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X-linked Hypophosphatemia (XLH) is the most common type of inherited rickets. Although the clinical features are well characterized, bone structure, mineralization, and biomechanical properties are poorly known. Our aim was to analyze bone properties in the appendicular and axial skeleton of adults with XLH. In this observational case-control study, each affected patient (N = 14; 9 females; age 50 ± 15 years) was matched by sex, age and body mass index to a minimum of two healthy controls (N = 34). Dual-energy X-ray Absorptiometry (DXA) analyses revealed that areal bone mineral density (aBMD) was higher in XLH patients at the lumbar spine (Z score mean difference = +2.47 SD, P value = 1.4 × 10−3). Trabecular Bone Score was also higher at the lumbar spine (P value = 1.0 × 10−4). High Resolution peripheral Quantitative Computed Tomography (HRpQCT) demonstrated that bone cross-sectional area was larger at the distal radius (P value = 6 × 10−3). Total and trabecular volumetric BMD were lower at both sites. Trabecular bone volume fraction was also lower with fewer trabecular numbers at both sites. However, bone strength evaluated by micro-finite element analyzes revealed unaffected bone stiffness and maximum failure load. Evaluation of bone mineralization with aBMD by DXA at the distal radius correlated with vBMD by HRpQCT measurements at both sites. PTH levels were inversely correlated with trabecular vBMD and BV/TV at the tibia. We then followed a subset of nine patients (median follow-up of 4 years) and reassessed HRpQCT. At the tibia, we observed a greater decrease than expected from an age and sex standardized normal population in total and cortical vBMD as well as a trabecularization of the cortical compartment. In conclusion, in adult patients with XLH, bone mineral density is high at the axial skeleton but low at the appendicular skeleton. With time, microarchitectural alterations worsen. We propose that noninvasive evaluation methods of bone mineralization such as DXA including the radius should be part of the management of XLH patients. Larger studies are needed to evaluate the clinical significance of BMD changes in XLH patients under conventional or targeted therapies. • Adults with XLH exhibit high BMD in the axial skeleton, normal BMD at the hip, and low BMD at the distal radius. • HR-pQCT parameters in adult XLH patients are correlated with DXA measurements at the hip and distal radius. • Longitudinal follow-up by HR-pQCT over 4 years indicate a deterioration in bone density and microarchitecture. • These negative changes in bone density and microarchitecture are more pronounced in post-menopausal women. • DXA of the distal radius is a potential marker in XLH adults and warrants further evaluation in clinical practice. [ABSTRACT FROM AUTHOR]

This work focuses on the growth patterns of the human fourth lumbar vertebra (L4) in a paediatric population, with specific attention to sexual dimorphism. The study aims to understand morphological and density changes in the vertebrae through age-dependent statistical shape and statistical appearance models, which can describe full three-dimensional anatomy. Results show that the main growth patterns are associated with isotropic volumetric vertebral growth, a decrease in the relative size of the vertebral foramen, and an increase in the length of the transverse processes. Moreover, significant sexual dimorphism was demonstrated during puberty. We observe significant age and sex interaction in the anterior vertebral body height (P = 0.005), where females exhibited an earlier increase in rates of vertebral height evolution. Moreover, we also observe an increase in cross-sectional area (CSA) with age (P = 0.020), where the CSA is smaller in females than in males (significant sex effect P = 0.042). Finally, although no significant increase in trabecular bone density with age is observed (P = 0.363), a trend in the statistical appearance model suggests an increase in density with age. • First statistical shape and statistical appearance model of a lumbar vertebra relating age and sex in a healthy population aged 9 to 19. • Similar height evolution trends observed in the total body height are also present at the individual vertebra level. • Significant difference in vertebral aspect ratio between sexes during growth • No significant variation in trabecular bone density with age and sex during growth [ABSTRACT FROM AUTHOR]

Osteoporotic fractures, prevalent in the elderly, pose a significant health and economic burden. Current methods for predicting fracture risk, primarily relying on bone mineral density, provide only modest accuracy. If better spatial resolution of trabecular bone in a clinical scan were available, a more complete assessment of fracture risk would be obtained using microarchitectural measures of bone (i.e. trabecular thickness, trabecular spacing, bone volume fraction, etc.). However, increased resolution comes at the cost of increased radiation or can only be applied at small volumes of distal skeletal locations. This study explores super-resolution (SR) technology to enhance clinical CT scans of proximal femurs and better reveal the trabecular microarchitecture of bone. Using a deep-learning-based (i.e. subset of artificial intelligence) SR approach, low-resolution clinical CT images were upscaled to higher resolution and compared to corresponding MicroCT-derived images. SR-derived 2-dimensional microarchitectural measurements, such as degree of anisotropy, bone volume fraction, trabecular spacing, and trabecular thickness were within 16 % error compared to MicroCT data, whereas connectivity density exhibited larger error (as high as 1094 %). SR-derived 3-dimensional microarchitectural metrics exhibited errors <18 %. This work showcases the potential of SR technology to enhance clinical bone imaging and holds promise for improving fracture risk assessments and osteoporosis detection. Further research, including larger datasets and refined techniques, can advance SR's clinical utility, enabling comprehensive microstructural assessment across whole bones, thereby improving fracture risk predictions and patient-specific treatment strategies. [ABSTRACT FROM AUTHOR]

The traditional understanding of bone mechanosensation implicates osteocytes, canaliculi, and the lacunocanalicular network in biomechanical adaptation. However, recent findings challenge this notion, as shown in advanced teleost fish where anosteocytic bone lacking osteocytes are nevertheless responsive to mechanical load. To investigate specific molecular mechanisms involved in bone mechanoadaptation in osteocytic and anosteocytic fish bone, we conducted a 5-min single swim-training experiment with zebrafish and ricefish, respectively. Through RNASeq analysis of fish spines, analyzed at various time points following swim training, we uncovered distinct gene expression patterns in osteocytic and anosteocytic fish bones. Notably, osteocytic fish bone exhibited an early response to mechanical load, contrasting to a delayed response observed in anosteocytic fish bones, both within 8 h following stimulation. We identified an increase in osteoblast differentiation in anosteocytic bone following training, while chordoblast activity was delayed. This temporal response suggests a time-dependent adaptation in anosteocytic bone, indicating the presence of intricate feedback networks within bone that lacks osteocytes. • Osteocytic and anosteocytic fish performed a single 5-minute swimming bout. • Osteocytic and anosteocytic fish bone has distinct gene expression patterns after swim training. • RNASeq reveals rapid increase in bone-related DEGs in osteocytic fish bone. • RNASeq reveals delayed expression of bone-related DEGs in anosteocytic fish bone. • The notion osteocytes are sole cells responsible for mechanoadaptation may require revision. [ABSTRACT FROM AUTHOR]

Hypercortisolism frequently induces trabecular bone loss, more pronounced at the lumbar spine, resulting in osteoporosis, and thus an increase in fracture risk. Several studies have shown bone mass recovery in patients with Cushing's disease (CD) after treatment. To examine treatment effects on TBS (trabecular bone score) in addition to aBMD (areal bone mineral density) in a cohort of patients with CD. Single-center retrospective longitudinal study in patients diagnosed with CD and successfully treated following surgery and/or medical treatment. We included 31 patients with median age and BMI (body mass index) of 37.7 [28.4;43.3] years old and 27.7 [25.8;30.4] kg/m2, respectively. Median 24 h urinary cortisol before treatment was 213.4 [168.5;478.5] μg/24 h. All subjects were completely biochemically controlled or cured after treatment. aBMD and TBS were evaluated at AP Spine (L1-L4) with DXA prodigy (GE-Lunar), QDR 4500 (Hologic), and TBS iNsight® (Med-Imaps) before and after treatment. Absolute TBS and aBMD gains following cure of CD were significant (p < 0.0001, and p < 0.001, respectively). aBMD and TBS increased by +3.9 and 8.2 % respectively after cure of CD. aBMD and TBS were not correlated before (p = 0.43) and after treatment (p = 0.53). Linear regression analyses showed that TBS gain was independent of baseline BMI and that low TBS at baseline was predictive of TBS gain after treatment. The more significant improvement of microarchitecture assessed by TBS than aBMD and the absence of correlation between TBS and aBMD suggest that TBS may be an adequate marker of bone restoration after cure of CD. To support this conclusion, future studies with larger sample sizes and longer follow-up periods should be carried out. • Trabecular Bone Score (TBS) is reduced in Cushing's disease (CD). • It significantly improves after cure of CD, more than bone mineral density (BMD). • TBS could be a better marker of bone microarchitecture damage in hypercortism. [ABSTRACT FROM AUTHOR]

Secondary hyperparathyroidism (SHPT) has adverse implications for bone health but is relatively understudied. In this study we examine the prevalence and determinants of SHPT and describe the relationship of SHPT with bone turnover markers and bone mineral density (BMD) in older Irish adults. Eligible participants (n = 4139) were identified from the Trinity-Ulster-Department of Agriculture (TUDA) study, a cohort of Irish adults aged ≥60 years. Exclusion criteria included an estimated glomerular filtration rate (eGFR) <30 ml/min and serum calcium >2.5 mmol/l to remove hyperparathyroidism due to advanced chronic kidney disease (CKD) and primary hyperparathyroidism respectively. The relationship between SHPT and bone turnover markers and BMD (measured by densitometry) was examined in a subsample (n = 1488). Vitamin D deficiency was defined as 25-hydroxyvitamin D [25 (OH)D] <30 nmol/l. Participants had a mean age of 73.6 ± 7.9 years, 65.1 % were female and 19.4 % were found to be vitamin D deficient. The prevalence of SHPT decreased as vitamin D increased, from 30.6 % in those deficient to 9.8 % in those with 25(OH)D ≥ 50 nmol/l and increased with declining kidney function. In non‑calcium supplement users, principal determinants of SHPT were vitamin D deficiency (OR 4.18, CI 3.05–5.73, p < 0.001), eGFR 30–44 ml/min (OR 3.69, CI 2.44–5.57, p < 0.001), loop diuretic use (OR 3.52, CI 2.59–4.79, p < 0.001) and to a lesser extent body mass index (p = 0.001), eGFR 45–59 ml/min (p < 0.001) and 25(OH)D level 30–49 nmol/l (p = 0.002). Similar findings were observed in calcium supplement users, though proton pump inhibitors were also associated with SHPT (OR 1.55, CI 1.08–2.22, p = 0.018) while vitamin D 30–49 nmol/l was not. In participants with SHPT versus those without, bone turnover markers were higher: bone alkaline phosphatase (p = 0.017) and tartrate-resistant acid phosphatase (p = 0.033), whilst there was lower BMD at the neck of femur (0.880 vs. 0.903 g/cm2, p = 0.033) and total hip (0.968 vs. 0.995 g/cm2, P = 0.017). The results show that up to one in six older Irish adults had SHPT and this was associated with lower BMD and higher concentrations of bone turnover markers. Both vitamin D deficiency and 25(OH)D level 30–49 nmol/l were important predictors of SHPT. Loop diuretics and PPIs may also increase the risk of SHPT, and their use may need to be carefully considered in this population. Further studies examining the potential impact of these factors on bone health in similar populations to our study sample are warranted. • Secondary hyperparathyroidism (SHPT) found in 16% of non-calcium supplement users, 9.9% of calcium supplement users. • SHPT associated with increased bone turnover markers. • SHPT associated with lower bone mineral density (BMD) at hip and neck of femur but not spine. • Higher parathyroid hormone levels within normal range also associated with higher bone turnover and lower BMD. • Predictors of SHPT were low vitamin D, renal impairment, loop diuretics, proton pump inhibitors, and body mass index. [ABSTRACT FROM AUTHOR]

Osteoporosis is a common condition that can lead to fractures, mobility issues, and death. Although dual-energy X-ray absorptiometry (DXA) is the gold standard for osteoporosis, it is expensive and not widely available. In contrast, kidney-ureter-bladder (KUB) radiographs are inexpensive and frequently ordered in clinical practice. Thus, it is a potential screening tool for osteoporosis. In this study, we explored the possibility of predicting the bone mineral density (BMD) and classifying high-risk patient groups using KUB radiographs. We proposed DeepDXA-KUB, a deep learning model that predicts the BMD values of the left hip and lumbar vertebrae from an input KUB image. The datasets were obtained from Taiwanese medical centers between 2006 and 2019, using 8913 pairs of KUB radiographs and DXA examinations performed within 6 months. The images were randomly divided into training and validation sets in a 4:1 ratio. To evaluate the model's performance, we computed a confusion matrix and evaluated the sensitivity, specificity, accuracy, precision, positive predictive value, negative predictive value, F1 score, and area under the receiver operating curve (AUROC). Moderate correlations were observed between the predicted and DXA-measured BMD values, with a correlation coefficient of 0.858 for the lumbar vertebrae and 0.87 for the left hip. The model demonstrated an osteoporosis detection accuracy, sensitivity, and specificity of 84.7 %, 81.6 %, and 86.6 % for the lumbar vertebrae and 84.2 %, 91.2 %, and 81 % for the left hip, respectively. The AUROC was 0.939 for the lumbar vertebrae and 0.947 for the left hip, indicating a satisfactory performance in osteoporosis screening. The present study is the first to develop a deep learning model based on KUB radiographs to predict lumbar spine and femoral BMD. Our model demonstrated a promising correlation between the predicted and DXA-measured BMD in both the lumbar vertebrae and hip, showing great potential for the opportunistic screening of osteoporosis. [ABSTRACT FROM AUTHOR]

There is some controversy regarding cytokines released from adipocytes, particularly adiponectin, leptin, and IL6 that regulate bone remodeling. In addition, IL6 is released from muscle contraction, which might have a distinct role in bone remodeling. Hence, this study investigated whether muscle contraction during a session of 40 min of high intensity interval training (40-min HIIT) and after 16 weeks of HIIT (16-wk HIIT) altered the release of those cytokines and bone remodeling in overweight women. In total, 22 overweight, premenopausal women were randomly assigned to either the exercise or the control group. The exercise participants engaged in the 40-min HIIT session at 80–90 % of their heart rate reserve (HRR) three times weekly for 16 weeks, while the control participants performed their routine daily activities. Blood was drawn after overnight fasting and immediately after completing the 40-min HIIT sessions to investigate the association of adiponectin, leptin, IL6, CTX, and P1NP through the acute effect of the 40-min HIIT sessions. This process was repeated after the 16-wk intervention program to observe the training effect of HIIT on cytokines linkage. The bone mineral density (BMD) levels of the distal tibia, femur, and lumbar spine were determined prior to and after the 16-wk intervention using dual-energy X-ray absorptiometry. The P1NP level increased by 8.29–20.52 % (95 % CI) and by 2.91–15.54 % after completing the first and last bouts of the 40-min HIIT sessions, respectively. In addition, IL6 increased by 13.39–28.03 % (95 % CI), while serum CTX and adiponectin were unaltered from the acute effect of the 40-min HIIT sessions. There was an association between the increases in P1NP and adiponectin (r = 0.682, p = 0.015); however, the increase in P1NP was mostly associated with the increase in IL6 (r = 0.572, p = 0.054) after completing a 40-min HIIT session. After the 16-wk HIIT program, the resting adiponectin level of the exercise participants increased; however, this was associated with neither bone biomarkers nor BMD. The BMDs of the exercise participants were maintained; however, the tibial BMD of the control participants decreased with an increase in the resting CTX level after 16 weeks. Muscle contraction during the 40-min HIIT session elevated the IL6 level, which might have subsequently enhanced bone formation. Furthermore, the association between acute changes in adiponectin and P1NP suggested the possibility of an increase in the sensitivity of the adiponectin receptor in osteoblasts. • The 40-min HIIT increased the release of myokine IL6 and adiponectin activation. • Elevated myokine IL6 and adiponectin activation induced bone formation. • The 16-wk HIIT increased adiponectin without changing resting P1NP and CTX levels. • The decrease of adiponectin in overweight promotes bone resorption. • Elevation of IL6 in overweight relates to the reduction of tibial BMD. [ABSTRACT FROM AUTHOR]

Mitofusin 2 (Mfn2) is one of two mitofusins involved in regulating mitochondrial size, shape and function, including mitophagy, an important cellular mechanism to limit oxidative stress. Reduced expression of Mfn2 has been associated with impaired osteoblast differentiation and function and a reduction in the number of viable osteocytes in bone. We hypothesized that the genetic absence of Mfn2 in these cells would increase their susceptibility to aging-associated metabolic stress, leading to a progressive impairment in skeletal homeostasis over time. Mfn2 was selectively deleted in vivo at three different stages of osteoblast lineage commitment by crossing mice in which the Mfn2 gene was floxed with transgenic mice expressing Cre under the control of the promoter for Osterix (OSX), collagen1a1, or DMP1 (Dentin Matrix Acidic Phosphoprotein 1). Mice in which Mfn2 was deleted using DMP1-cre demonstrated a progressive and dramatic decline in bone mineral density (BMD) beginning at 10 weeks of age (n = 5 for each sex and each genotype from age 10 to 20 weeks). By 15 weeks, there was evidence for a functional decline in muscle performance as assessed using a rotarod apparatus (n = 3; 2 males/ 1 female for each genotype), accompanied by a decline in lean body mass. A marked reduction in trabecular bone mass was evident on bone histomorphometry, and biomechanical testing at 25 weeks (k/o: 2 male/1 female, control 2 male/2 female) revealed severely impaired femur strength. Extensive regional myofiber atrophy and degeneration was observed on skeletal muscle histology. Electron microscopy showed progressive disruption of cellular architecture, with disorganized sarcomeres and a bloated mitochondrial reticulum. There was also evidence of neurodegeneration within the ventral horn and roots of the lumbar spinal cord, which was accompanied by myelin loss and myofiber atrophy. Deletion of Mfn2 using OSX-cre or Col1a1-cre did not result in a musculoskeletal phenotype. Where possible, male and female animals were analyzed separately, but small numbers of animals in each group limited statistical power. For other outcomes, where sex was not considered, small sample sizes might still limit the strength of the observation. Despite known functional overlap of Mfn1 and Mfn2 in some tissues, and their co-expression in bone, muscle and spinal cord, deletion of Mfn2 using the 8 kB DMP1 promoter uncovered an important non-redundant role for Mfn2 in maintaining the neuromuscular/bone axis. • Mitofusin 2 (Mfn2) plays a role in mitophagy and in the mitochondrial response to metabolic stress. • Deleting Mfn2 with an 8 kB DMP1-cre transgene caused bone loss, myopathy and neuropathy. • None of these changes were observed when Mfn2 was deleted with Col1a1-cre or OSX-cre. • DMP1-cre deleted Mfn2 in bone, muscle and spinal cord. • Mfn1 is expressed in these 3 tissues, but it didn't compensate for the loss of Mfn2. [ABSTRACT FROM AUTHOR]

Human evidence on the association between oxidative stress and osteoporosis is inconsistent. Fluorescent Oxidation Products (FlOPs) are global biomarkers of oxidative stress. We examined the associations of FlOPs (excitation/emission wavelengths 320/420 nm for FlOP_320, 360/420 nm for FlOP_360, and 400/475 nm for FlOP_400) with osteoporosis, bone microstructure, and bone turnover markers in humans and rats. In humans, we conducted a 1:2 age, sex, hospital, and specimen-matched case-control study to test the association between FlOPs and osteoporosis diagnosed from dual-energy X-ray absorptiometry. In eight-week-old male Wistar rats, we administrated D-galactose and 0.9 % saline for 90 days in treatment and control groups (n = 8/group); micro-CT was used to determine bone microstructure. In humans, higher levels of FlOP_320 (OR for per 1 SD increase = 1.49, 95 % CI: 1.01–2.20) and FlOP_360 (OR for per 1 SD increase = 1.59, 95 % CI: 1.07–2.37) were associated with increased odds of osteoporosis. FlOP_400 were not associated with osteoporosis. D-galactose treated rats, as compared with control rats, showed higher levels of FlOP_320 and MDA, and lower P1NP levels during 90 days of experiment (all P < 0.05). The D-galactose group had lower trabecular bone volume fraction (0.07 ± 0.03 vs. 0.13 ± 0.05; P = 0.008) and volumetric BMD (225.4 ± 13.8 vs. 279.1 ± 33.2 mg HA/cm3; P = 0.001) than the control group. In conclusion, higher FlOP_320 levels were associated with increased odds of osteoporosis, impaired bone microstructure and decreased bone formation. • Fluorescent Oxidation Products (FlOPs) are global biomarkers of oxidative stress. • FlOPs at 320/420 nm (FlOP_320) were positively associated with osteoporosis. • Greater levels of FlOP_320 were associated with impaired bone microstructure. • Higher levels of FlOP_320 were associated with decreased bone formation. [ABSTRACT FROM AUTHOR]

Most postmenopausal women who sustain fragility fracture (Fx) have their areal bone mineral density (BMD) above the osteoporosis threshold. A sizeable proportion of them have normal aBMD. This study aimed to prospectively investigate the association of fragility Fx with bone microarchitecture (MA) assessed by high-resolution peripheral computed tomography (HR-pQCT) in postmenopausal women without low BMD. At the 14th annual follow-up of the OFELY study, we measured bone MA at the distal radius and tibia with HR-pQCT in addition to areal BMD with DXA, in 586 postmenopausal women. Among them, 166 (29 %) women, mean (SD) age 65 (8) yr, had normal BMD defined as a T score ≥ −1 at the lumbar spine, femoral neck, and total hip. During a median [IQR] 15 [14–15] yr of follow-up, 46 of those women sustained incident fragility Fx, including 19 women with a major osteoporotic Fx (clinical spine, forearm, proximal humerus, hip). Women who sustained Fx did not differ for age, BMI, tobacco and alcohol use, diabetes, falls, FRAX®, aBMD, and TBS compared with women without incident Fx. In contrast, they had significant impairment of volumetric densities, cortical area (Ct. Ar) and thickness (Ct. Th), stiffness (K), and estimated failure load (FL) at the radius compared with women without incident Fx. At the radius, each SD decrease of volumetric densities, Ct.Ar, Ct.Th, K, and estimated FL were significantly associated with an increased risk of all fragility fractures with hazard ratios (HR) from 1.44 to 1.56 and of major osteoporotic fractures (HR from 1.66 to 2.57). Lesser impairment of bone MA was seen at the tibia. We conclude that even in women with normal areal BMD fragility fractures are associated with deterioration of bone microarchitecture. • Study of bone microarchitecture in postmenopausal women with normal BMD • Women who sustain incident fracture have deteriorated bone microarchitecture. • This deterioration was greater for major osteoporotic fractures. • This deterioration was more obvious at the distal radius compared to the tibia site. [ABSTRACT FROM AUTHOR]

Bone Health Index (BHI) has been proposed as a useful instrument for assessing bone health in children. However, its relationship with fracture risk remains unknown. We aimed to investigate whether BHI is associated with bone mineral density (BMD) and prevalent fracture odds in children from the Generation R Study. We also implemented genome-wide association study (GWAS) and polygenic score (PGS) approaches to improve our understanding of BHI and its potential. In total, 4150 children (49.4 % boys; aged 9.8 years) with genotyped data and bone assessments were included in this study. BMD was measured across the total body (less head following ISCD guidelines) using a GE-Lunar iDXA densitometer; and BHI was determined from the hand DXA scans using BoneXpert®. Fractures were self-reported collected with home questionnaires. The association of BHI with BMD and fractures was evaluated using linear models corrected for age, sex, ethnicity, height, and weight. We observed a positive correlation between BHI and BMD (ρ = 0.32, p-value<0.0001). Further, every SD decrease in BHI was associated with an 11 % increased risk of prevalent fractures (OR:1.11, 95 % CI 1.00–1.24, p-value = 0.05). Our BHI GWAS identified variants (lead SNP rs1404264-A, p-value = 2.61 × 10−14) mapping to the ING3/CPED1/WNT16 locus. Children in the extreme tails of the BMD PGS presented a difference in BHI values of −0.10 standard deviations (95% CI -0.14 to −0.07; p-value<0.0001). On top of the demonstrated epidemiological association of BHI with both BMD and fracture risk, our results reveal a partially shared biological background between BHI and BMD. These findings highlight the potential value of using BHI to screen children at risk of fracture. [ABSTRACT FROM AUTHOR]

The use of proton pump inhibitors (PPIs) has been associated with an increased fracture risk in observational studies. However, the reported association between PPI use and bone mineral density (BMD), bone microarchitecture, and bone strength is inconsistent. This study aims to assess the association between PPI use and bone microarchitecture and strength using high-resolution peripheral quantitative CT (HR-pQCT) in a three-year follow-up study in patients with a recent fracture visiting the Fracture Liaison Service (FLS). This three-year prospective cohort study included FLS patients aged ≥ 50 years with a recent fracture (median age 62 [IQR 56–69] years, 68.7 % females) and without anti-osteoporosis treatment indication. HR-pQCT scans (distal radius and tibia) were obtained at baseline (T0) and three-year follow-up (T3). Volumetric bone mineral density and bone area, microarchitecture, and strength (micro-finite element analysis) were determined. The association between three-year continuous PPI use and the percentage change in HR-pQCT parameters between T0 and T3 was assessed using sex-stratified multivariate linear regression analyses. Covariates included age, BMI, vitamin-D deficiency (< 50 nmol/l), glucocorticoid use, and cardiovascular co-morbidity (males and females) fracture type (major/hip vs. all others, only males) and probable sarcopenia (only females). In total, 282 participants had available medication data throughout follow-up, of whom 20.6 % were continuous PPI users. In both males and females with complete HR-pQCT follow-up data (males: N = 69 radius, N = 84 tibia; females: N = 147 radius, N = 168 tibia), PPI use was not associated with the percentage change of any of the bone microarchitecture or strength parameters between T0 and T3 at the radius and tibia as compared to non-use. Compared to non-use, PPI use was not associated with the change of bone microarchitecture and strength in FLS patients at three years of follow-up. These results do not support that an altered bone microarchitecture or strength may contribute to the increased fracture risk associated with PPI use, as reported in observational studies. • We assessed the association between PPI use and bone microarchitecture and strength. • The association was assessed in a three-year prospective follow-up study of FLS patients. • Included were 282 patients with a recent fracture, of which 20 % PPI users. • PPI use was not associated with the three-year change in bone microarchitecture and strength. • The results do not support the previously reported increased fracture risk in PPI users. [ABSTRACT FROM AUTHOR]

Down syndrome (DS), affecting ∼1 in 800 live births, is caused by the triplication of human chromosome 21 (Hsa21). Individuals with DS have skeletal features including craniofacial abnormalities and decreased bone mineral density (BMD). Lowered BMD can lead to increased fracture risk, with common fracture points at the femoral neck and lumbar spine. While the femur has been studied in DS mouse models, there is little research done on the vertebrae despite evidence that humans with DS have affected vertebrae. Additionally, it is important to establish when skeletal deficits occur to find times of potential intervention. The Dp(16)1Yey DS mouse model has all genes triplicated on mouse chromosome 16 orthologous to Hsa21 and displayed deficits in long bone, including trabecular and cortical deficits in male but not female mice, at 12 weeks. We hypothesized that the long bone and lumbovertebral microarchitecture would exhibit sexually dimorphic deficits in Dp(16)1Yey mice compared to control mice and long bone strength would be diminished in Dp(16)1Yey mice at 6 weeks. The trabecular region of the 4th lumbar (L4) vertebra and the trabecular and cortical regions of the femur were analyzed via micro-computed tomography and 3-point bending in 6-week-old male and female Dp(16)1Yey and control mice. Trabecular and cortical deficits were observed in femurs from male Dp(16)1Yey mice, and cortical deficits were seen in femurs of male and female Dp(16)1Yey mice. Male Dp(16)1Yey femurs had more deficits in bone strength at whole bone and tissue-estimate level properties, but female Dp(16)1Yey mice were also affected. Additionally, the L4 of male and female Dp(16)1Yey mice show trabecular deficits, which have not been previously reported in a DS mouse model. Our results indicate that skeletal deficits associated with DS occur early in skeletal development, are dependent on skeletal compartment and site, are sex dependent, and potential interventions should likely begin early in skeletal development of DS mouse models. [Display omitted] • Dp(16)1Yey mice model lumbar spine traits found in with Down syndrome. • Down syndrome mouse model skeleton is affected early in bone development. • Both the axial (lumbar vertebrae) and appendicular (femur) are affected. • There is a sexual dimorphism depending on skeletal site and bone compartment. • Mechanics of femur are affected in both sexes at the whole bone and tissue level. [ABSTRACT FROM AUTHOR]

Conventional bone imaging methods primarily use X-ray techniques to assess bone mineral density (BMD), focusing exclusively on the mineral phase. This approach lacks information about the organic phase and bone water content, resulting in an incomplete evaluation of bone health. Recent research highlights the potential of ultrashort echo time magnetic resonance imaging (UTE MRI) to measure cortical porosity and estimate BMD based on signal intensity. UTE MRI also provides insights into bone water distribution and matrix organization, enabling a comprehensive bone assessment with a single imaging technique. Our study aimed to establish quantifiable UTE MRI-based biomarkers at clinical field strength to estimate BMD and microarchitecture while quantifying bound water content and matrix organization. Femoral bones from 11 cadaveric specimens (n = 4 males 67–92 yrs of age, n = 7 females 70–95 yrs of age) underwent dual-echo UTE MRI (3.0 T, 0.45 mm resolution) with different echo times and high resolution peripheral quantitative computed tomography (HR-pQCT) imaging (60.7 μm voxel size). Following registration, a 4.5 mm HR-pQCT region of interest was divided into four quadrants and used across the multi-modal images. Statistical analysis involved Pearson correlation between UTE MRI porosity index and a signal-intensity technique used to estimate BMD with corresponding HR-pQCT measures. UTE MRI was used to calculate T 1 relaxation time and a novel bound water index (BWI), compared across subregions using repeated measures ANOVA. The UTE MRI-derived porosity index and signal-intensity-based estimated BMD correlated with the HR-pQCT variables (porosity: r = 0.73, p = 0.006; BMD: r = 0.79, p = 0.002). However, these correlations varied in strength when we examined each of the four quadrants (subregions, r = 0.11–0.71). T 1 relaxometry and the BWI exhibited variations across the four subregions, though these differences were not statistically significant. Notably, we observed a strong negative correlation between T 1 relaxation time and the BWI (r = −0.87, p = 0.0006). UTE MRI shows promise for being an innocuous method for estimating cortical porosity and BMD parameters while also giving insight into bone hydration and matrix organization. This method offers the potential to equip clinicians with a more comprehensive array of imaging biomarkers to assess bone health without the need for invasive or ionizing procedures. • UTE MRI porosity index correlated with porosity measured by HRpQCT. • Estimated BMD based on UTE MRI signal intensity correlated with HRpQCT BMD. • UTE MRI could additionally quantify bound water. • T 1 relaxation time by UTE MRI varied across cortical bone specimens. • UTE MRI could provide a comprehensive imaging evaluation of bone health. [ABSTRACT FROM AUTHOR]

Osteoporosis poses a major public health challenge, and it is characterized by low bone mass, deterioration of the microarchitecture of bone tissue, causing a consequent increase in bone fragility and susceptibility to fractures and complicating bone fixation, particularly screw implantation. In the present study, our aim was to improve implant stability in osteoporotic bone using a thermoresponsive hyaluronan hydrogel (HA-pNIPAM) to locally deliver the bisphosphonate zoledronic acid (ZOL) to prevent bone resorption and bone morphogenetic protein 2 (BMP2) to induce bone formation. Adult female Wistar rats (n = 36) were divided into 2 treatment groups: one group of SHAM-operated animals and another group that received an ovariectomy (OVX) to induce an osteoporotic state. All animals received a polyetheretherketone (PEEK) screw in the proximal tibia. In addition, subgroups of SHAM or OVX animals received either the HA-pNIPAM hydrogel without or with ZOL/BMP2, placed into the defect site prior to screw implantation. Periprosthetic bone and implant fixation were monitored using longitudinal in vivo microCT scanning post-operatively and at 3, 6, 9, 14, 20 and 28 days. Histological assessment was performed post-mortem. Our data showed that pure hydrogel has no impact of implant fixation The ZOL/BMP2-hydrogel significantly increased bone-implant contact and peri-implant bone fraction, primarily through reduced resorption. Local delivery of ZOL and BMP2 using a biocompatible hydrogel improved implant stability in osteoporotic bone. This approach could constitute a potent alternative to systemic drug administration and may be useful in avoiding implant loosening in clinical settings. • We sought to enhance implant stability in osteoporotic rats by using a thermoresponsive hyaluronan hydrogel (HA-pNIPAM) as a local delivery system. • Pure HA-pNIPAM did not affect peri-implant bone nor contralateral bone, confirming its biocompatibility for this application. • We used a combination of zoledronic acid and bone morphogenetic protein 2 (ZOL/BMP2) to induce both an osteogenic response and prevent bone resorption. • ZOL/BMP2-releasing HA-pNIPAM enhanced implant fixation in OVX animals to levels comparable or superior to those observed in SHAM animals. [ABSTRACT FROM AUTHOR]

Bone Mineral Density (BMD) is an important parameter in the development of orthopedic fracture-healing methods. A recent article (Inoue, S., et al. Bone. 2023, 177, 116916) investigated the use of higher intensity ultrasound to promote murine bone formation by measuring BMD levels. In this work, we present the numerical values of BMD, which show sigmoid kinetics and hyperbolic asymptotic increase with the application of higher intensity ultrasound. Our analysis may provide a foundation for the understanding and application of ultrasound to the human body. [ABSTRACT FROM AUTHOR]

Osteoporosis is characterized by low bone mineral density (BMD), which predisposes individuals to frequent fragility fractures. Quantitative BMD measurements can potentially help distinguish bone pathologies and allow clinicians to provide disease-relieving therapies. Our group has developed non-invasive and non-ionizing magnetic resonance imaging (MRI) techniques to measure bone mineral density quantitatively. Dual-energy X-ray Absorptiometry (DXA) is a clinically approved non-invasive modality to diagnose osteoporosis but has associated disadvantages and limitations. Evaluate the clinical feasibility of phosphorus (31P) MRI as a non-invasive and non-ionizing medical diagnostic tool to compute bone mineral density to help differentiate between different metabolic bone diseases. Fifteen ex-vivo rat bones in three groups [control, ovariectomized (osteoporosis), and vitamin-D deficient (osteomalacia - hypo-mineralized) were scanned to compute BMD. A double-tuned (1H/31P) transmit-receive single RF coil was custom-designed and in-house-built with a better filling factor and strong radiofrequency (B 1) field to acquire solid-state 31P MR images from rat femurs with an optimum signal-to-noise ratio (SNR). Micro-computed tomography (μCT) and gold-standard gravimetric analyses were performed to compare and validate MRI-derived bone mineral densities. Three-dimensional 31P MR images of rat bones were obtained with a zero-echo-time (ZTE) sequence with 468 μm spatial resolution and 12–17 SNR on a Bruker 7 T Biospec having multinuclear capability. BMD was measured quantitatively on cortical and trabecular bones with a known standard reference. A strong positive correlation (R = 0.99) and a slope close to 1 in phantom measurements indicate that the densities measured by 31P ZTE MRI are close to the physical densities in computing quantitative BMD. The 31P NMR properties (resonance linewidth of 4 kHz and T 1 of 67 s) of ex-vivo rat bones were measured, and 31P ZTE imaging parameters were optimized. The BMD results obtained from MRI are in good agreement with μCT and gravimetry results. Quantitative measurements of BMD on ex-vivo rat femurs were successfully conducted on a 7 T preclinical scanner. This study suggests that quantitative measurements of BMD are feasible on humans in clinical MRI with suitable hardware, RF coils, and pulse sequences with optimized parameters within an acceptable scan time since human femurs are approximately ten times larger than rat femurs. As MRI provides quantitative in-vivo data, various systemic musculoskeletal conditions can be diagnosed potentially in humans. • There are no satisfactory non-ionizing and non-invasive methods to quantify BMD accurately in patients. • We report the feasibility of 31PMRI as a non-ionizing diagnostic tool to compute BMD. • Quantitative measurements of BMD are feasible on humans in clinical MRI with suitable hardware and pulse sequences within an acceptable scan time [ABSTRACT FROM AUTHOR]

Introduction: Poor cognitive function and osteoporosis commonly co-exist in later life. In women, this is often attributed to post-menopausal estrogen loss. However, a common early life origin for these conditions and the associations between cognitive function and bone mineral density (BMD) in childhood have not previously been explored. We examined these relationships at age 6-7 years in the Southampton Women's Survey (SWS) mother-offspring cohort., Methods: Child occipitofrontal circumference (OFC), a proxy for brain volume, intelligence quotient (IQ) [Wechsler Abbreviated Scale of Intelligence] and visual recognition and working memory [CANTAB® Delayed Matching to Sample (DMS) and Spatial Span Length (SSP), respectively] were assessed. Whole-body-less-head (WBLH) and lumbar spine dual-energy X-ray absorptiometry [Hologic Discovery] (DXA) were performed to measure bone area (BA), bone mineral content (BMC), BMD and bone mineral apparent density (BMAD). Linear regression was used to examine associations between age and sex standardized variables (β represent standard deviation (SD) difference per SD of cognitive function)., Results: DXA was performed in 1331 children (mean (SD) age 6.8 (0.33) years, 51.5 % male), with OFC, IQ, DMS and SSP assessed in 1250, 551, 490 and 460, respectively. OFC (β = 0.25 SD/SD, 95%CI 0.20,0.30), IQ (β = 0.11 SD/SD, 95%CI 0.02,0.19), and DMS (β = 0.11, SD/SD, 95%CI 0.01,0.20) were positively associated with WBLH BA, with similar associations for lumbar spine BA. OFC and DMS were also positively associated with WBLH BMC, but only OFC was associated with BMD (WBLH: β = 0.38 SD/SD, 95%CI 0.33,0.43; LS: β = 0.19 SD/SD, 95%CI 0.13,0.24)., Conclusion: Childhood brain volume was positively associated with measures of skeletal size and BMD, whereas IQ and memory were associated only with skeletal size. These findings suggest that common early life determinants for skeletal growth and BMD and cognitive function should be explored to identify potential early-life approaches to preventing osteoporosis and cognitive decline., Competing Interests: Declaration of competing interest RJM has received travel bursaries from Kyowa Kirin unrelated to this work. KMG has received reimbursement for speaking at conferences sponsored by companies selling nutritional products, and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, BenevolentAI Bio Ltd. and Danone, outside the submitted work. JHD has received travel bursaries from Novo Nordisk, SANDOZ and Pfizer unrelated to this work. CC reports personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, UCB, Kyowa Kirin, Consilient Healthcare and Internis Pharma, outside the submitted work. SD, CG, MF and SRC declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic kidney disease (CKD) causes a progressive loss of muscle and bone mass, which frequently overlap with and affect clinical outcomes. However, the impact of sarcopenia, low bone mineral density (BMD; osteopenia or osteoporosis), and osteosarcopenia (sarcopenia and low BMD) on CKD progression is yet to be determined. We aimed to address these issues in patients with CKD without kidney replacement therapy (KRT). This prospective cohort study included 251 outpatients aged ≥65 years with CKD without KRT enrolled in our hospital between June 2016 and March 2017. Sarcopenia was defined according to the 2014 criteria of the Asian Working Group for Sarcopenia (AWGS), and low BMD was defined as a T-score of ≤−1.0. The patients were divided into four groups: normal (no sarcopenia/normal BMD), only low BMD (no sarcopenia/low BMD), only sarcopenia (sarcopenia/normal BMD), and osteosarcopenia (sarcopenia/low BMD). The primary outcome was a composite of all-cause deaths, initiating KRT, and admissions owing to major adverse cardiovascular and cerebrovascular events (MACEs). The secondary outcome was a kidney composite outcome that included a 30 % reduction in creatinine-based estimated glomerular filtration rate (eGFR) and initiating KRT. The outcome risk was determined using the Cox regression models adjusted for potential confounders. Median age (25th–75th percentile) and eGFR of the outpatients (35 % women) were 76 (69–81) years and 32.1 (20.8–41.7) ml/min/1.73 m2, respectively. During a median follow-up period of 5.2 years, there were 22 deaths, 117 30 % eGFR reductions, 48 KRTs, and 18 admissions owing to MACEs. The osteosarcopenia group rather than the only low BMD or only sarcopenia groups exhibited a higher risk of the primary (hazard ratio [HR]: 3.28, 95 % confidence interval [CI]: 1.52–7.08) and kidney composite (HR: 2.07, 95 % CI: 1.10–3.89) outcomes. Among the osteosarcopenia-related body compositions and physical functions, low handgrip strength (HGS) was strongly associated with a high risk of primary and kidney composite outcomes (HR: 2.44, 95 % CI: 1.46–4.08; HR: 1.48, 95 % CI: 0.97–2.24, respectively). The increase in HGS but not the body mass index, skeletal muscle mass index, or BMD was associated with lower risks of primary and kidney composite outcomes (HR: 0.93, 95 % CI: 0.89–0.98; HR: 0.96, 95 % CI: 0.92–0.99 per 1 kg, respectively). Osteosarcopenia was associated with poor survival and kidney outcomes in older patients with CKD. Low HGS, which is common in patients with osteosarcopenia and CKD, was associated with increased mortality risk and kidney function decline. These findings can help the risk prediction and pathogenesis of the kidney–bone–muscle axis and improving muscle strength can help mitigate CKD progression. • This study showed the effect of BMD, muscle mass, and physical functions on outcomes in older adults. • Osteosarcopenia was linked to risks of death, ESKD, and admissions owing to MACEs. • Low HGS common in osteosarcopenia was strongly related to mortality and CKD progression. • Integrating muscle and bone information helps the risk prediction in older CKD adults. • Improving muscle strength can help mitigate CKD progression. [ABSTRACT FROM AUTHOR]

BoneXpert (BX) performs digital radiogrammetry and reports metacarpal index (MCI) besides bone age (BA) evaluation. Its utility in subjects with type-1 diabetes (T1D) has not been reported. We conducted this study with following objectives: 1) To study the utility of BX in the assessment of BA in Indian children and youth (CY) with T1D and 2) To assess association of MCI (measured by BX) and bone health in Indian CY with T1D. The MCI and BA were assessed retrospectively in 1272 subjects with T1D using digitalised left-hand x-rays. The demographic, anthropometric, clinical, dietary, biochemistry, dual x-ray absorptiometry (DXA) data and peripheral quantitative computed tomography (pQCT) data collection were performed using standard protocols and were extracted from hospital records. The root mean square error of BX with respect to reference and true bone age by TW-3 method were estimated to be 0.72 years and 0.67 years respectively in Indian CY with T1D. The BX provided MCI results were in concordance with the DXA derived bone mineral density (r = 0.551) and pQCT derived cortical density (r = 0.318) measurements; MCI correlated with trabecular density at the tibia (r = 0.212). 51.5 % subjects with T1D had significantly decreased MCI. Height, tanner stage, vitamin D concentrations showed positive correlation while HbA1c and disease duration had negative correlation with MCI. BX may be used for accurate assessment of BA by TW-3 method and for screening for bone health in Indian CY with T1D. • The metacarpal index (MCI) in half the children with type 1 diabetes was low (<−2sds). • MCI had a positive correlation with DXA (BMD), pQCT (trabecular density) parameters. • MCI was negatively corelated with glycaemic control. • Height and tanner stage influenced MCI. • Vitamin D concentrations showed a significant positive correlation with the MCI-SDS. [ABSTRACT FROM AUTHOR]

To investigate the skeletal phenotype of adolescent girls with premature ovarian insufficiency (POI). Data are presented from two adolescent girls who participated in a clinical research protocol to evaluate axial bone mineral density (BMD) (via dual-energy x-ray absorptiometry, DXA) and appendicular bone density, microarchitecture, and strength (via high-resolution peripheral quantitative computed tomography, HRpQCT). Anthropometric data were also obtained, and pubertal staging was performed by a clinician. Both cases presented with an undetectable estradiol concentration and an elevated follicle stimulating hormone (FSH), meeting the criteria for POI. Each also received alkylating agents as part of their chemotherapy and radiotherapy, but in different locations as one presented with stage IV neuroblastoma and the other, metastatic medulloblastoma. Both had a low BMD of the axial and appendicular skeleton, as well as microarchitectural changes of the latter. The low BMD Z-score (<−2.0) seen when interpreting their DXA measurements for chronological age improved when adjusted for short stature, but it was not normalized. Lastly, most variables obtained by HRpQCT were abnormal for each participant, indicating that appendicular bone structure and strength were compromised. Chemotherapy and radiation affect growth, puberty, and bone accrual deleteriously. However, as these cases show, POI in an adolescent is not always classic primary ovarian insufficiency. Adolescents with brain cancer can present with signs of estrogen deficiency but may not be able to secrete FSH to the extent of elevation typically seen in long-term cancer survivors. Estrogen deficiency is almost universally present in either clinical setting and prompt recognition facilitates early provision of hormone replacement therapy that may then allow for a resumption of bone accrual as an adolescent approaches her peak bone mass. [ABSTRACT FROM AUTHOR]

The excess fracture risk observed in adults with type 1 diabetes (T1D) is inexplicable in the presence of only modest reductions in areal bone mineral density (BMD). Accumulation of advanced glycation endproducts (AGEs) in bone has been invoked as one explanation for the increased bone fragility in diabetes. The evidence linking AGEs and fractures in individuals with T1D is sparse, although the association has been observed in individuals with type 2 diabetes. Recent data show that in T1D, AGEs as measured by skin intrinsic fluorescence, are a risk factor for lower BMD. Further research in T1D is needed to ascertain whether there is a causal relationship between fractures and AGEs. If confirmed, this would pave the way for finding interventions that can slow AGE accumulation and thus reduce fractures in T1D. [ABSTRACT FROM AUTHOR]

Bone fragility in sickle cell disease (SCD) has been previously reported even in young patients, but the clinical consequences and specific management remain unclear. The objective of this study was to assess the prevalence of bone fragility in sickle cell patients and to evaluate the potential risk factors and associated complications. We conducted a single-center cross-sectional study. Bone mineral densitometry (BMD) at the lumbar spine and the hip, Vertebral Fracture Assessment (VFA) and biological measurements were performed in patients aged between 20 and 40 years. One hundred and thirty-eight patients with sickle cell disease were included between June 2020 and December 2021. One hundred and one patients (73.2 %) were from Sub-Saharan Africa, 13 from North Africa (9.4 %), 11 from the Caribbean (7.9 %), 6 from the Indian Ocean. A Z -score < −2 was found in 43 patients (31.2 %) at the lumbar spine, in 4 patients (3 %) at the total hip, and in 5 patients (3.7 %) at the femoral neck. 59 patients (46.8 %) had vertebral deformities. Fragility fractures were recorded in 9 patients (10.8 %). Patients with low BMD had lower BMI (21.3 (19.0, 24.0) versus 24.0 (20.7, 26.1) Kg/m2, p = 0.003), lower osteonecrosis history (7 % versus 25.3 %, p = 0.011) and lower hemoglobin levels (9.0 (8.0, 10.0) versus 10.0 (9.0, 11.0) g/dL, p < 0.01). No association was found between history of fracture and low BMD. Young patients with SCD commonly have low BMD at the lumbar spine, but the prevalence of fragility fracture was low. Low BMD - specifically at the spine - may not be tantamount to bone fragility. • The importance of bone fragility in patients with sickle cell disease remains unclear. • About a third of young patients in our population have low bone mineral density. • No association with fragility fractures in patients with low bone mineral density. • Low bone mineral density is not sufficient to assess their bone fragility. [ABSTRACT FROM AUTHOR]

Severe osteoporosis is often treated with one of three Food and Drug Administration (FDA)-approved osteoanabolics. These drugs act by (1) parathyroid hormone (PTH) receptor stimulation using analogues to PTH (teriparatide) or PTH-related peptide (abaloparatide) or by (2) monoclonal antibody neutralization of sclerostin, an innate Wnt inhibitor (Scl-mAb, romosozumab-aqqg). The efficacies of both strategies wane over time. The transcription factor Nmp4 (Nuclear Matrix Protein 4) is expressed in all tissues yet mice lacking this gene are healthy and exhibit enhanced PTH-induced bone formation. Conditional deletion of Nmp4 in mesenchymal stem progenitor cells (MSPCs) phenocopies the elevated response to PTH in global Nmp4 −/− mice. However, targeted deletion in later osteoblast stages does not replicate this response. In this study we queried whether loss of Nmp4 improves Scl-mAb potency. Experimental cohorts included global Nmp4 −/− and Nmp4 +/+ littermates and three conditional knockout models. Nmp4 -floxed (Nmp4 fl/fl ) mice were crossed with mice harboring one of three Cre-drivers (i) Prx1Cre + targeting MSPCs, (ii) BglapCre + (mature osteocalcin-expressing osteoblasts), and (iii) Dmp1Cre + (osteocytes). Female mice were treated with Scl-mAb or 0.9 % saline vehicle for 4 or 7 weeks from 10 weeks of age. Skeletal response was assessed using micro-computed tomography, dual-energy X-ray absorptiometry, bone histomorphometry, and serum analysis. Global Nmp4 −/− mice exhibited enhanced Scl-mAb-induced increases in trabecular bone in the femur and spine and a heightened increase in whole body areal bone mineral density compared to global Nmp4 +/+ controls. This improved Scl-mAb potency was primarily driven by enhanced increases in bone formation. Nmp4 fl/fl ;PrxCre+ mice showed an exaggerated Scl-mAb-induced increase in femoral bone but not in the spine since Prrx1 is not expressed in vertebra. The Nmp4 fl/fl ;BglapCre + and Nmp4 fl/fl ;Dmp1Cre+ mice did not exhibit an improved Scl-mAb response. We conclude that Nmp4 expression in MSPCs interferes with the bone anabolic response to anti-sclerostin therapy. [Display omitted] • FDA-approved osteoanabolics include PTH, PTHrp and sclerostin antibody (Scl-mAb). • These drugs have distinct mechanisms of action, but all rapidly lose efficacy. • Earlier we showed conditional loss of Nmp4 in MSPCs improves PTH-induced bone gain. • Deletion of Nmp4 in later osteoblast stages did not replicate this response. • In this study Nmp4 −/− MSPCs similarly improved Scl-mAb-induced bone gain. • We conclude Nmp4 sets osteoanabolic potency early in osteoblast differentiation. [ABSTRACT FROM AUTHOR]

There is a controversy over the influence of psychostimulant medications on bone mineral density (BMD) and bone mineral content (BMC) among children with attention-deficit-hyperactivity-disorder (ADHD). The aim of the present systematic review was to assess the influence of psychostimulant medications on BMD and BMC among children with ADHD. A comprehensive search of electronic databases, including PubMed, Scopus, Embase, and Cochrane Library, was conducted to identify relevant studies published up until July 2023. Clinical studies that addressed the focused question "Do psychostimulant medications affect bone mineral density and content in children with ADHD?" were included. Letters to the Editor, studies on animal-models, ex-vivo and in-vitro studies, commentaries and reviews were excluded. The primary outcome measures were changes in BMD and BMC. Study quality was assessed using the risk of bias for non-randomized studies-exposure tool. Five non-randomized clinical studies were included. The number of participants ranged from 18 to 6489 with mean ages ranging from 7.3 to 13.75 years. The study durations ranged between five and seven years. In all studies osseous evaluation was done using dual-energy X-ray absorptiometry. The bone locations examined included total body, lumbar-spine, femur, femoral-neck, femoral body, and pelvis. Two studies reported that psychostimulant medications reduce BMC and BMD. In one study, bone turnover, serum leptin and fat levels were reduced in children using psychostimulant medications but no unusual reduction recorded among controls. In general, 80 % of the studies concluded that psychostimulant medications compromise BMC and BMD. Power analysis was done in one study. One study had a low RoB and the remaining demonstrated some concerns. Given the methodological concerns observed in the included studies, arriving at a definitive conclusion regarding the effects of psychostimulant medications on BMC, BMD, and bone turnover in children with ADHD is challenging. However, it is important to acknowledge that an association between psychostimulant medications and these bone-related parameters cannot be disregarded., Competing Interests: Declaration of competing interest The authors declare that they have no conflict/s of interest related to the present study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Bone disorders may affect the skeleton in different ways, some bones being very impaired and others less severely. In translational studies using murine models of human skeletal diseases, the bone phenotype is mainly evaluated at the distal femur or proximal tibia. The sacroiliac joint (SIJ), which connects the spine to the pelvis, is involved in the balanced transfer of mechanical energy from the lumbar spine to the lower extremities. Because of its role in biomechanical stress, the SIJ is a region of particular interest in various bone diseases. Here we aimed to characterize the SIJ in several murine models to develop a highly reliable tool for studying skeletal disorders. We performed a 12-month in vivo micro-computed tomography (micro-CT) follow-up to characterize the SIJ in wild-type (WT) C57BL/J6 mice and compared the bone microarchitecture of the SIJ and the distal femur at 3 months by micro-CT and histology. To test the sensitivity of our methodology, the SIJ and distal femur were evaluated at 3 and 6 months, in 2 murine models of skeletal disorder, X-linked hypophosphatemia (Hyp mice) and HLA-B27 transgenic mice and compared to WT mice. A multimodal analysis was performed, using a combination of microCT and histological analysis. With the Hyp model, the SIJ displayed more bone microarchitecture alterations than the distal femur. Hyp mice showed a significant reduction in trabecular bone at both the distal femur and sacral slope as compared with WT mice, with a significant positive correlation between trabecular bone parameters of the distal femur and sacral side of the SIJ. Furthermore, trabecular bone parameters (Bone Volume/Total Volume (BV/TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), trabecular number (Tb.N), trabecular pattern factor (Tb.Pf)) were significantly increased compared to femoral parameters at the SIJ. The sacral articular cortical bone, which is indicative of osteoarticular lesions, was altered in Hyp mice. Interestingly, in accordance to previous studies, HLA-B27 transgenic mice did not show any osteoarticular lesions as compared with WT mice. Cortical bone parameters (thickness, porosity), as well as scoring performed with double blinding, did not show difference between the 2 genotypes. The characterization and evaluation of the SIJ surface appears very sensitive to emphasize alterations of bone and joint. The SIJ may represent a valuable tool to investigate both bone and local osteoarticular alterations in murine models of skeletal disorders and might be a relevant site for assessing the response to treatment of chronic bone diseases., Competing Interests: Declaration of competing interest Nothing to disclose for each author., (Copyright © 2023. Published by Elsevier Inc.)

Bone responds to mechanical loading by increasing bone mineral density (BMD) and/or bone area to enhance bone strength at the site of the greatest strain. Such localised adaptation has not been demonstrated at the spine. The aim of this study is to determine if BMD and/or bone mineral content (BMC) differs between dominant (ipsilateral to bowling/throwing arm) and non-dominant sides of the vertebrae in cricket fast bowlers, and whether this asymmetry differs according to stress fracture or disc injury history. A further aim was to determine if regional BMD and BMC in the lumbar spine differ between fast bowlers, other cricketers, rugby players and non-active controls, to highlight the site-specific response of lumbar vertebra to unilateral activity. 23 fast bowlers, 14 other cricketers, 22 rugby players and 20 controls underwent an antero-posterior (AP) and lateral DXA scans of their lumbar spine to assess BMD, BMC and area. A custom analysis measured BMD and BMC of the dominant and non-dominant sides (lateral 33%) of the AP lumbar spine. BMD and BMC were compared between groups, injury status, vertebrae and sides using ANOVA. Analysis of medical records showed that 6 fast bowlers had a history of lumbar stress fracture. Significantly greater BMD and BMC was found in the L4 non-dominant vertebra compared with the dominant vertebra in fast bowlers. BMD and BMC differed significantly according to vertebra, side and group, with fast bowlers having significantly greater BMD and BMC at the L3 and L4 non-dominant vertebra compared with other groups (L3: 13.3%–45.3%, L4: 15.7%–44.0%) compared with other groups. Fast bowlers who never suffered lumbar stress fracture had 3.6% and 1.7% greater BMD in the dominant and non-dominant sides of lumbar vertebrae respectively compared with those who did suffer lumbar stress fracture, but evidence of this was weaker (P = 0.08). The lumbar spine responds to a unique unilateral high loading activity through site-specific increased bone mass at the site of most strain. Fast bowlers had increased lumbar BMD, particularly on the non-dominant side of L4, although this adaptation was less marked in those with history of lumbar stress fracture. Site-specific low bone mineral density within the lumbar side may be implicated in the aetiology of lumbar stress fracture. • Cricket fast bowlers have greater BMD and BMC at the non-dominant (contralateral to bowling arm) side of the lumbar spine • This asymmetry increases in magnitude caudally, significantly differing to the dominant side at L4 • Fast bowlers have significantly greater BMD and BMC than rugby players at the non-dominant side of L2, L3 and L4 only • Reduced site-specific bone mineral accrual may be a risk factor to lumbar stress fracture in fast bowlers [ABSTRACT FROM AUTHOR]

In osteoporosis patients, antiresorptive treatments such as alendronate reduce the resorption of trabecular bone and thus minimize vertebral fracture risk. However, fracture risk reduction efficacy of antiresorptive drugs varies between skeletal sites and is highest for vertebral bone. In human vertebrae, cancellous bone is distributed heterogeneously between regions. This microstructural heterogeneity is changing with patient age and is likely to play a major role in vertebral failure mechanisms and fracture susceptibility. Whether antiresorptive treatment affects the heterogeneity of vertebral microstructure in osteoporosis has not been unraveled. Our aim was to assess whether antiresorptive treatment would have a region-dependent influence on vertebral trabecular bone. Therefore, we used high-resolution peripheral quantitative computed tomography (HR-pQCT), microcomputed tomography (microCT) and uniaxial compression testing to determine the structure and mechanical properties of trabecular bone cores from anterior and posterior regions of 22 lumbar vertebrae from elderly osteoporotic women. We analyzed age-matched ex vivo bone samples from bisphosphonate-treated female osteoporosis patients (age: 82 ± 7y, bisphosphonate treatment period: 4 ± 2 years) along treatment-naïve female controls (82 ± 7y). MicroCT analysis showed a significantly lower bone volume fraction (p = 0.006) and lower trabecular number (p = 0.003) for the anterior bone cores compared to posterior bone cores in the treatment-naïve group. The bisphosphonate-treated group had a more homogeneous bone volume distribution and did not show significant regional differences in bone volume, it however also displayed significantly different trabecular numbers (p = 0.016). In bone cores of the bisphosphonate-treated group, trabeculae were thicker in comparison to treatment-naïve controls (p = 0.011). Differences in bone volume further resulted in different maximum forces during compression testing between the samples. In addition, the percental difference between BV/TV μCT in anterior and posterior bone cores was lower in bisphosphonate-treated vertebrae when vertebrae with directly adjacent fractures (n = 3) were excluded. In conclusion, regional trabecular bone microstructure in lumbar vertebrae of bisphosphonate-treated women was more homogeneous compared to treatment-naïve controls. Bisphosphonate treatment, which specifically targets resorption surfaces common in anterior vertebral bone, might have resulted in a region-specific preservation of vertebral microstructure and loading capacity. This could have positive implications for the reduction of wedge fracture risk and add to the explanation of the higher efficacy of fracture risk reduction in vertebrae in comparison to other fracture regions. • Vertebral microstructural homogenization may help to explain bisphosphonates' high efficacy in reducing fractures risk. • After bisphosphonate treatment, regional microstructure and load-bearing capacity appears more balanced in vertebra. • Lumbar vertebrae from osteoporotic women display weaker microstructure in anterior regions. • Weaker anterior microstructure in vertebrae coincides with loss of load-bearing capacity. [ABSTRACT FROM AUTHOR]

Vertebral compression fracture (VCF) is a common and severe complication of osteogenesis imperfecta (OI). We prospectively observe the changes of vertebral shape during zoledronic acid (ZOL) treatment and assess influence factors of VCF in OI children. 32 children with VCF and 10 children without VCF (NVCF) were included and given ZOL treatment for 2 years, who were matched in age and gender. Control group included 17 treatment naïve OI patients with VCF who were matched in age, gender and clinical severity to 17 patients in VCF group received ZOL treatment for 1 year (as ZOL treated group). We performed quantitative vertebral morphometry and calculated concavity index (mh/ph), height-length ratio (ah/LL, mh/LL, ph/LL) and projection area (PA) of vertebrae from T4 to L4 before and after treatment. At baseline, patients in VCF group had significantly lower PA, mh/ph, ah/LL, mh/LL and ph/LL than patients in NVCF group (P < 0.01). PA, mh/ph, ah/LL, mh/ LL and ph/LL of patients with VCF were raised by (35.2 ± 19.5)%, (22.9 ± 15.1)%, (19.6 ± 13.9)%, (33.6 ± 25.5)%, and (8.1 ± 8.8)% (P < 0.01) after 1-year treatment of ZOL, and were increased by (71.8 ± 28.2)%, (42.8 ± 21.8)%, (35.1 ± 20.6)%, (65.4 ± 43.2)%, and (12.5 ± 11.4)% after 2-year treatment of ZOL (P < 0.01). Compared to control group, mh/ph, ah/LL and mh/LL were significantly higher (P < 0.01) in ZOL treated group. LS-BMD and its increase were positively correlated to vertebral height and PA at baseline and the improvement of vertebral height and PA after ZOL treatment, respectively. In conclusion, the compressive vertebrae of OI children could be effectively reshaped during ZOL treatment. Low LS-BMD was an independent risk factor for VCF and its increase was positively correlated to the improvement in vertebral shape after ZOL treatment. • The compressive vertebrae of osteogenesis imperfecta (OI) children could be reshaped during zoledronic acid treatment. • Low lumbar spine bone mass density (LS-BMD) was the independent risk factor of vertebral compression fracture (VCF). • The increase in LS-BMD was positively correlated to the improvement in vertebral shape after zoledronic acid treatment. • Our study made a useful exploration of the accurate diagnosis and effective treatment of VCF in OI children. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) improves survival in men with advanced prostate cancer (PCa), but has been associated with compromised skeletal health and increased fracture risk. However, limited previous research has investigated determinants of bone strength beyond DXA-derived areal bone mineral density (aBMD) in this population group. The aim of this cross-sectional study was to investigate the effects of ADT in men with PCa on BMD, bone structure, estimates of whole bone strength and cortical bone distribution. A total of 70 ADT-treated men, 52 PCa controls and 70 healthy controls had DXA lumbar spine and proximal femur aBMD and pQCT distal (4%) and proximal (66%) tibia and radius cortical and trabecular volumetric BMD (vBMD), bone structure, strength and cortical bone distribution assessed. Analyses included BMI and/or tibia/radius length as covariates. On average, ADT-treated men had a higher BMI than PCa (P < 0.05) but not healthy controls. ADT-treated men had 7.2–7.8% lower lumbar spine aBMD than PCa (P = 0.037) and healthy controls (P = 0.010), with a trend for a lower total hip aBMD in the ADT-treated men (P = 0.07). At the distal tibia, total bone area was 6.2–7.3% greater in ADT-treated men than both controls (P < 0.01), but total vBMD was 8.4–8.7% lower in ADT-treated men than both controls (P < 0.01). Moreover, bone strength index (BSI) was 10.8% lower relative to healthy controls only (P < 0.05). At the distal radius, ADT-treated men had lower total and trabecular vBMD (10.7–14.8%, P < 0.05) and BSI (23.6–27.5%, P < 0.001) compared to both controls. There were no other differences in bone outcomes at the proximal tibia or radius. In conclusion, ADT treatment for PCa was associated with lower BMD and estimated compressive bone strength, particularly at trabecular skeletal sites (lumbar spine, and distal tibia and radius), compared to controls, but there were no consistent differences in cortical bone structure, distribution or bending strength. • Bone density, structure, strength and distribution were compared between prostate cancer men treated with androgen deprivation therapy (ADT) and controls. • ADT treated men had lower bone density and estimated compressive strength at trabecular skeletal sites compared to controls. • Cortical bone structure, strength and distribution did not differ between ADT treated men and controls. [ABSTRACT FROM AUTHOR]

LRP5 encodes low-density lipoprotein receptor-related protein 5 (LRP5). When LRP5 with a Frizzled receptor join on the surface of an osteoblast and bind a member of the Wnt family of ligands, canonical Wnt/β-catenin signaling occurs and increases bone formation. Eleven heterozygous gain-of-function missense mutations within LRP5 are known to prevent the LRP5 inhibitory ligands sclerostin and dickkopf1 from attaching to LRP5's first β-propeller, and thereby explain the rare autosomal dominant (AD) skeletal disorder "high bone mass" (HBM). LRP6 is a cognate co-receptor of LRP5 and similarly controls Wnt signaling in osteoblasts, yet the consequences of increased LRP6-mediated signaling remain unknown. We investigated two multi-generational American families manifesting the clinical and routine laboratory features of LRP5 HBM but without an LRP5 defect and instead carrying a heterozygous LRP6 missense mutation that would alter the first β-propeller of LRP6. In Family 1 LRP6 c.602C>T, p.A201V was homologous to LRP5 HBM mutation c.641C>T, p.A214V, and in Family 2 LRP6 c.553A>C, p.N185H was homologous to LRP5 HBM mutation c.593A>G, p.N198S but predicting a different residue at the identical amino acid position. In both families the LRP6 mutation co-segregated with striking generalized osteosclerosis and hyperostosis. Clinical features shared by the seven LRP6 HBM family members and ten LRP5 HBM patients included a broad jaw, torus palatinus, teeth encased in bone and, reportedly, resistance to fracturing and inability to float in water. For both HBM disorders, all affected individuals were taller than average for Americans (Ps < 0.005), but with similar mean height Z-scores (P = 0.7606) and indistinguishable radiographic skeletal features. Absence of adult maxillary lateral incisors was reported by some LRP6 HBM individuals. In contrast, our 16 patients with AD osteopetrosis [i.e., Albers-Schönberg disease (A-SD)] had an unremarkable mean height Z-score (P = 0.9401) lower than for either HBM group (Ps < 0.05). DXA mean BMD Z-scores in LRP6 HBM versus LRP5 HBM were somewhat higher at the lumbar spine (+7.8 vs +6.5, respectively; P = 0.0403), but no different at the total hip (+7.9 vs +7.7, respectively; P = 0.7905). Among the three diagnostic groups, only the LRP6 HBM DXA BMD values at the spine seemed to increase with subject age (R = +0.7183, P = 0.0448). Total hip BMD Z-scores were not significantly different among the three disorders (Ps > 0.05), and showed no age effect (Ps > 0.1). HR-pQCT available only for LRP6 HBM revealed indistinct corticomedullary boundaries, high distal forearm and tibial total volumetric BMD, and finite element analysis predicted marked fracture resistance. Hence, we have discovered mutations of LRP6 that cause a dento-osseous disorder indistinguishable without mutation analysis from LRP5 HBM. LRP6 HBM seems associated with generally good health, providing some reassurance for the development of anabolic treatments aimed to enhance LRP5/LRP6-mediated osteogenesis. • LRP6 and LRP5 are cognate cell-surface receptors for Wnt/β-catenin signaling. • Activating mutations in LRP5 cause autosomal dominant "high bone mass" (HBM). • We found that mutations in LRP6 can mimic LRP5 HBM. • The features of LRP6 HBM seem reassuring for bone anabolic therapy development. [ABSTRACT FROM AUTHOR]

Leptin, a small polypeptide hormone secreted by the adipocytes, controls body weight and gonadal function by binding to a special receptor located in the hypothalamus. Observational studies have demonstrated a controversial association between leptin and bone mineral density (BMD), and functional studies of the relationship between leptin and BMD still largely vary by different studies. Using SNPs strongly associated with leptin levels in 52,140 individuals, we conducted a two-sample Mendelian randomization study to identify whether genetically lowered leptin levels were associated with BMD by using an inverse-variance weighted method, a weighted median method, MR-Egger and Robust Adjusted Profile Score. We found that circulating leptin levels may causally decrease lumbar spine BMD (effect size = −0.45, 95% CI: −0.82, −0.083; p value = 0.016). The association estimates of circulating leptin levels on femoral neck, forearm and total body BMD were not significant. Our study suggests that genetically predicted higher circulating leptin was associated with lower LS-BMD. • We inferred the causal relationship between leptin and BMD in large samples by using summary statistics from GWAS. • We estimated the causal relationships between leptin and BMD at different skeletal sites. • Four methods of Mendelian randomization were used to examine the causal relationship between leptin and BMD. [ABSTRACT FROM AUTHOR]

Anastrozole has been shown to prevent breast cancer in postmenopausal women at high risk of the disease, but has been associated with substantial accelerated loss of bone mineral density (BMD) and increased fractures. Here, we investigate the effect of risedronate on BMD after 5 years of follow-up in the IBIS-II prevention trial. 1410 women were enrolled in the bone sub-study and stratified into three strata according to the lowest baseline T-score at spine or femoral neck. The objective was to compare the effect of oral risedronate (35 mg weekly) versus placebo in osteopenic women in stratum II who were randomised to anastrozole in the main study. 258 osteopenic, postmenopausal women at high risk of developing breast cancer for whom baseline and follow-up bone mineral density measurements were available. 5-year mean BMD change at the lumbar spine for osteopenic women randomised to anastrozole and risedronate was −0.4% compared to −4.2% for those not on risedronate (P < 0.0001) but not significantly different between risedronate users and non-users at the hip (P = 0.2). 5-year mean PINP change was −20% for those randomised to anastrozole and risedronate compared to 3% for those not on risedronate but on anastrozole (P < 0.0001). Our results confirm the bone loss associated with the use of anastrozole and show that anastrozole-induced BMD loss in the spine can be controlled with risedronate treatment. However, our results suggest that weekly oral risedronate is unable to completely prevent anastrozole induced bone loss at the hip. • Results confirm anastrozole induced bone mineral density decrease in women at increased risk of developing breast cancer • Risedronate counterbalances the negative effect of anastrozole induced bone mineral density loss at the lumbar spine • Long-term intake of risedronate did not prevent bone loss at the total hip in osteopenic women • N-Terminal Propeptide of Type I Collagen (PINP) can predict bone mineral density changes [ABSTRACT FROM AUTHOR]

It has been demonstrated that bone mineral density (BMD) loss is substantial within the first 12 months after allogeneic hematopoietic stem cell transplantation (alloHSCT). Declines in BMD showed a disproportionate cortical bone loss even though trabecular bone is metabolically more active than cortical bone. This finding suggests a unique mechanism. However, the structural bone deficits after alloHSCT have not been well characterized. The trabecular bone score (TBS) has emerged as a method to assess bone microarchitecture. The aim of this study was to evaluate the changes in BMD and TBS in patients who received alloHSCT with follow-up of two years. All patients 18 years and older who received alloHSCT between 2009 and 2015 at Seoul St. Mary's Hospital, Korea were included. They were segregated into a first group (A, n = 24) that was evaluated for BMD at the time of alloHSCT and 12 months posttransplant and a second group (B, n = 44) that was evaluated for BMD at 12 and 24 months following alloHSCT. Subjects in group A experienced a decrease in BMD at the femoral neck and total hip between the time of transplantation and 12 months posttransplantation: 0.056 ± 0.057 (5.48%) and 0.072 ± 0.063 (6.84%), respectively. Subjects in group B experienced an increase in BMD at the lumbar spine and total hip between 12 and 24 months post-alloHSCT: 0.047 ± 0.064 (4.90%) and 0.017 ± 0.045 (2.16%), respectively. In group A, TBS at 12 months post-alloHSCT decreased 0.028 ± 0.067 (1.92%) from the baseline (p = 0.086). In group B, TBS at 24 months post-alloHSCT increased 0.010 ± 0.049 (0.78%) from the 12 months post-alloHSCT evaluation (p = 0.149). TBS change was positively associated with BMD changes at all measured sites. The cumulative dose of glucocorticoid therapy was associated with loss of BMD at all measured sites and TBS. In addition, the dose of total body irradiation (TBI) was negatively associated with TBS. In summary, this study delineated longitudinal microarchitectural changes in bone structure occurring in the context of alloHSCT. TBS change per 12 months was insignificant during the two years following alloHSCT. Therefore, our data represented disproportionate cortical bone loss in the context of the microarchitecture. • Before alloHSCT, 29% of patients had a partially degraded TBS. • TBS at 12 and 24 months post-alloHSCT insignificantly changed -1.92% and +0.78% from the baseline and 12 months post-alloHSCT, respectively. • TBS change was associated with BMD changes at all measured sites, cumulative dose of glucocorticoids, and TBI. [ABSTRACT FROM AUTHOR]

Patients with epilepsy frequently develop hyponatremia due to the treatment with antiepileptic drugs and have an increased risk of developing metabolic bone disease. Hyponatremia is known to be associated with osteoporosis. The aim of the study was to investigate the association between hyponatremia and osteoporosis in patients with epilepsy. This cross-sectional study included patients with epilepsy from a tertiary epilepsy out-patient clinic in Denmark, who had a Dual Energy X-ray Absorptiometry scan performed and an accompanying plasma sodium (p-Na) measured prior to or a maximum of 14 days after the scan. Information regarding the patients' health and medical conditions were obtained from their medical reports. A total of 695 patients (females 53.8%, age 49 (34:63) years (median (quartiles)) were included. 10.4% had hyponatremia (p-Na ≤ 135 mmol/L). The hyponatremic patients had significantly lower T-scores in the lumbar spine, femoral neck and total femur (all p < 0.023) and the odds ratio of osteoporosis (T-score < −2.5) was significantly increased (2.91 (1.61–5.27) (95% confidence interval) (p = 0.001)). When adjusting for potential confounders the patients with moderate and severe hyponatremia (p-Na < 129 mmol/L) had a significantly lower mean T-score in the lumbar spine (p = 0.030). We conclude that hyponatremia is common in patients with epilepsy and that moderate and severe hyponatremia is independently associated with decreased bone mineral density in the lumbar spine. Therefore, hyponatremia in a patient with epilepsy should warrant further examination of the patient for bone loss and osteoporosis. • Hyponatremia occurs frequently (10.4%) in patients with epilepsy. • Moderate and severe hyponatremia (p-Na ≤ 129 mmol/L) is independently associated with decreased BMD in the lumbar spine. • Hyponatremia in patients with epilepsy should warrant further examination of the patient's bone health to exclude or treat existing osteoporosis. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have repeatedly identified genetic variants associated with bone mineral density (BMD) and osteoporotic fracture in non-coding regions of C7ORF76, a poorly studied gene of unknown function. The aim of the present study was to elucidate the causality and molecular mechanisms underlying the association. We re-sequenced the genomic region in two extreme BMD groups from the BARCOS cohort of postmenopausal women to search for functionally relevant variants. Eight selected variants were tested for association in the complete cohort and 2 of them (rs4342521 and rs10085588) were found significantly associated with lumbar spine BMD and nominally associated with osteoporotic fracture. cis -eQTL analyses of these 2 SNPs, together with SNP rs4727338 (GWAS lead SNP in Estrada et al., Nat Genet. 44:491–501, 2012), performed in human primary osteoblasts, disclosed a statistically significant influence on the expression of the proximal neighbouring gene SLC25A13 and a tendency on the distal SHFM1. We then studied the functionality of a putative upstream regulatory element (UPE), containing rs10085588. Luciferase reporter assays showed transactivation capability with a strong allele-dependent effect. Finally, 4C-seq experiments in osteoblastic cell lines showed that the UPE interacted with different tissue-specific enhancers and a lncRNA (LOC100506136) in the region. In summary, this study is the first one to analyse in depth the functionality of C7ORF76 genomic region. We provide functional regulatory evidence for the rs10085588, which may be a causal SNP within the 7q21.3 GWAS signal for osteoporosis. • Two SNPs in the C7ORF76 genomic region (rs4342521 and rs10085588) were statistically associated with BMD in the BARCOS cohort. • rs4342521, rs10085588 and rs4727338 may be eQTLs of SLC25A13 on human primary osteoblasts. • A regulatory element containing rs10085588 (UPE) is able to stimulate transcription in an allele-dependent manner. • UPE interacts with other enhancers in the region and with a lncRNA previously found associated with BMD. [ABSTRACT FROM AUTHOR]

Abstract Duchenne Muscular Dystrophy (DMD) is a progressive muscle disorder caused by genetic mutations of the dystrophin encoding gene. In the absence of functional dystrophin, DMD patients suffer from muscle inflammation and wasting, as well as compromised bone health with increased risk of fracture. The use of high dose glucocorticoids (GC) as the standard therapy also contributes to bone fragility. This study examined the effects of intermittent, daily administered parathyroid hormone (iPTH), an approved bone anabolic therapy, on growing bone and dystrophic muscle in the presence and absence of prednisone treatment using the Mdx mouse model of DMD. Five-weeks of prednisone treatment in Mdx mice decreased cortical bone thickness and area (p < 0.001), with a large increase in endocortical osteoclasts that were significantly improved by PTH treatment (p < 0.001). GC-induced decreases in cortical bone toughness and modulus were improved with iPTH therapy (p < 0.05). Mdx mice showed significantly less bone mass in trabecular compartments of lumbar vertebrae and iPTH treatment, with or without glucocorticoids, significantly improved structural and material properties of this bone. Prednisone improved grip strength and endurance of treadmill running, which were maintained and further improved, respectively, in co-treated Mdx mice. Altogether, our study demonstrates that iPTH therapy significantly ameliorated GC-induced bone loss and maintained or further enhanced the positive effects of GCs on dystrophic muscle function. These findings give insight into the potential for use of teriparatide to treat growing bone in children with DMD. Highlights • Vertebral bone density and toughness are improved by PTH in Mdx mice. • Glucocorticoids decrease cortical bone thickness and toughness are increased by PTH. • PTH treatment decreased inflammatory gene expression in skeletal muscle. • PTH increased type 1 and decreased type 2c skeletal muscle fibers in Mdx mice. [ABSTRACT FROM AUTHOR]

Abstract Over the past two decades, a low frequency variant (rs1800012) within the first intron of the type I collagen alpha 1 (COLIA1) gene has been implicated in lower areal BMD (aBMD) and increased risk of osteoporotic fracture. This association is particularly strong in postmenopausal women, in whom net bone loss arises in the context of high bone turnover. High bone turnover also accompanies childhood linear growth; however, the role of rs1800012 in this stage of net bone accretion is less well understood. Thus, we assessed the association between rs1800012 and aBMD and bone mineral content (BMC) Z -scores for the 1/3 distal radius, lumbar spine, total hip, and femoral neck total body less head in the Bone Mineral Density in Childhood Study, a mixed-longitudinal cohort of children and adolescents (total n = 804 girls and 771 boys; n = 19 girls and 22 boys with the TT genotype). Mixed effects modeling, stratified by sex, was used to test for associations between rs1800012 and aBMD or BMC Z -scores and for pubertal stage interactions. Separately, SITAR growth modeling of aBMD and BMC in subjects with longitudinal data reduced the complex longitudinal bone accrual curves into three parameters representing a-size , b-timing , and c-velocity. We tested for differences in these three parameters by rs1800012 genotype using t -tests. Girls with the TT genotype had significantly lower aBMD and BMC Z -scores prior to puberty completion (e.g. spine aBMD-Z P-interaction = 1.0 × 10−6), but this association was attenuated post-puberty. SITAR models revealed that TT girls began pubertal bone accrual later (b-timing ; e.g. total hip BMC, P = 0.03). BMC and aBMD Z-scores also increased across puberty in TT homozygous boys. Our data, along with previous findings in post-menopausal women, suggest that rs1800012 principally affects female bone density during periods of high turnover. Insights into the genetics of bone gain and loss may be masked during the relatively quiescent state in mid-adulthood, and discovery efforts should focus on early and late life. Highlights • Sp1 COL1A1 variant rs1800012 associates with pediatric bone density. • Using longitudinal data, we found that this variant delays bone accrual in girls. • Mirrors postmenopausal reports, suggesting impact in high bone turnover states • Genetic discovery efforts should focus on variants acting during bone gain and loss. [ABSTRACT FROM AUTHOR]

Abstract Background NF-κB essential modulator (NEMO), encoded by IKBKG , is necessary for activation of the ubiquitous transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Animal studies suggest NEMO is required for NF-κB mediated bone homeostasis, but this has not been thoroughly studied in humans. IKBKG loss-of-function mutation causes incontinentia pigmenti (IP), a rare X-linked disease featuring linear hypopigmentation, alopecia, hypodontia, and immunodeficiency. Single case reports describe osteopetrosis (OPT) in boys carrying hypomorphic IKBKG mutations. Method We studied the bone phenotype in women with IP with evaluation of radiographs of the spine and non-dominant arm and leg; lumbar spine and femoral neck aBMD using DXA; μ-CT and histomorphometry of trans-iliac crest biopsy specimens; bone turnover markers; and cellular phenotype in bone marrow skeletal (stromal) stem cells (BM-MSCs) in a cross-sectional, age-, sex-, and BMI-matched case-control study. X-chromosome inactivation was measured in blood leucocytes and BM-MSCs using a PCR method with methylation of Hpa II sites. NF-κB activity was quantitated in BM-MSCs using a luciferase NF-κB reporter assay. Results Seven Caucasian women with IP (age: 24–67 years and BMI: 20.0–35.2 kg/m2) and IKBKG mutation (del exon 4–10 (n = 4); c.460C>T (n = 3)) were compared to matched controls. The IKBKG mutation carriers had extremely skewed X-inactivation (>90:10%) in blood, but not in BM-MSCs. NF-κB activity was lower in BM-MSCs from IKBKG mutation carriers (n = 5) compared to controls (3094 ± 679 vs. 5422 ± 1038/μg protein, p < 0.01). However, no differences were identified on skeletal radiographics, aBMD, μ-architecture of the iliac crest, or bone turnover markers. The IKBKG mutation carriers had a 1.7–fold greater extent of eroded surfaces relative to osteoid surfaces (p < 0.01), and a 2.0–fold greater proportion of arrested reversal surface relative to active reversal surface (p < 0.01). Conclusion Unlike mutation-positive males, the IKBKG mutation-positive women did not manifest OPT. Highlights • Opposite to boys, women with IKBKG (NEMO) mutations did not present an osteopetrosis bone phenotype. • IKBKG mutation-positive women had a greater extent of eroded bone surfaces relative to osteoid surfaces. • In IKBKG mutation carriers, X-inactivation was extremely skewed (>90:10%) in blood, but not in BM-MSCs. [ABSTRACT FROM AUTHOR]

Abstract Weekly teriparatide treatment is reported to reduce the incidence of osteoporotic vertebral fractures. However, the effect of weekly teriparatide on cortical bone has not been clarified. This study aimed to examine the effects of weekly teriparatide treatment on bone mass, intracortical structure, and remodeling of the lumbar vertebral cortical shell and its relation to mechanical properties in ovariectomized cynomolgus monkeys. Female monkeys, aged 9 to 15 years, were divided into four groups: (1) SHAM group, (2) ovariectomized group (OVX group), (3) OVX with 1.2 μg/kg once-weekly teriparatide group (LOW group), (4) OVX with 6.0 μg/kg once-weekly teriparatide group (HIGH group). After 18 months, all animals were double-labeled with calcein, and lumbar vertebrae were analyzed with histomorphometry and compressive mechanical tests. Following ovariectomy, we found reductions in the anterior cortical shell area of the vertebrae and reductions in nearly all of the tested vertebral mechanical properties. Weekly teriparatide significantly preserved the anterior cortical shell area and the energy absorption capacity of the lumbar vertebrae in a dose-dependent manner. Multiple regression analyses indicated that improved mechanical properties were more associated with the increased anterior cortical shell area rather than the cancellous bone volume. The intracortical structure of the Haversian canals was also preserved following teriparatide treatment after ovariectomy. These findings suggest the importance of the cortical shell as a therapeutic target in the treatment of osteoporosis. Weekly teriparatide treatment increases the compressive mechanical strength of the lumbar vertebrae by thickening the anterior cortical shell. Highlights • Ovariectomy led to reduced anterior cortical shell area and vertebral mechanical strength in cynomolgus monkeys. • Weekly teriparatide treatment dose-dependently preserved anterior cortical shell area and mechanical properties of the lumbar vertebrae. • Improved mechanical properties were associated more with increased anterior cortical shell area than with cancellous bone volume. [ABSTRACT FROM AUTHOR]

Abstract Previous studies have shown that vertebral height increases until the early twenties, but very few studies have been conducted on other vertebral dimensions. Growth in vertebral size is believed to take place in elderly age but not in early adulthood. In this study, we wanted to clarify the potential changes in the dimensions of the lumbar vertebrae during early adulthood. We used the Northern Finland Birth Cohort 1986 as our study material, with a final sample size of 375 individuals. We performed lumbar magnetic resonance imaging (MRI) when the participants were 20 and 30 years of age (baseline and follow-up, respectively). We recorded the width, depth, height, and cross-sectional area (CSA) of the fourth lumbar vertebra (L4) using the MRI scans. We used generalized estimating equation (GEE) models to analyse the data. Men had 7.6%–26.5% larger vertebral dimensions than women at both baseline and follow-up. The GEE models demonstrated that all the studied dimensions increased during the follow-up period among both sexes (p < 0.001). Men had a higher growth rate in vertebral depth and CSA than women (p < 0.001). Among women, small vertebral width (p = 0.001), depth (p = 0.05) and height (p = 0.02) at baseline were associated with a higher vertebral growth rate during the follow-up than among those with large dimensions at baseline. Among men, small baseline width was associated with higher vertebral growth rate (p = 0.001). Our results clearly indicate that vertebral dimensions increase after 20 years of age among both sexes. Highlights • Our results showed a clear increase in all the observed measurements in both sexes. • We detected some differences between men and women regarding the increase of dimensions. • We found that vertebral CSA and depth increases more among men than among women. • A small vertebral size at baseline predicted larger growth in some of our measurements, but not in the CSA. [ABSTRACT FROM AUTHOR]

Abstract Objective Quantitative computed tomography (QCT) measurements of volumetric bone mineral density (vBMD) are subject to errors due to variations in the amount of bone marrow adipose tissue (BMAT). The purpose of our study was to describe and validate a novel method to correct lumbar spine trabecular vBMD measurements for BMAT using chemical shift-encoded magnetic resonance imaging (CSE-MRI). Methods CSE-MRI measurements of proton density fat fraction (PDFF) were used to correct QCT spine vBMD measurements for BMAT based on the H 2 O and K 2 HPO 4 basis set equivalent densities of bone, red and yellow bone marrow. BMAT corrected and uncorrected vBMD measurements of the L1 vertebra were compared with dual-energy QCT (DEQCT) measurements in 18 subjects (mean age: 68 y, range 60 to 93 y). A further 400 subjects (mean age: 53 y, range 21 to 82 y) had 120 kV p single-energy QCT and CES-MRI scans of L2–L4 and the data used to simplify the adipose tissue correction by deriving a linear equation between the CSE-MRI vBMD correction and fractional BMAT content. Results Application of the CSE-MRI derived vBMD correction changed the bias (95% limits of agreement) compared with DEQCT from 26.7 (11.0 to 42.4) mg/cm3 to 2.2 (−9.5 to 13.9) mg/cm3 at 80 kV p , and from 22.4 (3.3 to 41.6) mg/cm3 to 2.9 (−12.6 to 18.4) mg/cm3 at 120 kV p. Data for the 400 subjects gave the following relationship valid at 120 kV p : vBMD correction (mg/cm3) = −12.96 + 75.76 × BMAT. Conclusion CSE-MRI measurements of PDFF can be used to correct for BMAT content and improve the accuracy of lumbar spine QCT vBMD measurements calibrated using a K 2 HPO 4 phantom. Highlights • Single energy QCT vBMD measurements are subject to errors due to variations in the amount of marrow adipose tissue • We describe and validate a method of using MRI measurements of marrow adipose tissue to correct spine vBMD • The method was validated in 18 subjects who had vBMD measurements using dual-energy QCT scans • Measurements in 400 subjects were used to develop a linear equation between the vBMD correction and marrow adipose tissue [ABSTRACT FROM AUTHOR]

Abstract Background Lower skeletal muscle density, indicating greater infiltration of adipose tissue into muscles, is associated with higher fracture risk in older adults. We aimed to determine whether mid-calf muscle density is associated with falls risk and bone health in community-dwelling older adults. Methods 2214 community-dwelling men and women who participated in the Healthy Ageing Initiative (Sweden) study at age 70 were included in this analysis. Mid-calf muscle density (mg/cm3) at the proximal tibia, and volumetric bone mineral density (vBMD) and architecture at the distal and proximal tibia and radius, were assessed by peripheral quantitative computed tomography. Whole-body lean and fat mass, lumbar spine and total hip areal bone mineral density (aBMD) were assessed by dual-energy X-ray absorptiometry. Participants completed seven-day accelerometer measurements of physical activity intensity, and self-reported falls data were collected 6 and 12 months later. Results 302 (13.5%) participants reported a fall at the 6- or 12-month interview, and 29 (1.3%) reported a fall at both interviews. After adjustment for confounders, each standard deviation decrease in mid-calf muscle density was associated with a trend towards greater likelihood of experiencing a fall (OR 1.13; 95% CI 1.00, 1.29 per SD lower) and significantly greater likelihood of multiple falls (1.61; 1.16, 2.23). Higher muscle density was not associated with total hip aBMD, and was associated with lower lumbar spine aBMD (B = -0.003; 95% CI -0.005, -0.001 per mg/cm3) and higher proximal cortical vBMD (0.74; 0.20, 1.28) at the radius. At the tibia, muscle density was positively associated with distal total and trabecular vBMD, and proximal total and cortical vBMD, cortical thickness, cortical area and stress-strain index (all P < 0.05). Only moderate/vigorous (%) intensity physical activity, not sedentary time or light activity, was associated with higher mid-calf muscle density (0.086; 0.034, 0.138). Conclusions Lower mid-calf muscle density is independently associated with higher likelihood for multiple incident falls and appears to have localised negative effects on bone structure in older adults. Highlights • Lower mid-calf muscle density was associated with increased likelihood for multiple incident falls over 12 months • Muscle density was inconsistently associated with bone parameters at the hip, lumbar spine and proximal and distal radius • Muscle density was consistently positively associated with tibial bone parameters suggesting local effects on bone health • Moderate/vigorous physical activity was positively associated with mid-calf muscle density [ABSTRACT FROM AUTHOR]

Abstract Purpose Osteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD). Methods The Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged >65 years and measured hemoglobin twice, in 1989–90 and 1992–93, as well as BMD by dual-energy X-ray absorptiometry (DXA) in 1994–95. In a subset of 1513 men and women with a Hgb in 1992–93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992–93; Hgb <13 g/dL in men; <12 g/dL in women) with "low BMD" defined as T-score less than −1 at the TH. In 1277 participants with Hgb measured on average 2.9 years apart and BMD, we used linear regression to estimate the associations of annualized change in Hgb with TH, LS and TB BMD. All models included age, sex, study-site, race, smoking, alcohol use, weight, height, steroid use, physical activity score, self-reported health, previous cardiovascular disease and prior anti-fracture medication use. Results No significant association was observed between Hgb, measured a mean 2.2 years prior to BMD, and BMD at the TH and LS in men (TH beta = −0.60 [x 10−2 g/cm2per 1.1 g/dL Hgb], 95% CI: -1.88 to 0.68; LS beta = −1.69, 95% CI: -3.83 to 0.45) or women (TH beta = −0.49 [x 10−2 g/cm2per 1.3 g/dL Hgb], 95% CI: -1.57 to 0.59; LS beta = −0.40, 95% CI: -2.57 to 1.76). Anemia was not observed to be significantly associated with low BMD in men (RR = 0.99, 95% CI: 0.72–1.40) nor women (RR = 0.98, 95% CI: 0.82–1.17). The mean change in Hgb was a loss of 0.06 g/dL/year (SD = 0.32). Change in Hgb was not observed to be significantly associated with BMD in men (TH beta = −0.55[x 10−2 g/cm2per 1 g/dL annualized Hgb change], 95% CI: -4.28 to 3.19; LS beta = 0.63, 95% CI: -5.38 to 6.65) or women (TH beta = 0.92, 95% CI: -1.96 to 3.79; LS beta = −1.77, 95% CI: -7.52 to 3.98). No significant association was observed between anemia and low bone density by T-score in men and women. Conclusions These findings support neither the hypothesis that low Hgb prior to bone density or decreases in Hgb are associated with bone density in older community-dwelling adults nor the use of Hgb level as a case-finding tool to prompt BMD measurement. [ABSTRACT FROM AUTHOR]

Abstract Purpose Vigorous physical activity (VPA) has been proven to promote osteogenesis in adolescents; however the specifics of the optimal pattern of frequency and duration of VPA are unknown. The main goal of the present study was to analyze the associations of different length of VPA bouts with bone health. Methods 180 healthy male adolescents (11–13 years) had their bone mineral content and density assessed by dual-energy X-ray absorptiometry scans at the whole body, femoral neck (FN) and lumbar spine and their physical activity measured by an accelerometer during one week. Results VPA was the intensity with the strongest associations with bone mineral parameters especially at the FN. Subjects whose longest VPA bout was 5 min or above had higher FN bone mineral density (BMD) than those who did not complete any 5-min bout and these differences were greater with participants who reached 15 consecutive minutes of VPA (>15′: 0.977 ± 0.020 g/cm2; 5′-15′: 0.907 ± 0.009 g/cm2; <5′: 0.876 ± 0.009 g/cm2; all p < 0.05). When comparing the relevance of VPA bouts and volume of physical activity, the group with low volume and having a VPA bout had better FN BMD compared to the group with high volume but no VPA bout. Additionally, the group with both high volume and VPA bout showed better FN BMD than the rest of the groups. Conclusions VPA may be the most effective activity intensity to improve bone mineral density and content of adolescent boys, with greater benefits if VPA periods either long or frequent. Highlights • Vigorous physical activity is related with bone health in early pubertal boys. • Frequency and duration of vigorous physical activity are linked with bone status. • Benefits are higher if vigorous physical activity lasts longer than 15 min. • Both volume and intensity of physical activity are important for bone health. [ABSTRACT FROM AUTHOR]

Abstract Although it is suggested that chronic obstructive pulmonary disease (COPD) and bone are related, almost all of the pathological mechanisms of COPD-related osteoporosis remain unknown. There is a mouse model showing a deterioration of bone quality after cigarette smoke exposure; however, in smoking exposure models, various factors exist that affect bone metabolism, such as smoking and body weight loss (muscle and fat mass loss). We considered it appropriate to use an elastase-induced emphysema model to exclude factors influencing bone metabolism and to investigate the influence of pulmonary emphysema on bone metabolism. The purpose of this study was to establish a COPD/emphysema-related osteoporosis mouse model by using the elastase-induced emphysema model. The lumbar vertebrae and femurs/tibiae exhibited trabecular bone loss and impaired osteogenic activity in 24-week-old male elastase-induced emphysema model mice. In addition, the model mice showed atrophy of type I muscle fibers without atrophy of type II muscle fibers. We believe that the mice described in this experimental protocol will be accepted as a COPD/emphysema-related osteoporosis mouse model and contribute to further investigations. Highlights • Elastase-induced pulmonary emphysema mice showed systemic bone loss. • Elastase-induced pulmonary emphysema mice showed impaired bone formation. • Elastase-induced pulmonary emphysema mice showed type I muscle fiber atrophy. • Emphysema may systemically induce bone/type I fiber loss and impair bone formation. • The model in our study may be useful as a COPD/emphysema-related osteoporosis model. [ABSTRACT FROM AUTHOR]

Abstract Background Abaloparatide is a 34–amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE. Methods Proportions of patients experiencing BMD gains from baseline of >0%, >3%, and >6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites. Results At months 6, 12, and 18, there were significantly more >3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P < 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the >0% and >6% responder thresholds. Conclusions In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide. Highlights • Significantly more abaloparatide patients were all-site BMD responders versus placebo or teriparatide • At each individual anatomic site, there were significantly more abaloparatide BMD responders versus placebo • For TH, there were significantly more abaloparatide BMD responders for each threshold and timepoint versus teriparatide • For FN, at all timepoints, significantly more abaloparatide patients were >3% and >6% responders versus teriparatide • Results are consistent with the early nonvertebral fracture risk reduction with abaloparatide observed in ACTIVE [ABSTRACT FROM AUTHOR]

Abstract Male osteoporosis can occur with advanced age and with hypogonadism, with increased bone resorption and/or inadequate bone formation contributing to reduced bone mass and increased fracture risk. Abaloparatide is a selective PTH receptor agonist that increases bone formation and bone mass in postmenopausal women with osteoporosis and in estrogen-deficient animals. The current study evaluated the effects of abaloparatide in orchiectomized (ORX) rats, a model of male osteoporosis. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery; 8 weeks later the ORX groups exhibited relative osteopenia vs sham controls, based on dual X-ray absorptiometry (DXA) and/or peripheral quantitative computed tomography (pQCT) assessments at the total body, lumbar spine, femur, and tibia. ORX rats (n = 10/group) were then injected daily (s.c.) for 8 weeks with vehicle or abaloparatide at 5 (ABL5) or 25 μg/kg/d (ABL25). Sham controls (n = 10) received s.c. vehicle. DXA and pQCT showed that one or both abaloparatide groups gained more areal and volumetric BMD at all sites analyzed compared with vehicle controls, leading to substantial or complete reversal of ORX-induced BMD deficits. pQCT also indicated greater gains in tibial cortical thickness in both abaloparatide groups versus vehicle controls. Tibial bone histomorphometry showed greater trabecular bone formation and bone volume and improved micro-architecture with abaloparatide, with no increase in osteoclasts. Abaloparatide also led to significant improvements in the balance of biochemical bone formation markers versus bone resorption markers, which correlated with BMD changes. These findings suggest that abaloparatide may have therapeutic benefits in men with osteoporosis. Highlights • Orchiectomized (ORX) rats develop cortical and trabecular bone loss and are a common model for male osteoporosis • Abaloparatide was previously shown to increase bone formation and BMD in female ovariectomized rats and non-human primates • Abaloparatide-treated ORX rats gained more bone mass at the whole body, lumbar vertebrae, femur, and tibia versus controls • Abaloparatide improved cortical and trabecular geometry and microarchitecture by increasing bone formation • These results provide preclinical support and rationale for future studies of abaloparatide in men with osteoporosis [ABSTRACT FROM AUTHOR]

Abstract Purpose Prior osteoporosis therapies may affect the skeletal response to denosumab. We compared the effect of denosumab (60 mg every 6 months for 12 months) on bone mineral density and bone metabolism parameters in postmenopausal women with low bone mass who were either treatment-naïve (n = 30), or previously treated either with zoledronic acid (n = 30), or teriparatide (n = 22). Methods We assessed lumbar spine bone mineral density (BMD) and measured serum concentrations of the bone turnover markers pro-collagen type 1 N -terminal propeptide (PINP) and C-terminal-cross-linking telopeptide of type 1 collagen (CTX), as well as sclerostin, dickkopf-1 (Dkk-1), and myostatin. Results Lumbar spine BMD increased equivalently in all three groups after 12 months of denosumab compared to baseline (p < 0.001). Serum PINP and CTX decreased significantly with denosumab in pre-treated women reaching the same nadir levels as in treatment-naïve patients (p < 0.001). Women pre-treated with teriparatide displayed lower baseline myostatin concentrations as compared to the other two groups (p < 0.001). Changes in lumbar spine BMD in teriparatide pre-treated women correlated with changes in bone turnover markers and myostatin. Conclusions Denosumab induced similar increases in lumbar spine BMD in treatment-naïve and pre-treated patients and suppressed serum PINP and CTX to the same levels regardless of prior treatments. In teriparatide pre-treated patients the magnitude of change in bone turnover markers is associated with BMD response. Highlights • Lumbar spine BMD increases in postmenopausal women treated with denosumab were independent of previous treatments • PINP and CTX decreased significantly with denosumab reaching the same nadir levels in pre-treated and treatment-naïve women • Changes in lumbar spine BMD in women pre-treated with teriparatide women correlated with changes in bone turnover markers [ABSTRACT FROM AUTHOR]