Ashok Vaswani

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.

Coherence treatment of postmenopausal osteoporosis with growth hormone and calcitonin

SummaryFourteen women with postmenopausal osteoporosis, all having at least one vertebral crush fracture, were randomly assigned to two treatment arms, each lasting 24 months. The coherence treatment group (7 patients) was treated in the following sequence: human growth hormone (hGH) 7 IU subcutaneously daily for 2 months, followed by 3 months of salmon calcitonin (CT), 100 MRC units every other day. After a 3 month rest period, this sequence was repeated twice. The contrast group (7 patients) was treated intermittently with salmon CT given in the same time periods and at the same dose as in the coherence treatment group. Bone mass was measured every 4 months by neutron activation analysis for total body calcium (TBCa) and by single photon absorptiometry for bone mineral content (BMC) of the distal radius. Although there were no significant differences between the two groups (two-way ANOVA), the rate of change in TBCa in the coherence treatment group was significantly different from zero (F=3.8,P<.05) and was +2.3%/year. The increase in bone mass appeared to be sustained throughout the 2 year study, in contrast with previous studies where a plateau effect was observed with calcitonin given alone or continuously with growth hormone. No significant change was found in bone histomorphometric values measured before and after treatment in 4 patients from each group.

Racial differences in femoral dimensions and their relation to hip fracture

White women have a higher rate of age-specific hip fractures than black women. Recently, femoral dimensions have been implicated in osteoporotic fractures. To study racial differences in femoral dimensions, dual X-ray absorptiometry scans were obtained for two similar groups of 50 white women and 50 black women. We measured the hip axis length (the distance from below the lateral aspect of the greater trochanter to the inner pelvic brim), the neck width and the neck/shaft angle on the scan print-out. The observer was masked to the race of the subject. The results were analyzed using the independentt-test and showed that the hip axis length and the neck width were significantly longer in the white women than in the black women (p values <0.05 and <0.02 respectively) but that the neck/shaft angle was not statistically different in the two groups. We conclude that femoral geometry differs among races. Whether this contributes to the lower risk of hip fracture in black women will require prospectively based studies.

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.

A multi-center comparison of dual energy X-ray absorptiometers: In vivo and in vitro soft tissue measurement

Objective: To assess intra- and inter-site soft tissue variability by dual energy X-ray absorptiometry (DXA). Design: Cross-sectional trial. Setting: Three medical research institutions. Subjects: Five humans (in vivo) and four phantoms (in vitro), configured from two whole body phantoms with artificial skeletons and thickness overlays. Interventions: Duplicate total-body DXA scans were performed on all subjects at each institution within a 15 d period. Results: All intra-site coefficients of variation (CV) were <0.5% for total tissue mass, but in vitro and in vivo Cvs were 7.2% and 2.3% for fat mass (FM) and 2.5% and 0.9% for lean mass (LM), respectively. Several total-body and regional FM and LM measurements were significantly different between sites (P < 0.05), with percent differences between sites ranging from 2.6–13.3% for FM and from 1.6–13.6% for LM. Site 2 was consistently lower for FM and Site 3 was consistently lower for LM. Conclusions: These results stress the need for both rigorous and standardized cross-calibration procedures for soft tissue measurement by DXA. Sponsorship: This work has been supported in part by NIH Training Grant #T32AG00209, grant P01-DK42618 from the National Institutes of Health, federal funds from the US Department of Agriculture, and Agricultural Research Services contract 53-3K06-5-10. Dr Nelson is currently a Brookdale National Fellow.

Coexisting hyperparathyroidism with thyrotoxicosis

The coexistence of hyperparathyroidism complicating thyrotoxicosis is quite rare. We report the case of one patient who presented with thyrotoxicosis, (total thyroxine of 15.1 µg/dl (5–13), free thyroxine index of 18 (4–15) and triiodothyronine by RIA of 305 ng/dl (70–230) and asymptomatic hypercalcemia of 15 mg/dl (8.5–10.6), who was also initially noted to have an elevated (C-terminal) serum immunoreactive parathyroid hormone (iPTH) level of 8,800 pg/ml (50–340). With propylthiouracil and propranolol, however, this patient became normocalcemic with a decrease in iPTH values to 714 pg/ml. As the patient was tapered from medication, after being rendered euthyroid, a recurrence of hypercalcemia with rising iPTH levels occurred. PTH levels should be helpful in defining coexisting hyperparathyroidism in patients with thyrotoxicosis since in the latter iPTH is usually suppressed. Our findings support the recommendation that in patients suspected of having both hyperparathyroidism and hyperthyroidism, a diagnosis of the former can only be made with certainty after the patient has been rendered euthyroid with persistently elevated serum calcium and iPTH levels. While there are no clinical features which permit the easy identification of patients who present with dual lesions, the determination of iPTH values may be the most consistently helpful test initially, whereas other parameters such as vitamin D, serum phosphate are less reliable.

Combination Therapy for Osteoporosis with Estrogen, Fluoride, and Calcium*

Nine women with postmenopausal spinal osteoporosis were treated with combination therapy consisting of estrogen, fluoride, and calcium. Their data were compared with those of a control group treated with fluoride and calcium without estrogen. Bone mass was measured about every six months by photon absorptiometry [bone mineral content/bone width (BMC/BW)] and total‐body neutron activation analysis [total‐body calcium (TB Ca)]. Time‐trend analysis revealed positive slopes for TB Ca (P = 0.002) and BMC/BW (P = N.S.) for the combination therapy group. The change in BMC/BW in the combination therapy group was significantly different from the response in the fluoride‐calcium group. These data suggest that combination therapy may be successful in increasing bone mass in postmenopausal osteoporosis. A clinical trial to establish efficacy and examine risk/benefit ratios should be performed.

Differential effects of dietary calcium augmentation and hormone replacement therapy on bone turnover and serum levels of calcitrophic hormones

The mechanism of action of retardation of postmenopausal bone loss may be different for dietary calcium augmentation and hormonal replacement therapy (HRT). We performed a three-arm, placebo-controlled, randomized clinical trial comparing an intake of calcium of 1700 mg with: (1) calcium augmentation with HRT and (2) placebo. One hundred and eighteen women entered the study; 17 patients dropped out of the study. The vast majority of women were less than 2 years postmenopause. Bone mineral density declined significantly in the placebo group. The previously reported rates of change in the HRT group were significantly positive for total body calcium and the trochanter and not significantly different from zero for the others. The rate of change in the calcium augmentation group was intermediate between that in the two other groups, and achieved statistical significance compared with placebo for the total body calcium measurement and for the neck of the femur. Measurements were made prior to treatment and at the end of the study (2.9 years ±1.1 SD) for parameters of bone turnover and the calcitrophic hormones, to examine whether the mechanism of action was different for calcium augmentation versus hormonal therapy. There were no changes in the placebo group. The calcium augmentation group had a significant increase in 24-h urinary calcium and declining values for urinary collagen cross-links (pyridi-nium and deoxypyridinium), urinary hydroxyproline and calcitriol. The group treated with HRT and dietary calcium augmentation also had an increase in urinary calcium and a decline in collagen cross-links and urinary hydroxyproline and skeletal alkaline phosphatase; serum calcitriol did not change. The HRT group also displayed a drop in serum osteocalcin, and an increase in nephrogenous cAMP. Serum parathyroid hormone remained unchanged in all groups. Dietary calcium augmentation retards postmenopausal bone loss by decreasing resorption. The addition of HRT results in a more marked decline in bone resorption parameters and a suppression of parameters of bone formation. Whereas calcium augmentation suppressed calcitriol levels, the addition of HRT resulted in maintenance of calcitriol levels, possibly through enhancement of the renal effects of parathyroid hormone, although other mechanisms are possible.