Trabecular and Cortical Microarchitecture in Postmenopausal HIV-Infected Women

Our objective was to assess the effects of HIV infection and antiretroviral therapy on trabecular and cortical microarchitecture in postmenopausal minority women. A subgroup of 106 (46 HIV-infected, 60 uninfected) postmenopausal Hispanic and African American women from an established cohort had areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry and trabecular and cortical volumetric BMD (vBMD) and microarchitecture measured by high-resolution peripheral quantitative computed tomography (HRpQCT) at the radius and tibia. HIV-infected women were slightly younger (58 ± 1 vs. 61 ± 1 years, p = 0.08), and had lower body mass index (BMI; 28 ± 1 vs. 32 ± 1 kg/m², p < 0.01). BMI-adjusted aBMD Z scores were lower in HIV-infected women at the lumbar spine, total hip, and ultradistal radius. Serum N-telopeptide and C-telopeptide levels were also higher in HIV-infected women. Trabecular and cortical vBMD were similar at the radius, but cortical area (105.5 ± 2.4 vs. 120.6 ± 2.0 mm², p < 0.01) and thickness (956 ± 33 vs. 1,075 ± 28 μm, p < 0.01) at the tibia were approximately 11–12 % lower in HIV-infected women. Differences remained significant after adjusting for age, BMI, and race/ethnicity. In contrast, cortical porosity was similar in the two groups. Although HIV-infected postmenopausal women had lower aBMD at the spine, total hip, and ultradistal radius and higher levels of bone resorption markers, the only differences detected by HRpQCT were lower cortical thickness and area at the tibia.     

3D Analysis of Cortical and Trabecular Bone From Hip DXA:Precision and Trend Assessment Interval in PostmenopausalWomen

The 3D distribution of the cortical and trabecular bone mass is a critical component in determining the resistance of a bone to fracture that is not assessed in standard dual-energy X-ray absorptiometry (DXA) exams. In this work, we assessed in vivo short-term precision of measurements provided by 3D modeling techniques from DXA scans and trend assessment intervals (TAIs) in postmenopausal women. Subjects included to study precision errors were scanned twice, with repositioning for duplicate hip scans, using either a Lunar iDXA scanner (GE Healthcare, Madison, WI) or a Discovery W scanner (Hologic, Inc., Waltham, MA). Postmenopausal women having baseline and 18-mo follow-up visit were scanned using a Lunar iDXA device to assess TAIs. TAIs indicate what time intervals are required to allow accurate assessment of response to treatment or progression of disease. The 3D-SHAPER software (Galgo Medical, Barcelona, Spain) was used to derive 3D measurements from hip DXA scans. Least significant changes were 10.39 and 8.72 mg/cm³ for integral volumetric bone mineral density (BMD), 9.64 and 9.59 mg/cm³ for trabecular volumetric BMD, and 6.25 and 5.99 mg/cm² for cortical surface BMD, using the Lunar iDXA and Discovery W scanners, respectively. TAIs in postmenopausal women were 2.9 yr (integral volumetric BMD), 2.6 yr (trabecular volumetric BMD), and 3.5 yr (cortical surface BMD), using the Lunar iDXA scanner. As a comparison, TAIs for areal BMD were 2.8 yr at neck and 2.7 yr at total femur. Least significant changes of measurements provided by 3D modeling techniques from DXA were assessed. TAIs in postmenopausal women were similar to those measured for areal BMD measurements. DXA-derived 3D measurements could potentially provide additional indicators to improve patient monitoring in clinical practices.     

Risedronate Slows or Partly Reverses Cortical and Trabecular Microarchitectural Deterioration in Postmenopausal Women

During early menopause, steady‐state bone remodeling is perturbed; the number of basic multicellular units (BMUs) excavating cavities upon the endosteal surface exceeds the number (generated before menopause) concurrently refilling. Later in menopause, steady‐state is restored; the many BMUs generated in early menopause refill as similarly large numbers of BMUs concurrently excavate new cavities. We hypothesized that risedronate reduces the number of cavities excavated. However, in younger postmenopausal women, the fewer cavities excavated will still exceed the fewer BMUs now refilling, so net porosity increases, but less than in controls. In older postmenopausal women, the fewer cavities excavated during treatment will be less than the many (generated during early menopause) now refilling, so net porosity decreases and trabecular volumetric bone mineral density (vBMD) increases. We recruited 324 postmenopausal women in two similarly designed double‐blind placebo‐controlled studies that included 161 younger (Group 1, ≤ 55 years) and 163 older (Group 2, ≥ 55 years) women randomized 2:1 to risedronate 35 mg/week or placebo. High‐resolution peripheral computed tomography was used to image the distal radius and tibia. Cortical porosity was quantified using the StrAx1.0 software. Risedronate reduced serum carboxyterminal cross‐linking telopeptide of type 1 bone collagen (CTX‐1) and serum amino‐terminal propeptide of type 1 procollagen (P1NP) by ～50%. In the younger group, distal radius compact‐appearing cortex porosity increased by 4.2% ± 1.6% (p = 0.01) in controls. This was prevented by risedronate. Trabecular vBMD decreased by 3.6% ± 1.4% (p = 0.02) in controls and decreased by 1.6% ± 0.6% (p = 0.005) in the risedronate‐treated group. In the older group, changes did not achieve significance apart from a reduction in compact‐appearing cortex porosity in the risedronate‐treated group (0.9% ± 0.4%, p = 0.047). No between‐group differences reached significance. Results were comparable at the distal tibia. Between‐group differences were significant for compact‐appearing cortex porosity (p = 0.005). Risedronate slows microstructural deterioration in younger and partly reverses it in older postmenopausal women, features likely to contribute to antifracture efficacy. © 2014 American Society for Bone and Mineral Research.     

Prediction and Discrimination of Osteoporotic Hip Fracture in Postmenopausal Women

Osteoporotic hip fractures increase dramatically with age and are responsible for considerable morbidity and mortality. Several treatments to prevent the occurrence of hip fracture have been validated in large randomized trials and the current challenge is to improve the identification of individuals at high risk of fracture who would benefit from therapeutic or preventive intervention. We have performed an exhaustive literature review on hip fracture predictors, focusing primarily on clinical risk factors, dual X-ray absorptiometry (DXA), quantitative ultrasound, and bone markers. This review is based on original articles and meta-analyses. We have selected studies that aim both to predict the risk of hip fracture and to discriminate individuals with or without fracture. We have included only postmenopausal women in our review. For studies involving both men and women, only results concerning women have been considered. Regarding clinical factors, only prospective studies have been taken into account. Predictive factors have been used as stand-alone tools to predict hip fracture or sequentially through successive selection processes or by combination into risk scores. There is still much debate as to whether or not the combination of these various parameters, as risk scores or as sequential or concurrent combinations, could help to better predict hip fracture. There are conflicting results on whether or not such combinations provide improvement over each method alone. Sequential combination of bone mineral density and ultrasound parameters might be cost-effective compared with DXA alone, because of fewer bone mineral density measurements. However, use of multiple techniques may increase costs. One problem that precludes comparison of most published studies is that they use either relative risk, or absolute risk, or sensitivity and specificity. The absolute risk of individuals given their risk factors and bone assessment results would be a more appropriate model for decision-making than relative risk. Currently, a group appointed by the World Health Organization and lead by Professor John Kanis is working on such a model. It will therefore be possible to further assess the best choice of threshold to optimize the number of women needed to screen for each country and each treatment.     

Association Between Global Biomarkers of Oxidative Stress and Hip Fracture in Postmenopausal Women: A Prospective Study

Human studies suggest that oxidative stress is a risk factor for osteoporosis, but its relationship with fracture risk is poorly understood. The purpose of the present study was to investigate the association between biomarkers of oxidative stress and hip fracture in postmenopausal women. We conducted a prospective study in the Nurses' Health Study among 996 women aged 60 years or older at baseline blood collection in 1989–1990. Plasma fluorescent oxidation products (FlOPs) were measured at three excitation/emission wavelengths (360/420 nm named as FlOP_360; 320/420 nm named as FlOP_320; and 400/475 nm named as FlOP_400). FlOPs are generated from many different pathways (lipid, protein, and DNA) and reflect a global oxidation burden. FlOP assay is 10–100 times more sensitive than measurement of malondialdehyde. We used Cox proportional hazards regression model to investigate the association between baseline plasma FlOPs and the risk of hip fracture, adjusting for multiple hip fracture risk factors such as age, history of osteoporosis, history of hypertension, prior fracture, and smoking status. Forty‐four hip fractures (4.4%) were identified during the follow‐up (maximum = 23 years). In the multivariable model, the hazard ratios (HRs) of hip fracture in the second and third tertiles of FlOP_320 were 2.11 (95% confidence interval [CI] = 0.88–5.10) and 2.67 (95% CI = 1.14–6.27), respectively, in comparison with the lowest tertile, and the risk increased linearly with increasing FlOP_320 (p for trend = 0.021). Neither FlOP_360 nor FlOP_400 was significantly associated with risk of hip fracture (tertile 3 versus tertile 1: HR = 0.70, 95% CI = 0.32–1.54, p for trend = 0.386 for FlOP_360; and HR = 0.88, 95% CI = 0.40–1.96, p for trend = 0.900 for FlOP_400). In this prospective study, higher plasma FlOP_320 was an independent risk factor for hip fracture. Our results need further confirmation. © 2014 American Society for Bone and Mineral Research.     

Hip Fractures and the Contribution of Cortical Versus Trabecular Bone to Femoral Neck Strength

Osteoporotic fractures are caused by both cortical thinning and trabecular bone loss. Both are seen to be important for bone fragility. The relative contributions of cortical versus trabecular bone have not been established. The aim of this study was to test the contribution of cortical versus trabecular bone to femoral neck stability in bone strength. In one femur from each pair of 18 human cadaver femurs (5 female; 4 male), trabecular bone was completely removed from the femoral neck, providing one bone with intact and the other without any trabecular structure in the femoral neck. Geometrical, X‐ray, and DXA measurements were carried out before biomechanical testing (forces to fracture). Femoral necks were osteotomized, slices were analyzed for cross‐sectional area (CSA) and cross‐sectional moment of inertia (CSMI), and results were compared with biomechanical testing data. Differences between forces needed to fracture excavated and intact femurs (ΔF/F mean) was 7.0% on the average (range, 4.6–17.3%). CSA of removed spongiosa did not correlate with difference of fracture load (ΔF/F mean), nor did BMD. The relative contribution of trabecular versus cortical bone in respect to bone strength in the femoral neck seems to be marginal and seems to explain the subordinate role of trabecular bone and its changes in fracture risk and the effects of treatment options in preventing fractures.     

Age-Related Decline in Trabecular and Cortical Density: A 5-Year Peripheral Quantitative Computed Tomography Follow-Up Study of Pre- and Postmenopausal Women

This 5-year prospective study assessed changes in trabecular and cortical volumetric bone density at the non-weight-bearing radius and weight-bearing tibia among clinically healthy pre- and postmenopausal women. Altogether 79 premenopausal (mean age ± SD at baseline 33 ± 2 years) and 108 postmenopausal (68 ± 2 years) women participated in the baseline and follow-up measurements. Trabecular density (TrD) of the distal radius and tibia and cortical density (CoD) of the radial and tibial shafts were assessed by peripheral quantitative computed tomography (pQCT). Repeated measures analysis of variance was used to analyze differences of means and mean changes between the age groups. As expected, TrD and CoD values were greater among premenopausal than postmenopausal women. Changes in radial TrD were similar in both age groups: mean (95% confidence interval) TrD of the distal radius declined by 3.0 mg/cm³ (−0.9 to 7.0) and 5.1 mg/cm³ (1.8–8.5) in the younger and older age groups, respectively. The respective declines in TrD of the distal tibia were 4.1 mg/cm³ (2.1–6.0) and 2.8 mg/cm³ (1.2–4.3). Decline in CoD was greater in the older than younger age group at both the radial and tibial shafts (P < 0.001). The mean absolute declines in radial CoD were 33.3 mg/cm³ (27.9–38.7) and 49.4 mg/cm³ (44.9–53.9) in younger and older women, and the declines in tibial CoD were 16.5 mg/cm³ (12.6–20.2) and 28.1 mg/cm³ (25.0–31.2), respectively. In conclusion, volumetric TrD in the weight-bearing tibia and non-weight-bearing radius showed similar age-related declines among pre- and postmenopausal women, while the decline in CoD was greater among postmenopausal women.     

Spinal Trabecular Bone Loss and Fracture in American and Japanese Women

This study examined trabecular bone mineral density (BMD) in Japanese women with and without spinal fracture, and compared the results to American women with and without fracture. The quantitative computed tomography (QCT) systems used at the University of California, San Francisco (UCSF) and at Nagasaki University were cross-calibrated. Normative BMD was assessed with the K₂HPO₄ liquid phantom in 538 Americans aged 20–85 years, and with the B-MAS200 phantom in 577 Japanese aged 20–83 years. These BMD were adjusted for use with the Image Analysis solid phantom using the result of cross-calibration. The trabecular BMD in 111 postmenopausal American women (55 with fracture), and in 185 postmenopausal Japanese women (67 with fracture) were compared for investigation of the difference in BMD values relative to fracture status. The absolute BMD values in Japanese were lower than those in Americans, and the differences were greater with advancing age. The magnitude of the BMD difference was 8.6, 20.5, 38.1 mg/cm³ in women aged 20–24 years, 40–44 years, 60–64 years, respectively. In premenopausal women, BMD began to decrease at the age of 20 in Japanese, whereas the peak bone mass was maintained until the age of 35 in the American women. In immediate postmenopausal women, BMD significantly decreased in both populations. In later postmenopausal women, BMD significantly decreased with age in the Japanese women but decreased less rapidly in the American women. The aging decrease of BMD was 1.4% and 2.2% per year in the later postmenopausal American and Japanese women, respectively. The fracture threshold is considered to be lower in Japanese women. However, the BMD difference between American and Japanese women with fracture was similar to that without fracture. The Z-scores of fracture subjects versus controls were 2.9 in American and 1.8 in Japanese women. In conclusion, Japanese women were found to have a lower BMD and lower fracture threshold than American women. The significant decrease of spinal trabecular BMD in late postmenopause is potentially responsible for the higher prevalence of spinal fracture in Japanese women. Received: 18 December 1995 / Accepted: 23 September 1996     

Deterioration of Cortical and Trabecular Microstructure Identifies Women With Osteopenia or Normal Bone Mineral Density at Imminent and Long-Term Risk for Fragility Fracture: A Prospective Study

More than 70% of women sustaining fractures have osteopenia or “normal” bone mineral density (BMD). These women remain undetected using the BMD threshold of −2.5 SD for osteoporosis. As microstructural deterioration increases bone fragility disproportionate to the bone loss producing osteopenia/normal BMD, we hypothesized that the structural fragility score (SFS) of ≥70 units, a measure capturing severe cortical and trabecular deterioration, will identify these women. Distal radial images were acquired using high-resolution peripheral quantitative tomography in postmenopausal French women, mean age 67 years (range 42–96 years); 1539 women were followed for 4 years (QUALYOR) and 561 women followed for 8 years (OFELY). Women with osteopenia or normal BMD accounted for ~80% of fractures. Women ≥70 years, 29.2% of the cohort, accounted for 39.2% to 61.5% of fractures depending on follow-up duration. Women having fractures had a higher SFS, lower BMD, and a higher fracture risk assessment score (FRAX) than women remaining fracture-free. In each BMD category (osteoporosis, osteopenia, normal BMD), fracture incidence was two to three times higher in women with SFS ≥70 than <70. In multivariable analyses, associations with fractures remained for BMD and SFS, not FRAX. BMD was no longer, or weakly, associated with fractures after accounting for SFS, whereas SFS remained associated with fracture after accounting for BMD. SFS detected two-to threefold more women having fractures than BMD or FRAX. SFS in women with osteopenia/normal BMD conferred an odds ratio for fracture of 2.69 to 5.19 for women of any age and 4.98 to 12.2 for women ≥70 years. Receiver-operator curve (ROC) analyses showed a significant area under the curve (AUC) for SFS, but not BMD or FRAX for the women ≥70 years of age. Targeting women aged ≥70 years with osteopenia indicated that treating 25% using SFS to allocate treatment conferred a cost-effectiveness ratio < USD $21,000/QALY saved. Quantifying microstructural deterioration complements BMD by identifying women without osteoporosis at imminent and longer-term fracture risk. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Denosumab Rapidly Increases Cortical Bone in Key Locations of the Femur: A 3D Bone Mapping Study in Women With Osteoporosis

Women with osteoporosis treated for 36 months with twice‐yearly injections of denosumab sustained fewer hip fractures compared with placebo. Treatment might improve femoral bone at locations where fractures typically occur. To test this hypothesis, we used 3D cortical bone mapping of postmenopausal women with osteoporosis to investigate the timing and precise location of denosumab versus placebo effects in the hips. We analyzed clinical computed tomography scans from 80 female participants in FREEDOM, a randomized trial, wherein half of the study participants received subcutaneous denosumab 60 mg twice yearly and the others received placebo. Cortical 3D bone thickness maps of both hips were created from scans at baseline, 12, 24, and 36 months. Cortical mass surface density maps were also created for each visit. After registration of each bone to an average femur shape model followed by statistical parametric mapping, we visualized and quantified statistically significant treatment effects. The technique allowed us to pinpoint systematic differences between denosumab and control and to display the results on a 3D average femur model. Denosumab treatment led to an increase in femoral cortical mass surface density and thickness, already evident by the third injection (12 months). Overall, treatment with denosumab increased femoral cortical mass surface density by 5.4% over 3 years. One‐third of the increase came from increasing cortical density, and two‐thirds from increasing cortical thickness, relative to placebo. After 36 months, cortical mass surface density and thickness had increased by up to 12% at key locations such as the lateral femoral trochanter versus placebo. Most of the femoral cortex displayed a statistically significant relative difference by 36 months. Osteoporotic cortical bone responds rapidly to denosumab therapy, particularly in the hip trochanteric region. This mechanism may be involved in the robust decrease in hip fractures observed in denosumab‐treated women at increased risk of fracture. © 2014 American Society for Bone and Mineral Research.     

Relationship of Circulating Total Homocysteine and C-Reactive Protein to Trabecular Bone in Postmenopausal Women

Homocysteine (Hcy) and C-reactive protein (CRP) are novel risk factors for osteoporosis. The purpose of this analysis was to determine the relationship of Hcy and CRP to volumetric trabecular bone, but also to assess their relationship to areal composite bone in healthy postmenopausal women (N = 184). We used peripheral quantitative computed tomography to assess volumetric bone at the distal tibia and dual-energy X-ray absorptiometry to assess areal composite bone at the proximal femur and lumbar spine. Multiple regression revealed that 22% of the variability in trabecular bone mineral content (F = 9.59, p ≤ 0.0001) was accounted for by weight (12.4%; p ≤ 0.0001), hemoglobin (5.5%; p = 0.0006), uric acid (4.2%; p = 0.003), and blood glucose (1.5%; p = 0.07). Multiple regression revealed that 5.4% of the variability in trabecular bone mineral density (F = 3.36; p = 0.020) was accounted for by hemoglobin (4.2%; p = 0.006) and Hcy (1.5%; not significant, p = 0.10). Total Hcy and CRP were not significantly related to trabecular bone, perhaps because these were nonosteoporotic women. However, our results suggested a weak but negative relationship between Hcy and trabecular bone. Further investigation is needed to examine the relationship of Hcy as an endogenous bioactive molecule to trabecular bone loss in early postmenopausal women and the response of trabecular bone to dietary intervention.     

Ultrasound-Based Estimates of Cortical Bone Thickness and Porosity Are Associated With Nontraumatic Fractures in Postmenopausal Women: A Pilot Study

Recent ultrasound (US) axial transmission techniques exploit the multimode waveguide response of long bones to yield estimates of cortical bone structure characteristics. This pilot cross-sectional study aimed to evaluate the performance at the one-third distal radius of a bidirectional axial transmission technique (BDAT) to discriminate between fractured and nonfractured postmenopausal women. Cortical thickness (Ct.Th) and porosity (Ct.Po) estimates were obtained for 201 postmenopausal women: 109 were nonfractured (62.6 ± 7.8 years), 92 with one or more nontraumatic fractures (68.8 ± 9.2 years), 17 with hip fractures (66.1 ± 10.3 years), 32 with vertebral fractures (72.4 ± 7.9 years), and 17 with wrist fractures (67.8 ± 9.6 years). The areal bone mineral density (aBMD) was obtained using DXA at the femur and spine. Femoral aBMD correlated weakly, but significantly with Ct.Th (R = 0.23, p < 0.001) and Ct.Po (R = -0.15, p < 0.05). Femoral aBMD and both US parameters were significantly different between the subgroup of all nontraumatic fractures combined and the control group (p < 0.05). The main findings were that (1) Ct.Po was discriminant for all nontraumatic fractures combined (OR = 1.39; area under the receiver operating characteristic curve [AUC] equal to 0.71), for vertebral (OR = 1.96; AUC = 0.84) and wrist fractures (OR = 1.80; AUC = 0.71), whereas Ct.Th was discriminant for hip fractures only (OR = 2.01; AUC = 0.72); there was a significant association (2) between increased Ct.Po and vertebral and wrist fractures when these fractures were not associated with any measured aBMD variables; (3) between increased Ct.Po and all nontraumatic fractures combined independently of aBMD neck; and (4) between decreased Ct.Th and hip fractures independently of aBMD femur. BDAT variables showed comparable performance to that of aBMD neck with all types of fractures (OR = 1.48; AUC = 0.72) and that of aBMD femur with hip fractures (OR = 2.21; AUC = 0.70). If these results are confirmed in prospective studies, cortical BDAT measurements may be considered useful for assessing fracture risk in postmenopausal women. © 2019 American Society for Bone and Mineral Research.     

How Hip and Whole-Body Bone Mineral Density Predict Hip Fracture in Elderly Women: The EPIDOS Prospective Study

We conducted a population-based cohort study in 7598 white healthy women, aged 75 years and over, recruited from the voting lists. We measured at baseline bone mineral density (BMD g/cm²) of the proximal femur (neck, trochanter and Ward's triangle) and the whole body, as well as fat and lean body mass, by dual-energy X-ray absorptiometry (DXA). One hundred and fifty-four women underwent a hip fracture during an average 2 years follow-up. Each standard deviation decrease in BMD increased the risk of hip fracture adjusted for age, weight and centre by 1.9 (95% CL 1.5, 2.3) for the femoral neck, 2.6 times (2.0, 3.3) for the trochanter, 1.8 times (1.4, 2.2) for Ward's triangle, 1.6 times (1.2, 2.0) for the whole body, and 1.3 times (1.0, 1.5) for the fat mass. The areas under the receiver operating characteristic (ROC) curves were not significantly different between trochanter and femoral neck BMD, whereas ROC curves of femoral neck and trochanter BMD were significantly better than those for Ward's triangle and whole-body BMD. emsp;Women who sustained an intertrochanteric fracture were older (84 ± 4.5 years) than women who had a cervical fracture (81 ± 4.5 years) and trochanter BMD seemed to be a stronger predictor of intertrochanteric ([RR = 4.5 (3.1, 6.5)] than cervical fractures ([RR = 1.8 (1.5, 2.3]). emsp;In very elderly women aged 80 years and more, hip BMD was still a significant predictor of hip fracture but the relative risk was significantly lower than in women younger than 80 years. emsp;In the 48% of women who had a femoral neck BMD T-score less than –2.5, the relative risk of hip fracture was increased by 3, and the unadjusted incidence of hip fracture was 16.4 per 1000 woman-years compared with 1.1 in the population with a femoral neck BMD T-score 5–1. Received: 19 May 1997 / Accepted: 16 October 1997     

Odanacatib Treatment Affects Trabecular and Cortical Bone in the Femur of Postmenopausal Women: Results of a Two‐Year Placebo‐Controlled Trial

Odanacatib, a selective cathepsin K inhibitor, increases areal bone mineral density (aBMD) at the spine and hip of postmenopausal women. To gain additional insight into the effects on trabecular and cortical bone, we analyzed quantitative computed tomography (QCT) data of postmenopausal women treated with odanacatib using Medical Image Analysis Framework (MIAF; Institute of Medical Physics, University of Erlangen, Erlangen, Germany). This international, randomized, double‐blind, placebo‐controlled, 2‐year, phase 3 trial enrolled 214 postmenopausal women (mean age 64 years) with low aBMD. Subjects were randomized to odanacatib 50 mg weekly (ODN) or placebo (PBO); all participants received calcium and vitamin D. Hip QCT scans at 24 months were available for 158 women (ODN: n = 78 women; PBO: n = 80 women). There were consistent and significant differential treatment effects (ODN‐PBO) for total hip integral (5.4%), trabecular volumetric BMD (vBMD) (12.2%), and cortical vBMD (2.5%) at 24 months. There was no significant differential treatment effect on integral bone volume. Results for bone mineral content (BMC) closely matched those for vBMD for integral and trabecular compartments. However, with small but mostly significant differential increases in cortical volume (1.0% to 1.3%) and thickness (1.4% to 1.9%), the percentage cortical BMC increases were numerically larger than those of vBMD. With a total hip BMC differential treatment effect (ODN‐PBO) of nearly 1000 mg, the proportions of BMC attributed to cortical gain were 45%, 44%, 52%, and 40% for the total, neck, trochanter, and intertrochanter subregions, respectively. In postmenopausal women treated for 2 years, odanacatib improved integral, trabecular, and cortical vBMD and BMC at all femur regions relative to placebo when assessed by MIAF. Cortical volume and thickness increased significantly in all regions except the femoral neck. The increase in cortical volume and BMC paralleled the increase in cortical vBMD, demonstrating a consistent effect of ODN on cortical bone. Approximately one‐half of the absolute BMC gain occurred in cortical bone. © 2014 American Society for Bone and Mineral Research.