Reference Intervals for bone impact microindentation in healthy adults: a multi-centre international study

Impact microindentation (IMI) is a novel technique for assessing bone material strength index (BMSi) in vivo, by measuring the depth of a micron-sized, spherical tip into cortical bone that is then indexed to the depth of the tip into a reference material. The aim of this study was to define the reference intervals for men and women by evaluating healthy adults from the United States of America, Europe and Australia. Participants included community-based volunteers and participants drawn from clinical and population-based studies. BMSi was measured on the tibial diaphysis using an OsteoProbe in 479 healthy adults (197 male and 282 female, ages 25 to 98 years) across seven research centres, between 2011 and 2018. Associations between BMSi, age, sex and areal bone mineral density (BMD) were examined following an a posteriori method. Unitless BMSi values ranged from 48 to 101. The mean (+/- standard deviation) BMSi for men was 84.4 +/- 6.9 and for women, 79.0 +/- 9.1. Healthy reference intervals for BMSi were identified as 71.0 to 97.9 for men and 59.8 to 95.2 for women. This study provides healthy reference data that can be used to calculate T- and Z-scores for BMSi and assist in determining the utility of BMSi in fracture prediction. These data will be useful for positioning individuals within the population and for identifying those with BMSi at the extremes of the population.Metabolic health: pathophysiological trajectories and therap

Influence of early and late Zoledronic acid administration on vertebral structure and strength in ovariectomized rats

An annual infusion of zoledronic acid (ZOL) reduces fracture risk in osteoporotic patients. Previously, we showed that a single ZOL injection inhibited changes in bone microstructure and strength in rat tibiae after ovariectomy. Here, we determined the effects of a single ZOL injection as preventive and restorative treatment on the bone microstructure and strength in lumbar and caudal vertebrae of ovariectomized (OVX) rats. Twenty-nine female 35-week-old Wistar rats were divided into four groups: SHAM-OVX (n = 9), OVX (n = 5), OVX and early ZOL (n = 8), and OVX and late ZOL (n = 7). ZOL was given once (20 µg/kg body weight s.c.) at OVX in the early ZOL group and 8 weeks later in the late ZOL group; rats were killed 16 weeks after OVX. Trabecular and cortical bone microarchitecture were measured in lumbar (L3) and caudal (Cd6) vertebrae using micro-computed tomography, and compressive mechanical properties were determined in L3 vertebrae. Compared to SHAM-OVX, OVX rats had significantly lower BV/TV; SMI, Tb.N, Tb.Sp, and Conn.D tended to be deteriorated in lumbar vertebrae, while both ZOL groups did not differ from the SHAM-OVX group. Both ZOL groups had significantly higher BV/TV than OVX; the early ZOL group also had significantly lower SMI and higher Tb.Th. OVX tended to decrease mechanical properties, while early and late ZOL treatment inhibited OVX-induced degeneration. Neither OVX nor ZOL induced changes in the trabecular microarchitecture of caudal vertebrae. In summary, in adult rats a single ZOL injection inhibited OVX-induced changes in lumbar vertebral bone microarchitecture and strength

Determination of rat vertebral bone compressive fatigue properties in untreated intact rats and zoledronic-acid-treated, ovariectomized rats

Summary Compressive fatigue properties of whole vertebrae, which may be clinically relevant for osteoporotic vertebral fractures, were determined in untreated, intact rats and zoledronic-acid-treated, ovariectomized rats. Typical fatigue behavior was found and was similar to that seen in other species. Fatigue properties were comparable between both groups. Introduction Osteoporosis is often treated with bisphosphonates, which reduce fracture risk. Effects of bisphosphonates on fatigue strength, which may be clinically relevant for vertebral fractures, are unknown. We determined vertebral, compressive fatigue properties in normal and zoledronic acid (ZOL)-treated, OVX rats. Methods Thirty-five-week old Wistar rats were divided into SHAM-OVX (n¿=¿7) and OVX with ZOL treatment (n¿=¿5; single injection, 20 µg/kg b.w. s.c.). After 16 weeks, vertebral trabecular microarchitecture and cortical thickness were determined using micro-CT. Vertebrae were cyclically compressed in load-control at 2 Hz starting at 0.75% apparent strain. A line parallel to the apparent strain curve was drawn at 0.5% higher offset, after which the intersection was defined as the time to failure and the apparent strain at failure. Data were compared using Student’s t test. Results Morphology and fatigue properties were the same in both groups. Samples failed between 10 min and 15 h. Force–displacement curves displayed typical fatigue behavior. Displacement increased over time due to mostly creep and to decreasing secant stiffness. Conclusions We established a technique to determine compressive fatigue properties in the rat vertebral body. Our initial results indicate that ZOL-treated OVX rats have similar vertebral fatigue properties as SHAM-OVX controls

Local and global microarchitecture is associated with different features of bone biomechanics.

Beside areal bone mineral density (aBMD), evaluation of fragility fracture risk mostly relies on global microarchitecture. However, microarchitecture is not a uniform network. Therefore, this study aimed to compare local structural weakness to global microarchitecture on whole vertebral bodies and to evaluate how local and global microarchitecture was associated with bone biomechanics. From 21 human L3 vertebrae, aBMD was measured using absorptiometry. Parameters of global microarchitecture were measured using HR-pQCT: trabecular bone volume fraction (Tb.BV/TV <sub>global</sub> ), trabecular number, structure model index and connectivity density (Conn.D). Local minimal values of aBMD and Tb.BV/TV were identified in the total (Tt) or trabecular (Tb) area of each vertebral body. "Two dimensional (2D) local structural weakness" was defined as Tt.BMD <sub>min</sub> , Tt.BV/TV <sub>min</sub> and Tb.BV/TV <sub>min</sub> . Mechanical testing was performed in 3 phases: 1/ initial compression until mild vertebral fracture, 2/ unloaded relaxation, and 3/ second compression until failure. Initial and post-fracture mechanics were significantly correlated with bone mass, global and local microarchitecture. Tt.BMD <sub>min</sub> , Tt.BV/TV <sub>min</sub> , Tb.BV/TV <sub>min</sub> , and initial and post-fracture mechanics remained significantly correlated after adjustment for aBMD or Tb.BV/TV <sub>global</sub> (p < 0.001 to 0.038). The combination of the most relevant parameter of bone mass, global and local microarchitecture associated with failure load and stiffness demonstrated that global microarchitecture explained initial and post-fracture stiffness, while local structural weakness explained initial and post-fracture failure load (p < 0.001). Local and global microarchitecture was associated with different features of vertebral bone biomechanics, with global microarchitecture controlling stiffness and 2D local structural weakness controlling strength. Therefore, determining both localized low density and impaired global microarchitecture could have major impact on vertebral fracture risk prediction

The predictive value of trabecular bone score (TBS) on whole lumbar vertebrae mechanics: an ex vivo study.

We investigated the association of trabecular bone score (TBS) with microarchitecture and mechanical behavior of human lumbar vertebrae. We found that TBS reflects vertebral trabecular microarchitecture and is an independent predictor of vertebral mechanics. However, the addition of TBS to areal BMD (aBMD) did not significantly improve prediction of vertebral strength. INTRODUCTION: The trabecular bone score (TBS) is a gray-level measure of texture using a modified experimental variogram which can be extracted from dual-energy X-ray absorptiometry (DXA) images. The current study aimed to confirm whether TBS is associated with trabecular microarchitecture and mechanics of human lumbar vertebrae, and if its combination with BMD improves prediction of fracture risk. METHODS: Lumbar vertebrae (L3) were harvested fresh from 16 donors. The anteroposterior and lateral bone mineral content (BMC) and areal BMD (aBMD) of the vertebral body were measured using DXA; then, the TBS was extracted using TBS iNsight software (Medimaps SA, France). The trabecular bone volume (Tb.BV/tissue volume, TV), trabecular thickness (Tb.Th), degree of anisotropy, and structure model index (SMI) were measured using microcomputed tomography. Quasi-static uniaxial compressive testing was performed on L3 vertebral bodies to assess failure load and stiffness. RESULTS: The TBS was significantly correlated to Tb.BV/TV and SMI (râeuro0/00=âeuro0/000.58 and -0.62; pâeuro0/00=âeuro0/000.02, 0.01), but not related to BMC and BMD. TBS was significantly correlated with stiffness (râeuro0/00=âeuro0/000.64; pâeuro0/00=âeuro0/000.007), independently of bone mass. Using stepwise multiple regression models, we failed to demonstrate that the combination of BMD and TBS was better at explaining mechanical behavior than either variable alone. However, the combination TBS, Tb.Th, and BMC did perform better than each parameter alone, explaining 79 % of the variability in stiffness. CONCLUSIONS: In our study, TBS was associated with microarchitecture parameters and with vertebral mechanical behavior, but TBS did not improve prediction of vertebral biomechanical properties in addition to aBMD

Finite Element Analyses Based on In Vivo HR-pQCT Images of the Distal Radius is Associated with Wrist Fracture in Postmenopausal Women

BMD, bone microarchitecture, and bone mechanical properties assessed in vivo by finite element analysis were associated with wrist fracture in postmenopausal women. Introduction: Many fractures occur in individuals with normal BMD. Assessment of bone mechanical properties by finite element analysis (FEA) may improve identification of those at high risk for fracture. Materials and Methods: We used HR-pQCT to assess volumetric bone density, microarchitecture, and µFE-derived bone mechanical properties at the radius in 33 postmenopausal women with a prior history of fragility wrist fracture and 33 age-matched controls from the OFELY cohort. Radius areal BMD (aBMD) was also measured by DXA. Associations between density, microarchitecture, mechanical parameters and fracture status were evaluated by univariate logistic regression analysis and expressed as ORs (with 95% CIs) per SD change. We also conducted a principal components (PCs) analysis (PCA) to reduce the number of parameters and study their association (OR) with wrist fracture. Results: Areal and volumetric densities, cortical thickness, trabecular number, and mechanical parameters such as estimated failure load, stiffness, and the proportion of load carried by the trabecular bone at the distal and proximal sites were associated with wrist fracture (p <0.05). The PCA revealed five independent components that jointly explained 86.2% of the total variability of bone characteristics. The first PC included FE-estimated failure load, areal and volumetric BMD, and cortical thickness, explaining 51% of the variance with an OR for wrist fracture = 2.49 (95% CI, 1.32–4.72). Remaining PCs did not include any density parameters. The second PC included trabecular architecture, explaining 12% of the variance, with an OR = 1.82 (95% CI, 0.94–3.52). The third PC included the proportion of the load carried by cortical versus trabecular bone, assessed by FEA, explaining 9% of the variance, and had an OR = 1.61 (95% CI, 0.94–2.77). Thus, the proportion of load carried by cortical versus trabecular bone seems to be associated with wrist fracture independently of BMD and microarchitecture (included in the first and second PC, respectively). Conclusions: These results suggest that bone mechanical properties assessed by µFE may provide information about skeletal fragility and fracture risk not assessed by BMD or architecture measurements alone and are therefore likely to enhance the prediction of wrist fracture risk

Balloon kyphoplasty and vertebroplasty in the management of vertebral compression fractures

Vertebral compression fractures (VCFs) are the most prevalent fractures in osteoporotic patients. The classical conservative management of these fractures is through rest, pain medication, bracing and muscle relaxants. The aim of this paper is to review prospective controlled studies comparing the efficacy and safety of minimally invasive techniques for vertebral augmentation, vertebroplasty (VP) and balloon kyphoplasty (BKP), versus non-surgical management (NSM). The Fracture Working Group of the International Osteoporosis Foundation conducted a literature search and developed a review paper on VP and BKP. The results presented for the direct management of osteoporotic VCFs focused on clinical outcomes of these three different procedures, including reduction in pain, improvement of function and mobility, vertebral height restoration and decrease in spinal curvature (kyphosis). Overall, VP and BKP are generally safe procedures that provide quicker pain relief, mobility recovery and in some cases vertebral height restoration than conventional conservative medical treatment, at least in the short term. However, the long-term benefits and safety in terms of risk of subsequent vertebral fractures have not been clearly demonstrated and further prospective randomized studies are needed with standards for reporting. Referral physicians should be aware of VP/BKP and their potential to reduce the health impairment of patients with VCFs. However, VP and BKP are not substitutes for appropriate evaluation and treatment of osteoporosis to reduce the risk of future fractures. © 2011 International Osteoporosis Foundation and National Osteoporosis Foundation

Differential effects of high fat diet and diet-induced obesity on skeletal acquisition in female C57BL/6J vs. FVB/NJ Mice☆

The effects of obesity on bone metabolism are complex, and may be mediated by consumption of a high fat diet and/or by obesity-induced metabolic dysregulation. To test the hypothesis that both high fat (HF) diet and diet-induced metabolic disease independently decrease skeletal acquisition, we compared effects of HF diet on bone mass and microarchitecture in two mouse strains: diet-induced obesity (DIO)-susceptible C57BL/6J (B6) and DIO-resistant FVB/NJ (FVB). At 3 wks of age we weaned 120 female FVB and B6 mice onto normal (N, 10% Kcal/fat) or HF diet (45% Kcal/fat) and euthanized them at 6, 12 and 20 weeks of age (N = 10/grp). Outcomes included body mass; percent fat and whole-body bone mineral density (WBBMD, g/cm2) via DXA; cortical and trabecular bone architecture at the midshaft and distal femur via μCT; and marrow adiposity via histomorphometry. In FVB HF, body mass, percent body fat, WBBMD and marrow adiposity did not differ vs. N, but trabecular bone mass was lower at 6 wks of age only (p < 0.05), cortical bone geometric properties were lower at 12 wks only, and bone strength was lower at 20 wks of age only in HF vs. N (p < 0.05). In contrast, B6 HF had higher body mass, percent body fat, and leptin vs. N. B6 HF also had higher WBBMD (p < 0.05) at 9 and 12 wks of age but lower distal femur trabecular bone mass at 12 wks of age, and lower body mass-adjusted cortical bone properties at 20 wks of age compared to N (p < 0.05). Marrow adiposity was also markedly higher in B6 HF vs. N. Overall, HF diet negatively affected bone mass in both strains, but was more deleterious to trabecular bone microarchitecture and marrow adiposity in B6 than in FVB mice. These data suggest that in addition to fat consumption itself, the metabolic response to high fat diet independently alters skeletal acquisition in obesity