Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors.

Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/ß5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health.

Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice.

Osteoporosis is a major public health problem. Currently, there are no orally available therapies that increase bone formation. Intermittent parathyroid hormone (PTH) stimulates bone formation through a signal transduction pathway that involves inhibition of salt-inducible kinase isoforms 2 and 3 (SIK2 and SIK3). Here, we further validate SIK2/SIK3 as osteoporosis drug targets by demonstrating that ubiquitous deletion of these genes in adult mice increases bone formation without extraskeletal toxicities. Previous efforts to target these kinases to stimulate bone formation have been limited by lack of pharmacologically acceptable, specific, orally available SIK2/SIK3 inhibitors. Here, we used structure-based drug design followed by iterative medicinal chemistry to identify SK-124 as a lead compound that potently inhibits SIK2 and SIK3. SK-124 inhibits SIK2 and SIK3 with single-digit nanomolar potency in vitro and in cell-based target engagement assays and shows acceptable kinome selectivity and oral bioavailability. SK-124 reduces SIK2/SIK3 substrate phosphorylation levels in human and mouse cultured bone cells and regulates gene expression patterns in a PTH-like manner. Once-daily oral SK-124 treatment for 3 wk in mice led to PTH-like effects on mineral metabolism including increased blood levels of calcium and 1,25-vitamin D and suppressed endogenous PTH levels. Furthermore, SK-124 treatment increased bone formation by osteoblasts and boosted trabecular bone mass without evidence of short-term toxicity. Taken together, these findings demonstrate PTH-like effects in bone and mineral metabolism upon in vivo treatment with orally available SIK2/SIK3 inhibitor SK-124.

Risk of wrist fracture, estimated by the load-to-strength ratio, declines following sleeve gastrectomy in adolescents and young adults.

To understand whether the bone loss which occurs after vertical sleeve gastrectomy increases the risk of fracture, we used an engineering model to estimate risk in participants before and after surgery. We found that estimated risk decreased 1 year after surgery and remained lower, though had rebounded, at year 2. PURPOSE: Vertical sleeve gastrectomy (VSG) improves metabolic health in young people with obesity but is accompanied by substantial loss of bone mass and estimated bone strength. We thus estimated fracture risk following VSG using the load-to-strength ratio (LSR), which integrates bone strength estimates with the predicted force of a fall. METHODS: Prospective 2-year study of youth ages 13-24 years with obesity undergoing VSG (n = 24) or lifestyle therapy (n = 34). We performed high-resolution peripheral quantitative computed tomography of the distal radius and microfinite element analysis to estimate bone strength and calculated LSR. RESULTS: VSG participants lost 26.4 ± 8.1% weight at year 1 (p < 0.001), which was sustained at year 2, while control participants gained weight at year 2 (4.5 ± 8.3%, p = 0.009). The predicted impact force decreased at years 1 and 2 following VSG (p < 0.001) but increased at year 2 among controls (p = 0.011). Estimated bone strength was unchanged at year 1 but decreased (p < 0.001) at year 2 following VSG, while bone strength did not change in controls. At year 1, the LSR decreased among VSG participants (p < 0.001), implying a lower risk of fracture. At year 2, the LSR was lower than baseline (p < 0.001), but higher compared to year 1 (p = 0.001). LSR did not change in the control group. CONCLUSIONS: Short-term estimated fracture risk at the radius following VSG decreases. However, ongoing bone loss despite stable weight between years 1 and 2 leads to a concerning rise in estimated fracture risk. Longer follow-up will be critical to evaluate the trajectory of fracture risk. (ClinicalTrials.gov NCT02557438, registered 9/23/2015).

Hypothalamic-pituitary-ovarian axis suppression is common among women during US Army Basic Combat Training.

OBJECTIVE: Less than half of servicewomen report loss of menses during initial military training. However, self-reported menstrual status may not accurately reflect hypothalamic-pituitary-ovarian (HPO) axis suppression and may underestimate reproductive health consequences of military training. Our aim was to characterise HPO axis function during US Army Basic Combat Training (BCT) in non-hormonal contraceptive-using women and explore potential contributors to HPO axis suppression. METHODS: In this 10-week prospective observational study, we enrolled multi-ethnic women entering BCT. Trainees provided daily first-morning voided urine, and weekly blood samples during BCT. Urinary luteinising hormone, follicle stimulating hormone, and metabolites of estradiol and progesterone were measured by chemiluminescent assays (Siemens Centaur XP) to determine hormone patterns and luteal activity. We measured body composition, via dual-energy X-ray absorptiometry, at the beginning and end of BCT. RESULTS: Trainees (n=55) were young (mean (95% CI): 22 (22, 23) years) with average body mass index (23.9 (23.1, 24.7) kg/m2). Most trainees (78%) reported regular menstrual cycles before BCT. During BCT, 23 (42%) trainees reported regular menses. However, only seven trainees (12.5%) had menstrual cycles with evidence of luteal activity (ELA) (ie, presumed ovulation), all with shortened luteal phases. 41 trainees (75%) showed no ELA (NELA), and 7 (12.5%) were categorised as indeterminant. Overall, women gained body mass and lean mass, but lost fat mass during BCT. Changes in body mass and composition appear unrelated to luteal activity. CONCLUSIONS: Our findings reveal profound HPO axis suppression with NELA in the majority of women during BCT. This HPO axis suppression occurs among women who report normal menstrual cycles.

Two-year Skeletal Effects of Sleeve Gastrectomy in Adolescents with Obesity Assessed with Quantitative CT and MR Spectroscopy.

Background Sleeve gastrectomy (SG) is effective in the treatment of cardiometabolic complications of obesity but is associated with bone loss. Purpose To determine the long-term effects of SG on vertebral bone strength, density, and bone marrow adipose tissue (BMAT) in adolescents and young adults with obesity. Materials and Methods This 2-year prospective nonrandomized longitudinal study enrolled adolescents and young adults with obesity who underwent either SG (SG group) or dietary and exercise counseling without surgery (control group) at an academic medical center from 2015 to 2020. Participants underwent quantitative CT of the lumbar spine (L1 and L2 levels) to assess bone density and strength, proton MR spectroscopy to assess BMAT (L1 and L2 levels), and MRI of the abdomen and thigh to assess body composition. Student t and Wilcoxon signed-rank tests were used to compare 24-month changes between and within groups. Regression analysis was performed to evaluate associations between body composition, vertebral bone density, strength, and BMAT. Results A total of 25 participants underwent SG (mean age, 18 years ± 2 [SD], 20 female), and 29 underwent dietary and exercise counseling without surgery (mean age, 18 years ± 3, 21 female). Body mass index (BMI) decreased by a mean of 11.9 kg/m2 ± 5.21 [SD] after 24 months in the SG group (P < .001), while it increased in the control group (mean increase, 1.49 kg/m2 ± 3.10; P = .02). Mean bone strength of the lumbar spine decreased after surgery compared with that in control subjects (mean decrease, -728 N ± 691 vs -7.24 N ± 775; P < .001). BMAT of the lumbar spine increased after SG (mean lipid-to-water ratio increase, 0.10 ± 0.13; P = .001). Changes in vertebral density and strength correlated positively with changes in BMI and body composition (R = 0.34 to R = 0.65, P = .02 to P < .001) and inversely with vertebral BMAT (R = -0.33 to R = -0.47, P = .03 to P = .001). Conclusion SG in adolescents and young adults reduced vertebral bone strength and density and increased BMAT compared with those in control participants. Clinical trial registration no. NCT02557438 © RSNA, 2023 See also the editorial by Link and Schafer in this issue.

Reference Intervals for Bone Impact Microindentation in Healthy Adults: A Multi-Centre International Study.

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

Impact of Low Energy Availability on Skeletal Health in Physically Active Adults.

For decades researchers reported that pre-menopausal women who engage in extensive endurance exercise and have menstrual dysfunction can develop low bone mineral density (BMD) or osteoporosis. More recently, low energy availability has been recognized as the initiating factor for low BMD in these women. Furthermore, the relationship between low energy availability and poor skeletal health is not exclusive to women engaging in endurance exercise. Rather, both males and females commonly experience endocrine dysfunction resulting from low energy availability and high exercise levels that degrades skeletal health. Consequences to skeletal health can range from short-term changes in bone metabolism and increased risk of bone stress injuries to long-term consequences of low BMD, such as osteoporosis and related fragility fractures. The degree to which low energy availability degrades skeletal health may be dependent on the length and extent of the energy deficit. However, the complex relationships between under-fueling, short- and long-term skeletal consequences and the factors that mediate these relationships are not well described. In this review, we discuss the consequences of low energy availability on sex hormones and skeletal health in two highly-active populations-athletes and military trainees-and provide a summary of existing knowledge gaps for future study.

Insulin-like growth factor binding protein 2 null mice (Igfbp2-/-) are protected against trabecular bone loss after vertical sleeve gastrectomy.

BACKGROUND: Bariatric surgery has been shown to result in weight loss, improved hemoglobin A1C, and decreased mortality but can also lead to bone loss and increased fracture rates. Serum IGFBP-2 is elevated in patients after bariatric surgery and although it may lead to improved blood glucose, may also drive bone resorption, and inhibit IGF-I action. This study tested the hypothesis that Igfbp2-/- mice were acutely protected from bone loss after vertical sleeve gastrectomy (VSG). METHODS: Thirty-four mice, 17 Igfbp2-/- and 17 + / + underwent a hand-sewn VSG or sham surgery, at 16 weeks of age. Mice were harvested at 20 weeks of age. DXA was measured for body composition, areal bone mineral density (aBMD), areal bone mineral content (aBMC), femoral bone mineral density (fBMD), and femoral bone mineral content (fBMC) at 15, 18, and 20 weeks of age. Micro-computed tomography and serum ELISA assays were measured and analyzed at 20 weeks of age. RESULTS: Both Igfbp2-/- and + / + mice lost significant weight (P = 0.0251, P = 0.0003, respectively) and total fat mass (P = 0.0082, P = 0.0004, respectively) at 4 weeks after VSG. Igfbp2+/+ mice lost significant aBMD, fBMD, fBMC, trabecular BMD, trabecular BV/TV and cortical tissue mineral density (P = 0.0150, P = 0.0313, P = 0.0190, P = 0.0072, and 0.0320 respectively). The Igfbp2-/- mice did not show significant bone loss in these parameters nor in trabecular BV/TV. Both Igfbp2-/- and + / + mice had less cortical bone area (P = 0.0181, P = < .00001), cortical area over total area (P = 0.0085, P = 0.0007), and cortical thickness (P = 0.0050, P = < 0.0001), respectively. Igfbp2+/+ mice demonstrated significantly lower polar, minimum, and maximum moments of inertia (P = 0.0031, P = 0.0239, and P = 0.0037, respectively). Igfbp2+/+ had significantly higher levels of IGFBP-2 at 2 weeks postoperatively after VSG (P = 0.035), and elevated levels of CTx and P1NP (P = 0.0127, P = 0.0058, respectively). CONCLUSIONS: Igfbp2-/- mice were protected against trabecular bone loss and had attenuated cortical bone loss 4 weeks after VSG.

Proceedings of the 2022 Santa Fe Bone Symposium: Current Concepts in the Care of Patients with Osteoporosis and Metabolic Bone Diseases.

The 22nd Annual Santa Fe Bone Symposium (SFBS) was a hybrid meeting held August 5-6, 2022, with in-person and virtual attendees. Altogether, over 400 individuals registered, a majority of whom attended in-person, representing many states in the USA plus 7 other countries. The SFBS included 10 plenary presentations, 2 faculty panel discussions, satellite symposia, Bone Health & Osteoporosis Foundation Fracture Liaison Service Boot Camp, and a Project ECHO workshop, with lively interactive discussions for all events. Topics of interest included fracture prevention at different stages of life; how to treat and when to change therapy; skeletal health in cancer patients; advanced imaging to assess bone strength; the state of healthcare in the USA; osteosarcopenia; vitamin D update; perioperative bone health care; new guidelines for managing primary hyperparathyroidism; new concepts on bone modeling and remodeling; and an overview on the care of rare bone diseases, including hypophosphatasia, X-linked hypophosphatemia, tumor induced osteomalacia, osteogenesis imperfecta, fibrodysplasia ossificans progressiva, and osteopetrosis. The SFBS was preceded by the Santa Fe Fellows Workshop on Osteoporosis and Metabolic Bone Diseases, a collaboration of the Endocrine Fellows Foundation and the Osteoporosis Foundation of New Mexico. From the Workshop, 4 participating fellows were selected to give oral presentations at the bone symposium. These proceedings represent the clinical highlights of 2022 SFBS presentations and the discussions that followed, all with the aim of optimizing skeletal health and minimizing the consequences of fragile bones.

Restrictive Eating and Prior Low-Energy Fractures Are Associated With History of Multiple Bone Stress Injuries.

Bone stress injuries (BSIs) are common among athletes and have high rates of recurrence. However, risk factors for multiple or recurrent BSIs remain understudied. Thus, we aimed to explore whether energy availability, menstrual function, measures of bone health, and a modified Female Athlete Triad Cumulative Risk Assessment (CRA) tool are associated with a history of multiple BSIs. We enrolled 51 female runners (ages 18-36 years) with history of ≤1 BSI (controls; n = 31) or ≥3 BSIs (multiBSI; n = 20) in this cross-sectional study. We measured lumbar spine, total hip, and femoral neck areal bone mineral density by dual-energy X-ray absorptiometry, bone material strength index using impact microindentation, and volumetric bone mineral density, microarchitecture, and estimated strength by high-resolution peripheral quantitative computed tomography. Participants completed questionnaires regarding medical history, low-energy fracture history, and disordered eating attitudes. Compared with controls, multiBSI had greater incidence of prior low-energy fractures (55% vs. 16%, p = .005) and higher modified Triad CRA scores (2.90 ± 2.05 vs. 1.84 ± 1.59, p = .04). Those with multiBSI had higher Eating Disorder Examination Questionnaire (0.92 ± 1.03 vs. 0.46 ± 0.49, p = .04) scores and a greater percentage difference between lowest and highest body mass at their current height (15.5% ± 6.5% vs. 11.5% ± 4.9% p = .02). These preliminary findings indicate that women with a history of multiple BSIs suffered more prior low-energy fractures and have greater historical and current estimates of energy deficit compared with controls. Our results provide strong rationale for future studies to examine whether subclinical indicators of energy deficit contribute to risk for multiple BSIs in female runners.

The oestrous cycle and skeletal muscle atrophy: Investigations in rodent models of muscle loss.

NEW FINDINGS: What is the central question of this study? Is the oestrous cycle affected during disuse atrophies and, if so, how are oestrous cycle changes related to musculoskeletal outcomes? What is the main finding and its importance? Rodent oestrous cycles were altered during disuse atrophy, which was correlated with musculoskeletal outcomes. However, the oestrous cycle did not appear to be changed by Lewis lung carcinoma, which resulted in no differences in muscle size in comparison to healthy control animals. These findings suggest a relationship between the oestrous cycle and muscle size during atrophic pathologies. ABSTRACT: Recent efforts have focused on improving our understanding of female muscle physiology during exposure to muscle atrophic stimuli. A key feature of female rodent physiology is the oestrous cycle. However, it is not known how such stimuli interact with the oestrous cycle to influence muscle health. In this study, we investigated the impact of muscle atrophic stimuli on the oestrous cycle and how these alterations are correlated with musculoskeletal outcomes. A series of experiments were performed in female rodents, including hindlimb unloading (HU), HU followed by 24 h of reloading, HU combined with dexamethasone treatment, and Lewis lung carcinoma. The oestrous cycle phase was assessed throughout each intervention and correlated with musculoskeletal outcomes. Seven or 14 days of HU increased the duration in dioestrus or metoestrus (D/M; low hormones) and was negatively correlated with gastrocnemius mass. Time spent in D/M was also negatively correlated with changes in grip strength and bone density after HU, and with muscle recovery 24 h after the cessation of HU. The addition of dexamethasone strengthened these relationships between time in D/M and reduced musculoskeletal outcomes. However, in animals with Lewis lung carcinoma, oestrous cyclicity did not differ from that of control animals, and time spent in D/M was not correlated with either gastrocnemius mass or tumour burden. In vitro experiments suggested that enhanced protein synthesis induced by estrogen might protect against muscle atrophy. In conclusion, muscle atrophic insults are correlated with changes in the oestrous cycle, which are associated with deterioration in musculoskeletal outcomes. The magnitude of oestrous cycle alterations depends on the atrophic stimuli.

Progenitor recruitment and adipogenic lipolysis contribute to the anabolic actions of parathyroid hormone on the skeleton.

Intermittent administration of parathyroid hormone (PTH) stimulates bone formation in vivo and also suppresses the volume of bone marrow adipose tissue (BMAT). In contrast, a calorie-restricted (CR) diet causes bone loss and induces BMAT in both mice and humans. We used the CR model to test whether PTH would reduce BMAT in mice by both altering cell fate and inducing lipolysis of marrow adipocytes. Eight-week-old mice were placed on a control (Ctrl) diet or CR diet. At 12 wk, CR and Ctrl mice were injected daily with PTH (CR/PTH or Ctrl/PTH) or vehicle for 4 wk. Two other cohorts were CR and simultaneously injected (CR + PTH or CR + Veh) for 4 wk. CR mice had low bone mass and increased BMAT in the proximal tibias. PTH significantly increased bone mass in all cohorts despite calorie restrictions. Adipocyte density and size were markedly increased with restriction of calories. PTH reduced adipocyte numbers in CR + PTH mice, whereas adipocyte size was reduced in CR/PTH-treated mice. In contrast, osteoblast number was increased 3-8-fold with PTH treatment. In vitro, bone marrow stromal cells differentiated into adipocytes and, treated with PTH, exhibited increased production of glycerol and fatty acids. Moreover, in cocultures of bone marrow adipocyte and osteoblast progenitors, PTH stimulated the transfer of fatty acids to osteoblasts. In summary, PTH administration to CR mice increased bone mass by shifting lineage allocation toward osteogenesis and inducing lipolysis of mature marrow adipocytes. The effects of PTH on bone marrow adiposity could enhance its anabolic actions by providing both more cells and more fuel for osteoblasts during bone formation.-Maridas, D. E., Rendina-Ruedy, E., Helderman, R. C., DeMambro, V. E., Brooks, D., Guntur, A. R., Lanske, B., Bouxsein, M. L., Rosen, C. J. Progenitor recruitment and adipogenic lipolysis contribute to the anabolic actions of parathyroid hormone on the skeleton.

The Central Role of Osteocytes in the Four Adaptive Pathways of Bone's Mechanostat.

We review evidence supporting an updated mechanostat model in bone that highlights the central role of osteocytes within bone's four mechanoadaptive pathways: 1) formation modeling and 2) targeted remodeling, which occur with heightened mechanical loading, 3) resorption modeling, and 4) disuse-mediated remodeling, which occur with disuse. These four pathways regulate whole-bone stiffness in response to changing mechanical demands.

Regional Changes in Density and Microarchitecture in the Ultradistal Tibia of Female Recruits After U.S. Army Basic Combat Training.

Musculoskeletal injuries, such as stress fracture, are responsible for over 10-million lost-duty days among U.S. Army Soldiers. During Basic Combat Training (BCT), an 8- to 10-week program that transforms civilians into Soldiers, women are four times more likely than men to sustain a stress fracture. In this work, we performed high-resolution peripheral quantitative computed tomography scans on the ultradistal tibia of 90 female recruits [age = 21.5 ± 3.3 (mean ± standard deviation) years] before the start of BCT and after 8 weeks into BCT. Then, we divided the scanned bone volume into four sectors-lateral, posterior, medial, and anterior-and computed the bone density and microarchitectural parameters in each of the four sectors pre- and post-BCT. We used linear mixed models to estimate the mean difference for bone density and microarchitectural parameters, while controlling for age, race, and pre-BCT body mass index. Our results revealed that the total volumetric bone mineral density, trabecular volumetric bone mineral density, and trabecular thickness increased (p < 0.05) in each of the four sectors. In addition, cortical thickness and trabecular bone volume/total volume increased in both medial and posterior sectors (p < 0.05). Overall, six and five out of nine parameters improved in the medial and posterior sectors, respectively, after BCT. In conclusion, the heightened physical activity during BCT led to the most beneficial bone adaptation in the medial and posterior sectors of the ultradistal tibia, which is indicative of higher loading in these sectors during activities performed in the course of BCT.

A prospective field study of U.S. Army trainees to identify the physiological bases and key factors influencing musculoskeletal injuries: a study protocol.

BACKGROUND: Musculoskeletal injuries (MSKIs) are common in military trainees and present a considerable threat to occupational fitness, deployability, and overall military readiness. Despite the negative effects of MSKIs on military readiness, comprehensive evaluations of the key known and possible risk factors for MSKIs are lacking. The U.S. Army Research Institute of Environmental Medicine (ARIEM) is initiating a large-scale research effort, the ARIEM Reduction in Musculoskeletal Injury (ARMI) Study, to better understand the interrelationships among a wide range of potential MSKI risk factors in U.S. Army trainees in order to identify those risk factors that most contribute to MSKI and may be best targeted for effective mitigation strategies. METHODS: This prospective study aims to enroll approximately 4000 (2000 male and 2000 female) U.S. Army trainees undergoing Basic Combat Training (BCT). Comprehensive in-person assessments will be completed at both the beginning and end of BCT. Participants will be asked to complete surveys of personal background information, medical history, physical activity, sleep behaviors, and personality traits. Physical measurements will be performed to assess anthropometrics, tibial microarchitecture and whole body bone mineral density, muscle cross-sectional area, body composition, and muscle function. Blood sampling will be also be conducted to assess musculoskeletal, genetic, and nutritional biomarkers of risk. In addition, participants will complete weekly surveys during BCT that examine MSKI events, lost training time, and discrete risk factors for injury. Participants' medical records will be tracked for the 2 years following graduation from training to identify MSKI events and related information. Research hypotheses focus on the development of a multivariate prediction model for MSKI. DISCUSSION: Results from this study are expected to inform current understanding of known and potential risk factors for MSKIs that can be incorporated into solutions that optimize Soldier health and enhance military readiness.

Oestrogen replacement improves bone mineral density in oligo-amenorrhoeic athletes: a randomised clinical trial.

OBJECTIVE: Normal-weight oligo-amenorrhoeic athletes (OAA) are at risk for low bone mineral density (BMD). Data are lacking regarding the impact of oestrogen administration on bone outcomes in OAA. Our objective was to determine the effects of transdermal versus oral oestrogen administration on bone in OAA engaged in weight-bearing activity. METHODS: 121 patients with OAA aged 14-25 years were randomised to receive: (1) a 17ß-estradiol transdermal patch continuously with cyclic oral micronised progesterone (PATCH), (2) a combined ethinyl estradiol and desogestrel pill (PILL) or (3) no oestrogen/progesterone (NONE). All participants received calcium and vitamin D supplementation. Areal BMD was assessed at the lumbar spine, femoral neck, total hip and total body less head using dual-energy X-ray absorptiometry at baseline, 6 and 12 months. Intention-to-treat (ITT) and completers analyses were performed. RESULTS: Randomised groups did not differ for age, body mass index or BMD Z-scores at baseline. For ITT analysis, spine and femoral neck BMD Z-scores significantly increased in the PATCH versus PILL (p=0.011 and p=0.021, respectively) and NONE (p=0.021 and p=0.033, respectively) groups, and hip BMD Z-scores significantly increased in the PATCH versus PILL group (p=0.018). Similar findings were noted in completers analysis. CONCLUSION: Transdermal estradiol over 12 months improves BMD in young OAA, particularly compared with an ethinyl estradiol-containing contraceptive pill/oral contraceptives. TRIAL REGISTRATION NUMBER: NCT00946192; Pre-results.

Loss of Intestinal Alkaline Phosphatase Leads to Distinct Chronic Changes in Bone Phenotype.

BACKGROUND: The gut is becoming increasingly recognized as the source of various systemic diseases, and recently, it has been linked to bone metabolism via the so-called gut-bone axis. The microbiome and gut-derived mediators are thought to impact upon bone metabolism, and administration of probiotics has been shown to have beneficial effects in bone. The gut brush border enzyme intestinal alkaline phosphatase (IAP) plays an important role in controlling calcium absorption, inhibiting lipopolysaccharides, and other inflammatory mediators responsible for endotoxemia and appears to preserve the normal gut microbiota. Interestingly, IAP-deficient mice (AKP3-/-) also display a significant decrease in fecal Lactobacillus, the genus shown to be beneficial to bone. MATERIALS AND METHODS: IAP mRNA levels in mouse bone were measured using quantitative real-time polymerase chain reaction. Femurs of IAP-knockout (KO) and wild-type (WT) mice were analyzed by microcomputed tomography and histopathology. Serum levels of alkaline phosphatase, calcium, and phosphorus were measured. Target cell response upon exposure to serum from IAP-KO and WT mice was quantified using primary bone marrow macrophages. RESULTS: IAP was not significantly expressed in bones of WT or KO animals. IAP (alkaline phosphatase 3) expression in bone was vanishingly low compared to the duodenum (bone versus duodenum, 56.9 ± 17.7 versus 25,430.3 ± 10,884.5 relative expression, P = 0.01). Bone histology of younger IAP-KO and WT animals was indistinguishable, whereas older IAP-deficient mice showed a distinctly altered phenotype on histology and computed tomography scan. Younger KO mice did not display any abnormal levels in blood chemistry. Older IAP-KO animals showed an isolated increase in serum alkaline phosphatase levels reflecting an environment of active bone formation (IAP-WT versus IAP-KO, 80 ± 27.4 U/I versus 453 ± 107.5 U/I, P = 0.004). There was no significant difference in serum calcium or phosphorus levels between KO and WT mice. Serum from IAP-KO mice induced a significantly higher inflammatory target cell response. CONCLUSIONS: Through its multiple functions, IAP seems to play a crucial role in connecting the gut to the bone. IAP deficiency leads to chronic changes in bone formation, most likely through dysbiosis and systemic dissemination of proinflammatory mediators.

Fracture Prediction by Computed Tomography and Finite Element Analysis: Current and Future Perspectives.

PURPOSE OF REVIEW: This review critiques the ability of CT-based methods to predict incident hip and vertebral fractures. RECENT FINDINGS: CT-based techniques with concurrent calibration all show strong associations with incident hip and vertebral fracture, predicting hip and vertebral fractures as well as, and sometimes better than, dual-energy X-ray absorptiometry areal biomass density (DXA aBMD). There is growing evidence for use of routine CT scans for bone health assessment. CT-based techniques provide a robust approach for osteoporosis diagnosis and fracture prediction. It remains to be seen if further technical advances will improve fracture prediction compared to DXA aBMD. Future work should include more standardization in CT analyses, establishment of treatment intervention thresholds, and more studies to determine whether routine CT scans can be efficiently used to expand the number of individuals who undergo evaluation for fracture risk.