Vitamin D receptor gene polymorphisms modulate the skeletal response to vitamin D supplementation in healthy girls

ObjectivesVitamin D receptor (VDR) gene plays an important role in bone mass regulation. We have previously shown a beneficial effect of vitamin D supplementation on bone mass in girls. This study investigated whether the musculo-skeletal response to Vitamin D was modulated by polymorphisms in VDR gene.DesignRandomized placebo-controlled trial.Methods179 girls (10–17 years), were randomly assigned to placebo or Vitamin D3 for one year. VDR genotypes were determined in 167 girls using BsmI, TaqI and ApaI restriction enzymes. Bone mass at the spine, hip, forearm and total body, and lean mass were measured by DXA at baseline and at one year.ResultsAfter one year, VDR gene polymorphisms using Bsm1 and TaqI restriction enzymes were associated with percent changes in bone area, BMC and BMD at multiple skeletal sites in the Vitamin D3 group but not in the placebo group. The least increments were observed in the BB and tt genotypes. No similar effect was observed with ApaI enzyme. This relationship between VDR genotypes and changes in BMD and BMC remained significant after adjustment for puberty, changes in lean mass, height and bone area.ConclusionVDR gene polymorphisms influence the skeletal response to vitamin D supplementation in healthy adolescent girls.     

A positive dose-response effect of vitamin D supplementation on site-specific bone mineral augmentation in adolescent girls: a double-blinded randomized placebo-controlled 1-year intervention.

The effect of vitamin D supplementation on bone mineral augmentation in 212 adolescent girls with adequate calcium intake was studied in a randomized placebo-controlled setting. Bone mineral augmentation determined by DXA increased with supplementation both in the femur and the lumbar vertebrae in a dose-responsive manner. Supplementation decreased the urinary excretion of resorption markers, but had no impact on formation markers. INTRODUCTION: Adequate vitamin D intake protects the elderly against osteoporosis, but there exists no indisputable evidence that vitamin D supplementation would benefit bone mineral augmentation. The aim of this 1-year study was to determine in a randomized double-blinded trial the effect of 5 and 10 microg vitamin D3 supplementation on bone mineral augmentation in adolescent girls with adequate dietary calcium intake. MATERIALS AND METHODS: Altogether, 228 girls (mean age, 11.4 +/- 0.4 years) participated. Their BMC was measured by DXA from the femur and lumbar spine. Serum 25-hydroxyvitamin D [S-25(OH)D], intact PTH (S-iPTH), osteocalcin (S-OC), and urinary pyridinoline (U-Pyr) and deoxypyridinoline (U-Dpyr) were measured. Statistical analysis was performed both with the intention-to-treat (IT) and compliance-based (CB) method. RESULTS: In the CB analysis, vitamin D supplementation increased femoral BMC augmentation by 14.3% with 5 microg and by 17.2% with 10 microg compared with the placebo group (ANCOVA, p = 0.012). A dose-response effect was observed in the vertebrae (ANCOVA, p = 0.039), although only with the highest dose. The mean concentration of S-25(OH)D increased (p < 0.001) in the 5-microg group by 5.7 +/- 15.7 nM and in the 10-microg group by 12.4 +/- 13.7 nM, whereas it decreased by 6.7 +/- 11.3 nM in the placebo group. Supplementation had no effect on S-iPTH or S-OC, but it decreased U-DPyr (p = 0.042). CONCLUSIONS: Bone mineral augmentation in the femur was 14.3% and 17.2% higher in the groups receiving 5 and 10 microg of vitamin D, respectively, compared with the placebo group, but only 10 mug increased lumbar spine BMC augmentation significantly. Vitamin D supplementation decreased the concentration of bone resorption markers, but had no impact on bone formation markers, thus explaining increased bone mineral augmentation. However, the positive effects were noted with the CB method but not with IT.     

Odanacatib Treatment Affects Trabecular and Cortical Bone in the Femur of Postmenopausal Women: Results of a Two‐Year Placebo‐Controlled Trial

Odanacatib, a selective cathepsin K inhibitor, increases areal bone mineral density (aBMD) at the spine and hip of postmenopausal women. To gain additional insight into the effects on trabecular and cortical bone, we analyzed quantitative computed tomography (QCT) data of postmenopausal women treated with odanacatib using Medical Image Analysis Framework (MIAF; Institute of Medical Physics, University of Erlangen, Erlangen, Germany). This international, randomized, double‐blind, placebo‐controlled, 2‐year, phase 3 trial enrolled 214 postmenopausal women (mean age 64 years) with low aBMD. Subjects were randomized to odanacatib 50 mg weekly (ODN) or placebo (PBO); all participants received calcium and vitamin D. Hip QCT scans at 24 months were available for 158 women (ODN: n = 78 women; PBO: n = 80 women). There were consistent and significant differential treatment effects (ODN‐PBO) for total hip integral (5.4%), trabecular volumetric BMD (vBMD) (12.2%), and cortical vBMD (2.5%) at 24 months. There was no significant differential treatment effect on integral bone volume. Results for bone mineral content (BMC) closely matched those for vBMD for integral and trabecular compartments. However, with small but mostly significant differential increases in cortical volume (1.0% to 1.3%) and thickness (1.4% to 1.9%), the percentage cortical BMC increases were numerically larger than those of vBMD. With a total hip BMC differential treatment effect (ODN‐PBO) of nearly 1000 mg, the proportions of BMC attributed to cortical gain were 45%, 44%, 52%, and 40% for the total, neck, trochanter, and intertrochanter subregions, respectively. In postmenopausal women treated for 2 years, odanacatib improved integral, trabecular, and cortical vBMD and BMC at all femur regions relative to placebo when assessed by MIAF. Cortical volume and thickness increased significantly in all regions except the femoral neck. The increase in cortical volume and BMC paralleled the increase in cortical vBMD, demonstrating a consistent effect of ODN on cortical bone. Approximately one‐half of the absolute BMC gain occurred in cortical bone. © 2014 American Society for Bone and Mineral Research.     

The effects of whole‐body vibration training and vitamin D supplementation on muscle strength,muscle mass,and bone density in institutionalized elderly women: A 6‐month randomized,controlled trial

Sarcopenia and osteoporosis represent a growing public health problem. We studied the potential benefit of whole‐body vibration (WBV) training given a conventional or a high dose of daily vitamin D supplementation in improving strength, muscle mass, and bone density in postmenopausal women. In a 2 × 2 factorial‐design trial, 113 institutionalized elderly females aged over 70 years (mean age 79.6 years) were randomly assigned either to a WBV or a no‐training group, receiving either a conventional dose (880 IU/day) or a high dose (1600 IU/day) of vitamin D₃. The primary aim was to determine the effects of 6 months of WBV and/or vitamin D supplementation on isometric and dynamic strength, leg muscle mass, and hip bone mineral density (BMD). Additionally, the increase in 25‐hydroxyvitamin D [25(OH)D] levels between conventional and high‐dose supplementation was compared. After 6 months of treatment, dynamic muscle strength, hip BMD, and vitamin D serum levels improved significantly in all groups, whereas isometric strength and muscle mass did not change. When compared with no training, the WBV program did not result in additional improvements. When compared with 880 IU, a high dose of 1600 IU of vitamin D did result in higher serum vitamin D levels but did not result in additional improvements. In institutionalized women older than 70 years, the WBV training protocol tested is not more efficient in enhancing muscle mass, strength, and hip BMD compared with vitamin D supplementation. A higher dose of 1600 IU of vitamin D does not provide additional musculoskeletal benefit in this population compared with conventional doses. © 2011 American Society for Bone and Mineral Research.     

Impact of Calcium and Two Doses of Vitamin D on Bone Metabolism in the Elderly: A Randomized Controlled Trial

The optimal dose of vitamin D to optimize bone metabolism in the elderly is unclear. We tested the hypothesis that vitamin D, at a dose higher than recommended by the Institute of Medicine (IOM), has a beneficial effect on bone remodeling and mass. In this double‐blind trial we randomized 257 overweight elderly subjects to receive 1000 mg of elemental calcium citrate/day, and the daily equivalent of 3750 IU/day or 600 IU/day of vitamin D3 for 1 year. The subjects’ mean age was 71 ± 4 years, body mass index 30 ± 4 kg/m², 55% were women, and 222 completed the 12‐month follow‐up. Mean serum 25 hydroxyvitamin D (25OHD) was 20 ng/mL, and rose to 26 ng/mL in the low‐dose arm, and 36 ng/mL in the high‐dose arm, at 1 year (p < 0.05). Plasma parathyroid hormone, osteocalcin, and C‐terminal telopeptide (Cross Laps) levels decreased significantly by 20% to 22% in both arms, but there were no differences between the two groups for any variable, at 6 or 12 months, with the exception of serum calcitriol, which was higher in the high‐dose group at 12 months. Bone mineral density (BMD) increased significantly at the total hip and lumbar spine, but not the femoral neck, in both study arms, whereas subtotal body BMD increased in the high‐dose group only, at 1 year. However, there were no significant differences in percent change BMD between the two study arms at any skeletal site. Subjects with serum 25OHD <20 ng/mL and PTH level >76 pg/mL showed a trend for higher BMD increments at all skeletal sites, in the high‐dose group, that reached significance at the hip. Adverse events were comparable in the two study arms. This controlled trial shows little additional benefit in vitamin D supplementation at a dose exceeding the IOM recommendation of 600 IU/day on BMD and bone markers, in overweight elderly individuals. © 2017 American Society for Bone and Mineral Research.     

A prospective study of the effects of 1-year calcium-fortified soy milk supplementation on dietary calcium intake and bone health in Chinese adolescent girls aged 14 to 16

The Chinese diet is low in calcium, including among adolescent girls, with an average intake around 500 mg per day. In this study, we compared the percentage change in bone mineral density and content of the spine and hip region in a 1-year follow-up study between 104 adolescent girls aged 14 to 16 years receiving 375 ml calcium-fortified soymilk supplementation and 95 girls in the control group. The mean percentage changes of bone mineral density/content (BMD/BMC) and standard deviation (SD) at 1 year for the supplementation and control groups were as follows: neck of the femur BMD 2.7±2.94%, 1.8±3.49% (P =0.08); trochanter BMD 3.3±3.27%, 1.6±2.94% (P <0.001); intertrochanter BMD 3.6±3.05%, 2.32±2.95% (P =0.002); total hip BMD 3.1±2.39%, 2.05±2.22% (P =0.001); total hip BMC 3.8±3.05%, 2.6±2.96% (P =0.006). The percent difference between the percentage of bone changes in the supplementation and control groups [100× (soymilk-control)/control] ranged from 45 to 113%. We observed no differences in the spine BMD/C and no differences in changes of height and weight between the soymilk supplementation and control groups, which yielded similar results. Stepwise multivariate regression analysis including height, weight, growth stage, dietary energy, protein, calcium from usual diet and physical activity also showed that supplementation was significantly associated with a percentage increase in BMD/C at the hip. We conclude that 375 ml calcium-fortified soymilk supplementation, or an equivalent of about two glasses, is among the effective strategies for bone acquisition and the optimization of peak bone mass in adolescent girls.     

Influence of a 3‐year exercise intervention program on fracture risk,bone mass,and bone size in prepubertal children

Published prospective pediatric exercise intervention studies are short term and use skeletal traits as surrogate endpoints for fractures, whereas other reports infer exercise to be associated with more trauma and fractures. This prospective, controlled exercise intervention study therefore followed both skeletal traits and fracture risk for 36 months. Fractures were registered in children aged 7 to 9 years; there were 446 boys and 362 girls in the intervention group (2129 person‐years) and 807 boys and 780 girls in the control group (4430 person‐years). The intervention included school physical education of 40 minutes per day for 3 years. The control children achieved the Swedish standard of 60 minutes per week. In a subsample of 76 boys and 48 girls in the intervention group and 55 boys and 44 girls in the control group, bone mineral content (BMC, g) and bone width (cm) were followed in the lumbar spine and hip by dual‐energy X‐ray absorptiometry (DXA). The rate ratio (RR) for fractures was 1.08 (0.71, 1.62) [mean (95% confidence interval)]. In the DXA‐measured children, there were no group differences at baseline in age, anthropometrics, or bone traits. The mean annual gain in the intervention group in lumbar spine BMC was 0.9 SD higher in girls and 0.8 SD higher in boys (both p < .001) and in third lumbar vertebra width 0.4 SD higher in girls and 0.3 SD higher in boys (both p < .05) than in control children. It is concluded that a moderately intense 3‐year exercise program in 7‐ to 9‐year‐old children increases bone mass and possibly also bone size without increasing fracture risk. © 2011 American Society for Bone and Mineral Research     

A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs.

Vitamin D supplementation, when given with calcium, has been shown to increase bone mineral density (BMD) and reduce the incidence of hip fracture in elderly subjects. Despite its widespread use, the benefits of vitamin D supplementation in younger women and as a single agent are less clear. We performed a randomized co-twin, placebo-controlled, double-blind trial over 2 years to measure the effect of vitamin D3 supplementation on bone density and bone metabolism in young postmenopausal women. Seventy-nine monozygotic (MZ) twin pairs (mean age, 58.7 years; range, 47-70 years) were recruited. For each twin pair, one was randomized to 800 IU cholecalciferol/day for 2 years and the other was randomized to placebo. BMD was measured at the spine and hip and heel ultrasound at baseline, 12, 18, and 24 months. Samples were collected at 0, 3, and 6 months to measure serum calcium, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, and urinary deoxypyridinoline (DPD). In total, 64 pairs completed the study. No differences in baseline characteristics were seen between the groups. At 6 months, the treatment group had an increase in serum vitamin D [mean +/- SEM intrapair difference, 14.1+/-2.4 microg/liter (p < 0.001)]. There were no significant differences in other serum measurements or bone markers at 3 months or 6 months. At 24 months, no significant treatment effect was seen on BMD or calcaneal ultrasound change within pairs. Subanalysis of treatment response by vitamin D receptor (VDR) genotype revealed no significant difference in effect on BMD variables with treatment. On the basis of these results, vitamin D supplementation, on its own, cannot be recommended routinely as an osteoporosis prevention for healthy postmenopausal women with normal vitamin D levels under the age of 70 years.     

Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.

Dietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius. INTRODUCTION: The putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age. MATERIALS AND METHODS: Healthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables. RESULTS: Significant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049). CONCLUSIONS: These results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.     

Randomized Controlled Trial of the Effects of Calcium With or Without Vitamin D on Bone Structure and Bone‐Related Chemistry in Elderly Women With Vitamin D Insufficiency

There are few data on the relative effects of calcium supplementation with or without extra vitamin D on BMD in patients selected for low vitamin D status. The aim of this study is to evaluate the relative importance of vitamin D and calcium treatment on BMD and bone‐related chemistry in elderly women with vitamin D insufficiency. Three hundred two elderly women (age, 77.2 ± 4.6 yr) with serum 25(OH)D concentrations <60 nM participated in a 1‐yr randomized, double‐blind, placebo‐controlled trial. All subjects received 1000 mg calcium citrate per day with either 1000 IU ergocalciferol (vitamin D₂) or identical placebo (control). The effects of time and time treatment interactions were evaluated by repeated‐measures ANOVA. At baseline, calcium intake was 1100 mg/d, and 25(OH)D was 44.3 ± 12.9 nM; this increased in the vitamin D group by 34% but not the control group after 1 year (59.8 ± 13.8 versus 45.0 ± 13.3 nM, p < 0.001). Total hip and total body BMD increased significantly, and procollagen type I intact N‐terminal propeptide (PINP) decreased during the study with no difference between the treatment groups (hip BMD change: vitamin D, +0.5%; control, +0.2%; total body BMD change: vitamin D, +0.4%; control, +0.4%; PINP change: vitamin D, ?3.9%; placebo, ?2.8%). Although the fasting plasma and urine calcium increased in both groups equally, there was no detectable change in serum PTH. The increase in 25(OH)D achieved with vitamin D supplementation had no extra effect on active fractional intestinal calcium absorption, which fell equally in both groups (vitamin D, ?17.4%; control, ?14.8%). In patients with a baseline calcium intake of 1100 mg/d and vitamin D insufficiency, vitamin D₂ 1000 IU for 1 year has no extra beneficial effect on bone structure, bone formation markers, or intestinal calcium absorption over an additional 1000 mg of calcium. Vitamin D supplementation adds no extra short‐term skeletal benefit to calcium citrate supplementation even in women with vitamin D insufficiency.     

Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: A 1‐year double‐blind RCT in postmenopausal women

Few year‐long vitamin D supplementation trials exist that match seasonal changes. The aim of this study was to determine whether daily oral vitamin D₃ at 400 IU or 1000 IU compared with placebo affects annual bone mineral density (BMD) change in postmenopausal women in a 1‐year double‐blind placebo controlled trial in Scotland. White women aged 60 to 70 years (n = 305) were randomized to one of two doses of vitamin D or placebo. All participants started simultaneously in January/February 2009, attending visits at bimonthly intervals with 265 (87%) women attending the final visit and an additional visit 1 month after treatment cessation. BMD (Lunar iDXA) and 1,25‐dihydroxyvitamin D[1,25(OH)₂D], N‐terminal propeptide of type 1 collagen [P1NP], C‐terminal telopeptide of type I collagen [CTX], and fibroblast growth factor‐23 [FGF23] were measured by immunoassay at the start and end of treatment. Circulating PTH, serum Ca, and total 25‐hydroxyvitamin D [25(OH)D] (latter by tandem mass spectrometry) were measured at each visit. Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group (0.05% ± 1.46%) compared with the 400 IU vitamin D or placebo groups (0.57% ± 1.33% and 0.60% ± 1.67%, respectively) (p < 0.05). Mean (± SD) baseline 25(OH)D was 33.8 ± 14.6 nmol/L; comparative 25(OH)D change for the placebo, 400 IU, and 1000 IU vitamin D groups was ?4.1 ± 11.5 nmol/L, +31.6 ± 19.8 nmol/L, and +42.6 ± 18.9 nmol/L, respectively. Treatment did not change markers of bone metabolism, except for a small reduction in PTH and an increase in serum calcium (latter with 1000 IU dose only). The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome, nor how much vitamin D is being stored. © 2013 American Society for Bone and Mineral Research.     

Odanacatib,a cathepsin‐K inhibitor for osteoporosis: A two‐year study in postmenopausal women with low bone density

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1‐year dose‐finding trial with a 1‐year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T‐scores of ?2.0 or less but not less than ?3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty‐four months of treatment produced progressive dose‐related increases in BMD. With the 50‐mg dose of odanacatib, lumbar spine and total‐hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (?0.2% and ?0.9%). Biochemical markers of bone turnover exhibited dose‐related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose‐related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well‐tolerated and increased lumbar spine and total‐hip BMD in a dose‐related manner in postmenopausal women with low BMD. © 2010 American Society for Bone and Mineral Research     

Skeletal Effects of Vitamin D Supplementation in Postmenopausal Black Women

Black women have lower serum 25-hydroxyvitamin D (25[OH]D) levels and higher parathyroid hormone (PTH) levels than white peers but lower bone turnover, suggesting skeletal resistance to PTH. Our objective was to determine if vitamin D supplementation (1,000?IU/day) would prevent bone loss and whether vitamin D receptor (VDR) polymorphisms modify the response. We performed a 2-year randomized, controlled, double-blind study of 1,000?IU vitamin D₃ vs. placebo in postmenopausal black women with serum 25(OH)D levels <20?ng/mL (n?=?103). Measurements of 25(OH)D, PTH, and bone turnover were evaluated at baseline and 3, 6, 12, 18, and 24?months. DNA was extracted from peripheral blood leukocytes, and genotyping was conducted using standard techniques. Spine and hip bone mineral density (BMD) was measured at baseline and every 6?months. Serum 25(OH)D increased 11?ng/mL with vitamin D supplementation (p?<?0.001), with no change in the placebo group. Vitamin D supplementation produced a significant decline in PTH at 3?months only, with no differences in bone turnover between placebo and vitamin D at any time point. Two-year changes in BMD were not significantly different between placebo- and vitamin D-treated black women at any skeletal site. Despite similar elevations in 25(OH)D, femoral neck BMD was only responsive to vitamin D supplementation in FF subjects (n?=?47), not Ff/ff subjects (n?=?31). Vitamin D supplementation does not appear to influence bone loss in black women. However, in the FF polymorphism of the VDR gene group, vitamin D supplementation may retard the higher rate of bone loss.     

Denosumab Rapidly Increases Cortical Bone in Key Locations of the Femur: A 3D Bone Mapping Study in Women With Osteoporosis

Women with osteoporosis treated for 36 months with twice‐yearly injections of denosumab sustained fewer hip fractures compared with placebo. Treatment might improve femoral bone at locations where fractures typically occur. To test this hypothesis, we used 3D cortical bone mapping of postmenopausal women with osteoporosis to investigate the timing and precise location of denosumab versus placebo effects in the hips. We analyzed clinical computed tomography scans from 80 female participants in FREEDOM, a randomized trial, wherein half of the study participants received subcutaneous denosumab 60 mg twice yearly and the others received placebo. Cortical 3D bone thickness maps of both hips were created from scans at baseline, 12, 24, and 36 months. Cortical mass surface density maps were also created for each visit. After registration of each bone to an average femur shape model followed by statistical parametric mapping, we visualized and quantified statistically significant treatment effects. The technique allowed us to pinpoint systematic differences between denosumab and control and to display the results on a 3D average femur model. Denosumab treatment led to an increase in femoral cortical mass surface density and thickness, already evident by the third injection (12 months). Overall, treatment with denosumab increased femoral cortical mass surface density by 5.4% over 3 years. One‐third of the increase came from increasing cortical density, and two‐thirds from increasing cortical thickness, relative to placebo. After 36 months, cortical mass surface density and thickness had increased by up to 12% at key locations such as the lateral femoral trochanter versus placebo. Most of the femoral cortex displayed a statistically significant relative difference by 36 months. Osteoporotic cortical bone responds rapidly to denosumab therapy, particularly in the hip trochanteric region. This mechanism may be involved in the robust decrease in hip fractures observed in denosumab‐treated women at increased risk of fracture. © 2014 American Society for Bone and Mineral Research.     

Eight Months of Regular In‐School Jumping Improves Indices of Bone Strength in Adolescent Boys and Girls: The POWER PE Study

The POWER PE study was an 8‐mo, randomized, controlled, school‐based exercise intervention designed to apply known principles of effective bone loading to practical opportunities to improve life‐long musculoskeletal outcomes. A total of 99 adolescents (46 boys and 53 girls) with a mean age of 13.8 ± 0.4 yr (peri‐ to postpubertal) volunteered to participate. Intervention subjects performed 10 min of jumping activity in place of regular physical education (PE) warm up. Control subjects performed usual PE warm‐up activities. Bone mass (DXA and QUS) was assessed at baseline and follow‐up along with anthropometry, maturity, muscle power, and estimates of physical activity and dietary calcium. Geometric properties (such as femoral neck [FN] moment of inertia) were calculated from DXA measures. Boys in the intervention group experienced improvements in calcaneal broadband ultrasound attenuation (BUA) (+5.0%) and fat mass (?10.5%), whereas controls did not (+1.4% and –0.8%, respectively). Girls in the intervention group improved FN BMC (+13.9%) and lumbar spine (LS) BMAD (+5.2%) more than controls (+4.9% and +1.5%, respectively). Between‐group comparisons of change showed intervention effects only for whole body (WB) BMC (+10.6% versus +6.3%) for boys. Boys in the intervention group gained more lean tissue mass, trochanter (TR) BMC, LS BMC, and WB BMC and lost more fat mass than girls in the intervention group (p < 0.05). Ten minutes of jumping activity twice a week for 8 mo during adolescence seems to improve bone accrual in a sex‐specific manner. Boys increased WB bone mass and BUA, and reduced fat mass, whereas girls improved bone mass at the hip and spine.     

Skeletal benefits from calcium supplementation are limited in children with calcium intakes near 800 mg daily

Introduction and Hypothesis Calcium supplementation enhances bone mass accrual during administration, with a sustained benefit observed using milk-based calcium but not calcium salts. We tested the hypothesis that calcium from milk minerals but not calcium carbonate will be sustained after supplementation was discontinued.Methods Ninety-nine pre-pubertal boys and girls aged 5–11 years were followed for 12 months after being randomized to receive 800 mg/day of calcium from milk minerals (MM) or calcium carbonate (CC), or a placebo (Pla) in a 10-month double blind study. Total body and regional BMC, and femoral shaft bone dimensions were measured using dual energy x-ray absorptiometry. Group differences were determined using ANCOVA.Results In the intention to treat analysis of the entire sample, no group differences were observed in increments in BMC or bone dimensions during or after supplementation. In those children who remained pre-pubertal, greater gains in pelvis BMC in the milk mineral group than controls were sustained (37.9 versus 29.3% respectively, p<0.02).Conclusion In healthy children consuming about 800 mg calcium daily, calcium supplementation with milk minerals or calcium carbonate does not appear to be produce biologically meaningful benefits to skeletal health. A benefit of calcium supplementation in pre-pubertal was evident, but inconclusive, with the biological significance of the effect of calcium supplementation at the pelvis, and the longevity of this effect to be determined.Supported by a grant from Dairy Australia.     

Relationship between grip strength and bone mineral density in healthy Hong Kong adolescents

Summary  This study evaluated the magnitude of the correlations among grip strength, bone mineral density (BMD) and bone mineral content (BMC), after controlling for weight, height, pubertal development, weight-bearing activities and calcium intake. The results lead to the conclusion that grip strength is an independent predictor of bone mass in both sexes. The relationship between muscle strength and bone mass is systemic. Introduction  Previous studies had shown a site-specific relationship between muscle strength and bone in pubertal children. This study evaluated the magnitude of the correlations among grip strength, bone mineral density (BMD) and bone mineral content (BMC) at distant bone. Methods  Cross-sectional data of 169 11- to 12-year-old boys and 173 10- to 11-year-old girls came from the baseline result of a cohort study. Grip strength, BMD, BMC, weight, height, pubertal development, weight-bearing activities and calcium intake were measured. Pearson correlations and multiple regressions were used to calculate univariate and adjusted associations among grip strength and bone mass at distant bone. Results  Significant correlations were shown between grip strength and bone mass at hip, spine and whole body (boys: BMC:0.72–0.74, BMD:0.38–0.60; girls: BMC:0.71–0.72, BMD:0.44–0.63; p<0.0001). Multiple regressions with all covariates showed that about 70% and 50%, respectively, of the variations in BMC and BMD could be explained but not for whole body BMD. Grip strength was an independent predictor of bone mass, except hip BMD in boys and whole body BMD in girls. Stepwise regression showed that grip strength was a robust predictor in both sexes. Prediction models by grip strength and weight explained about 60% and 40% of the variations in BMC of different sites and in BMD of hip and spine, respectively. Conclusions  We found that grip strength is an independent predictor of bone mass in both sexes. The relationship between muscle strength and bone mass is systemic.     

Effects of Repetitive Loading on Bone Mass and Geometry in Young Male Tennis Players: A Quantitative Study Using MRI

Pre‐ and early puberty seem to be the most opportune times for exercise to improve bone strength in girls, but few studies have addressed this issue in boys. This study investigated the site‐, surface‐, and maturity‐specific exercise‐induced changes in bone mass and geometry in young boys. The osteogenic effects of loading were analyzed by comparing the playing and nonplaying humeri of 43 male pre‐, peri‐, and postpubertal competitive tennis players 10–19 yr of age. Total bone area, medullary area, and cortical area were determined at the mid (40–50%) and distal humerus (60–70%) of both arms using MRI. Humeral bone mass (BMC) was derived from a whole body DXA scan. In prepubertal boys, BMC was 17% greater in the playing compared with nonplaying arm (p < 0.001), which was accompanied by a 12–21% greater cortical area, because of greater periosteal expansion than medullary expansion at the midhumerus and periosteal expansion associated with medullary contraction at the distal humerus. Compared with prepuberty, the side‐to‐side differences in BMC (27%) and cortical area (20–33%) were greater in peripuberty (p < 0.01). No differences were found between peri‐ and postpuberty despite longer playing history in the postpubertal players. The osteogenic response to loading was greater in peri‐ compared with prepubertal boys, which is in contrast with our previous findings in girls and may be caused by differences in training history. This suggests that the window of opportunity to improve bone mass and size through exercise may be longer in boys than in girls.     

Higher Milk Requirements for Bone Mineral Accrual in Adolescent Girls Bearing Specific Caucasian Genotypes in the VDR Promoter

Low milk intakes hamper bone mineral acquisition during adolescence, especially in European girls. We hypothesized that ethnic‐specific polymorphisms of the vitamin D receptor gene promoter (VDRp) influence this milk/bone association. We evaluated lumbar spine BMC and BMD, milk/dairy products and calcium intakes, markers of P‐Ca metabolism, and VDRp polymorphisms at the Cdx‐2 binding (rs11568820) and ?1012 (rs4516035) loci in 117 healthy European peri‐ and postmenarcheal girls (14.9 ± 1.6 yr) during a 4‐yr follow‐up. Calcium intakes from milk, nonmilk dairy products, and nondairy products averaged 199, 243, and 443 mg/d at the initiation of the study. Results show no association between milk intakes and bone mass accrual in girls bearing an A/A genotype at the ?1012 VDRp locus (30% of the cohort). In contrast, A/G or G/G girls had lower spine BMC (?13%, p = 0.031), BMD (?10%, p = 0.004), and BMD Z‐score (?0.84 SD, p = 0.0003) when their milk intakes were <260 ml/d compared with genotype‐matched girls with higher milk intakes and with girls with an A/A genotype. The negative impact of low milk intake persisted up to 19.0 ± 1.7 yr. These findings suggest that European girls bearing a ?1012 A/G or G/G VDRp genotype should have higher milk/calcium intakes for optimal vertebral mass accrual during adolescence than girls bearing an A/A genotype, a genotype found in 30% of European and 98% of Asian and Sub‐Saharan African populations. VDRp genotype diversity may contribute to the ethnic differences observed in milk requirements for bone health during adolescence.     

Effect of calcium, vitamins K1 and D3 on bone in galactosemia

Classical galactosemia is an inherited disorder of galactose metabolism. Recently, diminished bone mineral content (BMC) in children and adolescents has been found. The aim of this study was to evaluate the effect of calcium, vitamins K(1) and D(3) supplementation on bone in children with galactosemia. A 2-year randomized, double-blind, placebo-controlled clinical trial was undertaken in which 40 children with classical galactosemia (13 males and 27 females, aged 3-17 years) were included to receive daily either 750 mg calcium, 1.0 mg vitamin K(1) and 10.0 microg vitamin D(3) or placebo. BMC of femoral neck, lumbar spine and total body and body composition data were determined by dual energy X-ray absorptiometry (DXA) at baseline and after 1 and 2 years. Diet was assessed using a food frequency questionnaire and a 3-day food diary. Biochemical measurements were determined at baseline and after 1 and 2 years. In the children receiving treatment, carboxylated osteocalcin (cOC) concentration significantly increased (P < 0.001) and undercarboxylated osteocalcin (ucOC) concentration significantly decreased (P = 0.001) when compared to the children receiving placebo. Furthermore, there was a statistically significant increase in BMC of lumbar spine (P = 0.001), lean tissue mass (LTM: P = 0.016) and fat mass (FM: P = 0.014) in the treatment group when compared to the placebo group. The significant increase in cOC and decrease in ucOC concentration in the treatment group were present in prepubertal (P < 0.001 and P = 0.006 respectively) and pubertal children (P = 0.004 and P = 0.042 respectively). The significant increase in BMC of lumbar spine in the treatment group was present only in the prepubertal children (P = 0.015). Supplementation of calcium, vitamins K(1) and D(3) given in this dose (750 mg, 1.0 mg and 10.0 mug respectively) is likely to have a role in the treatment of BMC abnormalities in galactosemia.