Tibial vBMD Research Articles

Limosilactobacillus reuteri 6475 and Prevention of Early Postmenopausal Bone Loss

Daily supplementation with the probiotic Limosilactobacillus reuteri ATCC PTA 6475 (L reuteri) vs placebo has previously been demonstrated to reduce bone loss in an estrogen deficiency mice model and older women, although the magnitude of the effect was small. We hypothesized that long-term treatment with L reuteri could result in clinically relevant skeletal benefits in postmenopausal osteoporosis. To evaluate whether daily supplementation with L reuteri vs placebo could reduce early postmenopausal bone loss and whether the effects remained or increased over time during 2 years of treatment. A double-blind, randomized, placebo-controlled clinical trial was conducted between December 4, 2019, and October 6, 2022, at a single center in Gothenburg, southwestern Sweden. Participants were recruited by online advertisements, and letters were sent to 10 062 women aged 50 to 60 years. Responding women (n = 752) underwent telephone screening, resulting in 292 women being invited to a screening visit. Of those who were screened, 239 women met all inclusion criteria and had no exclusion criteria. Capsules with L reuteri in 2 doses, 5 × 108 (low dose) or 5 × 109 (high dose) colony-forming units, taken twice daily or placebo were administered. All capsules also included cholecalciferol, 200 IU. The primary outcome was the relative change in tibia total volumetric bone mineral density (vBMD) over 2 years. Secondary outcomes included relative change in areal BMD of the lumbar spine and total hip, bone turnover markers C-terminal telopeptide cross-links of collagen type I and type I procollagen intact N-terminal propeptide, as well as tibia trabecular bone volume fraction and cortical vBMD. Both intention-to-treat and per-protocol analyses were conducted. A total of 239 postmenopausal women (median age, 55 [IQR, 53-56] years) were included. Tibia vBMD (primary outcome), hip and spine vBMD, and tibia cortical area and BMD decreased significantly in all groups, with no group-to-group differences (percent change tibia vBMD high dose vs placebo least-squares means, -0.08 [95 CI, -0.85 to 0.69] and low dose vs placebo least-squares means, -0.22 [95% CI, -0.99 to 0.55]). There were no significant treatment effects on any other predefined outcomes. A prespecified sensitivity analysis found a significant interaction between body mass index (BMI) and treatment effect at 2 years. No significant adverse effects were observed. In this randomized clinical trial of 239 early postmenopausal women, supplementation with L reuteri had no effect on bone loss or bone turnover over 2 years. The observed interaction between BMI and treatment effect warrants further investigation. ClinicalTrials.gov Identifier: NCT04169789.

Distal Tibial Bone Properties and Bone Stress Injury Risk in Young Men Undergoing Arduous Physical Training

Trabecular microarchitecture contributes to bone strength, but its role in bone stress injury (BSI) risk in young healthy adults is unclear. Tibial volumetric BMD (vBMD), geometry, and microarchitecture, whole-body areal BMD, lean and fat mass, biochemical markers of bone metabolism, aerobic fitness, and muscle strength and power were measured in 201 British Army male infantry recruits (age 20.7 [4.3] years, BMI 24.0 ± 2.7 kg·m2) in week one of basic training. Tibial scans were performed at the ultra-distal site, 22.5 mm from the distal endplate of the non-dominant leg using High Resolution Peripheral Quantitative Computed Tomography (XtremeCT, Scanco Medical AG, Switzerland). Binary logistic regression analysis was performed to identify associations with lower body BSI confirmed by MRI. 20 recruits (10.0%) were diagnosed with a lower body BSI. Pre-injured participants had lower cortical area, stiffness and estimated failure load (p = 0.029, 0.012 and 0.011 respectively) but tibial vBMD, geometry, and microarchitecture were not associated with BSI incidence when controlling for age, total body mass, lean body mass, height, total 25(OH)D, 2.4-km run time, peak power output and maximum dynamic lift strength. Infantry Regiment (OR 9.3 [95%CI, 2.6, 33.4]) Parachute versus Line Infantry, (p ≤ 0.001) and 2.4-km best effort run time (1.06 [95%CI, 1.02, 1.10], p < 0.033) were significant predictors. Intrinsic risk factors, including ultradistal tibial density, geometry, and microarchitecture, were not associated with lower body BSI during arduous infantry training. The ninefold increased risk of BSI in the Parachute Regiment compared with Line Infantry suggests that injury propensity is primarily a function of training load and risk factors are population-specific.

RF30 | PSAT172 Effects of 12 Months of Alendronate Therapy Subsequent to 12 Months of Denosumab Administration in Women With Anorexia Nervosa

Abstract Low bone mineral density (BMD) and increased fracture risk are common complications of anorexia nervosa. We assessed whether 12 months of alendronate subsequent to 12 months of denosumab would 1) maintain the increases in BMD observed with denosumab and 2) result in higher BMD than alendronate for 12 months alone in 30 ambulatory women with anorexia nervosa and areal BMD (aBMD) Z- or T-score &amp;lt;-1.0. Participants were randomized in a 2: 1 ratio to 12 months of denosumab (60mg subcutaneously q6 months) followed by 12 months of open-label alendronate (70mg orally qweek)("denosumab-to-alendronate" n=20) or 12 months of subcutaneous placebo followed by 12 months of open-label alendronate (70mg orally qweek)("placebo-to-alendronate" n=10). The prespecified primary outcome was PA lumbar spine aBMD by DXA. Secondary outcome measures included tibial and radial volumetric BMD (vBMD) and microarchitecture by high-resolution peripheral quantitative CT (HR-pQCT), and markers of bone turnover. Twelve-month results were reported in abstract form; 24-month results have not been published. At baseline, mean age [29±8 y (mean±SD)], BMI (18.6±1.9 kg/m2), and aBMD (PA lumbar spine Z-score -1.6±1.1) were similar between groups. From 12 to 24 months in the denosumab-to-alendronate group, favorable changes in spine aBMD, radial vBMD, and radial and tibial microarchitecture from 12 months of denosumab were maintained after 12 months of alendronate. However, there was a rebound increase in markers of bone turnover (p&amp;lt;0.003), and PA and lateral lumbar spine aBMD decreased in 6 and 9 participants, respectively. Both a greater suppression of bone turnover markers and a greater increase in aBMD from baseline to 12 months were predictors of partial reversal of BMD gains from 12 to 24 months in the denosumab-to-alendronate group. Over 24 months, PA lumbar spine aBMD (3.9±4.3%), femoral neck aBMD (3.1±5.5%), tibial vBMD and failure load increased within the denosumab-to-alendronate group, and PA lumbar spine aBMD (5.8±5.3%) increased within the placebo-to-alendronate group (p&amp;lt;0.05). In a 24-month between-group comparison, there was no difference in change in aBMD at any site; however, the denosumab-to-alendronate group demonstrated favorable changes in tibial vBMD and trabecular microarchitecture compared to the placebo-to-alendronate group (p&amp;lt;0.05). In conclusion, this pilot study suggests that 12 months of alendronate maintains BMD gains achieved with 12 months of denosumab administration in some, but not all, women with anorexia nervosa. A more robust response to denosumab may be a risk factor for partial reversal of denosumab-related BMD gains despite alendronate. Therefore, a more effective antiresorptive agent may be necessary to maintain gains in BMD achieved with denosumab therapy in some women with anorexia nervosa. Moreover, sequential therapy of denosumab followed by alendronate over 24 months results in greater improvements in tibial vBMD and microarchitecture than 12 months of alendronate, although increases in aBMD were similar between groups. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:30 p.m. - 12:35 p.m.

RF06 | PSAT171 Impact of GH Administration on Skeletal Endpoints in Adults with Overweight/Obesity

Abstract Background Obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity. Methods 77 adults ages 18-65 years, BMI ≥25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized in a double-blind protocol to daily subcutaneous GH or placebo for 18 months, targeting IGF-1 in the upper quartile of the age-appropriate normal range. There was a post-treatment observation period from 18-24 months. DXA and high-resolution peripheral quantitative CT were performed at baseline, 18 months and 24 months. Volumetric quantitative CT was performed at baseline and 18 months. Results are reported as mean ±SD or mean (95% confidence interval). Results There were no pretreatment differences between the GH (n=39) and placebo groups (n=38), including mean age (48±12y), BMI (33.1±5.7kg/m2) and BMD at any site. Forty-nine subjects (47% female) completed 18 months. P1NP, osteocalcin and CTX increased (p&amp;lt;0.005) and visceral adipose tissue decreased (p=0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased at 18 months in the GH vs placebo group (p&amp;lt;0.05). During the post-treatment observation period (18 to 24 months), total radius aBMD and tibia cortical thickness increased in the GH vs placebo group (p&amp;lt;0.05); there was also a trend toward an increase in total hip aBMD in the GH vs placebo group (p=0.06). At 24 months, none of the differences between the GH and placebo groups remained significant. There was a higher incidence of numbness and tingling (33% vs 8%, p=0.01) and joint pain or stiffness (33% vs 5%, p=0.003) in the GH vs placebo group. There were no other differences in adverse events between groups. Conclusions We demonstrated that GH administration for 18 months to individuals with overweight/obesity and low BMD decreased some measures of BMD, bone microarchitecture, and bone strength compared with placebo. None of these differences remained significant after 6 months off therapy. A longer duration of treatment, or a longer duration of observation post-treatment, may be necessary to see the expected biphasic decline and then increase in BMD reflecting an expanding remodeling space followed by mineralization that has previously been seen with GH administration in other populations, including individuals with and without GH deficiency. Although future investigation of the effects of GH on bone is required to assess the true long-term impact on skeletal integrity as well as fracture reduction, our study suggests that GH administration for 18 months to adults with overweight/obesity does not improve BMD, bone microarchitecture, or bone strength. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m.

Do bone turnover markers reflect changes in bone microarchitecture during treatment of patients with thyroid dysfunction?

This study aimed to compare changes in the bone turnover markers (BTMs)-C-terminal telopeptide of type I collagen (CTX-I) and procollagen I N-terminal peptide (PINP)-with changes in the bone microarchitecture, assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), during treatment of patients with thyroid dysfunction. In women with newly diagnosed hypo- or hyperthyroidism, HR-pQCT variables, obtained from the tibia and the radius, were compared with BTMs. Data were collected at diagnosis and after at least 12months of euthyroidism. 73 women completed the study (hypothyroidism, n = 27; hyperthyroidism, n = 46). Among hyperthyroid patients, correlations were found between changes in BTMs and HR-pQCT variables, primarily for cortical variables in the tibia, i.e. cortical thickness (CTX-I, p < 0.001; PINP, p < 0.001), and volumetric bone mass density (vBMD) (CTX-I, p < 0.001; PINP, p < 0.001). Moreover, correlations between BTMs and estimated bone strength were found. In the hypothyroid subgroup, no significant findings existed after adjustment. Following treatment, less decrease in tibial vBMD was seen among patients with increasing CTX-I compared to those with a decreasing CTX-I level (p = 0.009). Opposite findings applied to PINP, as patients with decreasing PINP showed an increase in tibial vBMD, in contrast to a decline in this parameter among patients with increasing PINP (p < 0.001). Changes in CTX-I and PINP correlated with HR-pQCT variables during the treatment of women with thyroid dysfunction. To some extent, these BTMs reflected the restoration of bone microarchitecture. CTX-I seems to be the most sensitive BTM in treatment-naïve thyroid diseases, while PINP is more useful for monitoring during treatment. NCT02005250. Date: December 9, 2013.

Impact of GH administration on skeletal endpoints in adults with overweight/obesity.

Overweight/obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity. An 18-month, randomized, double-blind, placebo-controlled study of GH, followed by 6-month observation. In this study, 77 adults (53% men), aged 18-65 years, BMI ≥ 25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized to daily subcutaneous GH or placebo, targeting IGF1 in the upper quartile of the age-appropriate normal range. Forty-nine completed 18 months. DXA, volumetric quantitative CT, and high-resolution peripheral quantitative CT were performed. Pre-treatment mean age (48 ± 12 years), BMI (33.1 ± 5.7 kg/m2), and BMD were similar between groups. P1NP, osteocalcin, and CTX increased (P < 0.005) and visceral adipose tissue decreased (P = 0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased in the GH vs placebo group (P < 0.05). Between 18 and 24 months (post-treatment observation period), radius aBMD and tibia cortical thickness increased in the GH vs placebo group. At 24 months, there were no differences between the GH and placebo groups in bone density, structure, or strength compared to baseline. GH administration for 18 months increased bone turnover in adults with overweight/obesity. It also decreased some measures of BMD, bone microarchitecture, and bone strength, which all returned to pre-treatment levels 6 months post-therapy. Whether GH administration increases BMD with longer treatment duration, or after mineralization of an expanded remodeling space post-treatment, requires further investigation.

Bone microarchitecture impairment in prolactinoma patients assessed by HR-pQCT.

Prolactinoma may reduce bone mineral density (BMD) and increase fracture risk, but its influence on bone microarchitecture remains to be elucidated. The purpose of this study is to evaluate bone microarchitecture parameters by high-resolution peripheral quantitative computed tomography (HR-pQCT) in prolactinoma patients. 31 prolactinoma patients and 62 age- and sex-matched healthy controls in our center were included, and HR-pQCT was used to evaluate their bone microarchitecture at the radius and tibia. Z-scores for bone microarchitecture parameters were calculated based on previously published reference. After adjusting for height and weight, prolactinoma patients had lower trabecular (- 0.011mm, p = 0.005) and cortical thickness (- 0.116mm, p = 0.008) and cortical area (- 6.0 mm2, p = 0.013) at radius, as well as lower trabecular (- 0.014mm, p = 0.008) and cortical (- 0.122mm, p = 0.022) thickness at tibia compared with the controls. Patients with higher prolactin level had more severe bone microarchitecture impairments. After adjusting for prolactin level and age, male patients had lower trabecular volumetric BMD (vBMD), trabecular number, trabecular thickness, and cortical porosity at radius, as well as lower trabecular vBMD, trabecular bone volume fraction, trabecular number, and cortical area, and higher trabecular separation at tibia compared with female patients. Z-score for radius vBMD was correlated with Z-score for areal BMD (aBMD) at lumbar and femoral neck, while Z-score for tibia vBMD was correlated with Z-score for lumbar aBMD, and some patients with vBMD Z-score below - 2.0 had aBMD Z-score within normal range. Peripheral bone microarchitecture was impaired in prolactinoma patients, especially in patients with higher prolactin level. We compared the bone microarchitecture of prolactinoma patients and healthy controls by high-resolution peripheral quantitative computed tomography (HR-pQCT), and found that many bone microarchitecture parameters were impaired among prolactinoma patients. Such impairment was more prominent among patients with higher prolactin level.

Once daily calcium (1000mg) and vitamin D (1000IU) supplementation during military training prevents increases in biochemical markers of bone resorption but does not affect tibial microarchitecture in Army recruits.

Basic combat training (BCT) is a period of novel physical training including load carriage resulting in higher risk of stress fracture compared to any other time during military service. Prior trials reported a 20% reduction in stress fracture incidence with Ca and vitamin D (Ca+D) supplementation (2000mg Ca, 800IU vitamin D), and greater increases in tibia vBMD during BCT compared to placebo. The primary objective of this randomized, double-blind, placebo-controlled trial was to determine the efficacy of a lower dose of Ca (1000mg/d Ca, 1000IU vit D) on PTH, bone biomarkers and tibial microarchitecture during BCT. One hundred volunteers (50 males, 50 females; mean age 21.8±3.5 y) were block randomized by race and sex to receive a daily Ca+D fortified food bar or placebo. Anthropometrics, dietary intake, fasted blood draws and high resolution pQCT scans of the distal and mid-shaft tibia were obtained at the start of BCT and 8 wks later at the conclusion of training. As compliance was 98% in both treatment groups, an intent-to-treat analysis was used. At the distal tibia, total vBMD, Tb.vBMD, Tb.N, Th.Th and Tb.BV/TV increased (+1.07 to 2.12% for all, p<0.05) and Tb.Sp decreased (0.96 to 1.09%, p<0.05) in both treatment groups. At the mid-shaft, Ct.Pm increased (+0.18 to 0.21%, p=0.01) and Ct.vBMD decreased (-0.48 to -0.77%, p<0.001) in both groups. Ca+D prevented increases in CTX and TRAP, which were observed in the placebo group (group-by-time, p<0.05). Mean circulating 25OHD, BAP, P1NP and iCa increased and PTH decreased in both treatment groups (p<0.05). These results, in agreement with other studies, suggest that bone microarchitectural changes indicative of bone formation occur during BCT. While Ca+D supplementation at lower doses than those tested in previous studies prevented increases in biochemical markers of bone resorption in this study, there were no significant changes in bone tissue after 8 wks of Army BCT.

Association Between DXA And HR-pQCT Measurements Of BMD In Active, Recruit-aged Men And Women

Dual-energy X-ray absorptiometry (DXA) areal bone mineral density (aBMD) measurements are routinely employed to assess fracture risk despite the limitations of a two-dimensional, estimated projection of bone volume. Conversely, high-resolution peripheral quantitative computed tomography (HR-pQCT) provides three-dimensional volumetric BMD (vBMD) measurements of total, trabecular, and cortical bone, offering better characterization of fracture risk. It remains unclear whether regional aBMD accurately reflects vBMD of specific bone compartments in the distal tibia, a common injury site for military personnel. PURPOSE: To determine if lower limb aBMD correlates with distal total (Tt), trabecular (Tb) and cortical (Ct) vBMD in healthy, recruit-aged men and women. METHODS: Seventy-six recreationally active men (n = 43;26.4 ± 0.8 yrs.), and women (n = 33;26.2 ± 4.7 yrs.), free of any musculoskeletal conditions that could influence BMD, completed two HR-pQCT (XtremeCT; Scanco Medical) and one total body DXA (Lunar iDXA; GE Healthcare) scans. Total body DXA and non-dominant tibial HR-pQCT scans at the metaphysis (4% site) and diaphysis (30% site) were obtained. Lower leg aBMD was assessed in DXA scans with custom region of interest (ROI) analysis between the ultradistal tibia and the tibial plateau. Associations between variables were analyzed with Pearson’s correlation coefficient (r2); alpha was set at p < 0.05. RESULTS: aBMD positively correlated with Tt vBMD at the 4% site for men (r2 = 0.42; p < 0.001) and women (r2 = 0.17; p = 0.016) but only in men at the 30% site (r2 = 0.16; p = 0.008). aBMD positively correlated with Tb vBMD at the 4% site for men (r2 = 0.35; p < 0.001) and women (r2 = 0.20; p = 0.010), but not at the 30% site for either sex. aBMD was not correlated with Ct vBMD at the 4% site for either sex but was positively correlated with Ct vBMD at the 30% site in men (r2 = 0.12; p = 0.032). CONCLUSIONS: There is poor to moderate association between lower limb aBMD and tibial vBMD at both sites, with greater association in men than in women. aBMD is unlikely to provide a suitable assessment of distal tibial bone health. aBMD and tibial vBMD should, therefore, not be used interchangeably to examine the bone response to interventions or for the prediction of fracture risk. Supported by UK Ministry of Defence (WGCC 5.5.6-Task 0107).

Testosterone Therapy Effects on Bone Mass and Turnover in Hypogonadal Men with Type 2 Diabetes.

Male hypogonadism is associated with low bone mineral density (BMD) and increased fragility fracture risk. Patients with type 2 diabetes (T2D) have relatively higher BMD, but greater fracture risk. Evaluate the skeletal response to testosterone therapy in hypogonadal men with T2D compared with hypogonadal men without T2D. Single arm, open-label clinical trial (NCT01378299) involving 105 men (40-74 years old), with average morning testosterone <300 ng/dL. Subjects were injected intramuscularly with testosterone cypionate (200 mg) every 2 weeks for 18 months. Testosterone and estradiol were assessed by liquid chromatography/mass spectrometry; serum C-terminal telopeptide of type I collagen (CTX), osteocalcin and sclerostin by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) by high-performance liquid chromatography, areal BMD (aBMD) and body composition by dual-energy x-ray absorptiometry; tibial volumetric BMD (vBMD) and bone geometry by peripheral quantitative computed tomography. Among our population of hypogonadal men, 49 had T2D and 56 were non-T2D. After 18 months of testosterone therapy, there were no differences in circulating testosterone and estradiol between the groups. Hypogonadal men with T2D had increased osteocalcin, reflecting increased osteoblast activity, compared with non-T2D men (P < .01). T2D men increased lumbar spine aBMD (P < .05), total area at 38% tibia (P < .01) and periosteal and endosteal circumferences at the same site (P < .01 for both). T2D men had reduced tibial vBMD (P < .01), but preserved bone mineral content (P = .01). Changes in HbA1c or body composition were similar between the 2 groups. Testosterone therapy results in greater improvements in the skeletal health of hypogonadal men with T2D than their nondiabetic counterparts.

Effect of Testosterone Treatment on Bone Microarchitecture and Bone Mineral Density in Men: A 2-Year RCT.

Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown. We aimed to determine the effect of testosterone treatment on bone microarchitecture using high resolution-peripheral quantitative computed tomography (HR-pQCT). Men ≥ 50 years of age were recruited from 6 Australian centers and were randomized to receive injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. The primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (1 center). Secondary endpoints included other HR-pQCT parameters and bone remodeling markers. Areal BMD (aBMD) was measured by dual-energy x-ray absorptiometry (DXA) in 601 men (5 centers). Using a linear mixed model for repeated measures, the mean adjusted differences (95% CI) at 12 and 24 months between groups are reported as treatment effect. Over 24 months, testosterone treatment, versus placebo, increased tibial cortical vBMD, 9.33 mg hydroxyapatite (HA)/cm3) (3.96, 14.71), P < 0.001 or 3.1% (1.2, 5.0); radial cortical vBMD, 8.96 mg HA/cm3 (3.30, 14.62), P = 0.005 or 2.9% (1.0, 4.9); total tibial vBMD, 4.16 mg HA/cm3 (2.14, 6.19), P < 0.001 or 1.3% (0.6, 1.9); and total radial vBMD, 4.42 mg HA/cm3 (1.67, 7.16), P = 0.002 or 1.8% (0.4, 2.0). Testosterone also significantly increased cortical area and thickness at both sites. Effects on trabecular architecture were minor. Testosterone reduced bone remodeling markers CTX, -48.1 ng/L [-81.1, -15.1], P < 0.001 and P1NP, -6.8 μg/L[-10.9, -2.7], P < 0.001. Testosterone significantly increased aBMD at the lumbar spine, 0.04 g/cm2 (0.03, 0.05), P < 0.001 and the total hip, 0.01 g/cm2 (0.01, 0.02), P < 0.001. In men ≥ 50 years of age, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.

Modest Changes in Sex Hormones During Early and Middle Adulthood Affect Bone Mass and Size in Healthy Men: A Prospective Cohort Study.

Bone metabolism in men is in part determined by sex steroid exposure. This is especially clear during puberty and senescence but it remains to be established whether declines in sex steroid levels during young and middle adulthood are associated with changes in bone mass and size. This study investigated changes in bone mineral content (BMC), areal bone mineral density (aBMD), volumetric BMD (vBMD), and bone size in relation to sex steroid levels in 999 young adult men (age 24-46 years) of whom 676 were re-evaluated after a mean period of 12 years. Sex hormone-binding globulin (SHBG) levels were measured using immunoassay, testosterone (T) and estradiol (E2) using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and free fractions were calculated (cFT and cFE2, respectively). Areal bone parameters and BMC were measured at the hip and lumbar spine using dual-energy X-ray absorptiometry (DXA). Radial and tibial vBMD and bone size were determined using peripheral quantitative computed tomography (pQCT). Linear mixed models were used for statistical analyses. With aging, we observed decreases in almost all bone mass and density indices, whereas changes in bone geometry resulted in larger bones with thinner cortices. These changes in bone mass and size appeared related to sex steroid levels. Specifically, decreases in cFT (but not total T) levels were associated with larger decreases in lumbar spine BMC and especially with geometric changes in cortical bone at the tibia. Similarly, decreases in total E2 and cFE2 were associated with larger decreases in bone mass (all sites) and also with some geometric changes. Also increases in SHBG were independently associated with aging-related changes in bone mass and size in these men. In summary, even small changes in T, E2, and SHBG levels during young and middle adulthood in healthy men are associated with changes in bone mass and size. © 2022 American Society for Bone and Mineral Research (ASBMR).

Feasibility, safety and effectiveness of a pilot 16-week home-based, impact exercise intervention in postmenopausal women with low bone mineral density.

The feasibility and efficacy of impact exercise in postmenopausal women with low bone mineral density (BMD) are unclear. We aimed to determine adherence, safety and changes in BMD, bone microarchitecture and physical function following a pilot home-based, impact exercise intervention in postmenopausal women with low BMD. Fifty community-dwelling postmenopausal women with BMD T-scores < - 1.0 participated in 16 weeks of home-based impact exercise progressively increasing to 50 multi-directional unilateral hops on each leg daily. Bone density and structure were assessed by lumbar spine and hip dual-energy X-ray absorptiometry (DXA), 3D modelling (3D-SHAPER) of hip DXA scans and distal tibial high-resolution peripheral quantitative computed tomography scans. Physical performance was assessed by repeated chair stand time and stair climb time. Forty-four women (mean ± SD age 64.5 ± 7.5 years) completed the intervention, with adherence of 85.3 ± 17.3%. Reasons for withdrawal were related soreness (n = 2), unrelated injury (n = 1) and loss of interest (n = 3). Femoral neck areal BMD increased by 1.13 ± 3.76% (p = 0.048). Trabecular volumetric BMD (vBMD) increased at the total hip (2.27 ± 7.03%; p = 0.038) and femoral neck increased (3.20 ± 5.39%; p < 0.001). Distal tibia total vBMD increased by 0.32 ± 0.88% (p = 0.032) and cortical cross-sectional area increased by 0.55 ± 1.54% (p = 0.034). Chair stand and stair climb time improved by 2.34 ± 1.88 s (p < 0.001) and 0.27 ± 0.49 s (p < 0.001), respectively. A 16-week home-based, impact exercise was feasible and may be effective in improving femoral neck areal BMD, total hip and distal tibial vBMD and physical function in postmenopausal women. Appropriately designed randomised controlled trials are now required to determine whether such interventions can reduce fracture risk in older populations.

Continuous decline in bone mineral density and deterioration of bone microarchitecture 7 years after Roux-en-Y gastric bypass surgery.

ObjectiveRoux-en-Y-gastric bypass (RYGB) surgery is an effective treatment for morbid obesity. A possible overlooked side effect is negative bone metabolic consequences. DesignA seven-year prospective study following ten women and seven men after RYGB (baseline mean age 43 ± 8 years, BMI 42 ± 6 kg/m2).MethodsLumbar spine and total hip bone mineral density (BMD) using dual energy x-ray absorptiometry, distal radius and tibia bone geometry, volumetric BMD, microarchitecture and finite element estimated bone strength using high-resolution peripheral quantitative CT and biochemical markers of bone remodelling were assessed at baseline, 2 and 7 years.ResultsCompared to baseline, body weight was 24 ± 10% lower after 2 years and 21 ± 11% after 7 years. During the 7 years of follow-up, radius and tibia vBMD had declined 13 ± 8% and 8 ± 7% from baseline to 2 years and further 10 ± 7% and 7 ± 8% from 2 to 7 years (all P < 0.001). At both radius and tibia, cortical thickness declined and cortical porosity increased. From baseline to 7 years, there were clear indications of deteriorations of the trabecular network with fewer, more widely spaced and more in-homogeneously distributed trabeculae in both radius and tibia. Overall, declines in estimated bone strength of 16 ± 9% in radius and 16 ± 7% in tibia were observed (both P < 0.001).ConclusionSeven years after RYGB, evidence of continuous declines in BMD and ongoing deterioration of bone microarchitecture and reduced estimated bone strength compared to baseline and 2 years post-surgery results were found. These findings emphasize the need for regular assessment of bone health in patients with prior RYGB.

Marrow adipose tissue in adolescent girls with obesity.

Marrow adipose tissue (MAT) is increasingly recognized as an active and dynamic endocrine organ that responds to changes in nutrition and environmental milieu. Compared to normal weight controls, adolescent girls with anorexia nervosa have higher MAT content, which is associated with impaired skeletal integrity, but data are limited regarding MAT content in adolescents with obesity and how this interacts with bone endpoints. To evaluate (i) MAT content in adolescents with obesity compared to normal-weight controls, (ii) the association of MAT with bone endpoints, and (iii) whether these associations of MAT are affected by body weight. We assessed MAT, bone endpoints, and body composition in 60 adolescent girls 14-21 years old: 45 with obesity (OB) and 15 normal-weight controls (NW-C). We used (i) DXA to assess areal bone mineral density (aBMD) at the lumbar spine and total hip, and total body fat and lean mass, (ii) proton magnetic resonance spectroscopy (1H-MRS) to assess MAT at the 4th lumbar vertebra and femur, and MRI to assess visceral (VAT) and subcutaneous adipose tissue (SAT), (iii) high resolution peripheral quantitative CT (HR-pQCT) to assess volumetric BMD (vBMD), (iv) individual trabeculae segmentation to evaluate trabecular bone (plate-rod morphology), and (v) finite element analysis to assess stiffness (a strength estimate) at the distal radius and tibia. Groups did not differ for age or height. Weight, BMI, and areal BMD Z-scores at all sites were higher in the OB group (p<0.0001). MAT was lower in OB at the femoral diaphysis (p= <0.0001) and the lumbar spine (p=0.0039). For the whole group, MAT at the lumbar spine and femoral diaphysis was inversely associated with BMI, total fat mass, lean mass, and VAT. Even after controlling for body weight, independent inverse associations were observed of femoral diaphyseal and lumbar MAT with total tibial vBMD, and of lumbar MAT with radial trabecular vBMD. Adolescent girls with obesity have lower MAT than normal-weight controls despite having an excess of total body fat. These findings confirm that MAT is regulated uniquely from other adipose depots in obesity. MAT was inversely associated with vBMD, emphasizing an inverse relationship between MAT and bone even in adolescent girls with obesity.

Associations of Health-Related Quality of Life, Fear of Falling and Objective Measures of Physical Function with Bone Health in Postmenopausal Women with Low Bone Mass.

Health-related quality of life (HRQoL) and physical function deteriorate with age and may adversely impact bone health in older adults. We determined associations of objective measures of physical function and HRQoL with bone health in postmenopausal women with low areal bone mineral density (aBMD). Fifty postmenopausal women (64.4 ± 7.7 years old, mean ± standard deviation) with low spine, hip or femoral neck aBMD (T- or Z-score < −1.0) on dual-energy X-ray absorptiometry (DXA) participated. Femoral surface BMD, trabecular, integral and cortical volumetric BMD (vBMD) measurements were obtained using 3D-SHAPER software on DXA. Distal tibial vBMD and microarchitecture were assessed using high-resolution peripheral quantitative computed tomography (HRpQCT). Participants completed self-administered EuroQol-5D (EQ-5D) and modified falls efficacy scale (MFES) questionnaires, and physical function assessments. Stair climb power was positively associated with bone parameters at the hip, femoral neck, and distal tibia (all p < 0.05) in multivariable linear regression. EQ-5D demonstrated no significant associations with bone parameters and MFES was positively associated only with distal tibial cortical vBMD and cortical von Mises stress (both p < 0.05). Objective measures of physical function, particularly muscle power, are more consistently associated with bone parameters compared with self-administered HRQoL questionnaires.

Skeletal Responses To An All-female Unsupported Antarctic Expedition

Arduous training can result in an energy deficit, the consequences of which include impaired bone health and increased stress fracture risk, as determined by acute interventional or cross-sectional studies. Women are more prone to stress fractures than men, and possibly more susceptible to metabolic perturbations associated with reduced energy availability. No study has longitudinally examined the effect of a prolonged severe energy deficit on bone in women. PURPOSE: To investigate the skeletal effects of the first all-female trans-Antarctic expedition. METHODS: Six women (mean ± SD, age 32 ± 3 years, height 1.72 ± 0.07 m, body mass 72.1 ± 3.8 kg) each hauled an 80 kg sledge over 1700 km in 61 days from coast-to-coast across the Antarctic. Whole-body areal bone mineral density (aBMD) (dual energy x-ray absorptiometry) and tibial volumetric BMD (vBMD), geometry, microarchitecture and mechanical properties (high-resolution peripheral quantitative computed tomography) were assessed 39 days before (pre-expedition) and 15 days after (post-expedition) the expedition. Serum and plasma markers of bone turnover were assessed pre-expedition, and 4 and 15 days after the expedition. RESULTS: There were reductions in trunk (−2.6%), ribs (−5.0%) and spine (−3.4%) aBMD from pre- to post-expedition (all P ≤ 0.046); arms, legs, pelvis and total body aBMD were not different (all P ≥ 0.075). Tibial vBMD, geometry, microarchitecture and mechanical properties at the distal metaphysis (4% site) and diaphysis (30% site) were not different between pre- and post-expedition (all P ≥ 0.082). Bone-specific alkaline phosphatase was higher 15 days post- than 4 days post-expedition (18.0 vs 16.3 μg∙l-1, respectively, P = 0.028). Total 25(OH)D decreased markedly from pre- to 4 days post-expedition (112 vs 76 nmol∙l-1, respectively, P = 0.008). Sclerostin, procollagen 1 N-terminal propeptide, C-telopeptide cross-links of type 1 collagen and adjusted calcium were unchanged (all P ≥ 0.154). CONCLUSION: The deleterious effect of the expedition on aBMD may be due to indirect and direct effects of prolonged energy deficit on bone turnover. We propose that weight-bearing exercise was protective against the effects of low energy availability on tibial vBMD, geometry, microarchitecture and strength. Supported by UK Ministry of Defence (Army)

Large cortical bone pores in the tibia are associated with proximal femur strength.

Alterations of structure and density of cortical bone are associated with fragility fractures and can be assessed in vivo in humans at the tibia. Bone remodeling deficits in aging women have been recently linked to an increase in size of cortical pores. In this ex vivo study, we characterized the cortical microarchitecture of 19 tibiae from human donors (aged 69 to 94 years) to address, whether this can reflect impairments of the mechanical competence of the proximal femur, i.e., a major fracture site in osteoporosis. Scanning acoustic microscopy (12 μm pixel size) provided reference microstructural measurements at the left tibia, while the bone vBMD at this site was obtained using microcomputed tomography (microCT). The areal bone mineral density of both left and right femoral necks (aBMDneck) was measured by dual‐energy X‐ray absorptiometry (DXA), while homogenized nonlinear finite element models based on high-resolution peripheral quantitative computed tomography provided hip stiffness and strength for one-legged standing and sideways falling loads. Hip strength was associated with aBMDneck (r = 0.74 to 0.78), with tibial cortical thickness (r = 0.81) and with measurements of the tibial cross-sectional geometry (r = 0.48 to 0.73) of the same leg. Tibial vBMD was associated with hip strength only for standing loads (r = 0.59 to 0.65). Cortical porosity (Ct.Po) of the tibia was not associated with any of the femoral parameters. However, the proportion of Ct.Po attributable to large pores (diameter > 100 μm) was associated with hip strength in both standing (r = -0.61) and falling (r = 0.48) conditions. When added to aBMDneck, the prevalence of large pores could explain up to 17% of the femur ultimate force. In conclusion, microstructural characteristics of the tibia reflect hip strength as well as femoral DXA, but it remains to be tested whether such properties can be measured in vivo.

Skeletal responses to an all-female unassisted Antarctic traverse.

To investigate the skeletal effects of the first all-female trans-Antarctic traverse. Six women (mean ± SD, age 32 ± 3 years, height 1.72 ± 0.07 m, body mass 72.8 ± 4.0 kg) hauled 80 kg sledges over 1700 km in 61 days from coast-to-coast across the Antarctic. Whole-body areal bone mineral density (aBMD) (dual-energy X-ray absorptiometry) and tibial volumetric BMD (vBMD), geometry, microarchitecture and estimated mechanical properties (high-resolution peripheral quantitative computed tomography) were assessed 39 days before (pre-expedition) and 15 days after the expedition (post-expedition). Serum and plasma markers of bone turnover were assessed pre-expedition, and 4 and 15 days after the expedition. There were reductions in trunk (-2.6%), ribs (-5.0%) and spine (-3.4%) aBMD from pre- to post-expedition (all P ≤ 0.046); arms, legs, pelvis and total body aBMD were not different (all P ≥ 0.075). Tibial vBMD, geometry, microarchitecture and estimated mechanical properties at the metaphysis (4% site) and diaphysis (30% site) were not different between pre- and post-expedition (all P ≥ 0.082). Bone-specific alkaline phosphatase was higher 15 days post- than 4 days post-expedition (1.7 μg∙l-1, P = 0.028). Total 25(OH)D decreased from pre- to 4 days post-expedition (-36 nmol∙l-1, P = 0.008). Sclerostin, procollagen 1 N-terminal propeptide, C-telopeptide cross-links of type 1 collagen and adjusted calcium were unchanged (all P ≥ 0.154). A decline in aBMD of the axial skeleton may be due to indirect and direct effects of prolonged energy deficit. We propose that weight-bearing exercise was protective against the effects of energy deficit on tibial vBMD, geometry, microarchitecture and strength.

Volumetric Bone Mineral Density Increases Following a Period of Heightened Physical Activity in Female U.S. Army Soldiers

Background/Aim: Basic combat training (BCT) for military recruits is a time of heightened physical activity when stress fracture risk is increased. Animal studies demonstrate that bones can mount an anabolic response to physical activity, which confers mechanical benefits that may offset risk of injury. During BCT, this anabolic response may be more robust in those with lower bone density at the start of training, where a greater loading stimulus is perceived by the skeleton. We hypothesized that the BCT setting would result in increases in volumetric bone mineral density (vBMD; suggesting bone anabolism) and that individuals with lowest baseline vBMD would see the greatest change. Methods: We quantified the tibia vBMD of 90 female recruits before and after BCT, using a high-resolution peripheral quantitative computed tomography (XtremeCTII, Scanco Medical). Using a linear mixed model, we estimated the mean change in vBMD following BCT. To evaluate the effect of baseline vBMD on the change in vBMD we used a generalized additive model, applying a naturalized spline to baseline vBMD. We adjusted for baseline 25-hydroxyvitamin D and serum calcium, exercise prior to BCT, and race/ethnicity. Results: Tibial vBMD increased following BCT (Effect Estimate: 1.79%, 95% CI: 1.32, 2.25). The relationship between the change in vBMD and baseline vBMD was significantly non-linear (p&lt;0.001). Individuals with the lowest baseline values for vBMD saw the greatest increases in vBMD where the slope of this effect diminished as baseline vBMD increased. Conclusions: BCT results in new bone formation, as suggested by increased vBMD. This anabolic response to training was most evident in Soldiers with lowest baseline bone density. These findings suggest that Soldiers with less dense bones at BCT entry are capable of bone anabolism—a biological process that can be targeted for stress fracture mitigation.