Citations

Abstract Appendicular bone mass is inversely related to the risk of hip fracture in short-term prospective studies, but hip fractures typically occur about 30 years after menopause. We developed a model that estimates a woman's lifetime risk of hip fracture based on measurement of radial bone mass at age 50 using short-term prospective data relating bone mass to hip fracture, the correlation between bone mass at age 50 and later years, the age-specific incidence of hip fracture and mortality, and prospective data about bone mass and mortality. We estimate that a 50-year-old white woman has a 19% lifetime risk of hip fracture if her radial bone mass is at the 10th percentile for her age and an 11% lifetime risk if her bone mass is at the 90th percentile. Improved measurement techniques that have a higher predictive value for hip fracture in short-term studies could substantially increase this gradient of lifetime risk and therefore be more clinically useful.

Abstract Gallium nitrate lowers the serum calcium in patients with hypercalcemia caused by malignancy and is available for clinical use. The mechanism for the hypocalcemic action is unknown, however. The present studies were undertaken to determine the effects of gallium on bone metabolism. Normal male rats were implanted subcutaneously with mineralized allogeneic bone matrix. Histomorphometry of the implants and of tibiae was determined after three doses of tetracycline administered at intervals of 1 week. Gallium as nitrate was administered daily by intraperitoneal injection at doses of 0.9, 1.8, and 3.6 mg elemental gallium per kg body weight for 21 days in one study and at 3.5 mg/kg for 33 days in a second study. All the gallium-treated rats gained weight. Rats given gallium at doses of 3.5 mg/kg or more grew at a lower rate than untreated controls (-7 and -10% at doses of 3.5 and 3.6 mg/kg, respectively; p < 0.05). At a dose of 0.9 mg/kg, gallium did not inhibit bone resorption or lower serum calcium but inhibited bone formation by 32% and bone apposition by 36% at the endosteal surface of the tibia. At a dose of 1.8 mg/kg, gallium produced modest hypocalcemia, prevented a rise in circulating 1,25-dihydroxyvitamin D [1,25-(OH)2D], inhibited bone resorption in implants, and inhibited bone formation by 19% and bone apposition by 18%. At a dose of 3.5 mg/kg, gallium lowered the serum calcium and serum 1,25-(OH)2D, inhibited growth, and accentuated the antiresorptive and antiformative effects seen at the two lower doses. The results indicate that gallium inhibits bone resorption, produces hypocalcemia, alters vitamin D metabolism, and inhibits bone formation at doses below those that inhibit bone resorption. The mechanism for hypocalcemia may be by direct action on bone and could involve an indirect effect on calcium metabolism mediated by changes in the metabolism of vitamin D.

Abstract Mutations in one of the two genes encoding type I procollagen (COL1A1 and COL1A2) are frequently the cause of osteogenesis imperfecta (OI), a disorder characterized by brittle bones. Here we tested whether patients with low bone density also have mutations in these genes. The 26 patients studied had no apparent metabolic bone disease, but most had a positive family history of osteopenia or osteoporosis. Although a diagnosis of OI was considered by the clinician in some cases, the clinical criteria for OI were not satisfied. Our strategy for mutation analysis consisted of PCR amplification of cDNA made to fibroblast mRNA using primers specific for the coding regions of COL1A1 and COL1A2. The PCR products were then sequenced directly with primers located within each PCR product. We found that 3 of 26 patients had mutations that altered the encoded amino acid. One mutation, at position α2(I)-661 has been reported (Spotila et al. 1991 Proc Natl Acad Sci USA PNAS 88: 5423). The other 2 patients, who were not related to each other, had a mutation that altered the proline codon at α1(I)-27 to alanine. This mutation was not found in 81 normal individuals or in 37 additional osteopenic individuals. However, its effect on the biologic function of type I collagen, as well as its role in osteopenia, is uncertain. In addition to the two mutations, we found a polymorphism in codon α2(I)-459. Although this polymorphism involved an amino acid substitution, it was present with equal frequency in the patient and the normal population. By analyzing this and previously reported neutral sequence variants in the COL1A2 gene, we determined that all patients expressed both alleles of the COL1A2 gene. The 12 patients who were heterozygous for a COL1A1 neutral sequence variant also expressed both alleles. Here we present all PCR primer and sequencing primer information. The results suggest that surveying a larger group of similarly selected individuals may reveal additional mutations in the COL1A1 or COL1A2 genes.

Abstract In a 4 year clinical trial in 202 postmenopausal osteoporotic women receiving NaF at 75 mg/day or placebo (both groups received supplementary calcium at 1500 mg/day), we found (N Engl J Med 322:801, 1990) that NaF increased bone mineral density in the lumbar spine (LS-BMD) substantially but did not decrease vertebral fracture rate (VFR), and it increased the nonvertebral fracture rate. Additional analyses and extended observations are now available on 50 women from the NaF group followed for up to 6 years of treatment. In these women, LS-BMD increased linearly over the 6 years (median rate, 8.7%/year or 0.063 g/cm2/year). Because during the 4 year trial the NaF dosage was decreased (because of side effects) in 54 of the 101 women randomized to NaF, dose-response relationships could be evaluated. For the entire study population, serum F level correlated directly with increase in LS-BMD (r = 0.61, P < 0.001). When individual person-years of observation were grouped by deciles of LS-BMD, VFR (per 100 person-years) decreased to a nadir of 24 as mean LS-BMD for the group increased from 0.6 to 1.2 g/cm2 and then doubled to 52 in the group with mean LS-BMD of 1.6 g/cm2. Multivariate analyses and inspection of three-dimensional plots revealed a complex pattern in which VFR was influenced by interaction of several variables. When the effects of LS-BMD, changes in LS-BMD, and serum F were assessed simultaneously, VFR was seen to decrease with increasing LS-BMD except when the higher LS-BMD was associated with rapid rate of increase in LS-BMD or a large increase from baseline serum F. For some patients (noncompliers or nonresponders), serum F or LS-BMD failed to increase. Thus, it is possible that lower dosages of NaF produce moderate decreases in VFR.

Abstract Bone mass and its mineral content are under genetic control. The vitamin D receptor (VDR) gene has been shown to be a major locus for genetic effects on bone mineral density (BMD), and polymorphisms in this gene accounted for a large proportion of genetic variance in BMD in an Australian population. In this study, we investigated whether similar associations are present in a North American population. We studied 139 normal healthy women (age 53.2 ± 14.5, mean ± SD) and 43 severely osteoporotic postmenopausal women (age 65.8 ± 5.9). In the 127 of them with complete genetic studies, the distribution of genotypes, determined by polymerase chain reaction on leukocyte DNA samples, agreed closely with that in the Australian population. BMD was strongly related to age and weight, and, thus was adjusted for these parameters prior to genetic analysis. We found that age modulated the effect of VDR genotypes on femoral neck BMD (FN-BMD) (TaqI, p = 0.036;BsmI, p = 0.118; ApaI, p = 0.041) such that the effect of genotype was greatest among younger (premenopausal) women and declined with age so that there was no discernible difference by age 70. Among the younger women, a high FN-BMD was associated with the TT (or aa or bb) genotype while low FN-BMD was associated with the tt (or AA or BB) genotype. In osteoporotic women, although the difference in FN-BMD between alternate TaqI homozygotes (TT vs. tt) was 0.13 g/cm2 (or about 18%), the overall difference among the genotype groups was not significant (TaqI, p = 0.13; BsmI, p = 0.21; ApaI, p = 0.09), possibly due to the small sample of osteoporotic women. There was no relationship of VDR genotype to lumbar spine BMD. We conclude that the VDR gene modulates differences in BMD in premenopausal women. Subsequent interaction of the gene and environmental factors and the role of VDR genotypes in predisposing to osteoporosis needs further study.

Abstract To assess the influence on the risk of hip fractures in men of medical conditions associated with secondary osteoporosis or with an increased likelihood of falling, we conducted a population-based nested case-control study among the 232 Rochester, Minnesota, men with an initial hip fracture due to moderate trauma in 1965–1989 and an equal number of age-matched control men from the general population. Information on selected medical and surgical conditions and certain behavioral risk factors prior to fracture (or comparable index date for controls) was obtained from inpatient and outpatient medical records in the community that averaged over 36 years in duration. After adjusting for age, obesity, and inactivity, disorders linked with secondary osteoporosis were associated with a 2-fold increase in the risk of hip fracture in men (odds ratio [OR] 2.3; 95% confidence interval [CI] 1.3–4.3), while conditions linked with an increased risk of falling were associated with almost a 7-fold increase in risk (OR 6.9; 95% CI 3.3–14.8). These factors together appeared to account for about 72% of the hip fractures in men. Increased attention must be paid to these conditions which, in aggregate, are very common in elderly men and lead to a substantial increase in the risk of hip fracture with its devastating sequelae of death, disability, and cost.

Abstract Increasing body weight is associated both with higher bone mass and with lower rates of bone loss. Whether the effects of body weight are mediated by lean body mass (LBM) or fat body mass (FBM) is, however, uncertain because different studies have used different measures of bone mass and arrived at contradictory conclusions. The parameter actually measured is bone mineral content (BMC). Bone mineral density (BMD), bone mineral apparent density (BMAD), and the BMD/height attempt to “correct” BMC for differences in bone or body size, but these corrections may bias the analysis of the effects of body composition on the skeleton. To resolve this issue, we measured BMC at the total body, lumbar spine, proximal femur, and forearm using dual energy X-ray absorptiometry (DXA) in a population-based sample including 138 premenopausal women (age range 21–54 years, mean 35 years) and 213 postmenopausal women (age range 34–94 years, mean 68 years). BMD, BMAD, and BMD/ height were also calculated for each site. LBM and FBM were determined from the DXA whole body scan. In a multivariate analysis that included age and height, both LBM and FBM predicted total body BMC in pre- and postmenopausal women (p < 0.002 for LBM and FBM in both groups). LBM had a dominant effect on spine and forearm BMC in both groups (p < 0.004) and hip BMC in premenopausal women (p < 0.001), whereas both LBM and FBM predicted hip BMC in postmenopausal women (p < 0.001). However, as BMC was adjusted for bone or body size using BMD, BMAD, or BMD/height, FBM tended to become more important than LBM in the analysis. This was, in part, due to the fact that each of the correction factors in the BMD and BMAD calculations, as well as height, were highly correlated with LBM (r = 0.57 and 0.52 for height versus LBM in pre- and postmenopausal women, respectively [p < 0.001]), and weakly or not at all with FBM (r = 0.08 and 0.11, respectively). Therefore, dividing BMC by these correction factors tended to bias the analysis against potential effects of LBM on bone mass. Thus, the relationship between body composition and bone mass is critically dependent on which bone mass parameter is used in the analysis. Both LBM and FBM have important effects on bone mass, depending on the bone mass parameter used, the skeletal site measured, and menopausal status.