The association between physical activity in different domains of life and risk of osteoporotic fractures

A large body of epidemiological evidence suggests an inverse relationship between physical activity and risk of fractures. However, it is unclear how this association varies according to the domain of life in which the activity is undertaken. In this analysis of the European Prospective Investigation of Cancer-Norfolk study, we assessed total and domain-specific physical activity using a validated questionnaire (EPAQ2) in 14,903 participants (6514 men, mean age 62 year) who also underwent quantitative ultrasound of the heel. After a median follow-up of 7.5 years, there were 504 fractures of which 164 were hip fractures. In multivariable linear regression analysis, broadband ultrasound attenuation (BUA) was positively associated with total and leisure-time activities while showing no association with transportation and work activities. Home activities were associated with a lower BUA among younger participants. In multivariable Cox proportional-hazards models, moderate activities at home and in leisure time were associated with lower hip fracture risk among women (hazard ratios [HR] 0.51 and 0.55, p value 0.02 and 0.03, respectively). Among men, leisure-time activities were associated with lower risk of hip fracture (HR = 0.58; p for trend < 0.001) whereas activities at home were associated with higher risk of any fracture (HR = 1.25; p for trend = 0.008). Walking for leisure or transport was associated with lower risk of fracture in both men and women. Multivariable fractional polynomial modelling showed a U-shaped association between home activities and fracture risk especially among women. This study suggests that different domains of physical activity may relate differently to fracture risk and these relationships may vary by sex.     

Vitamin D status and common risk factors for bone fragility as determinants of quantitative ultrasound variables in a nationally representative population sample

Calcaneal quantitative ultrasound (QUS) can predict bone strength and fracture risk. Bone fragility has no single cause but results from a complex interplay of several etiologic or contributing factors. Vitamin D is essential for bone health even though it is still unclear how much of this vitamin is required to maintain bone strength and prevent fractures. Measurements of serum 25-hydroxyvitamin D [S-25(OH)D] have indicated a high prevalence of inadequate vitamin D status in a number of studies mostly based on selected study populations. The objective of this study was to examine the associations between S-25(OH)D, common risk factors for bone fragility, and QUS variables in a large unselected population sample.The study population consisted of 2736 men and 3299 women from a nationally representative population sample, aged 30 years or over. Information on lifestyle was elicited by means of interviews and questionnaires. Body fat mass was estimated using an impedance-meter. S-25(OH)D was measured by radioimmunoassay. Calcaneal QUS was performed on the Hologic Sahara apparatus recording broadband ultrasound attenuation (BUA) and speed of sound (SOS). The potential determinants of BUA and SOS were analysed using separate multiple linear regression models for men and women.S-25(OH)D proved to be an independent determinant of BUA (P < 0.0001 for men, P < 0.001 for women) and SOS (P < 0.0001 for men, P < 0.05 for women). BUA was also independently associated with age, height, weight, alcohol consumption, and postmenopausal status in women, and with weight, alcohol consumption, smoking and physical activity in men. All of the above variables, except for weight in women, were also found to be independent determinants of SOS in both men and women. A reverse association was found between S-25(OH)D and adiposity in spite of higher intakes of vitamin D in those with higher fat mass.In this unselected sample of men and women, vitamin D status, several lifestyle factors and physical characteristics proved to be significant determinants of BUA and SOS. Inadequate vitamin D status was common, and measures ensuring adequate intakes of vitamin D in the population thus deserve continued attention. Obesity should be taken into account in future assessments of vitamin D status in Finland as in other countries.     

Higher Undercarboxylated to Total Osteocalcin Ratio Is Associated With Reduced Physical Function and Increased 15-Year Falls-Related Hospitalizations: The Perth Longitudinal Study of Aging Women

Evidence from animal models suggests that undercarboxylated osteocalcin (ucOC) is involved in muscle mass maintenance and strength. In humans, the ucOC to total (t)OC ratio may be related to muscle strength and perhaps physical function and falls risk, but data are limited. We tested the hypothesis that ucOC and ucOC/tOC ratio are associated with muscle function (muscle strength and physical function) in older women and 15-year falls-related hospitalizations. Serum tOC and ucOC were assessed in 1261 older women (mean age 75.2 ± 2.7 years) forming the Perth Longitudinal Study of Aging Women (1998 to 2013). Timed-up-and-go (TUG) and grip strength were assessed at baseline and at 5 years. Falls-related hospitalizations (14.5-year follow-up) were captured by the Hospital Morbidity Data Collection, via the Western Australian Data Linkage System. At baseline, women with higher ucOC/tOC ratio (quartile 4) had slower TUG performance compared with quartile 1 (~0.68 seconds, p < .01). Grip strength and 5-year change of TUG and grip were not different (p > .05) between quartiles. Fear of falling limiting house, outdoor, and combined activities was significantly different across quartiles (p < .05). Higher ucOC/tOC was significantly associated with poorer TUG performance at baseline and 5-year change in performance, increased walking aid use, and fear of falling (all p < .05). Higher ucOC was related to lower grip strength at baseline (p < .05) but not 5-year change in strength. Those with the highest ucOC/tOC had greater falls-related hospitalizations (unadjusted log rank, p = .004) remaining significant after adjusting for key variables (hazard ratio [HR] = 1.31, 95% confidence interval [CI] 1.09–1.57, p = .004). We identified a large proportion of older women with high ucOC/tOC ratio who had reduced physical function, including its long-term decline and increased risk of falls-related hospitalizations. Early identification of women at higher risk can enable prevention and intervention strategies to occur, reducing risk for injurious falls. © 2020 American Society for Bone and Mineral Research (ASBMR)..     

Tibia and radius bone geometry and volumetric density in obese compared to non-obese adolescents

Childhood obesity is associated with biologic and behavioral characteristics that may impact bone mineral density (BMD) and structure. The objective was to determine the association between obesity and bone outcomes, independent of sexual and skeletal maturity, muscle area and strength, physical activity, calcium intake, biomarkers of inflammation, and vitamin D status. Tibia and radius peripheral quantitative CT scans were obtained in 91 obese (BMI > 97th percentile) and 51 non-obese adolescents (BMI > 5th and < 85th percentiles). Results were converted to sex- and race-specific Z-scores relative to age. Cortical structure, muscle area and muscle strength (by dynamometry) Z-scores were further adjusted for bone length. Obese participants had greater height Z-scores (p < 0.001), and advanced skeletal maturity (p < 0.0001), compared with non-obese participants. Tibia cortical section modulus and calf muscle area Z-scores were greater in obese participants (1.07 and 1.63, respectively, both p < 0.0001). Tibia and radius trabecular and cortical volumetric BMD did not differ significantly between groups. Calf muscle area and strength Z-scores, advanced skeletal maturity, and physical activity (by accelerometry) were positively associated with tibia cortical section modulus Z-scores (all p < 0.01). Adjustment for muscle area Z-score attenuated differences in tibia section modulus Z-scores between obese and non-obese participants from 1.07 to 0.28. After multivariate adjustment for greater calf muscle area and strength Z-scores, advanced maturity, and less moderate to vigorous physical activity, tibia section modulus Z-scores were 0.32 (95% CI − 0.18, 0.43, p = 0.06) greater in obese, vs. non-obese participants. Radius cortical section modulus Z-scores were 0.45 greater (p = 0.08) in obese vs. non-obese participants; this difference was attenuated to 0.14 with adjustment for advanced maturity. These findings suggest that greater tibia cortical section modulus in obese adolescents is attributable to advanced skeletal maturation and greater muscle area and strength, while less moderate to vigorous physical activities offset the positive effects of these covariates. The impact of obesity on cortical structure was greater at weight bearing sites.     

Calcaneous quantitative ultrasound measurements predicts vertebral fractures in idiopathic male osteoporosis

ObjectivesThe aim of this study was to identify the differences in ultrasound bone variables (QUS) and to test the ability to discriminate male patients with and without vertebral fractures.MethodsWe therefore measured broadband ultrasound attenuation (BUA) and speed of sound (SOS) matched for bone mineral density (BMD) and vertebral deformity in idiopathic male osteoporosis.ResultsOne hundred and seventeen men (age 56.6 range 27–78) were divided into three groups (osteoporosis n = 25, osteopenia n = 58 and age-matched control n = 34) according to BMD T-score by WHO criteria. We found 66 patients (56%) with at least one vertebral deformity during the study. BMD and BUA did not differ, while SOS was lower in osteoporosis (p < 0.001) and control group (p < 0.001) between the patients with and without vertebral compression. Strong positive correlation was demonstrated between BUA and BMD (lumbar spine r = 0.44, p < 0.001, femoral neck r = 0.56, p < 0.001, radius r = 0.40, p < 0.001), while similar association between SOS and BMD values was not shown. There was no relationship between the BUA and vertebral fracture risk (Odds ratio: 1.14 95% CI: 0.80–1.61). However, the relative risk of vertebral fracture by SOS was 1.56 (95% CI: 1.08–2.62). Adjusting for age and BMI the risk of vertebral fracture did not change (odds ratio for SOS 1.50 95% CI: 1.02–2.22). After adjustment for BMD SOS was still associated with fracture risk at all measured sites (odds ratio: 1.43, 95% CI: 1.02–2.22; 1.41, 95% CI: 1.02–2.17 and 1.32, 95% CI: 1.02–2.0).ConclusionOur results suggest that BUA values are more closely related to density and structure while SOS values are able to predict fractures.     

The Effect of Age,Sex Hormones,and Bone Turnover Markers on Calcaneal Quantitative Ultrasonometry in Healthy German Men

The aim of this cross-sectional study was to determine the age-dependent variations of calcaneal quantitative ultrasonometry (QUS) and the association with sex hormones and biochemical bone turnover markers in a large sample of unselected healthy German men. Bone measurements are expected to behave differently among men and women. The speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index (SI) of the os calcaneus were measured in 506 German men aged 20–79 yr (mean age: 45.7 yr). Additionally, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin, testosterone, dehydroepiandrosterone sulfate (DHEA-S), sex hormone–binding globulin (SHBG) as well as N-terminal propeptide of human procollagen type I (PINP), C-terminal telopeptide of type I collagen (ICTP), osteocalcin, bone-specific alkaline phosphatase, and CrossLaps were measured with standardized essays and correlated with the QUS results. The QUS results comprised an overall change of 12.4%, 3.2%, and 23.2% for BUA, SOS, and SI, respectively, between the 20–29 and 70–79 yr age groups (p ≤ 0.001). The annual rate of the age-related differences was 0.33% (standard deviation [SD]: 0.31), 0.06% (SD: 0.08), and 0.53% (SD: 0.56) for BUA, SOS, and SI, respectively. Testosterone and DHEA-S were significantly associated with QUS parameters and increasing age, whereas SHBG showed an age-related increase and was inversely related with QUS values (p < 0.05). Bone turnover markers present lower values gradually, and we found a significant correlation between carboxy-terminal collagen crosslinks (CTX), osteocalcin (OC), bone alkaline phosphatase (BAP), and QUS variables (p < 0.05).     

Adults with spastic cerebral palsy have lower bone mass than those with dyskinetic cerebral palsy

Adults with cerebral palsy (CP) are known to have low bone mass with an increased risk of fragility fracture. CP is classified into two major types: spastic (pyramidal) and dyskinetic (extrapyramidal). Spastic CP is the most common and is characterized by muscle hypertonicity and impaired neuromuscular control. By contrast, dyskinetic CP is characterized by mixed muscle tone with involuntary movements. The aim of this study was to elucidate the relationship between bone metabolism and subtype of CP. Fifty-eight adults with CP (aged 18 to 49 years, mean age 33.2 years; 32 men, 26 women) were included in this cross-sectional analysis. Lumbar spine and femoral bone mineral density (BMD) Z-scores were measured. Bone markers, including C-telopeptide of type I collagen (CTx) and osteocalcin (OCN), were also analyzed. Among these participants, 30 had spastic CP and 28 had dyskinetic CP. The Z-scores of lumbar spine BMD did not differ between the two types. However, the Z-scores of femur trochanteric BMD were significantly lower in participants with spastic CP than in those with dyskinetic CP (− 1.6 ± 1.2 vs. − 0.9 ± 1.1, p < 0.05). Seventy-four percent of participants with either type of CP had abnormally elevated CTx, while about 90% of participants showed normal OCN levels. When participants were subclassified into nonambulatory and ambulatory groups, the nonambulatory group had significantly lower BMD in the femur, including the trochanteric and total regions, whether they were spastic or dyskinetic (p < 0.05). Because the type of CP affects bone mass, nonambulatory spastic CP participants showed the lowest total hip region BMD among the four groups. These results reveal that reduced weight bearing and immobility related to CP cause a negative bone balance because of increased bone resorption, which leads to a lower bone mass. In addition, hypertonicity of the affected limbs in participants with spastic CP resulted in lower bone mass than in those with dyskinetic CP. Type of CP and degree of ambulatory function in adults with CP should be regarded as important factors affecting bone metabolism.     

Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures

IntroductionOsteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization.We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event.MethodsIn this case-control study, fragility fracture patients submitted to hip replacement surgery were evaluated and compared to a group of osteoarthritis patients submitted to the same procedure. Fasting blood samples were collected to assess apolipoproteinE (apoE) levels, total OC and undercarboxylated osteocalcin (ucOC), vitamin K, LDL cholesterol, triglycerides and bone turnover markers. The frequency of the apoε4 isoform was determined.Femoral epiphyses were collected and trabecular bone cylinders drilled in order to perform compression mechanical tests. Gene expression of bone matrix components was assessed by quantitative RT-PCR analysis.Results64 patients, 25 submitted to hip replacement surgery due to fragility fracture and 39 due to osteoarthritis, were evaluated. Bone OC/collagen expression (OC/COL1A1) ratio was significantly lower in hip fracture compared to osteoarthritis patients (p < 0.017) adjusted for age, gender and body mass index. Moreover, OC/COL1A1 expression ratio was associated with the hip fracture event (OR ~ 0; p = 0.003) independently of the group assigned, or the clinical characteristics. Apoε4 isoform was more frequent in the hip fracture group (p = 0.029). ucOC levels were higher in the fracture group although not significantly (p = 0.058). No differences were found regarding total OC (p = 0.602), apoE (p = 0.467) and Vitamin K (p = 0.371).In hip fracture patients, multivariate analysis, adjusted for clinical characteristics, serum factors related to OC metabolism and gene expression of bone matrix proteins showed that low OC/COL1A1 expression ratio was significantly associated with worse trabecular strength (β = 0.607; p = 0.013) and stiffness (β = 0.693; p = 0.003). No association was found between ucOC and bone mechanics. Moreover, in osteoarthritis patients, the multivariate analysis revealed that serum total OC was negatively associated with strength (β = ? 0.411; p = 0.030) and stiffness (β = ? 0.487; p = 0.009).ConclusionWe demonstrated that low bone OC/COL1A1 expression ratio was an independent predictor of worse trabecular mechanical behavior and of the hip fracture event. These findings suggest that in hip fracture patients the imbalance of bone OC/COL1A1 expression ratio reflects disturbances in osteoblast activity leading to bone fragility.     

Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures

IntroductionOsteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization.We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event.MethodsIn this case-control study, fragility fracture patients submitted to hip replacement surgery were evaluated and compared to a group of osteoarthritis patients submitted to the same procedure. Fasting blood samples were collected to assess apolipoproteinE (apoE) levels, total OC and undercarboxylated osteocalcin (ucOC), vitamin K, LDL cholesterol, triglycerides and bone turnover markers. The frequency of the apoε4 isoform was determined.Femoral epiphyses were collected and trabecular bone cylinders drilled in order to perform compression mechanical tests. Gene expression of bone matrix components was assessed by quantitative RT-PCR analysis.Results64 patients, 25 submitted to hip replacement surgery due to fragility fracture and 39 due to osteoarthritis, were evaluated. Bone OC/collagen expression (OC/COL1A1) ratio was significantly lower in hip fracture compared to osteoarthritis patients (p < 0.017) adjusted for age, gender and body mass index. Moreover, OC/COL1A1 expression ratio was associated with the hip fracture event (OR ~ 0; p = 0.003) independently of the group assigned, or the clinical characteristics. Apoε4 isoform was more frequent in the hip fracture group (p = 0.029). ucOC levels were higher in the fracture group although not significantly (p = 0.058). No differences were found regarding total OC (p = 0.602), apoE (p = 0.467) and Vitamin K (p = 0.371).In hip fracture patients, multivariate analysis, adjusted for clinical characteristics, serum factors related to OC metabolism and gene expression of bone matrix proteins showed that low OC/COL1A1 expression ratio was significantly associated with worse trabecular strength (β = 0.607; p = 0.013) and stiffness (β = 0.693; p = 0.003). No association was found between ucOC and bone mechanics. Moreover, in osteoarthritis patients, the multivariate analysis revealed that serum total OC was negatively associated with strength (β = − 0.411; p = 0.030) and stiffness (β = − 0.487; p = 0.009).ConclusionWe demonstrated that low bone OC/COL1A1 expression ratio was an independent predictor of worse trabecular mechanical behavior and of the hip fracture event. These findings suggest that in hip fracture patients the imbalance of bone OC/COL1A1 expression ratio reflects disturbances in osteoblast activity leading to bone fragility.     

The effect of including quantitative heel ultrasound in models for estimation of 10-year absolute risk of fracture

The role of quantitative ultrasound (QUS) in clinical practice is debatable. An unanswered question is that whether combining QUS and BMD measurements could improve the prediction of fracture risk. We examined this in a sample of men and women in the European Prospective Investigation into Cancer (EPIC)-Norfolk who had both heel QUS and hip DXA between 1995 and 1997 and were followed for any incident fracture up to 2007. From 1455 participants (703 men) aged 65–76 years at baseline, 79 developed a fracture over 10.3 ± 1.4 years of follow-up. Two separate sex-stratified Cox proportional-hazard models were used including clinical risk factors and total hip BMD. Heel broadband ultrasound attenuation (BUA) was also included in the second model. Global measures of model fit, area under ROC curve, and the Hosmer–Lemeshow statistic showed relative superiority of the model including BUA. Using each model, we calculated 10-year absolute risk of fracture for all participants and categorized them in groups of < 5%, 5% to < 15%, and ≥ 15%. Comparison of groupings showed a total re-classification of 16.6% of participants after inclusion of BUA with the greatest re-classification (30.7%) among the group with intermediate risk. Adding a QUS measurement to models based on clinical risk factors and BMD improves the predictive power of models and suggests that further attention should be paid to QUS as a clinical tool for fracture risk assessment.     

The muscle–bone interaction in Turner syndrome

ObjectivesTurner syndrome (TS) is associated with an increased fracture rate due to reduced bone strength, which is mainly determined by skeletal muscle force. This study aimed to assess the muscle force–bone strength relationship in TS and to compare it with that of healthy controls.MethodsThis study included 39 girls with TS and 67 healthy control girls. Maximum muscle force (F_max) was assessed through multiple one-legged hopping with jumping mechanography. Peripheral quantitative computerized tomography assessed the bone strength index at the tibial metaphysis (BSI 4) and the polar strength–strain index at the diaphysis (SSI polar 66). The effect of TS on the muscle–bone unit was tested using multiple linear regression.ResultsTS had no impact on F_max (p = 0.14); however, a negative effect on bone strength (p < 0.001 for BSI 4 and p < 0.01 for SSI polar 66) was observed compared with healthy controls. Bone strength was lower in the TS group (by 18%, p < 0.01, for BSI 4 and by 7%, p = 0.027, for SSI polar 66), even after correcting for F_max.ConclusionsSimilar muscle force induces lower bone strength in TS compared with healthy controls, which suggests altered bone-loading sensitivity in TS.     

Discrepancy Between the Quantitative Ultrasound Value of Malaysian Men and the Manufacturer’s Reference and the Impact on Classification of Bone Health Status

The local normative value in quantitative ultrasound (QUS) equipment needs to be established for wider application and accurate classification of patients into respective fracture risk groups. The present study aimed to establish the calcaneal speed of sound (SOS) value for Chinese and Malay men in Malaysia and determine the difference between calcaneal SOS of the local population and the reference values provided by the manufacturer for each age group. This study will also determine the effect of using the manufacturer’s young adult (20–29 yr) reference or the local young adult reference to classify the subjects into the respective risk groups. Eight hundred forty Malay and Chinese men residing in central peninsular Malaysia were recruited and their calcaneal QUS value was determined using the CM-200 machine (Furuno Electric, Nishinomiya City, Japan). The results showed that the differences in SOS values between Chinese and Malay men were not significant across all the age groups studied (p > 0.05). The age-dependent reduction of SOS value assumed a biphasic form, which was evident at 30–39 yr and older than 60 yr. The calcaneal SOS of the subject under study was significantly higher as compared with the manufacturer’s reference (based on Japanese population) in all groups aged 40 yr and older (p < 0.05). A significant proportion of the subjects in the osteoporosis group was misclassified using the manufacturer’s young adult reference as compared with using the local young adult reference (p < 0.05). In conclusion, the overall normative value of SOS obtained was suitable for Chinese and Malay men in Malaysia, and a local reference value should be applied to avoid misclassification of subjects into the respective risk groups.     

The effects of beta-2 adrenergic agonist and antagonist on human bone metabolism: A randomized controlled trial

PurposeGenetic knockout or pharmacological inhibition of the beta-2 adrenergic receptor (B2AR) increased bone mass, whereas stimulation decreased bone mass in rodents. In humans, observational studies support sympathetic nervous system regulation of bone metabolism, but intervention studies are lacking. We aimed to determine the effects of a selective beta-2 adrenergic agonist and non-selective antagonist on human bone metabolism.Methods32 healthy postmenopausal women were included in a randomized controlled trial conducted in the Academic Medical Center Amsterdam. Participants were randomized to receive treatment with 17-β estradiol 2 mg/day; 17-β estradiol 2 mg/day and terbutaline 5 mg/day (selective B2AR agonist); propranolol 80 mg/day (non-selective B-AR antagonist); or no treatment during 12 weeks. Main outcome measure was the change in serum concentrations of procollagen type I N propeptide (P1NP) and C-terminal crosslinking telopeptides of collagen type I (CTx) as markers of bone formation and resorption after 12 weeks compared between the treatment groups. Data were analyzed with mixed model analysis.Results17-β estradiol decreased bone turnover compared to control (P1NP p < 0.001, CTx p = 0.003), but terbutaline combined with 17-β estradiol failed to increase bone turnover compared to 17-β estradiol alone (P1NP p = 0.135, CTx p = 0.406). Propranolol did not affect bone turnover compared to control (P1NP p = 0.709, CTx p = 0.981).ConclusionSelective beta-2 adrenergic agonists and non-selective beta-antagonists do not affect human bone turnover although we cannot exclude small changes below the detection limit of this study.     

Histopathological,immunohistochemical, and image analytic parameters characterizing the stromal component in primary and recurrent giant cell tumor of bone

Giant cell tumor (GCT) of bone is a benign locally aggressive tumor whose biological behavior is unpredictable. Currently, there are no definitive clinical, histological, biochemical, or immunological parameters that can predict its behavior. This study was undertaken to examine whether delineation of reactive and neoplastic stromal component of GCT can help in this regard. 55 cases of GCT (30 primary, 25 recurrent) were subjected to histopathological grading, immunohistochemistry, and image analysis. Spindling of stroma was more frequent in recurrent GCT with 64% cases having more than 50% spindled stroma (p < 0.001). Number of mitosis/10 HPF and higher grade were more in recurrent GCT. Mean percentage positivity for CD68 (38.36%) and α1-ACT (70.86%) was higher in primary than recurrent GCT. PCNA and MiB-1 labeling indices were higher in recurrent (42.62% and 9.18%, respectively) than in primary group (24.75% and 7.7%, respectively). A single numerical parameter encompassing stromal cell population and its proliferation was derived as ratio of PCNA/CD68 and PCNA/α1-ACT. Both ratios were higher in recurrent (0.81 ± 0.38; 1.58 ± 1.50) than in primary GCT (0.58 ± 0.62; 0.34 ± 0.29) (p = 0.002; 0.01). On image analysis, parameters significantly different between the two groups were nuclear area and nuclear integrated optical density. It was thus concluded that recurrent GCT shows higher grade, increased mitosis, more spindling, fewer reactive components, and higher proliferation than primary GCT. Delineation of reactive component (α1-ACT positive) and proliferating component (PCNA positive cells) using immunohistochemistry with calculation of the PCNA/ACT ratio delivers more information than image analysis.     

Association Between Lean Mass and Handgrip Strength With Bone Mineral Density in Physically Active Postmenopausal Women

The present study evaluated 117 physically active postmenopausal women (67.8 ± 7.0 yr) who performed neuromotor physical tests (strength, balance, and mobility). Body composition (lean mass [g], fat mass [g], and % fat) and bone mineral density (BMD) of lumbar spine (L1–L4), femoral neck, and total body were measured by dual-energy X-ray absorptiometry. Following the World Health Organization criteria, osteoporosis was found in at least 1 analyzed site in 33 volunteers (28.2%): 30 (25.6%) in lumbar spine and 9 (7.7%) in femoral neck. Body weight was strongly and positively related to BMD in all sites, but the most important component of body composition was lean mass, also significantly related to all BMD sites, whereas fat mass was weakly related to the femoral neck BMD. Percent fat did not correlate with any BMD site. Of all the physical tests, the handgrip strength was most importantly related to lumbar spine, femoral neck, and total body (r = 0.49, p < 0.001; r = 0.56, p < 0.001; and r = 0.52, p < 0.001, respectively). The static body balance presented a weak but significant positive correlation only with lumbar spine. Our results suggest that strategies aiming to improve muscle strength and lean mass must contribute to the bone health of physically active postmenopausal women.     

Meta analysis identifies a novel susceptibility locus associated with heel bone strength in the Korean population

IntroductionCalcaneal quantitative ultrasound has been recognized as a non-invasive method for evaluation of bone strength and prediction of osteoporotic fracture.MethodsTo extend a thorough genetic catalog for osteoporotic bone properties, we performed a genome-wide association study (rural cohort I, n = 1895) of speed of sound (SOS) using the 1000 genome-based imputation in the discovery stage and then carried out in silico lookups (rural cohort II and III, n = 2,967) and de novo genotyping (rural cohort IV, n = 4,296) in the replication stage.ResultsIn the combined meta-analysis (n = 9,158), we identified a novel variant associated with SOS (rs2445771 in the GLDN gene, P = 2.27 × 10^− 9) reaching genome-wide significance in the Korean population. We further demonstrated that allele-specific regulatory modifications found to be associated with functional enrichments by ENCODE annotations. Conclusion: Our findings could provide additional insights into understanding of genetic and epigenetic regulations on bone metabolism.     

The association between plasma homocysteine levels and bone quality and bone mineral density parameters in older persons

IntroductionHigh plasma homocysteine levels have been associated with incident osteoporotic fractures, but the mechanisms underlying this association are still unknown. It has been hypothesized that homocysteine might interfere with collagen cross-linking in bone, thereby weakening bone structure. Therefore, we wanted to investigate whether plasma homocysteine levels are associated with bone quality parameters, rather than with bone mineral density.MethodsCross-sectional data of the B-PROOF study (n = 1227) and of two cohorts of the Rotterdam Study (RS-I (n = 2850) and RS-II (n = 2023)) were used. Data on bone mineral density of the femoral neck and lumbar spine were obtained in these participants using dual-energy X-ray assessment (DXA). In addition, participants of B-PROOF and RS-I underwent quantitative ultrasound measurement of the calcaneus, as a marker for bone quality. Multiple linear regression analysis was used to investigate the associations between natural-log transformed plasma levels of homocysteine and bone mineral density or ultrasound parameters.ResultsNatural-log transformed homocysteine levels were inversely associated with femoral neck bone mineral density in the two cohorts of the Rotterdam Study (B = − 0.025, p = 0.004 and B = − 0.024, p = 0.024). In B-PROOF, no association was found. Pooled data analysis showed significant associations between homocysteine and bone mineral density at both femoral neck (B = − 0.032, p = 0.010) and lumbar spine (B = − 0.098, p = 0.021). Higher natural-log transformed homocysteine levels associated significantly with lower bone ultrasound attenuation in B-PROOF (B = − 3.7, p = 0.009) and speed of sound in both B-PROOF (B = − 8.9, p = 0.001) and RS-I (B = − 14.5, p = 0.003), indicating lower bone quality. Pooled analysis confirmed the association between homocysteine and SOS (B = − 13.1, p = 0.016). Results from ANCOVA-analysis indicate that differences in SOS and BUA between participants having a plasma homocysteine level above or below median correspond to 0.14 and 0.09 SD, respectively.DiscussionIn this study, plasma levels of homocysteine were significantly inversely associated with both bone ultrasound parameters and with bone mineral density. However, the size of the associations seems to be of limited clinical relevance and may therefore not explain the previously observed association between plasma homocysteine and osteoporotic fracture incidence.     

SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice

Persons with type 1 and type 2 diabetes have increased fracture risk, attributed to deficits in the microarchitecture and strength of diabetic bone, thought to be mediated, in part, by the consequences of chronic hyperglycemia. Therefore, to examine the effects of a glucose-lowering SGLT2 inhibitor on blood glucose (BG) and bone homeostasis in a model of diabetic bone disease, male DBA/2J mice with or without streptozotocin (STZ)-induced hyperglycemia were fed chow containing the SGLT2 inhibitor, canagliflozin (CANA), or chow without drug, for 10 weeks of therapy. Thereafter, serum bone biomarkers were measured, fracture resistance of cortical bone was assessed by μCT analysis and a three-point bending test of the femur, and vertebral bone strength was determined by compression testing. In the femur metaphysis and L6 vertebra, long-term diabetes (DM) induced deficits in trabecular bone microarchitecture. In the femur diaphysis, a decrease in cortical bone area, cortical thickness and minimal moment of inertia occurred in DM (p < 0.0001, for all) while cortical porosity was increased (p < 0.0001). These DM changes were associated with reduced fracture resistance (decreased material strength and toughness; decreased structural strength and rigidity; p < 0.001 for all). Significant increases in PTH (p < 0.0001), RatLAPs (p = 0.0002), and urine calcium concentration (p < 0.0001) were also seen in DM. Canagliflozin treatment improved BG in DM mice by ~ 35%, but did not improve microarchitectural parameters. Instead, in canagliflozin-treated diabetic mice, a further increase in RatLAPs was evident, possibly suggesting a drug-related intensification of bone resorption. Additionally, detrimental metaphyseal changes were noted in canagliflozin-treated control mice. Hence, diabetic bone disease was not favorably affected by canagliflozin treatment, perhaps due to insufficient glycemic improvement. Instead, in control mice, long-term exposure to SGLT2 inhibition was associated with adverse effects on the trabecular compartment of bone.     

Dynamic acoustic radiation force retains bone structural and mechanical integrity in a functional disuse osteopenia model

Disuse osteopenia and bone loss have been extensively reported in long duration space mission and long term bed rest. The pathology of the bone loss is similar to osteoporosis but highly confined to weight bearing bones. The current anabolic and/or anti-resorptive drugs have systemic effects and are costly over extended time, with concerns of long term fracture risk. This study use Low Intensity Pulsed Ultrasound (LIPUS) as a non-invasive acoustic force and anabolic stimulus to countermeasure disuse induced bone loss. Four-month old C57BL/6 mice were randomized into five groups, 1) age-matched (AM), 2) non-suspended sham (NS), 3) non-suspended-LIPUS (NU), 4) suspended sham (SS), and 5) suspended-LIPUS (SU) groups. After four weeks of suspension, μCT analyses showed significant decreases in trabecular bone volume fraction (BV/TV) (− 36%, p < 0.005), bone tissue mineral density (TMD) (− 3%, p < 0.05), trabecular thickness (Tb.Th) (− 12.5%, p < 0.005), and increase in bone surface/bone volume (+ BS/BV) (+ 16%, p < 0.005), relative to age-matched (AM). The application of LIPUS for 20 min/day for 5 days/week, significantly increased TMD (+ 3%, p < 0.05), Tb.Th (+ 6%, p < 0.05), and decreased BS/BV (− 10%, p < 0.005), relative to suspension alone (SS) mice. Histomorphometry analyses showed a breakdown of bone microstructure under disuse conditions consist with μCT results. In comparison to SS mice, LIPUS treated bone showed increased structural integrity with increased bone formation rates at metaphysical endosteal and trabecular surfaces (+ 0.104 ± 0.07 vs 0.031 ± 0.30 μm³/μm²/day) relative to SS. Four-point bending mechanical tests of disused SS femurs showed reduced elastic modulus (− 53%, p < 0.05), yield (− 33%, p < 0.05) and ultimate strength (− 45%, p < 0.05) at the femoral diaphysis relative to AM bone. LIPUS stimulation mitigated the adverse effects of disuse on bone elastic modulus (+ 42%, p < 0.05), yield strength (+ 29%, p < 0.05), and ultimate strength (+ 39%, p < 0.05) relative to SS femurs. LIPUS provides the essential mechanical stimulus to retain bone morphological and mechanical integrity in disuse conditions. This study demonstrates LIPUS potential as regional therapeutic agent to countermeasure disuse induced bone loss while maintaining bone's integrity.     

Alternate hot and cold application in the management of heel pain: A pilot study

BackgroundDespite a long-standing tradition of naturopathic physical therapy and hydrotherapy use in the treatment of musculoskeletal conditions, neither naturopathy, nor specific aspects of hydrotherapy have been tested for efficacy in the treatment of heel pain.MethodsPatients (n = 20) were assigned to standard naturopathic physiotherapy care (NPC) with two adjuvant therapy groups: a control group (therapeutic ultrasound, n = 10), or alternating compresses (n = 10). Pain scores were measured before and after treatment using Visual Analog Scale (VAS) and foot functionality was measured using the Foot Function Index (FFI).ResultsFFI reduced from 46.97 to 31.98 (p = 0.005) among normal protocol patients and from 49.72 to 21.35 (p = <0.001) among patients receiving the alternating compress protocol. Average VAS pain intensity in the seven days of treatment decreased from 3.53 to 2.53 cm (p = <0.001) among patients receiving NPC and from 4.09 to 2.61 cm (p = <0.001) amongst those receiving NPC plus alternating compresses. There was no significant difference in pain score reduction between the two groups (p = 0.206), but patients with alternating compresses as part of their treatment had significant improvements in foot functionality (p = 0.007).DiscussionNaturopathic physical therapy significantly improves foot functionality and pain scores in heel pain. Additionally, alternating compresses improve foot functionality scores.