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Context: Several genome-wide association studies (GWAS) have been performed to identify genes contributing to bone mineral density (BMD), typically in samples of elderly women and men. Objective: The objective of the study was to identify genes contributing to BMD in premenopausal women. Design: GWAS using the Illumina 610Quad array in premenopausal European-American (EA) women and replication of the top 50 single-nucleotide polymorphisms (SNPs) for two BMD measures in African-American (AA) women. Subjects: Subjects included 1524 premenopausal EA women aged 20–45 yr from 762 sibships and 669 AA premenopausal women aged 20–44 yr from 383 sibships. Interventions: There were no interventions. Main Outcome Measures: BMD was measured at the lumbar spine and femoral neck by dual-energy x-ray absorptiometry. Age- and weight-adjusted BMD values were tested for association with each SNP, with P values determined by permutation. Results: SNPs in CATSPERB on chromosome 14 provided evidence of association with femoral neck BMD (rs1298989, P = 2.7 × 10−5; rs1285635, P = 3.0 × 10−5) in the EA women, and some supporting evidence was also observed with these SNPs in the AA women (rs1285635, P = 0.003). Genes identified in other BMD GWAS studies, including IBSP and ADAMTS18, were also among the most significant findings in our GWAS. Conclusions: Evidence of association to several novel loci was detected in a GWAS of premenopausal EA women, and SNPs in one of these loci also provided supporting evidence in a sample of AA women.

Autosomal dominant osteopetrosis type II (ADO2) is typically diagnosed from radiographs, which demonstrate the pathognomonic findings of osteosclerosis and endobone formation. Individuals with ADO2 also have elevated serum levels of tartrate-resistant acid phosphatase (TRAP) and the BB isoenzyme of creatine kinase (CK-BB). In the current study, we tested the utility of these enzymes in making or refuting a diagnosis of ADO2. Furthermore, because ADO2 has incomplete penetrance, we examined whether TRAP and CK-BB were helpful in identifying gene carriers. We studied eight families, measured serum levels of TRAP and CK-BB in 52 affected individuals and 12 obligate gene carriers, and compared their values with age-matched controls. Our results demonstrate that affected patients have significantly elevated levels of both TRAP and CK-BB. In contrast, gene carriers have values that are not different from controls. Furthermore, in our study population, TRAP and CK-BB have a high diagnostic sensitivity and specificity, particularly in children. From this large study of ADO2 patients and carriers, we conclude that: 1) TRAP and CK-BB are significantly elevated in patients with ADO2, 2) obligate carriers cannot be adequately identified by measurement of these analytes, and 3) TRAP and CK-BB are highly sensitive and specific diagnostic tests that can efficiently and effectively screen high-risk individuals who have not had previous radiographic assessment.

This study measured bone mineral content (BMC), bone mineral density (BMD), and bone area at the spine and hip to learn whether bone loss takes place premenopausally. Participants were 130 non-Hispanic white women 31 to 50 years of age who were in good general health and had taken no drugs that affect bone metabolism. Measurements were made by dual-energy x-ray absorptiometry at the L2-4 segment of the lumbar spine, in the femoral neck, and in the total hip. The studies were repeated at least twice over 1 to 9 years. Both BMC and bone area increased significantly over time in the spine, as did BMD. If, however, BMC was normalized by bone volume, there was no age-related change in volumetric density. Measurements of the total hip showed no significant change with age. BMD in the femoral neck declined at a rate of about 0.0036 g/cm2 per year. BMC was lost as well, so the drop in BMD was not an artifact of bone expansion. Changes in BMD correlated positively with weight change and estradiol levels and negatively with gonadotropin levels. Somewhat less bone loss was noted in subjects who gained more weight during the study. Higher levels of LH and FSH were documented in women who lost more than 1% of BMD per year. Estrogen levels were highest in women who manifested no bone loss. Declining BMD was more a result of a loss of BMC in women with high FSH levels, but due more to an expansion in bone area in those with relatively low FSH levels. The positive association between body weight change and BMD was not entirely mediated by higher estrogen. Premenopausal women more than 30 years of age in this study lost BMD at the femoral neck at an average annual rate of 0.4%. Bone loss was less in women who gained more weight but greater in those with reduced estrogen levels even in the absence of symptoms. Early bone loss might be preventable if premenopausal women with suboptimal sex hormone levels are detected at an early stage.

A major determinant of the risk for osteoporosis is peak bone mineral density (BMD), which is largely determined by genetic factors. We recently reported linkage of peak BMD in a large sample of healthy sister pairs to chromosome 11q12–13. To identify additional loci underlying normal variations in peak BMD, we conducted an autosomal genome screen in 429 Caucasian sister pairs. Multipoint LOD scores were computed for BMD at four skeletal sites. Chromosomal regions with LOD scores above 1.85 were further pursued in an expanded sample of 595 sister pairs (464 Caucasians and 131 African-Americans). The highest LOD score attained in the expanded sample was 3.86 at chromosome 1q21–23 with lumbar spine BMD. Chromosome 5q33–35 gave a LOD score of 2.23 with femoral neck BMD. At chromosome 6p11–12, the 464 Caucasian pairs achieved a LOD score of 2.13 with lumbar spine BMD. Markers within the 11q12–13 region continued to support linkage to femoral neck BMD, although the peak LOD score was decreased to 2.16 in the sample of 595 sibling pairs. Our study is the largest genome screen to date for genes underlying variations in peak BMD and represents an important step toward identifying genes contributing to osteoporosis in the general population.

A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. BMD is a complex trait that presumably is influenced by multiple genes. Insulin-like growth factor I (IGF-I) is an attractive candidate gene for osteoporosis susceptibility, because IGF-I has marked effects on bone cells and has been implicated in the pathogenesis of osteoporosis. The IGF-I gene contains a microsatellite repeat polymorphism approximately 1 kb upstream from the IGF-I gene transcription start site, and previous investigators have found a higher prevalence of the 192/192 genotype of this polymorphism among men with idiopathic osteoporosis compared to controls. In this study we used this IGF-I polymorphism to test for an association between this polymorphism and BMD in our large population of premenopausal women (1 sister randomly chosen from 292 Caucasian and 71 African-American families). We also used this polymorphism to detect linkage to BMD elsewhere in the IGF-I gene or in a nearby gene using sibling pair linkage analysis in healthy premenopausal sister pairs (542 sibling pairs: 418 Caucasian and 124 African-American). Neither test provided any evidence of linkage or association between the IGF-I gene locus and spine or femoral neck BMD in Caucasians or AfricanAmericans. (J Clin Endocrinol Metab 84: 4467‐ 4471, 1999)

To determine whether menstrual status had an effect on plasma sex hormone-binding globulin (SHBG) capacity and nonprotein-bound estradiol (% free E2) and testosterone (% free T), we measured these as well as plasma FSH, total E2, and T and the MCRs of E2 and T in a group of 78 perimenopausal women. The women were allocated to 4 groups: women with cycles whose plasma FSH level was less than 40 mIU/mL (A; n = 16), women with cycles whose plasma FSH level was greater than 40 mIU/mL (B; n = 19), women who were amenorrheic for less than 1 yr (C; n = 13), and women who were amenorrheic for more than 1 yr (D; n = 30). The mean plasma SHBG values were 51.4 +/- 5.7 (+/- SE), 48.3 +/- 4.3, 45.9 +/- 5.4, and 51.1 +/- 3.7 nM in groups 1-4 respectively, and were not significantly different from one another. The mean % free E2 and % free T values also were not different between the groups. However, the mean total E2 and free E2 (% free E2 X E2/100) concentrations were significantly (P less than 0.05) higher in both groups A and B than in groups C and D. The E2 concentration was also higher in group A than in group B. There were strong correlations between the E2 and free E2 concentrations between the T and free T (% free T X T/100); (P less than 0.0001) concentrations, between SHBG capacity and weight, and between the MCRs of both E2 and T and % free E2 and % free T. In normal women, the menopause is not associated with changes in SHBG or % free steroids. Hence, the measurement of E2 could be used to predict the mass of free E2 in these women.

Sixty-nine patients with type I diabetes mellitus were followed for from 1-4 yr (mean, 3 yr). Their overall growth, as measured by height and weight, was normal; however, repeated measurements of their bone mass using photon absorptiometry and radiogrammetry showed that, relative to normal subjects, the patients had a persistent bone deficit throughout the course of the study. This deficit was not attributable to bone width, which was normal. On the average, the magnitude of the deficit did not change with time; furthermore, an individual's rate of change in bone mass deficit during the study was not correlated with the patient's glucose control, as measured by hemoglobin A-1 or fasting blood glucose levels. Initial levels of serum ionized calcium and magnesium were decreased in the patients with diabetes. During the study, the mean level of ionized calcium increased, but that of magnesium decreased further, compared to the initial values. In a group of 19 patients with newly diagnosed diabetes, bone mass was found to be significantly below normal among the girls, but not among the boys.