Is PPARα intron 7 G/C polymorphism associated with muscle strength characteristics in nonathletic young men?

Peroxisome proliferator-activated receptor alpha (PPARα), a ligand-dependent transcription factor, regulates fatty acid metabolism in heart and skeletal muscle. The intron 7 G/C polymorphism (rs4253778) has been associated with athletic performance. The rare C-allele was predominant in power athletes, whereas the G-allele was more frequent in endurance athletes. In the present study, we investigated the association between this polymorphism and strength characteristics in nonathletic, healthy young adults (n = 500; age 24.2 ± 4.4 years). Knee torque was measured during concentric knee flexion and extension movements at 60°/s, 120°/s, and 240°/s during 3, 25, and 5 repetitions, respectively. Also, resistance to muscle fatigue (i.e. work last 20% repetitions/work first 20% repetitions *100) was calculated. Differences in knee strength phenotypes between GG homozygous individuals and C-allele carriers were analyzed. The polymorphism did not influence the ability to produce isometric or dynamic knee flexor or extensor peak torque during static or dynamic conditions in this population (0.23 < P < 0.95). Similar results were found for the endurance ratio, a measure for resistance to muscle fatigue. In conclusion, the PPARα intron 7 G/C polymorphism does not seem to influence strength characteristics in a nonathletic population.

Genome-wide linkage scan for resistance to muscle fatigue.

Repeated, intense use of muscles leads to a decline in performance known as muscle fatigue. Resistance to muscle fatigue depends on age, sex, muscle fiber type, activation by the nervous system and training. Heritability of muscle strength phenotypes ranges between 31% and 78%, although little is known about heritability of muscle fatigue. A first aim of this study was to estimate the heritability for fatigue resistance after a short bout of intense exercise of the knee musculature. The main purpose was to identify chromosomal regions linked to muscle fatigue applying genome-wide linkage analyses. A selection of 283 informative male siblings (17-36 years old), belonging to 105 families, was used to conduct a genome-wide SNP-based multipoint linkage analysis. Heritabilities for resistance to muscle fatigue ranged from 21% to 54%. The strongest linkage signal was found at 19q13.11 (LOD=2.158; P<0.0001) and at 1q32.1 (LOD=2.142; P<0.0001) for resistance to fatigue of the knee flexors; however, no marker reached genome-wide significance. Several other regions with LOD>1.5 were found (1p31.3, 3q29, 8p22, 11q25 and 19q12). When replicated in an independent sample, these results warrant further fine mapping studies aiming to detect genes that underlie variation in muscle fatigue.

Genome-wide linkage scan for maximum and length-dependent knee muscle strength in young men: significant evidence for linkage at chromosome 14q24.3.

BACKGROUND: Maintenance of high muscular fitness is positively related to bone health, functionality in daily life and increasing insulin sensitivity, and negatively related to falls and fractures, morbidity and mortality. Heritability of muscle strength phenotypes ranges between 31% and 95%, but little is known about the identity of the genes underlying this complex trait. As a first attempt, this genome-wide linkage study aimed to identify chromosomal regions linked to muscle and bone cross-sectional area, isometric knee flexion and extension torque, and torque-length relationship for knee flexors and extensors. METHODS: In total, 283 informative male siblings (17-36 years old), belonging to 105 families, were used to conduct a genome-wide SNP-based multipoint linkage analysis. RESULTS: The strongest evidence for linkage was found for the torque-length relationship of the knee flexors at 14q24.3 (LOD = 4.09; p<10(-5)). Suggestive evidence for linkage was found at 14q32.2 (LOD = 3.00; P = 0.005) for muscle and bone cross-sectional area, at 2p24.2 (LOD = 2.57; p = 0.01) for isometric knee torque at 30 degrees flexion, at 1q21.3, 2p23.3 and 18q11.2 (LOD = 2.33, 2.69 and 2.21; p<10(-4) for all) for the torque-length relationship of the knee extensors and at 18p11.31 (LOD = 2.39; p = 0.0004) for muscle-mass adjusted isometric knee extension torque. CONCLUSIONS: We conclude that many small contributing genes rather than a few important genes are involved in causing variation in different underlying phenotypes of muscle strength. Furthermore, some overlap in promising genomic regions were identified among different strength phenotypes.

Activation of the cannabinoid 2 (CB2) receptor inhibits murine mesenteric afferent nerve activity.

Abstract Cannabinoid 2 (CB2) receptors have both antinociceptive and antihypersensitivity effects, although the precise mechanisms of action are still unclear. In this study, the modulatory role of CB2 receptors on the mesenteric afferent response to the endogenous immunogenic agent bradykinin (BK) was investigated. Mesenteric afferent recordings were obtained from anaesthetized wild-type and CB2(-/-) mice using conventional extracellular recording techniques. Control responses to BK were obtained in all experiments prior to administration of either CB2 receptor agonist AM1241, or AM1241 plus the CB2 receptor antagonist AM630. Bradykinin consistently evoked activation of mesenteric afferents (n = 32). AM1241 inhibited the BK response in a dose dependent manner. In the presence of AM630 (10 mg kg(-1)), however, AM1241 (10 mg kg(-)1) had no significant effect on the BK response. Moreover, AM1241 had also no significant effect on the BK response in CB2(-/-) mice. Activation of the CB2 receptor inhibits the BK response in mesenteric afferents, demonstrating that the CB2 receptor is an important regulator of neuroimmune function. This may be a mechanism of action for the antinociceptive and antihypersensitive effects of CB2 receptor agonists.

Biallelic alterations of both ETV6 and CDKN1B genes in a t(12;21) childhood acute lymphoblastic leukemia case.

Recently, a new recurrent t(12;21)(pl3;q22) has been identified in a B-cell lineage childhood acute lymphoblastic leukemia (ALL). The translocation results in a fusion of two known genes, ETV6/TEL (12p13) and AML1 (21q22), previously shown to be involved in the pathogenesis of myeloid disorders. We report results of cytogenetic fluorescence in situ hybridization and molecular studies of a B-cell childhood common ALL with a cryptic 12;21 translocation. Aberrations identified in this case involve both chromosomes 12 and include not only the ETV6-AML1 gene fusion and two different microdeletions of ETV6 but also the hemizygous loss of CDKN1B, D12S119, and KRAS2 loci and a putative rearrangement of the second CDKN1B allele as a result of an inv(12)(p13q24). Moreover, it was shown that the AML1-ETV6 reciprocal chimeric transcript was not present in the malignant cells, and hence may not play a major role in leukemogenesis. In addition, the putative loss of wild-type function of CDKN1B and ETV6 could indicate a synergistic effect of both genes in the pathogenesis of this leukemia case.

Quantitative trait loci for human muscle strength: linkage analysis of myostatin pathway genes.

This study reports the results of a multipoint linkage study that aims to unravel the genetic basis of muscle strength and muscle mass in humans. Myostatin (GDF8) is known to be a strong inhibitor of muscle growth in animals. However, studies examining human myostatin polymorphisms are rare and are limited to the GDF8 gene itself. Here, the contribution to isometric and concentric knee strength of nine key proteins involved in the myostatin pathway is studied in a nonparametric multipoint linkage analysis by means of a variance components and regression method. A sample of 367 healthy young male siblings was phenotyped on an isokinetic dynamometer and genotyped for markers of the myostatin pathway genes. Three of the loci were found significantly linked with a quantitative trait locus (QTL) for knee muscle strength. First, D13S1303 showed replication of an explorative single-point linkage study with a maximum LOD score of 2.7 (P = 0.0002). Second, maximum LOD scores of 3.4 (P = 0.00004) and 3.3 (P = 0.00005) were observed for markers D12S1042 and D12S85, respectively, at 12q12-14. Finally, marker D12S78 showed an LOD score of 2.7 at 12q22-23. We conclude that several genes involved in the myostatin pathway, but not the myostatin gene itself, are important QTLs for human muscle strength. An additional set of valuable candidate genes that were not part of the myostatin pathway was found in the chromosome 12 and 13 genomic regions.

Risk factors for drug-induced long-QT syndrome.

Congenital long-QT syndrome (cLQTS) is a ventricular arrhythmia that is characterised by a prolonged QT interval on the surface electro-cardiogram (ECG). Clinical symptoms include sudden loss of consciousness (syncopes), seizures, cardiac arrest and sudden death. The prevalence of this inherited disease is approximately one in 10,000 in Caucasians. Over the last decade, more than 200 different diseases causing mutations have been identified in five genes that encode ion channels involved in the delicate balance of inward and outward K/Ca currents during the cardiac action potential. A prolonged QT interval accompanied by very similar clinical symptoms as in cLQTS can also occur in otherwise healthy individuals after the intake of specific drug(s). This phenomenon is known as 'acquired' or 'drug-induced' long-QT syndrome. Because the clinical symptoms of the two forms are very similar, the question arises whether a common underlying genetic basis also exists. Several studies indicate that only a minority (approximately 10%) of the drug-induced LQTS cases can be explained by a mutation or polymorphism in one of the known LQTS genes. Even though the disease can often at least partially be explained by environmental factors, mutations or polymorphisms in other genes are also expected to be involved, including genes encoding drug-metabolising enzymes, adrenergic receptors, hormone-related genes and mitochondrial genes. This article reviews the current knowledge on risk factors for drug-induced LQTS, with a special emphasis on the role of genetic determinants.

Plasma levels of growth-related oncogene (CXCL1-3) associated with fibrosis and platelet counts in HCV-infected patients.

BACKGROUND: Fibrosis progression in hepatitis C virus (HCV)-infected patients varies greatly between individuals. Chemokines recruit immune cells to the infected liver and may thus play a role in the fibrosis process. AIM: To investigate plasma levels of a diverse chemokine panel in relation to liver fibrosis. METHODS: African-American and Caucasian HCV genotype 1 infected patients were treated with peginterferon (pegIFN) and ribavirin (RBV) for 48 weeks (VIRAHEP-C cohort). Plasma levels of 13 cytokines were studied at baseline (n = 386). Subsequently, GROα levels were assessed in a sub cohort (n = 99) at baseline, and at 4 and 12 weeks after start of pegIFN/RBV treatment. RESULTS: Increased severity of fibrosis (Ishak fibrosis score 0-2 vs. 3-6) was associated with increased plasma IP-10 (CXCL10) and IL-8 (CXCL8) levels, and decreased plasma levels of the chemokine growth-related oncogene (GRO, CXCL1-3). Plasma GRO levels were also positively correlated with platelet counts, and were higher in African-American as compared to Caucasian patients. In response to pegIFN/RBV treatment, GROα levels increased in Caucasian but not African-American patients from week 4 onwards. CONCLUSIONS: The association with severity of fibrosis and platelet count positions plasma GRO as a potential biomarker for liver fibrosis in HCV-infected patients. The secretion of GRO by platelets may explain the correlation between GRO plasma level and platelet count. The ethnic difference in GRO levels both pre-treatment and in response to pegIFN/RBV might be driven by a genetic polymorphism in GROα associated with higher plasma levels and more common in the African-American population.

Distraction bone healing versus osteotomy healing: a comparative biochemical analysis.

This study investigates the biochemical changes in a canine tibia lengthening model in comparison with a nonlengthened osteotomy model. The lengthened and the osteotomized callus and a contralateral corresponding segment were analyzed for their mineralization profile, collagen content, osteocalcin, insulin-like growth factor I (IGF-I), and transforming growth factor beta1 (TGF-beta1). Examinations of bone samples were performed using specimens excised at different time intervals (respectively at 3, 5, 7, 9, and 13 weeks postoperatively). Several serum parameters (alkaline phosphatase [ALP], osteocalcin, IGF-I, and TGF-beta1) were also measured during the experimental period. A progressive increase in mineral parameters was noticed in both the lengthened and the osteotomized areas. A higher level of hydroxyproline and TGF-beta1 was observed in the lengthened area compared with the osteotomized area. IGF-I showed a significant increase in both the lengthened and contralateral control area at the later stage of the experimental period in the lengthened group. In serum, a high level of TGF-beta1 and a progressively increasing osteocalcin concentration were observed in the lengthened dogs in comparison with the osteotomized dogs. Serum ALP was significantly increased in both models during the experimental period. Serum IGF-I was increased in the lengthened models during the distraction period and decreased in the osteotomized models at the early stage of the experimental period. These results suggest that the mechanical strain induced by the Ilizarov distraction procedure stimulates osteoblast proliferation and promotes biosynthesis of bone extracellular matrix in distracted callus. Our data furthermore show that this process is different compared with normal fracture healing.

Prediction of vertebral strength in vitro by spinal bone densitometry and calcaneal ultrasound.

Spinal bone mineral density (BMD) measurements and calcaneal ultrasound were compared in terms of their ability to predict the strength of the third lumbar vertebral body using specimens from 62 adult cadavers (28 females, 34 males). BMD was measured using dual X-ray absorptiometry (DXA) in both vertebra and calcaneus. Quantitative computed tomography (QCT) was used to determine trabecular BMD, cortical BMD, cortical area, and total cross-sectional area (CSA) of the vertebral body. Bone velocity (BV) and broadband ultrasonic attenuation (BUA) were measured in the right calcaneus. Vertebral strength was determined by uniaxial compressive testing. Vertebral ultimate load was best correlated with DXA-determined vertebral BMD (r2 = 0.64). Of the QCT parameters, the best correlation with strength was obtained using the product of trabecular BMD and CSA (r2 = 0.61). For vertebral ultimate stress, however, the best correlation was observed with QCT-measured trabecular BMD (r2 = 0.51); the correlation with DXA-determined BMD was slightly poorer (r2 = 0.44). Calcaneal ultrasound correlated only weakly with both ultimate load and stress with correlation coefficients (r2) of 0.10-0.17, as did calcaneal BMD (r2 = 0.18). Both spinal DXA and spinal QCT were significantly (p < 0.001) better predictors of L3 ultimate load and stress than were either calcaneal ultrasound or calcaneal DXA. Multiple regression analysis revealed that calcaneal ultrasound did not significantly improve the predictive ability of either DXA or QCT for L3 ultimate load or stress. Calcaneal DXA BMD, bone velocity, and BUA correlated well with each other (r2 = 0.67-0.76), but were only modestly correlated with the DXA and QCT measurements of the vertebra. These data indicate that spinal DXA and spinal QCT provide comparable prediction of vertebral strength, but that a substantial proportion (typically 40%) of the variability in vertebral strength is unaccounted for by BMD measurements. Ultrasonic measurements at the calcaneus are poor predictors of vertebral strength in vitro, and ultrasound does not add predictive information independently of BMD. These findings contrast with emerging clinical data, suggesting that calcaneal ultrasound may be a valuable predictor of vertebral fracture risk in vivo. A possible explanation for this apparent discrepancy between in vivo and in vitro findings could be that current clinical ultrasound measurements at the calcaneus reflect factors that are related to fracture risk but not associated with bone fragility.

Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis.

Both a decrease in bone formation and an increase in bone resorption have been implicated in the pathogenesis of age-related (type II) femoral neck osteoporosis. While the increase in the bone resorption rate has been shown to be partially related to secondary hyperparathyroidism, the mechanisms underlying the decline in bone formation have not yet been identified. The aim of the present study was to test the hypothesis that the bone formation deficit associated with type II osteoporosis might be due to secondary hyperparathyroidism and/or to a deficiency of the insulin-like growth factor (IGF) system. Circulating concentrations of IGF-I, IGF-II, IGF binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, 25-hydroxycholecalciferol (25(OH)D3), and intact parathyroid hormone (PTH) were measured in 50 elderly women after sustaining a hip fracture and in 50 healthy age-matched controls. In addition, serum levels of osteocalcin (OC), skeletal alkaline phosphatase, and N-terminal procollagen peptide and urinary pyridinium cross-links were determined as markers of bone remodeling, and bone mineral density (BMD) was assessed at the proximal femur. In the patient group, serum was drawn within 18 h of the fracture and prior to surgery. Circulating protein concentrations did not change over this time frame. No difference was found between mean IGFBP-4 serum levels in the two groups studied, while mean levels of IGF-I, IGF-II, IGFBP-3, IGFBP-5, 25(OH)D3, and markers of bone formation were significantly lower (p < 0.006) in patients as compared with healthy subjects. Serum PTH and urinary pyridinium cross-links, however, were markedly increased (p < 0.001) in the osteoporotic group. In pooled data from the normal and osteoporotic populations, age-adjusted multiple regression models based on IGF-I, IGF-II, IGFBP-3, and IGFBP-5 were found to be highly predictive of serum OC (R2 = 19%, p < 0.001) and BMD of femoral neck (R2 = 49%, p < 0.0001), consistent with an effect of the anabolic IGF components on overall bone formation rate. Similar models based on 25(OH)D3 and PTH, however, were statistically unrelated to OC. To address further the potential impact of trauma on circulating IGF system components, we measured IGF system component levels in 10 male patients within 18 h following tibial fracture and in 10 age-matched normal male subjects. There was no significant difference in serum level of any of the IGF system components between the two groups. Although limited by its cross-sectional design, the present study suggests that, in addition to bone resorption resulting from secondary hyperparathyroidism, impaired bone formation associated with deficiency of the IGF system might predispose elderly women to fragility fracture of the proximal femur.

Measurement of femoral geometry in type I and type II osteoporosis: differences in hip axis length consistent with heterogeneity in the pathogenesis of osteoporotic fractures.

The epidemiologic patterns of vertebral and femoral fractures are sufficiently different to suggest that they represent distinct disorders (type I versus type II osteoporosis) although osteopenia is common in both. To determine whether differences in femoral geometry, one of the main determinants of bone quality, might contribute to the heterogeneity in osteoporotic fractures, we obtained dual energy X-ray absorptiometry scans on 210 women age 60 or older, including 105 type I fracture cases, 30 type II patients, and 75 controls. Hip axis length, measured on the scan printout, was significantly increased (p < 0.01) in hip fracture patients compared with women with postmenopausal osteoporosis, whereas femoral neck density (BMD) was equal in both groups. The best discrimination between both fracture types was obtained by a logistic regression model based on age and axis length. Adding BMD to the model did not improve the discriminative power (p = 0.67). These data provide further evidence that geometric characteristics may be implicated in hip fracture risk. Furthermore, these findings suggest that an increase in hip axis length may predispose osteopenic subjects to a femoral localization of fragility fractures, consistent with the postulated heterogeneity in the pathogenesis of osteoporotic fractures.

Linkage of myostatin pathway genes with knee strength in humans.

This study was the first to explore the potential role of the myostatin (GDF8) pathway in relation to muscle strength and estimated muscle cross-sectional area in humans using linkage analysis with a candidate gene approach. In young male sibs (n = 329) 11 polymorphic markers in or near 10 candidate genes from the myostatin pathway were genotyped. Muscle mass was estimated by anthropometric measurements, and maximal knee strength was evaluated using isokinetic dynamometers (Cybex NORM). Single-point nonparametric variance components and linear quantitative trait locus regression linkage analysis methods were used. Linkage patterns were observed between knee extension and flexion peak torque with markers D2S118 (GDF8), D6S1051 (CDKN1A), and D11S4138 (MYOD1), and a maximum LOD score of 2.63 (P = 0.0002) was observed with D2S118. The ratios of peak torque over muscle and bone area of the midthigh of the lower contraction velocity (60 degrees/s) showed more frequently significant LOD scores than the torques at high velocity (240 degrees/s). Although myostatin is physiologically more related to muscle mass through possible effects of hyperplasia and hypertrophy than it is to strength, only two estimated muscle cross-sectional areas were marginally linked (LOD 1.06 and 1.07, P = 0.01) with marker D2S118 near GDF8 (2q32.2). The present results gave suggestive evidence that the myostatin pathway might be important for strength phenotypes, and GDF8, CDKN1A, and MYOD1 are potential candidate regions for a further and denser mapping with respect to these phenotypes.

Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research.

This study compares bone composition, density, and quality in bone samples derived from seven vertebrates that are commonly used in bone research: human, dog, pig, cow, sheep, chicken, and rat. Cortical femoral bone samples were analyzed for their content of ash, collagen, extractable proteins, and insulin-like growth factor-I. These parameters were also measured in bone powder fractions that were obtained after separation of bone particles according to their density. Large interspecies differences were observed in all analyses. Of all species included in the biochemical analyses, rat bone was most different, whereas canine bone best resembled human bone. In addition, bone density and mechanical testing analyses were performed on cylindrical trabecular bone cores. Both analyses demonstrated large interspecies variations. The lowest bone density and fracture stress values were found in the human samples; porcine and canine bone best resembled these samples. The relative contribution of bone density to bone mechanical competence was largely species-dependent. Together, the data reported here suggest that interspecies differences are likely to be found in other clinical and experimental bone parameters and should therefore be considered when choosing an appropriate animal model for bone research.

Effect of 1alpha-vitamin D3 and estrogen therapy on cortical bone mechanical properties in the ovariectomized rat model.

It is well documented that both bone mass and size of ovariectomized rats can be increased by 1alpha-vitamin D3 therapy. The repercussion of this therapy on bone mechanical competence is far less clear. Therefore, the objective of this study was to examine the mechanical properties of the shaft femur in ovariectomized rats (3 months old) receiving estrogen (0.25 mg/kg-week) and /or 1alpha-vitamin D3 (0.5 microgram/kg-day). The medication was given during 6 months starting immediately after ovariectomy or starting 3 months later. Torsional testing was performed from which the parameters strength, stiffness, maximum angular displacement, and energy-absorbing capacity (toughness) were derived. Multiple regression models were generated to estimate the relative importance of the therapies on bone mechanical properties. Bone stiffness increased with age. Ovariectomy improved bone mechanical parameters until 6 months postovariectomy, whereas estrogen treatment resulted in similar mechanical properties as those in intact age-matched controls. A significant improvement of all mechanical parameters was observed after 1alpha-vitamin D3 therapy. The combined therapy of 1alpha-vitamin D3 and estrogen was less effective than 1alpha-vitamin D3 alone, but better than estrogen therapy alone, suggesting interactive effects between both therapies. We conclude that 1alpha-vitamin D3 treatment of ovariectomized rats improves bone mechanical competence, which might be partially related to alterations in both bone mass and size.

Mineral density quantitation of the human cortical iliac crest by backscattered electron image analysis: variations with age, sex, and degree of osteoarthritis.

Bone samples from the rim of the iliac crest were obtained at autopsy from 59 patients aged 23 to 75 years, of whom 10 men and 10 women aged 50-75 years had osteoarthritis diagnosed by hand X-rays. An equal number in the same age group and 10 men and 9 women aged less than 50 years were without osteoarthritis. After embedding the bone in PMMA, the blocks were cut, polished, and coated with carbon. The fractions of bone falling within four consecutive bands of signal level were derived from digital backscattered electron imaging. Normal males had more low and medium density bone and normal females more very high density phase tissue proportionately. In both male and female osteoarthritis cases, low and medium fractions were low. The very high density fraction was mainly calcified fibrocartilage; when it was excluded from the calculations, the low, medium, and high phases occurred equally in normal males but increased stepwise in normal females and in osteoarthritis cases of both sexes. The results suggest a lower rate of bone renewal in females than males, and in male osteoarthritis subjects than normal males. An increased proportion of bone of high density would reduce the quality of the bone by increasing its stiffness.

Age-related endocrine deficiencies and fractures of the proximal femur. II implications of vitamin D deficiency in the elderly.

In the United Kingdom, as many as 60% of institutionalized people who are not taking vitamin D supplements may be deficient. Both impaired mineralization and a hyperparathyroidism-related increase in bone turnover have been identified in the presence of vitamin D deficiency. Recent interventional data have confirmed the role of vitamin D deficiency in the pathogenesis of senile osteoporosis and indicated the need to maintain serum cholecalciferol levels within the normal range in elderly people.

Age-related endocrine deficiencies and fractures of the proximal femur. I implications of growth hormone deficiency in the elderly.

Growth hormone activates osteoblasts to increase local synthesis of IGF-I, which acts in an autocrine or paracrine way to enhance bone matrix apposition, suggesting a role in the preservation of bone mass. Growth hormone deficiency in the elderly may therefore be of pathogenetic significance in senile osteoporosis. However, critical evidence does not yet support the concept that the decreased activity of the growth hormone-IGF-I axis alters bone remodelling, and the extent to which geriatric hyposomatotropism contributes to the age-related femoral bone loss remains to be elucidated. Despite the fact that biochemical estimates of bone turnover indicate that (short-term) administration of rhGH and IGF-I stimulates bone metabolism in non-osteoporotic older people, no significant changes have been observed in bone mineral density at the proximal femur. Additional studies are needed to assess the therapeutic potential for rhGH in attenuating or reversing bone loss in elderly people. Moreover, data on long-term adverse side effects of rhGH therapy are not yet available. Because of the known mitogenic action of IGF-I, the neoplastic potential of long-term rhGH therapy needs to be considered.

Variations in trabecular bone composition with anatomical site and age: potential implications for bone quality assessment.

Skeletal site-related differences in trabecular bone composition have been studied in autopsy samples from 63 individuals (age range 23-92 years). From each individual, bone samples were excised from the iliac crest, lumbar spine, femoral neck, and calcaneus. Samples were analyzed for their content of ash, calcium, collagen, extractable proteins, osteocalcin, and IGF-I. Significant differences were found between the skeletal sites, the lumbar spine being the least mineralized site and the femur the most. The femur and lumbar spine had a higher osteocalcin and IGF-I content compared with the other skeletal sites, suggesting a higher bone turnover rate. The intercorrelations between the anatomical sites were low for minerals and collagen but high for osteocalcin and IGF-I. The latter might indicate that the presence of these proteins in the bone matrix is mainly controlled by endocrine mechanisms which may influence the osteoblast function. Finally, regression analysis showed a significant age-related decrease of skeletal IGF-I at all sites examined. This finding supports the hypothesis of an IGF-I-mediated pathogenesis of senile osteoporosis. In summary, our data imply that a global assessment of skeletal function and bone quality, based upon analyses at one anatomical site, should be applied with caution.

Relationship between baseline insulin-like growth factor-I (IGF-I) and femoral bone density in women aged over 70 years: potential implications for the prevention of age-related bone loss.

OBJECTIVE: To test the hypothesis that the decline in femoral bone mass associated with healthy aging is partially accounted for by deficiency of the growth hormone-insulin-like growth factor-I (IGF-I) axis. DESIGN: Cross-sectional study. STUDY PARTICIPANTS: A sample of 245 community-dwelling healthy women aged 70 and older. Exclusion criteria were diseases or medications known to affect the musculoskeletal system or the somatotrophic axis. MEASUREMENTS: Serum levels of IGF-I, calcitriol, and osteocalcin were determined by radioimmunoassay; serum calcidiol was measured by competitive binding assay, and serum parathyroid hormone (PTH) was assessed immunochemically. Urinary pyridinium crosslinks were measured by fluorescent detection after high-pressure liquid chromatography. Isometric and isokinetic quadriceps strength was evaluated using an isokinetic dynamometer. Bone density (BMD) was assessed by dual-energy X-ray absorptiometry at the proximal femur. Multiple regression was used to adjust for potential confounders. RESULTS: At the proximal femur, BMD declined by 0.59-0.84% per year. In addition to body mass index and muscle strength, serum IGF-I was found to be an independent predictor of BMD at all femoral sites. CONCLUSION: The data support the hypothesis that circulating IGF-I not only reflects the integrated growth hormone secretion but also has a direct role in the endocrine regulation of bone remodeling. The present findings support the need for further studies to assess the potential of IGF-I in attenuating age-related femoral bone loss.