Edith Flaster

Calcium Supplementation with and without Hormone Replacement Therapy To Prevent Postmenopausal Bone Loss

Postmenopausal bone loss is a major factor in the increasing prevalence of osteoporotic fractures. Evidence is abundant that hormonal replacement therapy prevents the bone loss that follows natural or surgical menopause and reduces the prevalence of osteoporotic fractures in later life [1-4]. However, only about 10% of American women elect to receive replacement therapy because of attitudes of physicians and patients, the undesirability of menstrual bleeding, and unresolved questions about the relation of the use of estrogen to breast cancer [5]. Moreover, the duration of hormonal therapy may need to be prolonged because bone loss recurs when therapy is discontinued, yet the incidence of some adverse effects increases with the duration of estrogen use. Safer alternatives to estrogen use have been sought. Epidemiologic and cross-sectional studies have suggested that increasing calcium intake might prevent postmenopausal bone loss, and prospective studies have yielded conflicting results [6-17]. Moreover, some investigators have suggested that effects differ on the various skeletal sites used to determine the rate of bone loss [18]. We compared the efficacy of calcium augmentation in early postmenopause with calcium augmentation plus hormonal replacement therapy and with placebo. The study had a three-arm, randomized, parallel design. The patients receiving hormonal replacement therapy were obviously not blinded nor were their physicians, whereas the placebo and calcium groups were double blinded. Methods Healthy, white women between 6 months and 6 years after a natural menopause were recruited to participate in the study. The protocol was approved by the Human Investigation Review Committees of Winthrop-University Hospital and Brookhaven National Laboratory; written informed consent was obtained from each participant. Participants were recruited by announcements in the local press and in hospital and university publications and through a direct mail campaign. All participants had a history and physical examination. Exclusion characteristics included any disorder known to affect bone metabolism such as glucocorticoid use, gastrointestinal disease, or any chronic illness. Previous or current malignancy was an exclusion characteristic as were absolute contraindications to estrogen replacement or calcium supplements. Absolute contraindications to estrogen replacement therapy included estrogen-dependent neoplasm (breast or uterus), undiagnosed vaginal bleeding, thrombophlebitis or thromboembolism, and acute liver disease. Women with the following problems considered by some investigators to be relative contraindications to estrogen therapy were also excluded: gallbladder disease, history of liver disease, first-degree relatives with breast cancer, and hypertension. Calcium urolithiasis was also an exclusion factor. Women with known osteoporosis or with a vertebral compression fracture were not eligible for the study. One hundred eighteen women entered the study. The women were randomly assigned to three groups: 1) hormonal replacement [estrogen-progesterone-calcium carbonate], 2) calcium carbonate, or 3) placebo. Assignment to the groups was based on computer-generated random numbers provided by the statistician, with stratification for years postmenopause. The women in the hormonal replacement group took conjugated equine estrogens (Premarin, Wyeth-Ayerst Laboratories, Inc.; Philadelphia, Pennsylvania), 0.625 mg daily for 25 days of the month along with medroxyprogesterone (Provera, Upjohn; Kalamazoo, Michigan), 10 mg from days 16 to 25. All women received 400 IU of vitamin D daily in the form of a multivitamin, and calcium supplementation (as Caltrate, Lederle; Clifton, New Jersey) was provided to the two treatment groups. The duration of the study was 2.9 1.1 years (mean SD). A 7-day dietary history was reviewed with a nutritionist every 2 months; calcium was provided as calcium carbonate, 600 mg (Caltrate), and used to supplement the diet to approximate a total daily intake of 1700 mg of elemental calcium (the mean + 2 SD found by Heaney and colleagues [7] to result in zero calcium balance in estrogen-deprived women). The calcium supplements were taken with meals in divided doses. The placebo appeared identical to the calcium carbonate tablets. No patients took antacids or histamine-2 blockers. All women had a baseline mammogram. Measurements Routine laboratory studies included a complete blood count, urinalysis, and serum fasting calcium, phosphorus, urea nitrogen, creatinine, alkaline phosphatase, cholesterol, and aminotransferase measurements [19, 20]. In addition, follicle-stimulating hormone, estradiol, parathyroid hormone, osteocalcin, free thyroxine, and bone alkaline phosphatase were measured, and a urine specimen was collected after an overnight fast for hydroxyproline, calcium, and creatinine determinations, following a 3-day low-hydroxyproline diet [21-23]. Total body calcium was measured annually in the participants, using the delayed neutron activation method at Brookhaven National Laboratory [24, 25]. This method uses a whole-body counter to measure the characteristic rays emitted from the neutron capture of Calcium-48 (natural abundance of 0.187%) in the body. The Brookhaven National Laboratory whole-body counter was upgraded in 1987 to use 32 NaI (T1) detectors of 10 cm 10 cm 46 cm positioned symmetrically above and below the patient [25]. The activated isotope, Calcium-49, decays with a half-life of 8.72 minutes, emitting a 3.08 MeV characteristic line. More than 99.5% of the body calcium is contained in the bone [26]. The method provides total body calcium with a coefficient of variation of about 1.5% when no substantial change in the body weight occurs during the period of repeated studies. The measurements were made annually. The bone mineral density of the distal radius site was measured using a Lunar Radiation (Madison, Wisconsin) single-photon absorptiometer (SP2). Bone mineral density of the spine (L2-L4) and femur (neck, trochanter, and Ward triangle) was measured using a Lunar Radiation DP4 dual-photon absorptiometer. The software version used for the analysis of scans was DP4 Lunar Corporation Version 1.1. All scans were analyzed using the same software version, which corrects for source decay. Instruments were calibrated daily, and the radioactive source was changed annually. Each measurement was done every 6 months. The coefficient of variation of these measurements was 2%, except for the Ward triangle (2.5%). Activity was measured using activity monitors (large-scale integrated monitors), which were worn about the waist [27]. The average of 2 weekdays and 1 weekend day was used as an activity score. Activity was measured at baseline and at one other point during the study to ensure that differences among the groups were not due to varied levels of exercise. Statistical Analysis Total body calcium was selected as the primary criterion for efficacy for the following reasons: It measures mass rather than density per unit area; it measures calcium balance precisely and accurately in the free living state and may be better related to previous studies using the balance technique; it is more precise than the other measurements; and it avoids sampling error by measuring the entire skeleton rather than a specific region of the appendicular or axial skeleton. The rate of change in bone mineral was calculated for each woman at each of the sites used in the study. Standard linear regression procedures were used to estimate the rate of bone mineral change for each woman, and the regression intercept was used as the best estimate of the baseline value. Because some women terminated their participation in the study before others, the rate-of-change data were weighted by the inverse variance to reflect the fit of the regression line for each woman [28]. Analyses of covariance were done using body mass index, activity scores, cigarette smoking, calcium intake, age, and years postmenopause as covariates. The data reported in this article are based on all women who provided at least three observations for a particular skeletal site. We considered other criteria, such as using data only from women who had participated in the study for at least 2 years, and all data analyses were done for this subgroup as well. The results of these analyses were invariably similar to those reported here and therefore are not presented separately. The mean rates of change in bone mineral for each condition at each site were characterized in terms of both raw units and percentages; separate analyses were carried out for each. The two indices were similar. Evidence from recent research is substantial that estrogen replacement therapy is effective, whereas the efficacy of calcium supplements is questionable. Our expectation was that our data would confirm the efficacy of estrogen-progesterone-calcium therapy, and the critical question was whether or not a beneficial effect of calcium supplements given alone could be shown. A separate one-way analysis of covariance was done for each of the bone mineral measurements to compare the mean rates of change in bone mineral for each of the three conditions. We used two a priori contrasts: the first contrasting women taking estrogen with those receiving calcium and the second comparing women receiving calcium supplements with those on placebo. All P values reported are two-tailed. Results Baseline data for historical data and bone mineral measurements and chemical studies are given in Table 1. Analysis of variance showed no significant differences in the baseline variables. The initial and final activity scores did not differ significantly. Table 1. Baseline Values for Patient Characteristics, Bone Mineral Measurements, and Chemical Variables The range of initial daily calcium intake in the overall study group was 150 to 1263 mg; in the calcium augmentation group, it was 222 to 806

The influence of menopause and hormonal replacement therapyon body cell mass and body fat mass

OBJECTIVE Our purpose was to determine the efficacy of dietary calcium augmentation in the prevention of early postmenopausal bone density loss in comparison with hormonal replacement therapy and placebo. STUDY DESIGN A three-arm parallel randomized trial comparing the influence of placebo, dietary calcium augmentation, and estrogen-progesterone-calcium in 118 women who were within 6 years of menopause was conducted. Dual photon absorptiometry was performed annually to measure lean and fat mass. In addition, the ratio of fat in the trunk/extremities was measured. RESULTS Body weight increased in each group. The increase was statistically significant in the hormone replacement group (0.8 kg/year). The percent of body fat increased in each group from baseline measurements, with the greatest increase in the hormonal replacement group. There was a decline in the extremity/trunk ratio in the hormonal replacement group as a result of a relatively greater increase in the trunk fat mass. There was a rapid rate of loss in lean body mass that was equal among groups. CONCLUSIONS Menopause is associated with a gain in fat mass and a loss of lean body mass, but these changes in body composition are not prevented by hormone replacement therapy.

Risk for osteoporosis in black women

Models of involutional bone loss and strategies for the prevention of osteoporosis have been developed for white women. Black women have higher bone densities than white women, but as the black population ages there will be an increasingly higher population of black women with osteoporosis. Strategies should be developed to reduce the risk of black women for fragility fractures.Dual energy X-ray absorptiometry measurements of the total body, femur, spine, and radius were performed on 503 healthy black and white women aged 20–80 years. Indices of bone turnover, the calcitrophic hormones, and radioisotope calcium absorption efficiency were also measured to compare the mechanisms of bone loss.The black women had higher BMD values at every site tested than the white women throughout the adult life cycle. Black women have a higher peak bone mass and a slightly slower rate of adult bone loss from the femur and spine, which are skeletal sites comprised predominantly of trabecular bone. Indices of bone turnover are lower in black women as are serum calcidiol levels and urinary calcium excretion. Serum calcitriol and parathyroid hormone levels are higher in black women and calcium absorption efficiency is the same in black and white women, but dietary calcium intake is lower in black women.Black and white women have a similar pattern of bone loss, with substantial bone loss from the femur and spine prior to menopause and an accelerated bone loss from the total skeleton and radius after menopause. The higher values for bone density in black women as compared with white women are caused by a higher peak bone mass and a slower rate of loss from skeletal sites comprised predominantly of trabecular bone. Low-risk strategies to enhance peak bone mass and to lower bone loss, such as calcium and vitamin D augmentation of the diet, should be examined for black women. The risk vs. benefits of hormonal replacement therapy should be determined, especially in older women.

Ankle-arm blood pressure index as a predictor of mortality in hemodialysis patients

The ankle-arm blood pressure index (AAI, ratio of ankle to arm systolic blood pressure), a simple, noninvasive, and inexpensive screening test, has recently been found to be highly predictive of subsequent mortality in several populations. The purpose of this study was to evaluate the relationship of the AAI to cardiovascular and all-cause mortality in hemodialysis patients. A cohort of 132 patients was followed for 1 year. The primary outcome measures were cardiovascular and all-cause mortality. An AAI of <0.9 was associated with a relative risk (RR) of cardiovascular mortality of 7.5, (95% CI, 2.3 to 24.8). Other predictive variables included diabetes mellitus RR 3.0, (95% CI, 1.2 to 7.3), and a history of any vascular disease RR 2.6 (95% CI, 1.0 to 7.0). An AAI of <0.9 was also predictive of all-cause mortality, RR 2.4 (95% CI, 1.2 to 4.7). Other predictive variables for all-cause mortality included older age, RR 1.4 per 10 years (95% CI, 1.0 to 2.1), decreased serum albumin RR 0.9 per 0.1 mg/dL (95% CI, 0.8 to 1.0), and diabetes mellitus RR 2.0 (95% CI, 1.0 to 3.7). Multivariate analysis showed an AAI of <0.9 and diabetes mellitus to be the only independent predictors of cardiovascular mortality, and an AAI of <0.9, older age, and a decreased serum albumin were independent predictors of all-cause mortality. In conclusion, we have found an AAI of <0.9 to be a powerful, independent predictor of mortality in hemodialysis patients.

Biochemical and hormonal variables in black and white women matched for age and weight

Weight and age may influence the levels of indexes of bone remodeling and the calciotropic hormones. In a study of interracial differences in these women, our black population was heavier than our white population. We therefore matched a subset of 96 black and 96 white women from our larger population for age and weight to determine whether a racial difference exists independent of the effects of weight and age. In addition, we were able to measure other indexes of bone remodeling (N-telopeptide of cross-linked collagen and pyridinoline cross-links), as well as hormones that may influence calcium metabolism (insulin-like growth factor-1 (IGF-1), insulin, calcitonin, and gastrin) in this subset. All indexes of bone remodeling were lower in black women. Black postmenopausal women had lower serum levels of calcidiol and higher parathyroid hormone (PTH) levels. The higher bone mass of black women is associated with lower bone remodeling in the presence of skeletal resistance to PTH. Serum IGF- 1, insulin, and calcitonin levels did not differ significantly between races. Serum gastrin levels were higher in black women. The higher levels of gastrin in black women should be investigated further for its possible effect on the absorption of calcium salts.

Self-Assessed Quality of Life in Peritoneal Dialysis Patients

Background/Aims: Studies comparing quality of life (QOL) between peritoneal and hemodialysis patients have yielded inconsistent results. Physical (PCS) and mental component summary (MCS) scales of Short Form 36 (SF-36) health survey are highly validated measures of self-assessed QOL. We sought to evaluate these indices in PD patients: (1) as measures of QOL, (2) predictors of QOL, (3) to study change in QOL over time, and (4) to compare QOL in PD vs. hemodialysis patients. Methods: SF-36 questionnaires were administered every 3 months to patients over a 2-year period and PCS and MCS were calculated. Mean follow-up was 15.3 ± 6.6 months for PD and 14.5 ± 5.7 months for HD. Results: Average PCS in PD (31.8 ± 7.8) was lower than HD (36.9 ± 9.8) (p < 0.02), while MCS was similar in the groups (p = NS). The prevalence of depression was 26.1% in PD and 25.4% in HD patients (p = NS). Serum albumin was the only significant predictor of PCS among PD patients and explained much of the decrease in PCS in them. The number of hospitalizations and in-hospital days were significantly lower for PD compared to HD patients (p < 0.05). PCS as well as MCS remained stable in both groups throughout the observation period. Conclusion: Self-assessed physical function is diminished, while mental function is similar in PD compared to HD patients. When corrected for serum albumin, this difference is eliminated. Over time, QOL in patients treated with PD remained stable.

Body Composition by Dual-Energy X-ray Absorptiometry in Black Compared with White Women

Abstract: Dual-energy X-ray absorptiometry (DXA) has recently been applied to the measurement of body composition using a three-compartment model consisting of fat, lean and bone mineral. The mass of skeletal muscle may be approximated by measurement of the lean tissue mass of the extremities. In addition, body fat distribution can be estimated by determining the ratio of fat in the trunk to the fat in the extremities. In the current study, DXA was used to compare body composition and fat distribution between black (n= 162) and white women (n= 203). Black women had a higher mineral mass and a higher skeletal muscle mass. The ratio of mineral to muscle mass was higher in black women, even when the data were adjusted for age, height and weight. Both total body bone mineral and muscle mass declined with age in both races, with evidence for an accelerated loss of bone mineral after menopause. Body size (height and weight) was generally a significant variable in developing regressions of each compartment against age. Their higher musculoskeletal mass may lead to misclassification of 12% of black women as obese if body mass index is used as an index of obesity. Body fat distribution (trunk/leg) did not differ between races in the raw data. However, for women of the same age, height and weight, white women have a significantly higher trunk/leg fat ratio. Body composition values for fat, lean and bone mineral obtained from DXA should be adjusted not only for gender but also for age, height, weight and ethnicity.

Presence of Fever and Leukocytosis in Acute Cholecystitis

STUDY OBJECTIVE To determine the frequency of fever and leukocytosis in patients presenting to the emergency department with acute cholecystitis (AC). METHODS We carried out a retrospective review of charts from 1990 to 1993 at a university-affiliated hospital. Our subjects were ED patients with hepato-iminodiacetic acid (HIDA) scans interpreted as showing AC and who had undergone cholecystectomy during hospitalization. Final diagnosis was determined on the basis of the pathology report. Fever was defined as an oral temperature of 100 degrees F (37.7 degrees C) or greater or a rectal temperature of 100.4 degrees F (38.0 degrees C) or greater. Leukocytosis was defined as a WBC count of 11,000/mm3 or greater. RESULTS Of the 198 cases studied, the pathologic diagnosis of nongangrenous AC was made in 103 (52%), gangrenous AC was diagnosed in 51 (26%), and chronic cholecystitis was diagnosed in 44 (22%). In patients with nongangrenous AC, 71% were afebrile, 32% lacked leukocytosis, and 28% lacked fever and leukocytosis. In patients with gangrenous AC, 59% were afebrile, 27% lacked leukocytosis, and 16% lacked fever and leukocytosis. CONCLUSION We found that patients with AC diagnosed in the ED frequently lacked fever or leukocytosis. The clinician should not rely on the presence of these signs in making the diagnosis of acute cholecystitis.

Stiffness in Discrimination of Patients with Vertebral Fractures

Abstract: We measured the ultrasound parameters of the heels of 49 women with vertebral fractures and 87 age-matched controls using an Achilles ultrasound device. Average broadband ultrasound attenuation (BUA), speed of sound (SOS) and Stiffness were significantly lower in fracture patients (p<0.0001). We also estimated the ultrasound parameters of patients compared with age-matched non-fracture controls and found the mean BUA to be −1.02 SD below control values. The mean SOS was −0.97 SD and the mean Stiffness was −1.12 SD below control values. Femoral bone mineral density (BMD) at the neck, Ward’s triangle and the trochanter, the total-body BMD and L2–4 BMD were measured with dual-energy X-ray absorptiometry (DXA) and found to be significantly lower in fracture patients (p<0.0001). All correlation coefficients between ultrasound parameters and DXA measurements were >0.5 and statistically significant (p<0.0001). A stepwise logistic regression with presence or absence of vertebral fracture as the response variable and all ultrasound – DXA parameters as the explanatory variables indicated that the best predictor of fracture was Stiffness, with additional predictive ability provided by spine BMD. Sensitivity and specificity of all measures were determined by the areas under the receiver operating characteristic (ROC) curve, which were 0.76 ± 0.04 for BUA, 0.77 ± 0.04 for SOS, 0.78 ± 0.04 for Stiffness and 0.78 ± 0.03 for spine BMD. The areas under the ROC curves of BUA, SOS, Stiffness and spine BMD were compared and it was found that Stiffness and spine BMD were significantly better predictors of fracture than BUA and SOS. These results support many recent studies showing that ultrasound measurements of the os-calcis have diagnostic sensitivity comparable to DXA, and also demonstrated that Stiffness was a better predictor of fracture than spine BMD.

Discordance Between Ultrasound of the Calcaneus and Bone Mineral Density in Black and White Women

Abstract. Black women have 40% of the incidence rate for hip fracture and have a higher bone mineral density (BMD) than white women. The possibility was raised that bone quality may be disproportionately greater than the advantage in bone density in protection against osteoporotic fractures in black versus white women. Ultrasound (US) of the calcaneus is believed to measure properties of bone in addition to its density. We performed bone density measurements and US of the calcaneus in 108 black and 177 healthy white women, aged 20–70 years. The highest correlation was seen between total body bone density and speed of sound (r = 0.75). The interracial differences in BMD were all statistically significant and varied from 3.4 to 7.6%. The US measurements had lesser interracial differences than the bone density measurements, with velocity barely different between races. These findings suggest that US of the calcaneus measures properties of bone different from density. Fracture prediction data using US from prospective data in white women should not be extrapolated to black women because of the discordance between bone density and US measurements. Prospective studies are needed comparing US measurements in black women to the occurrence of osteoporotic fractures.