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Background Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences. Objective To compare the effects of 4 doses of vitamin D3 supplements on falls. Design 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333). Setting 2 community-based research units. Participants 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L. Intervention 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D3 doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose. Measurements Time to first fall or death over 2 years (primary outcome). Results During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d; n = 308) and those randomly assigned to receive 200 IU/d (n = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15]; P = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46]). Limitations The control group received 200 IU of vitamin D3 per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached. Conclusion In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D3 supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D3 doses of 1000 IU/d or higher. Primary funding source National Institute on Aging.

BACKGROUND There are few controlled studies of the effect of different doses of vitamin D3 on bone mineral density (BMD). OBJECTIVES We conducted a randomized placebo-controlled trial of increasing doses of vitamin D3 in 163 Caucasian and 31 African American women with serum 25-hydroxyvitamin D (25OHD) ≤50 nmol/L. This is an analysis of secondary outcome BMD to see if there is an association between percent change in BMD and dose of vitamin D3. METHODS Participants were randomly assigned to placebo, vitamin D3 400, 800, 1600, 2400, 3200, 4000, or 4800 IU/day; calcium supplements, average 600mg, were given to provide a total calcium intake of 1200 mg/d. The primary outcome was 12-month serum 25OHD level. Analysis methods include ANOVA and Pearson correlations. RESULTS The mean percent increase (±SD) in BMD at 12 months for all women was small; total body, 0.62% (± 2.72), femoral neck 0.59% (±3.58) and spine 0.43% (±2.80). There was no difference in BMD or serum N-telopeptide in response to vitamin D by dose or race. The increase in total body, spine and hip BMD in elderly women given vitamin D doses between 400 and 4800 IU daily and calcium supplementation is small, unrelated to dose or 12-month serum 25OHD, free 25OHD or 1,25(OH)2D. There was no evidence of a threshold change in BMD with increasing serum 25OHD or free 25OHD in this population. CONCLUSIONS We found no significant effect of daily vitamin D dose ranging from 400 to 4800 IU/day on BMD or serum N-terminal telopeptides in elderly women with initially low serum 25OHD.

BACKGROUND: It is questionable as to whether total serum 25 hydroxyvitamin D (T25D) levels are lower in African Americans. We measured serum T25D, free 25hydroxyvitamin D (F25D), and serum parathyroid hormone (PTH) in African American and Caucasian women and studied the effect of vitamin D dosing to determine if differences by race or age occur. METHODS: Healthy young and older Caucasian and African American women who were vitamin D insufficient were randomized in two clinical trials to escalating daily doses of vitamin D from 400 IU - 4800IU and placebo for 12 months. RESULTS: Baseline F25D and T25D were significantly lower in young but not older African American compared to Caucasian women. At baseline the rate of change (slope) in F25D with T25D was significantly greater in younger women than in older women, but difference in the rate of change (slope) in F25D with T25D is similar in African American and Caucasian women. After vitamin D supplementation there was an increase in F25D, and the dose response was not significantly different by age or race. The ratio of F25D/T25D decreased in all groups once T25D exceeded ~ 60nmol/L. There was a progressive decrease in serum PTH with increasing vitamin D doses and the percent change was similar for F25D and T25D. CONCLUSION: Serum F25D and T25D are lower in younger African American women and since dietary vitamin D is similar in the groups, it is likely that the cause of low serum 25OHD in African American women is due to reduced UV exposure and reduced skin production of vitamin D.

In 1970, there were no drugs under study for osteoporosis. Estrogen was used, but little was known about the correct dose for preventing bone loss. At that time, fractures were not even recognized as a disease, but regarded as part of normal aging. From 1970 to this year (2018), there have been extensive advances in the osteoporosis field ranging from fracture epidemiology to the remarkable invention of bone density measurements. There have been major advances in therapeutic options available for patients for prevention and treatment of osteoporosis. In parallel, the advances in the laboratory helped elucidate the process of bone remodeling, not only at the macroscopic level but also at the cellular level. This led to rapid advances in translational research from cellular biology to new therapies exemplified by the development of monoclonal antibodies for osteoporosis. Further understanding of the signaling pathways in bone cells will lead to new small molecules made for osteoporosis treatment, perhaps causing less adverse events. University-based research throughout the world has been a leader in most of these advances, and Pharma support for phase 1 to 4 studies helped bring these discoveries to patients. In the osteoporosis field alone, one sees the tremendous value of grant support for university research by National funding agencies such as the National Institute of Health in this country and similar agencies in other countries. There are clinical challenges that have to be solved with long-term compliance with osteoporosis medication if we want to reduce fracture incidence in the long term.

Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies.We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary.A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P

OBJECTIVE A post hoc exploratory analysis was conducted to examine correlations between changes in bone density, bone markers, and hot flushes after the treatment of postmenopausal women with bazedoxifene (BZA)/conjugated estrogens (CE). METHODS In a 2-year phase 3 study, 3,397 postmenopausal women were randomized to BZA 10 mg/CE 0.45 mg, BZA 20 mg/CE 0.45 mg, BZA 40 mg/CE 0.45 mg, BZA 10 mg/CE 0.625 mg, BZA 20 mg/CE 0.625 mg, BZA 40 mg/CE 0.625 mg, raloxifene 60 mg, or placebo. In this analysis, bone density changes at 2 years were compared with baseline levels of the bone markers serum C-telopeptide and osteocalcin. Correlations between changes in bone density and changes in 12-week hot flush composite scores in symptomatic women were also analyzed. RESULTS Treatment with BZA 20 mg/CE 0.45 mg or BZA 20 mg/CE 0.625 mg increased lumbar spine bone density more in women with higher bone resorption and formation, categorized by baseline levels of C-telopeptide and osteocalcin (P < 0.001, both BZA/CE doses). With placebo, larger decreases in lumbar spine bone density were seen in the highest tertile of serum C-telopeptide. There was no correlation between changes in total hip bone density and baseline bone markers. There were significant correlations between percent change in hot flush score at week 12 and percent changes in lumbar spine (r = -0.31, P = 0.006) and total hip (r = -0.23, P = 0.044) bone densities at month 24. CONCLUSIONS With 2-year BZA/CE treatment, women with larger increases in lumbar spine and total hip densities also have higher baseline bone markers. Early reductions in hot flush score (12 wk) are predictive of long-term increases in bone density (24 mo).

The recent concept that estrogen agonist-antagonists, often referred to as selective estrogen receptor modulators, can be combined with an estrogen has led to the development of a novel form of menopausal therapy called Tissue-Selective Estrogen Complex (TSEC). This paper reviews the TSEC bazedoxifene and conjugated equine estrogens (BZA/CE).This review is based on clinical trials and a PubMed search. The pharmacokinetics and pharmacodynamics of BZA in BZA plus CE are reviewed. This review outlines the effects of this particular TSEC, which maintains or increases bone mineral density in women at high risk for osteoporosis, and has clinical qualities of a promising new menopausal therapy. The potential adverse effects of BZA/CE combinations are summarized.A TSEC that contains CE and BZA that has both estrogen agonist and antagonist effects has reached clinical development. Phase III clinical trials show this TSEC relieves hot flashes, improves vulvo-vaginal atrophy and its symptoms, does not stimulate the endometrium, and prevents bone loss. In the trials so far it appears to have a good safety and tolerability profile. The optimum combination of BZA/CE combination is 20 mg BZA with CE 0.45 and 0.625 mg daily.

Although the menopause has been associated with increased bone loss at several skeletal sites, it has not previously been noted in the hip, yet estrogen therapy has been reported to reduce the incidence of hip fractures. We investigated the effect of age and menopause on bone loss in the proximal femur by measuring bone mineral density (BMD) of the femoral neck, Ward's triangle, and trochanter by dual-photon absorptiometry in 263 normal women aged 20-84. Multiple regression analyses revealed a significant decrease in BMD of the femoral neck and Ward's triangle with age in both pre- and postmenopausal women (p less than 0.001). In the trochanter the decrease with age was significant only in postmenopausal women (p less than 0.001). Further analysis revealed that BMD decreased faster at all sites in the early postmenopausal years. During the first 6 years postmenopause, the decrease in BMD of the femoral neck and trochanter was 3-10 times higher than the change in the decade prior to menopause. About 20% of the lifetime femoral neck loss and 30% of the trochanteric loss occurred in the early postmenopausal period. It is concluded that both age and menopause are major determinants of BMD in the proximal femur. These findings could explain why estrogen therapy has been reported to prevent hip fracture. The rapid early postmenopausal loss in BMD of the proximal femur demonstrates the importance of starting estrogen replacement therapy immediately after menopause for maximum effect.

This study is the first reported administration of 1α-hydroxyvitamin D2 (1α-OHD2) to human subjects. A total of 15 postmenopausal osteopenic women were given increasing oral doses of 1α-OHD2, beginning with a low dose of 0.5 μg/day. In 15 subjects, the doses were raised at weekly intervals to 1.0, 2.0, 4.0, and 5.0 μg/day, and in 5 of these subjects, the dose was further increased to 8.0 or 10.0 μg/day. Mean urine calcium ± SEM showed a dose-related increase from 134 ± 17 mg/24 h on 0.5 μg/day to 198 ± 21 mg/24 h on 4.0 μg/day (p 350 mg/24 h, the upper limit of the laboratory normal range) at doses less than 5.0 μg/day; 5 subjects had hypercalciuria at or above 5.0 μg/day (3 at 5.0 μg/day, 1 at 8.0 μg/day, and 1 at 10.0 μg/day). Mean serum calcium increased slightly on the 4.0 μg dose only (p < 0.05) but remained well within the normal range. Mean creatinine clearance and BUN, used as measures of renal function, showed no significant changes. Routine blood and urine assays also showed no significant changes. Serum osteocalcin, a marker of osteoblast activity, showed mean ± SEM dose-related increases of 10 ± 7% on 1.0 μg/day (p < 0.05), 19 ± 7% on 2.0 μg/day (p < 0.05), 21 ± 6% on 4.0 μg/day (p < 0.05), and 28% on 5.0 μg/day (p < 0.05); in the 5 subjects receiving higher dosages, mean serum osteocalcin increased 32 ± 12% on 8.0 μg/day and 55 ± 29% on 10.0 μg/day. Mean urine hydroxyproline/creatinine ratios did not change significantly at any dose of 1α-OHD2 but trended downward with increasing dosages. These findings indicate that 1α-OHD2 is well tolerated at dosages that stimulate osteoblastic activity, as evidenced by increased serum osteocalcin, and that 1α-OHD2 may be a useful agent for treating postmenopausal osteoporosis.

Objective Postmenopausal decreases in body composition, physical performance, and bone mass have been shown to be reversed by estrogen, but given the concerns regarding its use, women are looking for alternatives such as soy isoflavones. Most studies on the effects of soy on bone mineral density (BMD) in postmenopausal women have been short-term, that is, 3 to 6 months, and failed to provide conclusive evidence. There is no evidence of its effects on physical performance. The aim of the present study was to investigate the effects of soy plus isoflavones on BMD and physical performance in postmenopausal women. Methods This was a 2-year randomized controlled trial. A total of 203 healthy postmenopausal women were given either 25 g of soy protein without isoflavones, 25 g of soy protein with 90 mg of isoflavones, or 25 g of milk protein (casein and whey) as a control agent for 24 months. Women were followed every 6 months with BMD and physical performance measurements for 2 years. Primary analysis was intent-to-treat analysis. Analysis of variance, chi and Fisher's exact tests, and analysis of covariance were used. Results There was a significant decrease in the BMD of the lumbar spine and femoral neck in those who completed the study in all groups. Soy isoflavones prevented major bone loss from baseline at the femoral trochanter with no between-group significance. Physical performance measurements decreased in all the groups. Conclusions : Twenty-five grams of soy protein with 90 mg of isoflavones has no added benefit in preventing bone loss or improving physical performance.

Objectives A history of prior fracture is one of the strongest predictors of a future fragility fracture. In FREEDOM, denosumab significantly reduced the risk of new vertebral, non-vertebral, and hip fractures. We carried out a post-hoc analysis of FREEDOM to characterize the efficacy of denosumab in preventing secondary fragility fractures in subjects with a prior fracture.Methods A total of 7808 women aged 60–90 years with a bone mineral density T-score of less than − 2.5 but not less than − 4.0 at either the lumbar spine or total hip were randomized to subcutaneous denosumab 60 mg or placebo every 6 months for 36 months. The anti-fracture efficacy of denosumab was analyzed by prior fracture status, to assess secondary fragility fracture, and by subject age, prior fracture site and history of prior osteoporosis medication use.Results A prior fragility fracture was reported for 45% of the overall study population. Compared with placebo, denosumab significantly reduced the risk of a secondary fragility fracture by 39% (incidence, 17.3% vs. 10.5%; p < 0.0001). Similar results were observed regardless of age or prior fracture site. In the overall population, denosumab significantly reduced the risk of a fragility fracture by 40% (13.3% vs. 8.0%; p < 0.0001), with similar results observed regardless of history of prior osteoporotic medication use.Conclusions Denosumab reduced the risk of fragility fractures to a similar degree in all risk subgroups examined, including those with prior fragility fractures. Identifying and treating high-risk individuals could help to close the current care gap in secondary fracture prevention.

Purpose: It is desirable for clinicians to know what bone mineral density (BMD) response they can expect in women treated with osteoporosis therapies. The focus of this analysis was to determine what percentage of women attained a lumbar spine BMD response to teriparatide that equaled or exceeded the least significant change (LSC) value of 3%. Methods: Data from three clinical trials involving postmenopausal women with osteoporosis were examined. The Fracture Prevention Trial was a double-blinded, placebo-controlled clinical trial examining the safety and efficacy of teriparatide 20 and 40 μg/day. The other two trials were double-blinded, head-to-head comparisons of alendronate 10 mg/day and teriparatide 20 or 40 μg/day, respectively. Only treatment-compliant women who had lumbar spine BMD measurements at all specified time points in these trials were included. For reference, we also examined the percentage of women with lumbar spine BMD responses to alendronate. Hip BMD responses that equaled or exceeded 3% were also examined. Results: According to the LSC criteria, 91% of the teriparatide 20 μg/day group and 94% of the teriparatide 40 μg/day group were lumbar spine BMD responders at 18 months in the Fracture Prevention Trial. In the teriparatide 20 μg/alendronate head-to-head trial, 94% of women receiving teriparatide had a lumbar spine BMD response that equaled or exceeded the 3% criterion at 18 months compared to 75% of those receiving alendronate 10 mg/day (p

Objective This study aims to prospectively assess the incidence of hypercalciuria and hypercalcemia with different doses of vitamin D and with a calcium intake of approximately 1,200 mg/day. Methods This was a 1-year randomized placebo-controlled study of vitamin D (400-4,800 IU/d) in 163 white women aged 57 to 90 years. Calcium citrate tablets (200 mg) were added to the diet to achieve a total calcium intake of approximately 1,200 mg/day in all groups. All women had vitamin D insufficiency at baseline, with serum 25-hydroxyvitaminD levels lower than 20 ng/mL (50 nmol/L). Serum and 24-hour urine calcium were collected every 3 months on supplementation, any test result above the upper reference range represented an episode of hypercalcemia or hypercalciuria. Mixed-effects models and multivariate logistic regression were used in the analysis. Results Hypercalcemia (>10.2 mg/dL [2.55 mmol/L]) occurred in 8.8% of white women. Hypercalciuria (>300 mg/d [7.5 mmol]) occurred in 30.6% of white women. Episodes of hypercalciuria were transient in half of the group and recurrent in the other half. No relationship between hypercalcemia or hypercalciuria and vitamin D dose was found, and hypercalciuria was equally common in the placebo group. Conclusions Hypercalciuria and hypercalcemia commonly occur with vitamin D and calcium supplements. Whether hypercalciuria and hypercalcemia are caused by calcium, vitamin D, or both is unclear. These findings may have relevance to the reported increase in kidney stones in the Women's Health Initiative trial. Because calcium 1,200 mg and vitamin D 800 IU/day are widely recommended in postmenopausal women, systematic evaluation of the safety of supplements is warranted in clinical management and in future studies.

Vitamin D 2 and D 3 are generally considered equipotent in humans. As Vitamin D 2 supplements are commonly used by elderly in United States, we determined the contribution of 25OHD 2 to the total serum 250HD levels by HPLC in elderly women who reported taking Vitamin D 2 supplements (n = 56) and also in a group of randomly selected unsupplemented women (n = 60). In addition, we compared the total serum 250HD measured by HPLC with competitive protein-binding assay (CPBA), a method routinely employed to measure Vitamin D status. A correlation of 0.91 (P < 0.001) was observed between the two methods for the serum total 250HD measurement. The mean serum 250HD level in Vitamin D 2 supplemented group was significantly higher than in unsupplemented group measured by HPLC (32 versus 28 ng/ml) and marginally higher measured by CPBA (33 vs. 31 ng/ml). Seventy eight percent of women taking Vitamin D 2 supplements had appreciable amounts of circulating 250HD 2 , which constituted about 25 percent of their total serum 250HD. It is also interesting to note that Vitamin D deficiency was less prevalent in elderly women taking Vitamin D 2 supplements (1.8%) compared to women not taking any supplements (12%).

The association between the restriction length polymorphisms of the Vitamin D receptor (VDR) gene and the bone mineral density (BMD) or the rate of bone loss is still under debate. In a longitudinal study of untreated postmenopausal elderly women, we evaluated the relationship between the VDR gene polymorphisms (BsmI, TaqI, ApaI, and FokI) and the rate of bone loss over a 3-year period. We also examined the effect of adjustments for dietary and lifestyle factors on these associations. Before adjustments, the rate of femoral neck bone loss was - 3.76 +/- 1.58% in women with BB genotype and 0.45 +/- 0.65% in women with bb genotype, which was not significantly different. Upon adjustment for dietary and lifestyle factors, statistically significant (P = 0.03) bone loss was observed at femoral neck in women with BB genotype (- 3.66 +/- 2.44%) compared to that of bb genotype (2.39 +/- 1.32%). Similar results were observed with TaqI genotypes. The rates of bone loss at other skeletal sites were not different between VDR genotypes defined by BsmI and TaqI. VDR gene polymorphisms defined by ApaI and FokI were not related to the rate of bone loss.

Vitamin D2 and D3 are generally considered equipotent in humans. A few studies have reported that serum 25OHD levels are higher in vitamin D3- compared with vitamin D2-supplemented subjects. As both vitamin D2 and D3 supplements are commonly used by elderly in United States, in the present study we determined the effect of self-reported vitamin D2 and vitamin D3 supplement use on serum total 25OHD levels according to season in elderly women aged 65-77 years. Serum total 25OHD levels were determined in winter and summer in unsupplemented women ( N = 307) and in women who reported taking vitamin D2 ( N = 56) and vitamin D3 ( N = 55) supplements by competitive protein binding assay. In vitamin D2-supplemented women, the contribution of vitamin D2 and D3 to the mean serum total 25OHD level was assessed by HPLC. In summer, there were no significant differences in the mean total serum 25OHD levels (ng/ml) among the vitamin D2 (32 +/- 2.1), vitamin D3 (36.7 +/- 1.95), and unsupplemented (32.2 +/- 0.95) groups. In winter, the mean serum total 25OHD levels were higher in women on vitamin D2 (33.6 +/- 2.34, P0.05) and vitamin D3 (29.7 +/- 1.76, NS) supplements compared with unsupplemented women (27.3 +/- 0.72). In vitamin D2-supplemented women, about 25% of the mean serum total 25OHD was 25OHD2, in both summer and winter. Twelve percent of unsupplemented women and 3.6% of vitamin D-supplemented women had a mean serum total 25OHD level below 15 ng/ml in winter. In elderly subjects, both vitamin D2 and Vitamin D3 supplements may contribute equally to circulating 25OHD levels, with the role of vitamin D supplement use being more predominant during winter.

The concern for the development of breast cancer, stroke, cardiovascular disease and deep venous thrombosis with the use of hormonal therapy has led to the development of alternative nonhormonal forms of therapy like desvenlafaxine for the management of hot flashes.This review is based upon a PubMed search and clinical trials. The pharmacokinetics and pharmacodynamics of desvenlafaxine are reviewed. This review outlines the effects of desvenlafaxine in management of severity and frequency of vasomotor symptoms, sleep quality and quality of life in postmenopausal women. The potential adverse effects of desvenlafaxine are summarized.Based on the evidence from randomized clinical trials, desvenlafaxine is an alternate viable option for reducing the frequency and severity of hot flashes when other treatments fail. In clinical trials, it has been shown that desvenlafaxine reduced the frequency of hot flashes by 55 - 69%. In the trials so far it appears to have good safety and tolerability profile when the drug is initiated in titrating doses. The optimum dose is 100 mg/day and is to be started at 50 mg/day for 3 days and titrated to 100 mg/day. The most common adverse events reported were nausea, dry mouth, fatigue, constipation, diarrhea and somnolence.

OBJECTIVE To determine whether there are differences between continuous combined hormone replacement therapies on bleeding control. DESIGN Nine hundred and forty-five postmenopausal women were randomized to one of seven double-blind treatment groups (placebo, 0.25 mg norethindrone acetate (NA)/5 microg ethinyl estradiol (EE), 1 mg NA/5 microg EE, 0.5 mg NA/10 microg EE, 1 mg NA/10 microg EE, 5 microg EE, and 10 micro EE) or unmasked 0.625 mg conjugated equine estrogens (CEE)/2.5 mg medroxyprogesterone acetate (MPA). Treatment was for 12 months; subjects kept daily diaries recording whether they had bleeding and/or spotting. RESULTS The results focused on currently commercially available hormone replacement therapy products (femhrt [1 mg NA/5 microg EE] and Prempro [0.625 mg CEE/2.5 mg MPA]) as well as a high-dose NA/EE dose combination (1/10) over the first 6 months of use, the most critical period in establishing treatment adherence. At the end of month 6 there was a greater incidence of amenorrhea with both NA/EE dose combinations compared with CEE/MPA (p = 0.009 for 1 mg NA/5 microg EE and p = 0.006 for 1 mg NA/10 microg EE). Statistically significantly more women were amenorrheic at every month based on cumulative amenorrhea for 1 mg NA/5 microg (p < 0.05) compared with CEE/MPA; at months 3 and 6 more women were amenorrheic on 1 mg NA/10 microg EE compared with CEE/MPA using the cumulative amenorrhea parameter. CONCLUSIONS The results indicate that statistically significantly more women attained amenorrhea based on various parameters when administered continuous combined NA/EE compared with CEE/MPA. The potential for long-term treatment compliance based on better bleeding control may optimize the opportunity to prevent osteoporosis as well as other associated health benefits.

Background: Published reports on the effect of alcohol consumption on bone mineral density (BMD) are inconsistent. Objective: The objective of this study was to examine the relation between alcohol intake and BMD, calcitropic hormones, calcium absorption, and other biochemical indexes of bone and mineral metabolism in elderly women. Design: The results presented are derived from baseline observations of 489 elderly women (aged 65-77 y) recruited for an osteoporosis study. The nondrinking group comprised 297 women and the drinking group comprised 148 women. Furthermore, the effect of different alcohol intakes (≤ 28.6, >28.6 to ≤ 57.2, >57.2 to ≤ 142.9, and > 142.9 g/wk) was studied. Results: Women who consumed alcohol had significantly higher spine (10%), total body (4.5%), and midradius (6%) BMD than did nondrinkers. An alcohol intake >28.6 g/wk was associated with higher BMD; maximum effect was seen with an intake of > 28.6 to ≤ 57.2 g/wk (16%, 12%, and 14% increase in spine, total body, and midradius BMD, respectively). There was a marked reduction in bone remodeling markers, serum osteocalcin, and the ratio of urinary cross-linked N-telopeptides of type 1 collagen to creatinine with alcohol consumption, suggesting that increased BMD with alcohol consumption could be due to reduced bone remodeling. Further, serum parathyroid hormone concentrations were significantly lower in alcohol drinkers than in nondrinkers and could be one of the causes of decreased bone resorption. Conclusions: Moderate alcohol intake was associated with higher BMD in postmenopausal elderly women. The protective effect of alcohol may have been a result of lower bone remodeling due to reduced parathyroid hormone concentrations or factors such as increased estrogen concentrations.

Cigarette smoking has been implicated as a risk factor for osteoporosis. In the present study, the relationship between smoking and bone mineral density, calcitropic hormones, calcium absorption, and biochemical indices related to bone and mineral metabolism was examined at baseline, in subjects recruited for an osteoporotic study. The subjects included 489 elderly women, aged 65-77 years. After exclusions (thiazide users), 54 women constituted the smoking group and 390 women were classified as nonsmokers. The effect of frequency of smoking was also examined in this population (33 light smokers [1 pack/day] and 21 heavy smokers [1 pack/day]). Adjusted mean total body bone mineral density was 4% lower (0.968 +/- 0.019 vs. 1.009 +/- 0.004) and the total hip density was 6% lower (0.778 +/- 0.024 vs. 0.826 +/- 0.006) in heavy smokers compared with nonsmokers. At the other sites measured (spine, midradius, femoral neck, trochanter, and Ward's triangle), a similar nonsignificant trend was observed. The adjusted mean calcium absorption corrected for weight was lower (13%) both in light and heavy smokers compared with nonsmokers, and serum 25-hydroxyvitamin D was significantly lower (16%) in heavy smokers than nonsmokers. Serum parathryroid hormone (PTH) was higher in heavy smokers, but was not significantly different from that of nonsmokers. A significant increase in bone remodeling markers, serum osteocalcin (4.35 +/- 0.271 vs. 3.79 +/- 0. 066) and urine N-telopeptide/creatinine (NTx/Cr) ratio (74.5 +/- 5. 75 vs. 49.8 +/- 1.4) was seen in heavy smokers compared with nonsmokers. These results suggest that smoking lowers bone mineral density, and is a result of decreased calcium absorption associated with secondary hyperparathyroidism and increased bone resorption.

Introduction and methods: Osteoporosis is the most common bone disease in clinical practice. Between 30% and 50% of postmenopausal women and almost 50% of all people over the age of 75 are estimated to have osteoporosis. HRT is well known for reducing the risk of osteoporosis in postmenopausal women but compliance with long-term HRT therapy remains low. The use of low dose HRT reduces the estrogenic adverse events which often cause patients to stop therapy. In this paper, the current literature on the benefits of low dose HRT and osteoporosis prevention are reviewed. Results: Various studies have assessed the efficacy of low-dose HRT (25 mcg/day transdermally; 0.3 mg/day orally) in the prevention of osteoporosis. Low dose HRT is effective at reducing bone loss in postmenopausal and oophorectomised women. In one study of 218 postmenopausal women, a dose of 0.3 mg/day of esterified estrogen resulted in a small but significant increase in whole body BMD compared to a decrease in the placebo group. The addition of calcium supplements may have a synergistic effect on the reduction of bone loss. Conclusion: Low dose estrogen, taken either orally or transdermally, can prevent or reverse postmenopausal bone loss and appears to be a useful alternative to higher dosages in the prevention and treatment of osteoporosis. The option of starting HRT at low dose gives physicians the ability to titrate doses to suit individual patients whilst ensuring adequate bone protection and the minimum of hyperestrogenic side effects.

In this study, the effect of dietary calcium and vitamin D on serum parathyroid hormone and vitamin D metabolites was measured in 376 free-living women aged 65-77 y. Mean calcium intake in both groups was close to the recommended dietary allowance of 800 mg/d. Mean vitamin D intake in the 245 women not taking vitamin D supplements was 3.53 microg/d (141 IU/d), which is below the recommended dietary allowance of 5 microg/d (200 IU/d). To test the hypothesis that vitamin D is more important than calcium in reducing serum parathyroid hormone, the source of dietary calcium intake was subdivided into milk, which is fortified with vitamin D, and nonmilk sources. The serum parathyroid hormone concentration was inversely correlated with calcium intake derived from milk (r = -0.20, P < 0.01) but not from nonmilk sources (r = -0.06). Furthermore, serum calcidiol correlated with milk calcium intake (r = 0.35, P < 0.001) but not with nonmilk calcium intake (r = 0.10). Multivariate analysis showed a significant effect of season on serum calcidiol but not on serum parathyroid hormone. Serum parathyroid hormone was inversely correlated with serum calcidiol (r = -0.33, P < 0.001) and the regression predicted that mean serum parathyroid hormone would be reduced in the elderly to concentrations considered normal in the young when serum calcidiol is 122 nmol/L (49 ng/mL); this would require a much higher recommended dietary allowance for vitamin D than 5 microg/d (200 IU/d).

It is well established that bone mineral density is under strong genetic control. Recently it was reported that the Bsm I restriction fragment length polymorphism of the vitamin D receptor (VDR) gene could account for up to 75% of the genetic variance in bone mineral density. However, the physiological basis for such an effect has not been established. The VDR gene codes for the vitamin D receptor protein which regulates intestinal calcium absorption. In order to assess the biochemical basis we studied the effect of common allelic variation of the VDR gene on intestinal VDR protein concentration, calcium absorption, and serum 1,25 dihydroxyvitamin D (1,25(OH)2D). Ninety-two Caucasian women were genotyped for Bsm I and Taq I polymorphism at the VDR gene locus. From these we compared 49 young women aged 25-35 years and 43 elderly women aged 65-83 years, who had all three measurements performed. There were no significant differences in intestinal VDR protein concentration, serum 1, 25(OH)2D, or radioactive calcium absorption among VDR genotype groups. Therefore, the small intestine does not seem to be a target for VDR gene polymorphism.

Vitamin D deficiency, which causes osteomalacia, may also be important in the pathogenesis of age-related osteoporosis. We studied serum vitamin D metabolites in 52 young women (mean age: 30 +/- 3 y; range: 25-35 y), 64 elderly free-living women (mean age: 71 +/- 4 y; range: 65-82 y), and 60 elderly women living in nursing homes (mean age: 84 +/- 9 y; range: 61-102 y). Mean serum 25-hydroxyvitamin D (calcidiol) was 10.8 +/- 4.4 nmol/L (27 +/- 11 ng/mL) in women living in nursing homes and was similar to that of free-living young (11.3 +/- 4.2 nmol/L, or 28 +/- 10 ng/mL) and elderly (11.5 +/- 3.2 nmol/L, or 29 +/- 8 ng/mL) women. Vitamin D deficiency (defined as serum calcidiol < 4.8 nmol/L, or 12 ng/mL) occurred in 8% of women living in nursing homes, in 6% of the young women, and in 1.6% of the free-living elderly women. Serum calcidiol was significantly correlated with vitamin D intake (r = 0.25, P < 0.05) and inversely correlated with serum intact parathyroid hormone (iPTH) (r = -0.16, P < 0.03). Serum iPTH increased with age and secondary hyperparathyroidism was observed in 17% of the women living in nursing homes. Calcium absorption declined with age, but calcium absorption and serum 1 alpha,25-dihydroxyvitamin D (calcitriol) were significantly lower in women living in nursing homes, which probably contributed to the secondary hyperparathyroidism. In conclusion, normal serum calcidiol may avoid the problem of osteomalacia, but it does not correct malabsorption of calcium. Although calcitriol corrects the malabsorption of calcium, it remains to be seen whether higher amounts of vitamin D can normalize the calcium malabsorption of aging.

Background: The largest increase in bone mass occurs during childhood and adolescence. A subnormal bone mass is associated with increased risk of fracture. Bone mass is influenced by height, age, race, exercise, and stage of puberty. It is adversely affected by chronic disease states and corticosteroid use. We performed a cross-sectional study of bone density in children with moderate to severe asthma who were treated with inhaled corticosteroids, inhaled cromolyn, oral corticosteroids, or a combination of these, and we compared them with normal children. Methods: A cross-sectional study of bone density, measured either by dual-photon or dual-energy absorptiometry, was performed on 97 normal white and 30 asthmatic white children, aged 5 to 18. Average daily calcium intake, height, weight, and Tanner stage were determined. The total daily and lifetime doses of inhaled corticosteroids in children with asthma were calculated. T tests, multiple regression, chi square analysis, and analysis of covariance were performed. Results: No significant difference in bone density was demonstrated between children with asthma and normal control subjects. No measure (including calcium intake, Tanner stage, daily or lifetime inhaled corticosteroid dose, or duration of illness), except for height and age, provided a significant contribution to the explanation of bone density in children with asthma. Conclusion: Children and adolescents with moderate to severe asthma, including those treated with inhaled corticosteroids, do not appear to have adversely affected bone mass. There was, however, the possibility of a type II error in this study because of the sample size. (J ALLERGY CLIN IMMUNOL 1994;94:490-7.)

The aim of this study was to examine the effect of conjugated equine estrogens alone (ET), conjugated equine estrogens + medroxyprogesterone (EPT), calcitriol alone, calcitriol + EPT/ET, or placebo on serum lipid profile and analyze the interaction with estrogen receptor-α gene single nucleotide polymorphisms (ESR-α SNPs) on the response to therapy.A total of 489 postmenopausal women older than 65 years were enrolled into a 3-year double-blind, placebo-controlled clinical trial.In both intent-to-treat and complier (80% adherent) analysis, there was a significant increase in serum high-density lipoproteins and a significant decrease in serum low-density lipoproteins (LDLs) and the LDL/high-density lipoprotein ratio in all hormone treatment groups compared with placebo (P0.05). However, serum triglycerides and very low-density lipoproteins increased in the EPT and ET + calcitriol groups versus placebo (P0.05). ESR-α SNPs PvuII and XbaI seemed to have a significant effect on the response to treatment. Genotypes containing the p allele showed a significantly greater decrease in serum cholesterol and very low-density lipoprotein than those having the P allele in the ET + calcitriol group (P0.05), and those with the x allele had a significantly greater decrease in serum cholesterol in the hormone therapy + calcitriol group at the end of 3 years versus the X allele, and a greater decrease in serum LDL in alleles x versus the X in the ET + calcitriol group (P0.05).ET with or without progesterone had a favorable effect on lipid profile in postmenopausal older women, and this was dependent on estrogen receptor SNPs--PvuII and XbaI. However, this interaction with ESR-α SNPs needs to be confirmed in larger studies.

Bone mineral density (BMD) is dependent on multiple influences including genetics, mechanical forces, hormonal changes and nutritional mechanisms. The mechanical forces are, in part, influenced by muscle strength. This study examined the relationships between BMD of the spine and femur with muscle strength. Eighty-one healthy, non-athletic women aged 20-30 years were the subjects in the study. BMD was measured by dual energy x-ray absorptiometry. Trunk strength was measured by a Wagner Dynamometer or a Cable Tensiometer and leg strength was measured with a Cybex II isokinetic dynamometer. Trunk, leg and hip strength was also measured using 1 RM (one repetition maximum). There were significant correlations between spine density and trunk extension (r = 0.40, P = 0.0001) and spine density and trunk flexion (r = 0.30, P = 0.0037). There were significant correlations between femoral neck density and knee extension (r = 0.40, P = 0.003) and femoral neck density and knee flexion (r = 0.24, P = 0.0240). Multiple regression analysis showed that amongst young adult females weight and trunk extensor muscle strength contributed about equally to spine density. Flexor muscle strength did not influence bone density.

There is a controversy regarding the definition of vitamin D insufficiency as it relates to bone health.The objective of the study was to examine the evidence for a threshold value of serum 25-hydroxyvitamin D (25OHD) that defines vitamin D insufficiency as it relates to bone health.This was a cross-sectional analysis of baseline data in 488 elderly Caucasian women, mean age 71 yr, combined with a literature review of 70 studies on the relationship of serum PTH to serum 25OHD.The study was conducted in independent-living women in the midwest United States.The relationship between serum 25OHD, serum PTH, and serum osteocalcin and 24-h urine N-telopeptides was evaluated.Serum PTH was inversely correlated with serum 25OHD (r = -0.256, P0.0005), but no threshold as defined by suppression of serum PTH was found within the serum 25OHD range 6-60 ng/ml (15-150 nmol/liter). However, in contrast, there was a threshold for bone markers, serum osteocalcin and urine N-telopeptides, that increased only below a serum 25OHD of approximately 18 ng/ml (45 nmol/liter). Calcium absorption was not correlated with serum PTH and serum 25OHD, and no threshold was found. A literature review of 70 studies generally showed a threshold for serum PTH with increasing serum 25OHD, but there was no consistency in the threshold level of serum 25OHD that varied from 10 to 50 ng/ml (25-125 nmol/liter).Vitamin D insufficiency should be defined as serum 25OHD less than 20 ng/ml (50 nmol/liter) as it relates to bone.

A case report of a 53 year old postmenopausal woman with severe osteoporosis occurring in association with beta thalassemia trait is presented. She was found to have marked axial osteopenia with lumbar spine bone mineral density that was more than three standard deviations below the mean, but had normal bone mineral density of the proximal radius. A biopsy of the iliac crest showed evidence of high turnover osteoporosis. Bone densitometry of the spine and hip in a consecutive series of eleven asymptomatic individuals with thalassemia trait also is reported. Bone mineral density was diminished in the spine (z-score = -0.78, P less than 0.03) and hip (z-score = -0.54, P = 0.05) of patients with thalassemia trait. It is postulated that thalassemia minor may be a risk factor for osteoporosis.

Transilial bone biopsies following in vivo fluorochrome labeling were obtained from 90 women with postmenopausal osteoporosis and 34 healthy post-menopausal women. Standard histomorphometric data were collected from undecalcified sections. The distribution of values for both structural and remodelling indices was the same for each group. Bone volume was 35% lower (P less than 0.001), wall thickness was 12% lower (P less than 0.001), and trabecular thickness was 11% lower (P less than 0.02) in osteoporotics. Trabecular separation was 34% greater (P less than 0.001) and trabecular number was 36% lower (P less than 0.001) in osteoporotics. Biopsy core width was 11% less (P less than 0.02) and cortical width was 35-50% less (P less than 0.001) in osteoporotics. Static indices of remodelling, mineralizing surfaces, and mineral apposition rate were similar in the two groups. The absolute values for bone histomorphometric variables for both groups are similar to most published data. Osteoporotics had poorer bone structure, marked by decreased trabecular connectivity and thin cortices. There were no major differences in dynamic indices of remodelling. Since the histomorphometric data were distributed the same in both groups, special subsets of osteoporotic subjects not in the normal population did not exist.

In a double blind placebo controlled 3-year osteoporosis study in elderly women, we collected prospective data on falls. The study population comprised 489 normal elderly women aged 65-77 years randomized to four groups: placebo, calcitriol 0.25 mcg b.i.d., conjugated equine estrogens (0.625 mg/day) and calcitriol+estrogen. Falls occurred in 57% of all women. Using a Poisson regression model, the placebo group with low GFR-creatinine clearance (CrCl60 ml/min) had 60% more falls compared to the group with CrClor =60 ml/min. Further sub group analyses showed that there is no increased risk of falls with CrCl 60-70, 70-80 and90 ml/min. Calcitriol treatment significantly reduced the number of falls by 50% (OR=0.5, 95% CI: 0.4-0.9, p=0.010) compared to placebo in the low CrCl group. The group with lower CrCl had lower calcium absorption (p0.001), lower serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) (p0.001) and normal serum 25OHD suggesting that there is decreased conversion of 25OHD to 1,25(OH)(2)D by the aging kidney. It is postulated that the decrease in falls on calcitriol therapy is related to an increase in serum 1,25(OH)(2)D, upregulation of VDR and improvement in muscle strength although one cannot exclude an effect on the central nervous system.

Association studies between estrogen receptor alpha (ERalpha) gene polymorphisms and bone mineral density (BMD) have yielded inconsistent results. In the present study we evaluated the influence of XbaI and PvuII ERalpha gene polymorphisms on BMD, biochemical markers, rates of bone loss and the response to estrogen/hormone therapy (ET/HT) in elderly postmenopausal women.At baseline, we measured the association between ERalpha genotypes and BMD and biochemical markers in 489 elderly women, mean age 71 +/- 3 years. In the longitudinal study, the changes in the same measures were determined in 96 women on placebo and in 79 women receiving the ET/HT for 3 years. The XbaI and PvuII ERalpha polymorphisms were determined by polymerase chain reaction (PCR). BMD measurements for spine, femoral neck and total body were performed by DEXA, and biochemical indices were measured by standard methods.Neither the PvuII nor the XbaI ERalpha gene polymorphisms were associated with baseline BMD and biochemical indices. In the longitudinal study, there were trends for higher bone loss in the placebo group in the genotypes pp or xx compared to PP or XX genotypes, but the changes were not significant. However, the changes in the bone markers were significantly (p0.05) higher in genotype group pp compared to PP (serum osteocalcin, 4.9 +/- 7.0% versus -13.4 +/- 6.7%; urine NTx:Cr ratio, 32.3+/-10.3% versus -2.5 +/- 10.3%) or xx compared to XX (serum osteocalcin, 7.5 +/- 6.4% versus -15.6+/-7.3%; urine NTx:Cr ratio, 39.4 +/- 9.2% versus -8.84+/-10.7%). At the end of 3 years, the mean urine NTx:Cr ratio was 78.7 +/- 9.0 versus 44.6 +/- 4.9 in pp versus PP (p0.05) and 75.5 +/- 10.7 versus 48.7 +/- 5.4 in xx versus XX (p0.05) genotypes. The response in total body BMD to ET/HT treatment was significantly higher in women with the PP genotype compared to pp genotype (2.48 +/- 0.55% versus 0.66 +/- 0.46%). Similar trends were seen at other skeletal sites for both XX and PP compared to pp and xx genotypes.Women with ERalpha, PP and XX genotypes have lower bone remodeling, lower rates of bone loss and benefit more from hormone therapy.

Tibolone, a novel compound with tissue-specific effects, has been found to have antiresorptive properties in bone. To confirm the efficacy of tibolone and determine its minimum effective dose for prevention of bone loss in early postmenopausal women, two randomized, double-blind, placebo-controlled, dose-finding studies were performed. Seven hundred seventy healthy women postmenopausal within 1-4 yr, with normal bone density for their age, were treated for 2 yr with 0.3, 0.625, 1.25, or 2.5 mg tibolone daily or placebo. All subjects took supplemental calcium carbonate (500 mg daily). Bone mineral density (BMD) of the lumbar spine and right proximal femur was measured by dual-energy x-ray absorptiometry for up to 2 yr. At each dose level, except the lowest (0.3 mg), tibolone produced a progressive increase in lumbar spine and total hip BMD over the 2-yr treatment period; at 0.3 mg, total hip density was maintained. However, only the doses 1.25 mg and 2.5 mg produced a progressive increase in femoral neck BMD. The differences in mean percent change from baseline in spine and total hip density were significant (P < 0.05) for all tibolone dose groups compared with placebo at all time points. Tibolone was well tolerated, with a similar overall incidence of adverse events compared with placebo. Tibolone 1.25 mg per day is recommended because it shows a positive and statistically significant change in BMD of spine and femoral neck.

Estrogen deficiency and declining calcium absorption due to reduced calcitriol levels or intestinal resistance to calcitriol, are important factors in the pathogenesis of age-related bone loss. The main objective of this study was to examine the effect of estrogen and 1,25-dihydroxyvitamin D therapy given individually or in combination on bone loss in elderly women. Four hundred eighty-nine elderly women with normal bone density for their age, aged 65-77 yr, were entered into a randomized double blind, placebo-controlled trial. Women were randomized to one of four groups: conjugated estrogens (0.625 mg, daily) to women without a uterus (estrogen replacement therapy) plus medroxyprogesterone acetate (2.5 mg, daily) to women with a uterus (hormone replacement therapy), calcitriol (0.25 microg twice daily), a combination of hormone replacement therapy/estrogen replacement therapy plus calcitriol, or placebos for 3 yr. The primary outcome was the change in bone mineral density of the femoral neck and spine. In the intent to treat analysis, hormone therapy (hormone replacement therapy/estrogen replacement therapy) produced a mean (+/-1 SD) increase in bone mineral density of 2.98% (+/-5.45%) at the femoral neck (P < 0.0001) and 4.36% (+/-6.42%) at the spine (P < 0.0001). There were parallel increases in total hip and trochanter bone mineral density. Calcitriol increased bone mineral density 0.10% (+/- 4.27%) at the femoral neck (P = 0.57) and 1.65% (+/- 4.83%) at the spine (P < 0.0124). The combination of hormone replacement therapy/estrogen replacement therapy + calcitriol increased bone mineral density 3.80% (+/-4.95%) at the femoral neck (P < 0.001), 4.91% (+/-6.0%) at the spine (P < 0.0001), and parallel changes at the total hip and trochanter. All three treatment groups differed significantly from placebo at the spine and for the hormone replacement therapy/estrogen replacement therapy groups at the femoral neck, spine, total hip and trochanter. There were no significant differences between combination therapy and hormone replacement therapy/estrogen replacement therapy alone on bone mineral density at any site in the intent to treat analysis. In a secondary analysis of the effect in women who were adherent to treatment, calcitriol had a more significant effect on spine (P = 0.003) and total hip (P = 0.004). The increase in bone mineral density in the adherent groups of women was always higher compared with the intent to treat groups. Combination therapy compared with hormone replacement therapy/estrogen replacement therapy alone produced a significantly greater response in trochanter (P = 0.007) and total hip bone mineral density (P = 0.0017). In summary, hormone replacement therapy/estrogen replacement therapy alone and in combination with calcitriol therapy was highly effective in reducing bone resorption and increasing bone mineral density at the hip and other clinically relevant sites in a group of elderly women, with normal bone density for their age. Calcitriol was effective in increasing spine bone mineral density. In the adherent women, combination therapy with hormone replacement therapy/estrogen replacement therapy and calcitriol increased bone mineral density significantly more in the total hip and trochanter than did hormone replacement therapy/estrogen replacement therapy alone.

Introduction: Hormone replacement therapy (HRT) has many benefits yet compliance rates remain low. One of the main reasons for discontinuing therapy is hyperestrogenic side effects which may be dose related, and the initiation of treatment is critical to a patient’s chances of gaining long-term benefits. The introduction of low dose HRT means that physicians have an option to initiate or titrate patients to a low dose. The purpose of this review is to examine current literature on the benefits for patients of low dose HRT. Results: Low dose estrogen (25 mcg/day transdermally or 0.3 mg/day orally) are effective in controlling postmenopausal symptoms, reducing bone loss and reducing cardiovascular risk factors. Low dose therapy is also effective at reducing vasomotor symptoms in highly symptomatic women. In one study, patients on a daily dose of 25 mcg estrogen experienced an 86% reduction in vasomotor symptoms compared to a 55% reduction in patients on placebo. In addition, many adverse events related to estrogens were reduced using a low dose. Conclusion: Compliance with traditional doses of HRT is currently a problem for many women who may stop taking therapy because they experience hyperestrogenic side effects. Low dose HRT is effective at reducing vasomotor symptoms and controlling symptoms even in highly symptomatic women. Hyperestrogenic side effects may be reduced by initiating treatment at the lowest dose and titrating upwards if necessary. This may have benefits for patients in terms of offering effective control of symptoms whilst minimising hyperestrogenic effects.

Our purpose was to evaluate the efficacy and safety of 3 dosages of Esclim, delivering 0.025 mg, 0.050 mg, or 0.100 mg 17beta-estradiol per 24 hours, in the treatment of moderate to severe vasomotor symptoms.In this double-blind, placebo-controlled, parallel-group, multicenter trial, 196 highly symptomatic menopausal women received 12 weeks of continuous unopposed treatment with 1 of the 3 dosages of Esclim or a matching placebo patch.The reduction in frequency of moderate to severe vasomotor symptoms was statistically significant compared with placebo (P.05) from week 2 onward in the Esclim 50 and 100 groups and from week 3 onward in the Esclim 25 group. Symptom severity was also reduced. Estrogen-related adverse events, particularly metrorrhagia and endometrial hyperplasia, were less frequent in the Esclim 25 group than in the higher-dosage groups.All 3 dosages of Esclim were effective in the treatment of vasomotor symptoms. The efficacy and safety of Esclim 25 indicate a good risk-benefit ratio.

BACKGROUND Osteoporosis risk in middle-aged women is twofold greater than that in men, and the difference increases with age. Gender differences in bone mineral density, estimated rates of bone loss, and usefulness of markers of bone metabolism for predicting bone density have not been well described in healthy elders aged 65 and above. The purpose of this cross-sectional analysis was to describe associations of bone mineral density at the hip, spine, and whole body with age, serum osteocalcin, and urinary N-telopeptide crosslinks of Type I collagen in healthy elderly men and women. METHODS A total of 1,087 healthy adults (273 men and 814 women) aged 65 to 87 years were enrolled in a collaborative study at 3 sites: Tufts University (Boston, MA), University of Connecticut Health Center (Farmington, CT), and Creighton University (Omaha, NE). Bone mineral density (BMD) at three regions of the hip, the lumbar spine, and whole body was determined by dual-energy x-ray absorptiometry. Serum osteocalcin was measured by immunoassay, and measurement of N-telopeptide crosslinks (Ntx) in urine was made using an enzyme-linked radioimmunoassay (ELISA). RESULTS Among women, the age-related decline in BMD at all non-spine skeletal sites was significantly different from zero, with the largest decline seen at the femoral neck (-.0038 g/cm2/y, p < .001) and the smallest at the trochanter of the hip (-.0023 g/cm2/y, p = .03). Among men, the changes at all non-spine sites were not significant. In both sexes, spine BMD tended to increase with age (men, +.0045 g/cm2/y, women, +.0003 g/cm2/y). Serum osteocalcin and urinary Ntx were inversely related to BMD at all skeletal sites, but the weakest associations were observed at the spine. Individuals whose values of both osteocalcin and Ntx were in the lowest quartiles of the respective sex-specific distributions had mean femoral neck BMD that were 11% higher than individuals with marker values in the highest quartiles. CONCLUSIONS These findings suggest that age-related decreases in BMD may vary by gender and skeletal site. Determinations of osteocalcin and N-telopeptide crosslinks at a single point in time may potentially be used as indicators of current bone status, particularly at non-spine skeletal sites.

It is well recognized that patients with postmenopausal osteoporosis usually exhibit some degree of calcium malabsorption and commonly have low serum concentrations of 1,25-dihydroxyvitamin D (calcitriol). Administration of calcitriol has been shown to normalize calcium absorption in patients with osteoporosis and, over the long term may have a stimulating effect on bone formation. Clinical trials have shown a significant reduction in osteoporotic fractures among calcitriol-treated patients. Hypercalcemia and hypercalciuria are infrequent complications of calcitriol therapy with physiologic doses (0.25 microgram twice daily), and are most commonly related to excessive calcium intake (i.e.,1000 mg daily).

PURPOSE: To measure changes and predictors of change in mammograms obtained in postmenopausal women undergoing continuous combined hormonal replacement therapy (HRT). MATERIALS AND METHODS: Mammograms of 41 postmenopausal women obtained before and 1 year after the initiation of HRT were evaluated blindly according to the quantitative density percentage method and the Wolfe classification system. RESULTS: Mammographic densities increased compared with baseline values in 73% of subjects (mean increase, 6.7%; 95% confidence interval, 2.5%, 11.0%; P = .003). A shift in Wolfe classification from lower to greater parenchymal density was noted in 24% of subjects (P = .016). Multivariate analysis results indicated that the lower the tissue density percentage before treatment, the greater the increase in density percentage after treatment. CONCLUSION: An increase in mammographic density was demonstrated in most subjects undergoing continuous combined HRT and was most pronounced in subjects with a lower baseline de...

The effects of cyclical treatment with estrone sulfate (0.3, 0.625, or 1.25 mg), plus calcium carbonate, on spinal trabecular bone density were compared with placebo in 120 postmenopausal women in this 2-year, multicenter, double-blind study. While the placebo and 0.3-mg treatment groups lost bone density (-3.6% and -5.1%), the 0.625- and 1.25-mg treatment groups experienced no significant change from baseline at 24 months (-0.8% and +0.7%). The 1.25-mg treatment group was significantly different from the placebo group at 12, 18, and 24 months. Although the 0.625-mg treatment group was significantly different from the placebo group only at 18 months, the data suggest that 0.625 and 1.25 mg of estrone sulfate had different effects than placebo and 0.3 mg of estrone sulfate and, given with supplemental calcium, are effective doses for the prevention of spinal bone loss.

Bone mineral content of different areas of the skeleton was measured by dual photon absorptiometry in 20 children with juvenile rheumatoid arthritis (JRA) and compared to 20 age and sex matched healthy children. Spinal density was similar in both groups in prepubertal children but decreased in the postpubertal girls with JRA. Total bone density was also decreased in the postpubertal girls. Six children with JRA had repeat scans 12 to 24 months later; in 3 children total bone mineral content increased significantly with an intensive management program. Our study suggests that bone mineral density does not show a pubertal increase in children with JRA, as it does in healthy children.

To determine the effect of progestin therapy on bone mineral density in postmenopausal women and to compare its effects to those of estrogen.A prospective, randomized clinical trial was performed in 81 postmenopausal women aged 51.7 +/- 4.4 years (mean +/- SD). They were assigned to one of four groups: Provera 20 mg, Premarin 0.6 mg, Premarin 0.3 mg plus Provera 10 mg, and a placebo. In addition, all women received calcium supplementation, if necessary, to a calcium intake of 1,000 mg/day. We used single- and dual-photon absorpiometry, metacarpal radiogrammetry, and computed axial tomography to measure bone mineral density in the total skeleton, spine, radius, and metacarpal.Women receiving placebo lost bone at all sites (p less than 0.01). The Provera-treated group showed no change in total body calcium, but there were decreases in radial density (p less than 0.01), metacarpal cortex (p less than 0.01), and spine density (p less than 0.01). The Premarin-treated group had an increase in spine density and total body density (p less than 0.05), but a decrease in radial density (p less than 0.05). The Premarin-plus-Provera group showed no change in spine density, total body calcium, or radial density but had a decrease in metacarpal cortex (p less than 0.01).Compared to placebo, Provera reduced the rate of loss in cortical areas of the skeleton, but not in the spine, which contains more trabecular bone. In contrast, Premarin reduced the rate of loss in both cortical and trabecular areas of the skeleton. The low-dose combination of Premarin plus Provera was similar in its effect on bone to that of Premarin alone, suggesting that there may be a synergistic effect of this hormone combination on bone. Serum cholesterol levels decreased with Provera, Premarin, and the combination of both, whereas levels of serum triglycerides increased with Premarin treatment, decreased with the Provera regimen, and were unchanged with the combination therapy. Provera does not adversely affect the lipid profile.This study attempted to determine the effect of progestin therapy on bone mineral density in postmenopausal women and to compare its effects to those of estrogen. A prospective, randomized, clinical trial was performed on 81 postmenopausal women ages 51.7 +or- 4.4 years (mean +or- SD). They were assigned to either Provera 20 mg, Premarin 0.6 mg. Premarin 0.3 mg + Provera 10 mg, or placebo. In addition, all women received calcium supplementation, if necessary, up to a calcium intake of 1000 mg/day. The authors used single and dual-photon absorptiometry, metacarpal radiogrammetry, and computed axial tomography to measure bone mineral density in the total skeleton, spine, radius, and metacarpal. Women receiving the placebo lost bone at all sites (p0.01). The Provera-treated group showed no change in total body calcium, but there were decreases in radial density (p0.01). The Premarin-treated group has an increase in spine density and total body density (p0.05), but a decrease in radial density (p0.05). The Premarin + Provera group showed no change in spine density, total body calcium, or radial density, but had a decrease in metacarpal cortex (p0.01). Compared to placebo, Provera reduced the rate of loss in cortical areas of the skeleton, but not in the spine, which contains more trabecular bone. In contrast, Premarin reduced the rate of loss in both cortical and trabecular areas of the skeleton. The low-dose combination of Premarin + Provera was similar in its effects on bone to that of Premarin alone. This suggests that there may be a synergistic effect of this hormone combination on bone. Serum cholesterol levels decreased with provera, Premarin, and the combination of both, whereas levels of serum triglycerides increased with Premarin treatment, decreased with the Provera regimen, and were unchanged with the combination therapy. Provera does not adversely affect the lipid profile.

Estrogen replacement therapy confers many beneficial effects to postmenopausal women, such as slowing the rate of bone loss and decreasing the risk of coronary artery disease. This multicenter, placebo-controlled study evaluated the lowest effective daily dose of estrone sulfate (0.3, 0.625, or 1.25 mg) combined with 1000 mg elemental calcium supplementation for preventing bone loss in the immediate supplementation for preventing bone loss in the immediate postmenopausal period. Spinal bone mineral density was measured using quantitative computed tomography. Compared with baseline, bone mineral density increased significantly (P less than .05) after 12 months of 0.625 mg daily (+ 1.9%) or 1.25 mg daily (+ 2.5%). The difference between the 0.625-mg and 1.25-mg doses was not statistically significant. Estrone sulfate administration (0.625 and 1.25 mg) produced significant changes in various lipid measurements at both the 6- and 12-month observation points. The prevalence rates for adverse events were comparable among the estrone sulfate groups and the placebo group. Estrone sulfate 0.625 mg daily, combined with 1000 mg elemental calcium supplementation, was the minimum effective dosage to prevent loss of spinal bone mineral density in postmenopausal women over a 12-month period.

Menopause constitutes a sizable proportion of the adult woman's life, and it is reasonable to consider that most women will benefit from hormone-replacement therapy. Also, it is important to realize that cardiovascular disease is a major cause of morbidity and death in the menopausal patient. Two regimens of hormone-replacement therapy were evaluated in postmenopausal women with 0.625 mg of conjugated equine estrogen with either 2.5 or 5 mg of medroxyprogesterone acetate taken continuously for 52 weeks in 92 patients. The data demonstrated an improvement in menopausal symptoms, a beneficial effect in lipoprotein profiles, the establishment of an atrophic endometrium, and a marked decrease in vaginal bleeding after 13 weeks and a further decrease after 26 weeks. Ideally this regimen will offer better patient compliance and, if the favorable lipoprotein profiles offer protection to the cardiovascular system, the overall health of the American woman will be markedly affected.

Changes in the calciotropic hormones with age contribute significantly to the pathogenesis of osteoporosis. In both postmenopausal (Type I) and senile osteoporosis (Type II) it is common to find reduced levels of serum 1,25-dihydroxyvitamin D and malabsorption of calcium. In Type I patients a reduced level of serum parathyroid hormone causes a real decrease in serum 1,25-dihydroxyvitamin D production and malabsorption of calcium, whereas in Type II patients the decline in 1α-hydroxylase activity in the kidney causes a decline in serum 1,25-dihydroxyvitamin D which leads to malabsorption of calcium and secondary hyperparathyroidism. In the final analysis both pathways lead to bone loss. In some Type II patients there may be a decline also in the function or number of the vitamin D-binding receptors in the gut. Treatment of patients with vitamin D analogues, however, normalizes calcium absorption and improves calcium balance. The improvement in calcium balance reduces bone resorption and prevents further bone loss; in addition recent studies have shown that therapy with vitamin D analogues leads to a reduction in fracture incidence.

Three regimens of hormone replacement therapy were administered to 62 postmenopausal women for a period of 12 weeks and evaluated for their effect on blood lipids. Each group was given a continuous dose of 0.625 mg of conjugated estrogens combined with either a continuous dose of 2.5 mg of medroxyprogesterone acetate or 5.0 mg of medroxyprogesterone acetate, or a cyclic dose of 5.0 mg of medroxyprogesterone acetate on days 17-28 of the cycle. After treatment there was a significant decrease in the total cholesterol (P less than .0007) and low density lipoprotein cholesterol (P less than .0001) together with a significant increase in high density lipoprotein cholesterol (P less than .0029). There was no significant difference in the response of the blood lipids to the three hormone groups. Therefore, preference would depend on the combination that caused the least bleeding or amenorrhea.

In postmenopausal osteoporotics, malabsorption of calcium is associated with reduced levels of serum 1,25-dihydroxyvitamin D. Metabolic studies have shown that calcium absorption can be normalized and calcium balance improved after administration of oral doses of synthetic 1,25-dihydroxyvitamin D3 (Rocaltrol) 0.25 micrograms twice daily. Further studies performed at two centers compared the effect of Rocaltrol 0.25 micrograms twice daily versus placebo on vertebral fracture rates in osteoporotics. A significant reduction in vertebral fracture rates was seen at the end of 1 year. Those patients who continued on Rocaltrol for a second and third year showed a progressive decrease in vertebral fractures. Rocaltrol, administered at a dose of 0.25 micrograms twice daily, seldom causes hypercalcuria or hypercalcemia in osteoporotic patients on a typical calcium intake of 700 to 800 mg/d. Careful measurements of renal function over a period of 3 years in patients treated with Rocaltrol, 0.25 micrograms twice daily, showed no deterioration in renal function. These data suggest that 1,25-dihydroxyvitamin D3 is a useful therapy in the management of patients with postmenopausal osteoporosis, particularly those who have malabsorption of calcium. We found that it improves calcium balance, reduces the vertebral fracture rate, and is safe to use provided that the dietary calcium is monitored and does not exceed 800 mg/d.