Peak Bone Mineral Density Research Articles

Quantitative Trait Loci for Femoral and Lumbar Vertebral Bone Mineral Density in C57BL/6J and C3H/HeJ Inbred Strains of Mice

AbstractSignificant differences in vertebral (9%) and femoral (50%) adult bone mineral density (BMD) between the C57BL/6J (B6) and C3H/HeJ (C3H) inbred strains of mice have been subjected to genetic analyses for quantitative trait loci (QTL). Nine hundred eighty‐six B6C3F2 females were analyzed to gain insight into the number of genes that regulate peak BMD and their locations. Femurs and lumbar vertebrae were isolated from 4‐month‐old B6C3F2 females at skeletal maturity and then BMD was determined by peripheral quantitative computed tomography (pQCT). Estimates of BMD heritability were 83% for femurs and 72% for vertebrae. Genomic DNA from F2 progeny was screened for 107 polymerase chain reaction (PCR)–based markers discriminating B6 and C3H alleles on all 19 autosomes. The regression analyses of markers on BMD revealed ten chromosomes (1, 2, 4, 6, 11, 12, 13, 14, 16, and 18) carrying QTLs for femurs and seven chromosomes (1, 4, 7, 9, 11, 14, and 18) carrying QTLs for vertebrae, each with log10 of the odds ratio (LOD) scores of 2.8 or better. The QTLs on chromosomes (Chrs) 2, 6, 12, 13, and 16 were unique to femurs, whereas the QTLs on Chrs 7 and 9 were unique to vertebrae. When the two bone sites had a QTL on the same chromosome, the same marker had the highest, although different, LOD score. A pairwise comparison by analysis of variance (ANOVA) did not reveal significant gene × gene interactions between QTLs for either bone site. BMD variance accounted for by individual QTLs ranged from 1% to 10%. Collectively, the BMD QTLs for femurs accounted for 35.1% and for vertebrae accounted for 23.7% of the F2 population variances in these bones. When mice were homozygous c3/c3 in the QTL region, 8 of the 10 QTLs increased, while the remaining two QTLs on Chrs 6 and 12 decreased, femoral BMD. Similarly, when mice were homozygous c3/c3 in the QTL region for the vertebrae, five of the seven QTLs increased, while two QTLs on Chrs 7 and 9 decreased, BMD. These findings show the genetic complexity of BMD with multiple genes participating in its regulation. Although 5 of the 12 QTLs are considered to be skeleton‐wide loci and commonly affect both femurs and vertebrae, each of the bone sites also exhibited unique QTLs. Thus, the BMD phenotype can be partitioned into its genetic components and the effects of these loci on normal bone biology can be determined. Importantly, the BMD QTLs that we have identified are in regions of the mouse genome that have known human homology, and the QTLs will become useful experimental tools for mechanistic and therapeutic analyses of bone regulatory genes.

Polymorphisms in the Estrogen Receptor β (ESR2) Gene Are Associated with Bone Mineral Density in Caucasian Men and Women

A major determinant of osteoporotic fractures is peak bone mineral density (BMD), which is a highly heritable trait. Recently, we identified significant linkage for hip BMD in premenopausal sister pairs at chromosome 14q (LOD score = 3.5), where the estrogen receptor beta gene (ESR2) is located. The objective of the study was to determine whether ESR2 polymorphisms are associated with normal BMD variation. This was a population-based genetic association study, using 11 single nucleotide polymorphisms (SNPs) distributed across the ESR2 gene. The study was conducted at an academic research laboratory and medical center. A total of 411 healthy men (aged 18-61 yr) and 1291 healthy premenopausal women (aged 20-50 yr) living in Indiana participated in the study. There were no interventions. The main outcome measures were SNP genotype distributions and their association with BMD at the femoral neck and lumbar spine. Significant association of spine BMD was found with three SNPs in men and one SNP in women (P < or = 0.05). The conditional linkage analysis using the ESR2 haplotypes showed that the ESR2 gene accounts for, at most, 18% of the original linkage. ESR2 polymorphisms are significantly associated with bone mass in both men and women. However, the ESR2 gene is not entirely responsible for our original linkage, and an additional gene(s) in chromosome 14q contributes to the determination of BMD.

Bone mineral density of the proximal femur is not related to dynamic joint loading during locomotion in young women

We characterized the extent to which body mass influences the relationship between hip joint moments during locomotion and bone mineral density (BMD) of the proximal femur in healthy young women ( n = 24). There is some evidence of a direct relationship between hip joint moments during locomotion and BMD of the proximal femur in patients with osteoarthritis. Nevertheless, based on expected simultaneous influences of body mass on BMD and joint moments during locomotion, we hypothesized that BMD would not be significantly associated with hip joint moments during locomotion independently of body mass. BMD of the nondominant proximal femur was determined using DXA. The hip joint moments were determined by gait analysis. The correlation between peak internal rotation moment and BMD of the intertrochanteric region was significant ( r = 0.48; P = 0.019). However, body mass was significantly correlated to both BMD and the internal rotation moment ( r = 0.59 and 0.70; P = 0.002 and <0.001, respectively). After accounting for the relationship between body mass and hip joint moment, the internal rotation moment was not significantly correlated to BMD of the proximal femur ( r = 0.04, P = 0.34) indicating that BMD is not significantly associated with hip joint moments during locomotion independent of body mass in young healthy women.

Prevalence of low central bone mineral density in a bulgarian female referral population: a pilot study

Osteoporosis is one of the most important health problems among elderly women. The prevalence of central osteoporosis in Bulgaria is still unknown. We tried to retrospectively determine the prevalence of osteopenia and osteoporosis at the spine and hip in a female referral population. Bulgarian women (2,600) aged group 25-87 years referred for bone densitometry screening were included. Information about known risk factors for low bone mass was recorded. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (Hologic QDR 4500 A) at the lumbar spine (2,547 participants, 1,954 of whom were postmenopausal) and left hip (723 participants, 605 of whom were postmenopausal). T-scores were calculated from Hologic-provided and own Bulgarian peak BMD data (the latter based on 122 healthy premenopausal 25- to 39-year-old women). Peak lumbar spine BMD was 0.994 g/cm2 (SD 0.095 g/cm2), and thus lower than the manufacturer-provided value of 1.047 g/cm2. The peak BMD of the total hip was 0.959 g/cm2 (SD 0.129 g/cm2) and thus higher than the manufacturer-provided BMD of 0.942. T-scores differed according to the database used. The osteoporosis threshold of -2.5 SD was reached at the spine in the age group 70-74 years. Left hip T-scores showed a much slower decline with age. In women aged 50 and older the prevalence of osteoporosis reached 37.31% at the spine, and 16.14% at the left hip. Osteopenia was found in 39.74% at the spine and in 65.57% at the total hip. This is the first Bulgarian study looking for the prevalence of central osteoporosis in a female referral population. It may become the starting point for future epidemiological work.

Genome screen for bone mineral density phenotypes in Fisher 344 and Lewis rat strains

In humans, peak bone mineral density (BMD) is the primary determinant of osteoporotic fracture risk among older individuals, with high peak BMD levels providing protection against osteoporosis in the almost certain event of bone loss later in life. A genome screen to identify quantitative trait loci (QTLs) contributing to areal BMD (aBMD) and volumetric BMD (vBMD) measurements at the lumbar spine and femoral neck was completed in 595 female F2 rats produced from reciprocal crosses of inbred Fischer 344 and Lewis rats. Significant evidence of linkage was detected to rat Chromosomes 1, 2, 8, and 10, with LOD scores above 8.0. The region on rat Chromosome 8 is syntenic to human Chromosome 15, where linkage to spine and femur BMD has been previously reported and confirmed in a sample of premenopausal women.

Age of Attainment of Peak Bone Mass Is Site Specific in Swedish Men—The GOOD Study

Results from this study suggest that PBM has been attained in the spine and femoral neck, but not in the radius or tibia, in 18- to 20-year-old men, in which an endosteal contraction and increase in cortical volumetric BMD is observed. Peak bone mass (PBM) is an important determinant for the risk of osteoporosis. In men, the age of attainment of PBM has been under some controversy. The objective of this study was to determine if peak bone mass had been attained, and whether it is site specific, in 18- to 20-year-old Swedish men. The Gothenburg Osteoporosis and Obesity Determinants (GOOD) Study consists of 1068 men, 18.9 +/- 0.6 years of age. BMD was measured using both DXA and pQCT. Environmental factors, such as dietary intake and physical activity, were assessed through questionnaires. The independent predictors of BMD were assessed through multiple linear regression, including age, height, weight, calcium intake, smoking, and physical activity. We show, in a large well-characterized cohort, that age was not an independent predictor of BMD of the lumbar spine, femoral neck, or total body, indicating that peak BMD has been achieved in these skeletal sites, whereas it was an independent predictor of BMD of the radius, suggesting that peak BMD has not yet been attained in the long bones. pQCT analyses of the radius and the tibia revealed that age was associated with cortical volumetric BMD and endosteal contraction of the radius and tibia. These results show that the age of attainment of PBM is site specific.

Impaired skeletal growth in mice with haploinsufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density differences

Although it is well established that there is considerable inter-individual variation in the circulating levels of IGF-I in normal, healthy individuals and that a genetic component contributes substantially to this variation, the direct evidence that inter-individual variation in IGF-I contributes to differences in peak bone mineral density (BMD) is lacking. To examine if differences in IGF-I expression could contribute to peak BMD differences, we measured skeletal changes at days 23 (prepubertal), 31 (pubertal) and 56 (postpubertal) in mice with haploinsufficiency of IGF-I (+/-) and corresponding control mice (+/+). Mice (MF1/DBA) heterozygous for the IGF-I knockout allele were bred to generate +/+ and +/- mice (n=18-20 per group). Serum IGF-I was decreased by 23% (P<0.001) in mice with IGF-I haploinsufficiency (+/-) group at day 56 compared with the control (+/+) group. Femoral bone mineral content and BMD, as determined by dual energy X-ray absorptiometry, were reduced by 20% (P<0.001) and 12% respectively in the IGF-I (+/-) group at day 56 compared with the control group. The peripheral quantitative computed tomography measurements at the femoral mid-diaphysis revealed that periosteal circumference (7%, P<0.01) and total volumetric BMD (5%, P<0.05) were decreased significantly in the +/- group compared with the +/+ group. Furthermore, serum IGF-I showed significant positive correlations with both areal BMD (r=0.55) and periosteal circumference (r=0.66) in the pooled data from the +/+ and +/- groups. Our findings that haploinsufficiency of IGF-I caused significant reductions in serum IGF-I level, BMD and bone size, together with the previous findings, are consistent with the notion that genetic variations in IGF-I expression could, in part, contribute to inter-individual differences in peak BMD among a normal population.

Sex-Specific and Non-Sex-Specific Quantitative Trait Loci Contribute to Normal Variation in Bone Mineral Density in Men

A major determinant of osteoporotic fracture is peak bone mineral density (BMD). In women peak BMD is highly heritable and several quantitative trait loci (QTL) have been reported. There are few comparable data in men. This study in men aimed to establish the heritability of peak BMD, identify QTL contributing to normal variation in BMD, and determine which QTL might be sex specific. BMD at the spine and hip were measured in 323 pairs of brothers aged 18-61 yr (264 white pairs; 59 black pairs). Heritability was calculated and linkage analysis performed with spine and hip BMD phenotypes. Heritability estimates ranged from 0.61 to 0.87 and were not significantly different between white and black men. A 9-cM genome-wide scan followed by genotyping with more closely spaced markers identified suggestive QTL (logarithm of the odds > 2.2) for BMD on chromosomes 1q (spine), 2p (spine), 2q (hip), 14p (spine), 18 (hip), and 21 (hip). Comparison with published data in 774 pairs of premenopausal sisters suggested that the QTL on 1q (spine), 2q (hip), 14p (spine), and 21q (hip) were male specific, whereas those on 2p (spine) and 18 (hip) were not sex specific. This study demonstrates that BMD in healthy men is highly heritable with similar estimates of the genetic contribution to BMD in both whites and blacks. Of the six QTL identified, three were specific for spine BMD and three were specific for hip BMD. When compared with published QTL for peak BMD in women from the same geographical region, four of the QTL appeared to be male specific. The occurrence of sex-specific genes in humans for BMD has potentially important implications for the pathogenesis and treatment of osteoporosis.

Contribution of the LRP5 Gene to Normal Variation in Peak BMD in Women

The role of the LRP5 gene in rare BMD-related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5 and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5 in our sample. Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been implicated as the cause of multiple distinct BMD-related rare Mendelian phenotypes. We sought to examine whether the LRP5 gene contributes to the observed variation in peak BMD in the normal population. We genotyped 12 single nucleotide polymorphisms (SNPs) in LRP5 using allele-specific PCR and mass spectrometry methods. Linkage disequilibrium between the genotyped LRP5 SNPs was measured. We tested for association between these SNPs and both hip and spine BMD (adjusted for age and body weight) in 1301 healthy premenopausal women who took part in a sibling pair study aimed at identifying the genes underlying peak bone mass. Our study used both population-based (ANOVA) and family-based (quantitative transmission disequilibrium test) association methodology. The linkage disequilibrium pattern and haplotype block structure within the LRP5 gene were consistent with that observed in other studies. Although significant evidence of association was found between LRP5 SNPs and both hip and spine BMD, only a small proportion of the total variation in these phenotypes was accounted for. The genotyped SNPs accounted for approximately 0.8% of the variation in femoral neck BMD and 1.1% of the variation in spine BMD. Results from our sample suggest that natural variation in and around LRP5 is not a major contributor to the observed variability in peak BMD at either the femoral neck or lumbar spine in white women.

Genetics and bone disease

Bone diseases are a common cause of morbidity and mortality in developed countries, and genetic factors play an important role in the pathogenesis of these diseases. The most common form of bone disease is osteoporosis, which is characterized by reduced bone mineral density (BMD) and an increased risk of fracture. Environmental factors such as diet and exercise influence BMD but genetic factors play a predominant role, accounting for up to 85% of the variation in peak BMD. Several candidate genes have been identified that regulate BMD and susceptibility to fracture, including bone morphogenic protein 2, collagen type I alpha 1, the vitamin D receptor, the estrogen receptor and lipoprotein receptor related protein 5 (LRP5). Paget's disease of the bone (PDB) is characterised by focal abnormalities of increased bone turnover. Mutations in several genes have been identified as causes of PDB and related syndromes including receptor activator of NF-κB (RANK), osteoprotegerin, sequestosome 1 and valosin containing protein. All of these genes play a role in the RANK signalling pathway, which is essential for osteoclast activation. Rare bone diseases such as osteopetrosis and hereditary osteoscleroses are also caused by mutations in genes that affect bone cell function. Osteopetrosis is characterised by increased BMD, and failure of osteoclastic bone resorption due to mutations in genes that encode proteins that are essential for osteoclast activity like the chloride pump and proton pump, or mutations in genes like cathepsin K, which breakdown bone matrix. Although the bones are dense, fractures are common in osteopetrosis because of reduced bone quality. Osteosclerosis occurs because of mutations in genes that increase osteoblast activity, including SOST, transforming growth factor beta and LRP5. Osteosclerotic patients also have increased BMD but fractures are rare, because bone quality is normal. From a clinical standpoint, advances in knowledge about the genetic basis of bone disease offers the prospect of developing new markers for assessing fracture risk and the identification of new molecular targets that will form the basis for the design of new treatments.

Contribution of the LRP5 Gene to Normal Variation in Peak BMD in Women

Contribution of the LRP5 Gene to Normal Variation in Peak BMD in Women

The COMT val158met Polymorphism Is Associated With Peak BMD in Men

The associations between the functional val158met polymorphism of the estrogen-degrading COMT enzyme and skeletal properties in young men were investigated. BMD was associated with COMT genotype. Peak BMD is an important predictor of future risk of osteoporosis, and it is to a large extent determined by genetic factors. Estrogens are involved in the accretion of bone mass during puberty. Catechol-O-methyltransferase (COMT) is involved in the degradation of estrogens. There is a functional polymorphism in the COMT gene (val158met), resulting in a 60-75% difference in enzyme activity between the val (high activity [H]) and met (low activity [L]) variants. The aim of this cross-sectional study was to investigate the associations between this polymorphism and peak BMD in young men. A total of 458 healthy men (mean age, 19 +/- 0.6 years) were genotyped and classified as COMT(LL), COMT(HL), or COMT(HH). Areal BMD (aBMD) was measured by DXA. Cortical and trabecular volumetric BMD (vBMD) were measured by pQCT. The associations between COMT genotype and skeletal phenotypes were determined. Regression models using physical activity, height, weight, age, and COMT genotype as covariates showed that COMT genotype was an independent predictor of aBMD in the total body and in all femur locations investigated, but not in the spine. The values for COMT(HL) and COMT(HH) were very similar, and therefore, they were pooled into one group. aBMD at Ward's triangle, trochanter, and total femur were 4.9%, 4.5%, and 3.7% lower, respectively, in the COMT(LL) than in the COMT(HL/HH) group (p < 0.01). pQCT analyses showed that COMT genotype was an independent predictor of trabecular vBMD of the tibia, radius, and fibula. Trabecular vBMD of the radius and fibula in COMT(LL) was 5.3% and 7.4% lower, respectively, than that of the combined COMT(HL/HH) group. COMT genotype was associated with cortical vBMD but not with cortical cross-sectional area in the tibia. These findings show that the COMT polymorphism is associated with BMD in young adult men.

Bone Mineral Density and Hip Axis Length in Singapore's Multiracial Population

Ethnic differences in bone density and hip geometry are known to exist, even within the same population. A recent study in Singapore showed that there were significant racial differences in hip fracture rates, with Chinese having the highest incidence of hip fractures. The aim of this study was to compare the bone mineral density (BMD) and hip axis length in Chinese, Malay, and Indian women. A total of 1575 women aged 20-59 yr were recruited, of which 77.6% (1222) were Chinese, 7.7% (122) Malays, and 14.7% (231) Indians. There was no significant difference in peak BMD of both lumbar spine and femoral neck among the three ethnic groups. However, in the older age group (50-59 yr), both Chinese and Malay women had significantly lower femoral neck BMD compared to Indian women. There was no significant loss in BMD of the lumbar spine between the second and fifth decades in all the three races. Between the second and fifth decade, Chinese and Malay women had significant bone loss in the femoral neck of 6.6% and 8.2%, respectively, whereas Indian women did not show any significant bone loss. Chinese women had significantly longer hip axis length compared to either Malay or Indian women (9.87 +/- 0.52 cm vs 9.67 +/- 0.49 cm; p < 0.005; and 9.69 +/- 0.55 cm, p < 0.05, respectively). The initial findings suggest racial differences in bone density and hip geometry exist in the local community. Future research should include prospective, longitudinal studies to determine the age-related bone loss in these three racial groups. It is also important to investigate the differences of spine and hip fracture rates and their relationship with bone density and hip axis length.

Congenic mice with low serum IGF-I have increased body fat, reduced bone mineral density, and an altered osteoblast differentiation program

Targeted gene studies have demonstrated the importance of insulin-like growth factor-I (IGF-I) for osteoblast (OB) differentiation and the acquisition of peak bone mineral density (BMD). The skeletal response to allelic differences in IGF-I expression can also be measured in vivo, using congenic mice. We created a congenic strain with reduced (approximately 20%) circulating IGF-I (C3H.B6-6T [6T]) by backcrossing a small genomic region (30 cM) of Chromosome 6 (Chr6) from C3H/HeJ (C3H) onto a C57Bl/6J (B6) background. 6T female mice have lower serum IGF-I ( P < 0.001 vs. B6) but similar growth hormone (GH) and serum IGF binding protein (IGFBP) concentrations as B6. At 16 weeks of age, congenics have greater body fat ( P < 0.02 vs. B6) despite less total body weight, and exhibit smaller femoral cross-sectional size ( P = 0.001), reduced cortical thickness ( P < 0.001) and lower trabecular BV/TV ( P < 0.05) than B6. 6T mice also have suppressed serum leptin ( P < 0.01), but compared to B6 have similar markers of bone resorption (i.e., urine CTx and serum TRAP 5B). At 8 weeks of age, skeletal IGF-I mRNA from long bones was reduced by 40% ( P < 0.05) as were liver mRNA transcripts (i.e., 50%, P < 0.01). Osteoblast progenitors from the bone marrow of 6T mice formed less colony forming unit fibroblasts by crystal violet staining than B6 ( P < 0.007) and had significantly reduced alkaline phosphatase-positive colonies than B6( P < 0.0001). In addition, staining of bone marrow with oil red O revealed greater numbers of adipocytes in 6T than B6. Several candidate genes in the Chr6 QTL were excluded by lack of strain-related expression differences in bone, but genes positively regulating adipocyte differentiation including Alox 5 and PPAR-γ require further study as either “pathway” or candidate genes. In summary, allelic differences in a QTL on Chr6 result in altered IGF-I gene expression, changes in OB lineage allocation, and reduced peak bone mass. Congenic mice are useful models not only for mapping genes related to bone mass but also for elucidating the biology underlying various skeletal phenotypes associated with more subtle manipulation of the mouse genome.

Insertion torque and pullout force of rescue screws for anterior cervical plate fixation in a fatigued initial pilot hole.

The purpose of this study was to investigate whether thicker-core-diameter screws increase fixation strength in the cervical spine. Bone mineral density (BMD) was determined for each vertebral body (VB) obtained in six human C4-7 segments. Based on their BMD, the specimens were assigned to one of two groups in which torque and pullout force were tested. Two initial pilot holes were drilled into the VBs and tests were first performed using a standard screw. The test was repeated using a thicker rescue screw inserted into the same initial pilot hole. The mean value of peak torque and pullout force resulting from the single left/right measurements was used for statistical analysis. A t-test was performed to determine the effect of screw design on peak torque and pullout force. Moment correlation coefficients were calculated to determine the effect of BMD on peak torque and pullout force. Mean insertional peak torque for the standard screw was 82.1 N/cm and that for the rescue screw was 47.6 Ncm (p < 0.001). There was a strong correlation between insertional peak torque and BMD for both standard screws (r = 0.71, p = 0.02) and rescue screws (r = 0.59, p = 0.07). The mean pullout force for standard screws was 464.7 N, whereas it was 164.5 N for rescue screws (p < 0.001). There was a strong correlation between pullout force and BMD for both standard (r = 0.75, p = 0.0081) and rescue screws (r = 0.7, p = 0.025). Uncemented rescue screws that have been inserted into a fatigued hole in the cervical VB do not strengthen the screw-bone interface compared with the strength initially conferred by a standard screw.

Osteoporosis in Men

Hip fractures in men account for one third of all hip fractures and have a higher mortality than in women. The public health burden will increase as the increase in the numbers of elderly men in the community increases. In addition, the age-specific incidence of hip fractures may be increasing in some, but not all, countries. Vertebral fractures may be a public health problem as recent studies suggest that the prevalence in the community is 20-30%, similar to that reported in women. Forearm fractures should probably not be regarded as a public health problem. Peak bone mass is higher in men than women because men have bigger bones. Peak bone mineral density is the same. The amount of trabecular bone lost at the spine and iliac crest during ageing is similar in men and women. Cortical bone loss is less in men because endocortical resorption is less and periosteal formation is greater. Bone loss accelerates in elderly men because endocortical resorption and increasing cortical porosity increase the surface available for resorption. Bone fragility is less in men than women because: (a) the cross-sectional surface of the bone is larger; (b) trabecular bone loss is less as a percentage of the higher peak bone mass; (c) trabecular bone loss occurs by thinning rather than perforation; and (d) periosteal appositional growth compensates for endocortical resorption by maintaining the bending strength of bone. Reduced BMD in men with fractures may be due to reduced peak bone size and mass, and bone loss. Bone loss occurs by reduced bone formation. Whether men with fractures have increased bone fragility due to reduced periosteal appositional growth during ageing is unknown. The age-related decline in testosterone, adrenal androgens, growth hormone, and insulin-like growth factor 1 may contribute to reduced bone formation and bone loss. Men with vertebral fractures often have hypogonadism or illnesses with few clinical features that should be considered with a high index of suspicion (alcoholism, myeloma, malabsorption, primary hyperparathyroidism, haemochromatosis, Cushing's disease). Secondary hyperparathyroidism may contribute to bone loss by activating bone turnover and so increasing the number of bone remodelling units with impaired bone formation in each. There is no proven treatment for osteoporosis in men because there have been no trials using anti-fracture efficacy as an end point. Testosterone replacement should be considered in men with proven hypogonadism and vitamin D deficiency should be corrected if present. Calcium supplements and bisphosphonates are reasonable options given the lack of information.

Consistency of low bone density across bone sites in SAMP6 laboratory mice.

The development of bone densitometry has made it clear that there are discrepancies in bone density at various measurement sites in a given individual. This study examined the consistency of bone density measurements across various sites in a strain of laboratory mouse (senescence-accelerated mouse; SAM). A systemic evaluation of the bone density was performed by dual-energy X-ray absorptiometry (DXA) on SAMP6 (P6) mice, a strain with low peak bone density, as measured by microphotodensitometry of the femoral bones, whereas the SAMP2 (P2) and SAMR1 (R1) strains have high peak bone density. We modified Jilka's method to more comprehensively measure the whole body and additional regions of interest (ROIs; head, right foreleg, left foreleg, right hindleg, left hindleg, spine, and tail). The age-related changes in the total (whole-body) BMD showed a common pattern among the strains studied, and the peak value was seen at 4 months old. P6 showed the lowest peak BMD. A detailed comparison of the bone density between P6 and P2 at the age of 4 months revealed significantly lower regional BMD values for P6 in all seven ROIs. The strain difference in BMD could not be attributed to a difference in size. In conclusion, P6 mice showed low bone density not only in their femurs but also in the subregions and over their entire body. This strain can be potentially useful in the investigation of the genetic basis of senile osteoporosis.

The association between environmental lead exposure and bone density in children.

Osteoporosis is a decrease in bone mineral density (BMD) that predisposes individuals to fractures. Although an elderly affliction, a predisposition may develop during adolescence if a sufficient peak BMD is not achieved. Rat studies have found that lead exposure is associated with decreased BMD. However, human studies are limited. We hypothesized that the BMD of children with high lead exposure would be lower than the BMD of children with low lead exposure. We collected data on 35 subjects; 16 had low cumulative lead exposure (mean, 6.5 μg/dL), and 19 had high exposure (mean, 23.6 μg/dL). All were African American; there was no difference between the groups by sex, age, body mass index, socioeconomic status, physical activity, or calcium intake. Significant differences in BMD between low and high cumulative lead exposure were noted in the head (1.589 vs. 1.721 g/cm2), third lumbar vertebra (0.761 vs. 0.819 g/cm2), and fourth lumbar vertebra (0.712 vs. 0.789 g/cm2). Contrary to our hypothesis, subjects with high lead exposure had a significantly higher BMD than did subjects with low lead exposure. This may reflect a true phenomenon because lead exposure has been reported to accelerate bony maturation by inhibiting the effects of parathyroid hormone–related peptide. Accelerated maturation of bone may ultimately result in a lower peak BMD being achieved in young adulthood, thus predisposing to osteoporosis in later life. Future studies need to investigate this proposed model.

Genetically based influences on the site-specific regulation of trabecular and cortical bone morphology.

The degree of site-specificity by which genes influence bone quantity and architecture was investigated in the femur of three strains of mice. Morphological indices were highly dependent on both genetic makeup as well as anatomical location showing that the assessment of bone structure from a single site cannot be extrapolated to other sites even within a single bone. The identification of genes responsible for establishing peak BMD will yield critical information on the regulation of bone quantity and quality. Whereas such knowledge may eventually uncover novel molecular drug targets or enable the identification of individuals at risk of osteoporosis, the site-specificity by which putative genotypes cause low or high bone mass (and effective bone morphology) is essentially unknown. microCT was used to determine morphological and microarchitectural features of the femora harvested from three genetically distinct strains of 4-month-old female mice, each with distinct skeletal mass (low: C57BL/6J [B6], medium: BALB/cByJ [BALB], high: C3H/HeJ [C3H]). Two trabecular regions (distal epiphysis and metaphysis) were considered in addition to four cortical regions within the metaphysis and diaphysis. Comparing morphological properties of the different trabecular and cortical femoral regions between the three strains of mice, it was apparent that high or low values of specific parameters of bone morphology could not be consistently attributed to the same genetic strain. Trabecular metaphyseal bone volume, for instance, was 385% larger in C3H mice than in B6 mice, yet the two strains displayed similar bone volume fractions in the epiphysis. Similarly, BALB mice had 48% more trabecular bone than C3H mice in the epiphysis, but there were no strain-specific differences in cortical bone area at the diaphysis. These data suggest that the genetic control of bone mass and morphology, even within a given bone, is highly site-specific and that a comprehensive search for genes that are indicative of bone quantity and quality may also have to occur on a very site-specific basis.

Effect of osteoprotegerin gene polymorphism on bone mass in postmenopausal women

To investigate the effect of promoter region polymorphism of osteoprotegerin (OPG) gene on bone mineral density (BMD) and markers of bone turnover in postmenopausal women. The OPG genotype were determined by PCR-RFLP in 259 postmenopausal women of Han race in Shanghai area, and BMD at lumbar-spine, femoral neck, trochanter and Ward's triangle etc., were measured by dual-energy X-ray absorptiometry (DEXA). Some markers of bone turnover were also detected. Hardy-Weinberg equilibrium was evident for OPG polymorphism. The frequency of the genotype is as following: TT59%, TC28%, CC13%. Postmenopausal women were divided into two groups. Women aged less than 65 years old were in group I, and aged 65 years old and over were in group II. In group I the BMD at femur neck area was 0.64 g/cm(2) +/- 0.11 g/cm(2), 0.67 g/cm(2) +/- 0.11 g/cm(2), 0.68 g/cm(2) +/- 0.14 g/cm(2) of TT, TC, CC genotypes respectively, among which a significant difference was observed (P < 0.05 by ANOVA), and the significant difference also presented after adjusted by age and BMI, but not found the significant difference in other markers. In group II, significant link was not observed between OPG polymorphism and BMD with markers of bone turnover. OPG polymorphism may have an effect on the BMD of postmenopausal women aged less than 65. It is possibly that the role of OPG gene mainly on the obtaining of peak BMD in women.