Abstract Study Objective:To determine whether clinically available data on risk factors are adequate to identify perimenopausal women with either low or high bone mass. Design:Cross-sectional obser...

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

BACKGROUND:Adherence to oral bisphosphonates is often low, but even adherent patients may remain at elevated fracture risk. The goal of this study was to estimate the proportion of bisphosphonate-adherent women remaining at high risk of fracture.METHODS:A retrospective cohort of women aged 50years and older, adherent to oral bisphosphonates for at least two years was identified, and data were extracted from a multi-system health information exchange. Adherence was defined as having a dispensed medication possession ratio≥0.8. The primary outcome was clinical occurrence of: low trauma fracture (months 7-36), persistent T-score≤-2.5 (months 13-36), decrease in bone mineral density (BMD) at any skeletal site≥5%, or the composite of any one of these outcomes.RESULTS:Of 7435 adherent women, 3110 had either pre- or post-adherent DXA data. In the full cohort, 7% had an incident osteoporotic fracture. In 601 women having both pre- and post-adherent DXA to evaluate BMD change, 6% had fractures, 22% had a post-treatment T-score≤-2.5, and 16% had BMD decrease by ≥5%. The composite outcomes occurred in 35%. Incident fracture was predicted by age, previous fracture, and a variety of co-morbidities, but not by race, glucocorticoid treatment or type of bisphosphonate.CONCLUSION:Despite bisphosphonate adherence, 7% had incident osteoporotic fractures and 35% had either fracture, decreases in BMD, or persistent osteoporotic BMD, representing a substantial proportion of treated patients in clinical practices remaining at risk for future fractures. Further studies are required to determine the best achievable goals for osteoporosis therapy, and which patients would benefit from alternate therapies.

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Alzheimer's disease (AD), a leading cause of dementia among the elderly, is a complex neurodegenerative disorder with a strong genetic component. Recent genome-wide association studies (GWAS) have identified loci that alter the risk of AD, but little is known about the genetic risk factors involved with rate of cognitive decline (ROD). Here we report on one of the first GWAS with disease progression in AD patients from the EU funded AddNeuroMed (ANM) project. Alzheimer's patients provided MMSE, CDR and ADAS-cog scores at baseline and for four additional visits over the subsequent year. Rates of decline were calculated over this period using mixed models and the slopes were used as quantitative traits for association analysis. The models included significant covariates such as education and medication. We imputed ∼37 million SNPs from the 1000 Genomes reference panel b37, June 2011 release into the ANM samples using IMPUTEv2. After stringent quality control, 5, 561, 292 SNPs remained for association analysis with ADAS-cog, CDR and MMSE. All analyses were performed under an additive model adjusting for age, sex and APOE4 status using SNPTESTv2 . We corrected for population stratification using principle component analysis (Genomic inflation factors for ADAS-cog, CDR and MMSE were 1.00, 1.02 and 1.01 respectively). We identified 21 novel signals with p<5x10–8: 13 with ADAS-cog, two with CDR and six with MMSE. We also observed nominal association (P <0.05, min-P = 5x10–6) with multiple variants in and around ( ± 250kb) many of the previously identified GWAS AD loci and candidate genes: CLU, ABCA7, CR1, PICALM, CD33, MS4A6A, MS4A4E, BIN1, CD2AP, EXOC3L2, TNF, SORL1, FTO, ACE, MTHFD1L and ATXN1, and with the recently identified GWAS hits for ROD in subjects with mild cognitive impairment (MCI): ACOT11, MYO9A and UBR5. We have identified new loci associated with ROD in AD patients and provide further evidence for known AD/MCI candidate loci with ROD. We will report results of a meta-analysis with the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

Black adults have higher bone mass than whites in the United States, but it is not clear when black children gain bone mineral faster than white children. We performed a cohort study to compare the growth velocity of total-body bone mineral content (TBMC) between black and white children of the same sex at different ages and stages of sexual maturity. TBMC and total-body area were measured in a cohort of 188 black and white boys and girls aged 5 to 15 years annually for up to 4 years. Rates of change in TBMC and area were found to vary with age and with Tanner stage. For both TBMC and area, growth velocities between black and white children differed significantly across Tanner stages. Age-specific velocities were higher in black children during prepuberty and initial entry into puberty but reversed in subsequent Tanner stages. Despite earlier entry into each Tanner stage, black children spent only an average of only 0.2 year longer in Tanner stages II through IV, and total gain in TBMC from age 5 to 15 was not higher in whites. In conclusion, the higher bone mass in black adults compared with whites cannot be attributed to faster accrual during puberty. It is due to black children's higher rate of bone mineral accrual in prepuberty and plausibly in postpuberty. Most of the racial difference in TBMC velocity can be explained by growth in size.

Femoral neck area expands and BMD decreases in premenopausal women. We used longitudinal DXA measurements on 388 premenopausal white sisters to show significant heritability of the rates of change in femoral neck area, BMC, and BMD.

CONTEXT: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.OBJECTIVE:The objective of the study was to determine whether ESR2 polymorphisms are associated with normal BMD variation.DESIGN:This was a population-based genetic association study, using 11 single nucleotide polymorphisms (SNPs) distributed across the ESR2 gene.SETTING:The study was conducted at an academic research laboratory and medical center.PATIENTS AND OTHER PARTICIPANTS: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.INTERVENTION(S):There were no interventions.MAIN OUTCOME MEASURE(S):The main outcome measures were SNP genotype distributions and their association with BMD at the femoral neck and lumbar spine.RESULTS: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.CONCLUSIONS: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.

UNLABELLED: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. INTRODUCTION: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. MATERIALS AND METHODS: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. RESULTS AND CONCLUSIONS: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.

BACKGROUND:Race and sex differences in the effect of diet on bone mineral density (BMD) at the hip in the elderly are unknown.OBJECTIVES:This study related cross-sectional nutrient and dairy product consumption to hip BMD in white and black men and women aged >60 y and evaluated the influence of nutrient and dairy product consumption on changes in BMD in a white cohort participating in a calcium, vitamin D, or placebo trial.DESIGN:The Health Habits and History Questionnaire was used in 289 white women and 116 white men who participated in the trial and in 265 black women and 75 black men to predict total hip and femoral neck BMD or changes in BMD.RESULTS:Blacks had higher calcium intakes than did whites (700 and 654 mg/d, respectively; P = 0.0094), and men had higher calcium intakes than did women (735 and 655 mg/d, respectively; P = 0.0007). For men, the correlation between total hip BMD and dairy calcium intake after adjustment for age, race, and weight was 0.23 (P < 0.005); this relation was not significant in women (r = 0.02, P = 0.12). Similar results were found for femoral neck BMD. In the longitudinal study, calcium supplementation reduced bone loss from the total hip and femoral neck in those who consumed <1.5 servings of dairy products/d and were <72 y old.CONCLUSIONS:Cross-sectional results indicated that higher dairy product consumption is associated with greater hip BMD in men, but not in women. Calcium supplementation protected both men and women from bone loss in the longitudinal study of whites.

Peak bone mineral density (BMD) is a highly heritable trait and is a good predictor of the risk of osteoporosis and fracture in later life. Recent studies have sought to identify the genes underlying peak BMD. Linkage analysis in a sample of 464 premenopausal white sister pairs detected linkage of spine BMD to chromosome 1q (LOD 3.6). An independent sample of 254 white sister pairs has now been genotyped, and it also provides evidence of linkage to chromosome 1q (LOD 2.5) for spine BMD. Microsatellite markers were subsequently genotyped for a 4-cM map in the chromosome 1q region in all available white sister pairs (n=938), and a LOD score of 4.3 was obtained near the marker D1S445. Studies in the mouse have also detected evidence of linkage to BMD phenotypes in the region syntenic to our linkage finding on chromosome 1q. Thus, we have replicated a locus on 1q contributing to BMD at the spine and have found further support for the region in analyses employing an enlarged sample. Studies are now ongoing to identify the gene(s) contributing to peak spine BMD in women.

A major determinant of osteoporotic hip fracture is peak hip BMD which is a highly heritable trait. Caucasian American women have lower BMD and higher hip fracture rates than African American women. This study examines linkage of hip BMD in 570 Caucasian sister pairs and 204 African American sister pairs. It compares the results with our published study in a smaller overlapping sample of Caucasian sisters. Hip BMD was measured at neck, trochanter, Ward’s, shaft, and total hip. Principal component analysis provided a novel BMD phenotype comprising neck and trochanter, common sites of fracture, and Ward’s, site of lowest BMD. A 9 cM genome scan was performed for these phenotypes. Significant linkage was found at chromosomes 14q and 15q. At 14q, the 774 African American and Caucasian sister pairs together yielded the highest LOD score for trochanter (3.5) and at 15q the highest LOD score for femoral neck (4.3). This linkage study in Caucasian and African American healthy premenopausal sisters demonstrates that chromosomes 14q and 15q harbor genes that affect peak bone mass at the hip in women. Principal component had comparable LOD scores with those of the component phenotypes suggesting pleiotropic effects of these genes on hip phenotypes.

OBJECTIVE:Raloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DESIGN:The current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturer's database for the lumbar spine and the National Health and Nutrition Examination Survey's 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. RESULTS:Compared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: -10.9%, P < 0.001; bone-specific alkaline phosphatase: -7.2%, P = 0.042; urinary C-telopeptide: -11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (-5.5%; P < 0.001) and low-density lipoprotein cholesterol (-8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P >/= 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. CONCLUSIONS:Five years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.

A cross-sectional study of 232 healthy children, with about equal numbers of boys and girls and blacks and whites, aged 4 to 16 yr, was conducted to investigate the racial differences in bone mineral. Bone mineral content (BMC) by dual x-ray absorptiometry was found to be similar between blacks and whites at the spine after controlling for age and Tanner stage. However, total body BMC was higher in blacks, compared with whites of the same age and Tanner stage. Height and weight alone reduced the racial difference in BMC from 152 g to 66 g in girls and from 163 g to 105 g in boys, in whom the difference was further reduced to 66 g after accounting for lean and fat body mass and subscapular skinfold. The only significant sex hormone was androstenedione, which explained another 4-5 g of the racial difference in total body BMC for both boys and girls. Among the biochemical variables, only 25OH vitamin D reduced the residual racial difference in total body BMC to 39 g in girls, whereas serum PTH, urine free deoxypyridinoline ratio, and 1,25(OH)(2) vitamin D reduced the residual difference to 25 g in boys. The residual racial differences in bone mass were not statistically significant.

Suppression of bone turnover using anti-resorptive agents such as bisphosphonates prevents bone loss but also may increase tissue mineralization. This may make the bone more prone to initiate microcracks. The objective of this study was to determine whether suppression of remodeling caused by treatment of dogs for 1 year with five times the clinical dose of either alendronate or risedronate is associated with increased tissue mineralization and whether it changes the nature of the mineral crystal. Thirty-five dogs were divided into three weight-matched groups and treated daily for 1 year with a subcutaneous injection of saline (CON, n = 12), oral risedronate (RIS, 0.5 mg/kg/day, n = 11), or oral alendronate (ALN, 1.0 mg/kg/day, n = 12). Density fractionation, peripheral quantitative computerized tomography (pQCT), and quantitative backscattered electron microscopy (qBSE) were used to evaluate changes in mineral content of bone tissue from the vertebrae or ribs. Infrared microspectroscopy (IR) and X-ray diffraction were used to assess the quality of the mineral and some aspects of collagen structure in the thoracic vertebrae and iliac crest. Following 12 months of treatment, there was a significant shift toward higher density bone in both ALN (P = 0.04) and RIS (P = 0.002) by density fractionation methods. IR, pQCT, and qBSE did not detect any significant differences in mineralization, probably because of their lower sensitivity and/or because of the smaller region of interest they sample. No significant differences were found in the maturity of the mineral crystals or in their length or size. We conclude that treatment for 1 year with high doses of bisphosphonates which suppress bone remodeling up to 90% increases tissue mineralization, but does not change the nature of the mineral crystal.

Journal of Bone and Mineral ResearchVolume 18, Issue 11 p. 2079-2080 ReplyFree Access Interpretation of Genetic Linkage Findings DL Koller, DL Koller Department of Medical and Molecular Genetics, Indiana, USASearch for more papers by this authorKE White, KE White Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorG Liu, G Liu Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorSL Hui, SL Hui Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorPM Conneally, PM Conneally Department of Medical and Molecular Genetics, Indiana, USASearch for more papers by this authorCC Johnston, CC Johnston Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorMJ Econs, MJ Econs Department of Medical and Molecular Genetics, Indiana, USA Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorT Foroud, T Foroud Department of Medical and Molecular Genetics, Indiana, USASearch for more papers by this authorM Peacock, M Peacock Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this author DL Koller, DL Koller Department of Medical and Molecular Genetics, Indiana, USASearch for more papers by this authorKE White, KE White Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorG Liu, G Liu Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorSL Hui, SL Hui Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorPM Conneally, PM Conneally Department of Medical and Molecular Genetics, Indiana, USASearch for more papers by this authorCC Johnston, CC Johnston Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorMJ Econs, MJ Econs Department of Medical and Molecular Genetics, Indiana, USA Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this authorT Foroud, T Foroud Department of Medical and Molecular Genetics, Indiana, USASearch for more papers by this authorM Peacock, M Peacock Department of Medicine Indiana University School of Medicine Indianapolis, Indiana, USASearch for more papers by this author First published: 02 December 2009 https://doi.org/10.1359/jbmr.2003.18.11.2079Citations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat To the Editor: We welcome the opportunity to respond to the letter of Liu et al.1 on our study. There are two fundamental areas in which we disagree with Liu et al. with regard to their interpretation of the results of our genome screen to identify genes contributing to femoral structure. First, the significance threshold used in their power calculations is extremely stringent and unrealistic for the identification of genes underlying a complex trait (i.e., LOD score threshold >5, corresponding to a genomewide significance = 0.003). Second, the central argument of Liu et al. is that a statistical result is "reliable" only when the power of the study is high. In fact, once linkage has been detected using an appropriate threshold of significance, the primary issue is no longer the power of the study to detect linkage but whether the statistical results are likely to be true and not represent a false positive. The positive predictive value (PPV) or a similar statistic is often calculated to quantify this probability. We show (Fig. 1) that the PPV associated with a significant linkage result2 (LOD > 3.6; genomewide significance = 0.05) is greater than 95%, even for studies with extremely low a priori power to detect linkage. Figure FIG. 1.Open in figure viewerPowerPoint The relationship between the power of a study (x axis) and the PPV (y axis) for the significance threshold typically used in linkage studies2 (LOD > 3.6) and for that used in Table 1 of Liu et al.1 (LOD > 5.0). PPV is computed through the application of Bayes Theorem and is the probability that the observed significant linkage result is not a false positive. The prior probability of linkage is estimated as 1 in 46.3 The sample sizes required for linkage studies presented in Table 1 of the Letter to the Editor of Liu et al. are unduly intimidating to investigators designing studies to detect genes underlying complex diseases. The significance threshold (LOD = 5) and power (80%) assumed are much more stringent than those currently used by most researchers. A threshold for significance of linkage findings is well established at LOD = 3.6 for sibling pair studies.2 Importantly, a genome screen is typically considered the hypothesis-generating portion of the study used to identify chromosomal regions for further study. In most studies, the power of the genome screen is less than 80% to detect a particular gene affecting the complex trait. However, with a realistic significance threshold, a genome screen in large, but attainable, samples of sibling pairs such as we have reported is adequate for identifying chromosomal regions worthy of further study. The central assumption of Liu et al. is that only a QTL result from a sample with high power is "reliable" (or has high PPV, i.e., the probability that a significant result is true). Power and PPV are indeed positively correlated. However, once a QTL has exceeded the significance threshold, it will have very high PPV, even when the a priori power for QTL detection is low. As shown in Fig. 1, when the type I error is adequately controlled (e.g., by use of the Lander and Kruglyak significant linkage criterion of LOD = 3.6), the likelihood that a significant linkage result reflects a true QTL is very high (PPV > 90%) for all but studies of the lowest power. When the extremely stringent threshold of Liu et al. is chosen (LOD > 5.0; genomewide p < 0.003), PPV has remarkably little dependence on the power of the study. In this case, even a study with only 1% power has a PPV of greater than 88% (Fig. 1). For this reason, a post hoc evaluation of statistical findings in which type I error was adequately controlled is irrelevant. Liu et al. have questioned both our sample and genotyping. We believe that there are several distinct advantages to our sample, which increase the likelihood that it can be used to detect linkage to phenotypes related to bone strength. First, we have recruited healthy premenopausal women to focus on genes underlying peak bone strength and to avoid the confounding effects of genes underlying bone loss. Second, we have studied only women, because gender-specific bone mineral density (BMD) effects have been reported in mice. Third, we have used well-established phenotypes that contribute to bone strength for genetic analyses. Fourth, our sample is primarily of Northern European descent. However, we are also recruiting black sister pairs which, because of their well-established greater average bone strength, are a valuable resource to compare with our larger sample of whites. Regarding the genotyping, we first published an analysis of 309 white sister pairs to identify QTLs linked to variation in femoral structure.4 These samples were genotyped as part of a collaboration with Axys Pharmaceuticals. Subsequently, we continued to recruit sister pairs and have completed a genome screen, performed at the Center for Inherited Disease Research (CIDR), in a sample of 437 white and 201 black sister pairs. CIDR is a genotyping resource whose error rate (0.1%) and missing genotype rate (5.7%) is typical of most such facilities. As noted in Koller et al.,5 191 of the white sister pairs in the recent study overlapped with those initially reported. However, data could not be combined because different marker sets were used in the genome screens performed by Axys and CIDR, and we were unable to correlate allele sizes from the two laboratories. Thus, in our recent publication, we used only sister pairs genotyped in the CIDR laboratory. Independent confirmation of QTL linkage findings is highly desirable. However, at present, the number of human genome screens completed for bone-related phenotypes is small, and even when two studies have measured the same phenotype, other differences in study design may well produce discrepant findings. Our studies focus on genetic variation underlying peak bone mass and femoral structure in premenopausal women. Other published studies include subjects with a wide age range, and may include the effects of different genetic influences on bone loss and bone gain. The identification of genes contributing to bone strength is of critical importance to the development of new therapies and the estimation of an individual's risk for osteoporosis. Achieving this goal requires the genetic analysis of a variety of samples, both human and animal. Importantly, to expedite this goal, it is essential that human QTL analyses be reported so that other researchers can examine their samples for similar linkages. In this way, susceptibility genes will be identified most efficiently. REFERENCES 1 Liu Y, Xu F, Recker RR, Deng H-W 2003 Interpretation of genetic linkage findings. J Bone Miner Res 18: 2077– 2078. Wiley Online LibraryPubMedGoogle Scholar 2 Lander E, Kruglyak L 1995 Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nat Genet 11: 241– 247. CrossrefCASPubMedWeb of Science®Google Scholar 3 Conneally PM, Rivas M 1980 Linkage analysis in man. In: H Harris, K Hirschhorn (eds.) Advances in Human Genetics, Vol. 10. Plenum Press, New York, NY, USA, pp. 209– 266. CrossrefGoogle Scholar 4 Koller DL, Liu G, Econs MJ, Hui SL, Morin PA, Joslyn G, Rodriguez LA, Conneally PM, Christian JC, Johnston CC Jr, Foroud T, Peacock M 2003 Genome screen for quantitative trait loci underlying normal variation in femoral structure. J Bone Miner Res 16: 985– 991. Wiley Online LibraryGoogle Scholar 5 Koller DL, White KE, Liu G, Hui SL, Conneally PM, Johnston CC, Econs MJ, Foroud T, Peacock M 2003 Linkage of structure at the proximal femur to chromosomes 3, 7, 8, and 19. J Bone Miner Res 18: 1057– 1065. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Citing Literature Volume18, Issue11November 2003Pages 2079-2080 FiguresReferencesRelatedInformation

A major determinant of the risk of osteoporosis is peak bone mineral density (BMD), which has been shown to have substantial heritability. The genes for 3 BMD-related phenotypes (autosomal dominant high bone mass, autosomal recessive osteoporosis-pseudoglioma, and autosomal recessives osteopetrosis) are all in the chromosome 11q12-13 region. We reported linkage of peak BMD in a large sample of healthy premenopausal sister pairs to this same chromosomal region, suggesting that the genes underlying these 3 disorders may also play a role in determining peak BMD within the normal population. To test this hypothesis, we examined the gene responsible for 1 form of autosomal recessive osteopetrosis, TCIRG1, which encodes an osteoclast-specific subunit (OC116) of the vacuolar proton pump. We identified 3 variants in the sequence of TCIRG1, but only one, single nuclear polymorphism 906713, had sufficient heterozygosity for use in genetic analyses. Our findings were consistent with linkage to femoral neck BMD, but not to spine BMD, in a sample of 995 healthy premenopausal sister pairs. However, further analysis, using both population and family-based disequilibrium approaches, did not demonstrate any evidence of association between TCIRG1 and the spine or femoral neck BMD. Therefore, our linkage data suggest that the chromosomal region that contains OC116 harbors a gene that affects peak BMD, but our association results indicate that polymorphisms in the OC116 gene do not affect peak BMD.

To investigate whether bone loss occurs in the premenopause, we measured the bone mineral content (BMC), bone mineral density (BMD), and bone area in the spine (L2-L4), femoral neck, and total hip, as well as the sex hormone levels of 130 healthy premenopausal white women (age, 31-50 yr) at least three times over 1-9 yr. We found an increase in all three bone measurements at the spine but no change in volumetric density. Neither could we detect any age-related changes in any of the three measurements in the total hip. In contrast, we detected a significant decrease in femoral neck BMD over time, due to a decrease in BMC and increase in bone area. Greater loss in femoral neck BMD was associated independently with weight loss and lower levels of estrone sulfate or E2. Separating the women into those with FSH spikes (>20 IU/liter) and women with consistently low FSH, we found the latter group had smaller decrease in BMD and that the decrease was due less to a decline in BMC and more to an increase in bone area. In summary, femoral neck BMD decreases in premenopausal women, particularly those with lower levels of estrogens resulting from slowing ovarian function despite regular menses. This decrease can be offset by more rapid weight gain.