Bone Mass Acquisition Research Articles

Physiological and lifestyle determinants of bone mass in minority children/adolescents from the MetA-Bone Trial.

Adolescence leads to enormous skeletal growth. Therefore, understanding predictors of bone mass in this period is paramount to prevent future fractures/osteoporosis. This was a cross-sectional secondary analysis of the baseline visit of children/adolescents from the MetA-Bone Trial to evaluate the physiological (age, maturity stage, body composition) and lifestyle (diet, physical activity, stress, and sleep) determinants of whole-body and lumbar spine bone mineral content (BMC) and density (BMD). In this sample of 213 predominantly Hispanic boys and girls, we found sex similarities and differences in the predictors of bone mass. Lean mass was a significant positive predictor across all bone outcomes in both boys and girls. In boys, BMI percentile was a negative predictor of lumbar spine BMC (B = -0.035, p = 0.030) while sleep duration was a significant positive predictor of whole-body BMC (B = 8.7, p = 0.036). In girls, physical activity was a significant positive predictor of whole-body BMD (B = 2950-E-5, p = 0.029). The other variables studied were not significant predictors of bone mass in this sample. There were important determinants of bone mass in this sample, but longitudinal studies are needed to understand their role in bone mass acquisition during puberty. Physiological and lifestyle determinants of bone mass in this sample of predominately Hispanic children and adolescents were mainly lean mass. Self-reported race, ethnicity, family history of osteoporosis, diet quality (HEI-2020), and stress did not significantly predict bone mass in this sample. Identifying physiological and novel modifiable lifestyle factors to maximize bone mass acquisition in Hispanic children and adolescents is paramount to designing targeted interventions to promote long-term bone health and quality of life.

Dietary acidity and bone mass in minority children and adolescents: a cross-sectional analysis from the MetA-Bone trial.

Childhood/adolescence is key for developing strong bones. With the continuing rise in osteoporosis rates in Western societies, attention has turned to the possible impact of diets that create high levels of acid in the body. Some studies have shown an association between dietary acid load and bone mass, but there are limited studies in children/adolescents and none in Hispanics. This study aimed to evaluate the associations between dietary acid load (assessed as dietary potential renal acid load, PRAL, and protein to potassium ratio) and whole-body bone mineral content (BMC) and density (BMD) in a sample of 123 children and adolescents of predominantly Hispanic ethnicity. This study is a secondary cross-sectional analysis. Dietary PRAL was positively associated with BMC and BMD overall (p < 0.05) and with BMC in boys (p < 0.05) when adjusted for energy misreporting only. The vegetable protein to potassium ratio was inversely associated with BMC (p = 0.004) in boys only, after adjusting for important factors. Dietary acid load seems to be associated with BMC in boys in this sample of primarily Hispanic children. Long-term studies are needed to confirm these results and to understand the importance of protein intake in relation to other key nutrients in bone mass acquisition among Hispanic boys.

Total body irradiation is associated with long-term deficits in femoral bone structure but not mechanical properties in male rhesus macaques.

Exposure to ionizing radiation for oncological therapy increases the risk for late-onset fractures in survivors. However, the effects of total body irradiation (TBI) on adult bone are not well-characterized. The primary aim of this study was to quantify the long-term effects of TBI on bone microstructure, material composition, and mechanical behavior in skeletally mature rhesus macaque (Macaca mulatta) non-human primates. Femora were obtained post-mortem from animals exposed to an acute dose of TBI (6.0-6.75Gy) nearly a decade earlier, age-matched non-irradiated controls, and non-irradiated young animals. The microstructure of femoral trabecular and cortical bone was assessed via micro-computed tomography. Material composition was evaluated by measuring total fluorescent advanced glycation end products (fAGEs). Cortical bone mechanical behavior was quantified via four-point bending and cyclic reference point indentation (cRPI). Animals exposed to TBI had slightly worse cortical microstructure, including lower cortical thickness (-11%, p = 0.037) and cortical area (-24%, p = 0.049), but similar fAGE content and mechanical properties as age-matched controls. Aging did not influence cortical microstructure, fAGE content, or cRPI measures but diminished femoral cortical post-yield properties, including toughness to fracture (-32%, p = 0.032). Because TBI was administered after the acquisition of peak bone mass, these results suggest that the skeletons of long-term survivors of adulthood TBI may be resilient, retaining or recovering their mechanical integrity during the post-treatment period, despite radiation-induced architectural deficits. Further investigation is necessary to better understand radiation-induced skeletal fragility in mature and immature bone to improve care for radiation patients of all ages.

Phlpp1 alters the murine chondrocyte phospho-proteome during endochondral bone formation

Appendicular skeletal growth and bone mass acquisition are controlled by a variety of growth factors, hormones, and mechanical forces in a dynamic process called endochondral ossification. In long bones, chondrocytes in the growth plate proliferate and undergo hypertrophy to drive bone lengthening and mineralization. Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 and 2 (Phlpp1 and Phlpp2) are serine/threonine protein phosphatases that regulate cell proliferation, survival, and maturation via Akt, PKC, Raf1, S6k, and other intracellular signaling cascades. Germline deletion of Phlpp1 suppresses bone lengthening in growth plate chondrocytes. Here, we demonstrate that Phlpp2 does not regulate endochondral ossification, and we define the molecular differences between Phlpp1 and Phlpp2 in chondrocytes. Phlpp2−/− mice were phenotypically indistinguishable from their wildtype (WT) littermates, with similar bone length, bone mass, and growth plate dynamics. Deletion of Phlpp2 had moderate effects on the chondrocyte transcriptome and proteome compared to WT cells. By contrast, Phlpp1/2−/− (double knockout) mice resembled Phlpp1−/− mice phenotypically and molecularly, as the chondrocyte phospho-proteomes of Phlpp1−/− and Phlpp1/2−/− chondrocytes had similarities and were significantly different from WT and Phlpp2−/− chondrocyte phospho-proteomes. Data integration via multiparametric analysis showed that the transcriptome explained less variation in the data as a result of Phlpp1 or Phlpp2 deletion than proteome or phospho-proteome. Alterations in cell proliferation, collagen fibril organization, and Pdpk1 and Pak1/2 signaling pathways were identified in chondrocytes lacking Phlpp1, while cell cycle processes and Akt1 and Aurka signaling pathways were altered in chondrocytes lacking Phlpp2. These data demonstrate that Phlpp1, and to a lesser extent Phlpp2, regulate multiple and complex signaling cascades across the chondrocyte transcriptome, proteome, and phospho-proteome and that multi-omic data integration can reveal novel putative kinase targets that regulate endochondral ossification.

Total Flavonoids Isolated from the Leaves of Eucommia ulmoides Augment Peak Bone Mass in Female Rats and Show no Side Effects in Other Organs.

Eucommia ulmoides is a unique monophyletic and tertiary relict in China and is listed as a national second-class precious protected tree species. Eucommia ulmoides, recognized as a traditional Chinese medicine, can tonify the liver and kidneys and strengthen bones and muscles. Modern pharmacological research has proved that Eucommia ulmoides has multiple osteoprotective effects, including prohibiting the occurrence of osteoporosis and arthritis and enhancing the healing of bone fractures and bone defects. To check its osteotropic effects, which may provide ideas for its potential use for the development of novel drugs to treat osteoporosis, this study evaluated the effect of total flavonoids from Eucommia ulmoides leaves (TFEL) on the acquisition of Peak Bone Mass (PBM) in young female rats. TFEL was isolated, and its purity was confirmed by using a UV spectrophotometer. TFEL with a purity of 85.09% was administered to 6-week-old female rats by oral gavage at a low (50), mid (100), or high (200 mg/kg/d) dose, and the control group was administrated only with the same volume of water. After 13 weeks of treatment, the rats were sacrificed, and serum, different organs, and limb bones (femurs and tibias) were harvested, and the bone turnover markers, organ index, Bone Mineral Density (BMD), biomechanical property, and microstructure parameters were assayed. Furthermore, molecular targets were screened, and network pharmacology analyses were conducted to reveal the potential mechanisms of action of TFEL. Oral administration of TFEL for 13 weeks decreased the serum level of bone resorption marker TRACP-5b. As revealed by micro-computer tomography analysis, it elevated BMD even at a low dose (50 mg/kg/d) and improved the microstructural parameters, which were also confirmed by H&E histological staining. However, TFEL showed no effects on body weights, organ index, and micromorphology in the uterus. In our network pharmacology study, an intersection analysis screened out 64 shared targets, with quercetin, kaempferol, naringenin, and apigenin regulating the greatest number of targets associated with osteoporosis. Flavonoids in Eucommia ulmoides inhibited the occurrence of osteoporosis potentially through targeting signaling pathways for calcium, VEGF, IL-17, and NF-κB. Furthermore, AKT1, EGFR, PTGS2, VEGFA, and CALM were found to be potentially important target genes for the osteoprotective effects of flavonoids in Eucommia ulmoides. The above results suggested that TFEL can be used to elevate the peak bone mass in adolescence in female individuals, which may prevent the occurrence of postmenopausal osteoporosis, and the good safety of TFEL also suggests that it can be used as a food additive for daily life to improve the bone health.

Acquisition of peak bone mass in a Norwegian youth cohort: longitudinal findings from the Fit Futures study 2010–2022

SummaryIn a Norwegian youth cohort followed from adolescence to young adulthood, bone mineral density (BMD) levels declined at the femoral neck and total hip from 16 to 27 years but continued to increase at the total body indicating a site-specific attainment of peak bone mass.PurposeTo examine longitudinal trends in bone mineral density (BMD) levels in Norwegian adolescents into young adulthood.MethodIn a prospective cohort design, we followed 980 adolescents (473 (48%) females) aged 16–19 years into adulthood (age of 26–29) on three occasions: 2010–2011 (Fit Futures 1 (FF1)), 2012–2013 (FF2), and 2021–2022 (FF3), measuring BMD (g/cm2) at the femoral neck, total hip, and total body with dual x-ray absorptiometry (DXA). We used linear mixed models to examine longitudinal BMD changes from FF1 to FF3.ResultsFrom the median age of 16 years (FF1), femoral neck BMD (mean g/cm2 (95% CI)) slightly increased in females from 1.070 (1.059–1.082) to 1.076 (1.065–1.088, p = 0.015) at the median age of 18 years (FF2) but declined to 1.041 (1.029–1.053, p < 0.001) at the median age of 27 years (FF3). Similar patterns were observed in males: 16 years, 1.104 (1.091–1.116); 27 years, 1.063 (1.050–1.077, p < 0.001); and for the total hip in both sexes (both p < 0.001). Total body BMD increased from age 16 to 27 years in both sexes (females: 16 years, 1.141 (1.133–1.148); 27 years, 1.204 (1.196–1.212), p < 0.001; males: 16 years, 1.179 (1.170–1.188); 27 years, 1.310 (1.296–1.315), p < 0.001).ConclusionBMD levels increased from 16 to 18 years at the femoral and total hip sites in young Norwegian females and males, and a small decline was observed at the femoral sites when the participants were followed up to 27 years. Total body BMD continued to increase from adolescence to young adulthood.

Effects of puberty suppression on bone, body composition, handgrip strength and glucolipid profile in early-pubertal transgender adolescents

Introduction The effects of puberty suppression for more than 2 years before the start of gender-affirming hormones (GAH) on bone mass acquisition and body composition are understudied. Materials and methods Retrospective study on 46 transgender adolescents (20 trans boys and 26 trans girls) receiving a gonadotropin-releasing hormone analogue (GnRHa) from Tanner stage 2-3, followed by GAH around the age of 16 years. At start of GnRHa and at start of GAH, dual-energy X-ray absorptiometry (DXA) at lumbar spine (LS), femoral neck (FN) and total body (TB), handgrip strength test and fasting blood sampling were performed. Z-scores were calculated using reference values for both cis girls and cis boys. Results GnRHa were administered for a median of 3.2 years (± 0.69) in trans boys and 2.7 years (± 1.05) in trans girls. Bone mineral apparent density (BMAD)-LS Z-scores decreased significantly in both trans boys and trans girls, while BMAD-FN Z-scores decreased only in trans boys. Fat% and Fat Mass Index Z-scores significantly increased in both groups, while Lean Mass Index Z-scores significantly decreased. Handgrip strength Z-scores for the sex registered at birth (SRAB) remained stable in trans boys while they decreased in trans girls. There was no significant influence of the treatment on either insulin sensitivity or lipid profile. Discussion GnRHa administration for more than two years during the physiological time of puberty decreases bone mass acquisition, mainly at the lumbar spine and induces a general increase in fat mass. Although lean mass acquisition is undermined in both groups, handgrip strength is affected mainly in trans girls compared with age-matched peers for the SRAB.

Osteocyte-mediated mechanical response controls osteoblast differentiation and function.

Low bone mass is a pervasive global health concern, with implications for osteoporosis, frailty, disability, and mortality. Lifestyle factors, including sedentary habits, metabolic dysfunction, and an aging population, contribute to the escalating prevalence of osteopenia and osteoporosis. The application of mechanical load to bone through physical activity and exercise prevents bone loss, while sufficient mechanical load stimulates new bone mass acquisition. Osteocytes, cells embedded within the bone, receive mechanical signals and translate these mechanical cues into biological signals, termed mechano-transduction. Mechano-transduction signals regulate other bone resident cells, such as osteoblasts and osteoclasts, to orchestrate changes in bone mass. This review explores the mechanisms through which osteocyte-mediated response to mechanical loading regulates osteoblast differentiation and bone formation. An overview of bone cell biology and the impact of mechanical load will be provided, with emphasis on the mechanical cues, mechano-transduction pathways, and factors that direct progenitor cells toward the osteoblast lineage. While there are a wide range of clinically available treatments for osteoporosis, the majority act through manipulation of the osteoclast and may have significant disadvantages. Despite the central role of osteoblasts to the deposition of new bone, few therapies directly target osteoblasts for the preservation of bone mass. Improved understanding of the mechanisms leading to osteoblastogenesis may reveal novel targets for translational investigation.

FRI038 Differences In Bone Accrual Over One Year In Young Girls With Obesity Compared To Normal Weight Controls

Abstract Disclosure: S. Kaur: None. V. Singhal: None. L.A. Haidar: None. M. Bredella: None. M. Misra: None. Introduction: Despite higher bone mineral density (BMD), women with obesity are at an increased risk of fracture compared to normal-weight women. Optimal adolescent bone accrual is critical for normal peak bone mass acquisition and future bone health. Whereas several studies have examined the impact of low body weight on bone accrual in youth, data are lacking regarding the impact of obesity on bone accrual. We aimed to assess changes in areal and volumetric BMD, bone geometry and microarchitecture, and estimates of bone strength over one year in young females with moderate to severe obesity compared to their normal-weight counterparts. Methods: We recruited females between 13-25 years of age with moderate to severe obesity (OB) (n=21) and compared their bone accrual over one year with normal-weight controls (NWC) (n=50). Dual-energy X-ray absorptiometry to assess areal BMD (aBMD), high-resolution peripheral quantitative computed tomography (distal radius and tibia) to assess volumetric BMD (vBMD), bone geometry, and microarchitecture, and micro finite element analysis for estimates of bone strength was used. Analyses were controlled for age and race. Results: The mean age was 18.7 ± 2.7 years. OB and NWC were similar for age, race, height, and physical activity at baseline. OB had higher weight and BMI (p&amp;lt;0.0001 for both) and younger menarchal age (p=0.022) than NWC. Over one year, there was no difference between the groups for change in height, weight, and BMI. However, OB did not demonstrate the increase in total hip BMD observed in NWC (p=0.03) over a year. OB also had lesser increases in percent cortical area, cortical thickness, cortical and total vBMD at the radius over a year than the NWC group (p≤0.037 for all). The groups did not differ for tibial bone accrual. Conclusions: Our study demonstrates that longitudinal bone accrual over one year is impaired at the total hip and radius in adolescents and young adult females with obesity compared to normal-weight controls, while no differences are observed in tibial bone accrual. This raises concerns regarding future bone health in women with obesity, particularly at certain skeletal sites. Presentation: Friday, June 16, 2023

TESTOSTERONE RESTORES BODY COMPOSITION, BONE MASS AND BONE STRENGTH FOLLOWING EARLY PUBERTY SUPPRESSION IN A MOUSE MODEL MIMICKING THE CLINICAL STRATEGY IN TRANS BOYS.

Transgender youth increasingly present at pediatric gender services. Some of them receive long-term puberty suppression with gonadotropin-releasing hormone analogues (GnRHa) before starting gender-affirming hormones (GAH). The impact of GnRHa use started in early puberty on bone composition and bone mass accrual is unexplored. It is furthermore unclear whether subsequent GAH fully restore GnRHa effects, and if the timing of GAH introduction matters. To answer these questions, we developed a mouse model mimicking the clinical strategy applied in trans boys. Prepubertal 4-week-old female mice were treated with GnRHa alone, or with GnRHa supplemented with testosterone (T) from 6 weeks (early puberty) or 8 weeks (late puberty) onwards. Outcomes were analyzed at 16 weeks and compared to untreated mice of both sexes. GnRHa markedly increased total body fat mass, decreased lean body mass and had a modest negative impact on grip strength. Both early and late T administration shaped body composition to adult male levels, while grip strength was restored to female values. GnRHa-treated animals showed lower trabecular bone volume, and reduced cortical bone mass and strength. These changes were reversed by T to female levels (cortical bone mass and strength) irrespective of the time of administration, or even fully up to adult male control values (trabecular parameters) in case of earlier T start. The lower bone mass in GnRHa-treated mice was associated with increased bone marrow adiposity, also reversed by T. In conclusion, prolonged GnRHa use started in prepubertal female mice modifies body composition towards more fat and less lean mass, and impairs bone mass acquisition and strength. Subsequent T administration counteracts GnRHa impact on these parameters, shaping body composition and trabecular parameters to male values while restoring cortical bone architecture and strength up to female but not male control levels. These findings could help guide clinical strategies in transgender care. This article is protected by copyright. All rights reserved.

Formation and Acquisition of Bone Mass: A Commitment of the Obstetrician-Gynecologist in an Interdisciplinary Program

This article provides an overview of the process of bone mass development and acquisition, starting from gestation until reaching peak bone mass, as well as the presence of certain disorders. Bone mass formation has been studied at various stages of development, from pregnancy, childhood, adolescence, and adulthood, where the greatest increase occurs to achieve peak bone mass. The increase in bone mass begins during the gestation process as a period of high fetal calcium demand and continues from birth through childhood and infancy, experiencing its maximum growth during adolescence until reaching the peak of bone mass in adulthood, around 20-30 years of age. Approximately 70% of bone mass is inherited from parents, while the remaining percentage is acquired through the processes of gestation, development, and growth, where environmental factors, nutrition, exercise, avoidance of toxic substances, and maintaining overall health contribute to achieving the highest concentration of bone mass. This becomes a reserve to respond to bone loss that typically starts around the age of 40, with the greatest loss during the transition to menopause and later, at a slower rate, during old age.

The influence of growth hormone deficiency on bone health and metabolisms.

Growth hormone (GH) is a key peptide hormone in the regulation of bone metabolism, through its systemic and paracrine action mediated directly as well as by insulin-like growth factor-1 (IGF-1). Growth hormone exerts pleiotropic effects leading to an increase in linear bone growth, accumulation of bone mineral content and preservation of peak bone mass. Furthermore, it influences protein, lipid, and carbohydrate metabolism.Growth hormone deficiency (GHD) causes a low bone turnover rate leading to reduced bone mineral density (BMD) and increased bone fragility. The results of GH insufficiency are the most pronounced among children as it negatively affects longitudinal bone growth, causing short stature and in adolescents, in whom it hinders the acquisition of peak bone mass. Most studies show that treatment with recombinant human growth hormone (rhGH) in GHD patients could improve BMD and decrease fracture risk. This review aims to summarize the pathophysiology, clinical picture and management of bone complications observed in GHD.

Regulation of Osteoblast to Osteocyte Differentiation by Cyclin-Dependent Kinase-1.

Osteocytes have recently been identified as a new regulator of bone remodeling, but the detailed mechanism of their differentiation from osteoblasts remains unclear. The purpose of this study is to identify cell cycle regulators involved in the differentiation of osteoblasts into osteocytes and determine their physiological significance. The study uses IDG-SW3 cells as a model for the differentiation from osteoblasts to osteocytes. Among the major cyclin-dependent kinases (Cdks), Cdk1 is most abundantly expressed in IDG-SW3 cells, and its expression is down-regulated during differentiation into osteocytes. Inhibition of CDK1 activity reduces IDG-SW3 cell proliferation and differentiation into osteocytes. Osteocyte and Osteoblast-specific Cdk1 knockout in mice (Dmp1-Cdk1KO ) results in trabecular bone loss. Pthlh expression increases during differentiation, but inhibiting CDK1 activity reduces Pthlh expression. Parathyroid hormone-related protein concentration is reduced in the bone marrow of Dmp1-Cdk1KO mice. Four weeks of Parathyroid hormone administration partially recovers the trabecular bone loss in Dmp1-Cdk1KO mice. These results demonstrate that Cdk1 plays an essential role in the differentiation from osteoblast to osteocyte and the acquisition and maintenance of bone mass. The findings contribute to a better understanding of the mechanisms of bone mass regulation and can help develop efficient therapeutic strategies for osteoporosis treatment.

Differences in bone accrual over one year in young girls with obesity compared to Normal weight controls.

Despite higher bone mineral density (BMD), women with obesity are at an increased risk of fracture compared to normal-weight women. Optimal adolescent bone accrual is critical for normal peak bone mass acquisition and future bone health. Whereas several studies have examined the impact of low body weight on bone accrual in youth, data are lacking regarding the impact of obesity on bone accrual. We examined bone accrual over one year in young women with moderate to severe obesity (OB) (n=21) versus normal-weight controls (NWC) (n=50). Participants were 13-25years old. We used dual-energy X-ray absorptiometry to assess areal BMD (aBMD) and high resolution peripheral quantitative computed tomography (distal radius and tibia) to assess volumetric BMD (vBMD), bone geometry, and microarchitecture. Analyses were controlled for age and race. The mean age was 18.7±2.7years. OB and NWC were similar for age, race, height, and physical activity. OB had a higher BMI (p<0.0001) and younger menarchal age (p=0.022) than NWC. Over one year, OB did not demonstrate the increase in total hip BMD observed in NWC (p=0.03). Increases in percent cortical area and cortical thickness, and cortical and total vBMD at the radius were lower in OB than in NWC (p≤0.037). Groups did not differ for tibial bone accrual. We demonstrate that longitudinal bone accrual is impaired at the total hip and radial cortex in young women with obesity, raising concerns regarding their future bone health.

Bone impact after two years of low-dose oral contraceptive use during adolescence.

Data regarding the use and effect of hormonal contraceptives on bone mass acquisition during adolescence are contradictory. The present study was designed to evaluate bone metabolism in two groups of healthy adolescents using combined oral contraceptives (COC). A total of 168 adolescents were recruited from 2014 to 2020 in a non-randomized clinical trial and divided into three groups. The COC1 group used 20 μg Ethinylestradiol (EE)/150 μg Desogestrel and the COC2 group used 30 μg EE/3 mg Drospirenone over a period of two years. These groups were compared to a control group of adolescent non-COC users. The adolescents were submitted to bone densitometry by dual-energy X-ray absorptiometry and measurement of bone biomarkers, bone alkaline phosphatase (BAP), and osteocalcin (OC) at baseline and 24 months after inclusion in the study. The three groups studied were compared at the different time points by ANOVA, followed by Bonferroni's multiple comparison test. Incorporation of bone mass was greater in non-users at all sites analyzed (4.85 g in lumbar Bone mineral content (BMC)) when compared to adolescents of the COC1 and COC2 groups, with a respective increase of 2.15 g and loss of 0.43g in lumbar BMC (P = 0.001). When comparing subtotal BMC, the control increased 100.83 g, COC 1 increased 21.46 g, and COC 2 presented a reduction of 1.47 g (P = 0.005). The values of bone markers after 24 months are similar for BAP, being 30.51 U/L (± 11.6) for the control group, 34.95 U/L (± 10.8) for COC1, and 30.29 U/L for COC 2 (± 11.5) (P = 0.377). However, when we analyzed OC, we observed for control, COC 1, and COC 2 groups, respectively, 13.59 ng/mL (± 7.3), 6.44 ng/mL (± 4.6), and 9.48 ng/mL (± 5.9), with P = 0.003. Despite loss to follow-up occurring in the three groups, there were no significant differences between the variables in adolescents at baseline who remained in the study during the 24-month follow-up and those who were excluded or lost to follow-up. Bone mass acquisition was compromised in healthy adolescents using combined hormonal contraceptives when compared to controls. This negative impact seems to be more pronounced in the group that used contraceptives containing 30 μg EE. http://www.ensaiosclinicos.gov.br, RBR-5h9b3c. "Low-dose combined oral contraceptive use is associated with lower bone mass in adolescents".

Influence of sex hormones status and type of training on regional bone mineral density in exercising females

ABSTRACT The primary objective of this study was to examine the influence of hormonal ovarian profile and training characteristics on spine, pelvis, and total body bone mineral density (BMD) in a group of well-trained females. Forty-two eumenorrheic females, twenty-eight monophasic oral contraceptive (OC) users and thirteen postmenopausal females participated in this study. Body composition was measured by total body dual-energy X-ray absorptiometry (DXA) to determine BMD of the areas of interest. Endurance-trained premenopausal females showed lower spine BMD compared to resistance-trained premenopausal females (1.03 ± 0.1 vs. 1.09 ± 0.09 g/cm2; p = 0.025). Postmenopausal females reported lower BMD level in comparison to eumenorrheic females in pelvis (1.079 ± 0.082 vs 1.19 ± 0.115 g/cm2; p = 0.005), spine (0.969 ± 0.097 vs 1.069 ± 0.109 g/cm2; p = 0.012) and total (1.122 ± 0.08 vs 1.193 ± 0.077 g/cm2; p = 0.018) and OC users whose duration of OC use was less than 5 years (OC < 5) in pelvis (1.235 ± 0.068 g/cm2; p < 0.001) and spine (1.062 ± 0.069 g/cm2; p = 0.018). In addition, lower BMD values were found in OC users who had been using OC for more than 5 years (OC ≥ 5) than eumenorrheic females in pelvis (1.078 ± 0.086 g/cm2; p = 0.029) and spine (0.966 ± 0.08 g/cm2; p = 0.05). Likewise, OC ≥ 5 showed lower values than and OC < 5 in pelvis (p = 0.004) and spine (p = 0.047). We observed a lower spine BMD value in premenopausal endurance-trained females compared to premenopausal resistance-trained females. Moreover, this research observed that prolonged use of OCs may reduce bone mass acquisition in the spine and pelvis, even in well-trained females. Finally, postmenopausal showed lower BMD despite being exercising women. Trial registration: ClinicalTrials.gov identifier: NCT04458662. Highlights Ovarian hormonal profile should be considered when assessing BMD in female athletes. The duration of oral contraceptive use influences spine and pelvis regional BMD in exercising females. Postmenopausal women show lower BMD when compared to premenopausal females despite being exercising females.

Loss of early B cell protein λ5 decreases bone mass and accelerates skeletal aging.

The early B cell protein λ5 is an essential component of the surrogate light chain and the preB cell receptor (preBCR), which is critical for optimal B cell development. To investigate the effect of λ5 and/or B cells on bone acquisition over time, we developed a panel of JH -/- , λ5-/-, JH -/- λ5-/-, and wild-type (WT) BALB/c mice and then studied postnatal bone development and aging in these mice at one, six, twelve, and twenty-two months of age. The trabecular bone volume over total volume (BV/TV) in JH -/- mice was similar to WT mice at all ages. In contrast, at six months of age and thereafter, λ5-/- and JH -/- λ5-/- mice demonstrated a severe decrease in trabecular bone mass. Surprisingly, bone mass in six-month-old λ5-/- and JH -/- λ5-/- mice was similar to or even lower than in aged (twenty-two-months) WT mice, suggesting accelerated skeletal aging. The postnatal development and the acquisition of cortical bone mass in JH -/- λ5-/- mice were generally comparable to WT. However, JH -/- λ5-/- mice showed a significant decrease in cortical BV/TV at six- and twelve months of age. To examine the contribution of λ5 and B cells to postnatal bone synthesis, we separately transplanted whole bone marrow cells from JH -/- λ5-/- and WT mice into irradiated JH -/- λ5-/- and WT recipients. WT recipients of JH -/- λ5-/- marrow cells failed to show acquisition of trabecular bone mass, whereas transplanting WT marrow cells into JH -/- λ5-/- recipients led to the recovery of trabecular bone mass. Transfer of WT marrow cells into JH -/- λ5-/- mice promoted synthesis of new cortical and trabecular bone. Our findings indicate that λ5 plays a major role in preserving bone mass during postnatal development and skeletal aging which is distinct from its role in B cell development. The absence of both λ5 and B cells in JH -/- λ5-/- mice leads to delayed acquisition of cortical bone during postnatal development. Dissecting the mechanism(s) by which λ5 regulates bone homeostasis may provide new avenues for the treatment of age-related loss of bone mass and osteoporosis.

Adiposity Metabolic Consequences for Adolescent Bone Health.

Infancy and adolescence are crucial periods for bone health, since they are characterized by intense physical growth and bone development. The unsatisfactory acquisition of bone mass in this phase has consequences in adult life and increases the risk of developing bone diseases at more advanced ages. Nutrient deficiencies, especially calcium and vitamin D, associated with a sedentary lifestyle; lack of sun exposure; and epigenetic aspects represent some of the main risk factors for poor bone quality. In addition, recent studies relate childhood obesity to impaired bone health; however, studies on the adiposity effects on bone health are scarce and inconclusive. Another gap concerns the implications of obesity on child sexual maturity, which can jeopardize their genetic potential bone mass and increase fracture risk. Therefore, we reviewed the analyzed factors related to bone health and their association with obesity and metabolic syndrome in adolescents. We concluded that obesity (specifically, accumulated visceral fat) harms bones in the infant–juvenile phase, thereby increasing osteopenia/osteoporosis in adults and the elderly. Thus, it becomes evident that forming and maintaining healthy eating habits is necessary during infancy and adolescence to reduce the risk of fractures caused by bone-metabolic diseases in adulthood and to promote healthy ageing.

Skeletal Characteristics of Children and Adolescents with Turner Syndrome

Turner syndrome (TS) is a chromosomal disorder characterized by a short stature and gonadal dysgenesis, the latter of which requires estrogen replacement therapy (ERT) to induce and maintain secondary sexual characteristics. Insufficient ERT is associated with compromised skeletal health, including bone fragility, in adults with TS. In particular, estrogen insufficiency during adolescence is critical because the acquisition of a defective bone mass during this period results in impaired bone strength later in the life. In addition to bone mass, bone geometry is also a crucial factor influencing bone strength; therefore, a more detailed understanding of the skeletal characteristics of both bone mass and geometry during childhood and adolescence and their relationships with the estrogen status is needed to prevent compromised skeletal health during adulthood in TS. Although a delay in the initiation of ERT is associated with a lower bone mineral density during adulthood, limited information is currently available on the effects of ERT during adolescence on bone geometry. Herein, we summarize the current knowledge on skeletal characteristics in children and adolescents with TS and their relationships with estrogen sufficiency, and discuss the potential limitations of the current protocol for ERT during adolescence in order to achieve better skeletal health in adulthood.

Functional hypothalamic amenorrhea: Impact on bone and neuropsychiatric outcomes.

Functional hypothalamic amenorrhea is a state of reversible hypogonadism common in adolescents and young women that can be triggered by energy deficit or emotional stress or a combination of these factors. Energy deficit may be a consequence of (i) reduced caloric intake, as seen in patients with eating disorders, such as anorexia nervosa, or (ii) excessive exercise, when caloric intake is insufficient to meet the needs of energy expenditure. In these conditions of energy deficit, suppression of the hypothalamic secretion of gonadotrophin-releasing hormone (with resulting hypoestrogenism) as well as other changes in hypothalamic-pituitary function may occur as an adaptive response to limited energy availability. Many of these adaptive changes, however, are deleterious to reproductive, skeletal, and neuropsychiatric health. Particularly, normoestrogenemia is critical for normal bone accrual during adolescence, and hypoestrogenemia during this time may lead to deficits in peak bone mass acquisition with longstanding effects on skeletal health. The adolescent years are also a time of neurological changes that impact cognitive function, and anxiety and depression present more frequently during this time. Normal estrogen status is essential for optimal cognitive function (particularly verbal memory and executive function) and may impact emotion and mood. Early recognition of women at high risk of developing hypothalamic amenorrhea and its timely management with a multidisciplinary team are crucial to prevent the severe and long-term effects of this condition.