O’Fallon, W. Michael

Background and Purpose —This study was conducted to determine the risk factors for ischemic stroke in a defined Russian population. Methods —Our data are based on a population-based case-control study of 237 patients with first-ever ischemic stroke and 237 age- and sex-matched controls. Logistic regression methods for matched pairs were used to estimate the relative risk for the variables studied. Results —In a multivariate analysis, hypertension, left ventricular hypertrophy on electrocardiography, ischemic heart disease, mitral valve disease, current cigarette smoking, and high body mass index were significant and independent risk factors for ischemic stroke in this Russian community. Conclusions —The significant risk factors for ischemic stroke in Novosibirsk are similar to those from other populations and cohorts. This study, the first of stroke risk factors in Russia, has implications for clinical practice and the planning of stroke prevention in the population.

Background and Purpose The present study was conducted to investigate the incidence of stroke and 30-day case-fatality rates for stroke in a defined Russian population. Methods This is a population-based study that was established in 1982. All residents of an administratively defined and typical district of Novosibirsk (approximately 150 000 subjects) who had an incident (first-ever) stroke from January 1, 1982, through December 31, 1992, were registered. Results During an 11-year study period, 3406 incident stroke patients were registered, for an overall crude average annual incidence rate of 202/100 000 population. The rates were higher with increasing age and were significantly higher for men than for women. The age- and sex-adjusted annual incidence rate of stroke declined from 271/100 000 in 1982 to 232/100 000 in 1992. Slowing of the decline in stroke incidence was observed after 1988, and stroke incidence increased slightly in 1992. No significant differences in 30-day stroke case-fatality rates were noted from 1982 through 1992, but a slight trend toward decreasing rates was observed after 1988. There was no major change in patient age at stroke onset. Conclusions Stroke incidence rates in Novosibirsk are among the highest in the world. We observed a decline in stroke incidence but little change in 30-day case-fatality rates in Novosibirsk from 1982 through 1992.

Background and Purpose —There is scant population-based information on incidence and risk factors for ischemic stroke subtypes. Methods —We identified all 454 residents of Rochester, Minn, with a first ischemic stroke between 1985 and 1989 from the Rochester Epidemiology Project medical records linkage system. We used Stroke Data Bank criteria to assign infarct subtypes after reviewing medical records and brain imaging. We adjusted average annual incidence rates by age and sex to the US 1990 population and compared the age-adjusted frequency of stroke risk factors across ischemic stroke subtypes. Results —Age- and sex-adjusted incidence rates (per 100 000 population) were as follows: large-vessel cervical or intracranial atherosclerosis with >50% stenosis, 27; cardioembolic, 40; lacuna, 25; uncertain cause, 52; other or uncommon cause, 4. Sex differences in incidence rates were detected only for atherosclerosis with stenosis (47 [95% CI, 34 to 61] for men; 12 [95% CI, 7 to 17] for women). There was no difference in prior transient ischemic attack and hypertension among subtypes, and diabetes was not more common among patients with lacunar infarction than other common subtypes. Conclusions —The age-adjusted incidence rate of stroke due to stenosis of the large cervicocephalic vessels is nearly 4 times higher for men than for women. There is no association between preceding transient ischemic attack and stroke mechanism. Diabetes and hypertension are not more common among patients with lacunae. Age- and sex-adjusted incidence rates for ischemic stroke subtypes in this population can be compared with similarly determined rates from other populations.

Abstract ABSTRACT: The cellular mechanisms for bone loss in type I (postmenopausal) osteoporosis are highly controversial. We attempted to resolve this by assessing rates of formation and resorption of iliac cancellous bone by a new histomorphometric method in 89 women with osteoporosis (mean age + SD, 66 + 6 years) and in 32 carefully selected normal postmenopausal women (64 + 6 years). In the osteoporotic women, bone resorption rate was increased by 39% (P <0.05) at the cellular level and by 67% (P <0.05) at the tissue level, whereas bone formation was unchanged at the tissue level but decreased by 14% (P <0.01) at the cellular (osteoblast) level. This pronounced remodeling imbalance (P <0.001) was probably exacerbated by a 45% increase (P < 0.1) in activation frequency of new remodeling foci. These abnormalities were associated with a high rate of cancellous bone loss (median, 5.8%/year versus 0.1%/year in controls). Thus, accelerated loss of cancellous bone in type I osteoporosis results from the combination of increased bone resorption and inadequate compensation by bone formation.

Abstract Lack of adequate data concerning the effect of age on biochemical variables relating to bone and mineral metabolism hampers research on age-related bone loss in women. Furthermore, to detect disease and to monitor therapy, clinical laboratories require reference values derived from an appropriate population sample. Therefore, we determined the age-specific distribution of values for serum concentrations of calcium, inorganic phosphorus, alkaline phosphatase, bone Gla protein, and parathyroid hormone; for creatinine clearance; for fasting urinary calcium:creatinine ratio; and for 24 h urinary excretion of calcium, hydroxyproline, and cyclic AMP in a population-based sample of 301 white women. From this sample, a healthy subgroup of 181 women was identified by medical record review. Age-related effects were seen in all variables except serum calcium and phosphorus. Moreover, substantial differences between the population sample and the healthy subgroup were noted in values for creatinine clearance, serum alkaline phosphatase, and 24 h urinary calcium excretion. These observations may prove useful for assessment of normality in other populations of aging white women.

Abstract High caffeine consumption has been proposed as a risk factor for osteoporotic fracture, but the evidence associating high caffeine intake with low bone density is inconsistent. We therefore examined the influence of caffeine consumption on bone mineral at six skeletal sites in an age-stratified random sample of white women residing in Rochester, Minnesota. After age adjustment, there was no association between overall caffeine consumption and bone mineral at five of the six sites. In the femoral shaft, however, there was a statistically significant interaction between age and caffeine consumption so that high caffeine intake was associated with slight reductions in bone mineral among elderly subjects but with modestly increased bone mineral at younger ages. When caffeine intake was categorized by source, no consistent influence of coffee, tea, or other caffeinated beverage consumption could be detected on bone mineral. Caffeine intake was, however, positively associated with cigarette smoking and alcohol consumption. After adjusting for age, caffeine consumption was not correlated with biochemical indices of bone turnover, circulating concentrations of estradiol and estrone, or other dietary and musculoskeletal variables. These data suggest that caffeine intake in the range consumed by a representative sample of white women is not an important risk factor for osteoporosis. Among elderly women, however, in whom calcium balance performance is impaired, high caffeine intake may predispose to cortical bone loss from the proximal femur.

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.