Impaired bone microarchitecture, assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), may contribute to bone fragility in type 2 diabetes (T2DM) but data on men are lacking.

To investigate the association between T2DM and HR-pQCT parameters in older men.

HR-pQCT scans were acquired on 1794 participants in the Osteoporotic Fractures in Men study. T2DM was ascertained by self-report or medication use. Linear regression models, adjusted for age, race, body mass index, limb length, clinic site, and oral corticosteroid use, were used to compare HR-pQCT parameters by diabetes status.

Among 1777 men, 290 had T2DM (mean age, 84.4 years). T2DM men had smaller total cross-sectional area at the distal tibia (P = .028) and diaphyseal tibia (P = .025), and smaller cortical area at the distal (P = .009) and diaphyseal tibia (P = .023). Trabecular indices and cortical porosity were similar between T2DM and non-T2DM. Among men with T2DM, in a model including HbA1c, diabetes duration, and insulin use, diabetes duration ≥ 10 years, compared with <10 years, was significantly associated with higher cortical porosity but with higher trabecular thickness at the distal radius. Insulin use was significantly associated with lower cortical area and thickness at the distal radius and diaphyseal tibia and lower failure load at all 3 scan sites. Lower cortical area, cortical thickness, total bone mineral density, cortical bone mineral density, and failure load of the distal sites were associated with increased risk of incident nonvertebral fracture in T2DM.

Older men with T2DM have smaller bone size compared to those without T2DM, which may contribute to diabetic skeletal fragility. Longer diabetes duration was associated with higher cortical porosity and insulin use with cortical bone deficits and lower failure load.

Brief rationale: To assess bone dimensions in the radius over 7 years.

Cross-sectional area did not change significantly, but endosteal circumference increased, leading to decreased cortical thickness. Significance of the paper: Bone mineral density loss is associated with a decrease in cortical thickness in the forearm.

To assess site-specific volumetric bone and muscle differences in women with and without forearm fracture in a longitudinal study.

One hundred four postmenopausal women with a forearm fracture and 99 age-matched controls were included and underwent peripheral quantitative computed tomography (pQCT) in the forearm at a mean age of 65 (range 44-88) years and were invited for a reassessment after mean 7 (6-11) years, at which 80 and 79 women took part, respectively. Three cases had movement artifacts on pQCT; 77 cases and 79 controls were finally analysed.

Twenty-two of the cases and 20 of the controls sustained a fracture during the follow-up. From baseline to follow-up, bone mineral content and bone mineral density decreased irrespective of group belonging at baseline, both at the 4% and the 66% level in the forearm. Cross-sectional area did not change significantly at the 4% and the 66% level. At the 66% level, periosteal circumference was unchanged and endosteal circumference increased, leading to decreased cortical thickness. Muscle area decreased, while muscle density was unchanged. A high cross-sectional area and low bone volumetric bone mineral density were predictive of fracture during the follow-up.

Over a mean follow-up of 7 years, postmenopausal women lose bone mineral density, associated with a decrease in cortical thickness in the forearm.

Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height, and weight, and then additionally adjusted for FN aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ -2.5, whereas 53% had T-scores between -1.0 and -2.5 and 37% had T-scores ≥-1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load (FL) was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, FL and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range.

With the aging of the population in our society, osteoporosis (OP) has become one of the chronic diseases that seriously threaten the physical health of the elderly, leading to a heavy burden on healthcare. In recent years, with the continuous development of dual-energy CT (DECT) technology, quantitative measurements of DECT parameters, which is highly sensitive to OP, provides accurate results, is convenient and cost-effective, and is expected to be widely used in bone density testing. This study was aimed to explore the value of quantitative measurements of DECT parameters in diagnosing OP, in order to better guide clinical judgments and treatment. A total of 187 patients who underwent dual-energy X-ray and DECT examinations at Tianjin hospital between January 2022 and June 2023 were included as participants in this study. The bone mineral density (BMD) values of the lumbar spine (L1-L4) were determined using dual-energy X-ray absorptiometry. Simultaneously, CT scans of the lumbar spine (L1-L4) were conducted to measure the CT values of contrast media (CM), mixed-energy image CT values (regular CT value [rCT]), calcium concentration (CaD), as well as fat fraction (FF). Pearson correlation analysis was used to examine the relationship between the quantitative measurements of L1 to L4 vertebral bodies obtained from DECT and BMD. The values of CM, rCT, and CaD in the OP group were all lower than those in the non-OP group with statistical significance (P < .001). Conversely, the fat fraction parameter value in the OP group was significantly higher in contrast with the non-OP group (P = .004); there was a positive correlation between CM, rCT, CaD, and BMD values (R = 0.579, P < .001; R = 0.604, P < .001; R = 0.563, P < .001); CM, rCT, and CaD had high diagnostic value for OP, as evidenced by AUCs of 0.935 (95% CI: 0.900-0.971), 0.956 (95% CI: 0.925-0.987), and 0.926 (95% CI: 0.858-0.954), respectively, all with P values < .001. Quantitative measurement of DECT parameters showed a high sensitivity as well as a high specificity in the diagnosis of OP. It is also highly feasible and holds significant clinical diagnostic value, making it a suitable candidate for widespread application.

The continued development of high-resolution peripheral quantitative computed tomography (HR-pQCT) has led to a second-generation scanner with higher resolution and longer scan region. However, large multicenter prospective cohorts were collected with first-generation HR-pQCT and have been used to develop bone phenotyping and fracture risk prediction (μFRAC) models. This study establishes whether there is sufficient universality of these first-generation trained models for use with second-generation scan data.

HR-pQCT data were collected for a cohort of 60 individuals, who had been scanned on both first- and second-generation scanners on the same day to establish the universality of the HR-pQCT models. These data were each used as input to first-generation trained bone microarchitecture models for bone phenotyping and fracture risk prediction, and their outputs were compared for each study participant. Reproducibility of the models were assessed using same-day repeat scans obtained from first-generation (n = 37) and second-generation (n = 74) scanners.

Across scanner generations, the bone phenotyping model performed with an accuracy of 93.1%. Similarly, the 5-year fracture risk assessment by μFRAC was well correlated with a Pearson's (r) correlation coefficient of r > 0.83 for the three variations of μFRAC (varying inclusion of clinical risk factors, finite element analysis, and dual X-ray absorptiometry). The first-generation reproducibility cohort performed with an accuracy for categorical assignment of 100% (bone phenotyping) and a correlation coefficient of 0.99 (μFRAC), whereas the second-generation reproducibility cohort performed with an accuracy of 96.4% (bone phenotyping) and a correlation coefficient of 0.99 (μFRAC).

We demonstrated that bone microarchitecture models trained using first-generation scan data generalize well to second-generation scans, performing with a high level of accuracy and reproducibility. Less than 4% of individuals' estimated fracture risk led to a change in treatment threshold, and in general, these dissimilar outcomes using second-generation data tended to be more conservative.

Fracture risk increases with lower areal bone mineral density (aBMD); however, aBMD-related estimate of risk may decrease with age. This may depend on technical limitations of 2-dimensional (2D) dual energy X-ray absorptiometry (DXA) which are reduced with 3D high-resolution peripheral quantitative computed tomography (HR-pQCT). Our aim was to examine whether the predictive utility of HR-pQCT measures with fracture varies with age. We analyzed associations of HR-pQCT measures at the distal radius and distal tibia with two outcomes: incident fractures and major osteoporotic fractures. We censored follow-up time at first fracture, death, last contact or 8 years after baseline. We estimated hazard ratios (HR) and 95%CI for the association between bone traits and fracture incidence across age quintiles. Among 6835 men and women (ages 40-96) with at least one valid baseline HR-pQCT scan who were followed prospectively for a median of 48.3 months, 681 sustained fractures. After adjustment for confounders, bone parameters at both the radius and tibia were associated with higher fracture risk. The estimated HRs for fracture did not vary significantly across age quintiles for any HR-pQCT parameter measured at either the radius or tibia. In this large cohort, the homogeneity of the associations between the HR-pQCT measures and fracture risk across age groups persisted for all fractures and for major osteoporotic fractures. The patterns were similar regardless of the HR-pQCT measure, the type of fracture, or the statistical models. The stability of the associations between HR-pQCT measures and fracture over a broad age range shows that bone deficits or low volumetric density remain major determinants of fracture risk regardless of age group. The lower risk for fractures across measures of aBMD in older adults in other studies may be related to factors which interfere with DXA but not with HR-pQCT measures.

Fracture rate is increased in patients with active acromegaly and those in remission. Abnormalities of bone microstructure are present in patients with active disease and persist despite biochemical control after surgery. Effects of treatment with the GH receptor antagonist pegvisomant on bone microstructure were unknown.

We studied 25 patients with acromegaly (15 men, 10 women). In 20, we evaluated areal bone mineral density (BMD) by dual-energy X-ray absorptiometry and bone turnover markers (BTMs) longitudinally, before and during pegvisomant treatment. After long-term pegvisomant in 17, we cross-sectionally assessed volumetric BMD, microarchitecture, stiffness, and failure load of the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and compared these results to those of healthy controls and 2 comparison groups of nonpegvisomant-treated acromegaly patients, remission, and active disease, matched for other therapies and characteristics.

In the longitudinal study, areal BMD improved at the lumbar spine but decreased at the hip in men after a median ∼7 years of pegvisomant. In the cross-sectional study, patients on a median ∼9 years of pegvisomant had significantly larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to healthy controls. Microstructure was similar in the pegvisomant and acromegaly comparison groups. BTMs were lowered, then stable over time.

In this, the first study to examine bone microstructure in pegvisomant-treated acromegaly, we found deficits in volumetric BMD and microarchitecture of the peripheral skeleton. BTM levels remained stable with long-term therapy. Deficits in bone quality identified by HRpQCT may play a role in the pathogenesis of fragility in treated acromegaly.

Serum 25-hydroxyvitamin D (25(OH)D) is the current marker of vitamin D adequacy, but its relationship with bone health has been inconsistent. The ratio of 24,25-dihydroxyvitamin D3 to 25(OH)D3 (vitamin D metabolite ratio or VMR) is a marker of vitamin D that has been associated with longitudinal changes in bone mineral density (BMD) and fracture risk.

High-resolution peripheral quantitative computed tomography (HR-pQCT) provides information on bone health beyond standard dual-energy x-ray absorptiometry, in that it measures volumetric BMD (vBMD) as well bone strength. The relationship of the VMR with vBMD and bone strength remains unknown.

We evaluated the associations of the VMR and 25(OH)D3 with vBMD and bone strength in the distal radius and tibia, assessed by HR-pQCT in 545 older men participating in the Osteoporotic Fractures in Men (MrOS) Study. Primary outcomes were vBMD and estimated failure load (EFL, a marker of bone strength) at the distal radius and tibia.

The mean age was 84 ± 4 years, 88.3% were White, and 32% had an estimated glomerular filtration rate <60 mL/min/1.73 m2. In adjusted models, each twofold higher VMR was associated with a 9% (3%, 16%) higher total vBMD and a 13% (5%, 21%) higher EFL at the distal radius. Results were similar at the distal tibia. 25(OH)D3 concentrations were not associated with any of the studied outcomes.

Among older men, a higher VMR was associated with greater vBMD and bone strength while 25(OH)D3 was not. The VMR may serve as a valuable marker of skeletal health in older men.

Despite effective therapies for those at risk of osteoporotic fracture, low adherence to screening guidelines and limited accuracy of bone mineral density (BMD) in predicting fracture risk preclude identification of those at risk. Because of high adherence to routine mammography, bone health screening at the time of mammography using a digital breast tomosynthesis (DBT) scanner has been suggested as a potential solution. BMD and bone microstructure can be measured from the wrist using a DBT scanner. However, the extent to which biomechanical variables can be derived from digital wrist tomosynthesis (DWT) has not been explored. Accordingly, we measured stiffness from a DWT based finite element (DWT-FE) model of the ultra-distal (UD) radius and ulna, and correlate these to reference microcomputed tomography image based FE (μCT-FE) from five cadaveric forearms. Further, this method is implemented to determine in vivo reproducibility of FE derived stiffness of UD radius and demonstrate the in vivo utility of DWT-FE in bone quality assessment by comparing two groups of postmenopausal women with and without a history of an osteoporotic fracture (Fx; n = 15, NFx; n = 51). Stiffness obtained from DWT and μCT had a strong correlation (R2 = 0.87, p < 0.001). In vivo repeatability error was <5 %. The NFx and Fx groups were not significantly different in DXA derived minimum T-scores (p > 0.3), but stiffness of the UD radius was lower for the Fx group (p < 0.007). Logistic regression models of fracture status with stiffness of the nondominant arm as the predictor were significant (p < 0.01). In conclusion this study demonstrates the feasibility of fracture risk assessment in mammography settings using DWT imaging and FE modeling in vivo. Using this approach, bone and breast screening can be performed in a single visit, with the potential to improve both the prevalence of bone health screening and the accuracy of fracture risk assessment.

The gut microbiome affects the inflammatory environment through effects on T-cells, which influence the production of immune mediators and inflammatory cytokines that stimulate osteoclastogenesis and bone loss in mice. However, there are few large human studies of the gut microbiome and skeletal health. We investigated the association between the human gut microbiome and high resolution peripheral quantitative computed tomography (HR-pQCT) scans of the radius and tibia in two large cohorts; Framingham Heart Study (FHS [n=1227, age range: 32 - 89]), and the Osteoporosis in Men Study (MrOS [n=836, age range: 78 - 98]). Stool samples from study participants underwent amplification and sequencing of the V4 hypervariable region of the 16S rRNA gene. The resulting 16S rRNA sequencing data were processed separately for each cohort, with the DADA2 pipeline incorporated in the16S bioBakery workflow. Resulting amplicon sequence variants were assigned taxonomies using the SILVA reference database. Controlling for multiple covariates, we tested for associations between microbial taxa abundances and HR-pQCT measures using general linear models as implemented in microbiome multivariable association with linear model (MaAslin2). Abundance of 37 microbial genera in FHS, and 4 genera in MrOS, were associated with various skeletal measures (false discovery rate [FDR] ≤ 0.1) including the association of DTU089 with bone measures, which was independently replicated in the two cohorts. A meta-analysis of the taxa-bone associations further revealed (FDR ≤ 0.25) that greater abundances of the genera; Akkermansia and DTU089, were associated with lower radius total vBMD, and tibia cortical vBMD respectively. Conversely, higher abundances of the genera; Lachnospiraceae NK4A136 group, and Faecalibacterium were associated with greater tibia cortical vBMD. We also investigated functional capabilities of microbial taxa by testing for associations between predicted (based on 16S rRNA amplicon sequence data) metabolic pathways abundance and bone phenotypes in each cohort. While there were no concordant functional associations observed in both cohorts, a meta-analysis revealed 8 pathways including the super-pathway of histidine, purine, and pyrimidine biosynthesis, associated with bone measures of the tibia cortical compartment. In conclusion, our findings suggest that there is a link between the gut microbiome and skeletal metabolism.

We examined if an interaction exists between bone and muscle in predicting fractures in older men. Prospective data from the Osteoporotic Fractures in Men study was used to build Cox proportional hazards models. Predictors included HR-pQCT total volumetric BMD (Tt.BMD), trabecular BMD (Tb.BMD), cortical BMD (Ct.BMD) and cortical area (Ct.Ar) at distal radius/tibia, HR-pQCT muscle volume and density (diaphyseal tibia), D3 -creatine dilution (D3 Cr) muscle mass, and grip strength and leg force, analyzed as continuous variables and as quartiles. Incident fractures were self-reported every 4 months via questionnaires and centrally adjudicated by physician review of radiology reports. Potential confounders (demographics, comorbidities, lifestyle factors, etc.) were considered. A total of 1353 men (mean age 84.2 ± 4.0 years, 92.7% white) were followed for 6.03 ± 2.11 years. In the unadjusted (continuous) model, there were no interactions (p > 0.05) between any muscle variable (D3 Cr muscle mass, muscle volume, muscle density, grip strength or leg force) and Tt.BMD at distal radius/tibia for fractures (all: n = 182-302; nonvertebral: n = 149-254; vertebral: n = 27-45). No consistent interactions were observed when interchanging Tt.BMD for Tb.BMD/Ct.BMD or for Ct.Ar (bone structure) at the distal radius/tibia in the unadjusted (continuous) models. Compared with men in quartiles (Q) 2-4 of D3 Cr muscle mass and Q2-4 of distal tibia Tt.BMD, men in Q1 of both had increased risk for all fractures (hazard ratio (HR) = 2.00; 95% confidence interval [CI] 1.24-3.23, p = 0.005) and nonvertebral fractures (HR = 2.10; 95% CI 1.25-3.52, p < 0.001) in the multivariable-adjusted model. Confidence intervals overlapped (p > 0.05) when visually inspecting other quartile groups in the multivariable-adjusted model. In this prospective cohort study of older men, there was no consistent interactions between bone and muscle variables on fracture risk. Larger sample sizes and longer follow-up may be needed to clarify if there is an interaction between bone and muscle on fracture risk in men. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Fractures are increased in patients with acromegaly, both before and after successful acromegaly treatment. Abnormalities of bone microstructure, which may underlie this fragility, are present in active acromegaly but to what extent these improve with acromegaly treatment or persist despite biochemical remission remains unclear. To examine these questions, we studied the effects of acromegaly treatment and remission on bone quality.

Sixty-five women and men with acromegaly were studied. Subgroups underwent assessments of areal bone mineral density by dual x-ray absorptiometry, trabecular bone score (TBS), and volumetric bone mineral density, microarchitecture, stiffness and failure load of the distal radius and tibia by high-resolution peripheral quantitative tomography in a longitudinal study before and after acromegaly treatment and in a cross-sectional study in which patients were compared to sex-, age-, and body mass index-matched healthy controls.

In the longitudinal study, significant increases in total, cortical, and trabecular densities at the radius and tibia and increased stiffness and failure load of the tibia occurred with acromegaly treatment. In the cross-sectional study, patients in biochemical remission after surgery had larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to controls. TBS did not change with acromegaly treatment but correlated with some microstructural parameters.

We show, for the first time, that volumetric bone mineral density and microarchitecture of the peripheral skeleton improve with acromegaly treatment but remain abnormal in patients in remission after surgery compared to controls. These abnormalities, known to be associated with fractures in other populations, may play a role in the pathogenesis of persistent fragility in treated acromegaly.

Many individuals at high risk for fracture are never evaluated for osteoporosis and subsequently do not receive necessary treatment. Utilization of magnetic resonance imaging (MRI) is burgeoning, providing an ideal opportunity to use MRI to identify individuals with skeletal deficits. We previously reported that MRI-based bone texture was more heterogeneous in postmenopausal women with a history of fracture compared to controls.

The present study aimed to identify the microstructural characteristics that underlie trabecular texture features.

In a prospective cohort, we measured spine volumetric bone mineral density (vBMD) by quantitative computed tomography (QCT), peripheral vBMD and microarchitecture by high-resolution peripheral QCT (HRpQCT), and areal BMD (aBMD) by dual-energy x-ray absorptiometry. Vertebral trabecular bone texture was analyzed using T1-weighted MRIs. A gray level co-occurrence matrix was used to characterize the distribution and spatial organization of voxelar intensities and derive the following texture features: contrast (variability), entropy (disorder), angular second moment (ASM; uniformity), and inverse difference moment (IDM; local homogeneity).

Among 46 patients (mean age 64, 54% women), lower peripheral vBMD and worse trabecular microarchitecture by HRpQCT were associated with greater texture heterogeneity by MRI-higher contrast and entropy (r ∼ -0.3 to 0.4, P < .05), lower ASM and IDM (r ∼ +0.3 to 0.4, P < .05). Lower spine vBMD by QCT was associated with higher contrast and entropy (r ∼ -0.5, P < .001), lower ASM and IDM (r ∼ +0.5, P < .001). Relationships with aBMD were less pronounced.

MRI-based measurements of trabecular bone texture relate to vBMD and microarchitecture, suggesting that this method reflects underlying microstructural properties of trabecular bone. Further investigation is required to validate this methodology, which could greatly improve identification of patients with skeletal fragility.

This systematic review and meta-analysis examined the association between race and ethnicity and fracture risk in the United States. We identified relevant studies by searching PubMed and EMBASE for studies published from the databases' inception date to December 23, 2022. Only observational studies conducted in the US population that reported the effect size of racial-ethnic minority groups versus white people were included. Two investigators independently conducted literature searches, study selection, risk of bias assessment, and data abstraction; discrepancies were resolved by consensus or consultation of a third investigator. Twenty-five studies met the inclusion criteria, and the random-effects model was used to calculate the pooled effect size due to heterogeneity between the studies. Using white people as the reference group, we found that people of other races and ethnic groups had a significantly lower fracture risk. In Black people, the pooled relative risk (RR) was 0.46 (95% confidence interval (CI), 0.43-0.48, p < 0.0001). In Hispanics, the pooled RR was 0.66 (95% CI, 0.55-0.79, p < 0.0001). In Asian Americans, the pooled RR was 0.55 (95% CI, 0.45-0.66, p < 0.0001). In American Indians, the pooled RR was 0.80 (95% CI, 0.41-1.58, p = 0.3436). Subgroup analysis by sex in Black people revealed the strength of association was greater in men (RR = 0.57, 95% CI = 0.51-0.63, p < 0.0001) than in women (RR = 0.43, 95% CI = 0.39-0.47, p < 0.0001). Our findings suggest that people of other races and ethnic groups have a lower fracture risk than white people.

There is a great debate on the routine use of open reduction and internal fixation (ORIF) for midshaft clavicle fractures, and one concern is the adverse events after ORIF, such as implant removal after bone union. In this retrospective study, we assessed the incidence, risk factors, management and outcomes of refracture after plate removal of midshaft clavicle fractures after bone union.

Three hundred fifty-two patients diagnosed with acute midshaft clavicle fractures who had complete medical records from primary fractures to refracture were recruited. Details of imaging materials and clinical characteristics were carefully reviewed and analysed.

The incidence rate of refracture was 6.5% (23/352), and the average interval from implant removal to refracture was 25.6 days. Multivariate analysis showed that the risk factors were Robinson type-2B2 and fair/poor reduction. Females were 2.4 times more likely to have refracture, although it was not significant in multivariate analysis (p = 0.134). Postmenopausal females with a short interval (≤ 12 months) from primary surgery to implant removal had a significant risk for refracture. Tobacco use and alcohol use during bone healing were potential risk factors for male patients, although they were not significant in multivariate analysis. Ten patients received reoperation with or without bone graft, and they had a higher rate of bone union than 13 patients who refused reoperation.

The incidence of refracture following implant removal after bone union is underestimated, and severe comminute fractures and unsatisfactory reduction during primary surgery are risk factors. Implant removal for postmenopausal female patients is not recommended due to a high rate of refracture.

To inform recommendations by the Canadian Task Force on Preventive Health Care, we reviewed evidence on the benefits, harms, and acceptability of screening and treatment, and on the accuracy of risk prediction tools for the primary prevention of fragility fractures among adults aged 40 years and older in primary care.

For screening effectiveness, accuracy of risk prediction tools, and treatment benefits, our search methods involved integrating studies published up to 2016 from an existing systematic review. Then, to locate more recent studies and any evidence relating to acceptability and treatment harms, we searched online databases (2016 to April 4, 2022 [screening] or to June 1, 2021 [predictive accuracy]; 1995 to June 1, 2021, for acceptability; 2016 to March 2, 2020, for treatment benefits; 2015 to June 24, 2020, for treatment harms), trial registries and gray literature, and hand-searched reviews, guidelines, and the included studies. Two reviewers selected studies, extracted results, and appraised risk of bias, with disagreements resolved by consensus or a third reviewer. The overview of reviews on treatment harms relied on one reviewer, with verification of data by another reviewer to correct errors and omissions. When appropriate, study results were pooled using random effects meta-analysis; otherwise, findings were described narratively. Evidence certainty was rated according to the GRADE approach.

We included 4 randomized controlled trials (RCTs) and 1 controlled clinical trial (CCT) for the benefits and harms of screening, 1 RCT for comparative benefits and harms of different screening strategies, 32 validation cohort studies for the calibration of risk prediction tools (26 of these reporting on the Fracture Risk Assessment Tool without [i.e., clinical FRAX], or with the inclusion of bone mineral density (BMD) results [i.e., FRAX + BMD]), 27 RCTs for the benefits of treatment, 10 systematic reviews for the harms of treatment, and 12 studies for the acceptability of screening or initiating treatment. In females aged 65 years and older who are willing to independently complete a mailed fracture risk questionnaire (referred to as "selected population"), 2-step screening using a risk assessment tool with or without measurement of BMD probably (moderate certainty) reduces the risk of hip fractures (3 RCTs and 1 CCT, n = 43,736, absolute risk reduction [ARD] = 6.2 fewer in 1000, 95% CI 9.0-2.8 fewer, number needed to screen [NNS] = 161) and clinical fragility fractures (3 RCTs, n = 42,009, ARD = 5.9 fewer in 1000, 95% CI 10.9-0.8 fewer, NNS = 169). It probably does not reduce all-cause mortality (2 RCTs and 1 CCT, n = 26,511, ARD = no difference in 1000, 95% CI 7.1 fewer to 5.3 more) and may (low certainty) not affect health-related quality of life. Benefits for fracture outcomes were not replicated in an offer-to-screen population where the rate of response to mailed screening questionnaires was low. For females aged 68-80 years, population screening may not reduce the risk of hip fractures (1 RCT, n = 34,229, ARD = 0.3 fewer in 1000, 95% CI 4.2 fewer to 3.9 more) or clinical fragility fractures (1 RCT, n = 34,229, ARD = 1.0 fewer in 1000, 95% CI 8.0 fewer to 6.0 more) over 5 years of follow-up. The evidence for serious adverse events among all patients and for all outcomes among males and younger females (<65 years) is very uncertain. We defined overdiagnosis as the identification of high risk in individuals who, if not screened, would never have known that they were at risk and would never have experienced a fragility fracture. This was not directly reported in any of the trials. Estimates using data available in the trials suggest that among "selected" females offered screening, 12% of those meeting age-specific treatment thresholds based on clinical FRAX 10-year hip fracture risk, and 19% of those meeting thresholds based on clinical FRAX 10-year major osteoporotic fracture risk, may be overdiagnosed as being at high risk of fracture. Of those identified as being at high clinical FRAX 10-year hip fracture risk and who were referred for BMD assessment, 24% may be overdiagnosed. One RCT (n = 9268) provided evidence comparing 1-step to 2-step screening among postmenopausal females, but the evidence from this trial was very uncertain. For the calibration of risk prediction tools, evidence from three Canadian studies (n = 67,611) without serious risk of bias concerns indicates that clinical FRAX-Canada may be well calibrated for the 10-year prediction of hip fractures (observed-to-expected fracture ratio [O:E] = 1.13, 95% CI 0.74-1.72, I2 = 89.2%), and is probably well calibrated for the 10-year prediction of clinical fragility fractures (O:E = 1.10, 95% CI 1.01-1.20, I2 = 50.4%), both leading to some underestimation of the observed risk. Data from these same studies (n = 61,156) showed that FRAX-Canada with BMD may perform poorly to estimate 10-year hip fracture risk (O:E = 1.31, 95% CI 0.91-2.13, I2 = 92.7%), but is probably well calibrated for the 10-year prediction of clinical fragility fractures, with some underestimation of the observed risk (O:E 1.16, 95% CI 1.12-1.20, I2 = 0%). The Canadian Association of Radiologists and Osteoporosis Canada Risk Assessment (CAROC) tool may be well calibrated to predict a category of risk for 10-year clinical fractures (low, moderate, or high risk; 1 study, n = 34,060). The evidence for most other tools was limited, or in the case of FRAX tools calibrated for countries other than Canada, very uncertain due to serious risk of bias concerns and large inconsistency in findings across studies. Postmenopausal females in a primary prevention population defined as <50% prevalence of prior fragility fracture (median 16.9%, range 0 to 48% when reported in the trials) and at risk of fragility fracture, treatment with bisphosphonates as a class (median 2 years, range 1-6 years) probably reduces the risk of clinical fragility fractures (19 RCTs, n = 22,482, ARD = 11.1 fewer in 1000, 95% CI 15.0-6.6 fewer, [number needed to treat for an additional beneficial outcome] NNT = 90), and may reduce the risk of hip fractures (14 RCTs, n = 21,038, ARD = 2.9 fewer in 1000, 95% CI 4.6-0.9 fewer, NNT = 345) and clinical vertebral fractures (11 RCTs, n = 8921, ARD = 10.0 fewer in 1000, 95% CI 14.0-3.9 fewer, NNT = 100); it may not reduce all-cause mortality. There is low certainty evidence of little-to-no reduction in hip fractures with any individual bisphosphonate, but all provided evidence of decreased risk of clinical fragility fractures (moderate certainty for alendronate [NNT=68] and zoledronic acid [NNT=50], low certainty for risedronate [NNT=128]) among postmenopausal females. Evidence for an impact on risk of clinical vertebral fractures is very uncertain for alendronate and risedronate; zoledronic acid may reduce the risk of this outcome (4 RCTs, n = 2367, ARD = 18.7 fewer in 1000, 95% CI 25.6-6.6 fewer, NNT = 54) for postmenopausal females. Denosumab probably reduces the risk of clinical fragility fractures (6 RCTs, n = 9473, ARD = 9.1 fewer in 1000, 95% CI 12.1-5.6 fewer, NNT = 110) and clinical vertebral fractures (4 RCTs, n = 8639, ARD = 16.0 fewer in 1000, 95% CI 18.6-12.1 fewer, NNT=62), but may make little-to-no difference in the risk of hip fractures among postmenopausal females. Denosumab probably makes little-to-no difference in the risk of all-cause mortality or health-related quality of life among postmenopausal females. Evidence in males is limited to two trials (1 zoledronic acid, 1 denosumab); in this population, zoledronic acid may make little-to-no difference in the risk of hip or clinical fragility fractures, and evidence for all-cause mortality is very uncertain. The evidence for treatment with denosumab in males is very uncertain for all fracture outcomes (hip, clinical fragility, clinical vertebral) and all-cause mortality. There is moderate certainty evidence that treatment causes a small number of patients to experience a non-serious adverse event, notably non-serious gastrointestinal events (e.g., abdominal pain, reflux) with alendronate (50 RCTs, n = 22,549, ARD = 16.3 more in 1000, 95% CI 2.4-31.3 more, [number needed to treat for an additional harmful outcome] NNH = 61) but not with risedronate; influenza-like symptoms with zoledronic acid (5 RCTs, n = 10,695, ARD = 142.5 more in 1000, 95% CI 105.5-188.5 more, NNH = 7); and non-serious gastrointestinal adverse events (3 RCTs, n = 8454, ARD = 64.5 more in 1000, 95% CI 26.4-13.3 more, NNH = 16), dermatologic adverse events (3 RCTs, n = 8454, ARD = 15.6 more in 1000, 95% CI 7.6-27.0 more, NNH = 64), and infections (any severity; 4 RCTs, n = 8691, ARD = 1.8 more in 1000, 95% CI 0.1-4.0 more, NNH = 556) with denosumab. For serious adverse events overall and specific to stroke and myocardial infarction, treatment with bisphosphonates probably makes little-to-no difference; evidence for other specific serious harms was less certain or not available. There was low certainty evidence for an increased risk for the rare occurrence of atypical femoral fractures (0.06 to 0.08 more in 1000) and osteonecrosis of the jaw (0.22 more in 1000) with bisphosphonates (most evidence for alendronate). The evidence for these rare outcomes and for rebound fractures with denosumab was very uncertain. Younger (lower risk) females have high willingness to be screened. A minority of postmenopausal females at increased risk for fracture may accept treatment. Further, there is large heterogeneity in the level of risk at which patients may be accepting of initiating treatment, and treatment effects appear to be overestimated.

An offer of 2-step screening with risk assessment and BMD measurement to selected postmenopausal females with low prevalence of prior fracture probably results in a small reduction in the risk of clinical fragility fracture and hip fracture compared to no screening. These findings were most applicable to the use of clinical FRAX for risk assessment and were not replicated in the offer-to-screen population where the rate of response to mailed screening questionnaires was low. Limited direct evidence on harms of screening were available; using study data to provide estimates, there may be a moderate degree of overdiagnosis of high risk for fracture to consider. The evidence for younger females and males is very limited. The benefits of screening and treatment need to be weighed against the potential for harm; patient views on the acceptability of treatment are highly variable.

International Prospective Register of Systematic Reviews (PROSPERO): CRD42019123767.

Bone fragility is the susceptibility to fracture due to poor bone strength. This condition is usually associated with aging, comorbidities, disability, poor quality of life, and increased mortality. International guidelines for the management of patients with bone fragility include a nutritional approach, mainly aiming at optimal protein, calcium, and vitamin D intakes. Several biomechanical features of the skeleton, such as bone mineral density (BMD), trabecular and cortical microarchitecture, seem to be positively influenced by micro- and macronutrient intake. Patients with major fragility fractures are usually poor consumers of dairy products, fruit, and vegetables as well as of nutrients modulating gut microbiota. The COVID-19 pandemic has further aggravated the health status of patients with skeletal fragility, also in terms of unhealthy dietary patterns that might adversely affect bone health. In this narrative review, we discuss the role of macro- and micronutrients in patients with bone fragility during the COVID-19 pandemic.

Men with distal forearm fractures have reduced bone density, an increased risk of osteoporosis and of further fractures. The aim of the study was to investigate the structural determinants of these observations using quantitative CT (qCT). Ninety six men with low-trauma distal forearm fracture and 101 age-matched healthy control subjects were recruited. All subjects underwent a quantitative CT on a standard 64-slice whole body CT scanner. These were analysed on Mindways QCT PRO™ Software to generate volumetric and geometric data at the lumbar spine, femoral neck and total hip, ultra-distal and distal 33 % radius. Biochemical investigations, health questionnaires and measurements of bone turnover were made. Men with fracture had significantly lower total and trabecular vBMD at all sites. The greatest percentage reduction was at the ultra-distal radius (13.5 % total and 11.7 % trabecular vBMD). In the fracture group cortical vBMD was significantly higher in the femoral neck (p < 0.001) and maintained at the ultra-distal radius compared with control subjects. However, cortical cross-sectional area (CSA) and thickness were significantly reduced at the femoral neck (p < 0.001 and p = 0.002 respectively) and forearm sites (CSA ultradistal radius p = 0.001, cortical thickness p = 0.002, CSA distal one third radius p = 0.045 and cortical thickness p = 0.005). Cross sectional moment of inertia (CSMI) and section moduli were significantly reduced at the femoral neck (CSMI1 p = 0.002, CSMI2 p = 0.012 and section moduli Z1 p < 0.001, Z2 p = 0.004) and the ultra-distal radius (CSMI1 p = 0.008 and section moduli Z1 p = 0.018, Z2 p = 0.007). In stepwise logistic regression analysis distal forearm fracture showed the strongest association with a model comprising ultra-distal forearm trabecular vBMD (negative), procollagen type I N-terminal propeptide (PINP, positive) and sex hormone binding globulin (SHBG, negative). In conclusion, these observations explain the structural reasons for the increased fracture risk in men with distal forearm fractures.

Femoral neck areal bone mineral density (FN aBMD) is a key determinant of fracture risk in older adults; however, the majority of individuals who have a hip fracture are not considered osteoporotic according to their FN aBMD. This study uses novel tools to investigate the characteristics of bone microarchitecture that underpin bone fragility. Recent hip fracture patients (n = 108, 77% female) were compared with sex- and age-matched controls (n = 216) using high-resolution peripheral quantitative computed tomography (HR-pQCT) imaging of the distal radius and tibia. Standard morphological analysis of bone microarchitecture, micro-finite element analysis, and recently developed techniques to identify void spaces in bone microarchitecture were performed to evaluate differences between hip fracture patients and controls. In addition, a new approach for phenotyping bone microarchitecture was implemented to evaluate whether hip fractures in males and females occur more often in certain bone phenotypes. Overall, hip fracture patients had notable deterioration of bone microarchitecture and reduced bone mineral density compared with controls, especially at weight-bearing sites (tibia and femoral neck). Hip fracture patients were more likely to have void spaces present at either site and had void spaces that were two to four times larger on average when compared with non-fractured controls (p < 0.01). Finally, bone phenotyping revealed that hip fractures were significantly associated with the low density phenotype (p < 0.01), with the majority of patients classified in this phenotype (69%). However, female and male hip fracture populations were distributed differently across the bone phenotype continuum. These findings highlight how HR-pQCT can provide insight into the underlying mechanisms of bone fragility by using information about bone phenotypes and identification of microarchitectural defects (void spaces). The added information suggests that HR-pQCT can have a beneficial role in assessing the severity of structural deterioration in bone that is associated with osteoporotic hip fractures. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Prolactinoma may reduce bone mineral density (BMD) and increase fracture risk, but its influence on bone microarchitecture remains to be elucidated. The purpose of this study is to evaluate bone microarchitecture parameters by high-resolution peripheral quantitative computed tomography (HR-pQCT) in prolactinoma patients.

31 prolactinoma patients and 62 age- and sex-matched healthy controls in our center were included, and HR-pQCT was used to evaluate their bone microarchitecture at the radius and tibia. Z-scores for bone microarchitecture parameters were calculated based on previously published reference.

After adjusting for height and weight, prolactinoma patients had lower trabecular (- 0.011 mm, p = 0.005) and cortical thickness (- 0.116 mm, p = 0.008) and cortical area (- 6.0 mm2, p = 0.013) at radius, as well as lower trabecular (- 0.014 mm, p = 0.008) and cortical (- 0.122 mm, p = 0.022) thickness at tibia compared with the controls. Patients with higher prolactin level had more severe bone microarchitecture impairments. After adjusting for prolactin level and age, male patients had lower trabecular volumetric BMD (vBMD), trabecular number, trabecular thickness, and cortical porosity at radius, as well as lower trabecular vBMD, trabecular bone volume fraction, trabecular number, and cortical area, and higher trabecular separation at tibia compared with female patients. Z-score for radius vBMD was correlated with Z-score for areal BMD (aBMD) at lumbar and femoral neck, while Z-score for tibia vBMD was correlated with Z-score for lumbar aBMD, and some patients with vBMD Z-score below - 2.0 had aBMD Z-score within normal range.

Peripheral bone microarchitecture was impaired in prolactinoma patients, especially in patients with higher prolactin level. We compared the bone microarchitecture of prolactinoma patients and healthy controls by high-resolution peripheral quantitative computed tomography (HR-pQCT), and found that many bone microarchitecture parameters were impaired among prolactinoma patients. Such impairment was more prominent among patients with higher prolactin level.

In preclinical models, the composition and function of the gut microbiota have been linked to bone growth and homeostasis, but there are few available data from studies of human populations. In a hypothesis-generating experiment in a large cohort of community-dwelling older men (n = 831; age range, 78-98 years), we explored the associations between fecal microbial profiles and bone density, microarchitecture, and strength measured with total hip dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HRpQCT) (distal radius, distal and diaphyseal tibia). Fecal samples were collected and the 16S rRNA gene V4 hypervariable region sequenced. Sequences were bioinformatically processed through the DADA2 pipeline and then taxonomically assigned using SILVA. Generalized linear models as implemented in microbiome multivariable association with linear models (MaAsLin 2) were used to test for associations between skeletal measures and specific microbial genera. The abundances of four bacterial genera were weakly associated with bone density, structure, or strength (false discovery rate [FDR] ≤ 0.05), and the measured directions of associations of genera were generally consistent across multiple bone measures, supporting a role for microbiota on skeletal homeostasis. However, the associated effect sizes were small (log2 fold change < ±0.35), limiting power to confidently identify these associations even with high resolution skeletal imaging phenotypes, and we assessed the resulting implications for the design of future cohort-based studies. As in analogous examples from genomewide association studies, we find that larger cohort sizes will likely be needed to confidently identify associations between the fecal microbiota and skeletal health relying on 16S sequencing. Our findings bolster the view that the gut microbiome is associated with clinically important measures of bone health, while also indicating the challenges in the design of cohort-based microbiome studies. © 2022 American Society for Bone and Mineral Research (ASBMR).

Periosteosis refers to pathological woven bone formation beneath the cortical bone of the long bones. It is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO) and also considered as one of the major diagnostic criteria of PHO patients. Up to date, detailed information on bone quality changes in long bones of PHO patients is still missing. This study aimed to evaluate bone microarchitecture and bone strength in PHO patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT). The study comprised 20 male PHO patients with the average age of 27.0 years and 20 age- and sex-matched healthy controls. The areal bone mineral density (aBMD) was assessed at the lumbar spine (L₁ -L₄ ) and hip (total hip and femoral neck) by dual-energy X-ray absorptiometry (DXA). Bone geometry, volumetric bone mineral density (vBMD), and microstructure parameters at the distal tibia were evaluated by using HR-pQCT. Bone strength was evaluated by finite element analysis (FEA) based on HR-pQCT screening at distal tibia. Urinary prostaglandin E₂ (PGE₂ ), serum phosphatase (ALP), beta-C-telopeptides of type I collagen (β-CTX), soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and neuronal calcitonin gene-related peptide (CGRP) were investigated. As compared with healthy controls, PHO patients had larger bone cross-sectional areas; lower total, trabecular, and cortical vBMD; compromised bone microstructures with more porous cortices, thinned trabeculae, reduced trabecular connectivity, and relatively more significant resorption of rod-like trabeculae at distal tibia. The apparent Young's modulus was significantly lower in PHO patients. The concentration of PGE₂ , biomarkers of bone resorption (β-CTX and sRANKL/OPG ratio), and the neuropeptide CGRP were higher in PHO patients versus healthy controls. PGE₂ level correlated negatively with vBMD and estimated bone strength and positively with bone geometry at distal tibia. The present HR-pQCT study is the first one illustrating the microarchitecture and bone strength features in long bones. © 2021 American Society for Bone and Mineral Research (ASBMR).

This HR-pQCT study was conducted to examine bone properties of the distal tibia post-stroke and to identify clinical outcomes that were associated with these properties at this site. It was found that spasticity and gait speed were independently associated with estimated failure load in individuals with chronic stroke.

(1) To examine the influence of stroke on distal tibia bone properties and (2) the association between these properties and clinical outcomes in people with chronic stroke.

Sixty-four people with stroke (age, 60.8 ± 7.7 years; time since stroke, 5.7 ± 3.9 years) and 64 controls (age: 59.4 ± 7.8 years) participated in this study. High-resolution peripheral quantitative computed tomography (HR-pQCT) was used to scan the bilateral distal tibia, and estimated failure load was calculated by automated finite element analysis. Echo intensity of the medial gastrocnemius muscle and blood flow of the popliteal artery were assessed with ultrasound. The 10-m walk test (10MWT), Fugl-Meyer Motor Assessment (FMA), and Composite Spasticity Scale (CSS) were also administered.

The percent side-to-side difference (%SSD) in estimated failure load, cortical area, thickness, and volumetric bone mineral density (vBMD), and trabecular and total vBMD were significantly greater in the stroke group than their control counterparts (Cohen's d = 0.48-1.51). Isometric peak torque and echo intensity also showed significant within- and between-groups differences (p ≤ 0.01). Among HR-pQCT variables, the %SSD in estimated failure load was empirically chosen as one example of the strong discriminators between the stroke group and control group, after accounting for other relevant factors. The 10MWT and CSS subscale for ankle clonus remained significantly associated with the %SSD in estimated failure load after adjusting for other relevant factors (p ≤ 0.05).

The paretic distal tibia showed more compromised vBMD, cortical area, cortical thickness, and estimated failure load than the non-paretic tibia. Gait speed and spasticity were independently associated with estimated failure load. As treatment programs focusing on these potentially modifiable stroke-related impairments are feasible to administer, future studies are needed to determine the efficacy of such intervention strategies for improving bone strength in individuals with chronic stroke.

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.

We pooled 211 postmenopausal women with fractures aged 54-94 years at baseline and 232 fracture-free 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.

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.

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.

Markers of bone metabolism have been associated with muscle mass and function. Whether serum cross-linked C-terminal telopeptides of type I collagen (CTX) is also associated with these measures in older adults remains unknown.

In community-dwelling older adults at high risk of falls and fractures, serum CTX (biochemical immunoassays) was used as the exposure, while appendicular lean mass (dual-energy x-ray absorptiometry) and muscle function (grip strength [hydraulic dynamometer], short physical performance battery [SPPB], gait speed, sit to stand, balance, Timed Up and Go [TUG]) were used as outcomes. Potential covariates including demographic, lifestyle and clinical factors were considered in statistical models. Areas under the ROC curves were calculated for significant outcomes.

299 older adults (median age: 79 years, IQR: 73, 84; 75.6% women) were included. In multivariable models, CTX was negatively associated with SPPB (β = 0.95, 95% CI: 0.92, 0.98) and balance (β = 0.92, 0.86, 0.99) scores, and positively associated with sit to stand (β = 1.02, 95% CI: 1.00, 1.05) and TUG (β = 1.03, 95% CI: 1.00, 1.05). Trend line for gait speed (β = 0.99, 95% CI: 0.98, 1.01) was in the hypothesized direction but did not reach significance. AUC curves showed low diagnostic power (<0.7) of CTX in identifying poor muscle function (SPPB: 0.63; sit to stand: 0.64; TUG: 0.61).

In older adults, higher CTX levels were associated with poorer lower-limb muscle function (but showed poor diagnostic power for these measures). These clinical data build on the biomedical link between bone and muscle.

Proximal humerus fractures are commonly observed in postmenopausal women. The goal of this study was to investigate menopause-related changes in cortical structure of the humeral head.

Clinical computed tomography (CT) scans of 75 healthy women spanning a wide range of ages (20-72 years) were analyzed. For each subject, cortical bone mapping (CBM) was applied to create a color three-dimensional (3D) thickness map for the proximal humerus. Nine regions of interest (ROIs) were defined in three walls of the humeral head. Cortical parameters, including the cortical thickness (CTh), cortical mass surface density (CM), and the endocortical trabecular density (ECTD), were measured.

Compared to premenopausal women, postmenopausal women were characterized by a significantly lower CTh and CM value in the lateral part of the greater tuberosity. Similar changes were only found in ROI 4, but not in ROIs 5-6 in the lesser tuberosity. Linear regression analysis revealed that the CTh and CM value of ROIs 1, 3, and 4 were negatively associated with age. These results showed that menopause-related loss in CTh and CM was mainly in the greater tuberosity besides the proximal part of the lesser tuberosity. Trabecular bone variable measured as ECTD showed a notably lower value in ROIs 1-9 in postmenopausal vs. premenopausal group. Inverse linear associations for ECTD and age were found in ROIs 2, 3, 5, 6, 7, and 9, indicating no site-specific differences of endocortical trabecular bone loss between the greater and lesser tuberosity.

Menopause-related cortical loss of the humeral head mainly occurred in the lateral part of the greater tuberosity. The increased rate of humeral bone loss in the greater tuberosity may contribute materially to complex proximal humerus fractures.

Patients with ankylosing spondylitis (AS) have impaired volumetric bone mineral density (vBMD) assessed with high-resolution peripheral computed tomography (HRpQCT). This first longitudinal HRpQCT study in AS shows that cortical and trabecular vBMD decreased at tibia and that signs of inflammation were associated with cortical bone loss at tibia and radius.

Patients with ankylosing spondylitis (AS) have reduced volumetric bone mineral density (vBMD) in the peripheral skeleton assessed with high-resolution peripheral quantitative computed tomography (HRpQCT). The aims were to investigate longitudinal changes in vBMD, cortical area, and microarchitecture and to assess factors associated with changes in vBMD and cortical area in men with AS.

HRpQCT of radius and tibia was performed in 54 men with AS at baseline and after 5 years. Univariate and multivariable linear regression analyses were used.

At tibia, there were significant decreases exceeding least significant changes (LSC) in cortical and trabecular vBMD, mean (SD) percent change -1.0 (1.9) and -2.7 (5.0) respectively (p<0.001). In multivariable regression analyses, increase in disease activity measured by ASDAS_CRP from baseline to follow-up was associated with decreases in cortical vBMD (β -0.86, 95% CI -1.31 to -0.41) and cortical area (β -1.66, 95% CI -3.21 to -0.10) at tibia. At radius, no changes exceeded LSC. Nonetheless, increase in ASDAS_CRP was associated with decreases in cortical vBMD, and high time-averaged ESR was associated with decreases in cortical area. Treatment with TNF inhibitor ≥ 4 years during follow-up was associated with increases in cortical vBMD and cortical area at tibia, whereas exposure to bisphosphonates was associated with increases in cortical measurements at radius. No disease-related variables or treatments were associated with changes in trabecular vBMD.

The findings in this first longitudinal HRpQCT study in patients with AS strengthen the importance of controlling disease activity to maintain bone density in the peripheral skeleton.

Transcriptome-wide association studies (TWAS) systematically investigate the association of genetically predicted gene expression with disease risk, providing an effective approach to identify novel susceptibility genes. Osteoporosis is the most common metabolic bone disease, associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fractures, whereas genetic factors explain approximately 70% of the variance in phenotypes associated with bone. BMD is commonly assessed using dual-energy X-ray absorptiometry (DXA) to obtain measurements (g/cm2) of areal BMD. However, quantitative computed tomography (QCT) measured 3D volumetric BMD (vBMD) (g/cm3) has important advantages compared with DXA since it can evaluate cortical and trabecular microstructural features of bone quality, which can be used to directly predict fracture risk. Here, we performed the first TWAS for volumetric BMD (vBMD) by integrating genome-wide association studies (GWAS) data from two independent cohorts, namely the Framingham Heart Study (FHS, n = 3298) and the Osteoporotic Fractures in Men (MrOS, n = 4641), with tissue-specific gene expression data from the Genotype-Tissue Expression (GTEx) project. We first used stratified linkage disequilibrium (LD) score regression approach to identify 12 vBMD-relevant tissues, for which vBMD heritability is enriched in tissue-specific genes of the given tissue. Focusing on these tissues, we subsequently leveraged GTEx expression reference panels to predict tissue-specific gene expression levels based on the genotype data from FHS and MrOS. The associations between predicted gene expression levels and vBMD variation were then tested by MultiXcan, an innovative TWAS method that integrates information available across multiple tissues. We identified 70 significant genes associated with vBMD, including some previously identified osteoporosis-related genes such as LYRM2 and NME8, as well as some novel loci such as DNAAF2 and SPAG16. Our findings provide novel insights into the pathophysiological mechanisms of osteoporosis and highlight several novel vBMD-associated genes that warrant further investigation.

In this paper, we discuss how recent advancements in image processing and machine learning (ML) are shaping a new and exciting era for the osteoporosis imaging field. With this paper, we want to give the reader a basic exposure to the ML concepts that are necessary to build effective solutions for image processing and interpretation, while presenting an overview of the state of the art in the application of machine learning techniques for the assessment of bone structure, osteoporosis diagnosis, fracture detection, and risk prediction.

ML effort in the osteoporosis imaging field is largely characterized by "low-cost" bone quality estimation and osteoporosis diagnosis, fracture detection, and risk prediction, but also automatized and standardized large-scale data analysis and data-driven imaging biomarker discovery. Our effort is not intended to be a systematic review, but an opportunity to review key studies in the recent osteoporosis imaging research landscape with the ultimate goal of discussing specific design choices, giving the reader pointers to possible solutions of regression, segmentation, and classification tasks as well as discussing common mistakes.

Osteoporosis is a systemic skeletal disease characterized by low bone mass and bone structural deterioration that may result in fragility fractures. Use of bone imaging modalities to accurately predict fragility fractures is always an important issue, yet the current gold standard of dual-energy X-ray absorptiometry (DXA) for diagnosis of osteoporosis cannot fully satisfy this purpose. The latest high-resolution peripheral quantitative computed tomography (HR-pQCT) is a three-dimensional (3D) imaging device to measure not only volumetric bone density, but also the bone microarchitecture in a noninvasive manner that may provide a better fracture prediction power. This systematic review and meta-analysis was designed to investigate which HR-pQCT parameters at the distal radius and/or distal tibia could best predict fragility fractures. A systematic literature search was conducted in Embase, PubMed, and Web of Science with relevant keywords by two independent reviewers. Original clinical studies using HR-pQCT to predict fragility fractures with available full text in English were included. Information was extracted from the included studies for further review. In total, 25 articles were included for the systematic review, and 16 articles for meta-analysis. HR-pQCT was shown to significantly predict incident fractures and/or major osteoporotic fractures (MOFs). Of all the HR-pQCT parameters, our meta-analysis revealed that cortical volumetric bone mineral density (Ct.vBMD), trabecular thickness (Tb.Th), and stiffness were better predictors. Meanwhile, HR-pQCT parameters indicated better performance in predicting MOFs than incident fractures. Between the two standard measurement sites of HR-pQCT, the non-weight-bearing distal radius was a more preferable site than distal tibia for fracture prediction. Furthermore, most of the included studies were white-based, whereas very few studies were from Asia or South America. These regions should build up their densitometric databases and conduct related prediction studies. It is expected that HR-pQCT can be used widely for the diagnosis of osteoporosis and prediction of future fragility fractures. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Osteoporotic or fragility fractures affect one in two women and one in five men who are older than 50. These events are associated with substantial morbidity, increased mortality, and an impaired quality of life. Recommended general measures for fragility fracture prevention include a balanced diet with an optimal protein and calcium intake and vitamin D sufficiency, together with regular weight-bearing physical exercise. In this narrative Review, we discuss the role of nutrients, foods, and dietary patterns in maintaining bone health. Much of this information comes from observational studies. Bone mineral density, microstructure-estimated bone strength, and trabecular and cortical microstructure are positively associated with total protein intake. Several studies indicate that fracture risk might be lower with a higher dietary protein intake, provided that the calcium supply is sufficient. Dairy products are a valuable source of these two nutrients. Hip fracture risk appears to be lower in consumers of dairy products, particularly fermented dairy products. Consuming less than five servings per day of fruit and vegetables is associated with a higher hip fracture risk. Adherence to a Mediterranean diet or to a prudent diet is associated with a lower fracture risk. These various nutrients and dietary patterns influence gut microbiota composition or function, or both. The conclusions of this Review emphasise the importance of a balanced diet including minerals, protein, and fruit and vegetables for bone health and in the prevention of fragility fractures.

Bone health in psoriasis and psoriatic arthritis has been emphasized in recent years. Novel imaging modalities allow investigations into volumetric bone mineral density (vBMD) and bone microstructure in psoriatic patients. However, literature regarding vBMD measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) is inconclusive. We conducted a systematic review and meta-analysis to evaluate vBMD in patients with psoriatic disease. We searched PubMed, EMBASE, Web of Science, and Cochrane Library for relevant observational studies. A random-effects meta-analysis with trial sequential analysis (TSA) was performed. The pooled mean difference (MD) and 95% confidence interval (CI) were calculated. Five studies with 780 patients were included. Patients with psoriatic disease showed a lower average vBMD than controls (MD -14.90; 95% CI -22.90 to -6.89; TSA-adjusted CI -23.77 to -6.03; I² = 41%). Trabecular vBMD and cortical vBMD results were inconclusive because of the small sample size. Patients recruited in Asia and those whose vBMD were measured at the distal radius exhibited a lower average vBMD than controls. Further research should clarify the association of psoriasis with bone microstructure and the underlying pathophysiology.

High-resolution peripheral computed tomography (HR-pQCT) was developed to image bone microarchitecture in vivo at peripheral skeletal sites. Since the introduction of HR-pQCT in 2005, clinical research to gain insight into pathophysiology of skeletal fragility and to improve prediction of fractures has grown. Meanwhile, the second-generation HR-pQCT device has been introduced, allowing novel applications such as hand joint imaging, assessment of subchondral bone and cartilage thickness in the knee, and distal radius fracture healing. This article provides an overview of the current clinical applications and guidance on interpretation of results, as well as future directions. Specifically, we provide an overview of (1) the differences and reference data for HR-pQCT variables by age, sex, and race/ethnicity; (2) fracture risk prediction using HR-pQCT; (3) the ability to monitor response of anti-osteoporosis therapy with HR-pQCT; (4) the use of HR-pQCT in patients with metabolic bone disorders and diseases leading to secondary osteoporosis; and (5) novel applications of HR-pQCT imaging. Finally, we summarize the status of the application of HR-pQCT in clinical practice and discuss future directions. From the clinical perspective, there are both challenges and opportunities for more widespread use of HR-pQCT. Assessment of bone microarchitecture by HR-pQCT improves fracture prediction in mostly normal or osteopenic elderly subjects beyond DXA of the hip, but the added value is marginal. The prospects of HR-pQCT in clinical practice need further study with respect to medication effects, metabolic bone disorders, rare bone diseases, and other applications such as hand joint imaging and fracture healing. The mostly unexplored potential may be the differentiation of patients with only moderately low BMD but severe microstructural deterioration, which would have important implications for the decision on therapeutical interventions.