Marian T. Hannan

Risk Factors for Longitudinal Bone Loss in Elderly Men and Women: The Framingham Osteoporosis Study

Few studies have evaluated risk factors for bone loss in elderly women and men. Thus, we examined risk factors for 4‐year longitudinal change in bone mineral density (BMD) at the hip, radius, and spine in elders. Eight hundred elderly women and men from the population‐based Framingham Osteoporosis Study had BMD assessed in 1988‐1989 and again in 1992‐1993. BMD was measured at femoral neck, trochanter, Wards area, radial shaft, ultradistal radius, and lumbar spine using Lunar densitometers. We examined the relation of the following factors at baseline to percent BMD loss: age, weight, change in weight, height, smoking, caffeine, alcohol use, physical activity, serum 25‐OH vitamin D, calcium intake, and current estrogen replacement in women. Multivariate regression analyses were conducted with simultaneous adjustment for all variables. Mean age at baseline was 74 years ± 4.5 years (range, 67‐90 years). Average 4‐year BMD loss for women (range, 3.4‐4.8%) was greater than the loss for men (range, 0.2‐3.6%) at all sites; however, BMD fell with age in both elderly women and elderly men. For women, lower baseline weight, weight loss in interim, and greater alcohol use were associated with BMD loss. Women who gained weight during the interim gained BMD or had little change in BMD. For women, current estrogen users had less bone loss than nonusers; at the femoral neck, nonusers lost up to 2.7% more BMD. For men, lower baseline weight and weight loss also were associated with BMD loss. Men who smoked cigarettes at baseline lost more BMD at the trochanter site. Surprisingly, bone loss was not affected by caffeine, physical activity, serum 25‐OH vitamin D, or calcium intake. Risk factors consistently associated with bone loss in elders include female sex, thinness, and weight loss, while weight gain appears to protect against bone loss for both men and women. This population‐based study suggests that current estrogen use may help to maintain bone in women, whereas current smoking was associated with bone loss in men. Even in the elderly years, potentially modifiable risk factors, such as weight, estrogen use, and cigarette smoking are important components of bone health.

The effect of postmenopausal estrogen therapy on bone density in elderly women

Background Estrogen therapy prevents bone loss in postmenopausal women who take it early in the postmenopausal period. The risk of fracture is highest much later in life, however. We studied whether bone mass in elderly women was affected by earlier estrogen use and how long women needed to take estrogen for it to have a beneficial effect on bone density later in life. Methods In 1988 and 1989, we measured bone mineral density at the femur, spine, shaft of the radius, and ultradistal radius in 670 white women in the Framingham Study cohort (mean age, 76 years; range, 68 to 96). These women had been followed prospectively through menopause and had been asked repeatedly about estrogen therapy. After excluding women who began taking estrogen after a fracture, we investigated whether postmenopausal estrogen therapy affected bone density; in these analyses we adjusted for age, weight, height, cigarette smoking, physical activity, and age at menopause. Results A total of 212 women (31.6 percent) had received es...

Abdominal Aortic Calcific Deposits Are an Important Predictor of Vascular Morbidity and Mortality

BackgroundThe impact of abdominal arterial calcific deposits on the prediction of cardiovascular disease (CVD) over a long follow-up interval deserves greater scrutiny. Methods and ResultsLateral lumbar radiographs were studied as a predictor of incident coronary heart disease (CHD), CVD, and CVD mortality in 1049 men and 1466 women (mean age, 61 years) who were followed from 1967 to 1989. Anterior and posterior wall calcific deposits in the aorta at the level of the first through fourth lumbar vertebrae were graded according to increasing severity using a previously validated rating scale for abdominal aortic calcium (AAC) that ranges from 0 to 24 points. There were 454 cases of CHD, 709 cases of CVD, and 365 CVD deaths. Proportional hazards logistic regression was used to test for associations between AAC and later events after adjustment for age, cigarette use, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy, body mass index, cholesterol, and HDL cholesterol. In comparisons with the lowest AAC tertile, the multivariate age-adjusted relative risks (RR) for CVD were increased in tertile 2 (men: RR, 1.33; 95% confidence interval [CI], 1.02 to 1.74; women: RR, 1.25; 95% CI, 0.95 to 1.65) and tertile 3 (men: RR, 1.68; 95% CI, 1.25 to 2.27; women: RR, 1.78; 95% CI, 1.33 to 2.38). Similar results were obtained with CHD and CVD mortality. ConclusionsAAC deposits, detected by lateral lumbar radiograms, are a marker of subclinical atherosclerotic disease and an independent predictor of subsequent vascular morbidity and mortality.

Effect of Dietary Protein on Bone Loss in Elderly Men and Women: The Framingham Osteoporosis Study

Few studies have evaluated protein intake and bone loss in elders. Excess protein may be associated with negative calcium balance, whereas low protein intake has been associated with fracture. We examined the relation between baseline dietary protein and subsequent 4‐year change in bone mineral density (BMD) for 391 women and 224 men from the population‐based Framingham Osteoporosis Study. BMD (g/cm2) was assessed in 1988‐1989 and in 1992‐1993 at the femur, spine, and radius. Usual dietary protein intake was determined using a semiquantitative food frequency questionnaire (FFQ) and expressed as percent of energy from protein intake. BMD loss over 4 years was regressed on percent protein intake, simultaneously adjusting for other baseline factors: age, weight, height, weight change, total energy intake, smoking, alcohol intake, caffeine, physical activity, calcium intake, and, for women, current estrogen use. Effects of animal protein on bone loss also were examined. Mean age at baseline (±SD) of 615 participants was 75 years (±4.4; range, 68‐91 years). Mean protein intake was 68 g/day (±24.0; range, 14‐175 g/day), and mean percent of energy from protein was 16% (±3.4; range, 7‐30%). Proportional protein intakes were similar for men and women. Lower protein intake was significantly related to bone loss at femoral and spine sites (p ≤ 0.04) with effects similar to 10 lb of weight. Persons in the lowest quartile of protein intake showed the greatest bone loss. Similar to the overall protein effect, lower percent animal protein also was significantly related to bone loss at femoral and spine BMD sites (all p < 0.01) but not the radial shaft (p = 0.23). Even after controlling for known confounders including weight loss, women and men with relatively lower protein intake had increased bone loss, suggesting that protein intake is important in maintaining bone or minimizing bone loss in elderly persons. Further, higher intake of animal protein does not appear to affect the skeleton adversely in this elderly population.

Bone loss and the progression of abdominal aortic calcification over a 25 year period: the Framingham Heart Study.

Vascular calcification and osteoporosis are common age-related processes that are prominently displayed on routine lateral lumbar spine radiographs as dense calcium mineral deposits of the aorta that lie adjacent to osteopenic vertebrae. Using a population-based cohort of older men and women, we tested the hypothesis that the progression of vascular calcification of the abdominal aorta should be greatest in those individuals with the greatest amount of bone loss. From the original population-based Framingham Heart Study cohort, 364 women and 190 men had lateral lumbar spine and hand radiographs performed between 1966 and 1970 and repeated between 1992 and 1993. The lateral lumbar films were read for the presence of aortic calcification using a semiquantitative method, and the hand films were read for second metacarpal relative cortical area (MCA). Using multivariate regression techniques, the 25-year progression of the abdominal aortic calcification index was examined in relation to the change in the MCA, while adjusting for recognized risk factors for atherosclerotic cardiovascular disease. During the 25 years of followup, the MCA decreased by 22.4% in women (from 79.6±7.8 (SD) to 61.8±10.3) and by 13.3% in men (from 80.6±6.9 to 69.9±8.3). The aortic calcification score increased over eightfold in women (from 1.2±2.7 (SD) to 9.9±6.7) and sixfold in men (from 1.6±2.8 to 9.6±6.3). There was a significant association between percent change in MCA and change in aortic calcification index (P=0.01) in women after controlling for all potential confounders. No association was observed in men (P=0.50), including the 50% of men with the greatest bone loss. This is the first longitudinal study to show that women with the greatest magnitude of bone loss also demonstrate the most severe progression of abdominal aortic calcification, suggesting that the two processes may be related.

New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study

The purpose of the present study was to assess the location, severity and progression of radiopaque lumbar aortic calcifications and to evaluate the utility of summary scores of lumbar calcification in a population-based cohort. Lateral lumbar films, obtained in 617 Framingham heart study participants, were analysed for the presence of abdominal aortic wall calcification in the region corresponding to the first through fourth lumbar vertebrae. The severity of the anterior and posterior aortic calcification were graded individually on a 0-3 scale for each lumbar segment and the results were summarized to develop four different composite scores: (1) affected segments score (range 0-4); (2) anterior and posterior affected score (range 0-8); and (3) antero-posterior severity score (range 0-24). The prevalence of aortic calcification was 37% in men and 27% in women at baseline and 86% in both genders at the follow-up exam 25 years later. During the follow-up interval, the mean of the affected segments score increased from 0.7 in men (0.5 in women) to 2.7 (2.8 in women), the mean of the anterior and posterior affected score from 1.2 (0.8 in women) (P = 0.012 for difference between genders) and the mean of the antero-posterior severity score increased from 1.5 (1.3 in women) to 9.3 (10.3 in women). The antero-posterior severity score offered a slight advantage over other composite scores and had the highest inter-rater intra-class correlations. In summary, lumbar aortic calcification can be graded and composite summary scores are reproducible. This technique appears to provide a simple, low cost assessment of subclinical vascular disease.

Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study

Osteoporosis is not a problem confined to women; it has important medical and socioeconomic consequences for men as well (1-3). With advancing age, men lose bone mineral density (4, 5), which leads to increased risk for fracture after minimal trauma (6). It is estimated that 13% of white men older than 50 years of age will experience a fracture during their lifetime (7). Approximately 30% of all hip fractures occur in men (8), and the morbidity and mortality after such fractures are much greater in men than in women (9-11). As the aging population grows worldwide, a better understanding of risk factors that contribute to low bone mineral density in elderly men will be needed. The effect of sex hormones on bone mineral density in elderly men is of particular interest because it could have diagnostic and therapeutic implications, as it does in women (12, 13). Both androgens and estrogens have been shown to be important for bone health in young men, but their role in elderly men is not as clear (14, 15). Testosterone, the predominant circulating androgen in men, is produced mainly by Leydig cells of the testes and is regulated by luteinizing hormone (16, 17). Hypogonadism in men, whether caused by primary or secondary failure of Leydig cell function, results in low testosterone levels. Young adult men who are hypogonadal because of medical conditions or castration have low bone mineral density (18-20); testosterone replacement improves bone mineral density in these men (19, 21). Given the association between hypogonadism and bone mineral density in young men and the decrease in serum testosterone levels with increasing age (22, 23), it has been assumed that hypogonadism related to aging explains low bone mineral density in elderly men. However, evidence to support this association remains weak. Results of studies that include men of a wide age range or hypogonadal men with an identifiable medical cause (such as orchiectomy or pituitary tumors) are not generalizable to elderly men from the general population. Among studies specifically of elderly men from the general population, several failed to show an association between testosterone levels and bone mineral density (24-28). It could be that an association with bone mineral density exists only below the normal reference range for testosterone (29) and that continuous measurement of testosterone levels, as was done in most studies, missed this relation. Previous studies may have also been limited by the fact that single measurements of sex hormones obtained at the same time as bone mineral density measurement may not adequately reflect the influence of these hormones on bone metabolism. Recent evidence suggests that estrogens may also be important for bone health in young and older men (14, 27, 28, 30-36). However, the magnitude of effect of estrogen levels on bone mineral density in elderly men is not known, nor is the relative effect of testosterone and estrogens clearly defined. Only a small fraction of estradiol, the major circulating form of estrogen, is produced directly by the testes; the main source is peripheral conversion of testosterone and adrenal sex steroids by the aromatase enzyme (17, 37). Thus, some or all of the effect of low testosterone on bone mineral density in elderly men could be explained by low estradiol levels. We examined the association of testosterone and estradiol status with bone mineral density among men from the Framingham Study, a population-based cohort with a large number of elderly men who had repeated measurement of sex hormones before bone mineral density assessment. We explored the association of a threshold effect of low testosterone level on bone mineral density in these men by considering different definitions of hypogonadism based on sex hormone measures. Methods The Framingham Study began in 1948 in Framingham, Massachusetts, with the initial goal of evaluating risk factors for heart disease in a population-based cohort (38). As part of this ongoing study, participants have received comprehensive medical examinations every 2 years. The Framingham Osteoporosis Study, designed to study risk factors for osteoporosis, started in 19881989 as a component of the 20th biennial examination and involved surviving members of the cohort, most of whom were white (39). We studied the 448 men of the cohort who had bone mineral density measurements in 19881989 and sex hormones measurements during previous biennial examinations. Assessment of Sex Hormones Total testosterone, total estradiol, and luteinizing hormone were measured in all male participants at four consecutive biennial examinations from 1981 to 1989. Serum samples were measured by using radioimmunoassay for total testosterone (Diagnostic Products Corp., Los Angeles, California; interassay coefficient of variation, 11%; reference range for young adult men, 10 to 35 nmol/L [3 to 10 ng/mL]), total estradiol (Diagnostic Products Corp.; lower limit of assay detection, 2 pg/mL; interassay coefficient of variation, 4%; reference range for young adult men, 7 to 184 pmol/L [2 to 50 pg/mL]), and luteinizing hormone (Serono Laboratories, Randolph, Massachusetts, in 1981 to 1983, then Diagnostic Products Corp. for the three biennial examinations from 1983 to 1989; intraclass correlation, 0.92; interassay coefficient of variation, 6%; reference range for young adult men, 3 to 13 IU/L). Data were originally collected in traditional units, and cutoff values were defined on the basis of these units. Conversions to SI units were performed in accordance with the publication policy of Annals of Internal Medicine. Assessment of Bone Mineral Density In 19881989, bone mineral density was measured at the proximal femur (femoral neck, Ward triangle, and trochanter) and lumbar spine by using dual-photon absorptiometry (LUNAR DP3, Lunar Corp., Madison, Wisconsin) and at the radial shaft (measured at the junction of the proximal two thirds and the distal one third of the radius) by using single-photon absorptiometry (LUNAR SP2, Lunar Corp.) (39). If participants had a history of fracture or hip joint replacement, the contralateral side was scanned. Because the lumbar spine was assessed during a callback examination, the number of participants for whom this measurement was available is smaller than that for the proximal femur or radial shaft. All bone mineral density scans were reviewed to ensure that correct placement and analysis were performed according to the manufacturers recommendations. Scans for which placement was incorrect, those that did not include the complete anatomic region of interest, and those found to include metal or other attenuating material were considered technically inadequate and were deleted. The coefficients of variation in normal persons for bone mineral density at the proximal femur were 2.6% for the femoral neck, 4.1% for Ward triangle, and 2.8% for the trochanter; the coefficients of variation were 2.2% and 2.0% for the lumbar spine and radial shaft, respectively. Assessment of Other Covariates Factors previously shown to be associated with bone mineral density in men were also assessed (15, 39-46). These variables were age, body mass index, serum 25-hydroxyvitamin D level, calcium intake, physical activity, cigarette smoking, alcohol intake, thiazide diuretic use, and glucocorticoid use. Age, body mass index, serum 25-hydroxyvitamin D, calcium intake, and physical activity were determined in 19881989 at the time of the bone mineral density assessment. Serum 25-hydroxyvitamin D was measured by using a competitive binding-protein assay (47) (interassay coefficient of variation, 10%) and was categorized as low (<50 nmol/L), medium (50 to 75 nmol/L), or high (>75 nmol/L). Information on dietary calcium intake, including supplements, was collected by using the Willett 126-item food frequency questionnaire (48, 49) and was categorized as low (<500 mg/d), moderate (500 to 1000 mg/d), or high (>1000 mg/d). Physical activity was assessed by using the Framingham Physical Activity Index, a weighted 24-hour score of typical daily activity based on hours spent performing heavy, moderate, light, or sedentary activity (50, 51). Information on smoking and alcohol intake was available from previous biennial examinations. Participants were characterized as current smokers if they smoked cigarettes during 1981 to 1989, former smokers if they reported smoking before 1981 but not between 1981 and 1989, and never-smokers if they reported no cigarette use since inception of the study in 1948. Alcohol intake was defined according to the average ounces of alcohol consumed per week between 1981 and 1989. Information on thiazide diuretic use among participants was available from three consecutive examinations from 1983 to 1989, and information on glucocorticoid use was available from all four examinations from 1981 to 1989. Statistical Analysis To examine the association between sex hormone status and bone mineral density, we averaged hormone values for each participant if measurements were available from at least three of four examinations from 1981 to 1989. We excluded one participant whose serum estradiol value was considered unreliable. All analyses were performed by using SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Gonadal Status and Bone Mineral Density Hypogonadism in men is the loss of testicular function, which includes primary and secondary failure of the Leydig cell function in the testes, leading to a deficiency in serum testosterone levels. Studying hypogonadal elderly men from the general population is difficult, however, because there are no standard definitions of hypogonadism, and symptoms and signs are not well correlated with hormonal status (52, 53). Therefore, to examine whether hypogonadism was associated with low bone mineral density in our population-based sample of elderly men, we created a definition based on the mean total testosterone o

Impaired vision and hip fracture. The Framingham Study.

Falls affect a large proportion of the elderly and can result in a variety of injuries, including hip fractures. Several studies have suggested that visual impairment contributes to falls, but studies have not used standardized definitions of visual impairment and have not examined injurious falls or fractures. We looked at the risk of hip fracture associated with visual impairment in those members of the Framingham Study Cohort who took part in the Framingham Eye Study in 1973–75. Of 2,633 subjects followed for 10 years after the eye exam, 110 sustained hip fractures. The fracture rates in those with moderately impaired (20/30 to 20/80) vision (8.5%) and poor (20/100 or worse) vision (11.3%) were higher than in those with good (20/25 or better) vision (3.0%). After adjustment for age, sex, weight, alcohol consumption, and (in women) estrogen use, the relative risk of fracture in those with moderate impairment was 1.54 (95% CI = 0.95–2.49), while for those with poor vision, the relative risk was 2.17 (95% CI = 1.24–3.80). Of note, those with moderately impaired vision in one eye and good vision in the other had a higher risk of fracture (relative risk = 1.94) than those with a similar degree of binocular impairment (relative risk = 2.11). Poor vision in one or both eyes was linked to an elevated fracture risk. This suggests that good stereoscopic vision may be necessary to prevent falls. The risk of fracture with poor and moderately impaired vision combined was increased in women (relative risk = 1.96, 95% CI = 1.23–3.11) but not in men (relative risk = 0.79, 95% CI = 0.23–2.72). 17.5% (17/97) of women with poor vision in at least one eye sustained a hip fracture during the 10 years of the study. Cataracts were the most common cause of fracture‐related visual impairment, but neither cataracts nor other common eye diseases had an independent effect on fracture risk after adjustment for visual acuity. In sum, visual impairment is an important risk factor for hip fracture, especially among elderly women.

Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis the Framingham Study

OBJECTIVE To investigate the inheritance of generalized osteoarthritis (OA). METHODS OA was identified on hand and knee radiographs obtained from members of the Framingham Study cohort (the parents) in 1967-1970 and 1992-1993, and from their adult children in the Framingham Offspring Study in 1993-1994. All hand and knee radiographs evaluated for OA were graded using the Kellgren and Lawrence (K/L) scale. A measure of generalized OA was defined as the count of the number of hand and knee joints affected, as determined by the proportion of joints with a K/L grade > or =2. The OA count, treated as a continuous variable, was adjusted for age, body mass index, and a measure of physical activity for each joint area (hand or knee). Calculations were made separately for each generation and each sex, and correlations were analyzed against the standardized residual of OA. Segregation analysis was used to test whether OA aggregated in families, and if its transmission fit a Mendelian pattern. RESULTS A total of 337 nuclear families with 2 parents and at least 1 biologic offspring were studied. In parents, the mean age was 61.2 years at the time of hand radiographs and 72.8 years at the time of knee radiographs, which were mostly obtained at a later examination. The mean age at the time of radiographs in offspring was 53.9 years. Using standardized residuals, parent-offspring and sibling-sibling correlations ranged from 0.115 to 0.306. In segregation analyses, models testing the hypotheses of no familial aggregation, no familial transmission, or a Mendelian gene alone were all rejected (P < 0.001 for each of these models). The best-fitting models were mixed models with a Mendelian mode of inheritance and a residual multifactorial component. The Mendelian recessive model provided the best fit. CONCLUSION These analyses support a significant genetic contribution to OA, with evidence for a major recessive gene and a multifactorial component, representing either polygenic or environmental factors.

Low Plasma Vitamin B12 Is Associated With Lower BMD: The Framingham Osteoporosis Study

Vitamin B12 is important to DNA synthesis and may affect bone formation. We examined the association between this vitamin and BMD in 2576 adults. Men with plasma B12 < 148 pM had significantly lower BMD at the hip, and women at the spine, relative to those with higher B12, and trends were similar for both at all sites. Low vitamin B12 may be a risk factor for low BMD.