Sexual dimorphism in cortical bone size and strength but not density is determined by independent and time‐specific actions of sex steroids and IGF‐1: Evidence from pubertal mouse models

Although it is well established that males acquire more bone mass than females, the underlying mechanism and timing of this sex difference remain controversial. The aim of this study was to assess the relative contribution of sex steroid versus growth hormone–insulin‐like growth factor 1 (GH–IGF‐1) action to pubertal bone mass acquisition longitudinally in pubertal mice. Radial bone expansion peaked during early puberty (3 to 5 weeks of age) in male and female mice, with significantly more expansion in males than in females (+40%). Concomitantly, in 5 week old male versus female mice, periosteal and endocortical bone formation was higher (+70%) and lower (?47%), respectively, along with higher serum IGF‐1 levels during early puberty in male mice. In female mice, ovariectomy increased radial bone expansion during early puberty as well as the endocortical perimeter. In male mice, orchidectomy reduced radial bone expansion only during late puberty (5 to 8 weeks of age), whereas combined androgen and estrogen deficiency modestly decreased radial bone expansion during early puberty, accompanied by lower IGF‐1 levels. GHRKO mice with very low IGF‐1 levels, on the other hand, showed limited radial bone expansion and no skeletal dimorphism. From these data we conclude that skeletal sexual dimorphism is established during early puberty and depends primarily on GH–IGF‐1 action. In males, androgens and estrogens have stimulatory effects on bone size during late and early puberty, respectively. In females, estrogens limit bone size during early puberty. These longitudinal findings in mice provide strong evidence that skeletal dimorphism is determined by independent and time‐specific effects of sex steroids and IGF‐1. © 2010 American Society for Bone and Mineral Research     

Fracture Risk in Trans Women and Trans Men Using Long-Term Gender-Affirming Hormonal Treatment: A Nationwide Cohort Study

Concerns about bone health in transgender people using gender-affirming hormonal treatment (HT) exist, but the fracture risk is not known. In this nationwide cohort study, we aimed to compare the fracture incidence in transgender people using long-term HT with an age-matched reference population. All adult transgender people who started HT before 2016 at our gender-identity clinic were included and were linked to a random population-based sample of 5 age-matched reference men and 5 age-matched reference women per person. Fracture incidence was determined using diagnoses from visits to hospital emergency rooms nationwide between 2013 and 2015. A total of 1089 trans women aged <50 years (mean 38 ± 9 years) and 934 trans women aged ≥50 years (mean 60 ± 8 years) using HT for median 8 (interquartile range [IQR] 3–16) and 19 (IQR 11–29) years, respectively, were included. A total of 2.4% of the trans women aged <50 years had a fracture, whereas 3.0% of the age-matched reference men (odds ratio [OR] = 0.78, 95% confidence interval [CI] 0.51–1.19) and 1.6% of the age-matched reference women (OR = 1.49, 95% CI 0.96–2.32) experienced a fracture. In trans women aged ≥50 years, 4.4% experienced a fracture compared with 2.4% of the age-matched reference men (OR = 1.90, 95% CI 1.32–2.74) and 4.2% of the age-matched reference women (OR = 1.05, 95% CI 0.75–1.49). A total of 1036 trans men (40 ± 14 years) using HT for median 9 (IQR 2–22) years were included. Fractures occurred in 1.7% of the trans men, 3.0% of the age-matched reference men (OR = 0.57, 95% CI 0.35–0.94), and 2.2% of the age-matched reference women (OR = 0.79, 95% CI 0.48–1.30). In conclusion, fracture risk was higher in older trans women compared with age-matched reference men. In young trans women, fracture risk tended to be increased compared with age-matched reference women. Fracture risk was not increased in young trans men. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Gender-Affirming Hormone Treatment Decreases Bone Turnover in Transwomen and Older Transmen

Sex steroids play a key role in bone turnover and preserving BMD; hence, gender-affirming hormone treatment (HT) in transgender people affects bone metabolism. Most studies have looked into the effect of HT on changes in BMD; however, they do not provide insights into changes in bone metabolism caused by HT. This study investigated changes in bone turnover markers (BTMs) and sclerostin, as well as their correlations with change in BMD in transwomen and transmen during the first year of HT. Transwomen received estradiol and antiandrogens; transmen received testosterone. Sclerostin; P1NP; alkaline phosphatase (ALP); CTx; and BMD of the total hip, the femoral neck, and the lumbar spine were evaluated at baseline and after 1 year of HT. There were 121 transwomen (median age 30 years, interquartile range [IQR] 24 to 41 years) and 132 transmen (median age 24 years, IQR 21 to 33 years) included in the study. In transwomen, ALP decreased in 19% (95% CI, –21 to–16), CTx in 11% (95% CI, –18 to–4), and sclerostin in 8% (95%CI, –13 to–4) of study participants after 1 year of HT. In contrast, in transmen P1NP, ALP, and sclerostin increased in 33% (95% CI, 24 to 42), 16% (95% CI, 12 to 20), and 15% (95% CI, 10 to 20) of study participants, respectively, after 1 year of HT. No age differences were seen in transwomen, whereas in transmen aged ≥50 years a decrease in all BTMs was found in contrast with the other age groups. These transmen had low estrogen concentration at the start of HT based on their postmenopausal state before the start of HT; their estradiol concentrations increased during testosterone treatment. Changes in BTMs and BMD were weakly correlated (correlation coefficient all <0.30). To conclude, 1 year of HT resulted in decreased bone turnover in transwomen and older transmen, whereas it increased in younger transmen. The decrease in bone resorption in older transmen shows the importance of estrogen as a key regulator of bone turnover. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.     

Early Effects of Abaloparatide on Bone Formation and Resorption Indices in Postmenopausal Women With Osteoporosis

Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Vitamin D insufficiency is prevalent and vitamin D is inversely associated with parathyroid hormone and calcitriol in pregnant adolescents

Few large studies have assessed changes in calcitropic hormones and maternal 25‐hydroxyvitamin D (25(OH)D) status across pregnancy, and how this may impact maternal bone turnover and neonatal hormone status. We aimed to identify determinants of 25(OH)D, parathyroid hormone (PTH), and calcitriol across pregnancy in a longitudinal study of 168 pregnant adolescents (≤18 years of age). Maternal 25(OH)D, PTH, and calcitriol were assessed at mid‐gestation (～26 weeks), delivery, and in cord blood. Data were related to measures of maternal anthropometrics, dietary intake, physical activity, and bone turnover markers. Approximately 50% of teens and their infants had serum 25(OH)D ≤ 20 ng/mL; 25(OH)D was lower in African Americans versus whites (p < 0.001). PTH increased across gestation (p < 0.001). Elevated PTH (≥60 pg/mL) was detected in 25% of adolescents at delivery, and was associated with increased concentrations of serum N‐telopeptide (NTX) (p = 0.028). PTH and calcitriol did not significantly differ across the range of Ca intake consumed (257–3220 mg/d). In the group as a whole, PTH was inversely associated with 25(OH)D in maternal circulation at mid‐gestation (p = 0.023) and at delivery (p = 0.019). However, when the cohort was partitioned by 25(OH)D status, this relationship was only present in those with 25(OH)D ≤ 20 ng/mL, suggestive of a threshold below which 25(OH)D impacts PTH during pregnancy. Mid‐gestation 25(OH)D was inversely associated with calcitriol at delivery (p = 0.023), irrespective of Ca intake. Neonatal PTH and calcitriol were significantly lower than (p < 0.001), but unrelated to maternal concentrations. These findings indicate that maternal 25(OH)D status plays a role in calcitropic hormone regulation in pregnant adolescents. © 2012 American Society for Bone and Mineral Research     

Influence of long‐term postmenopausal hormone‐replacement therapy on estimated structural bone strength: A study in discordant monozygotic twins

Although postmenopausal hormone‐replacement therapy (HRT) is known to prevent fractures, knowledge on the influence of long‐term HRT on bone strength and its determinants other than areal bone mineral density is scarce. This study used a genetically controlled design with 24 monozygotic female twin pairs aged 54 to 72 years in which one cotwin was using HRT (mean duration 8 years) and the other had never used HRT. Estimated bone strength, cross‐sectional area, volumetric bone mineral density, bone mineral mass, and cross‐sectional density and mass distributions were assessed in the tibial shaft, distal tibia, and distal radius with peripheral computed tomography (pQCT). In the tibial shaft, HRT users had 9% [95% confidence interval (CI) 3%–15%] higher estimated bending strength than their nonusing cotwins. Larger cortical area and higher cortical bone mineral density accounted for this difference. The cortex was larger in the HRT users in the endocortical region. In the distal tibia, estimated compressive strength was 24% (95% CI 9%–40%) higher and in the distal radius 26% (95% CI 11%–41%) higher in the HRT users than in their nonusing cotwins owing to higher volumetric bone mineral density. No difference between users and nonusers was observed in total bone cross‐sectional area in any measured bone site. The added mineral mass in the HRT users was distributed evenly within and between bone sites. In postmenopausal women, long‐term HRT preserves estimated bone strength systemically by preventing bone mineral loss similarly in body weight–loaded and non‐weight‐loaded bone. © 2011 American Society for Bone and Mineral Research.     

High‐Impact Mechanical Loading Increases Bone Material Strength in Postmenopausal Women—A 3‐Month Intervention Study

Bone adapts to loading in several ways, including redistributing bone mass and altered geometry and microarchitecture. Because of previous methodological limitations, it is not known how the bone material strength is affected by mechanical loading in humans. The aim of this study was to investigate the effect of a 3‐month unilateral high‐impact exercise program on bone material properties and microarchitecture in healthy postmenopausal women. A total of 20 healthy and inactive postmenopausal women (aged 55.6 ± 2.3 years [mean ± SD]) were included and asked to perform an exercise program of daily one‐legged jumps (with incremental number, from 3×10 to 4×20 jumps/d) during 3 months. All participants were asked to register their performed jumps in a structured daily diary. The participants chose one leg as the intervention leg and the other leg was used as control. The operators were blinded to the participant's choice of leg for intervention. The predefined primary outcome was change in bone material strength index (BMSi), measured at the mid tibia with a handheld reference probe indentation instrument (OsteoProbe). Bone microstructure, geometry, and density were measured with high‐resolution peripheral quantitative computed tomography (XtremeCT) at the ultradistal and at 14% of the tibia bone length (distal). Differences were analyzed by related samples Wilcoxon signed rank test. The overall compliance to the jumping program was 93.6%. Relative to the control leg, BMSi of the intervention leg increased 7% or 0.89 SD (p = 0.046), but no differences were found for any of the XtremeCT‐derived bone parameters. In conclusion, a unilateral high‐impact loading program increased BMSi in postmenopausal women rapidly without affecting bone microstructure, geometry, or density, indicating that intense mechanical loading has the ability to rapidly improve bone material properties before changes in bone mass or structure. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Effects of a Specialist‐Led,School Physical Education Program on Bone Mass,Structure, and Strength in Primary School Children: A 4‐Year Cluster Randomized Controlled Trial

This 4‐year cluster randomized controlled trial of 365 boys and 362 girls (mean age 8.1 ± 0.3 years) from grade 2 in 29 primary schools investigated the effects of a specialist‐taught physical education (PE) program on bone strength and body composition. All children received 150 min/week of common practice (CP) PE from general classroom teachers but in 13 schools 100 min/week of CP PE was replaced by specialized‐led PE (SPE) by teachers who emphasized more vigorous exercise/games combined with static and dynamic postural activities involving muscle strength. Outcome measures assessed in grades 2, 4, and 6 included: total body bone mineral content (BMC), lean mass (LM), and fat mass (FM) by DXA, and radius and tibia (4% and 66% sites) bone structure, volumetric density and strength, and muscle cross‐sectional area (CSA) by pQCT. After 4‐years, gains in total body BMC, FM, and muscle CSA were similar between the groups in both sexes, but girls in the SPE group experienced a greater gain in total body LM (mean 1.0 kg; 95% CI, 0.2 to 1.9 kg). Compared to CP, girls in the SPE group also had greater gains in cortical area (CoA) and cortical thickness (CoTh) at the mid‐tibia (CoA, 5.0% [95% CI, 0.2% to 1.9%]; CoTh, 7.5% [95% CI, 2.4% to 12.6%]) and mid‐radius (CoA, 9.3% [95% CI, 3.5% to 15.1%]; CoTh, 14.4% [95% CI, 6.1% to 22.7%]), whereas SPE boys had a 5.2% (95% CI, 0.4% to 10.0%) greater gain in mid‐tibia CoTh. These benefits were due to reduced endocortical expansion. There were no significant benefits of SPE on total bone area, cortical density or bone strength at the mid‐shaft sites, nor any appreciable effects at the distal skeletal sites. This study indicates that a specialist‐led school‐based PE program improves cortical bone structure, due to reduced endocortical expansion. This finding challenges the notion that periosteal apposition is the predominant response of bone to loading during the prepubertal and early‐pubertal period. © 2015 American Society for Bone and Mineral Research.     

Growth patterns at distal radius and tibial shaft in pubertal girls: a 2-year longitudinal study.

Bone changes, in terms of both size and BMD, were assessed longitudinally in pubertal girls. Before puberty, BMD at the distal radius declined, whereas bone size increased, suggesting that normal growing girls experience a transient period of increased bone fragility. This could explain the elevated low-trauma forearm fracture rates reported in earlier studies. INTRODUCTION: Longitudinal data on bone growth during puberty are sparse. Such information is needed to understand the sequence of biological changes, the physical and mechanical consequences for the growing skeleton, and the implications for later life. MATERIALS AND METHODS: The geometric properties and volumetric BMD (vBMD) of the distal radius and tibial shaft were measured using pQCT in 258 pubertal girls followed over 2 years. A new hierarchical linear statistical modeling approach was used to determine true longitudinal trends. RESULTS: The growth rates of cross-sectional area (CSA) and BMC of the distal radius peaked at 16 and 9 months before menarche, respectively. This growth asynchrony between bone size and mass meant that total vBMD of the distal radius declined until 1 year before menarche. At the tibial shaft, total vBMD and cortical vBMD increased monotonically without any such transient reduction. Cortical thickness increased linearly, which was accounted for mainly by bone formation at the periosteal surface before menarche, but by both periosteal and endocortical apposition after menarche. During puberty, the ratio of cortical-to-total CSA of the tibial shaft increased and that of marrow-to-total CSA decreased. CONCLUSIONS: The temporal pattern of bone growth during puberty differs at the distal radius and tibial shaft. A transient decrease in vBMD, arising from asynchronous bone size and mass growth, occurs only at the radius. In the tibia, the mechanism of cortical thickening changes from periosteal apposition premenarche to both periosteal and endocortical apposition postmenarche.     

Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women.

The increase in bone fragility after menopause results from reduced periosteal bone formation and increased endocortical resorption. Women with highest remodeling had greatest loss of bone mass and estimated bone strength, whereas those with low remodeling lost less bone and maintained estimated bone strength. INTRODUCTION: Bone loss from the inner (endocortical) surface contributes to bone fragility, whereas deposition of bone on the outer (periosteal) surface is believed to be an adaptive response to maintain resistance to bending. MATERIALS AND METHODS: To test this hypothesis, changes in bone mass and estimated indices of bone geometry and strength of the one-third distal radius, bone turnover markers, and fracture incidence were measured annually in 821 women 30-89 years of age for 7.1 +/- 2.5 years. The analyses were made in 151 premenopausal women, 33 perimenopausal women, 279 postmenopausal women, and 72 postmenopausal women receiving hormone replacement therapy (HRT). RESULTS: In premenopausal women, periosteal apposition increased the radius width, partly offsetting endocortical resorption; therefore, the estimated cortical thickness decreased. Outward displacement of the thinner cortex maintained bone mass and cortical area and increased estimated bending strength. Estimated endocortical resorption accelerated during perimenopause, whereas periosteal apposition decreased. Further cortical thinning occurred, but estimated bending strength was maintained by modest outward cortical displacement. Endocortical resorption accelerated further during the postmenopausal years, whereas periosteal apposition declined further; cortices thinned, but because outward displacement was minimal, estimated cortical area and bending strength now decreased. Women with highest remodeling had the greatest loss of bone mass and strength. Women with low remodeling lost less bone and maintained estimated bone strength. In HRT-treated women, loss of bone strength was partly prevented. These structural indices predicted incident fractures; a 1 SD lower section modulus doubled fracture risk. CONCLUSIONS: Periosteal apposition does not increase after menopause to compensate for bone loss; it decreases. Bone fragility of osteoporosis is a consequence of reduced periosteal bone formation and increased endocortical resorption. Understanding the mechanisms of the age-related decline in periosteal apposition will identify new therapeutic targets. On the basis of our results, it may be speculated that the stimulation of periosteal apposition will increase bone width and improve skeletal strength.     

Vertebral morphology in aromatase inhibitor–treated males with idiopathic short stature or constitutional delay of puberty

Aromatase inhibitors (AIs), blockers of estrogen biosynthesis, delay bone maturation and therefore are used increasingly to promote growth in children and adolescents with growth disorders. The effects of treatment on skeletal health are largely unknown. Since estrogen deficiency is associated with various detrimental skeletal effects, we evaluated in this cross‐sectional posttreatment study vertebral body morphology, dimensions and endplates, and intervertebral disks by the use of magnetic resonance imaging (MRI) in two cohorts of males previously treated with the AI letrozole or placebo. Males with idiopathic short stature received treatment with letrozole or placebo for 2 years during prepuberty or early puberty; males with constitutional delay of puberty received letrozole or placebo in combination with low‐dose testosterone for 1 year during early or midpuberty. In males with idiopathic short stature, mild vertebral body deformities were found in 5 of 11 (45%) letrozole‐treated subjects, whereas in the placebo group no deformities were detected (p = .01). In the cohort of males with constitutional delay of puberty, a high prevalence of endplate and intervertebral disk abnormalities was observed in both the letrozole‐ and the placebo‐treated groups. We conclude that AI therapy during prepuberty or early puberty may predispose to vertebral deformities, which probably reflect impaired vertebral body growth rather than impaired bone quality and compression fractures. If AIs are used in growth indications, follow‐up of vertebral morphology is indicated. © 2010 American Society for Bone and Mineral Research     

Association of Mineral Bone Disorder With Decline in Residual Kidney Function in Incident Hemodialysis Patients

Abnormalities of mineral bone disorder (MBD) parameters have been suggested to be associated with poor renal outcome in predialysis patients. However, the impact of those parameters on decline in residual kidney function (RKF) is uncertain among incident hemodialysis (HD) patients. We performed a retrospective cohort study in 13,772 patients who initiated conventional HD during 2007 to 2011 and survived 6 months of dialysis. We examined the association of baseline serum phosphorus, calcium, intact parathyroid hormone (PTH), and alkaline phosphatase (ALP) with a decline in RKF. Decline in RKF was assessed by estimated slope of renal urea clearance (KRU) over 6 months from HD initiation. Our cohort had a mean ± SD age of 62 ± 15 years; 64% were men, 57% were white, 65% had diabetes, and 51% had hypertension. The median (interquartile range [IQR]) baseline KRU level was 3.4 (2.0, 5.2) mL/min/1.73 m². The median (IQR) estimated 6-month KRU slope was −1.47 (−2.24, −0.63) mL/min/1.73 m² per 6 months. In linear regression models, higher phosphorus categories were associated with a steeper 6-month KRU slope compared with the reference category (phosphorus 4.0 to <4.5 mg/dL). Lower calcium and higher intact PTH and ALP categories were also associated with a steeper 6-month KRU slope compared with their respective reference groups (calcium 9.2 to <9.5 mg/dL; intact PTH 150 to <250 pg/mL; ALP <60 U/L). The increased number of parameter abnormalities had an additive effect on decline in RKF. Abnormalities of MBD parameters including higher phosphorus, intact PTH, ALP and lower calcium levels were independently associated with decline in RKF in incident HD patients. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.     

Modeling-Based Bone Formation After 2 Months of Romosozumab Treatment: Results From the FRAME Clinical Trial

The bone-forming agent romosozumab is a monoclonal antibody that inhibits sclerostin, leading to increased bone formation and decreased resorption. The highest levels of bone formation markers in human patients are observed in the first 2 months of treatment. Histomorphometric analysis of bone biopsies from the phase 3 FRAME trial (NCT01575834) showed an early significant increase in bone formation with concomitant decreased resorption. Preclinical studies demonstrated that most new bone formation after romosozumab treatment was modeling-based bone formation (MBBF). Here we analyzed bone biopsies from FRAME to assess the effect of 2 months of romosozumab versus placebo on the surface extent of MBBF and remodeling-based bone formation (RBBF). In FRAME, postmenopausal women aged ≥55 years with osteoporosis were randomized 1:1 to 210 mg romosozumab or placebo sc every month for 12 months, followed by 60 mg denosumab sc every 6 months for 12 months. Participants in the bone biopsy substudy received quadruple tetracycline labeling and underwent transiliac biopsies at month 2. A total of 29 biopsies were suitable for histomorphometry. Using fluorescence microscopy, bone formation at cancellous, endocortical, and periosteal envelopes was classified based on the appearance of underlying cement lines as modeling (smooth) or remodeling (scalloped). Data were compared using the Wilcoxon rank-sum test, without multiplicity adjustment. After 2 months, the median percentage of MBBF referent to the total bone surface was significantly increased with romosozumab versus placebo on cancellous (18.0% versus 3.8%; p = 0.005) and endocortical (36.7% versus 3.0%; p = 0.001), but not on periosteal (5.0% versus 2.0%; p = 0.37) surfaces, with no significant difference in the surface extent of RBBF on all three bone surfaces. These data show that stimulation of bone formation in the first 2 months of romosozumab treatment in postmenopausal women with osteoporosis is predominately due to increased MBBF on endocortical and cancellous surfaces. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Geometric and Mechanical Bone Response to a Multidisciplinary Weight Loss Intervention in Adolescents With Obesity: The ADIBOX Study

The effectiveness of structured multidisciplinary weight loss (WL) programs combining nutrition and physical activity on bone geometry and strength remains uncertain in adolescents with obesity. The study investigated the impact of a structured WL intervention on bone geometry and strength in adolescents with obesity. Thirty-one adolescents with obesity (mean [standard deviation] 13.61 [1.27] yr, body mass index Z-score 2.26 [0.30]) experienced an 8-mo WL program. A group of 23 maturation-matched controls (mean [standard deviation] 15.90 [0.43] yr, body mass index Z-score −0.12 [0.48]) were recruited for calculating Z-scores. Body composition, bone density, geometry, and mechanical properties were assessed using dual-energy X-ray absorptiometry and dual-energy X-ray absorptiometry-derived hip structural analysis. Plasma concentration of leptin, estradiol, collagen type 1 cross-linked C-telopeptide (CTx), and procollagen type 1 N-terminal propeptide were measured. Longitudinal analysis showed that adolescents with obesity reduced body weight and fat mass (total [g, %; p < 0.007]). After 8 mo, body mineral density at total body less head (Δ 3.22 [3.58] % p < 0.001) and lumbar spine (Δ 3.67 [4.04] % p < 0.001) increased. At the narrow neck (NN) of the femur, lower body mineral density (Δ −7.19 [8.79] % p < 0.001) and higher endocortical diameter and width were observed (NN endocortical diameter Δ 2.85 [0.26] %, NN width Δ 5.48 [10.84] %, respectively). An increased buckling ratio (Δ 8.24 [2.00] % p = 0.005) was also evident. Similar concentration of procollagen type 1 N-terminal propeptide and CTx was seen from baseline to 8 mo. However, at 4 mo, lower CTx levels were observed. The 8-mo WL program was associated with some positive adaptations among bone density parameters for the whole body and spine. However, bone geometry and strength estimates appeared to weaken at the NN. Clinically, the buckling ratio score at the NN was close to the fracture threshold. An “androgynous-like” adaptation was observed with bone geometry changes demonstrating periosteal expansion and endocortical resorption.     

Bone Mass and Strength in School‐Age Children Exhibit Sexual Dimorphism Related to Differences in Lean Mass: The Generation R Study

Bone strength, a key determinant of fracture risk, has been shown to display clear sexual dimorphism after puberty. We sought to determine whether sex differences in bone mass and hip bone geometry as an index of strength exist in school‐age prepubertal children and the degree to which the differences are independent of body size and lean mass. We studied 3514 children whose whole‐body and hip scans were measured using the same densitometer (GE‐Lunar iDXA) at a mean age of 6.2 years. Hip dual‐energy X‐ray absorptiometry (DXA) scans underwent hip structural analyses (HSA) with derivation of bone strength indices. Sex differences in these parameters were assessed by regression models adjusted for age, height, ethnicity, weight, and lean mass fraction (LMF). Whole‐body bone mineral density (BMD) and bone mineral content (BMC) levels were 1.3% and 4.3% higher in girls after adjustment by LMF. Independent of LMF, boys had 1.5% shorter femurs, 1.9% and 2.2% narrower shaft and femoral neck with 1.6% to 3.4% thicker cortices than girls. Consequent with this geometry configuration, girls observed 6.6% higher stresses in the medial femoral neck than boys. When considering LMF, the sexual differences on the derived bone strength indices were attenuated, suggesting that differences in muscle loads may reflect an innate disadvantage in bone strength in girls, as consequence of their lower muscular acquisition. In summary, we show that bone sexual dimorphism is already present at 6 years of age, with boys having stronger bones than girls, the relation of which is influenced by body composition and likely attributable to differential adaptation to mechanical loading. Our results support the view that early life interventions (ie, increased physical activity) targeted during the pre‐ and peripubertal stages may be of high importance, particularly in girls, because before puberty onset, muscle mass is strongly associated with bone density and geometry in children. © 2015 American Society for Bone and Mineral Research.     

Metacarpal Growth During Adolescence in a Longitudinal South African Cohort

To monitor the drift of the periosteal and endocortical surfaces during metacarpal growth longitudinally, radiogrammetry was carried out on hand‐wrist X‐rays of 572 children from the Birth to Twenty Bone Health Cohort annually from ages 9 to 21 years. This is the largest collection of longitudinal X‐rays in African children. The second metacarpal bone length, bone width, and medullary width were measured using digital vernier calipers on a total of 4730 X‐rays. Superimposition by Translation and Rotation (SITAR) was used to obtain age at peak metacarpal length velocity (PLV). Bone width and medullary width were modeled using SITAR against both chronological age and age from PLV. In black and white females, tempo and velocity of metacarpal length growth was synchronized. Black males, however, attained PLV 7 months later than white males (p < 0.0001). Compared to white males, black males had a longer second metacarpal (p < 0.05), and greater bone width size (p < 0.02), tempo (p < 0.0009), and velocity (p < 0.0001). Medullary width growth velocity in black participants peaked 2 years prior to attainment of PLV and exceeded that of their white peers (p < 0.0001) in whom it peaked 6 to 12 months post‐PLV attainment. Black adolescents therefore had wider bones with relatively thinner cortices and wider medullary cavities than their white peers. Ethnic and sex differences also occurred in the timing of medullary width contraction that accompanied expansion in bone width and cortical thickness. In black males, medullary width contraction commenced approximately 3 years later than in black females, whereas in white males this occurred a year later than in white females. The ethnic and sex differences in bone acquisition reported in this study may differentially affect bone mass in later life. © 2017 American Society for Bone and Mineral Research.     

Prevalent fractures are related to cortical bone geometry in young healthy men at age of peak bone mass

Low areal bone mass is a risk factor for fractures in men. Limited data are available on fractures and bone geometry in men, and the relation with sex steroids is incompletely understood. We investigated prevalent fractures in relation to peak bone mass, bone geometry, and sex steroids in healthy young men. Healthy male siblings (n = 677) at the age of peak bone mass (25 to 45 years) were recruited in a cross‐sectional population‐based study. Trabecular and cortical bone parameters of the radius and cortical bone parameters of the tibia were assessed using peripheral quantitative computed tomography (pQCT). Areal bone mineral density (aBMD) was determined using dual‐energy X‐ray absorptiometry (DXA). Sex steroids were determined using immunoassays, and fracture prevalence was assessed using questionnaires. Fractures in young men were associated with a longer limb length, shorter trunk, lower trabecular BMD, smaller cortical bone area, and smaller cortical thickness (p < .005) but not with bone‐size‐adjusted volumetic BMD (vBMD). With decreasing cortical thickness [odds ratio (OR) 1.4/SD, p ≤ .001] and decreasing cortical area (OR 1.5/SD, p ≤ .001), fracture odds ratios increased. No association between sex steroid concentrations and prevalent fractures was observed. Childhood fractures (≤15 years) were associated with a thinner bone cortex (?5%, p ≤ .005) and smaller periosteal size (?3%, p ≤ .005). Fractures occurring later than 15 years of age were associated with a thinner bone cortex (?3%, p ≤ .05) and larger endosteal circumference (+3%, p ≤ .05) without differences in periosteal bone size. In conclusion, prevalent fractures in healthy young men are associated with unfavorable bone geometry and not with cortical vBMD when adjusting for bone size. Moreover, the data suggest different mechanisms of childhood fractures and fractures during adult life. © 2010 American Society for Bone and Mineral Research     

PTH Receptor Signaling in Osteoblasts Regulates Endochondral Vascularization in Maintenance of Postnatal Growth Plate

Longitudinal growth of postnatal bone requires precise control of growth plate cartilage chondrocytes and subsequent osteogenesis and bone formation. Little is known about the role of angiogenesis and bone remodeling in maintenance of cartilaginous growth plate. Parathyroid hormone (PTH) stimulates bone remodeling by activating PTH receptor (PTH1R). Mice with conditional deletion of PTH1R in osteoblasts showed disrupted trabecular bone formation. The mice also exhibited postnatal growth retardation with profound defects in growth plate cartilage, ascribable predominantly to a decrease in number of hypertrophic chondrocytes, resulting in premature fusion of the growth plate and shortened long bones. Further characterization of hypertrophic zone and primary spongiosa revealed that endochondral angiogenesis and vascular invasion of the cartilage were impaired, which was associated with aberrant chondrocyte maturation and cartilage development. These studies reveal that PTH1R signaling in osteoblasts regulates cartilaginous growth plate for postnatal growth of bone. © 2014 American Society for Bone and Mineral Research.