Trabecular Bone Structure Analysis in the Osteoporotic Spine Using a Clinical In Vivo Setup for 64‐Slice MDCT Imaging: Comparison to μCT Imaging and μFE Modeling

Assessment of trabecular microarchitecture may improve estimation of biomechanical strength, but visualization of trabecular bone structure in vivo is challenging. We tested the feasibility of assessing trabecular microarchitecture in the spine using multidetector CT (MDCT) on intact human cadavers in an experimental in vivo–like setup. BMD, bone structure (e.g., bone volume/total volume = BV/TV; trabecular thickness = Tb.Th; structure model index = SMI) and bone texture parameters were evaluated in 45 lumbar vertebral bodies using MDCT (mean in‐plane pixel size, 274 μm²; slice thickness, 500 μm). These measures were correlated with structure measures assessed with μCT at an isotropic spatial resolution of 16 μm and to microfinite element models (μFE) of apparent modulus and stiffness. MDCT‐derived BMD and structure measures showed significant correlations to the density and structure obtained by μCT (BMD, R² = 0.86, p < 0.0001; BV/TV, R² = 0.64, p < 0.0001; Tb.Th, R² = 0.36, p < 0.01). When comparing μCT‐derived measures with μFE models, the following correlations (p < 0.001) were found for apparent modulus and stiffness, respectively: BMD (R² = 0.58 and 0.66), BV/TV (R² = 0.44 and 0.58), and SMI (R² = 0.44 and 0.49). However, the overall highest correlation (p < 0.001) with μFE app. modulus (R² = 0.75) and stiffness (R² = 0.76) was achieved by the combination of QCT‐derived BMD with the bone texture measure Minkowski Dimension. In summary, although still limited by its spatial resolution, trabecular bone structure assessment using MDCT is overall feasible. However, when comparing with μFE‐derived bone properties, BMD is superior compared with single parameters for microarchitecture, and correlations further improve when combining with texture measures.     

Subpixel Enhancement of Nonuniform Tissue (SPENT): A Novel MRI Technique for Quantifying BMD

BMD is commonly obtained with DXA, but this is confounded by the length and composition of tissues that the X‐ray must traverse. Subpixel enhancement of nonuniform tissue (SPENT) is a novel MRI technique that can provide (direction specific) information based on the subvoxel structural uniformity of a sample. We hypothesized that the SPENT signal would be related to BMD. This hypothesis was tested using (1) 2D computer simulation of a simplified bone structure and (2) in vitro experiments. Simulation results suggested that a resolution of 610–800 μm was required for SPENT to be correlated well with the simulated bone volume fraction (BVF) and, at this resolution, a modest signal‐to‐noise ratio (SNR > 5) was required for reasonable data quality. For the experiments, 15‐mm³ human trabecular bone samples were used (1) to quantify BMD (through both physical measurement and DXA) and (2) to perform MRI on a 7T system. Standard and SPENT images were obtained. Normalized SPENT (NSPENT) images were calculated by pixel‐by‐pixel division of the SPENT images by the standard proton density images to remove any dependence on proton density and coil uniformity from the SPENT images. The average NSPENT values were determined over the sample volume and compared with the reference BMD measurements. Each of the individual NSPENT directions was highly correlated with BMD (x‐NSPENT, R² = 0.73, p < 0.001; y‐NSPENT, R² = 0.76, p < 0.001; z‐NSPENT, R² = 0.89, p < 0.001). With all three individual NSPENT directions combined, the correlation with BMD was found to be the highest (xyz‐NSPENT, R² = 0.95, p < 0.001). The results suggest that the SPENT technique can provide a noninvasive measure of BMD at resolution and SNR levels achievable in vivo.     

Use of high resolution dual‐energy x‐ray absorptiometry‐region free analysis (DXA‐RFA) to detect local periprosthetic bone remodeling events

Dual‐energy x‐ray absorptiometry (DXA) is the gold standard method for measuring periprosthetic bone remodeling, but relies on a region of interest (ROI) analysis approach. While this addresses issues of anatomic variability, it is insensitive to bone remodeling events at the sub‐ROI level. We have validated a high‐spatial resolution tool, termed DXA‐region free analysis (DXA‐RFA) that uses advanced image processing approaches to allow quantitation of bone mineral density (BMD) at the individual pixel (data‐point) level. Here we compared the resolution of bone remodeling measurements made around a stemless femoral prosthesis in 18 subjects over 24 months using ROI‐based analysis versus that made using DXA‐RFA. Using the ROI approach the regional pattern of BMD change varied by region, with greatest loss in ROI5 (20%, p < 0.001), and largest gain in ROI4 (6%, p < 0.05). Analysis using DXA‐RFA showed a focal zone of increased BMD localized to the prosthesis–bone interface (30–40%, p < 0.001) that was not resolved using conventional DXA analysis. The 20% bone loss observed in ROI5 with conventional DXA was resolved to a focal area adjacent to the cut surface of the infero‐medial femoral neck (up to 40%, p < 0.0001). DXA‐RFA enables high resolution analysis of DXA datasets without the limitations incurred using ROI‐based approaches. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:712–716, 2015.     

Quantitating the effect of prosthesis design on femoral remodeling using high‐resolution region‐free densitometric analysis (DXA‐RFA)

Dual energy X‐ray absorptiometry (DXA) is the reference standard method used to study bone mineral density (BMD) after total hip arthroplasty (THA). However, the subtle, spatially complex changes in bone mass due to strain‐adaptive bone remodeling relevant to different prosthesis designs are not readily resolved using conventional DXA analysis. DXA region free analysis (DXA RFA) is a novel computational image analysis technique that provides a high‐resolution quantitation of periprosthetic BMD. Here, we applied the technique to quantitate the magnitude and areal size of periprosthetic BMD changes using scans acquired during two previous randomized clinical trials (2004 to 2009); one comparing three cemented prosthesis design geometries, and the other comparing a hip resurfacing versus a conventional cementless prosthesis. DXA RFA resolved subtle differences in magnitude and area of bone remodeling between prosthesis designs not previously identified in conventional DXA analyses. A mean bone loss of 10.3%, 12.1%, and 11.1% occurred for the three cemented prostheses within a bone area fraction of 14.8%, 14.4%, and 6.2%, mostly within the lesser trochanter (p < 0.001). For the cementless prosthesis, a diffuse pattern of bone loss (−14.3%) was observed at the shaft of femur in a small area fraction of 0.6% versus no significant bone loss for the hip resurfacing prosthesis (p < 0.001). BMD increases were observed consistently at the greater trochanter for all prostheses except the hip‐resurfacing prosthesis, where BMD increase was widespread across the metaphysis (p < 0.001). DXA RFA provides high‐resolution insights into the effect of prosthesis design on the local strain environment in bone. © 2017 The Authors Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:2203–2210, 2017.

     

Deleterious Effect of Late Menarche on Distal Tibia Microstructure in Healthy 20‐Year‐Old and Premenopausal Middle‐Aged Women

Late menarche is a risk factor for fragility fractures. We hypothesized that pubertal timing–dependent alterations in bone structural components would persist from peak bone mass to menopause, independent of premenopausal bone loss. We studied the influence of menarcheal age (MENA) on femoral neck BMD (FN aBMD) by DXA and microstructure of distal tibia by HR‐pQCT in healthy young adult (YAD; 20.4 ± 0.6 [SD] yr, n = 124) and premenopausal middle‐aged (PREMENO; 45.8 ± 3.4 yr, n = 120) women. Median of MENA was 13.0 ± 1.2 and 13.1 ± 1.7 yr in YAD and PREMENO, respectively. In YAD and PREMENO (n = 244), FN aBMD (R = ?0.29, p = 0.013), as well as total volumetric BMD (Dtot; R = ?0.23, p = 0.006) and cortical thickness (Ct.Th; R = ?0.18, p = 0.011) of distal tibia were inversely correlated to MENA. After segregation by the median of MENA in EARLY and LATE subgroups, the significant influences of both MENA (p = 0.004) and chronological age (p < 0.0001) were observed for FN aBMD and trabecular bone volume fraction of the distal tibia with similar differences in T‐scores between LATE and EARLY subgroups in YAD (?0.36 and ?0.31 T‐scores) and PREMENO (?0.35 and ?0.42 T‐scores) women. Ct.Th was negatively influenced by MENA, whereas trabecular thickness (Tb.Th) was negatively influenced by chronological age. There was a striking inverse relationship between cross‐sectional area and Ct.Th (R = ?0.57, p < 0.001). In conclusion, the negative influence of late menarcheal age at weight‐bearing sites as observed by the end of skeletal growth remains unattenuated a few years before menopause and is independent of premenopausal bone loss. Alterations in both bone mineral mass and microstructural components may explain the increased risk of fragility fractures associated with later menarcheal age.     

Effect of Two‐Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non‐Obese Younger Adults: A Randomized Clinical Trial

Although caloric restriction (CR) could delay biologic aging in humans, it is unclear if this would occur at the cost of significant bone loss. We evaluated the effect of prolonged CR on bone metabolism and bone mineral density (BMD) in healthy younger adults. Two‐hundred eighteen non‐obese (body mass index [BMI] 25.1 ± 1.7 kg/m²), younger (age 37.9 ± 7.2 years) adults were randomly assigned to 25% CR (CR group, n = 143) or ad libitum (AL group, n = 75) for 2 years. Main outcomes were BMD and markers of bone turnover. Other outcomes included body composition, bone‐active hormones, nutrient intake, and physical activity. Body weight (–7.5 ± 0.4 versus 0.1 ± 0.5 kg), fat mass (–5.3 ± 0.3 versus 0.4 ± 0.4 kg), and fat‐free mass (–2.2 ± 0.2 versus –0.2 ± 0.2 kg) decreased in the CR group compared with AL (all between group p < 0.001). Compared with AL, the CR group had greater changes in BMD at 24 months: lumbar spine (–0.013 ± 0.003 versus 0.007 ± 0.004 g/cm²; p < 0.001), total hip (–0.017 ± 0.002 versus 0.001 ± 0.003 g/cm²; p < 0.001), and femoral neck (–0.015 ± 0.003 versus –0.005 ± 0.004 g/cm²; p = 0.03). Changes in bone markers were greater at 12 months for C‐telopeptide (0.098 ± 0.012 versus 0.025 ± 0.015 μg/L; p < 0.001), tartrate‐resistant acid phosphatase (0.4 ± 0.1 versus 0.2 ± 0.1 U/L; p = 0.004), and bone‐specific alkaline phosphatase (BSAP) (–1.4 ± 0.4 versus –0.3 ± 0.5 U/L; p = 0.047) but not procollagen type 1 N‐propeptide; at 24 months, only BSAP differed between groups (–1.5 ± 0.4 versus 0.9 ± 0.6 U/L; p = 0.001). The CR group had larger increases in 25‐hydroxyvitamin D, cortisol, and adiponectin and decreases in leptin and insulin compared with AL. However, parathyroid hormone and IGF‐1 levels did not differ between groups. The CR group also had lower levels of physical activity. Multiple regression analyses revealed that body composition, hormones, nutrients, and physical activity changes explained ～31% of the variance in BMD and bone marker changes in the CR group. Therefore, bone loss at clinically important sites of osteoporotic fractures represents a potential limitation of prolonged CR for extending life span. Further long‐term studies are needed to determine if CR‐induced bone loss in healthy adults contributes to fracture risk and if bone loss can be prevented with exercise. © 2015 American Society for Bone and Mineral Research.     

Cement penetration in the proximal femur does not depend on broach surface finish

In a cadaver study, we prepared 29 paired human cadaver femora using 3 different broaches of identical geometry but different surface characteristics. In one group of 20 pairs, preparation with chipped-toothed broaches was compared to diamond-shaped broaches; in the other group of 9 pairs, polished tamps for compaction of cancellous bone were compared with chipped-tooth broaches. Cancellous bone was irrigated with 1 liter pulsed lavage. The specimens were embedded in specially-designed pots. Palacos R and Simplex bone cements were used. After vacuum mixing, the cement was applied in a retrograde manner and subjected to a standard pressure protocol with a constant force of 3000 N. Radiographs were taken and horizontal sections were obtained at predefined levels using a diamond saw. Microradiographs were taken, digitized and analyzed to assess cement penetration into cancellous bone. In 6 of 9 femora prepared using smooth tamps, femoral fractures occurred despite careful preparation technique. The microradiographic evaluation showed no significant morphometric differences between diamond and chipped tooth or between polished and chipped-tooth broaches with regard to cement penetration into cancellous bone. Therefore, in the presence of pulsed lavage, one finds no significant effect of broach surface characteristics on cement penetration into cancellous bone of the proximal end of the femur.     

Effect of Surgery Versus Observation: Skeletal 5‐Year Outcomes in a Randomized Trial of Patients With Primary HPT (the SIPH Study)

Mild primary hyperparathyroidism (PHPT) is known to affect the skeleton, even though patients usually are asymptomatic. Treatment strategies have been widely discussed. However, long‐term randomized studies comparing parathyroidectomy to observation are lacking. The objective was to study the effect of parathyroidectomy (PTX) compared with observation (OBS) on bone mineral density (BMD) in g/cm² and T‐scores and on biochemical markers of bone turnover (P1NP and CTX‐1) in a prospective randomized controlled study of patients with mild PHPT after 5 years of follow‐up. Of 191 patients with mild PHPT randomized to either PTX or OBS, 145 patients remained for analysis after 5 years (110 with validated DXA scans). A significant decrease in P1NP (p < 0.001) and CTX‐1 (p < 0.001) was found in the PTX group only. A significant positive treatment effect of surgery compared with observation on BMD (g/cm²) was found for the lumbar spine (LS) (p = 0.011), the femoral neck (FN) (p < 0.001), the ultradistal radius (UDR) (p = 0.042), and for the total body (TB) (p < 0.001) but not for the radius 33% (Rad33), where BMD decreased significantly also in the PTX group (p = 0.012). However, compared with baseline values, there was no significant BMD increase in the PTX group, except for the lumbar spine. In the OBS group, there was a significant decrease in BMD (g/cm²) for all compartments (FN, p < 0.001; Rad33, p = 0.001; UDR, p = 0.006; TB, p < 0.001) with the exception of the LS, where BMD was stable. In conclusion, parathyroidectomy improves BMD and observation leads to a small but statistically significant decrease in BMD after 5 years. Thus, bone health appears to be a clinical concern with long‐term observation in patients with mild PHPT. © 2017 American Society for Bone and Mineral Research.     

Optimizing a micro‐computed tomography‐based surrogate measurement of bone‐implant contact

Histology and backscatter scanning electron microscopy (bSEM) are the current gold standard methods for quantifying bone‐implant contact (BIC), but are inherently destructive. Microcomputed tomography (μCT) is a non‐destructive alternative, but attempts to validate μCT‐based assessment of BIC in animal models have produced conflicting results. We previously showed in a rat model using a 1.5 mm diameter titanium implant that the extent of the metal‐induced artefact precluded accurate measurement of bone sufficiently close to the interface to assess BIC. Recently introduced commercial laboratory μCT scanners have smaller voxels and improved imaging capabilities, possibly overcoming this limitation. The goals of the present study were to establish an approach for optimizing μCT imaging parameters and to validate μCT‐based assessment of BIC. In an empirical parametric study using a 1.5 mm diameter titanium implant, we determined 90 kVp, 88 µA, 1.5 μm isotropic voxel size, 1600 projections/180°, and 750 ms integration time to be optimal. Using specimens from an in vivo rat experiment, we found significant correlations between bSEM and μCT for BIC with the manufacturer's automated analysis routine (r = 0.716, p = 0.003) or a line‐intercept method (r = 0.797, p = 0.010). Thus, this newer generation scanner's improved imaging capability reduced the extent of the metal‐induced artefact zone enough to permit assessment of BIC. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:979–986, 2018.

     

Identification of IDUA and WNT16 Phosphorylation‐Related Non‐Synonymous Polymorphisms for Bone Mineral Density in Meta‐Analyses of Genome‐Wide Association Studies

Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single‐nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome‐wide association (GWA) study, we conducted a three‐stage meta‐analysis targeting phosphorylation‐related SNPs (phosSNPs) for femoral neck (FN)‐bone mineral density (BMD), total hip (HIP)‐BMD, and lumbar spine (LS)‐BMD phenotypes. In stage 1, 9593 phosSNPs were meta‐analyzed in 11,140 individuals of various ancestries. Genome‐wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10^–6 (0.05/9593) and 1.00 × 10^–4, respectively. In stage 2, nine stage 1–discovered phosSNPs (based on α = 1.00 × 10^–4) were in silico meta‐analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10^–3, 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN‐BMD (p = 8.36 × 10^–10, p = 5.26 × 10^–10, and p = 3.01 × 10^–10, respectively) and HIP‐BMD (p = 3.26 × 10^–6, p = 1.97 × 10^–6, and p = 1.63 × 10^–12, respectively). Although in vitro studies demonstrated no differences in expressions of wild‐type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD‐associated non‐synonymous variants. © 2015 American Society for Bone and Mineral Research.     

Peri‐implant bone strains and micro‐motion following in vivo service: A postmortem retrieval study of 22 tibial components from total knee replacements

Biological adaptation following placement of a total knee replacements (TKRs) affects peri‐implant bone mineral density (BMD) and implant fixation. We quantified the proximal tibial bone strain and implant‐bone micro‐motion for functioning postmortem retrieved TKRs and assessed the strain/micro‐motion relationships with chronological (donor age and time in service) and patient (body weight and BMD) factors. Twenty‐two tibial constructs were functionally loaded to one body weight (60% medial/40% lateral), and the bone strains and tray/bone micro‐motions were measured using a digital image correlation system. Donors with more time in service had higher bone strains (p = 0.044), but there was not a significant (p = 0.333) contribution from donor age. Donors with lower peri‐implant BMD (p = 0.0039) and higher body weight (p = 0.0286) had higher bone strains. Long term implants (>11 years) had proximal bone strains 900 µ? that were almost twice as high as short term (<5 years) implants 570 µ?. Micro‐motion was greater for younger donors (p = 0.0161) and longer time in service (p = 0.0008). Increased bone strain with long term in vivo service could contribute to loosening of TKRs by failure of the tibial peri‐implant bone. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:355–361, 2014.

     

Exercise training in obese older adults prevents increase in bone turnover and attenuates decrease in hip bone mineral density induced by weight loss despite decline in bone‐active hormones

Weight loss therapy to improve health in obese older adults is controversial because it causes further bone loss. Therefore, it is recommended that weight loss therapy should include an intervention such as exercise training (ET) to minimize bone loss. The purpose of this study was to determine the independent and combined effects of weight loss and ET on bone metabolism in relation to bone mineral density (BMD) in obese older adults. One‐hundred‐seven older (age >65 years) obese (body mass index [BMI] ≥30 kg/m²) adults were randomly assigned to a control group, diet group, exercise group, and diet‐exercise group for 1 year. Body weight decreased in the diet (?9.6%) and diet‐exercise (?9.4%) groups, not in the exercise (?1%) and control (?0.2%) groups (between‐group p < 0.001). However, despite comparable weight loss, bone loss at the total hip was relatively less in the diet‐exercise group (?1.1%) than in the diet group (?2.6%), whereas BMD increased in the exercise group (1.5%) (between‐group p < 0.001). Serum C‐terminal telopeptide (CTX) and osteocalcin concentrations increased in the diet group (31% and 24%, respectively), whereas they decreased in the exercise group (?13% and ?15%, respectively) (between‐group p < 0.001). In contrast, similar to the control group, serum CTX and osteocalcin concentrations did not change in the diet‐exercise group. Serum procollagen propeptide concentrations decreased in the exercise group (?15%) compared with the diet group (9%) (p = 0.04). Serum leptin and estradiol concentrations decreased in the diet (?25% and ?15%, respectively) and diet‐exercise (?38% and ?13%, respectively) groups, not in the exercise and control groups (between‐group p = 0.001). Multivariate analyses revealed that changes in lean body mass (β = 0.33), serum osteocalcin (β = ?0.24), and one‐repetition maximum (1‐RM) strength (β = 0.23) were independent predictors of changes in hip BMD (all p < 0.05). In conclusion, the addition of ET to weight loss therapy among obese older adults prevents weight loss–induced increase in bone turnover and attenuates weight loss–induced reduction in hip BMD despite weight loss–induced decrease in bone‐active hormones. © 2011 American Society for Bone and Mineral Research     

Abdominal Aortic Calcification,BMD, and Bone Microstructure: A Population‐Based Study

To better define the relationship between vascular calcification and bone mass/structure, we assessed abdominal aortic calcification (AAC), BMD, and bone microstructure in an age‐stratified, random sample of 693 Rochester, MN, residents. Participants underwent QCT of the spine and hip and high‐resolution pQCT (HRpQCT) of the radius to define volumetric BMD (vBMD) and microstructural parameters. AAC was quantified with the Agatston scoring method. In men, AAC correlated with lower vertebral trabecular and femoral neck vBMD (p < 0.001), but not after age or multivariable (age, body mass index, smoking status) adjustment. Separation into <50 and ≥50 yr showed this pattern only in the older men. BV/TV and Tb.Th inversely correlated with AAC in all men (p < 0.001), and Tb.Th remained significantly correlated after age adjustment (p < 0.05). Tb.N positively correlated with AAC in younger men (p < 0.001) but negatively correlated in older men (p < 0.001). The opposite was true with Tb.Sp (p = 0.01 and p < 0.001, respectively). Lower Tb.N and higher Tb.Sp correlated with AAC in older men even after multivariable adjustment. Among all women and postmenopausal women, AAC correlated with lower vertebral and femoral neck vBMD (p < 0.001) but not after adjustment. Lower BV/TV and Tb.Th correlated with AAC (p = 0.03 and p = 0.04, respectively) in women, but not after adjustment. Our findings support an age‐dependent association between AAC and vBMD. We also found that AAC correlates with specific bone microstructural parameters in older men, suggesting a possible common pathogenesis for vascular calcification and deterioration in bone structure. However, sex‐specific differences exist.     

Preparation of the femoral bone cavity in cementless stems: broaching versus compaction

Background and purpose — Short-term experimental studies have confirmed that there is superior fixation of cementless implants inserted with compaction compared to broaching of the cancellous bone.

Patients and methods — 1-stage, bilateral primary THA was performed in 28 patients between May 2001 and September 2007. The patients were randomized to femoral bone preparation with broaching on 1 side and compaction on the other side. 8 patients declined to attend the postoperative follow-up, leaving 20 patients (13 male) with a mean age of 58 (36–70) years for evaluation. The patients were followed with radiostereometric analysis (RSA) at baseline, at 6 and 12 weeks, and at 1, 2, and 5 years, and measurements of periprosthetic bone mineral density (BMD) at baseline and at 1, 2, and 5 years. The subjective part of the Harris hip score (HHS) and details of complications throughout the observation period were obtained at a mean interval of 6.3 (3.0–9.5) years after surgery.

Results — Femoral stems in the compaction group had a higher degree of medio-lateral migration (0.21?mm, 95% CI: 0.03–0.40) than femoral stems in the broaching group at 5 years (p = 0.02). No other significant differences in translations or rotations were found between the 2 surgical techniques at 2 years (p > 0.4) and 5 years (p > 0.7) postoperatively. There were no individual stems with continuous migration. Periprosthetic BMD in the 7 Gruen zones was similar at 2 years and at 5 years. Intraoperative femoral fractures occurred in 2 of 20 compacted hips, but there were none in the 20 broached hips. The HHS and dislocations were similar in the 2 groups at 6.3 (3.0–9.5) years after surgery.

Interpretation — Bone compaction as a surgical technique with the Bi-Metric stem did not show the superior outcomes expected compared to conventional broaching. Furthermore, 2 periprosthetic fractures occurred using the compaction technique, so we cannot recommend compaction for insertion of the cementless Bi-Metric stem.     

The Contribution of Cortical and Cancellous Bone to Dual-Energy X-ray Absorptiometry Measurements in the Female Proximal Femur

Dual-energy X-ray absorptiometry (DXA) is the most common method for determining bone mineral density (BMD) in the proximal femur. However, there remain questions concerning the contribution of cortical and cancellous bone to this technology in the proximal femur. The purpose of this investigation was to identify structural and compositional characteristics of human bone in the proximal femur that significantly influence DXA BMD measurements. Twenty-four femora were obtained at autopsy from Caucasian females ranging in age from 17 to 92 years (mean ± SD, 61 ± 25 years). DXA scans were performed on each specimen with a Hologic QDR-2000 densitometer. Direct measurements were determined from proximal femoral sections for cancellous bone (volume fraction, ash fraction, cancellous cross-sectional area and percent cancellous cross-sectional area), cortical bone (thickness, ash fraction, porosity, cortical cross-sectional area and percent cortical cross-sectional area) and anteroposterior thickness. These parameters were compared with the associated DXA measurements by means of simple and multiple regressions. Cancellous volume fraction was the best predictor of variability of DXA measurements for both the neck and trochanter, with an R ² of 0.87 and 0.76, respectively (p<0.0001). There was only a minor influence of cortical factors such as thickness (neck and trochanter R ²= 0.51 and 0.42, respectively, p<0.001) and trochanteric cross-sectional area (R ²= 0.21, p<0.05). Although the accuracy for determining specific components of the proximal femur was low, the DXA BMD measurement was a strong predictor of cancellous bone factors, but not cortical bone factors that have been shown to change significantly with age. Received: 2 February 2000 / Accepted: 7 September 2000     

Meta‐analysis of genome‐wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

Previous genome‐wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta‐analyses of these results have identified numerous single‐nucleotide polymorphisms (SNPs) of modest effect at genome‐wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta‐analysis restricted to premenopausal white women from four cohorts (n = 4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age‐ and weight‐adjusted bone‐mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p = 1.7 × 10^?9) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p = 1.3 × 10^?8) achieved genome‐wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic‐American, and African‐American descent (combined n = 5597 for femoral neck; n = 4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p = 1.3 × 10^?11; ESR1/C6orf97 joint p = 1.4 × 10^?10). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p < 1 × 10^?5). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. © 2013 American Society for Bone and Mineral Research.     

Fetuin‐A and BMD in Older Persons: The Health Aging and Body Composition (Health ABC) Study

Fetuin‐A is a hepatic secretory protein that promotes bone mineralization in vitro. Whether fetuin‐A levels are associated with BMD in humans is unknown. The Health Aging and Body Composition study enrolled 3075 well‐functioning black and white persons 70–79 yr of age and measured BMD. This cross‐sectional study measured serum fetuin‐A using ELISA among a random sample of 508 participants within sex and race strata. Multivariate linear regression analysis evaluated the associations of fetuin‐A with BMD. Among women (n = 257), higher fetuin‐A levels were significantly associated with higher total hip (p = 0.02), lumbar spine (p = 0.03), and whole body BMD (p = 0.01) in models adjusted for age, race, diabetes, alcohol and tobacco use, physical activity, body mass index, C‐reactive protein levels, calcium supplement, and estrogen use. For example, each SD (0.38 g/liter) higher level of fetuin‐A was associated with 0.016 g/cm² higher total hip areal BMD. The association was of similar magnitude and direction for femoral neck BMD but did not reach statistical significance (p = 0.11). In contrast, among men (n = 251), fetuin‐A had no significant associations with total hip (p = 0.79), lumbar spine (p = 0.35), whole body (p = 0.46), or femoral neck BMD (p = 0.54) in multivariable models. We conclude that higher fetuin‐A levels are independently associated with higher BMD among well‐functioning community‐dwelling older women but not older men. Future studies should evaluate whether fetuin‐A may refine fracture risk assessment in older women.     

Collagen‐containing scaffolds enhance attachment and proliferation of non‐cultured bone marrow multipotential stromal cells

Large bone defects are ideally treated with autografts, which have many limitations. Therefore, osteoconductive scaffolds loaded with autologous bone marrow (BM) aspirate are increasingly used as alternatives. The purpose of this study was to compare the growth of multipotential stromal cells (MSCs) from unprocessed BM on a collagen‐containing bovine bone scaffold (Orthoss^® Collagen) with a non‐collagen‐containing bovine bone scaffold, Orthoss^®. Another collagen‐containing synthetic scaffold, Vitoss^® was included in the comparison. Colonization of scaffolds by BM MSCs (n = 23 donors) was evaluated using microscopy, colony forming unit‐fibroblast assay and flow‐cytometry. The number of BM MSCs initially attached to Orthoss^® Collagen and Vitoss^® was similar but greater than Orthoss^® (p = 0.001 and p = 0.041, respectively). Furthermore, the number of MSCs released from Orthoss^® Collagen and Vitoss^® after 2‐week culture was also higher compared to Orthoss^® (p = 0.010 and p = 0.023, respectively). Interestingly, collagen‐containing scaffolds accommodated larger numbers of lymphocytic and myelomonocytic cells. Additionally, the proliferation of culture‐expanded MSCs on Orthoss^® collagen and Vitoss^® was greater compared to Orthoss^® (p = 0.047 and p = 0.004, respectively). Collectively, collagen‐containing scaffolds were superior in supporting the attachment and proliferation of MSCs when they were loaded with unprocessed BM aspirates. This highlights the benefit of collagen incorporation into bone scaffolds for use with autologous bone marrow aspirates as autograft substitutes. © 2015 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 34:597–606, 2016.     

Pathway‐based genome‐wide association analysis identified the importance of regulation‐of‐autophagy pathway for ultradistal radius BMD

Wrist fracture is not only one of the most common osteoporotic fractures but also a predictor of future fractures at other sites. Wrist bone mineral density (BMD) is an important determinant of wrist fracture risk, with high heritability. Specific genes underlying wrist BMD variation are largely unknown. Most published genome‐wide association studies (GWASs) have focused only on a few top‐ranking single‐nucleotide polymorphisms (SNPs)/genes and considered each of the identified SNPs/genes independently. To identify biologic pathways important to wrist BMD variation, we used a novel pathway‐based analysis approach in our GWAS of wrist ultradistal radius (UD) BMD, examining approximately 500,000 SNPs genome‐wide from 984 unrelated whites. A total of 963 biologic pathways/gene sets were analyzed. We identified the regulation‐of‐autophagy (ROA) pathway that achieved the most significant result (p = .005, q_fdr = 0.043, p_fwer = 0.016) for association with UD BMD. The ROA pathway also showed significant association with arm BMD in the Framingham Heart Study sample containing 2187 subjects, which further confirmed our findings in the discovery cohort. Earlier studies indicated that during endochondral ossification, autophagy occurs prior to apoptosis of hypertrophic chondrocytes, and it also has been shown that some genes in the ROA pathway (e.g., INFG) may play important roles in osteoblastogenesis or osteoclastogenesis. Our study supports the potential role of the ROA pathway in human wrist BMD variation and osteoporosis. Further functional evaluation of this pathway to determine the mechanism by which it regulates wrist BMD should be pursued to provide new insights into the pathogenesis of wrist osteoporosis. © 2010 American Society for Bone and Mineral Research     

Levels of serotonin,sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high‐bone‐mass phenotype due to a mutation in Lrp5

Patients with an activation mutation of the Lrp5 gene exhibit high bone mass (HBM). Limited information is available regarding compartment‐specific changes in bone. The relationship between the phenotype and serum serotonin is not well documented. To evaluate bone, serotonin, and bone turnover markers (BTM) in Lrp5‐HBM patients, we studied 19 Lrp5‐HBM patients (T253I) and 19 age‐ and sex‐matched controls. DXA and HR‐pQCT were used to assess BMD and bone structure. Serum serotonin, sclerostin, dickkopf‐related protein 1 (DKK1), and BTM were evaluated. Z‐scores for the forearm, total hip, lumbar spine, forearm, and whole body were significantly increased (mean ± SD) between 4.94 ± 1.45 and 7.52 ± 1.99 in cases versus ?0.19 ± 1.19 to 0.58 ± 0.84 in controls. Tibial and radial cortical areas, thicknesses, and BMD were significantly higher in cases. In cases, BMD at the lumbar spine and forearm and cortical thickness were positively associated and trabecular area negatively associated with age (r = 0.49, 0.57, 0.74, and ?0.61, respectively, p < .05). Serotonin was lowest in cases (69.5 [29.9–110.4] ng/mL versus 119.4 [62.3–231.0] ng/mL, p < .001) and inversely associated with tibial cortical density (r = ?0.49, p < .05) and directly with osteocalcin (OC), bone‐specific alkaline phosphatase (B‐ALP), and procollagen type 1 amino‐terminal propeptide (PINP) (r = 0.52–0.65, p < .05) in controls only. OC and S‐CTX were lower and sclerostin higher in cases, whereas B‐ALP, PINP, tartrate‐resistant acid phosphatase (TRAP), and dickkopf‐related protein 1 (DKK1) were similar in cases and controls. In conclusion, increased bone mass in Lrp5‐HBM patients seems to be caused primarily by changes in trabecular and cortical bone mass and structure. The phenotype appeared to progress with age, but BTM did not suggest increased bone formation. © 2011 American Society for Bone and Mineral Research