Targeted Gene Sequencing, Bone Health, and Body Composition in Cornelia de Lange Syndrome

The aim of this study was to evaluate bone health and body composition by dual-energy X-ray absorptiometry (DXA) in individuals with Cornelia de Lange Syndrome (CdLS). Overall, nine individuals with CdLS (five females, all Caucasian, aged 5–38 years) were assessed. Total body less head (TBLH) and lumbar spine (LS) scans were performed, and bone serum biomarkers were determined. Molecular analyses were carried out and clinical scores and skeletal features were assessed. Based on deep sequencing of a custom target gene panel, it was discovered that eight of the nine CdLS patients had potentially causative genetic variants in NIPBL. Fat and lean mass indices (FMI and LMI) were 3.4–11.1 and 8.4–17.0 kg/m2, respectively. For TBLH areal bone mineral density (aBMD), after adjusting for height for age Z-score of children and adolescents, two individuals (an adolescent and an adult) had low BMD (aBMD Z-scores less than –2.0 SD). Calcium, phosphorus, 25-OH-vitamin D, parathyroid hormone, and alkaline phosphatase levels were 2.08–2.49 nmol/L, 2.10–3.75 nmol/L, 39.94–78.37 nmol/L, 23.4–80.3 pg/mL, and 43–203 IU/L, respectively. Individuals with CdLS might have normal adiposity and low levels of lean mass measured with DXA. Bone health in this population seems to be less of a concern during childhood and adolescence. However, they might be at risk for impaired bone health due to low aBMD in adulthood.

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Creatine Supplementation (3 g/d) and Bone Health in Older Women: A 2-Year, Randomized, Placebo-Controlled Trial

The Journals of Gerontology Series A ◽

10.1093/gerona/glz162 ◽

2019 ◽

Vol 75 (5) ◽

pp. 931-938 ◽

Cited By ~ 3

Author(s):

Lucas Peixoto Sales ◽

Ana Jéssica Pinto ◽

Samara Ferrari Rodrigues ◽

Jackeline Couto Alvarenga ◽

Natalia Gonçalves ◽

...

Keyword(s):

Postmenopausal Women ◽

Lean Mass ◽

Bone Health ◽

Dietary Intervention ◽

Bone Markers ◽

Controlled Trial ◽

Creatine Supplementation ◽

Areal Bone Mineral Density ◽

Mineral Density ◽

Group Randomized Trial

Abstract Background Creatine supplementation could be a nonexpensive, safe, and effective dietary intervention to counteract bone loss. The aim of this study was to investigate whether long-term creatine supplementation can improve bone health in older, postmenopausal women. Methods A double-blind, placebo-controlled, parallel-group, randomized trial was conducted between November 2011 and December 2017 in Sao Paulo, Brazil. Two hundred postmenopausal women with osteopenia were randomly allocated to receive either creatine monohydrate (3 g/d) or placebo for 2 years. At baseline and after 12 and 24 months, we assessed areal bone mineral density (aBMD; primary outcome), lean and fat mass (through dual X-ray absorptiometry), volumetric BMD and bone microarchitecture parameters, biochemical bone markers, physical function and strength, and the number of falls and fractures. Possible adverse effects were self-reported. Results Lumbar spine (p < .001), femoral neck (p < .001), and total femur aBMD (p = .032) decreased across time; however, no interaction effect was observed (all p > .050). Bone markers, microarchitecture parameters, and the number of falls/fractures were not changed with creatine (all p > .050). Lean mass and appendicular skeletal muscle mass increased throughout the intervention (p < .001), with no additive effect of creatine (p = .731 and p = .397, respectively). Creatine did not affect health-related laboratory parameters. Conclusion Creatine supplementation more than 2 years did not improve bone health in older, postmenopausal women with osteopenia, nor did it affect lean mass or muscle function in this population. This refutes the long-lasting notion that this dietary supplement alone has osteogenic or anabolic properties in the long run. Clinical trial registry Clinicaltrials.gov: NCT: 01472393.

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Factors Associated With Bone Health Status of Malaysian Pre-adolescent Children in the PREBONE-kids Study

10.21203/rs.3.rs-77049/v1 ◽

2020 ◽

Author(s):

Chung Yuan Chang ◽

Kanimolli Arasu ◽

Soon Yee Wong ◽

Shu Hwa Ong ◽

Wai Yew Yang ◽

...

Keyword(s):

Physical Activity ◽

Vitamin D ◽

Body Composition ◽

Health Status ◽

Bone Mineral ◽

Lean Mass ◽

Bone Health ◽

Calcium Intake ◽

Mineral Density ◽

25 Oh Vitamin D

Abstract Background: Modifiable lifestyle factors and body composition can affect the attainment of peak bone mass during childhood. This study performed a cross-sectional analysis of the determinants of bone health among pre-adolescent Malaysian children with habitually low calcium intakes and vitamin D status in Kuala Lumpur (PREBONE-Kids Study). Methods: Body composition, bone mineral density (BMD), and bone mineral content (BMC) at the lumbar spine (LS) and total body (TB) were assessed using dual-energy X-ray absorptiometry (DXA). Calcium intake was assessed using 1-week diet history, MET (metabolic equivalent of task) score using cPAQ questionnaire, and serum 25(OH) vitamin D using LC-MS/MS. Results: The mean calcium intake was 348.8 ± 180.1 mg/day and mean serum 25-OH vitamin D level was 43.9 ± 14.5nmol/L. In boys, lean mass (LM) was significantly associated with LSBMC (β = 0.539, p<0.001), LSBMD (β=0.607, p<0.001), TBBMC (β=0.675, p<0.001) and TBBMD (β= 0.481, p<0.01). Height was significantly associated with LSBMC (β =0.346, p<0.001) and TBBMC (β =0.282, p<0.001) while fat mass (FM) (β=0.261, p=0.034) and MET score (β =0.163, p=0.026) were significant predictors of TBBMD. Among girls, LM was significantly associated with LSBMC (β = 0.620, p<0.001), LSBMD (β=0.700, p<0.001), TBBMC (β=0.542, p<0.001) and TBBMD (β= 0.747, p<0.001). Calcium intake was a significant predictor of LSBMC (β=0.102, p=0.034), TBBMC (β=0.122, p<0.001) and TBBMD (β=0.196, p=0.002) in girls. Lean mass (LM) was weakly correlated with MET scores (r = 0.205, p = 0.001) but not protein (r = 0.055, p = 0.393) or energy intake (r = 0.101, p = 0.117). MET score (β = 0.207, p = 0.043) was a significant predictor of LM in boys but no factor was found to predict LM in girls. Conclusion: LM is the major determinant of BMC and BMD among pre-adolescent Malaysian children and physical activity is a significant predictor of LM in boys. Encouraging physical activity, calcium intake and optimum diets that build lean body mass should be the focus for developing public health guidance to ensure optimal bone health status during rapid growth.

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Body composition in childhood: effects of normal growth and disease

Proceedings of The Nutrition Society ◽

10.1079/pns2003261 ◽

2003 ◽

Vol 62 (2) ◽

pp. 521-528 ◽

Cited By ~ 38

Author(s):

J. C. K. Wells

Keyword(s):

Body Composition ◽

Childhood Obesity ◽

Fat Mass ◽

Lean Mass ◽

Normal Weight ◽

Fat Free Mass ◽

General Interest ◽

Childhood And Adolescence ◽

Adult Disease ◽

Increased Risk

Body composition in children is of increasing interest within the contexts of childhood obesity, clinical management of patients and nutritional programming as a pathway to adult disease. Energy imbalance appears to be common in many disease states; however, body composition is not routinely measured in patients. Traditionally, clinical interest has focused on growth or nutritional status, whereas more recent studies have quantified fat mass and lean mass. The human body changes in proportions and chemical composition during childhood and adolescence. Most of the weight gain comprises lean mass rather than fat. In general, interest has focused on percentage fat, and less attention has been paid to the way in which lean mass varies within and between individuals. In the general population secular trends in BMI have been widely reported, indicating increasing levels of childhood obesity, which have been linked to reduced physical activity. However, lower activity levels may potentially lead not only to increased fatness, but also to reduced lean mass. This issue merits further investigation. Diseases have multiple effects on body composition and may influence fat-free mass and/or fat mass. In some diseases both components change in the same direction, whereas in other diseases, the changes are contradictory and may be concealed by relatively normal weight. Improved techniques are required for clinical evaluations. Both higher fatness and reduced lean mass may represent pathways to an increased risk of adult disease.

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Influence of Mediterranean Diet Adherence and Physical Activity on Bone Health in Celiac Children on a Gluten-Free Diet

Nutrients ◽

10.3390/nu13051636 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1636

Author(s):

Teresa Nestares ◽

Rafael Martín-Masot ◽

Carlos de Teresa ◽

Rocío Bonillo ◽

José Maldonado ◽

...

Keyword(s):

Physical Activity ◽

Mediterranean Diet ◽

Bone Mineral ◽

Lean Mass ◽

Bone Health ◽

Gluten Free ◽

Z Score ◽

Mineral Density ◽

Diet Adherence ◽

Mediterranean Diet Adherence

We aimed to assess the influence of the Mediterranean Diet adherence and physical activity (PA) on body composition, with a particular focus on bone health, in young patients with celiac disease (CD). The CD group (n = 59) included children with CD with a long (>18 months, n = 41) or recent (<18 months, n = 18) adherence to a gluten-free diet (GFD). The non-celiac group (n = 40) included non-celiac children. After adjusting for potential confounders, the CD group showed lower body weight (p = 0.034), lean mass (p = 0.003), bone mineral content (p = 0.006), and bone Z-score (p = 0.036) than non-celiac children, even when the model was further adjusted for adherence to a GFD for at least 18 months. Among CD children, spending greater time in vigorous physical activity was associated with higher lean mass (p = 0.020) and bone mineral density with evidence of statistical significance (p = 0.078) regardless of the time they followed a GFD. In addition, a greater Mediterranean Diet adherence was associated with a higher bone Z-score (p = 0.020). Moreover, lean mass was strongly associated with bone mineral density and independently explained 12% of its variability (p < 0.001). These findings suggest the importance of correctly monitoring lifestyle in children with CD regarding dietary habits and PA levels to improve lean mass and, consequently, bone quality in this population.

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Muscular Fitness Mediates the Association between 25-Hydroxyvitamin D and Areal Bone Mineral Density in Children with Overweight/Obesity

Nutrients ◽

10.3390/nu11112760 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2760 ◽

Cited By ~ 3

Author(s):

Jose J. Gil-Cosano ◽

Luis Gracia-Marco ◽

Esther Ubago-Guisado ◽

Jairo H. Migueles ◽

Jose Mora-Gonzalez ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Bone Health ◽

Handgrip Strength ◽

Height Velocity ◽

Areal Bone Mineral Density ◽

Mineral Density ◽

Muscular Fitness ◽

Standing Long Jump ◽

Long Jump

The association between vitamin D [25(OH)D] and bone health has been widely studied in children. Given that 25(OH)D and bone health are associated with muscular fitness, this could be the cornerstone to understand this relationship. Hence, the purpose of this work was to examine if the relation between 25(OH)D and areal bone mineral density (aBMD) was mediated by muscular fitness in children with overweight/obesity. Eighty-one children (8-11 years, 53 boys) with overweight/obesity were included. Body composition was measured with dual energy X-ray Absorptiometry (DXA), 25(OH)D was measured in plasma samples and muscular fitness was assessed by handgrip and standing long jump tests (averaged z-scores were used to represent overall muscular fitness). Simple mediation analyses controlling for sex, years from peak height velocity, lean mass and season were carried out. Our results showed that muscular fitness z-score, handgrip strength and standing long jump acted as mediators in the relationship between 25(OH)D and aBMD outcomes (percentages of mediation ranged from 49.6% to 68.3%). In conclusion, muscular fitness mediates the association of 25(OH)D with aBMD in children with overweight/obesity. Therefore, 25(OH)D benefits to bone health could be dependent on muscular fitness in young ages.

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Serum FSH Is Associated with BMD, Bone Marrow Adiposity and Body Composition in the AGES-Reykjavik Study of Older Adults

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa922 ◽

2020 ◽

Author(s):

Annegreet G Veldhuis-Vlug ◽

Gina N Woods ◽

Sigurdur Sigurdsson ◽

Susan K Ewing ◽

Phuong T Le ◽

...

Keyword(s):

Older Adults ◽

Bone Marrow ◽

Body Composition ◽

Body Fat ◽

Fat Mass ◽

Lean Mass ◽

Mineral Density ◽

1H Mrs ◽

Testosterone Levels ◽

Marrow Adiposity

Abstract Context Follicle stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high post menopause. Loss of bone mineral density (BMD) and gain of bone marrow adiposity (BMA) and body fat mass also occur during this time. In mice, blocking the action of FSH increases bone mass and decreases fat mass. Objective To investigate the associations between endogenous FSH levels and BMD, BMA and body composition in older adults, independent of estradiol and testosterone levels. Design, setting and participants Older adults from the AGES-Reykjavik Study, an observational cohort study. Main outcome measures Areal BMD, total body fat, and lean mass were measured with DXA. Lumbar vertebral BMA was measured by 1H-MRS. Volumetric BMD and visceral and subcutaneous adipose tissue (VAT, SAT) areas were measured with QCT. The least squares means procedure was used to determine sex-hormone adjusted associations between quartiles of serum FSH and BMD, BMA, and body composition. Results In women (N=238, mean age 81y), those in the highest FSH quartile, compared with the lowest quartile, had lower adjusted mean spine integral BMD (-8.6%), lower spine compressive strength index (-34.8%), higher BMA (+8.4%), lower weight (-8.4%), lower VAT (-17.6%), lower lean mass (-6.1%), and lower fat mass (-11.9%) (all P < 0.05). In men, FSH level was not associated with any outcome. Conclusions Older postmenopausal women with higher FSH levels have higher BMA, but lower BMD and lower fat and lean mass, independent of estradiol and testosterone levels. Longitudinal studies are needed to better understand the underlying mechanisms.

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Body Composition and Its Relationship to Growth and Bone Mass in Patients with Thalassemia

Blood ◽

10.1182/blood.v112.11.3890.3890 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3890-3890

Author(s):

Ellen Fung ◽

Yan Xu ◽

Janet Kwiatkowski ◽

Sylvia Titi Singer ◽

Ashutosh Lal ◽

...

Keyword(s):

Physical Activity ◽

Body Composition ◽

Nutritional Status ◽

Bone Mass ◽

Body Fat ◽

Lean Mass ◽

Bone Health ◽

Calcium Intake ◽

Z Score ◽

Percentage Body Fat

Abstract Optimal nutritional status is imperative for achieving the genetic potential for growth and development in children as well as for robust immune function and bone health in adults. Patients with thalassemia (Thal) are known to have abnormal growth, altered development and immune function and deficits in bone mass. For children, weight and height is commonly used to assess overall nutritional status, whereas for adults, body composition is a gross marker of an individual’s overall nutritional health. Nutritional status and body composition has not been explored in patients with Thal. To examine this, we have assessed body composition (fat, lean) and bone density by dual energy x-ray absorptiometry (DXA, Hologic Delphi A) in 370 subjects enrolled in a cross-sectional study of the Thal Clinical Research Network (TCRN), a North American collaborative research group. In addition to DXA, weight and height were measured, medical history obtained and a brief calcium food frequency and physical activity questionnaire completed. The total sample was divided into 2 groups: (TxThal) 257 transfused thalassemia major and E-beta thal patients (23.7 ± 11 yr, 131 male), and (NTxThal) 113 never or minimally transfused patients with other thalassemia syndromes (21.3 ± 13 yr, 50 male). Body mass index (BMI) was calculated (kg/m2) and cutoffs determined for children (<17=underweight, ≥30 obese) and adults (<18.5=underweight, ≥30 obese). As expected there was a high correlation between BMI and fat and lean mass by DXA (r=0.7 to 0.86, p<0.001). 6.2% of adults and 39.3% of children were classified as underweight by BMI and nearly 1/3 of children with Thal had abnormally low percentage body fat; while only 3.4% of adults and 2.2% of children were considered obese. Compared to median data from NHANES, adult patients with Thal are much leaner (BMI: 22.8±0.4) compared to contemporary adult Americans (28.1±0.2, p<0.0001). TxThal had more total body fat mass (14.3 vs 11.4 g, p<0.0001) and percentage body fat (27.3% vs. 24.9% p=0.007) compared to NTxThal. As has been observed in epidemiological studies of healthy subjects, calcium intake was inversely related to fat mass (p=0.009) as well as lean mass (p=0.007) after controlling for the effects of age, gender and diagnosis. Current physical activity level was a strong predictor of reduced body fat (p=0.007), whereas hemoglobin level was positively related to lean mass (p=0.001). Moreover, body fat was a positive predictor for height Z-score (p<0.0001). Low bone mass (BMD Z-Score <−2.0) was found in 50% of subjects, and BMD Z-score was moderately correlated with height Z-score (p<0.0001) and weight Z-score (p<0.0001). Though the majority of patients with Thal were classified as having a healthy body composition with very few obese patients, nearly 40% of the children in this sample were underweight. NTxThal appear at particular risk for underweight. These results suggest that an adequate amount of body fat is necessary for optimal growth and bone health in patients with Thal, and that calcium intake is associated with optimal body composition. These preliminary findings support the need for more careful study of nutritional status and its relationship to overall health in patients with thalassemia.

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Bone turnover marker determinants in young women: results from the Safe-D study

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563217719734 ◽

2017 ◽

Vol 55 (3) ◽

pp. 328-340 ◽

Cited By ~ 1

Author(s):

Emma T Callegari ◽

Suzanne M Garland ◽

Alexandra Gorelik ◽

Cherie Y Chiang ◽

John D Wark

Keyword(s):

Bone Mineral Density ◽

Body Composition ◽

Bone Turnover ◽

Bone Mineral ◽

Young Women ◽

Bone Health ◽

Community Dwelling ◽

Hormonal Contraceptives ◽

Mineral Density

Background Bone turnover markers (BTMs) may provide insight into bone health in young women, but have been little studied in this demographic. We aimed to explore the association between body composition, hormonal contraception, bone mineral density and biochemical parameters and BTMs in young women. Methods Participants were community-dwelling females aged 16–25 years, living in Victoria, Australia. Carboxy-terminal cross-linking telopeptide of type 1 collagen (CTX) and total procollagen type 1 N-propeptide (P1NP) were analysed on the Roche Elecsys automated analyzer. A total of 305 were evaluated, after excluding participants with medical conditions or medications (except hormonal contraceptives), which may affect bone metabolism. Results Median (Q1, Q3) BTM values were 540 (410, 690) ng/L for CTX and 61.7 (46.2, 83.7) µg/L for P1NP. Serum CTX and P1NP were inversely associated with chronological age ( P < 0.001), transferrin ( P < 0.020) and serum dehydroepiandrosterone sulphate concentration ( P < 0.001). BTM values were up to 22% lower in combined oral contraceptive (COC) pill users ( P < 0.001). Serum CTX was inversely associated with per cent body fat ( P = 0.009) and tibial cortical volumetric bone mineral density (vBMD; P = 0.003). Serum P1NP concentrations were 23 µg/L higher in participants who reported using an osteopath in the previous year ( P = 0.007). Conclusions These data suggest that BTMs are influenced by age, COC use, body composition, iron status and hormonal profiles. Higher CTX values were associated with lower tibial cortical vBMD. Examining BTMs in relation to interventions aimed at improving bone health in young women is warranted.

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Paradoxical Relationships between Serum 25(OH)D and Ferritin with Body Composition and Burnout: Variation by Sex and Sports Team

Endocrines ◽

10.3390/endocrines2030030 ◽

2021 ◽

Vol 2 (3) ◽

pp. 320-333

Author(s):

Tamara Hew-Butler ◽

Carrie Aprik ◽

Brigid Byrd ◽

Kristin Landis-Piwowar ◽

Valerie Smith-Hale ◽

...

Keyword(s):

Vitamin D ◽

Body Composition ◽

Body Fat ◽

Serum Ferritin ◽

Lean Mass ◽

Serum Vitamin ◽

Collegiate Athletes ◽

Mineral Density ◽

Serum Vitamin D ◽

Athlete Burnout

Adequate serum vitamin D and iron levels are thought to influence physical training adaptations and mood positively. The primary purpose of this prospective, observational study was to investigate relationships between serum 25-OH vitamin D/25(OH)D and serum ferritin levels with body composition and athlete burnout symptoms. Seventy-three collegiate athletes (female: n = 49; male: n = 24) from indoor (swimming, basketball) and outdoor (soccer, cross-country) sports were tested pre-season and post-season for serum 25(OH)D and serum ferritin (nutrient biomarkers) via venipuncture; body composition (total lean mass, bone mineral density/BMD, and % body fat) via dual energy X-ray absorptiometry (DXA) scans; and athlete burnout symptoms (post-season) via the athlete burnout questionnaire (ABQ). When male and female cohorts were combined, significant correlations (Pearson’s r) were noted between pre-season serum 25(OH)D versus the change (∆: post-season minus pre-season) in both BMD (r = −0.34; p = 0.0003) and % body fat (r = −0.28; p = 0.015). Serum ferritin ∆ was significantly associated with lean mass ∆ (r = −0.34; p = 0.003). For burnout symptoms, serum 25(OH)D ∆ significantly explained 20.6% of the variance for devaluation of the sport in the male cohort only. Across time, serum 25(OH)D levels decreased while serum ferritin levels increased, non-significantly, in both males and females. Relationships between nutrient biomarkers and body composition were opposite of physiological expectations.

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

Archives of Osteoporosis ◽

10.1007/s11657-021-01003-7 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Ole Andreas Nilsen ◽

Nina Emaus ◽

Tore Christoffersen ◽

Anne Winther ◽

Elin Evensen ◽

...

Keyword(s):

Bone Mineral Density ◽

Fracture Risk ◽

Bone Mineral ◽

Late Adolescence ◽

Areal Bone Mineral Density ◽

Childhood And Adolescence ◽

Preventive Strategy ◽

Mineral Density ◽

Future Fracture

Abstract Summary Areal 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. Purpose Bone 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. Methods The 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. Results In 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. Conclusions Our 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.

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