture outcome categories, with a stronger relationship with future hip fracture (hazard ratios (HR, 95% CI) for hip and MOF 1.37, 1.23–1.52 and 1.19, 1.12–1.27, respectively). Associations were slightly reduced but remained significant when additionally adjusted for BMD and did not vary by baseline offspring age, follow-up time, or parent affected. In a more limited analysis, parental history of any fracture or a sibling history of hip or any fracture showed similar associations to those observed with parental history of hip fracture. Conclusions A family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. While parental hip fracture appears the strongest factor for future hip fracture, a family history of other fractures might be appropriate for inclusion in future iterations of the FRAX tool.