The effect of low dose micronized 17ss-estradiol on bone turnover, sex hormone levels, and side effects in older women: a randomized, double blind, placebo-controlled study.

The purpose of this study was to examine the effects of three doses (0.25, 0.5, and 1.0 mg/day) of micronized 17ss-estradiol on bone turnover, sex hormone levels, and side effects compared with placebo in healthy older women. The study design was randomized, double blind, and placebo controlled. The setting was a university clinical research center. Healthy, community-living women over 65 yr of age participated in the study. The main outcome measures were serum and urinary biochemical markers of bone resorption and formation at baseline, 6 and 12 weeks on treatment, and 6 and 12 weeks off treatment. Markers of bone resorption were N-telopeptides of type I collagen, C-telopeptides of type I collagen, and total deoxypyridinoline cross-links; formation markers were bone alkaline phosphatase, osteocalcin, and N-terminal procollagen peptides. We also measured serum estradiol, estrone, and sex hormone-binding globulin levels at baseline, 12 weeks on treatment, and 12 weeks posttreatment. All markers of bone resorption significantly decreased at 12 weeks on treatment compared with placebo and returned toward baseline at 12 weeks posttreatment. Two markers of bone formation, bone alkaline phosphatase and N-terminal procollagen peptides, significantly decreased 12 weeks posttreatment, but the decrease in osteocalcin varied with time and estrogen dose. Based on equivalence testing, the response of markers of bone turnover to therapy with 0.25 mg/day was similar to that seen with 1.0 mg/day. Serum estradiol increased compared with baseline in all treatment groups and compared with placebo in the two higher dose groups. Breast tenderness, bleeding, and endometrial changes were significantly less frequent in the 0.25 mg/day and placebo groups compared with the higher dose groups. We conclude that low dose of estrogen (0.25 mg/day 17ss-estradiol) reduced bone turnover to a similar degree as that seen with usual replacement therapy (1.0 mg/day 17ss-estradiol), but had a side effect profile similar to that of placebo. In our study additional increases in estradiol levels, as seen with 0.5 and 1.0 mg/day 17ss-estradiol treatment, resulted in more side effects without evidence of additional benefit to bone. These data suggest that 0.25 mg/day 17ss-estradiol may be an effective and tolerable agent for the treatment of osteoporosis in older women.

A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women.

Raloxifene HCl, a selective estrogen receptor modulator, has been shown to increase bone mineral density (BMD) and decrease biochemical markers of bone turnover in postmenopausal women without stimulatory effects on the breast and uterus. However, it is not known whether the changes in BMD and bone turnover are associated with changes at the tissue level, nor how changes with raloxifene compare with estrogen. In this randomized, double blind study, we evaluated the effects of raloxifene (Evista, 60 mg/day) or conjugated equine estrogens (CEE; Premarin, 0.625 mg/day) on bone architecture, bone turnover, and BMD. Iliac crest bone biopsies were obtained at baseline and at the end of the study after double tetracycline labeling and were analyzed for standard histomorphometric indexes. Serum and urinary biochemical markers of bone turnover were measured at baseline and at 4, 10, 18, and 24 weeks of treatment. Total body, lumbar spine, and hip BMD were measured at baseline and at the end of the study by dual energy x-ray absorptiometry. Activation frequency and bone formation rate/bone volume were significantly decreased from baseline in the CEE, but not in the raloxifene, group. Bone mineralization did not change in either group. Most markers of bone resorption and formation decreased in both groups, but to a greater degree in the CEE group (P < .05). Total body and lumbar spine BMD increased from baseline in both groups, with a greater increase in the CEE group (P < 0.05). Hip BMD significantly increased from baseline in the raloxifene group, but the change was not different from that in the CEE group. These results suggest that raloxifene reduces bone turnover and increases bone density, although to a lesser extent than CEE. Thus, raloxifene is an alternative to CEE for the prevention and treatment of osteoporosis in postmenopausal women.

The short term effects of tamoxifen on bone turnover in older women.

This study examined the effects of tamoxifen (TAM) on biochemical markers of bone turnover in healthy women, 20-30 yr past menopause. Ten women (mean age, 75 yr; range, 70-85 yr) were given TAM (20 mg/day) for 10 weeks. Serum and urine were collected twice at baseline, at weeks 9 and 10 of TAM treatment, and at weeks 9 and 10 post-TAM. Markers of bone formation were serum osteocalcin, total alkaline phosphatase, bone-specific alkaline phosphatase, and type I procollagen peptide. Markers of bone resorption were fasting urinary calcium, hydroxyproline, pyridinoline, and deoxypyridinoline, all corrected for urinary creatinine. Total cholesterol, triglycerides, and high density lipoproteins were measured; low density lipoprotein levels were calculated. Pyridinoline and deoxypyridinoline decreased during therapy by 23% and 25% and returned to baseline posttherapy (F = 37.01; P = 0.001), with no significant changes in urinary calcium and hydroxyproline. Markers of bone formation declined 17-36%, with a variable return toward baseline (F = 85.56; P < 0.001). Ionized calcium decreased 5% (P < 0.001) and PTH increased 21% (P = 0.05) during TAM treatment. Total cholesterol decreased 15% (P < 0.001), and calculated low density lipoprotein cholesterol decreased 22% (P < 0.001); levels of triglycerides and high density lipoprotein did not change significantly. We conclude that short term TAM treatment inhibits bone turnover in women over 70 yr of age.

The short-term effects of conjugated estrogen on bone turnover in older women.

Estrogen replacement therapy (ERT) prevents bone loss and fracture in early postmenopausal women, but its benefit for women over 70 yr of age has not been determined. We have examined the effect of a short course of ERT on biochemical markers of bone turnover in older women. Eleven women (mean age, 77 yr) were given conjugated estrogen (Premarin; 0.625 mg/day) for 6 weeks. Biochemical markers were measured on serum and urine collected at baseline (two samples), after 5 and 6 weeks of ERT, and 5 and 6 weeks post-ERT. Markers of bone formation were osteocalcin, bone alkaline phosphatase, and type I procollagen peptide. Markers of bone resorption were total urinary hydroxyproline, total and free pyridinoline and deoxypyridinoline cross-links, type I collagen cross-linked N-telopeptides, and serum C-terminal cross-linked telopeptide. Data were analyzed by repeated measures multivariate analysis of variance to estimate the overall effect of ERT on the biochemical markers. Markers of bone resorption decreased during ERT and returned to baseline after ERT (P < 0.05). Markers of bone formation declined less during ERT and continued to decline after ERT (P < 0.05). We conclude that ERT reduces bone turnover in older women and that markers of bone turnover may be useful in assessing the response to treatment in this age group.

Bone health is not affected by luteal phase abnormalities and decreased ovarian progesterone production in female runners.

The primary purpose of this study was to determine whether decreased ovarian progesterone production, associated with short and inadequate luteal phases in exercising women, was associated with decreased bone mineral density (BMD) and altered bone metabolism. Thirty-three eumenorrheic menstruating women participated in this study for 3 months. Subjects were required to collect daily urine samples for three consecutive menstrual cycles and have blood and urine collected weekly. Daily urine samples were analyzed for free LH, estrone conjugates (E1C), and pregnanediol 3-glucuronide (PdG), adjusted for creatinine, whereas weekly blood and urine samples were analyzed for bone markers, estradiol, progesterone, FSH, and LH. Based on the analyses of these samples, subjects were divided into three groups: sedentary ovulatory (SedOvul; n = 9), exercising ovulatory (ExOvul; n = 14), and exercising luteal phase defects (ExLPD; n = 10). The three groups were matched for age (27.6 +/- 1.0 yr), weight (60.6 +/- 1.9 cm), and reproductive maturity (14.5 +/- 1.0 yr), PdG production during the luteal phase was lower (P = 0.004) in the ExLPD women compared to that in the SedOvul group (2.4 +/- 0.4 vs. 5.1 +/- 0.6 ng/mL creatinine, respectively). The ExOvul group also had less (P < 0.01) PdG production during the luteal phase (3.5 +/- 0.3 ng/mL creatinine) compared to the SedOvul group. The total production of PdG, as assessed by area under the curve analysis, was also lower (P < 0.001) in the ExOvul and ExLPD groups compared to that in the SedOvul group. E1C production, however, was not different (P > 0.05) among the groups, except for E1C during the early follicular phase, which was lower (P = 0.043) in the ExLPD group than that in the SedOvul group. BMD and biochemical markers of bone metabolism were unaffected by and not associated with the compromised progesterone environment, but BMD values at the proximal femur (r = 0.354; P = 0.061) and total body (r = 0.359; P = 0.056) were associated with decreased early follicular E1C production. We conclude the following. 1) Luteal phase disturbances occur independent of training volume, and volume of training does not have to be severe to result in menstrual disturbances. 2) As a result of exercise, disturbance in progesterone production is not associated with decreased bone mass. 3) Long follicular phases are associated with reduced estrogen production during the early follicular phase, which are both associated with decreased bone mass. 4) Provided the estradiol status is adequately maintained, BMD is unaffected by decreased progesterone production associated with short and inadequte luteal phases in exercising women.

Low dose estrogen and calcium have an additive effect on bone resorption in older women.

Previous studies have shown that treatment with estrogen or calcium decreases bone turnover in older women. The mechanisms by which estrogen and calcium exert their effects are probably different. We therefore examined the possibility of an additive or synergistic effect of combined treatment with calcium and low dose estrogen on bone turnover in older women, using biochemical markers. Thirty-one healthy women over 70 yr of age were randomized to 12 weeks of treatment with either micronized 17beta-estradiol [0.5 mg/day Estrace (E2)] or 1500 mg/day elemental calcium, given as carbonate plus vitamin D (800 IU/day; Ca+D). At the end of the initial 12-week treatment period, both groups received both Ca+D and E2 for an additional 12 weeks. Eleven older women were followed for 36 weeks without any treatment and served as a control group. Serum and urine were collected at baseline, at 12 and 24 weeks on treatment, and at 12 weeks after treatment was terminated for measurement of biochemical markers of bone turnover. Markers of bone formation were bone alkaline phosphatase, osteocalcin, and type I procollagen peptide; markers of bone resorption were urinary cross-linked C-telopeptides and N-telopeptides of type I collagen, serum cross-linked N-telopeptides of type I collagen, urinary free deoxypyridinoline cross-links, and serum bone sialoprotein. Repeated measures ANOVA was used to determine changes in bone turnover measures over time by group. All markers of bone resorption decreased with initial treatment and decreased further with combination therapy (P < 0.001). Markers of bone formation decreased with Ca+D treatment, but not with E2 alone; there was no additional effect of combination therapy on formation markers compared to Ca+D alone. Neither markers of formation nor resorption changed in the control group. These results suggest that there is an additive effect of low dose estrogen and calcium on bone resorption, but not on bone formation, in older women. Thus, the combination of low dose estrogen plus calcium is likely to be more effective in older women than either treatment alone.

Process of care performance, patient characteristics, and outcomes in elderly patients hospitalized with community-acquired or nursing home-acquired pneumonia.

STUDY OBJECTIVES: To compare process of care performance, patient characteristics, and outcomes in a contemporary cohort of elderly (> or = 65 years) patients hospitalized with community-acquired pneumonia (CAP) or with nursing home-acquired pneumonia (NHAP). DESIGN: State-wide retrospective cohort study. SETTING: Thirty-four acute-care hospitals in Connecticut. PATIENTS: Elderly Medicare patients hospitalized in 1995-1996 with CAP (1,131) or with NHAP (528). MEASUREMENTS: Antibiotic administration within 8 h of hospital arrival, blood culture collection within 24 h of hospital arrival, oxygenation assessment within 24 h of hospital arrival, demographic and clinical characteristics, in-hospital complications, mortality, and length of stay. RESULTS: Process of care performance rates for patients with CAP and NHAP were equivalent for antibiotic administration within 8 h of hospital arrival (76.8% vs 76.3%, respectively; p = 0.82), blood culture collection within 24 h of hospital arrival (78.1% vs 81.1%, respectively; p = 0.31), and oxygenation assessment within 24 h of hospital arrival (94.7% vs 95. 3%, respectively; p = 0.70). Patients with CAP were younger than those with NHAP (median age, 80 vs 84 years, respectively; p < 0. 001), had less cerebrovascular disease (16.8% vs 34.7%, respectively; p < or = 0.001), and lower mortality risk scores at hospital presentation (median, 100 vs 137, respectively; p < or = 0. 001) than patients with NHAP. The median length of stay was equivalent (7 days), but the in-hospital mortality rate was lower in patients with CAP than in patients with NHAP (8.0% vs 18.6%, respectively; p < or = 0.001). CONCLUSION: Initial hospital processes of care are performed at the same rate in patients hospitalized with CAP or NHAP. However, patients with CAP are younger, are less acutely and chronically ill, and have lower in-hospital mortality rates than patients with NHAP.

How well are community-living women treated for osteoporosis after hip fracture?

OBJECTIVES: To examine whether women with recent hip fracture are receiving adequate treatment for osteoporosis. To examine patient and physician characteristics associated with adequate treatment for osteoporosis. DESIGN: Cross-sectional study with prospective and retrospective data collection. SETTING: Hartford County, Connecticut. PARTICIPANTS: Sixty community-living women age 65 and older identified from hospital databases with an International Classification of Diseases, Ninth Revision, code for nontraumatic hip fracture. MEASUREMENTS: Treatment for osteoporosis, healthcare utilization, primary care physician's specialty, Katz activities of daily living scale, Lawton instrumental activities of daily living scale, Short Portable Mental Status Questionnaire, Medical Outcomes Study Short Form 12, and Physical Activity Scale for the Elderly. RESULTS: Only 13% of participants were receiving adequate treatment for osteoporosis as defined by the National Osteoporosis Foundation (NOF) guidelines for osteoporosis, 47% reported partial treatment that did not meet NOF guidelines, and 40% were receiving no treatment for osteoporosis. No patient or physician characteristics were associated with the adequacy of treatment for osteoporosis in this small sample. CONCLUSIONS: Few of the women in our study were receiving adequate treatment for osteoporosis after hip fracture. There exists an opportunity to educate postmenopausal women and physicians about the importance of treatment for osteoporosis to increase the number of women offered and receiving osteoporosis treatment, especially older postmenopausal women with established, severe osteoporosis as evidenced by recent hip fracture.

Osteoporosis. Pathogenesis, diagnosis, and treatment in older adults.

Osteoporosis is a major cause of disability and excess mortality in older men and women. Hip fracture incidence accelerates approximately 10 years after menopause in women and after age 70 in men. Approximately 1 million Americans suffer fragility fractures each year at a cost of over 14 billion dollars. The disability, mortality, and cost of hip and vertebral fractures are substantial in the rapidly growing, aging population so that prevention of osteoporosis is a major public health concern. BMD is used to make the diagnosis of osteoporosis before incident fracture and predict fracture risk. Recommendations for treatment and prevention of osteoporosis based on BMD score have been published by the World Health Organization and the National Osteoporosis Foundation. In a process that continues throughout life, bone repairs itself by the coupled action of bone resorption followed by bone formation, sometimes referred to as bone turnover. Osteoblasts and osteoclasts are the primary cells involved in bone formation and resorption, respectively. The process of bone turnover is regulated by hormones, such as PIH and local factors such as IL-1 and prostaglandins. Following attainment of peak bone mass at age 25, bone loss begins, accelerates in women at menopause and slows again but continues into advanced years at a rate of 1% to 2% per year, similar to premenopausal bone loss rate. The leading theories of the mechanism of bone loss in older individuals is calcium deficiency leading to secondary hyperparathyroidism and sex hormone deficiency. Risk factors such as age, gender, ethnic background, smoking, exercise, and nutrition, and medical conditions associated with osteoporosis should be evaluated and modified when possible to prevent further bone loss. Osteoporosis treatment and prevention include weight-bearing exercise, calcium and vitamin D supplementation, estrogen replacement, bisphosphonates, selective estrogen receptor antagonists, and calcitonin. Although there is no currently approved treatment for osteoporosis in men, many of the treatments approved for osteoporosis in women hold promise to be beneficial in men.

Determinants of bone density in healthy older men with low testosterone levels.

BACKGROUND: Osteoporosis is a significant problem in older men, 30% of all hip fractures occur in men and the mortality rate following hip fracture exceeds that of women. Testosterone is thought to be important in the development of peak bone mass hut its role in age-related bone loss is not established. The purpose of this study was to define the predictors of bone mass ill healthy older men with low testosterone levels but without symptomatic osteoporosis. METHODS: Eighty-three community-dwelling white men, aged more than 65 years old, selected for low bioavailable testosterone levels (< or = 4.44 nmol/l) participated in a cross-sectional study located at a university general clinical research center. Sex hormone concentrations and markers of bone turnover were assayed in serum and urine. Risk factors for osteoporosis and physical activity were ascertained by physical examination and questionnaire, including the Physical Activity Scale in the Elderly (PASE) questionnaire. Bone mineral densities of the femoral neck (FN BMD), spine, and whole body were measured by dual x-ray absorptiometry. Lower extremity muscle strength (1 repetition maximum) was measured using a leg press machine. RESULTS: Mean bone mineral density values were 0.93 +/- 0.14 g/cm2 for femoral neck, 1.31 +/- 0.23 g/cm2 for spine, and 1.22 +/- 0.12 g/cm2 for whole body. Thirty-one of the 82 subjects (37%) had t scores < -1 and 12 of 82 subjects (15%) had t scores < -2.5 at the femoral neck. Multiple linear regression analysis demonstrated that bioavailable testosterone, body mass index (BMI), and PASE scores were positively correlated with, and significant predictors of, femoral neck BMD, accounting for 34.4% of the variance in FN BMD (F = 10.10, p = .001). Examining each variable independently, bioavailable testosterone accounted for 20.7%, physical activity score for 9.0%, and BMI for 6.5% of FN BMD. Using analysis of variance, mean values for FN BMD were significantly different between men grouped by tertile of bioavailable testosterone (F = 6.192, p = .003). FN BMD mean values were 0.86 +/- 0.14 g/cm2 for the lowest tertile, 0.94 +/- 0.16 for the middle tertile, and 0.99 +/- 0.14 for the highest tertile. Markers of bone turnover were inversely correlated, and strength directly correlated with BMD, but did not contribute to the multiple regression model. CONCLUSIONS: Fifty-two percent of older men with low bioavailable testosterone levels had BMD levels below the young adult normal range and are likely at an increased risk of fracture. Bioavailable testosterone, BMI, and physical activity scores were significant determinants of FN BMD in these men. These variables are potentially modifiable and, therefore, amenable to intervention. Hence, our results suggest the need for testosterone replacement and physical activity intervention trials in men at risk for osteoporotic fractures.

Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels.

BACKGROUND: A large proportion of men over 65 years of age have bioavailable testosterone levels below the reference range of young adult men. The impact of this on musculoskeletal health and the potential for improvement in function in this group with testosterone supplementation require investigation. METHODS: Sixty-seven men (mean age 76 +/- 4 years, range 65--87) with bioavailable testosterone levels below 4.44 nmol/l (lower limit for adult normal range) were randomized to receive transdermal testosterone (two 2.5-mg patches per day) or placebo patches for 1 year. All men received 500 mg supplemental calcium and 400 IU vitamin D. Outcome measures included sex hormones (testosterone, bioavailable testosterone, sex-hormone binding globulin [SHBG], estradiol, and estrone), bone mineral density (BMD; femoral neck, Ward's triangle, trochanter, lumbar spine, and total body), bone turnover markers, lower extremity muscle strength, percent body fat, lean body mass, hemoglobin, hematocrit, prostate symptoms, and prostate specific antigen (PSA) levels. RESULTS: Twenty-three men (34%) withdrew from the study; 44 men completed the trial. In these men, bioavailable testosterone levels increased from 3.2 +/- 1.2 nmol/l (SD) to 5.6 +/- 3.5 nmol/l (p <.002) at 12 months in the testosterone group, whereas no change occurred in the control group. Although there was no change in estradiol levels in either group, estrone levels increased in the testosterone group (103 +/- 26 pmol/l to 117 +/- 33 pmol/l; p <.017). The testosterone group had a 0.3% gain in femoral neck BMD, whereas the control group lost 1.6% over 12 months (p =.015). No significant changes were seen in markers of bone turnover in either group. Improvements in muscle strength were seen in both groups at 12 months compared with baseline scores. Strength increased 38% (p =.017) in the testosterone group and 27% in the control group (p =.06), with no statistical difference between the groups. In the testosterone group, body fat decreased from 26.3 +/- 5.8% to 24.6 +/- 6.5% (p =.001), and lean body mass increased from 56.2 +/- 5.3 kg to 57.2 +/- 5.1 kg (p =.001), whereas body mass did not change. Men receiving testosterone had an increase in PSA from 2.0 +/- 1.4 microg/l to 2.6 +/- 1.8 microg/l (p =.04), whereas men receiving placebo had an increase in PSA from 1.9 +/- 1.0 microg/l to 2.2 +/- 1.5 microg/l (p =.09). No significant differences between groups were seen in hemoglobin, hematocrit, symptoms or signs of benign prostate hyperplasia, or PSA levels. CONCLUSIONS: Transdermal testosterone (5 mg/d) prevented bone loss at the femoral neck, decreased body fat, and increased lean body mass in a group of healthy men over age 65 with low bioavailable testosterone levels. In addition, both testosterone and placebo groups demonstrated gains in lower extremity muscle strength, possibly due to the beneficial effects of vitamin D. Testosterone did result in a modest increase in PSA levels but resulted in no change in signs or symptoms of prostate hyperplasia.

Bone density, bone turnover, and hormone levels in men over age 75.

BACKGROUND: Osteoporosis is a substantial problem in older men, with 25% of all hip fractures occurring in men. The mechanisms of bone loss in older men are unknown, but elevated parathyroid hormone (PTH) and diminished testosterone (T) levels are postulated as contributing factors. METHODS: We measured bone mineral density (BMD), sex hormones, bone turnover markers, and calcium regulating hormones in a group of community-living men over the age of 75. RESULTS: Thirty-five men (mean age 79; range 75-88 years) without disease or medication known to affect bone metabolism participated in the study. Whole body BMD was 1.21+/-.15 g/cm2; lumbar spine BMD (L1-L4) was 1.10+/-.15 g/cm2; femoral neck BMD was .77+/-.14 g/cm2; and trochanteric region was .71+/-.13 g/cm2. The femoral neck and trochanteric region values were more than 1 SD below the mean for adult men (age 25-33 years) in 28/35 and 15/35 men, respectively. Deoxypyridinoline levels were above the normal range for premenopausal women in 23% of the men; N-telopeptide and C-telopeptide demonstrated a wide scatter, but the values remained in the normal range. T levels were found to be below normal range for adult men in 12 of 32 (38%) subjects and the PTH levels above the normal range in 8 of 35 (23%) subjects. Bone resorption markers correlated inversely with BMD of the whole body, femur, and spine (r=-.22 to -.48). There was an inverse correlation between total T and spine BMD which became insignificant after correcting for body mass index (BMI). In addition, there was no correlation between free or bioavailable testosterone and BMD. 1,25-(OH)2D levels correlated inversely with BMD at the femur and whole body, but no association was found with PTH or 25 OH-D. CONCLUSIONS: Men over 75 years of age had a wide range of BMD but frequently had low values at femoral sites. T levels were below the normal range in 38% of men, and PTH levels were elevated in 23% of men. There was an inverse correlation between total T and spine BMD which may have been dependent on the common effect of BMI. Bone mineral density was inversely related to markers of bone resorption.

Nonadherence and osteoporosis treatment preferences of older women: a qualitative study.

BACKGROUND: Physicians must have an understanding of patients' medication beliefs in order to enhance medication adherence. To increase understanding, this study examined how beliefs about medication and four osteoporosis treatments influenced treatment selection and adherence. METHODS: Six focus groups, three with 28 African Americans and one with 11 non-Hispanic white women, were conducted in English. Two groups with 16 Hispanics were conducted in Spanish. The convenience sample was recruited from senior centers and housing in lower socioeconomic geographic areas. The average age was 74.8 +/- 1.1 years. RESULTS: Adherence was associated with recognition of the serious consequences of nonadherence, realization of the beneficial effects, and the belief that medicines are not harmful. Doubts about physicians' competence to prescribe appropriate drugs were also revealed. Women who thought they were unlikely to fracture or perceived fracture outcomes as not severe chose no treatment. If they identified a need, they weighed benefits against the attendant risks to find the best alternative among the affordable options. Price considerations eliminated raloxifene and alendronate. Consideration of side effects eliminated estrogen and raloxifene. Calcium was viewed as a low-cost, low-risk alternative. Those who could afford alendronate and who viewed its side effects as preventable preferred it. Benefit and risk assessments may have been biased by fear of cancer and thromboembolic events. CONCLUSIONS: Women's beliefs about necessity of treatment, medication safety, cost of treatment, and treatment goals appear critical to osteoporosis treatment selection and adherence.

Osteoporosis: pathogenesis, diagnosis, and treatment in older adults.

Prevention of osteoporosis is a major health concern. Bone loss occurs throughout life in both women and men due to calcium deficiency, hormonal deficiency, and changes in bone formation. The diagnosis of osteoporosis can now be made prior to fragility fracture, allowing for prevention as well as treatment. Criteria for diagnosis of osteoporosis are reviewed, and a plan for the evaluation of secondary causes of osteoporosis is discussed. Also reviewed are prevention and treatment options such as exercise, calcium supplementation, hormone replacement, and new and investigational drugs.

Epidemiology and pathogenesis of osteoporosis.

Osteoporosis is likely to become the most common disorder of our aging population. An understanding of factors that affect the incidence of osteoporosis is critical if we are to successfully minimize the impact of this disorder on morbidity, mortality, and the cost of health care. This article will provide an overview of the frequency, distribution, and consequences of the various types of osteoporotic fractures in different populations. We will discuss the major risk factors, emphasizing those that are reversible. Fracture risk not only involves abnormalities of bone mass and architecture, but also factors that affect the incidence of falls. The racial, ethnic, and geographic differences in fracture incidence are associated with parallel differences in bone mineral density (BMD), but the differences are often relatively small, suggesting that other architectural or metabolic differences in the skeleton make an important contribution. On the other hand, when combined with low BMD, multiple risk factors and comorbid conditions increase the risk of fracture as well as morbidity and mortality from fracture. Osteoporosis can result pathogenetically from inadequate peak bone mass, excessive bone resorption, or impaired bone formation. These can be affected by genetics, nutrition, lifestyle, systemic hormones, and local factors. The relative importance of these mechanisms is not fully understood and may differ among patients. Nevertheless, our current understanding of epidemiology and pathogenesis can help clinicians to develop the optimal approach to diagnosis and management.

Prevention and treatment of osteoporosis.

Osteoporosis develops in older adults when the normal processes of bone formation and resorption become uncoupled or unbalanced, resulting in bone loss. Fractures are the result of decreased bone mass and strength and, in the case of wrist and hip fractures, usually involve a fall. Osteoporosis prevention and treatment programs should then focus on strategies that minimize bone resorption and maximize bone formation as well as on strategies that reduce falls. Optimal treatment and prevention of osteoporosis require modification of risk factors, particularly smoking cessation, adequate physical activity, and attention to diet, in addition to pharmacologic intervention. A number of pharmacologic options are now available to health care providers. This article focuses on US Food and Drug Administration--approved medications for osteoporosis and emphasizes the importance of using these agents as part of a comprehensive program that includes nonpharmacologic measures, complete diagnostic evaluation, and adequate follow-up with bone mineral density measurement.

The effects of knowledge, attitudes, and significant others on decisions to enroll in a clinical trial on osteoporosis: implications for recruitment of older African-American women.

This preliminary study explored the roles of knowledge, attitudes, and significant others on decisions of older African-American women to enroll in a clinical trial involving estrogen and osteoporosis. Sixteen older African-American women (average age 75 years) participated in three focus groups. Twelve of the women had enrolled in the clinical trial and four, although eligible, refused to enroll. Discussions revealed that knowledge of osteoporosis and estrogen and expectations of personal rewards and group benefits from medical research appear to differentiate the women who participated in the clinical trial from those who refused. The women who participated also perceived the research institution as accessible. In addition, assuring full disclosure of testing procedures and test results eased their apprehensions about participation. However, the women who refused to enroll saw no personal benefit and were unwilling to expose themselves, in part because of their age, to the risks of taking estrogen and the uncertain outcomes of the clinical trial. The study illustrates how focus groups can be used to develop multiple strategies to enable recruitment of older African-American women with different demographic characteristics, levels of knowledge, and attitudes toward a disease and medical research.

Estrogen replacement raises rat CRP without evidence of complement activation.

Given current controversies regarding anti- and pro-inflammatory effects of estrogen, there is a need to explore relationships between gonadal hormones and inflammation using appropriate animal models. It has been proposed that rats are not appropriate for such research since, contrary to the effect of estrogen in humans, earlier animal studies had reported that estrogen downregulates serum C-reactive protein (rCRP) levels in the rat. With these considerations in mind, we re-examined the effects of estrogen withdrawal and replacement on CRP expression and complement activation in the rat. F-344 rats underwent bilateral ovariectomy or sham surgery at 9-10 months of age. Four months later, ovariectomized rats were treated with traditional high-dose 17beta-estradiol (Hi-E2) capsules, lower-dose (Lo-E2) 17beta-estradiol capsules, or placebo capsules for 7 days prior to sacrifice. Levels of plasma rat C-reactive protein (rCRP) were significantly lower in ovariectomized vs. sham-operated animals (415.5 +/- 10.6 vs. 626.6 +/- 23.0 mg/L, p < 0.001). Estrogen replacement significantly raised rCRP levels in ovariectomized animals (690.0 +/- 28.0 mg/L in Lo-E2 and 735.5 +/- 35.8 mg/L in Hi-E2, respectively, p < 0.001). Plasma rCRP levels correlated significantly with both hepatic rCRP (r = 0.79, p < 0.001) and serum estradiol (r = 0.70, p < 0.001) levels. However, no significant differences were observed in indices of complement activation (C4b/c) or CRP-complement complex generation (rCRP-C3 complex). In the mature female rat, ovariectomy reduces and estrogen replacement raises rCRP. Effects of estrogen on plasma rCRP induction are mediated, at least in part, through hepatic mechanisms and do not appear to require or be associated with complement activation.