Mineral Accrual Research Articles

Per- and polyfluoroalkyl substances and bone mineral content in early adolescence: Modification by diet and physical activity

BackgroundPer- and polyfluoroalkyl substance (PFAS) exposures may negatively impact bone mineral accrual, but little is known about potential mitigators of this relation. We assessed whether associations of PFAS and their mixture with bone mineral content (BMC) in adolescence were modified by diet and physical activity. MethodsWe included 197 adolescents enrolled in a prospective pregnancy and birth cohort in Cincinnati, Ohio (2003–2006). At age 12 years, we collected serum for PFAS measurements and used dual-energy x-ray absorptiometry to measure BMC. We calculated dietary calcium intake and Health Eating Index (HEI) scores from repeated 24-h dietary recalls, physical activity scores using the Physical Activity Questionnaire for Older Children (PAQ-C), and average moderate to vigorous physical activity (MVPA) based on accelerometry. We estimated covariate-adjusted differences in BMC z-scores per interquartile range (IQR) increase of individual PFAS concentrations using linear regression and per simultaneous IQR increase in all four PFAS using g-computation. We evaluated effect measure modification (EMM) using interaction terms between each modifier and PFAS. ResultsHigher serum perfluorooctanoic acid, perfluorooctanesulfonic acid, and perfluorononanoic acid concentrations and the PFAS mixture were associated with lower BMC z-scores. An IQR increase in all PFAS was associated with a 0.27 (−0.54, 0.01) lower distal radius BMC z-score. Associations with lower BMC were generally stronger among adolescents classified as < median for calcium intake, HEI scores, or MVPA compared to those ≥ median. The difference in distal radius BMC z-score per IQR increase in all PFAS was −0.38 (−0.72, −0.04) for those with <median calcium intake versus −0.03 (−0.48, 0.35) for ≥ median (EMM p-value = 0.16); the corresponding differences by MVPA were −0.42 (−0.76, −0.07) for < median and −0.05 (−0.42, 0.32) for ≥ median (EMM p-value = 0.13). ConclusionHealthy, calcium-rich diets and higher intensity physical activity may mitigate the adverse impact of PFAS on adolescent bone health.

Relative Energy Deficiency in Sport (REDs) Indicators in Male Adolescent Endurance Athletes: A 3-Year Longitudinal Study.

Longitudinal measurements of Relative Energy Deficiency in Sport (REDs) among adolescent male elite athletes are lacking. We aimed to monitor REDs indicators and their possible impact on performance in elite high-school cross-country skiing and biathlon athletes (n = 13) (16.3 ± 0.4 years, 179.4 ± 7.6 cm, 63.6 ± 8.2 kg body mass (BM), and peak oxygen uptake (VO2peak): 61.5 ± 5.3 mL/kg BM/min) every 6 months for 3 years. Protocols included assessments of energy availability (EA), body composition and bone mineral density (BMD), resting metabolic rate (RMR), disordered eating behavior, exercise addiction, VO2peak, and muscle strength. Data were analyzed using a linear mixed model. At baseline, 38% had low lumbar BMD (Z-score ≤ -1), and overall, bone health increased only slightly. VO2peak and muscle strength improved (p < 0.001), RMR decreased (p = 0.016), and no change was observed in EA or physiological or psychological REDs indicators. Conclusively, many of these young male athletes had poor bone health at baseline, and most either lost or did not achieve the expected pubertal bone mineral accrual, although no other indication of REDs was observed, while performance improved during the study period. Our findings highlight the importance of elite sports high schools focusing on screening for early detection of impaired bone health in male athletes.

FRI412 A Case of 46,XX Gonadal Dysgenesis With Mayer-Rokitansky-Küster-Hauser Syndrome And Primary Hypothyroidism

Abstract Disclosure: S. Al Allawi: None. R. Osman: None. Introduction: The association between Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome and gonadal dysgenesis is rarely reported in the literature. Coexistence of hypothyroidism with this condition is scarce and clinical correlation remains unclear. We describe a case of this rare clinical entity in conjunction with primary hypothyroidism. Clinical case: A 27-year-old Female with a medical history of primary hypothyroidism was referred to our clinic for evaluation of primary amenorrhea. She was born with a female phenotype. Growth was appropriate, but puberty was delayed with self-reported late pubarche at age 19. She never had a menstrual cycle, and had received hormonal replacement therapy (HRT) for a few months but failed to trigger menarche. However due to financial constraints, treatment was not continued. She was diagnosed with hypothyroidism since birth, for which she is currently maintained on levothyroxine 225 mcg daily. On physical exam, blood pressure was 126/72 mmHg, pulse rate 83 BPM, height 5’9”, BMI 34 kg/m2. No facial dysmorphisms or skeletal deformity were apparent. She had normal pubic and axillary hair distribution, breast budding consistent with Tanner Stage II. Genital examination revealed normal external genitalia and a blind vaginal pouch. Hormonal workup revealed hypergonadotrophic hypogonadism with estradiol &amp;lt; 0.5 pg/mL and post-menopausal range follicle-stimulating hormone (FSH) 36.7 mIU/mL. Thyroid stimulating hormone (TSH) 2.19 uIU/ml (nl 0.45-4.5 uIU/mL) and anti-TPO antibodies 10 IU/mL (nl 0-34 IU/mL). Prior thyroid ultrasound reported a small thyroid gland. Fluorescence in situ hybridization (FISH) analysis revealed 46XX karyotype. Abdominal and pelvic ultrasound showed normal kidneys with a non-visualized uterus and ovaries. Pelvic MRI confirmed the absence of both and showed a blind end vaginal pouch, leading to the conclusion of the coexistence of gonadal dysgenesis with MRKH. She was then placed on transdermal estradioltherapy. Conclusion: The association between gonadal dysgenesis (the most common cause of primary amenorrhea) and MRKH syndrome (the second most common cause) is infrequent. HRT remains the only therapeutic option. It aims to trigger the development of secondary sexual characteristics and prevent osteoporosis by allowing appropriate bone mineral accrual. Unfortunately, infertility remains the most significant consequential issue; hence the availability of good caring and psychological counseling should not be underestimated. The co-existence of likely non-immune primary hypothyroidism is even less frequent. To our knowledge, our case is the second reported case of this trilogy. Given the paucity of data, the association of this condition with primary hypothyroidism cannot be well established and can be coincidental. More studies are needed to determine if this condition has a higher prevalence of hypothyroidism. Presentation: Friday, June 16, 2023

Bone health in children with recurrent and chronic pancreatitis: A multi-center cross sectional analysis

Background/objectivesBone health of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) is not well studied. MethodsThis retrospective study was performed at three sites and included data from INSPPIRE-2. ResultsOf the 87 children in the study: 46 had ARP (53%), 41 had CP (47%). Mean age was 13.6 ± 3.9 years at last DXA scan. The prevalence of low height-for-age (Z-score < −2) (13%, 10/78) and low bone mineral density (BMD) adjusted for height (Z-score < −2) (6.4%, 5/78) were higher than a healthy reference sample (2.5%, p < 0.0001 and p = 0.03, respectively). ConclusionChildren with ARP or CP have lower height and BMD than healthy peers. Attention to deficits in growth and bone mineral accrual in children with pancreatic disease is warranted.

Increasing muscle contractility through low-frequency stimulation alters tibial bone geometry and reduces bone strength in mdx and dko dystrophic mice.

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by mutations or deletions in the dystrophin gene, for which there remains no cure. As DMD patients also develop bone fragility because of muscle weakness and immobilization, better understanding of the pathophysiological mechanisms of dystrophin deficiency will help develop therapies to improve musculoskeletal health. Since alterations in muscle phenotype can influence bone structure, we investigated whether modifying muscle contractile activity through low-frequency stimulation (LFS) could alter bone architecture in mouse models of DMD. We tested the hypothesis that increasing muscle contractile activity could influence bone mass and structure in dystrophin-deficient (mdx) and dystrophin- and utrophin-deficient (dko) dystrophic mice. Tibial bone structure in dko mice was significantly different from that in mdx and wild-type (C57BL/10) control mice. Effects of LFS on bone architecture differed between dystrophic and healthy mice, with LFS thinning cortical bone in both dystrophic models. Bone mass was maintained in LFS-treated healthy mice, with a reduced proportion of high-density bone and concomitant increase in low-density bone. LFS-treated dko mice exhibited a net deficit in cortical thickness and reduced high-density bone but no equivalent increase in low-density bone. These alterations in bone structure and mineral density reduced mechanical strength in mdx and dko mice. The findings reveal that muscle activity can regulate bone mass, structure, mineral accrual, and strength, especially in the context of dystrophin and/or utrophin deficiency. The results provide unique insights into the development of bone fragility in DMD and for devising interventions to improve musculoskeletal health.NEW & NOTEWORTHY Patients with Duchenne muscular dystrophy (DMD) develop bone fragility because of muscle weakness and immobilization. We investigated whether increasing muscle contractile activity through low-frequency stimulation (LFS) could alter bone architecture in dystrophin-deficient (mdx) or dystrophin- and utrophin-deficient (dko) mouse models of DMD. Chronic LFS reduced tibial diaphysis cross sections in mdx and dko mice, without affecting bone shape in healthy mice. LFS affected the distribution of bone mineral density across all phenotypes, with the magnitude of effect being dependent on disease severity.

Bone Mineral Density and Vascular Calcification in Children and Young Adults With CKD 4 to 5 or on Dialysis

Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. Mineral accrual by the growing skeleton may protect young people with CKD from extraosseous calcification. Our hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. This was a multicenter longitudinal study in children and young people (5-30 years) with CKD stages 4 to 5 or on dialysis. BMD was assessed by tibial peripheral quantitative computed tomography (pQCT) and lumbar spine dual-energy X-ray absorptiometry (DXA). The following cardiovascular imaging tests were undertaken: cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima media thickness z-score (cIMTz), pulse wave velocity z-score (PWVz), and carotid distensibility for arterial stiffness. All measures are presented as age-adjusted and sex-adjusted z-scores. One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed up after a median of 1.45 years. Trabecular BMD z-score (TrabBMDz) decreased (P= 0.01), and there was a nonsignificant decrease in cortical BMD z-score (CortBMDz) (P= 0.09). Median cIMTz and PWVz showed nonsignificant increase (P= 0.23 and P= 0.19, respectively). The annualized increase in TrabBMDz (ΔTrabBMDz) was an independent predictor of cIMTz increase (R 2= 0.48, β= 0.40, P= 0.03). Young people who demonstrated statural growth (n= 33) had lower ΔTrabBMDz and also attenuated vascular changes compared with those with static growth (n= 24). This hypothesis-generating study suggests that children and young adults with CKD or on dialysis may develop vascular calcification even as their BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraosseous calcification.

OR05-5 Body Mass Index (BMI) as a Predictor of Bone Mineral Density (BMD) in Gender Diverse Youth

Abstract Objective GnRH agonists (GnRHa), used to prevent development of undesired secondary sex characteristics for gender diverse youth (GDY), may impede pubertal bone mineral accrual increasing the risk for osteopenia/osteoporosis during adulthood. Based on findings of low bone mineral density (BMD) scores (relative to natal sex) prior to GnRHa [1], we hypothesized BMD might be associated with body mass index (BMI) in GDY.Method: To test our hypothesis, we reviewed medical records for 27 GDY; 16 were designated female at birth (DFAB) and 11 were designated male at birth (DMAB). Age at presentation, gender identity, ages at initiation of GnRHa and gender affirming hormone treatment (GAHT), duration of GnRHa treatment prior to GAHT initiation, auxologic parameters including BMI, and lumbar spine BMD obtained from GE lunar IDXa dual-energy X-ray absorptiometry (DEXA) were extracted. Lumbar spine BMD was used for statistical analysis. Statistical analysis was performed with Microsoft Excel Analysis ToolPak. A linear regression model was used to determine significance of BMI and GnRHa as predictors of BMD Z-score using a significance level of 0.05. Legal gender marker was used to determine BMD Z-scores. Results BMI ranged from 16.93 kg/m2 to 35.79 kg/m2 (5th to the 99th percentile). DEXA scan results were available for 27 GDY with age range 10-25 years; mean age (±SD) was 17±3 years. BMD of the lumbar spine was obtained from 0-61 months (mean 30 ± 21 months) following initiation of GnRHa. Length of GnRHa treatment prior to GAHT initiation ranged from 0-53 months (mean 14 ± 12 months).Individuals were at different stages of the gender affirmation process including 1) No medical treatments, 2) GnRH agonist only, 3) GAHT only, and 4) combined GnRH agonist and GAHT. Using a linear regression model, length of GnRHa therapy and length of GnRHa without GAHT were not significantly associated with lumbar spine BMD in our sample (p = 0.44 and 0.29, respectively). Using a linear regression model, BMI was a significant positive predictor of higher lumbar bone mineral density (p = 0.03). Conclusion Sex hormone exposure during adolescence and young adulthood is essential for bone health. While GnRH agonists lower endogenous sex hormone exposure, in our sample, lower BMD was not associated with total duration of GnRHa therapy or duration of GnRHa treatment prior to GAHT. Rather BMD was positively associated with BMI regardless of gender affirming medical therapies. Limitations include small sample size, retrospective design, and the use of legal gender marker for normative values. The next step will be larger, prospective studies to identify predictors of low BMD in GD youth. This information will guide future management regarding BMD monitoring.

16.3 Do Genetic Variants Moderate Sexual and Skeletal Side Effects of SSRIs?

The objective is to examine whether genetic variants in serotonin pathway–related genes moderate the effects of SSRIs on bone mineral accrual and sexual functioning in older adolescents and young adults.

Early life organophosphate ester exposures and bone health at age 12 years: The Health Outcomes and Measures of the Environment (HOME) Study

BackgroundNo human studies have evaluated early life organophosphate ester (OPE) exposures with bone health outcomes, despite evidence of osteotoxicity. ObjectivesWe assessed associations of urinary OPE metabolites measured across early life with areal bone mineral density (aBMD) and bone mineral content (BMC) at age 12 years. MethodsAmong 223 mother-child dyads enrolled in the Health Outcomes and Measures of the Environment (HOME) Study, we quantified concentrations of bis-2-chloroethyl phosphate (BCEP), bis-(1,3-dichloro-2-propyl) (BDCIPP), di-n-butyl phosphate (DnBP), and diphenyl phosphate (DPHP) in urine collected from mothers during pregnancy and children at ages 1, 2, 3, 5, and 8 years. At age 12 years, we performed dual energy x-ray absorptiometry and calculated aBMD and BMC z-scores at six skeletal sites. We estimated overall and sex-stratified BMD/BMC z-score differences per interquartile range (IQR) increase in OPE concentrations at multiple exposure timepoints: gestation (average) and 1–3 (average), 5, and 8 years. ResultsIn adjusted models, overall associations of BCEP and BDCIPP with total hip and 1/3rd distal radius aBMD and BMC varied significantly by exposure timepoint, as did BDCIPP with whole body aBMD. For example, differences (95 % CI) in total hip aBMD z-score per IQR increase in BDCIPP were 0.33 (0.01, 0.64), −0.10 (−0.34, 0.14), −0.18 (−0.40, 0.05), and 0.14 (−0.09, 0.38) for concentrations during gestation and at 1–3, 5, and 8 years, respectively. Overall DnBP and DPHP associations were generally null at all timepoints. We observed sex-specific associations for some timepoints and skeletal sites. For example, an IQR increase in 8-year DPHP was associated with a 0.21 (0.05, 0.38) greater total hip aBMD z-score among females but −0.19 (−0.43, 0.05) lower z-score among males. DiscussionEarly life OPE exposures may be associated with sex- and exposure period-dependent alterations in early adolescent bone mineral accrual and strength.

Evaluation of risk factors associated with fragility fractures and recommendations to optimise bone health in children with long-term neurological condition.

The growing years are paramount for bone growth and mineral accrual. Children with long-term neurological condition (LTNC) have multiple risk factors for poor bone health and fragility fractures. In Singapore, this has not been studied systematically. Therefore, we aimed to evaluate the risk factors associated with fragility fractures in children with LTNC. In this study, the search for fragility fractures was done by a retrospective review of patients with LTNC on follow-up in the paediatric neurology clinic and patients who presented with fracture to the paediatric orthopaedic clinic. Information on patients' demographics, medical history, intervention, biochemical bone markers and fracture history was collected. In a tertiary clinic population of 136 patients with LTNC, 65% were dependent on mobility (Gross Motor Function Classification System [GMFCS] V), 60% were underweight and 60% were fed via gastrostomy or nasogastric tube, or were on oral pureed diet. Furthermore, 60% were on anticonvulsants. The fracture rate was 3% in this population and was associated with low-impact activities such as transfer and dressing. Only 7.4% and 33% of the patients had undergone measurements of vitamin D and calcium levels, respectively. The local prevalence of fragility fractures in children with LTNC on follow-up at the neurology clinic was found to be 3%. Risk factors identified were limited ambulation and compromised nutritional status associated with feeding difficulty. Recommendations to optimise bone health in children with LTNC were made. These include promoting weight-bearing activities, looking out for underweight children, avoiding vitamin D deficiency and ensuring adequate calcium intake.

The influence of snuff and smoking on bone accretion in late adolescence. The Troms\xf8 study, Fit Futures

SummaryAreal bone mineral density (aBMD) predicts future fracture risk. This study explores associations between use of tobacco and bone accretion in Norwegian adolescents. Our results indicate that use of snuff is negatively associated with accretion of aBMD in adolescence and may be a signal of increased future fracture risk.PurposeBone mineral accrual in childhood and adolescence is a long-term primary preventive strategy of osteoporosis. Areal bone mineral density (aBMD) is a surrogate measure of bone strength and a predictor of fracture risk. The aim of this population-based 2-year follow-up cohort study was to explore associations between use of snuff and smoking and changes (∆) in aBMD in Norwegian girls and boys aged 15–17 years at baseline.MethodsThe first wave of the Tromsø study, Fit Futures was conducted from 2010 to 2011. Femoral neck (FN), total hip (TH), and total body (TB) bone mineral content (BMC) and aBMD were measured by dual-energy X-ray absorptiometry. Information on use of snuff, smoking habits, and other lifestyle related variables were collected through self-administered questionnaires. Two years later, during 2012–2013, the measurements were repeated in the second wave. The present study included 349 girls and 281 boys and compared “non-users” (n = 243 girls, 184 boys) with “users” (n = 105 girls, 96 boys) of snuff and “non-smokers” (n = 327 girls, 249 boys) with “smokers” (n = 21 girls, 31 boys) using linear regression adjusted for age, baseline height and weight, change in height and weight, pubertal maturation, physical activity, ethnicity, alcohol consumption, diagnosis known to affect bone, and medication known to affect bone. The influence of “double use” on bone accretion was also explored.ResultsIn girls, no associations between use of snuff and ∆aBMD were found. In boys, use of snuff was associated with reduced bone accretion in all ∆aBMD models. Sensitivity analysis with exclusion of “sometimes” users of snuff strengthened associations at femoral sites in girls and attenuated all associations in boys. In girls, no associations between smoking and ∆aBMD were found. In boys, only the association with TB ∆aBMD was significant in the fully adjusted models. In girls, “double users” analyses showed similar association to smoking. In boys, nearly all models showed statistically significant associations with a difference of ~ 1–2% in ∆aBMD between “non-users” and “double users” during 2 years of follow-up.ConclusionsOur results indicate that tobacco use in late adolescence could be detrimental to bone accretion and may be a signal of increased fracture risk in adult life.

Bone mass in newborns and its predictors.

Optimal bone mass (a function of foetal programming and adequate intrauterine bone mineral accrual) is essential for prevention of osteoporosis. The present study was planned with the objectives to describe newborn bone mass (NBBM) and study the associated factors. Observational study Patients: Singleton pregnant women ≤16 weeks gestation. Maternal factors and antenatal events: Dietary assessment (3 days-24-h diet recalls at ≤16 and 32-34 weeks), fetal femoral volume (FFV) assessment at 19 and 34 weeks, serum 25 hydroxyvitamin D (S.25OHD) and placental weight. Newborn anthropometric parameters, cord S.25OHD & IGF-1 level and NBBM by DXA (whole-body bone mineral content (BMC), bone mineral density (BMD) and bone area). Total 224 subjects were studied: 198 full-term and 26 preterm. The mean BMC, BMD and bone area for term newborns was 46.5 g (95% confidence interval [CI]: 45.35-47.66), 0.209 g/cm2 (95% CI: 0.206-0.212) and 221.6 cm2 (95% CI: 218.52-224.62), respectively. The mean placental weight was 403.2 ± 75.01 g (n = 72) while FFV was 0.71 ± 0.28 ml (19 weeks; n = 59) and 4.4 ± 1.17 ml (34 weeks; n = 33). Factors significantly associated with NBBM -gestational age at delivery, gestational weight gain, FFV at 19 weeks, placental weight, third-trimester maternal serum albumin and newborn anthropometric parameters (univariable analysis) and newborn birth weight, placental weight and FFV at 19 weeks (multivariable analysis). This study described NBBM among term newborns and birth weight, second-trimester FFV and placental weight were the associated factors.

Associations of Maternal Serum Perfluoroalkyl Substances Concentrations with Early Adolescent Bone Mineral Content and Density: The Health Outcomes and Measures of the Environment (HOME) Study.

Background:Per- and polyfluoroalkyl substances (PFAS) may impair bone accrual and strength via endocrine disruption and nuclear receptor agonism, but human studies are primarily of adults or cross-sectional.Objectives:We assessed associations of individual PFAS and their mixture during pregnancy with child bone mineral content (BMC) and areal bone mineral density (aBMD) at age 12 y.Methods:Among 206 mother–child pairs enrolled in a prospective cohort (2003–2006), we quantified perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS) in maternal serum collected during gestation or delivery. When children were age 12 y, we performed dual energy X-ray absorptiometry and calculated BMC, aBMD, and bone mineral apparent density (BMAD) -scores for six skeletal sites. We estimated covariate-adjusted -score differences per doubling of individual PFAS using linear regression and assessed the PFAS mixture using quantile g-computation and Bayesian kernel machine regression. We explored whether associations were modified by child’s sex or mediated by whole-body lean mass.Results:In covariate-adjusted models, we found that higher maternal serum concentrations of PFOA, PFNA, and the PFAS mixture were associated with lower total hip and forearm (one-third distal radius) BMC -scores in children. Differences in forearm BMC -scores were [95% confidence interval (CI): , 0.01] and (95% CI: , ) per doubling of PFOA and PFNA, respectively, and (95% CI: , ) per quartile increase in the PFAS mixture. Child’s sex modified PFOA associations for some skeletal sites; for example, differences in spine BMAD -score per doubling were (95% CI: , ) among males and 0.07 (95% CI: , 0.30) among females (modification ). Except for PFNA among females, these associations were not mediated by whole-body lean mass.Discussion:Maternal PFAS concentrations during pregnancy may be associated with lower bone mineral accrual and strength in early adolescence. https://doi.org/10.1289/EHP9424

A Longitudinal Study of Bone Mineral Accrual during Growth in Competitive Premenarcheal Rhythmic Gymnasts

The purpose of this investigation was to study whether prolonged competitive rhythmic gymnastics training influenced bone mineral accrual in premenarcheal girls. Eighty-nine girls (45 rhythmic gymnasts [RG] and 44 untrained controls [UC]) between 7 and 9 years of age were recruited and measured annually for four years (not all participants were measured at every occasion). Dual energy x-ray absorptiometry was used to assess the development of whole body (WB), femoral neck (FN) and lumbar spine (LS) bone mineral content (BMC). In addition, body composition, blood adipokine and jumping performance characteristics were obtained. For longitudinal analyses, hierarchical mixed-effects models were constructed to predict differences in the development of WB, FN and LS BMC between RG and UC groups, while accounting for differences in body composition, blood adipokine and jumping performance values. It appeared that from 8 years of age, RG had lower (p < 0.05) fat mass and leptin values, and higher (p < 0.05) jumping performance measures in comparison with UC girls. Hierarchical mixed-effects models demonstrated that RG had 71.9 ± 12.0, 0.23 ± 0.11 and 1.39 ± 0.42 g more (p < 0.05) WB, FN and LS BMC, respectively, in comparison with UC girls. In addition, WB, FN and LS BMC increased more (p < 0.05) between 7 to 12 years of age in RG girls in comparison with UC. In conclusion, these findings suggest that the prolonged exposure to competitive rhythmic gymnastics trainings in premenarcheal girls is associated with greater bone mineral accrual despite lower body fat mass and leptin values.

Bone accrual in children and adolescents with type 1 diabetes: current knowledge and future directions.

Skeletal fragility is now recognized as a significant complication of type 1 diabetes (T1D). Many patients with T1D develop the disease in childhood and prior to the attainment of peak bone mass and strength. This manuscript will review recent studies investigating the effects of T1D on skeletal development. Mild-to-moderate deficits in bone density, structure, and mineral accrual were reported early in the course of T1D in some but not all studies. Childhood-onset disease was associated with a more severe skeletal phenotype in some adult studies. Lower than expected bone mass for muscle size was been described. Hemoglobin A1c was negatively associated with bone density and structure in several studies, though the mechanism was not clear. The use of advanced imaging techniques has shown that the adverse effects of T1D on the developing skeleton extend beyond bone density to include abnormalities in bone size, shape, microarchitecture, and strength. Despite these gains, a uniform understanding of the pathophysiology underlying skeletal fragility in this disorder remains elusive. Longitudinal studies, especially in association with interventions to reduce hyperglycemia or improve muscle strength, are needed to inform bone healthcare in T1D.

Correlation between mandibular bone density, CD4 T-cells, and duration of HAART in HIV-infected children

Introduction: Perinatal HIV infection has decreased adverse bone health effects and mineral accrual. HIV-infected patients have a multifactorial origin, including HIV bone cell infections, inflammatory cytokine effects on osteoblast and osteoclast activity, and HAART. The research objective was to examine the correlation between the mandibular bone density and CD4 T-cells with HAART duration in HIV-infected children. Methods: The mandibular bone density in the HIV-infected pediatric population was evaluated using a panoramic radiograph. The research design was a cross-sectional and univariate regression analysis for the sampling method. Mandibular density analysis using Spearman and Pearson correlation and HAART duration using Kendall correlation. Thirty-five HIV-infected children and seventeen non-HIV-infected children were recruited. Results: This study showed the correlation between HIV and non-HIV infected children (p&lt;0.05). The correlation between CD4 T-cells and mandibular bone density was significant (p&lt;0.05). Long term HAART and mandibular bone density have a significant correlation (p&lt;0.001). This research showed correlations between mandibular bone density CD4 T-cells and duration of HAART in HIV-infected children. Conclusion: HIV-infected children require a regular mandibular cortical bone examination to detect the onset of osteopenia and osteoporosis to obtain appropriate therapy.

Childhood adiposity, adult adiposity, and bone health.

ABSTRACTImportanceChildhood and adolescence are critical periods for lifelong bone mineral accrual, but few studies have determined the impact of childhood adiposity on adult bone density.ObjectiveTo determine the long‐term impact of childhood adiposity on adult areal bone mineral density (aBMD) and the effect of adult adiposity on this relationship.MethodsWe conducted a longitudinal study of 1156 adults (56.3% men), for whom skinfold thickness (SFT) had been measured during childhood (6–18 years) and fat mass percentage (FMP) and aBMD were measured during adulthood (29–43 years). Adult aBMD in the lumbar spine (LS), femoral neck (FN), arms, and legs was measured using dual‐energy X‐ray absorptiometry. The direct effect of childhood SFT and its indirect effect through adult FMP on adult aBMD were estimated using general linear regression and a causal steps approach.ResultsSignificant positive associations between childhood SFT and adult aBMD were found in the LS in men (β = 0.089, P = 0.044) and in all the skeletal sites in women. With respect to the adult fat–bone relationship, high adult FMP was associated with low aBMD in most of the sites in men, but with high FN aBMD in women (β = 0.144, P = 0.002). Moreover, suppressive effects of adult FMP on the associations between childhood SFT and adult aBMD in the LS (−34.8%) and legs (−67.1%) of men, and a positive effect on the FN aBMD in women (17.0%) were identified.InterpretationChildhood adiposity appears to have a positive long‐term effect on adult aBMD, which may be reduced by adiposity in adult men but reinforced by adiposity in adult women.

Catalysis-Independent ENPP1 Protein Signaling Regulates Mammalian Bone Mass.

Biallelic ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency induces vascular/soft tissue calcifications in generalized arterial calcification of infancy (GACI), and low bone mass with phosphate-wasting rickets in GACI survivors (autosomal hypophosphatemic rickets type-2). ENPP1 haploinsufficiency induces early-onset osteoporosis and mild phosphate wasting in adults. Both conditions demonstrate the unusual combination of reduced accrual of skeletal mineral, yet excess and progressive heterotopic mineralization. ENPP1 is the only enzyme that generates extracellular pyrophosphate (PPi), a potent inhibitor of both bone and heterotopic mineralization. Life-threatening vascular calcification in ENPP1 deficiency is due to decreased plasma PPi; however, the mechanism by which osteopenia results is not apparent from an understanding of the enzyme's catalytic activity. To probe for catalysis-independent ENPP1 pathways regulating bone, we developed a murine model uncoupling ENPP1 protein signaling from ENPP1 catalysis, Enpp1T238A mice. In contrast to Enpp1asj mice, which lack ENPP1, Enpp1T238A mice have normal trabecular bone microarchitecture and favorable biomechanical properties. However, both models demonstrate low plasma Pi and PPi, increased fibroblast growth factor 23 (FGF23), and by 23 weeks, osteomalacia demonstrating equivalent phosphate wasting in both models. Reflecting findings in whole bone, calvarial cell cultures from Enpp1asj mice demonstrated markedly decreased calcification, elevated transcription of Sfrp1, and decreased nuclear β-catenin signaling compared to wild-type (WT) and Enpp1T238A cultures. Finally, the decreased calcification and nuclear β-catenin signaling observed in Enpp1asj cultures was restored to WT levels by knockout of Sfrp1. Collectively, our findings demonstrate that catalysis-independent ENPP1 signaling pathways regulate bone mass via the expression of soluble Wnt inhibitors such as secreted frizzled-related protein 1 (SFRP1), whereas catalysis dependent pathways regulate phosphate homeostasis through the regulation of plasma FGF23. © 2022 American Society for Bone and Mineral Research (ASBMR).

Gestational perfluoroalkyl substance exposures and early adolescent bone mineral density in the HOME Study

Background/Aim: Perfluoroalkyl substances (PFAS) may impair bone health via endocrine disruption and nuclear hormone receptor activation. Bone mineral accrual during adolescence is important for long-term bone health, but human studies of PFAS and bone mineral density are primarily in adults or use a cross-sectional study design. We estimated associations of gestational PFAS exposures with early adolescent areal bone mineral density (aBMD) in a prospective cohort study. Methods: We examined 225 pregnant mothers enrolled from 2003-2006 in Cincinnati, OH and their children in the HOME Study. We measured concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononaoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS) in maternal serum collected at 16 weeks gestation. When children were 12 years old, we measured lean body mass and total body, spine, total hip, femoral neck, and distal forearm (1/3 radius) aBMD with dual x-ray absorptiometry and calculated height-, age-, sex-, and race-specific aBMD z-scores. Using linear regression, we estimated covariate-adjusted associations in aBMD z-scores per doubling of gestational PFAS concentrations overall and stratified by sex. We estimated the proportion of total effects that were mediated by lean mass using structural equation modeling. Results: In adjusted models, higher PFOA concentrations were associated with lower aBMD z-scores of the forearm (β: -0.28, 95% CI: -0.49, -0.08), total hip (β: -0.28, 95% CI: -0.54, -0.02), and spine (β: -0.34, 95% CI: -0.61, -0.06) in males but not females. Lean mass mediated 29-50% of these associations. Higher PFHxS and PFNA concentrations were associated with lower aBMD z-scores of the forearm (PFHxS β: -0.11, 95% CI: -0.23, 0.00; PFNA β: -0.14, 95% CI: -0.35, 0.06), with no modification by sex or mediation by lean mass. PFOS was not associated with aBMD measures in either sex. Conclusions: Gestational PFAS exposures may reduce bone accrual in early adolescence, possibly in a sex-dependent manner.

Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-Affirming Hormones.

ContextHormonal interventions in adolescents with gender dysphoria may have adverse effects, such as reduced bone mineral accrual.ObjectiveTo describe bone mass development in adolescents with gender dysphoria treated with gonadotropin-releasing hormone analogues (GnRHa), subsequently combined with gender-affirming hormones.DesignObservational prospective study.Subjects51 transgirls and 70 transboys receiving GnRHa and 36 transgirls and 42 transboys receiving GnRHa and gender-affirming hormones, subdivided into early- and late-pubertal groups.Main Outcome MeasuresBone mineral apparent density (BMAD), age- and sex-specific BMAD z-scores, and serum bone markers.ResultsAt the start of GnRHa treatment, mean areal bone mineral density (aBMD) and BMAD values were within the normal range in all groups. In transgirls, the mean z-scores were well below the population mean. During 2 years of GnRHa treatment, BMAD stabilized or showed a small decrease, whereas z-scores decreased in all groups. During 3 years of combined administration of GnRHa and gender-affirming hormones, a significant increase of BMAD was found. Z-scores normalized in transboys but remained below zero in transgirls. In transgirls and early pubertal transboys, all bone markers decreased during GnRHa treatment.ConclusionsBMAD z-scores decreased during GnRHa treatment and increased during gender-affirming hormone treatment. Transboys had normal z-scores at baseline and at the end of the study. However, transgirls had relatively low z-scores, both at baseline and after 3 years of estrogen treatment. It is currently unclear whether this results in adverse outcomes, such as increased fracture risk, in transgirls as they grow older.