IGF-1 is associated with estimated bone strength in anorexia nervosa.

IGF-1 and leptin are two nutritionally dependent hormones associated with low bone mass in women with anorexia nervosa. Using finite element analysis, we estimated bone strength in women with anorexia nervosa and found that IGF-1 but not leptin correlated significantly with estimated bone strength in both the radius and tibia. PURPOSE: Women with anorexia nervosa, a psychiatric disorder characterized by self-induced starvation and low body weight, have impaired bone formation, low bone mass, and an increased risk of fracture. IGF-1 and leptin are two nutritionally dependent hormones that have been associated with low bone mass in women with anorexia nervosa. We hypothesized that IGF-1 and leptin would also be positively associated with estimated bone strength in women with anorexia nervosa. METHODS: In this cross-sectional study of 38 women (19 with anorexia nervosa and 19 normal-weight controls), we measured serum IGF-1 and leptin and performed finite element analysis of high-resolution peripheral quantitative CT images to measure stiffness and failure load of the distal radius and tibia. RESULTS: IGF-1 was strongly correlated with estimated bone strength in the radius (R = 0.52, p = 0.02 for both stiffness and failure load) and tibia (R = 0.55, p = 0.01 for stiffness and R = 0.58, p = 0.01 for failure load) in the women with anorexia nervosa but not in normal-weight controls. In contrast, leptin was not associated with estimated bone strength in the group of women with anorexia nervosa or normal-weight controls. CONCLUSIONS: IGF-1 is strongly associated with estimated bone strength in the radius and tibia in women with anorexia nervosa. Further studies are needed to assess whether treatment with recombinant human IGF-1 will further improve bone strength and reduce fracture risk in this population.

Clinical implications of bone marrow adiposity.

Marrow adipocytes, collectively termed marrow adipose tissue (MAT), reside in the bone marrow in close contact to bone cells and haematopoietic cells. Marrow adipocytes arise from the mesenchymal stem cell and share their origin with the osteoblast. Shifts in the lineage allocation of the mesenchymal stromal cell could potentially explain the association between increased MAT and increased fracture risk in diseases such as postmenopausal osteoporosis, anorexia nervosa and diabetes. Functionally, marrow adipocytes secrete adipokines, such as adiponectin, and cytokines, such as RANK ligand and stem cell factor. These mediators can influence both bone remodelling and haematopoiesis by promoting bone resorption and haematopoietic recovery following chemotherapy. In addition, marrow adipocytes can secrete free fatty acids, acting as a energy supply for bone and haematopoietic cells. However, this induced lipolysis is also used by neoplastic cells to promote survival and proliferation. Therefore, MAT could represent a new therapeutic target for multiple diseases from osteoporosis to leukaemia, although the exact characteristics and role of the marrow adipocyte in health and diseases remain to be determined.

Type 2 Diabetes and Aging: A Not so Sweet Scenario for Bone.

Type 2 diabetes and fractures are associated with substantial mortality and morbidity in the aging population. Given the normal to high bone mineral density, skeletal fragility in type 2 diabetes is an intriguing topic of ongoing research. An improved understanding of the underlying mechanisms and regulators of bone pathology in diabetes is needed to formulate targeted prevention and intervention strategies in this high risk population. Although the changes in bone induced by aging and disease are divergent, the pathogenetic mechanisms of aging and type 2 diabetes, thus far known, are not mutually exclusive. These mechanisms may provide deeper insight into the quantitative and qualitative deficits to further our knowledge of diabetes-specific bone pathology.

HP1BP3 expression determines maternal behavior and offspring survival.

Maternal care is an indispensable behavioral component necessary for survival and reproductive success in mammals, and postpartum maternal behavior is mediated by an incompletely understood complex interplay of signals including effects of epigenetic regulation. We approached this issue using our recently established mice with targeted deletion of heterochromatin protein 1 binding protein 3 (HP1BP3), which we found to be a novel epigenetic repressor with critical roles in postnatal growth. Here, we report a dramatic reduction in the survival of pups born to Hp1bp3(-/-) deficient mouse dams, which could be rescued by co-fostering with wild-type dams. Hp1bp3(-/-) females failed to retrieve both their own pups and foster pups in a pup retrieval test, and showed reduced anxiety-like behavior in the open-field and elevated-plus-maze tests. In contrast, Hp1bp3(-/-) females showed no deficits in behaviors often associated with impaired maternal care, including social behavior, depression, motor coordination and olfactory capability; and maintained unchanged anxiety-associated hallmarks such as cholinergic status and brain miRNA profiles. Collectively, our results suggest a novel role for HP1BP3 in regulating maternal and anxiety-related behavior in mice and call for exploring ways to manipulate this epigenetic process.

PPARG Post-translational Modifications Regulate Bone Formation and Bone Resorption.

The peroxisome proliferator-activated receptor gamma (PPARγ) regulates osteoblast and osteoclast differentiation, and is the molecular target of thiazolidinediones (TZDs), insulin sensitizers that enhance glucose utilization and adipocyte differentiation. However, clinical use of TZDs has been limited by side effects including a higher risk of fractures and bone loss. Here we demonstrate that the same post-translational modifications at S112 and S273, which influence PPARγ pro-adipocytic and insulin sensitizing activities, also determine PPARγ osteoblastic (pS112) and osteoclastic (pS273) activities. Treatment of either hyperglycemic or normoglycemic animals with SR10171, an inverse agonist that blocks pS273 but not pS112, increased trabecular and cortical bone while normalizing metabolic parameters. Additionally, SR10171 treatment modulated osteocyte, osteoblast, and osteoclast activities, and decreased marrow adiposity. These data demonstrate that regulation of bone mass and energy metabolism shares similar mechanisms suggesting that one pharmacologic agent could be developed to treat both diabetes and metabolic bone disease.

Daily leptin blunts marrow fat but does not impact bone mass in calorie-restricted mice.

Starvation induces low bone mass and high bone marrow adiposity in humans, but the underlying mechanisms are poorly understood. The adipokine leptin falls in starvation, suggesting that hypoleptinemia may be a link between negative energy balance, bone marrow fat accumulation, and impaired skeletal acquisition. In that case, treating mice with leptin during caloric restriction (CR) should reduce marrow adipose tissue (MAT) and improve bone mass. To test this hypothesis, female C57Bl/6J mice were fed a 30% CR or normal (N) diet from 5 to 10 weeks of age, with daily injections of vehicle (VEH), 1mg/kg leptin (LEP1), or 2mg/kg leptin (LEP2) (N=6-8/group). Outcomes included body mass, body fat percentage, and whole-body bone mineral density (BMD) via peripheral dual-energy X-ray absorptiometry, cortical and trabecular microarchitecture via microcomputed tomography (µCT), and MAT volume via µCT of osmium tetroxide-stained bones. Overall, CR mice had lower body mass, body fat percentage, BMD, and cortical bone area fraction, but more connected trabeculae, vs N mice (P<0.05 for all). Most significantly, although MAT was elevated in CR vs N overall, leptin treatment blunted MAT formation in CR mice by 50% vs VEH (P<0.05 for both leptin doses). CR LEP2 mice weighed less vs CR VEH mice at 9-10 weeks of age (P<0.05), but leptin treatment did not affect body fat percentage, BMD, or bone microarchitecture within either diet. These data demonstrate that once daily leptin bolus during CR inhibits bone marrow adipose expansion without affecting bone mass acquisition, suggesting that leptin has distinct effects on starvation-induced bone marrow fat formation and skeletal acquisition.

Room temperature housing results in premature cancellous bone loss in growing female mice: implications for the mouse as a preclinical model for age-related bone loss.

UNLABELLED: Room temperature housing (22 °C) results in premature cancellous bone loss in female mice. The bone loss was prevented by housing mice at thermoneutral temperature (32 °C). Thermogenesis differs markedly between mice and humans and mild cold stress induced by standard room temperature housing may introduce an unrecognized confounding variable into preclinical studies. INTRODUCTION: Female mice are often used as preclinical models for osteoporosis but, in contrast to humans, mice exhibit cancellous bone loss during growth. Mice are routinely housed at room temperature (18-23 °C), a strategy that exaggerates physiological differences in thermoregulation between mice (obligatory daily heterotherms) and humans (homeotherms). The purpose of this investigation was to assess whether housing female mice at thermoneutral (temperature range where the basal rate of energy production is at equilibrium with heat loss) alters bone growth, turnover and microarchitecture. METHODS: Growing (4-week-old) female C57BL/6J and C3H/HeJ mice were housed at either 22 or 32 °C for up to 18 weeks. RESULTS: C57BL/6J mice housed at 22 °C experienced a 62 % cancellous bone loss from the distal femur metaphysis during the interval from 8 to 18 weeks of age and lesser bone loss from the distal femur epiphysis, whereas cancellous and cortical bone mass in 32 °C-housed mice were unchanged or increased. The impact of thermoneutral housing on cancellous bone was not limited to C57BL/6J mice as C3H/HeJ mice exhibited a similar skeletal response. The beneficial effects of thermoneutral housing on cancellous bone were associated with decreased Ucp1 gene expression in brown adipose tissue, increased bone marrow adiposity, higher rates of bone formation, higher expression levels of osteogenic genes and locally decreased bone resorption. CONCLUSIONS: Housing female mice at 22 °C resulted in premature cancellous bone loss. Failure to account for species differences in thermoregulation may seriously confound interpretation of studies utilizing mice as preclinical models for osteoporosis.

Early-onset type 2 diabetes impairs skeletal acquisition in the male TALLYHO/JngJ mouse.

Type 2 diabetes (T2D) incidence in adolescents is rising and may interfere with peak bone mass acquisition. We tested the effects of early-onset T2D on bone mass, microarchitecture, and strength in the TALLYHO/JngJ mouse, which develops T2D by 8 weeks of age. We assessed metabolism and skeletal acquisition in male TALLYHO/JngJ and SWR/J controls (n = 8-10/group) from 4 weeks to 8 and 17 weeks of age. Tallyho mice were obese; had an approximately 2-fold higher leptin and percentage body fat; and had lower bone mineral density vs SWR at all time points (P < .03 for all). Tallyho had severe deficits in distal femur trabecular bone volume fraction (-54%), trabecular number (-27%), and connectivity density (-82%) (P < .01 for all). Bone formation was higher in Tallyho mice at 8 weeks but lower by 17 weeks of age vs SWR despite similar numbers of osteoblasts. Bone marrow adiposity was 7- to 50-fold higher in Tallyho vs SWR. In vitro, primary bone marrow stromal cell differentiation into osteoblast and adipocyte lineages was similar in SWR and Tallyho, suggesting skeletal deficits were not due to intrinsic defects in Tallyho bone-forming cells. These data suggest the Tallyho mouse might be a useful model to study the skeletal effects of adolescent T2D.

Improved adherence with PTH(1-84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis.

UNLABELLED: The purpose of this study is to examine the effect of PTH(1-84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy. INTRODUCTION: There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy. METHODS: Seven hundred and eighty-one subjects who received active PTH(1-84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers. RESULTS: PTH(1-84) treatment over 24 months increased BMD at the lumbar spine by 6.8% above baseline (p<0.05).The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2% above baseline. Larger increases in spine BMD were observed in participants with ≥80% adherence to daily injections of PTH(1-84) (8.3% in adherent vs 4.9% in poorly adherent patients). Total hip BMD gains were 1.7% in adherent vs 0.6% in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1-84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1-84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group. CONCLUSIONS: PTH(1-84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1-84) for up to 24 months is also associated with greater efficacy.

New insights into osteoporosis: the bone-fat connection.

Osteoporosis and obesity are chronic disorders that are both increasing in prevalence. The pathophysiology of these conditions is multifactorial and includes genetic, environmental and hormonal determinants. Although it has long been considered that these are distinct disorders rarely found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. It is proposed that adiposity may influence bone remodelling through three mechanisms: (i) secretion of cytokines that directly target bone, (ii) production of adipokines that influence the central nervous system thereby changing sympathetic impulses to bone and (iii) paracrine influences on adjacent skeletal cells. Here we focus on the current understanding of bone-fat interactions and the clinical implications of recent studies linking obesity to osteoporosis.

Premenopausal women with idiopathic low-trauma fractures and/or low bone mineral density.

INTRODUCTION: In men, idiopathic osteoporosis (IOP) is often associated with low serum insulin-like growth factor (IGF-1) and reduced bone formation. The characteristics of premenopausal women with IOP are not well defined. We aimed to define the clinical, reproductive, and biochemical characteristics of premenopausal women with unexplained osteoporosis. METHODS: This is a cross-sectional study of 64 women with unexplained osteoporosis, 45 with fragility fractures, 19 with low bone mineral density (BMD; Z-score less than or equal to -2.0) and 40 normal controls. The following are the main outcome measures: clinical and anthropometric characteristics, reproductive history, BMD, gonadal and calciotropic hormones, IGF-1, and bone turnover markers (BTMs). RESULTS: Subjects had lower BMI and BMD than controls, but serum and urinary calcium, serum estradiol, vitamin D metabolites, IGF-1, and most BTMs were similar. Serum parathyroid hormone (PTH) and the resorption marker, tartrate-resistant acid phosphatase (TRAP5b), were significantly higher in both groups of subjects than controls and directly associated in all groups. Serum IGF-1 and all BTMs were directly associated in controls, but the association was not significant after controlling for age. There was no relationship between serum IGF-1 and BTMs in subjects. There were few differences between women with fractures and low BMD. CONCLUSIONS: Higher serum TRAP5b and PTH suggest that increased bone turnover, possibly related to subclinical secondary hyperparathyroidism could contribute to the pathogenesis of IOP. The absence of differences between women with fractures and those with very low BMD indicates that this distinction may not be clinically useful to categorize young women with osteoporosis.

Back to the future: revisiting parathyroid hormone and calcitonin control of bone remodeling.

This review reflects on the past, present, and future of translational research on calcitropic hormones and bone metabolism. Calcitonin (CT) and parathormone (PTH) are complementary hormones involved in the acquisition and maintenance of bone mass and regulation of calcium metabolism. Early research demonstrated that these hormones could have an important role in the treatment of osteoporosis. Calcitonin was approved for this indication by the FDA more than two decades ago, and PTH gained regulatory approval for the treatment of osteoporosis nearly ten years ago. Unfortunately, basic research underlying the mechanism of action of these agents has lagged behind drug approval, and the role of these hormones in bone remodeling is still not firmly established. Moreover, research in bone biology shifted from these hormones to smaller molecules and paracrine regulators of skeletal remodeling. Although important, this development was somewhat unfortunate because without a clearer understanding of how calcitropic hormones work, we cannot be sure that they are being used optimally in the management of osteoporosis. In this review, we look at what is known about CT and PTH and the cells that they target, namely osteoblasts, osteoclasts, and osteocytes. We then identify gaps in knowledge and the research needed to fill them. The conduct of mechanistic studies may point to important factors, such as diurnal variation and dose responsiveness that would lead to improved treatment regimens. By reopening lines of basic and clinical investigation and applying those findings at the bedside, we hope to restart the cycle of translational research in this area.

Alcohol alters whole body composition, inhibits bone formation, and increases bone marrow adiposity in rats.

UNLABELLED: Chronic alcohol abuse is a risk factor for osteoporosis and sarcopenia, but the long-term effects of alcohol on the immature musculoskeletal system are less clear. The present investigation in growing rats was designed to determine the effects of alcohol consumption on body composition, muscle mass, and bone mass, architecture, and turnover. INTRODUCTION: Few studies have focused on the long-term effects of drinking on bone and muscle during skeletal maturation. METHODS: Alcohol was included in the diet of 4-week-old male Sprague-Dawley rats (35% caloric intake) for 3 months. The controls were fed an isocaloric alcohol-free liquid diet ad libitum. A second study was performed in which the controls were pair-fed to the alcohol-fed animals. RESULTS: Compared to ad libitum-fed age-matched controls, alcohol-fed rats weighed less and had lower lean mass, fat mass, and percent body fat. In addition, they had lower slow- and fast-twitch muscle mass, lower total body bone mineral content and bone mineral density, and lower cancellous bone volume in the lumbar vertebra and proximal tibia. The effects of alcohol consumption on body composition were reduced when compared to the pair-fed control diet, indicating that caloric restriction was a comorbidity factor. In contrast, the effects of alcohol to decrease bone formation and serum leptin and IGF-I levels and to increase bone marrow adiposity appeared independent of caloric restriction. CONCLUSIONS: The skeletal abnormalities in growing alcohol-fed rats were due to a combination of effects specific to alcohol consumption and alcohol-induced caloric restriction.

Gender- and compartment-specific bone loss in C57BL/6J mice: correlation to season?

Seasonal variation in bone mineral density (BMD) has been documented in humans, and has been attributed to changes in 25-hydroxyvitamin D [25(OH)D] synthesis. To test the hypothesis that seasonal changes in bone mass occur in laboratory mice, we measured body composition, femoral bone phenotypes, and serum bone markers in 16-wk-old male and female C57BL/6 (B6) mice during the summer (June-August) and winter (December-February) months at The Jackson Laboratory in Bar Harbor, Maine. Both male and female B6 mice had higher volumetric BMD in the summer than winter. Females showed reduced trabecular bone, whereas males showed changes in bone volume. Males, but not females, had higher insulin-like growth factor 1 in summer than in winter, and only males showed an increase in body weight during the winter. No seasonal differences in serum TRAP5b, osteocalcin, or 25(OH)D were noted for either sex. We conclude that seasonal variation in skeletal and body composition parameters in B6 mice is significant and must be considered when performing longitudinal phenotyping of the skeleton. Further studies are needed to determine the environmental factors that cue seasonal changes in body composition and the mechanisms that produce these changes.

Whole-body vibration slows the acquisition of fat in mature female rats.

OBJECTIVE: To evaluate the effects of whole-body vibration on fat, bone, leptin and muscle mass. METHODS/DESIGN: Thirty 7-month-old female 344 Fischer rats were randomized by weight into three groups (baseline, vibration or control; n=8-10 per group). Rats in the vibration group were placed inside individual compartments attached to a Pneu-Vibe vibration platform (Pneumex, Sandpoint, ID, USA) and vibrated at 30-50 Hz (6 mm peak to peak) for 30 min per day, 5 days per week, for 12 weeks. The vibration intervention consisted of six 5-min cycles with a 1-min break between cycles. RESULTS: There were significant body composition differences between the whole-body vibration and the control group. The whole-body vibration group weighed approximately 10% less (mean+/-s.d.; 207+/-10 vs 222+/-15 g, P<0.03) and had less body fat (20.8+/-3.8 vs 26.8+/-5.9 g, P<0.05), a lower percentage of body fat (10.2+/-1.7 vs 12+/-2.0%, P<0.05), and lower serum leptin levels (1.06+/-0.45 vs 2.27+/-0.57 ng ml(-1), P<0.01) than the age-matched controls. No differences were observed for total lean mass, bone mineral content (BMC), bone mineral density (BMD), insulin-like growth factor-I (IGF-I) or soleus (SOL) and extensor digitorum longus (EDL) mass or function. Regional high-resolution dual-energy X-ray absoptiometry scans of the lumbar spine (L1-4) revealed that the whole-body vibration group had significantly greater BMC (0.33+/-0.05 vs 0.26+/-0.03 g, P<0.01) and BMD (0.21+/-0.01 vs 0.19+/-0.01 g cm(-2), P<0.01) than the control group. No differences between the groups were observed in the amount of food consumed. CONCLUSION: These findings show that whole-body vibration reduced body fat accumulation and serum leptin without affecting whole body BMC, BMD or lean mass. However, the increase in vertebral BMC and BMD suggests that vibration may have resulted in local increases in bone mass and density. Also, whole-body vibration did not affect muscle function or food consumption.

Effects of low-dose parathyroid hormone on bone mass, turnover, and ectopic osteoinduction in a rat model for chronic alcohol abuse.

Parathyroid hormone (PTH) is used clinically in osteoporotic patients to increase bone mass by enhancing bone formation. PTH therapy is not uniformly effective at all skeletal sites and "life-style" factors may modulate the skeletal response to PTH. Alcohol may represent one of these factors. Chronic alcohol abuse is associated with osteoporosis and impaired fracture healing. Therefore, the present study investigated the effects of alcohol on the bone anabolic response to a dose of PTH similar to a human therapeutic dose 1) during normal cancellous and cortical bone growth and turnover, and 2) in a model of demineralized allogeneic bone matrix (DABM)-induced osteoinduction. Three-month-old male Sprague Dawley rats were fed a Lieber-DeCarli liquid diet with 35% of the calories derived from ethanol. The controls were pair-fed an alcohol-free isocaloric diet containing maltose-dextran. Following adaptation to the liquid diets, the rats were implanted subcutaneously with DABM cylinders prepared from cortical bone of rats fed normal chow. The rats were subsequently treated daily with PTH (1 microg/kg/d sc, 5 d/week) or vehicle and measurements on bone and DABM implants performed 6 weeks later. Total bone mass was evaluated on the day of necropsy using DXA. Tibiae were processed for histomorphometry. Bone mass and architecture in tibial diaphysis and DABM implants were evaluated by muCT. PTH treatment increased whole body bone mineral content (BMC) and bone mineral density (BMD). The hormone also increased bone formation and bone area/tissue area in the proximal tibial metaphysis. In contrast, PTH treatment had no effect on periosteal bone formation and minimal effects on DABM-induced osteoinduction. Alcohol consumption decreased whole body BMC. Alcohol also decreased cancellous as well as cortical bone formation and bone mass in tibia and impaired DABM-mediated osteoinduction. There was no interaction between PTH treatment and alcohol consumption for any of the endpoints evaluated. Our results indicate that the bone anabolic response to a therapeutic dose of PTH in the rat is largely confined to cancellous bone. In contrast, alcohol consumption inhibits bone formation at all sites. Furthermore, alcohol inhibits osteoinduction and reduces periosteal and cancellous bone formation, irrespective of therapeutic PTH administration. Based on the animal model, our findings suggest that alcohol consumption could impair the beneficial effects of PTH therapy in osteoporosis.

Gender-specific changes in bone turnover and skeletal architecture in igfbp-2-null mice.

IGF-binding protein-2 (IGFBP-2) is a 36-kDa protein that binds to the IGFs with high affinity. To determine its role in bone turnover, we compared Igfbp2(-/-) mice with Igfbp2(+/+) colony controls. Igfbp2(-/-) males had shorter femurs and were heavier than controls but were not insulin resistant. Serum IGF-I levels in Igfbp2(-/-) mice were 10% higher than Igfbp2(+/+) controls at 8 wk of age; in males, this was accompanied by a 3-fold increase in hepatic Igfbp3 and Igfbp5 mRNA transcripts compared with Igfbp2(+/+) controls. The skeletal phenotype of the Igfbp2(-/-) mice was gender and compartment specific; Igfbp2(-/-) females had increased cortical thickness with a greater periosteal circumference compared with controls, whereas male Igfbp2(-/-) males had reduced cortical bone area and a 20% reduction in the trabecular bone volume fraction due to thinner trabeculae than Igfbp2(+/+) controls. Serum osteocalcin levels were reduced by nearly 40% in Igfbp2(-/-) males, and in vitro, both CFU-ALP(+) preosteoblasts, and tartrate-resistant acid phosphatase-positive osteoclasts were significantly less abundant than in Igfbp2(+/+) male mice. Histomorphometry confirmed fewer osteoblasts and osteoclasts per bone perimeter and reduced bone formation in the Igfbp2(-/-) males. Lysates from both osteoblasts and osteoclasts in the Igfbp2(-/-) males had phosphatase and tensin homolog (PTEN) levels that were significantly higher than Igfbp2(+/+) controls and were suppressed by addition of exogenous IGFBP-2. In summary, there are gender- and compartment-specific changes in Igfbp2(-/-) mice. IGFBP-2 may regulate bone turnover in both an IGF-I-dependent and -independent manner.

The effects of a high-fruit and -vegetable, high-fiber, low-fat dietary intervention on serum concentrations of insulin, glucose, IGF-I and IGFBP-3.

OBJECTIVE: To determine the effects of dietary change on serum concentrations of insulin, glucose, IGF-I and IGFBP-3. SUBJECTS: From among participants in a randomized clinical trial of men and women without a history of diabetes who were 35 years old or older and who had at least one histologically confirmed colorectal adenoma removed during a qualifying colonoscopy within the 6 months before randomization, 750 subjects were selected for this analysis. METHODS: The authors analyzed fasting serum from 375 subjects with and 375 subjects without a recurrent polyp among participants in a randomized trial of a low-fat (20% of energy), high-fiber (18 g per 1000 kcals of energy intake) and high-fruit and -vegetable (5-8 servings per day) dietary intervention. RESULTS: After 4 years of follow-up, IGF-I concentration in the intervention group (N=248) declined by 8.86 ng/ml (initial mean of 133 ng/ml) and 7.74 ng/ml (initial mean value of 139 ng/ml) in the non-intervention group (N=502). Based on an unpaired t-test, these declines were both statistically significant, but the difference between groups for the decline in IGF-I (1.12 ng/ml ((95% confidence interval, -3.24 to 5.48)) was not. After 4 years, concentrations of IGFBP-3, insulin and glucose were not statistically different from values at baseline, and there were no differences in these serum measures between the intervention and control groups. In analysis restricted to lean (body mass index <25 kg/m(2)) subjects only, however, glucose concentrations in the intervention group decreased by 0.28 mmol/l, while they increased in the control group by 0.01 mmol/l (t-test for mean differences P=0.0003) over 4 years. CONCLUSIONS: A low-fat, high-fiber, high-fruit and -vegetable dietary intervention had minimal impact on serum concentrations of insulin, glucose, IGF-I and IGFBP-3 overall, but in lean subjects the intervention resulted in a significant reduction in serum glucose concentration.

Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals.

Obesity, a global pandemic that debilitates millions of people and burdens society with tens of billions of dollars in health care costs, is deterred by exercise. Although it is presumed that the more strenuous a physical challenge the more effective it will be in the suppression of adiposity, here it is shown that 15 weeks of brief, daily exposure to high-frequency mechanical signals, induced at a magnitude well below that which would arise during walking, inhibited adipogenesis by 27% in C57BL/6J mice. The mechanical signal also reduced key risk factors in the onset of type II diabetes, nonesterified free fatty acid and triglyceride content in the liver, by 43% and 39%, respectively. Over 9 weeks, these same signals suppressed fat production by 22% in the C3H.B6-6T congenic mouse strain that exhibits accelerated age-related changes in body composition. In an effort to understand the means by which fat production was inhibited, irradiated mice receiving bone marrow transplants from heterozygous GFP+ mice revealed that 6 weeks of these low-magnitude mechanical signals reduced the commitment of mesenchymal stem cell differentiation into adipocytes by 19%, indicating that formation of adipose tissue in these models was deterred by a marked reduction in stem cell adipogenesis. Translated to the human, this may represent the basis for the nonpharmacologic prevention of obesity and its sequelae, achieved through developmental, rather than metabolic, pathways.

Hetereogeneity in skeletal response to full-length parathyroid hormone in the treatment of osteoporosis.

UNLABELLED: In the PaTH trial, among the 119 women randomized to parathyroid hormone PTH(1-84) and 60 to alendronate, we found much greater variation in BMD and markers in response to PTH(1-84) compared to alendronate. No baseline participant characteristic consistently predicted increased bone density response to PTH(1-84), although women with larger changes in 1,25 dihydroxyvitamin D during therapy had larger increases in BMD. INTRODUCTION: We examined variability in BMD and markers of bone turnover in response to treatment with PTH(1-84) or alendronate in the PaTH trial. METHODS: Differences in SD were examined using Levine's test for homogeneity of variance. Change in BMD across quartiles of participant characteristics was examined using ANOVA. RESULTS: We found much greater variation in response to PTH(1-84) compared to alendronate. The SD for change in cancellous spine BMD (by QCT) was 32% on PTH(1-84) compared to 13% on alendronate (p < 0.0001). The higher variability in the PTH(1-84) group was due to substantial numbers of women with large increases in BMD on PTH(1-84). Similarly, the SD of changes in markers of formation and resorption were significantly higher on PTH(1-84) than on ALN. No baseline participant characteristics predicted increased bone density response to PTH(1-84) therapy. However, change in 1,25-OH(2)D explained 16% of the variance in BMD response to PTH(1-84). CONCLUSION: There is significant variability in the skeletal response to PTH(1-84), which exceeds that observed with alendronate. Changes in 1,25-OH(2)D were related to larger gains in BMD. This finding may have implications for elucidating either the pathway by which PTH affects the skeleton or traits that result in particular responsiveness to PTH therapy.