Genetic Variants in WNT16 and PKD2L1 Locus Affect Heel Ultrasound Bone Stiffness: Analyses from the General Population and Patients Evaluated for Osteoporosis.

Osteoporosis, a complex chronic disease with increasing prevalence, is characterised by reduced bone mineral density (BMD) and increased fracture risk. The high heritability of BMD suggests substantial impact of the individual genetic disposition on bone phenotypes and the development of osteoporosis. In the past years, genome-wide association studies (GWAS) identified hundreds of genetic variants associated with BMD or osteoporosis. Here, we analysed 1103 single nucleotide polymorphisms (SNPs), previously identified as associated with estimated BMD (eBMD) in the UK Biobank. We assessed whether these SNPs are related to heel stiffness index obtained by quantitative ultrasound in 5665 adult participants of the Study of Health in Pomerania (SHIP). We confirmed 45 significant associations after correction for multiple testing. Next, we analysed six selected SNPs in 631 patients evaluated for osteoporosis [rs2707518 (CPED1/WNT16), rs3779381 (WNT16), rs115242848 (LOC101927709/EN1), rs10239787 (JAZF1), rs603424 (PKD2L1) and rs6968704 (JAZF1)]. Differences in minor allele frequencies (MAF) of rs2707518 and rs3779381 between SHIP participants (higher MAF) and patients evaluated for osteoporosis (lower MAF) indicated a protective effect of the minor allele on bone integrity. In contrast, differences in MAF of rs603424 indicated a harmful effect. Co-localisation analyses indicated that the rs603424 effect may be mediated via stearoyl-CoA desaturase (SCD) expression, an enzyme highly expressed in adipose tissue with a crucial role in lipogenesis. Taken together, our results support the role of the WNT16 pathway in the regulation of bone properties and indicate a novel causal role of SCD expression in adipose tissue on bone integrity.

Gorilla calcaneal morphological variation and ecological divergence.

OBJECTIVES: The primate foot has been extensively investigated because of its role in weight-bearing; however, the calcaneus has been relatively understudied. Here we examine entire gorilla calcaneal external shape to understand its relationship with locomotor behavior. MATERIALS AND METHODS: Calcanei of Gorilla gorilla gorilla (n = 43), Gorilla beringei graueri (n = 20), and Gorilla beringei beringei (n = 15) were surface or micro-CT scanned. External shape was analyzed through a three-dimensional geometric morphometric sliding semilandmark analysis. Semilandmarks were slid relative to an updated Procrustes average in order to minimize the bending energy of the thin plate spline interpolation function. Shape variation was summarized using principal components analysis of shape coordinates. Procrustes distances between taxa averages were calculated and resampling statistics run to test pairwise differences. Linear measures were collected and regressed against estimated body mass. RESULTS: All three taxa exhibit statistically different morphologies (p < .001 for pairwise comparisons). G. g. gorilla demonstrates an anteroposteriorly elongated calcaneus with a deeper cuboid pivot region and mediolaterally flatter posterior talar facet. G. b. beringei possesses the flattest cuboid and most medially-angled posterior talar facets. G. b. graueri demonstrates intermediate articular facet morphology, a medially-angled tuberosity, and an elongated peroneal trochlea. DISCUSSION: Articular facet differences separate gorillas along a locomotor gradient. G. g. gorilla is adapted for arboreality with greater joint mobility, while G. b. beringei is adapted for more stereotypical loads associated with terrestriality. G. b. graueri's unique posterolateral morphology may be due to a secondary transition to greater arboreality from a more terrestrial ancestor.

Using point clouds to investigate the relationship between trabecular bone phenotype and behavior: An example utilizing the human calcaneus.

OBJECTIVES: The objective of this study is to demonstrate a new method for analyzing trabecular bone volume fraction and degree of anisotropy in three dimensions. METHODS: We use a combination of automatic mesh registration, point-cloud correspondence registration, and P-value corrected univariate statistical tests to compare bone volume fraction and degree of anisotropy on a point by point basis across the entire calcaneus of two human groups with different subsistence strategies. RESULTS: We found that the patterns of high and low bone volume fraction and degree of anisotropy distribution between the Black Earth (hunter-gatherers) and Norris Farms (mixed-strategy agriculturalists) are very similar, but differ in magnitude. The hunter-gatherers exhibit higher levels of bone volume fraction and less anisotropic trabecular bone organization. Additionally, patterns of bone volume fraction and degree of anisotropy in the calcaneus correspond well with biomechanical expectations of relative forces experienced during walking and running. CONCLUSIONS: We conclude that comparing site-specific, localized differences in trabecular bone variables such as bone volume fraction and degree of anisotropy in three-dimensions is a powerful analytical tool. This method makes it possible to determine where similarities and differences between groups are located within the whole skeletal element of interest. The visualization of multiple variables also provides a way for researchers to see how the trabecular bone variables interact within the morphology, and allows for a more nuanced understanding of how they relate to one another and the broader mechanical environment.

Cross-sectional and longitudinal associations between physical activity, sedentary behaviour and bone stiffness index across weight status in European children and adolescents.

BACKGROUND: The associations between physical activity (PA), sedentary behaviour (SB) and bone health may be differentially affected by weight status during growth. This study aims to assess the cross-sectional and longitudinal associations between PA, SB and bone stiffness index (SI) in European children and adolescents, taking the weight status into consideration. METHODS: Calcaneus SI was first measured by quantitative ultrasound among children aged 2-9 years old in 2007/08. It was measured again after 2 years in the IDEFICS study and after 6 years in the I. Family study. A sample of 2008 participants with time spent at sports clubs, watching TV and playing computer/games self-reported by questionnaire, and a subsample of 1037 participants with SB, light PA (LPA) and moderate-to-vigorous PA (MVPA) objectively measured using Actigraph accelerometers were included in the analyses. Weight status was defined as thin/normal and overweight/obese according to the extended International Obesity Task Force criteria. Linear mixed-effects models were used to estimate the cross-sectional and longitudinal associations between PA, SB and SI percentiles, stratified by weight status. RESULTS: The cross-sectional association between weekly duration of watching TV and SI percentiles was negative in thin/normal weight group (ß = - 0.35, p = 0.008). However, baseline weekly duration of watching TV (ß = - 0.63, p = 0.021) and change after 2 years (ß = - 0.63, p = 0.022) as well as the change in weekly duration of playing computer/games after 6 years (ß = - 0.75, p = 0.019) were inversely associated with corresponding changes in SI percentiles in overweight/obese group. Change in time spent at sports clubs was positively associated with change in SI percentiles after 2 years (ß = 1.28, p = 0.001), with comparable effect sizes across weight status. In the subsample with accelerometer data, we found a positive cross-sectional association between MVPA and SI percentiles in thin/normal weight group. Baseline MVPA predicted changes in SI percentiles after 2 and 6 years in all groups. CONCLUSIONS: Our results suggested the beneficial effect of PA on SI. However, the increasing durations of screen-based SB might be risk factors for SI development, especially in overweight/obese children and adolescents.

Disparities in bone density across contemporary Amazonian forager-horticulturalists: Cross-population comparison of the Tsimane and Shuar.

OBJECTIVES: This study investigates bone density across the life course among Bolivian Tsimane and Ecuadorian Shuar of Amazonia. Both groups are rural, high-fertility forager-horticulturalists, with high lifetime physical activity levels. We test whether Tsimane and Shuar bone density patterns are different from each other, and if both groups are characterized by lower osteoporosis risk compared to U.S. references. METHODS: Anthropometric and calcaneal bone density data, obtained via quantitative ultrasonometry (QUS), were collected from 678 Tsimane and 235 Shuar (13-92 years old). Population and sex differences in QUS values (estimated bone mineral density, speed of sound, broadband ultrasound attenuation) by age group were assessed using Mann-Whitney U tests. Age-related change and age at peak QUS value were determined using polynomial regressions. One-way analyses of covariance assessed population-level differences in QUS values by age group adjusting for body mass index. Participants aged 50+ years at elevated osteoporosis risk were identified using a T score < -1.8; binomial tests assessed risk compared to U.S. references. RESULTS: Shuar males and females <50 years old have QUS values 3-36% higher than Tsimane, with differences evident in adolescence. Among Tsimane and Shuar, 49 and 23% of participants aged 50+ years old, respectively, are at high risk for osteoporosis, compared to 34% of Americans; Shuar osteoporosis risk is comparable to Americans, while Tsimane risk is elevated. CONCLUSIONS: Disparate patterns in QUS values are documented for Tsimane and Shuar, with pronounced differences early in life. Potential explanations for differences include gene-environment interactions and/or degree of market integration, which influences diet, activity profiles, pathogen exposures, and other lifestyle covariates. As Tsimane osteoporosis risk is greater than in the United States, findings point to alternative risk factors for low bone density that are not readily discernible in industrialized populations.

Advancing the deer calcaneus model for bone adaptation studies: ex vivo strains obtained after transecting the tension members suggest an unrecognized important role for shear strains.

Sheep and deer calcanei are finding increased use as models for studies of bone adaptation, including advancing understanding of how the strain (deformation) environment influences the ontogenetic emergence of biomechanically relevant structural and material variations in cortical and trabecular bone. These artiodactyl calcanei seem ideal for these analyses because they function like simply loaded short-cantilevered beams with net compression and tension strains on the dorsal and plantar cortices, respectively. However, this habitual strain distribution requires more rigorous validation because it has been shown by limited in vivo and ex vivo strain measurements obtained during controlled ambulation (typically walking and trotting). The conception that these calcanei are relatively simply and habitually loaded 'tension/compression bones' could be invalid if infrequent, though biologically relevant, loads substantially change the location of the neutral axis (NA) that separates 'compression' and 'tension' regions. The effect on calcaneus strains of the tension members (plantar ligament and flexor tendon) is also not well understood and measuring strains after transecting them could reveal that they significantly modulate the strain distribution. We tested the hypothesis that the NA location previously described during simulated on-axis loads of deer calcanei would exhibit limited variations even when load perturbations are unusual (e.g. off-axis loads) or extreme (e.g. after transection of the tension members). We also examined regional differences in the predominance of the three strain modes (tension, compression, and shear) in these various load conditions in dorsal, plantar, medial, and lateral cortices. In addition to considering principal strains (tension and compression) and maximum shear strains, we also considered material-axis (M-A) shear strains. M-A shear strains are those that are aligned along the long axis of the bone and are considered to have greater biomechanical relevance than maximum shear strains because failure theories of composite materials and bone are often based on stresses or strains in the principal material directions. We used the same load apparatus from our prior study of mule deer calcanei. Results showed that although the NA rotated up to 8° medially and 15° laterally during these off-axis loads, it did not shift dramatically until after transection of all tension members. When comparing results based on maximum shear strain data vs. M-A shear strain data, the dominant strain mode changed only in the plantar cortex - as expected (in accordance with our a priori view) it was tension when M-A shear strains were considered (shear : tension = 0.2) but changed to dominant shear when maximum shear strain data were considered (shear : tension = 1.3). This difference leads to different conclusions and speculations regarding which specific strain modes and magnitudes most strongly influence the emergence of the marked mineralization and histomorphological differences in the dorsal vs. plantar cortices. Consequently, our prior simplification of the deer calcaneus model as a simply loaded 'tension/compression bone' (i.e. plantar/dorsal) might be incorrect. In vivo and in finite element analyses are needed to determine whether describing it as a 'shear-tension/compression' bone is more accurate. Addressing this question will help to advance the artiodactyl calcaneus as an experimental model for bone adaptation studies.

Tea consumption and bone health in Chinese adults: a population-based study.

Tea is a worldwide drink with controversial effect on bone health. The sex-specific associations are unrevealed among general population. This study showed that prolonged moderate tea consumption benefited bone health in women, while no additional benefit with stronger tea. However, tea consumption was not associated with bone health in men. INTRODUCTION: Tea consumption has been shown a potentially beneficial effect on bone health in postmenopausal women. However, little is known about such association in men, and whether stronger tea instead harms bone health due to elevated urinary excretion of calcium associated with caffeine in the tea. The aim of this study was to examine the association between various metrics of tea consumption and bone health. METHODS: The present study included 20,643 participants from the China Kadoorie Biobank (CKB), who have finished both baseline survey (2004-2008) and a re-survey (2013-2014). They were aged 38-86 years at re-survey. Tea consumption was self-reported at both baseline and re-survey. Bone mineral density (BMD) was measured using calcaneal quantitative ultrasound once at re-survey. RESULTS: Compared with non-consumers, prolonged weekly tea consumers in women was associated with higher calcaneus BMD measures, with ß (95% CI) of 0.98 (0.22, 1.74) for BUA, 4.68 (1.74, 7.61) for SOS, and 1.95 (0.81, 3.10) for SI. Among prolonged weekly tea consumers, no linear increase in BMD measures with the amount of tea leaves added was observed. The SOS and SI were higher in consumers with tea leaves 3.0-5.9 g/day than in those with < 3.0 g/day, but were reduced to non-significant for those with ≥ 6.0 g/day. Tea consumption was not associated with calcaneus BMD measures in men. CONCLUSION: Prolonged moderate tea consumption benefited bone health in women but not in men. For stronger tea consumption with more tea leaves added, neither benefit nor harm to bone health was observed.

Relationship between physical activity, dietary intake and bone parameters in 10-12 years old Hungarian boys and girls.

OBJECTIVES: Physical activity (PA) and adequate macro- and micronutrient intake have favourable influence on the bone status. The aim of this study was to analyse the relationships among PA, anthropometric data, dietary intake and ultrasound bone characteristics in children. METHODS: 10-12 years old Hungarian children (N = 123, 59 girls, 64 boys) provided physical activity, diet, anthropometric and bone data. PA was measured with accelerometer (Actigraph GT3X+). Diet was evaluated with three-day, 24-hour food recall. Calcaneal quantitative ultrasound (QUS) bone parameters were registered with Sonost3000 bone densitometer. RESULTS: Nutrition and anthropometry did not differ by gender. The values of broadband ultrasound attenuation (BUA) were significantly higher in boys. Girls spent significantly more time being sedentary, boys had greater light, moderate, vigorous, and moderate to vigorous physical activity (MVPA) levels. The children accumulated more than twice the suggested amount of public health guidelines for MVPA. QUS parameters correlated significantly with vigorous physical activity in boys, and with age, height, weight, fat percentage, and body mass index (BMI) for both genders. There was no significant relationship between nutrition and QUS; however, inadequate vitamin K intake correlated with less favourable bone parameters. Multiple linear regression analysis confirmed the importance of vigorous PA - speed of sound (SOS): ß = 0.358, p = 0.006; BUA: ß = 0.340, p = 0.007; bone quality index (BQI): ß = 0.377, p = 0.002; vitamin K intake - SOS: ß = 0.256, p = 0.025; BUA: ß = 0.235, p = 0.033; BQI: ß = 0.295, p = 0.007; BMI - SOS: ß = 0.207, p = 0.064; BUA: ß = 0.455, p < 0.001; BQI: ß = 0.284, p = 0.008; and age - SOS: ß = 0.450, p < 0.001; BUA: ß = 0.318, p = 0.004; BQI: ß = 0.444, p < 0.001). CONCLUSIONS: Changes in the characteristics of ultrasound bone parameters among 10-12 years old children mainly depended on the amount of intense PA, adequate vitamin K intake and anthropometric variables related to age.

Calcaneal adduction and eversion are coupled to talus and tibial rotation.

The purpose of this study was to quantify isolated coupling mechanisms of calcaneal adduction/abduction and calcaneal eversion/inversion to proximal bones in vitro. The in vitro approach is necessary because in vivo both movements appear together, making it impossible to determine the extent of their individual contribution to overall ankle joint coupling. Eight fresh frozen foot-leg specimens were tested. Data describing bone orientation and coupling mechanisms between segments were obtained using bone pin marker triads. The bone movement was described in a global coordinate system to examine the coupling between the calcaneus, talus and tibia. The strength of coupling was determined by means of the slope of a linear least squares fit to an angle-angle plot. The coupling coefficients in the present study indicate that not only calcaneal eversion/inversion (coupling coefficient: 0.68 ± 0.15) but to an even greater extent calcaneal adduction/abduction (coupling coefficient: 0.99 ± 0.10) was transferred into talus and tibial rotation, highlighting the relevance of calcaneal adduction for the overall ankle joint coupling. The results of this study present the possibility that controlling calcaneal adduction/abduction can affect talus and tibial rotation and therefore the possible genesis of overuse knee injuries.

SOX6 rs7117858 polymorphism is associated with osteoporosis and obesity-related phenotypes.

BACKGROUND: SOX6 has been recently proposed as a pleiotropic gene for obesity and osteoporosis. The aim of this study was to investigate whether the rs7117858 genetic variant in SOX6 was associated with bone mass assessed by quantitative ultrasound (QUS) and obesity-related measures in a population of young adults. METHODS: A cross-sectional study was conducted in 550 unrelated healthy individuals of Caucasian ancestry (381 (69.3%) female and 169 (30.7%) male; mean age 20.46 ± 2.69). Bone mass was assessed through calcaneal QUS) parameter (BUA, dB/MHz). Obesity-related traits including weight, body mass index (BMI), fat mass (FM) and fat-free mass (FFM) were analysed. RESULTS: The linear regression analysis revealed that the rs7117858 SNP was significantly associated with FFM after adjustments for covariables in the whole sample (P = 0.027, ß (95% CI) = 0.053 (0.092, 1.516). In addition, a significant association with QUS measurement adjusted for confounding factors was found in females (P = 0.043, ß (95% CI) = 0.104 (0.138. 8.384). CONCLUSIONS: We demonstrate for the first time that SOX6 influence FFM and QUS trait in a population of young adults, suggesting the implication of this gene in obesity and osteoporosis-related phenotypes during early adulthood.

Ankle and Midfoot Power During Walking and Stair Ascent in Healthy Adults.

Ankle power dominates forward propulsion of gait, but midfoot power generation is also important for successful push-off. However, it is unclear if midfoot power generation increases or stays the same in response to propulsive activities that induce larger external loads and require greater ankle power. The purpose of this study was to examine ankle and midfoot power in healthy adults during progressively more demanding functional tasks. Multisegment foot motion (tibia, calcaneus, and forefoot) and ground reaction forces were recorded as participants (N = 12) walked, ascended a standard step, and ascended a high step. Ankle and midfoot positive peak power and positive total power, and the proportion of midfoot to ankle positive total power were calculated. One-way repeated-measures analyses of variance were conducted to evaluate differences across tasks. Main effects were found for ankle and midfoot peak and total powers (all Ps < .01), but not for the proportion of midfoot-to-ankle total power (P = .33). Ankle and midfoot power significantly increased across each task. Midfoot power increased in proportion to ankle power and in congruence to the external load of a task. Study findings may serve to inform multisegment foot modeling applications and internal mechanistic theories of normal and pathological foot function.

Clinical usefulness of hindfoot assessment for total knee arthroplasty: persistent post-operative hindfoot pain and alignment in pre-existing severe knee deformity.

PURPOSE: The purpose of this study was to compare the hindfoot alignment and symptoms in patients with pre-existing moderate and severe knee deformities after total knee arthroplasty (TKA). METHODS: Eighty knees of 75 patients who underwent TKA for varus osteoarthritis were enrolled retrospectively and evaluated the following pre-operatively and at 2 years post-operatively: the American Orthopaedic Foot and Ankle Society ankle-hindfoot scale (pain and function scores), calcaneal pitch, and naviculocuboid overlap as an indicator of hindfoot alignment. The knees were divided into two groups according to the pre-operative hip-knee-ankle angle defined as the angle between the mechanical axis of the femur and the tibia: group M with genu varus of ≤6°, and group S with varus >6°. RESULTS: The pain (p = 0.03) and function (p = 0.02) scores improved in group M; however, in group S, these measures did not change. The differences between the groups were not significant concerning the pre-operative calcaneal pitch and naviculocuboid overlap. The post-operative pitch (p = 0.03) and the overlap (p = 0.04) in group M was significantly greater and less than those in group S, respectively. Although the pitch (p < 0.01) and the overlap (p = 0.03) increased in group M, these did not change in group S. Post-operative hindfoot pain and valgus remained in patients in group S. CONCLUSIONS: For pre-existing moderate knee deformities, a relationship was observed between post-operative knee alignment and compensatory hindfoot alignment, whereas patients with severe deformities experienced persistent post-operative hindfoot pain and valgus alignment. It was concluded that evaluations and managements of residual symptoms after TKA including the hindfoot are important. These findings are clinically relevant that perioperative evaluation of the hindfoot should be required in knee surgery. To help improve the outcomes of TKA, clinicians may consider perioperative intervention in the insole and/or physical therapy of the foot and ankle. LEVEL OF EVIDENCE: Therapeutic study, Level III.

Reference data for ultrasound bone characteristics in Hungarian children aged 7-19 years.

Backround: Osteoporosis is a common disease and physical activity (PA) has a favourable influence on bone status. AIM: To establish normative data for calcaneal quantitative ultrasound (QUS) bone characteristics in children and to analyse the relationships between PA, anthropometric and bone parameters. SUBJECTS AND METHODS: Hungarian children aged 7-19 (n = 2674; 1325 girls, 1349 boys) provided PA, anthropometric and bone data. QUS parameters were registered with Sonost3000 densitometer (speed of sound: SOS, m/s; broadband ultrasound attenuation: BUA, dB/MHz; bone quantity index (BQI = αSOS + ßBUA). Reference centiles of QUS parameters were constructed by LMS method. Multivariate linear regression models were used to analyse the relationships. RESULTS: QUS bone parameters increased with age. There were no gender differences, except in 11- and 19-year-old children, where boys showed higher values. SOS (1497.15 ± 15.72 vs 1494.05 ± 14.81 m/s) and BQI (65.31 ± 16.71 vs 62.26 ± 15.78) were higher in athletic children. The regression model revealed significant relations between SOS and age, relative muscle mass and PA; BUA correlated with gender, morphological age, BMI, relative muscle mass and PA. CONCLUSIONS: Changes in the bone parameters among 7-19-year-old Hungarian children depended on age, anthropometric dimensions and the level of PA. The normative data could be used for monitoring QUS bone parameters in children, leading to more effective interventions for healthy bones.

Foot Structure and Function in Habitually Barefoot and Shod Adolescents in Kenya.

Habitually barefoot (HB) children from the Kalenjin tribe of Kenya are known for their high physical activity levels. To date, there has been no comprehensive assessment of foot structure and function in these highly active and HB children/adolescents and link with overuse injuries. PURPOSE: The aim of this research is to assess foot structure, foot function, injury and physical activity levels in Kenyan children and adolescents who are HB compared with those who were habitually shod (HS). METHODS: Foot structure, function, injury prevalence, and physical activity levels were studied using two studies with equal numbers of HS and HB. HS and HB children and adolescents were matched for age, sex, and body mass. Foot arch characteristics, foot strength, and lower-limb injury prevalence were investigated in Study 1 (n = 76). Heel bone stiffness, Achilles tendon moment arm length and physical activity levels in Study 2 (n=62). Foot muscle strength was measured using a strength device TKK 3360 and heel bone stiffness by bone ultrasonometry. The moment arm length of the Achilles tendon was estimated from photographs and physical activity was assessed using questionnaires and accelerometers. RESULTS: Foot shortening strength was greater in HB (4.8 ± 1.9 kg vs 3.5 ± 1.8 kg, P < 0.01). Navicular drop was greater in HB (0.53 ± 0.32 cm vs 0.39 ± 0.19 cm, P < 0.05). Calcaneus stiffness index was greater (right 113.5 ± 17.1 vs 100.5 ± 116.8, P < 0.01 left 109.8 ± 15.7 vs 101.7 ± 18.7, P < 0.05) and Achilles tendon moment arm shorter in HB (right, 3.4 ± 0.4 vs 3.6 ± 0.4 cm, P < 0.05; left, 3.4 ± 0.5 vs 3.7 ± 0.4 cm, P < 0.01). Lower-limb injury prevalence was 8% in HB and 61% in HS. HB subjects spent more time engaged in moderate to vigorous physical activity (60 ± 26 min·d vs 31 ± 13 min·d; P < 0.001). CONCLUSIONS: Significant differences observed in foot parameters, injury prevalence and general foot health between HB and HS suggest that footwear conditions may impact on foot structure and function and general foot health. HB children and adolescents spent more time engaged in moderate to vigorous physical activity and less time sedentary than HS children and adolescents.

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Polymorphisms of the WNT16 gene are associated with the heel ultrasound parameter in young adults.

SUMMARY: Bone mineral content is influenced by genetic factors. We investigated the role of WNT16 in bone properties determined using quantitative ultrasound (QUS) on young adults. Three WNT16 genetic markers (rs2908007, rs2908004, and rs2707466) were found to have a significant association with the broadband ultrasound attenuation (BUA) measurement, suggesting that WNT16 influences bone mass in young adults. INTRODUCTION: The aim of this study was to investigate whether genetic markers on the WNT16 gene are associated with bone mass, as assessed using QUS in a population of healthy young Spanish adults. METHODS: A cross-sectional study was conducted on 575 individuals (mean age 20.41 ± 2.69). Bone quality was assessed using BUA measurements (dB/MHz) on the right calcaneus. Six single nucleotide polymorphisms (SNPs) (rs2908007, rs2908004, rs3801387, rs3801385, rs2707466, and rs2536184) covering the WNT16 gene were selected as genetic markers and genotyped to test their association with BUA variations. RESULTS: The rs2908007, rs2908004, and rs2707466 SNPs were found to have a significant association with BUA (p = 0.004, p = 0.001, and p = 0.004, respectively). CONCLUSION: We demonstrate for the first time that WNT16 genetic polymorphisms influence QUS traits in a population of young adults. This finding suggests that WNT16 might be an important genetic factor in determining peak bone mass acquisition.

Peak Bone Mass and Quantitative Ultrasound Bone Properties in Young Adulthood: A Study in the PEAK-25 Cohort of Women.

Peak bone mass is normally reached in the third decade of life. Previously, in the population-based PEAK-25 cohort (n = 1061, age 25.5 ± 0.2), we demonstrated that bone mineral density in the population-based PEAK-25 cohort is comparatively high; therefore, this study aimed to determine if the calcaneus microarchitecture mirrored this. In the process, we describe normative quantitative ultrasound (QUS) values for 25-yr-old women and the relationship between QUS values and extremes of body weight. QUS variables speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index were measured. Young adult values were based on the manufacturer-supplied QUS reference values. Analyses were performed in the cohort as a whole, and additionally, to understand the relationship between body weight and QUS values in young women, the variables were categorized into octiles for weight or body mass index (BMI) and the lowest and highest octiles were compared. In the cohort, SOS values, reflecting bone density, were higher (108 ± 18%), whereas BUA values, reflecting bone complexity, were lower (90 ± 14%) compared to the young adult reference population. SOS did not correlate with body weight or BMI. In the cohort, overall correlations between BUA weight, and BMI were small and positive (Pearson's r coefficients 0.261 and 0.197, respectively; p < 0.001), although in the low-weight group, r coefficients were higher (r = 0.313 and 0.268; p < 0.05). In contrast, in the high-weight group, correlation with BUA values tended to be small, negative, and nonsignificant. Correlation between QUS and dual-energy X-ray absorptiometry-measured bone mineral density was low to moderate and significant at all skeletal sites (r = 0.37-0.52). Whereas coefficients tended to be higher in the low-weight group, the reverse was apparent for the low-BMI group. In these 25-yr-old women, a comparatively high dual-energy X-ray absorptiometry-measured bone mass is offset by less complex bone structures assessed by QUS. This may have implications for later osteoporosis assessment and future fracture risk.

Higher body mass index is associated with plantar fasciopathy/'plantar fasciitis': systematic review and meta-analysis of various clinical and imaging risk factors.

QUESTION: What (risk) factors are associated with plantar fasciopathy (PF)? DESIGN: Systematic review with meta-analyses. PARTICIPANTS: Patients with PF. FACTORS: All factors described in prospective, case-control or cross-sectional observational studies. RESULTS: 51 included studies (1 prospective, 46 case-control and 4 cross-sectional studies) evaluated a total of 104 variables. Pooling was possible for 12 variables. Higher body mass index (BMI) (BMI>27, OR 3.7 (95% CI 2.93 to 5.62)) in patients with PF was the only significant clinical association, and its effect was the strongest in the non-athletic subgroup. In people with PF compared to controls, pooled imaging data demonstrated a significantly thicker, hypoechogenic plantar fascia with increased vascular signal and perifascial fluid collection. In addition, people with PF were more likely to have a thicker loaded and unloaded heel fat pat, and bone findings, including a subcalcaneal spur and increased Tc-99 uptake. No significant difference was found in the extension of the first metatarsophalangeal joint. CONCLUSIONS: We found a consistent clinical association between higher BMI and plantar fasciopathy. This association may differ between athletic and non-athletic subgroups. While consistent evidence supports a range of bone and soft tissue abnormalities, there is lack of evidence for the dogma of clinical and mechanical measures of foot and ankle function. Clinicians can use this information in shared decision-making.

Normative rearfoot motion during barefoot and shod walking using biplane fluoroscopy.

PURPOSE: The ankle rearfoot complex consists of the ankle and subtalar joints. This is an observational study on two test conditions of the rearfoot complex. Using high-speed biplane fluoroscopy, we present a method to measure rearfoot kinematics during normal gait and compare rearfoot kinematics between barefoot and shod gait. METHODS: Six male subjects completed a walking trial while biplane fluoroscopy images were acquired during stance phase. Bone models of the calcaneus and tibia were reconstructed from computed tomography images and aligned with the biplane fluoroscopy images. An optimization algorithm was used to determine the three-dimensional position of the bones and calculate rearfoot kinematics. RESULTS: Peak plantarflexion was higher (barefoot: 9.1°; 95% CI 5.2:13.0; shod: 5.7°; 95% CI 3.6:7.8; p = 0.015) and neutral plantar/dorsiflexion occurred later in the stance phase (barefoot: 31.1%; 95% CI 23.6:38.6; shod: 17.7%; 95% CI 14.4:21.0; p = 0.019) during barefoot walking compared to shod walking. An eversion peak of 8.7° (95% CI 1.9:15.5) occurred at 27.8% (95% CI 18.4:37.2) of stance during barefoot walking, while during shod walking a brief inversion to 1.2° (95% CI -2.1:4.5; p = 0.021) occurred earlier (11.5% of stance; 95% CI 0.2:22.8; p = 0.008) during stance phase. The tibia was internally rotated relative to the calcaneus throughout stance phase in both conditions (barefoot: 5.1° (95% CI -1.4:11.6); shod: 3.6° (95% CI -0.4:7.6); ns.). CONCLUSIONS: Biplane fluoroscopy can allow for detailed quantification of dynamic in vivo ankle kinematics during barefoot and shod walking conditions. This methodology could be used in the future to study hindfoot pathology after trauma, for congenital disease and after sports injuries such as instability. LEVEL OF EVIDENCE: II.

Calcaneal Plantar Flexion During the Stance Phase of Gait.

When the rear- and forefoot are constrained, calcaneal plantar flexion may occur, deforming the longitudinal arch. Previous research has reported calcaneal motion relative to the tibia or forefoot; these joint rotations may not accurately describe rotation of the calcaneus alone. This investigation: (1) characterized the calcaneus and leg segment and ankle joint rotations during stance in gait, and (2) described the range of calcaneal plantar flexion in different structural arch types. Men (n = 14) and women (n = 16) performed gait in a motion analysis laboratory. From heel strike to heel off, the leg rotated forward while the calcaneus plantar flexed. Before foot flat, calcaneal plantar flexion was greater than forward leg rotation, resulting in ankle plantar flexion. After foot flat, forward leg rotation was greater than calcaneal plantar flexion, resulting in ankle dorsiflexion. Structural arch type was classified using the longitudinal arch angle. The range of calcaneal plantar flexion from foot flat to heel off was small in low (-2° to -8°), moderate in high (-3° to -12°), and large in normal (-2° to -20°) structural arches. Calcaneal plantar flexion in gait during midstance may reflect functional arch characteristics, which vary depending on structural arch type.