Total Body Body Bone Mineral Density Research Articles

The genetically predicted causal relationship of inflammatory bowel disease with bone mineral density and osteoporosis: evidence from two-sample Mendelian randomization.

Many existing studies indicated that patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), tend to have the risk of low total body bone mineral density (BMD), and are more likely to have osteoporosis (OS). To determine the causal relationship between IBD and bone metabolic disorders, we herein performed a two-sample Mendelian randomization analysis (TSMR) using publicly available summary statistics. Summary statistics of total body BMD, OS and IBD were downloaded from the Open Genome-Wide Association Study (GWAS), FinnGen consortium and International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The European and East Asian populations have consisted in this Mendelian Randomization (MR) work. A range of quality control procedures were taken to select eligible instrument SNPs closely associated with total body BMD, OS and IBD. To make the conclusions more reliable, we applied five robust analytical methods, among which the inverse variance weighting (IVW) method acted as the major method. Besides, heterogeneity, pleiotropy and sensitivity were evaluated. In the European population, the genetic association of UC on total body BMD (OR=0.97, 95%CI=0.96,0.99, P<0.001) and overall IBD on total body BMD (OR=0.98, 95%CI=0.97,1.00, P=0.013) were significant, while the effect of CD on total body BMD was not significant enough (OR=0.99, 95%CI=0.98,1.00, P=0.085). All of UC, CD and overall IBD can be the genetic risk factor of having OS with pathological fracture (UC: OR=1.13, 95%CI=1.02,1.26, P=0.024, CD: OR=1.14, 95%CI=1.05,1.25, P=0.003, overall IBD: OR=1.13, 95%CI=1.02,1.24, P=0.015). In East Asian groups, only CD had a causal relationship with OS (OR=1.04, 95% CI=1.01,1.07, P=0.019). Our study revealed genetically predicted associations between IBD on total body BMD and OS in European and East Asian populations. This work supplemented the results of previous retrospective studies and demonstrated the necessity of BMD monitoring in patients with IBD.

Bone turnover markers during the remission phase in children and adolescents with type 1 diabetes.

In rodents, osteocalcin (OCN) stimulates insulin production and insulin sensitivity, both important factors during partial remission in humans with type 1 diabetes (T1D). However, decreased OCN has been reported in both adult and pediatric T1D. This study aims at investigating bone turnover and partial remission in children and adolescents with recent onset T1D. Ninety-nine individuals (33% girls) were recruited within 3 months of T1D onset and examined three times, 6 months apart. Outcome variables were bone formation markers OCN and procollagen type 1 amino-terminal propeptide (P1NP) and the bone resorption marker C-terminal crosslinked telopeptide of type 1 collagen (CTX). Dependent variables included IDAA1c (surrogate marker of partial remission), total body bone mineral density (BMD) and stimulated C-peptide as representative of endogenous insulin production. OCN- and P1NP Z-scores were significantly decreased throughout the study, whereas CTX Z-scores were increased. None of the bone turnover markers changed significantly between visits. Total body BMD Z-score did not change during the study but was significantly higher than the reference population at visit 2 (P = .035). There were no differences in the bone turnover markers for those in partial remission as defined by either C-peptide or IDAA1c at any visit. The individual change in CTX Z-score was negatively associated with the increase of IDAA1c (P = .030) independent of C-peptide decline (P = .034). Bone turnover markers indicate increased bone resorption and decreased bone formation during the first year of T1D. The negative association between bone resorption and IDAA1c might represent compensatory mechanisms affecting insulin sensitivity.

Bone mineral density, body composition and metabolic profiles in adult women with complete androgen insensitivity syndrome and removed gonads using oral or transdermal estrogens.

To assess bone health in adult women with complete androgen insensitivity syndrome (CAIS) and removed gonads compared with age-matched healthy controls. To evaluate the effects of transdermal oestradiol 2 mg or oral estradiol valerate 2 mg on bone, biochemical and clinical characteristics. Cohort study. Bone, body composition and anthropometric parameters were assessed in 32 adult CAIS and 32 healthy controls. In 28 cases, CAIS evaluations of metabolic, bone and body composition were performed also after a maximum of 6 years of therapy. Lumbar, femoral and total body bone mineral density (BMD) were significantly lower in those with CAIS when compared with controls. The prevalence of vertebral osteoporosis and osteopenia was significantly higher in the CAIS group (P = 0.038, OR = 9.67, 95% CI: 1.13-82.83 and P = 0.012, OR= 3.85, 95% CI: 1.34-11.16, respectively). Prevalence of femoral osteopenia was significantly higher in the CAIS group (P = 0.0012, OR = 7.93, 95% CI: 2.26-27.9). During follow-up, lumbar BMD significantly increased suggesting a significant effect of treatment on BMD (P = 0.0016), while femoral and total body BMD did not show any significant change. Total body BMD values were positively associated to the duration and route of oestrogen administration and to serum estradiol levels. Transdermal administration of estrogens was associated with better total body BMD in comparison to oral administration. Our results reinforce the importance of adequate hormonal treatment for women living with CAIS, suggesting a better effect from the transdermal route over the oral route.

Inhibition of FGFR Signaling Partially Rescues Hypophosphatemic Rickets in HMWFGF2 Tg Male Mice.

Transgenic mice harboring high molecular weight fibroblast growth factor (FGF)2 isoforms (HMWTg) in osteoblast lineage cells phenocopy human X-linked hypophosphatemic rickets (XLH) and Hyp murine model of XLH demonstrating increased FGF23/FGF receptor signaling and hypophosphatemic rickets. Because HMWFGF2 was upregulated in bones of Hyp mice and abnormal FGF receptor (FGFR) signaling is important in XLH, HMWTg mice were used to examine the effect of the FGFR inhibitor NVP-BGJ398, now in clinical trials for cancer therapy, on hypophosphatemic rickets. Short-term treatment with NVP-BGJ398 rescued abnormal FGFR signaling and hypophosphatemia in HMWTg. Long-term treatment with NVP-BGJ398 normalized tail, tibia, and femur length. Four weeks NVP-BGJ398 treatment significantly increased total body bone mineral density (BMD) and bone mineral content (BMC) in HMWTg mice; however, at 8 weeks, total body BMD and BMC was indistinguishable among groups. Micro-computed tomography revealed decreased vertebral bone volume, trabecular number, and increased trabecular spacing, whereas femur trabecular tissue density was increased; however, NVP-BGJ398 rescued defective cortical bone mineralization, increased thickness, reduced porosity, and increased endosteal perimeter and cortical tissue density in HMWTg. NVP-BGJ398 improved femur cancellous bone, cortical bone structure, growth plate, and double labeling in cortical bone and also increased femur trabeculae double labeled surface, mineral apposition rate, bone formation rate, and osteoclast number and surface in HMWTg. The decreased NPT2a protein that is important for renal phosphate excretion was rescued by NVP-BGJ398 treatment. We conclude that NVP-BGJ398 partially rescued hypophosphatemic rickets in HMWTg. However, long-term treatment with NVP-BGJ398 further increased serum FGF23 that could exacerbate the mineralization defect.

The bone-sparing effects of estrogen and WNT16 are independent of each other

Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16(-/-) mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females is WNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. Obl-Wnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L3. Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx Obl-Wnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16(-/-) mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16(-/-) and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16-targeted therapies might be useful for treatment of postmenopausal trabecular bone loss.

Deficiency of β-arrestin 2 in mice-induced bone remodeling was associated with down-regulation of GPER1 expression

Objective To determine the role of β-arrestin 2 on bone mineral density and microarchitecture, and its underlying mechanisms. Methods Ex vivo dual-energy-X-ray-absorptiometry(DXA) was used to measure the total body bone mineral density (BMD) and micro-CT scan was performed on mouse femora from female mice of wild type(WT) and β-arrestin 2 knockout(KO) at 16, 26, 30 weeks of age. RT-PCR was applied for the mRNA expression. Results Started from 16 weeks of age, total body BMD and the bone volume/total volume(BV/TV), trabecular number(Tb.N) in the femoral metaphysis of β-arrestin 2 KO female mice decreased dramatically. BMD decreased by 8.10%, 7.53%, 8.56%, BV/TV by 53.3%, 49.4%, 55.7% and Tb.N by 53.2%, 52.1%, 49.3% at 16, 26, 30 weeks of age, respectively, compared with those in WT mice(all P<0.05). In contrast, the trabecular pattern factor(Tb.Pf), trabecular separation(Tb.Sp), and structure model index(SMI) of the mice increased gradually with age, and reached statistically significant at age of 30 weeks(increased by 32.0%, 54.3%, and 23.7%, respectively, all P<0.05). RT-PCR showed that mRNA expression levels of osteoprotegrin, RANKL, and G protein-coupled estrogen receptor 1 in tibia from β-arrestin 2 KO mice were significantly lower than those in WT mice. Conclusion The effects of β-arrestin 2 on bone remodeling might be associated with G protein-coupled estrogen receptor1 signaling pathway. (Chin J Endocrinol Metab, 2015, 31: 897-901) Key words: β-Arrestin 2; Bone mineral density; Microarchitecture; Osteoprotegrin; G protein-coupled estrogen receptor 1

Does Diet-Induced Weight Loss Lead to Bone Loss in Overweight or Obese Adults? A Systematic Review and Meta-Analysis of Clinical Trials.

Diet-induced weight loss has been suggested to be harmful to bone health. We conducted a systematic review and meta-analysis (using a random-effects model) to quantify the effect of diet-induced weight loss on bone. We included 41 publications involving overweight or obese but otherwise healthy adults who followed a dietary weight-loss intervention. The primary outcomes examined were changes from baseline in total hip, lumbar spine, and total body bone mineral density (BMD), as assessed by dual-energy X-ray absorptiometry (DXA). Secondary outcomes were markers of bone turnover. Diet-induced weight loss was associated with significant decreases of 0.010 to 0.015 g/cm(2) in total hip BMD for interventions of 6, 12, or 24 (but not 3) months' duration (95% confidence intervals [CIs], -0.014 to -0.005, -0.021 to -0.008, and -0.024 to -0.000 g/cm(2), at 6, 12, and 24 months, respectively). There was, however, no statistically significant effect of diet-induced weight loss on lumbar spine or whole-body BMD for interventions of 3 to 24 months' duration, except for a significant decrease in total body BMD (-0.011 g/cm(2); 95% CI, -0.018 to -0.003 g/cm(2)) after 6 months. Although no statistically significant changes occurred in serum concentrations of N-terminal propeptide of type I procollagen (P1NP), interventions of 2 or 3 months in duration (but not of 6, 12, or 24 months' duration) induced significant increases in serum concentrations of osteocalcin (0.26 nmol/L; 95% CI, 0.13 to 0.39 nmol/L), C-terminal telopeptide of type I collagen (CTX) (4.72 nmol/L; 95% CI, 2.12 to 7.30 nmol/L) or N-terminal telopeptide of type I collagen (NTX) (3.70 nmol/L; 95% CI, 0.90 to 6.50 nmol/L bone collagen equivalents [BCEs]), indicating an early effect of diet-induced weight loss to promote bone breakdown. These data show that in overweight and obese individuals, a single diet-induced weight-loss intervention induces a small decrease in total hip BMD, but not lumbar spine BMD. This decrease is small in comparison to known metabolic benefits of losing excess weight.

Additive effects of nutritional supplementation, together with bisphosphonates, on bone mineral density after hip fracture: a 12-month randomized controlled study.

BackgroundAfter a hip fracture, a catabolic state develops, with increased bone loss during the first year. The aim of this study was to evaluate the effects of postoperative treatment with calcium, vitamin D, and bisphosphonates (alone or together) with nutritional supplementation on total hip and total body bone mineral density (BMD).MethodsSeventy-nine patients (56 women), with a mean age of 79 years (range, 61–96 years) and with a recent hip fracture, who were ambulatory before fracture and without severe cognitive impairment, were included. Patients were randomized to treatment with bisphosphonates (risedronate 35 mg weekly) for 12 months (B; n=28), treatment with bisphosphonates along with nutritional supplementation (40 g protein, 600 kcal daily) for the first 6 months (BN; n=26), or to controls (C; n=25). All participants received calcium (1,000 mg) and vitamin D3 (800 IU) daily. Total hip and total body BMD were assessed with dual-energy X-ray absorptiometry at baseline, 6, and 12 months. Marker of bone resorption C-terminal telopeptide of collagen I and 25-hydroxy vitamin D were analyzed in serum.ResultsAnalysis of complete cases (70/79 at 6 months and 67/79 at 12 months) showed an increase in total hip BMD of 0.7% in the BN group, whereas the B and C groups lost 1.1% and 2.4% of BMD, respectively, between baseline and 6 months (P=0.071, between groups). There was no change in total body BMD between baseline and 12 months in the BN group, whereas the B group and C group both lost BMD, with C losing more than B (P=0.009). Intention-to-treat analysis was in concordance with the complete cases analyses.ConclusionProtein-and energy-rich supplementation in addition to calcium, vitamin D, and bisphosphonate therapy had additive effects on total body BMD and total hip BMD among elderly hip fracture patients.

Competitive Athletic Participation, Thigh Muscle Strength, and Bone Density in Elite Senior Athletes and Controls

The relationship between participation in highly competitive exercise, thigh muscle strength, and regional and total body bone mineral density (BMD) in elite senior athletes and healthy elderly controls was investigated. One hundred and four elite senior athletes (age: 72.6 ± 6.4 years, height: 168.7 ± 8.6 cm, mass: 72.6 ± 13.5 kg, 57 male:47 female) and 79 healthy controls (age: 75.4 ± 5.6 years, height: 170.8 ± 25.5 cm, mass: 79.5 ± 11.7 kg, 46 male:33 female) participated in this cross-sectional study. Vitamin D and calcium intake were assessed via a recall survey. Isometric knee extension and flexion peak torque were measured via a custom strength measurement device. Total body and regional BMD of the hip, radius, and spine were assessed with a dual-energy x-ray absorptiometer. For each BMD site assessed, multivariate linear regression analysis was performed in 4 steps (α = 0.10) to examine the contribution of (a) age, sex, bodyweight, and calcium and vitamin D intake; (b) group (elite senior athlete, control); (c) knee extension peak torque; and (d) knee flexion peak torque on BMD. Sex, age, bodyweight, and calcium and vitamin D intake explained a significant amount of variance in BMD in each site. Group was not significant. Knee extension peak torque explained an additional 3.8% of the variance in hip BMD (p = 0.06). Knee flexion peak torque was not correlated to BMD at any of the sites assessed. In conclusion, participation in highly competitive athletics was not related to total body or regional BMD. Age, sex, bodyweight, and vitamin D and calcium intake were significantly related to BMD at all the sites assessed. Quadriceps strength contributed slightly to hip BMD. Our results imply that participation in highly competitive senior athletics does not have a protective effect on BMD, perhaps because of a lower bodyweight or other confounding factors.

Decreased bone mineralization in children with Noonan syndrome: Another consequence of dysregulated RAS MAPKinase pathway?

IntroductionNoonan syndrome (NS) is a disorder of RAS- mitogen activated protein kinase (MAPK) pathway with clinical features of skeletal dysplasia. This pathway is essential for regulation of cell differentiation and growth including bone homeostasis. Currently, limited information exists regarding bone mineralization in NS. Materials and methodsUsing dual-energy X-ray absorptiometry (DXA), bone mineralization was evaluated in 12 subjects (mean age 8.7years) with clinical features of NS. All subjects underwent genetic testing which showed mutations in PTPN11 gene (N=8) and SOS1 gene (N=1). In a subgroup of subjects with low bone mass, indices of calcium-phosphate metabolism and bone turnover were obtained. Results50% of subjects had low bone mass as measured by DXA. Z-scores for bone mineral content (BMC) were calculated based on age, gender, height, and ethnicity. Mean BMC z-score was marginally decreased at −0.89 {95% CI −2.01 to 0.23; p=0.1}. Mean total body bone mineral density (BMD) z-score was significantly reduced at −1.87 {95% CI −2.73 to −1.0; p=0.001}. Mean height percentile was close to - 2 SD for this cohort, thus total body BMD z-scores were recalculated, adjusting for height age. Adjusted mean total body BMD z-score was less reduced but still significant at −0.82 {95% CI −1.39 to −0.25; p=0.009}. Biochemical evaluation for bone turnover was unremarkable except serum IGF-I and IGF-BP3 levels which were low-normal for age. DiscussionChildren with NS have a significantly lower total body BMD compared to age, gender, ethnicity and height matched controls. In addition, total BMC appears to trend lower in children with NS compared to controls. We conclude that the metabolic bone disease present resulted from a subtle variation in the interplay of osteoclast and osteoblast activity, without clear abnormalities being defined in the metabolism of either. Clinical significance of this finding needs to be validated by larger longitudinal studies. Also, histomorphometric analysis of bone tissue from NS patients and mouse model of NS may further elucidate the relationship between the RAS-MAPK pathway and skeletal homeostasis.

An altered hormonal profile and elevated rate of bone loss are associated with low bone mass in professional horse-racing jockeys

Horse-racing jockeys are a group of weight-restricted athletes, who have been suggested as undertaking rapid and extreme weight cycling practices in order to comply with stipulated body-mass standards. The aim of this study was to examine bone mass, turnover and endocrine function in jockeys and to compare this group with age, gender and body mass index matched controls. Twenty male professional jockeys and 20 healthy male controls participated. Dual energy X-ray absorptiometry scans and early morning fasting blood and urine samples were used to measure bone mass, turnover and a hormonal profile. Total body bone mineral density (BMD) was significantly lower in jockeys (1.143±0.05 vs. 1.27±0.06gcm(-3), p<0.01). Bone resorptive activity was elevated in the jockey group as indicated by significantly higher urinary NTx/creatinine (76.94±29.52 vs. 55.9±13.9nmolmmol(-1), p<0.01), resulting in a significantly negative uncoupling index between bone resorption and formation. Sex hormone binding globulin (SHBG) levels were significantly higher in jockeys (41.21±9.77 vs. 28.24±9.98nmolL(-1), p<0.01) with a lower percentage of bioavailable testosterone (48.89±7.38 vs. 59.18±6.74%, p<0.01). SHBG and insulin-like growth factor-1 were independent predictors of total body and femoral neck BMD, respectively (p<0.05). In conclusion, it appears that professional jockeys have an elevated rate of bone loss and reduced bone mass that appears to be associated with disrupted hormonal activity. It is likely that this may have occurred in response to the chronic weight cycling habitually experienced by this group.

Dose–response effect of 40 weeks of resistance training on bone mineral density in older adults

Resistance training is becoming popular for maintaining bone health. Previous studies examined high intensity exercise; we compared high and low intensity resistance training performed 2 or 3days per week in older adults. We found positive bone density responses for the hip and spine for all types of resistance training. This study determined the dose-response effect of resistance training on lumbar spine, proximal femur, and total body bone mineral density (BMD) in older men and women (55-74years). Subjects included 45 men and 79 women who were assigned to one of the following training groups: 1-high intensity (80% 1RM), 2days/week (2HI); 2-low intensity (40% 1RM), 2days/week (2LI); 3-high intensity (80% 1RM), 3days/week (3HI); and 4-low intensity (40% 1RM), 3days/week (3LI). Bone scans (dual energy X-ray absorptiometry) were performed at baseline and after 40weeks of training. Muscular strength (1-repetition maximum) was assessed every 5weeks. There were significant trial (p < 0.05) effects but no significant trial × training group interactions for the BMD sites. Spine, trochanter, and total hip BMD increased from baseline to 40weeks; however, the total body BMD site decreased in the 3LI group. Men and women exhibited similar improvements for the trochanter and total hip sites but the percent change in the spine tended (p = 0.054) to be higher for men (1.8%) than women (0.4%). The resistance training programs, regardless of intensity and frequency, were effective in improving BMD of the proximal femur and lumbar spine but not the total body. Both men and women responded similarly for the hip sites but men show a greater response at the lumbar spine than women.

Relationship Between Thigh Muscle Strength, Competitive Exercise, and BMD in Elderly Athletes and Controls

PURPOSE: This study investigated the relationship between competitive exercise, quadriceps and hamstring strength and regional and total body bone mineral density (BMD) in elite senior athletes and healthy elderly controls. METHODS: The 183 participants included 104 athletes of the National Senior Games (72.6±6.4 yrs, 72.6±13.5 kg, 168.7±8.6 cm) and 79 healthy controls (75.4±5.6 yrs, 79.5±11.7 kg, 170.8±25.5 cm). Three 5-sec trials of isometric knee flexion and extension were collected (100 Hz) using a load-cell affixed to a custom apparatus which held the knee at 45 degrees. Hip, radius, spine, and total body BMD were measured with a Hologic 4500A DXA scanner. For each of the 4 BMD sites assessed, multiple linear regression analysis was performed in four steps (α = 0.10). First, age, gender, and bodyweight were entered as a block into the statistical model to determine their correlation with the BMD variable. Secondly, group (athlete, control) was added. Subsequently, extension flexion peak torque was entered into the model. Lastly, because extension and flexion peak torque are highly correlated (R=0.67), extension peak torque was removed and flexion peak torque was added to the model. RESULTS: The variables of gender, age, and bodyweight explained 26%, 52%, 24%, and 33% of the variance in hip, radius, spine, and total body BMD, respectively. The inclusion of the group variable did not add significantly to any the model. The addition of extension peak torque into the model resulted in an increase of explained variance of 1.5% in hip BMD (p = 0.07). It was not related to BMD at any other site. Flexion peak was not related to BMD at any of the sites measured. CONCLUSIONS: Age, gender, and body weight were predictive of BMD at the hip, radius, spine, and in the total body. Highly competitive exercise was not related to BMD. Hip BMD was correlated with quadriceps strength after controlling for the effects of competitive exercise, gender, age, and bodyweight.

Osteopenia in children who have undergone posterior fossa or craniospinal irradiation for brain tumors.

To determine lumbar spine and total body bone mineral density (BMD) in pediatric patients who have undergone cranial or craniospinal irradiation for posterior fossa tumors, specifically medulloblastoma and ependymoma and to analyze the association between degree of osteopenia and factors that may affect BMD. Retrospective and prospective data collection included medical record review and examination, including pubertal, dietary, and activity assessment. Lumbar spine and total body BMD were measured by means of dual energy x-ray absorptiometry. Patients were routinely observed by the endocrinology department, and hormone deficiencies were corrected promptly. A subset of patients received calcium and vitamin D supplementation and underwent repeat BMD measurement 1 year later. Of 24 patients aged 4 to 20 years, 11 of whom were male, recruited from 1996 through 1999, 19 had medulloblastoma. All 19 underwent craniospinal radiotherapy plus a boost to the posterior fossa (mean +/- SD of 5410 +/- 130 rad [54.1 +/- 1.3 Gy] to the posterior fossa, mean +/- SD of 3470 +/- 460 rad [34.7 +/- 4.6 Gy] to the whole brain and spinal axis), and 8 of 19 underwent chemotherapy. The remaining 5 patients had ependymoma and underwent irradiation to the posterior fossa only (mean +/- SD of 5680 +/- 720 rad [56.8 +/- 7.2 Gy]). Therefore, there were 3 treatment groups: craniospinal irradiation and chemotherapy, only craniospinal irradiation, and only posterior fossa irradiation. Bone mineral studies were performed a mean +/- SD of 5.42 +/- 3.23 years after therapy. Our patients had lower total body BMD (mean z score, -0.47; 95% confidence interval, -0.85 to -0.09) and lumbar spine BMD (mean z score, -1.27; 95% confidence interval, -1.81 to -0.73) as compared with those of the the general population. There was no significant difference in mean lumbar spine BMD between patients in the 3 groups. Our patients consumed a diet deficient in vitamin D and calcium (mean +/- SD 53.6% +/- 24.1% and 70.0% +/- 37.4% of the amount recommended, respectively). Of 7 patients who underwent measurements 1 year later, 5 had in increase in BMD that was parallel to normal curves, with no compensatory increase. Four patients were hypothyroid, 6 were growth hormone deficient, and 6 were both. All hormones were replaced, with the exception of growth hormone in 1 patient. By using regression analysis, the factors that affected lumbar spine BMD, protectively in both cases, were calcium intake (beta = 0.015, 95% confidence interval, 0.001-0.029) and female sex (beta = 1.422, 95% confidence interval, 0.456-2.388). Children who have undergone irradiation for posterior fossa tumors have diminished total body and lumbar spine BMD, as compared with those of the general population. This reduction was similar within all 3 treatment groups, which suggests that chemotherapy did not play a major role and that localized irradiation may have systemic effects. This population often has balance and gait problems, so the risk of falling, coupled with osteopenia, may place them at considerably increased risk of fractures.

Influence of participation in high-impact sports during adolescence and adulthood on bone mineral density in middle-aged men: a 27-year follow-up study.

This study examined whether participation in high-impact sports during adolescence and adulthood contributes to bone health in males aged 40 years. Data were analyzed on 154 Belgian men aged 13 years at study onset in 1969 and aged 40 years at the end of the 27-year follow-up. In a second analysis, subjects were divided into three groups according to their sports participation history: participation during adolescence and adulthood in high-impact sports (HH; n=18), participation during adolescence in high-impact sports and during adulthood in nonimpact sports or no sports (HN; n=15), and participation during adolescence and adulthood in nonimpact sports or no sports (NN; n=14). Body mass and impact loading during adulthood were significant predictors of total body bone mineral density (BMD) and lumbar spine BMD. Analysis of variance revealed significant differences for lumbar spine BMD between the HH (1.12 g/cm2) group and the HN (1.01 g/cm2) and NN (0.99 g/cm2) groups (F=5.07, p=0.01). Total body BMD was also higher in the HH group at age 40 years, but not significantly (F=3.17, p=0.0515). Covariance analyses for total body BMD and lumbar spine BMD, with body mass and time spent participating in sports as covariates, confirmed these results. Continued participation in impact sports is beneficial for the skeletal health of males aged 40 years.

RELATIONSHIP OF BODY COMPOSITION, ANTHROPOMETRICS, AGE AND GENDER TO BONE MINERAL DENSITY IN CHILDREN

Total body bone mineral density (BMD) has been associated with both lean tissue mass (LTM) and fat tissue mass (FTM) in adults and children. However, the relationship between regional BMD and soft tissue mass has not been adequately studied in children. PURPOSE The purpose of this study was to determine the relationships between body composition, anthropometrics, age, gender and BMD in children. METHODS Total body BMD and body composition were measured using dual-energy x- ray absorptiometry (Lunar DPX). Values for regional arm and leg BMD, LTM and FTM were determined from the total body measurement. Pearson correlations were used to examine the relationships between body composition, height, weight, circumferences, age and BMD. Stepwise multiple regression was used to determine the predictors of total body, arm and leg BMD. RESULTS Participants were male (n = 121) and female (n = 115) children aged 5.0 to 12.2 yr. Mean (±SD) age, height, weight, arm and calf circumferences were 9.5 ± 1.2 yr, 135.8 ± 10.0 cm, 35.9 ± 11.5 kg, 20.6 ± 2.7 cm and 28.6 ± 3.8 cm, respectively. Mean (±SD) total body BMD, FTM and LTM were 0.91 ± 0.07 g/cm2, 9.7 ± 7.5 kg and 24.4 ± 4.8 kg, respectively. Significant correlations were found between BMD and LTM, FTM, weight, height, arm circumference, calf circumference and age (r = 0.46 to 0.85, p < 0.01). The significant predictors of total body BMD using stepwise multiple regression were total LTM, total FTM, age and height (R2 = 0.62, p < 0.001). The significant predictors of leg BMD were leg LTM, leg FTM, age and height (R2 = 0.79, p < 0.001). However, only arm LTM, age and height were significant predictors of arm BMD using stepwise multiple regression (R2 = 0.58, p < 0.001). Neither gender, weight, nor circumferences were significant predictors of BMD at any site. CONCLUSION In preadolescent children, LTM, age and height are better predictors of total body and regional BMD than FTM, total body weight, arm and calf circumferences or gender. Supported by General Mills, Inc. and NIH Grant R01 HD36616-03.

Effect of insulin-like growth factor-1 (IGF-1) plus alendronate on bone density during puberty in IGF-1-deficient MIDI mice

Insulin-like growth factor-1 (IGF-1) increases both bone formation and bone resorption processes. To test the hypothesis that treatment with an antiresorber along with IGF-1, during the pubertal growth phase, would be more effective than IGF-1 alone to increase peak bone mass, we used an IGF-1 MIDI mouse model, which exhibits a >60% reduction in circulating IGF-1 levels. We first determined an optimal IGF-1 delivery by evaluating IGF-1 administration (2 mg/kg body weight/day) by either a single daily injection, three daily injections, or by continuous delivery via a minipump during puberty. Of the three regimens, the three daily IGF-1 injections and IGF-1 through a minipump produced a significant increase in total body bone mineral density (BMD) (6.0% and 4.4%, respectively) and in femoral BMD (4.3% and 6.2%, respectively) compared with the control group. Single subcutaneous (s.c.) administration did not increase BMD. We chose IGF-1 administration three times daily for testing the combined effects of IGF-1 and alendronate (100 μg/kg per day). The treatment of IGF-1 + alendronate for a period of 2 weeks increased total body BMD at 1 week and 3 weeks after treatment (21.1% and 20.5%, respectively) and femoral BMD by 29% at 3 weeks after treatment. These increases were significantly greater than those produced by IGF-1 alone. IGF-1, but not alendronate, increased bone length. IGF-1 and/or alendronate increased both periosteal and endosteal circumference. Combined treatment caused a greater increase in the total body bone mineral content (BMC) and periosteal circumference compared with individual treatment with IGF-1 or alendronate. Our data demonstrate that: (1) inhibition of bone turnover during puberty increases net bone density; and (2) combined treatment with IGF-1 and alendronate is more effective than IGF-1 or alendronate alone in increasing peak bone mass in an IGF-1-deficient MIDI mouse model.

Predictors of bone mineral density in aging healthy men varies by skeletal site.

Factors contributing to the pathogenesis of osteoporosis in women are well defined. However, changes in bone mineral metabolism in aging men and the role of various factors in the pathogenesis of age-related bone loss in men are less well understood. To further clarify these changes, serum and urine biochemical parameters, and lumbar spine, hip, and total body bone mineral density (BMD) were evaluated in a small sample of 45 healthy men aged 20-80 years, and multiple regression models were developed to predict age-related bone loss. Serum calcium, phosphate, albumin, creatinine clearance, osteocalcin, C-terminal propeptide of type I procollagen, log-free androgen index, dehydroepiandrosterone sulfate (DHEA-S), and androstenedione decreased with age, and serum sex hormone binding globulin and urine total and free pyridinoline increased with age. Femoral neck BMD decreased with age, but remained stable at the other sites measured. Multiple regression analysis indicated that serum phosphate, DHEA-S, and intact parathyroid hormone (PTH) predicted lumbar spine BMD. Age, serum phosphate, and PTH predicted femoral neck BMD. Urine-free deoxypyridinoline alone predicted femoral greater trochanter BMD. Weight, serum creatinine, and urine-free deoxypyridinoline predicted total body BMD. We conclude that predictor variables of bone density vary by skeletal site in healthy men. Alterations in adrenal androgens, phosphate, and PTH may be important in the pathogenesis of bone loss with aging in men.

Measures of Bioavailable Serum Testosterone and Estradiol and Their Relationships with Muscle Strength, Bone Density, and Body Composition in Elderly Men*

In the present cross-sectional study of 403 independently living elderly men, we tested the hypothesis that the decreases in bone mass, body composition, and muscle strength with age are related to the fall in circulating endogenous testosterone (T) and estrogen concentrations. We compared various measures of the level of bioactive androgen and estrogen to which tissues are exposed. After exclusion of subjects with severe mobility problems and signs of dementia, 403 healthy men (age, 73-94 yr) were randomly selected from a population-based sample. Total T (TT), free T (FT), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG) were determined by RIA. Levels of non-SHBG-bound T (non-SHBG-T), FT (calc-FT), the TT/SHBG ratio, non-SHBG-bound E2, and free E2 were calculated. Physical characteristics of aging included muscle strength measured using dynamometry, total body bone mineral density (BMD), hip BMD, and body composition, including lean mass and fat mass, measured by dual-energy x-ray absorptiometry. In this population of healthy elderly men, calc-FT, non-SHBG-T, E1, and E2 (total, free, and non-SHBG bound) decreased significantly with age. T (total and non-SHBG-T) was positively related with muscle strength and total body BMD (for non-SHBG-T, respectively, beta = 1.93 +/- 0.52, P < 0.001 and beta = 0.011 +/- 0.002, P < 0.001). An inverse association existed between T and fat mass (beta = -0.53 +/- 0.15, P < 0.001). Non-SHBG-T and calc-FT were more strongly related to muscle strength, BMD, and fat mass than TT and were also significantly related to hip BMD. E1 and E2 were both positively, independently associated with BMD (for E2, beta = 0.21 +/- 0.08, P < 0.01). Non-SHBG-bound E2 was slightly strongly related to BMD than total E2. The positive relation between T and BMD was independent of E2. E1 and E2 were not related with muscle strength or body composition. In summary, bioavailable T, E1, total E2, and bioavailable E2 all decrease with age in healthy old men. In this cross-sectional study in healthy elderly men, non-SHBG-bound T seems to be the best parameter for serum levels of bioactive T, which seems to play a direct role in the various physiological changes that occur during aging. A positive relation with muscle strength and BMD and a negative relation with fat mass was found. In addition, both serum E1 and E2 seem to play a role in the age-related bone loss in elderly men, although the cross-sectional nature of the study precludes a definitive conclusion. Non-SHBG-bound E2 seems to be the best parameter of serum bioactive E2 in describing its positive relation with BMD.

Three year follow-up of body composition changes in pre-menopausal women with systemic lupus erythematosus.

To measure the change in body composition in a pre-menopausal female systemic lupus erythematosus (SLE) population over 3 yr, and to identify predictors of change in body composition including the effects of disease-, corticosteroid (CS)- and patient-related variables. All 55 pre-menopausal females with SLE who participated in a cross-sectional study of body composition in 1994 were invited to undergo interview, examination, medical record review, and body composition assessment by dual-energy X-ray absorptiometry (DXA). Twenty-eight subjects participated with a mean (S.E.M.) age of 34.4 (1.6) yr, duration of SLE of 6.8 (0.8) yr and mean (range) time to follow-up of 3.2 (2.9-3.4) yr. Seventeen subjects were exposed to CS during the study period with a mean (range) daily dose of prednisolone of 12.0 (2.8-22.9) mg. There was a significant increase in body mass index (BMI) (24.53+/-0.83 vs 25.37+/-1.04, P = 0.03) and fat-free mass (41.04+/-0.83 vs 41.53+/-0.92, P = 0.05) over the 3 yr period. Univariate analysis revealed that change in fat-free mass was significantly associated with change in total body bone mineral density (BMD) (P = 0.03). Stepwise multiple linear regression analysis revealed a significant independent association of disease activity with increases in both BMI (r2 = 0.41, P = 0.006) and fat mass (r2 = 0.39, P = 0.007), and of exercise and Modified Health Assessment Questionnaire with an increase in fat-free mass (r2 = 0.51, P = 0.007). Age at SLE diagnosis and smoking were significant independent predictors for loss of total body BMD, while CS duration was predictive of an increase in total body BMD (r2 = 0.80, P < 0.0001). In this SLE population, disease activity was predictive of deleterious changes in body composition, including increases in BMI and fat mass. Patient-related variables were also important predictors of body composition change with exercise independently predicting an increase in fat-free mass, and smoking predictive of loss of total body BMD. In contrast, CS-related variables were not found to have harmful effects on body composition. Change in fat-free mass, and not fat mass, was predictive of change in total body BMD.