Associations of urinary metabolite concentrations of phthalates and phthalate replacements with body composition from mid-childhood to early adolescence.

BACKGROUND: Phthalates may adversely influence body composition by lowering anabolic hormones and activating peroxisome-proliferator activated receptor gamma. However, data are limited in adolescence when body mass distributions rapidly change and bone accrual peaks. Also, potential health effects of certain phthalate/replacements [e.g., di-2-ethylhexyl terephthalate (DEHTP)] have not been well studied. METHODS: Among 579 children in the Project Viva cohort, we used linear regression to evaluate associations of urinary concentrations of 19 phthalate/replacement metabolites from mid-childhood (median: 7.6 years; 2007-2010) with annualized change in areal bone mineral density (aBMD) and lean, total fat, and truncal fat mass as measured by dual-energy X-ray absorptiometry between mid-childhood and early adolescence (median: 12.8 years). We used quantile g-computation to assess associations of the overall chemical mixture with body composition. We adjusted for sociodemographics and tested for sex-specific associations. RESULTS: Urinary concentrations were highest for mono-2-ethyl-5-carboxypentyl phthalate [median (IQR): 46.7 (69.1) ng/mL]. We detected metabolites of most replacement phthalates in a relatively small number of participants [e.g., 28% for mono-2-ethyl-5-hydrohexyl terephthalate (MEHHTP; metabolite of DEHTP)]. Detectable (vs. non-detectable) MEHHTP was associated with less bone and greater fat accrual in males and greater bone and lean mass accrual in females [e.g., change in aBMD Z-score/year (95% CI): -0.049 (-0.085, -0.013) in males versus 0.042 (0.007, 0.076) in females; pinteraction<0.01]. Children with higher concentrations of mono-oxo-isononyl phthalate and mono-3-carboxypropyl phthalate (MCPP) had greater bone accrual. Males with higher concentrations of MCPP and mono-carboxynonyl phthalate had greater accrual of lean mass. Other phthalate/replacement biomarkers, and their mixtures, were not associated with longitudinal changes in body composition. CONCLUSIONS: Concentrations of select phthalate/replacement metabolites in mid-childhood were associated with changes in body composition through early adolescence. As use of phthalate replacements such as DEHTP may be increasing, further investigation can help better understand the potential effects of early-life exposures.

Yoga as an intervention to promote bone and mental health in adolescent females with anorexia nervosa: a pilot study.

In this randomized pilot study, we examined the effects of yoga intervention on axial and peripheral bone mineral density (BMD), disordered eating cognitions, anxiety, and depression in adolescent girls with anorexia nervosa (AN). Fifteen young women aged 13-18 years with AN or atypical AN were randomized to either a Yoga group (n = 7), including twice-weekly yoga for 24 weeks plus standard outpatient care, or Non-Yoga group (n = 8), who received standard outpatient care alone. Data from anthropometrics, mental health and eating behavior questionnaires, dual-energy x-ray absorptiometry, and peripheral quantitative computed tomography measurements were obtained at baseline and 6 months. The adjunct of yoga to standard treatment resulted in statistically significant improvement of axial BMD, depression, and disordered eating cognitions in comparison to the Non-Yoga group. In conclusion, a gentle yoga intervention may be beneficial for improving bone and mental health in adolescent females with AN.

Changes in Bone Marrow Adipose Tissue in Transgender and Gender Non-Conforming Youth Undergoing Pubertal Suppression: A Pilot Study.

Pubertal suppression with gonadotropin-releasing hormone (GnRH) agonists in transgender and gender non-conforming (TGNC) youth may affect acquisition of peak bone mass. Bone marrow adipose tissue (BMAT) has an inverse relationship with bone mineral density (BMD). To evaluate the effect of pubertal suppression on BMAT, in this pilot study we prospectively studied TGNC youth undergoing pubertal suppression and cisgender control participants with similar pubertal status over a 12-month period. BMD was measured by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Magnetic Resonance T1 relaxometry (T1-R) and spectroscopy (MRS) were performed to quantify BMAT at the distal femur. We compared the change in BMD, T1-R values, and MRS lipid indices between the two groups. Six TGNC (two assigned female and four assigned male at birth) and three female control participants (mean age 10.9 and 11.7 years, respectively) were enrolled. The mean lumbar spine BMD Z-score declined by 0.29 in the TGNC group, but increased by 0.48 in controls (between-group difference 0.77, 95% CI: 0.05, 1.45). Similar findings were observed with the change in trabecular volumetric BMD at the 3% tibia site (-4.1% in TGNC, +3.2% in controls, between-group difference 7.3%, 95% CI: 0.5%-14%). Distal femur T1 values declined (indicative of increased BMAT) by 7.9% in the TGNC group, but increased by 2.1% in controls (between-group difference 10%, 95% CI: -12.7%, 32.6%). Marrow lipid fraction by MRS increased by 8.4% in the TGNC group, but declined by 0.1% in controls (between-group difference 8.5%, 95% CI: -50.2%, 33.0%). In conclusion, we observed lower bone mass acquisition and greater increases in BMAT indices by MRI and MRS in TGNC youth after 12 months of GnRH agonists compared with control participants. Early changes in BMAT may underlie an alteration in bone mass acquisition with pubertal suppression, including alterations in mesenchymal stem cells within marrow.

Safety and Efficacy of 48 and 96 Weeks of Alendronate in Children and Adolescents With Perinatal Human Immunodeficiency Virus Infection and Low Bone Mineral Density for Age.

No safety concerns were identified in a randomized, crossover study of alendronate/placebo in youth with perinatal HIV infection and low bone mineral density (BMD). BMD improved with 48 weeks of alendronate and continued to improve with an additional 48 weeks of therapy. Gains were largely maintained 48 weeks after stopping alendronate.

Bone Health in Pediatric Patients with IBD: What Is New?

PURPOSE OF THE REVIEW: Patients with inflammatory bowel disease (IBD) have increased bone fragility, demonstrated by increased fracture risk, and often have low bone density and altered bone geometry, but the underlying pathophysiology remains poorly understood. RECENT FINDINGS: Children and adolescents with IBD appear to have decreased bone formation, at diagnosis, which frequently improves with treatment of their underlying IBD. There is a growing body of evidence regarding how the immune system interacts with bone metabolism. There are likely multi-factorial etiologies that contribute to suboptimal bone accrual and subsequent lack of peak bone mass attainment in growing patients with IBD. There appears to be differential effects dependent upon IBD sub-type and bone compartment. Pediatric patients with IBD require recognition of several risk factors that may adversely impact their bone accrual. Future studies are necessary to further delineate the effects of IBD on pediatric bone health.

DXA in Children and Adolescents.

DXA plays a critical role in assessing skeletal health and disease, as well as, fat and muscle status in children and adolescents. Quality DXA requires training, expertise and attention to details, as in adults, but there are key differences in performing and interpretations in children. These include choice of measurement site, skills required, reference data and software, and considerations for indications and underlying disorders to facilitate correct interpretation. The International Society for Clinical Densitometry (ISCD) has been pivotal in establishing official positions and training for people who are interested in performing or interpreting such examinations, and guiding clinicians who may request such studies. However training in the performance and interpretation of scans of individuals with more complex needs falls outside the scope of this review, and consideration should be given to refer such examinations to a specialist pediatric DXA unit. Others may be scanned and reported by those with expertise in densitometry, as long as due diligence is paid to standard quality procedures, as well as knowledge of the special circumstances and training required for this field. In this invited review we outline some of these considerations, highlight key messages, and provide some appropriate references to help guide clinicians, technologists and scientists involved or interested in DXA use in children and adolescents.

Adolescents and Bone Health.

Adolescence is a critical time for the acquisition of peak bone mass. There are modifiable factors that may influence bone health in an adolescent. For those at risk for bone fragility, initial management includes optimization of calcium and vitamin D, weight-bearing exercise, and maintenance of a normal body weight. In certain scenarios, bisphosphonate treatment is indicated, as is reviewed. How hormonal contraceptives affect bone mineral density is unclear, but in patients with risk factors or known bone fragility, prescribers should consider their skeletal effects. Some conditions, including restrictive eating disorders and primary ovarian insufficiency, warrant long-term monitoring of bone health.

Vitamin D3 Supplementation Increases Spine Bone Mineral Density in Adolescents and Young Adults With Human Immunodeficiency Virus Infection Being Treated With Tenofovir Disoproxil Fumarate: A Randomized, Placebo-Controlled Trial.

Background: Tenofovir disoproxil fumarate (TDF) decreases bone mineral density (BMD). We hypothesized that vitamin D3 (VITD3) would increase BMD in youth receiving TDF. Methods: This was a randomized, double-blind, placebo-controlled trial of directly observed VITD3 vs placebo every 4 weeks for 48 weeks in youth aged 16-24 years with HIV, RNA load <200 copies/mL, taking TDF-containing combination antiretroviral therapy (TDF-cART) for ≥180 days. Participants (N = 214) received a daily multivitamin containing VITD3 400 IU and calcium 162 mg, plus monthly randomized VITD3 50000 IU (n = 109) or placebo (n = 105). Outcome was change from baseline to week 48 in lumbar spine BMD (LSBMD). Data presented are median (Q1, Q3). Results: Participants were aged 22.0 (21.0, 23.0) years, 84% were male, and 74% were black/African American. At baseline, 62% had 25-hydroxy vitamin D (25-OHD) <20 ng/mL. Multivitamin adherence was 49% (29%, 69%), and VITD3/placebo adherence 100% (100%, 100%). Vitamin D intake was 2020 (1914, 2168) and 284 (179, 394) IU/day, and serum 25-OHD concentration was 36.9 (30.5, 42.4) and 20.6 (14.4, 25.8) ng/mL at 48 weeks in VITD3 and placebo groups, respectively (P < .001). From baseline to week 48, LSBMD increased by 1.15% (-0.75% to 2.74%) in the VITD3 group (n = 99; P < .001) and 0.09% (-1.49% to 2.61%) in the placebo group (n = 89; P = .25), without between-group difference (P = .12). VITD3 group changes occurred with baseline 25-OHD <20 ng/mL (1.17% [-.82% to 2.90%]; P = .004) and ≥20 ng/mL (0.93% [-.26% to 2.15%]; P = .033). Conclusions: For youth taking TDF-cART, LSBMD increased through 48 weeks with VITD3 plus multivitamin, but not with placebo plus multivitamin, independent of baseline vitamin D status. Clinical Trials Registration: NCT01751646.

Single Ultra-High-Dose Cholecalciferol to Prevent Vitamin D Deficiency in Pediatric Hematopoietic Stem Cell Transplantation.

Vitamin D deficiency is prevalent among childhood hematopoietic stem cell transplantation (HSCT) recipients and associated with inferior survival at 100 days after transplantation. Achieving and maintaining therapeutic vitamin D levels in HSCT recipients is extremely challenging in the first 3 to 6 months after transplantation due to poor compliance in the setting of mucositis and the concomitant use of critical transplantation drugs that interfere with vitamin D absorption. We sought to evaluate the safety and efficacy of a single, ultra-high-dose of vitamin D given before childhood HSCT to maintain levels in a therapeutic range during the peritransplantation period. Ten HSCT recipients with pretransplantation 25-OH vitamin D (25OHD) level <50 ng/mL and with no history of hypercalcemia, nephrolithiasis, or pathological fractures were enrolled on this pilot study. A single enteral vitamin D dose (maximum 600,000 IU) was administered to each patient based on weight and pretransplantation vitamin D level before the day of HSCT. Vitamin D levels between 30 and 150 ng/mL were considered therapeutic. All patients received close clinical observation and monitoring of 25OHD levels, calcium, phosphate, parathyroid hormone, urine calcium/creatinine ratio, and n-telopeptide for safety and efficacy assessment. The mean age of the study subjects was 5.8 ± 4.9 years, and the mean pretransplantation 25OHD level was 28.9 ± 13.1 ng/mL. All patients tolerated single, ultra-high-oral dose of vitamin D under direct medical supervision. No other oral vitamin D supplements were administered during the observation window of 8 weeks. Three of 10 patients received 400 IU/day of vitamin D in parenteral nutrition only for 5 days during the study window. A mean peak serum vitamin D level of 80.4 ± 28.6 ng/mL was reached at a median of 9 days after the vitamin D dose. All patients achieved a therapeutic vitamin D level of >30 ng/mL. Mean vitamin D levels were sustained at or above 30 ng/mL during the 8-week observation window. There were no electrolyte abnormalities attributed to the ultra-high-dose of vitamin D. Most patients had mildly elevated urine calcium/creatinine ratios during treatment, but none showed clinical or radiologic signs of nephrocalcinosis or nephrolithiasis. Our findings indicate that single ultra-high-oral dose vitamin D treatment given just before HSCT is safe and well tolerated in the immediate peritransplant period in children. Patients in our study were able to achieve and sustain therapeutic vitamin D levels throughout the critical period during which vitamin D insufficiency is associated with decreased overall survival. Larger prospective studies are needed to address the impact of single ultra-high-dose vitamin D treatment on HSCT outcomes.

Bone fragility in Turner syndrome: Fracture prevalence and risk factors determined by a national patient survey.

OBJECTIVE: Osteoporosis is considered a comorbidity of adult women with Turner syndrome (TS). Limited data are available on fracture prevalence in girls and women with this diagnosis. We aimed to determine the prevalence of fractures in individuals with TS in the United States and identify risk factors for fracture. DESIGN: Girls and women with TS were invited to participate in an anonymous, self-report, national survey from November 2016 to March 2017. Non-TS controls were obtained through direct contacts of TS participants. RESULTS: During childhood (0-12 years), adolescence (13-25 years) and young adulthood (26-45 years), there was no difference between TS and controls in fracture prevalence. Girls and women with TS were more likely to report upper extremity fractures, whereas controls were more likely to report phalangeal fractures. Older women (>45 years) with TS were more likely to fracture than non-TS controls (P = .01). Balance problems were more common in individuals with TS than controls (26.5% vs 14.8%, P = .0006). In TS, those reporting balance problems were 54% more likely to have a prior fracture than those without balance problems (OR=1.54, 95% CI 1.03, 2.30), even after controlling for age. There was no significant association between balance problems and fractures among controls. CONCLUSIONS: In a nationwide survey, there was no difference in fracture prevalence in younger women with TS compared with controls. However, the location of fractures differed. After controlling for age, impaired balance was associated with an increased fracture risk in TS and may be an underrecognized risk factor for fracture in this population.

Proton Pump Inhibitor Use, H2-Receptor Antagonist Use, and Risk of Incident Clinical Vertebral Fracture in Women.

The few prospective studies examining the relation between proton pump inhibitor (PPI) use and risk of vertebral fracture (VF) suggest a higher risk, but the magnitude of the association has been inconsistent. Moreover, no prospective studies have examined the association between substantially longer duration of PPI use and VF risk. Our objective was to determine the association between PPI use, H2RA use, and incident clinical VF in women. We conducted a prospective study in 55,545 women participating in the Nurses' Health Study. PPI and H2RA use was assessed by questionnaire every 4 years. Self-reports of VF were confirmed by medical record. Our analysis included 547 incident VF cases (2002-2014). The multivariate adjusted relative risk (MVRR) of VF for women taking PPIs was 1.29 (95% CI 1.04-1.59) compared with non-users. Longer duration of PPI use was associated with higher VF risk (MVRR 1.16 [0.90-1.49] for < 4 years; 1.27 [0.93-1.73] for 4-7.9 years; 1.64 [1.02-2.64] for ≥ 8 years; ptrend = 0.01). The MVRR of VF for women taking H2RAs was 1.22 (0.90-1.67) compared with non-users. Longer duration of H2RA use was not associated with VF risk (MVRR 1.16 [0.88-1.53] for < 4 years; 0.98 [0.60-1.59] for ≥ 4 years; ptrend = 0.72). PPI use is independently associated with a modestly higher risk of VF and the risk increases with longer duration of use. There was no statistically significant association between H2RA use and VF risk. Our findings add to the growing evidence suggesting caution with PPI use, particularly with longer duration of use.

Proceedings of the 2017 Santa Fe Bone Symposium: Insights and Emerging Concepts in the Management of Osteoporosis.

The 18th Annual Santa Fe Bone Symposium was held on August 4-5, 2017, in Santa Fe, New Mexico, USA. The symposium convenes health-care providers and clinical researchers to present and discuss clinical applications of recent advances in research of skeletal diseases. The program includes lectures, oral presentations by endocrinology fellows, case-based panel discussions, and breakout sessions on topics of interest, with emphasis on participation and interaction of all participants. Topics included the evaluation and treatment of adult survivors with pediatric bone diseases, risk assessment and management of atypical femur fractures, nonpharmacologic strategies in the care of osteoporosis, and skeletal effects of parathyroid hormone with opportunities for therapeutic intervention. Management of skeletal complications of rheumatic diseases was discussed. Insights into sequential and combined use of antiresorptive agents were presented. Individualization of patient treatment decisions when clinical practice guidelines may not be applicable was covered. Challenges and opportunities with osteoporosis drug development were discussed. There was an update on progress of Bone Health TeleECHO (Bone Health Extension for Community Healthcare Outcomes), a teleconferencing strategy for sharing knowledge and expanding capacity to deliver best-practice skeletal health care.

Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. METHODS: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. RESULTS: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. CONCLUSIONS: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.

Decline in Bone Mass With Tenofovir Disoproxil Fumarate/Emtricitabine Is Associated With Hormonal Changes in the Absence of Renal Impairment When Used by HIV-Uninfected Adolescent Boys and Young Men for HIV Preexposure Prophylaxis.

BACKGROUND: We aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)-related bone toxicity. METHODS: In a study of daily TDF/emtricitabine (FTC) preexposure prophylaxis (PrEP) in human immunodeficiency virus (HIV)-uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis, creatinine, and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups. RESULTS: There were 101 participants, median age 20 years (range 15 to 22). Compared with low drug exposure, high-exposure participants showed increase from baseline in PTH and decline in FGF23 by study week 4, with no differences in creatinine, phosphate, or TRP. At 48 weeks, the median (interquartile range) percent decline in total hip BMD was greater in those with high- compared to low- exposure (-1.59 [2.77] vs +1.54 [3.34] %, respectively; P = .001); in high-exposure participants, this correlated with week 4 TFV-DP (inversely; r = -0.60, P = .002) and FGF23 (directly; r = 0.42; P = .039) but not other variables. CONCLUSIONS: These findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group. CLINICAL TRIALS REGISTRATION: NCT01769469.

Restrictive Eating Disorders and Skeletal Health in Adolescent Girls and Young Women.

This article reviews the effects of restrictive eating disorders on bone health. The relationship between eating disorders and amenorrhea is discussed in detail. The pathologic impact of malnutrition on bone is explored by examining the results of studies using various available imaging techniques. The multiple hormonal alterations seen in adolescents and young women with anorexia nervosa are reviewed, as well as how these alterations may influence bone turnover, density, structure, and strength. The diagnostic clinical evaluation for adolescents and young women with these disorders is also outlined. Available treatment options, including those that hold promise for efficacy, as well as those we deemed to be ineffective, are considered from both the clinical and mechanistic standpoints. Finally, future research opportunities are offered, including intriguing work in the area of fat and bone interactions.

Bone Mineralization and Fracture Risk Assessment in the Pediatric Population.

Identifying children most susceptible to clinically significant fragility fractures (low trauma fractures or vertebral compression fractures) or recurrent fractures is an important issue facing general pediatricians and subspecialists alike. Over the last decade, several imaging technologies, including dual-energy X-ray absorptiometry and peripheral quantitative computed tomography, have become useful to identify abnormal bone mineralization in children and in adolescents. This review aimed to summarize the latest literature on the utility of these modalities as they pertain to use in pediatrics. In addition, we review several disease states associated with poor bone health and increased fracture risk in children, and discuss the implications of low bone mineral density in these patients. Finally, we will highlight the gaps in knowledge with regard to pediatric bone health and make recommendations for future areas of research.

Bone marrow fat content in 70 adolescent girls with anorexia nervosa: Magnetic resonance imaging and magnetic resonance spectroscopy assessment.

BACKGROUND: Adolescents and women with anorexia nervosa have increased bone marrow fat and decreased bone formation, at least in part due to hormonal changes leading to preferential stem cell differentiation to adipocytes over osteoblasts. OBJECTIVE: The purpose of this study was to evaluate marrow fat content and correlate with age and disease severity using knee MRI with T1 relaxometry (T1-R) and MR spectroscopy (MRS) in 70 adolescents with anorexia nervosa. MATERIALS AND METHODS: We enrolled 70 girls with anorexia nervosa who underwent 3-T knee MRI with coronal T1-W images, T1-R and single-voxel proton MRS at 30 and 60 ms TE. Metaphyses were scored visually on the T1-W images for red marrow. Visual T1 score, T1 relaxometry values, MRS lipid indices and fat fractions were analyzed by regression on age, body mass index (BMI) and bone mineral density (BMD) as disease severity markers. MRS measures included unsaturated fat index, T2 water, unsaturated and saturated fat fractions. RESULTS: All red marrow measures declined significantly with age. T1-R values were associated negatively with BMI and BMD for girls ≤16 years (P=0.03 and P=0.002, respectively) and positively for those≥17 years (P=0.05 and P=0.003, respectively). MRS identified a strong inverse association between T2 water and saturated fat fraction from 60 ms TE data (r=-0.85, P<0.0001). There was no association between unsaturated fat index and BMI or BMD. CONCLUSIONS: The association between T1 and BMI and BMD among older girls suggests more marrow fat in those with severe anorexia nervosa. In contrast, the physiological association between marrow fat content and age remained dominant in younger patients. The strong association between T2 water and saturated fat may relate to the restricted mobility of water with increasing marrow fat.