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This section summarizes the results of the seven systematic reviews of osteoporosis therapies published in this series [calcium, vitamin D, hormone replacement therapy (HRT), alendronate, risedronate, raloxifene, and calcitonin] and systematic reviews of etidronate and fluoride we have published elsewhere. We highlight the methodological strengths and weaknesses of the individual studies, and summarize the effects of treatments on the risk of vertebral and nonvertebral fractures and on bone density, including effects in different patient subgroups. We provide an estimate of the expected impact of antiosteoporosis interventions in prevention and treatment populations using the number needed to treat (NNT) as a reference. In addition to the evidence, judgements about the relative weight that one places on weaker and stronger evidence, attitudes toward uncertainty, circumstances of patients' and societal values or preferences will, and should, play an important role in decision-making regarding anti-osteoporosis therapy.
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Our studies showed that 5 mg alendronate per day was the lowest, most effective dose that persistently prevented bone loss in recently postmenopausal women with normal bone mass. The effect on bone mass and biochemical markers was found comparable to that of commonly recommended regimens of postmenopausal HRT, and 5 mg alendronate per day is suggested as a new option for prevention of postmenopausal osteoporosis. HRT must, however, still be considered the first choice for this indication because of additional beneficial effects on other organ systems. The effect of alendronate was unaffected by bone or fat mass status, but increased with increasing postmenopausal age. The implications were that alendronate stabilized bone mass to a comparable extent in women at particular risk of osteoporosis because of thin body habitus or low bone mass and in healthy postmenopausal women with normal bone mass. Calcium supplementation was insufficient to prevent bone loss and did not add an effect on bone metabolism when combined with alendronate treatment in recently postmenopausal women. The gastrointestinal risk and adverse event profile of 5 mg alendronate per day was comparable to that of placebo, and this dose of alendronate appeared safe for long-term use. Bone loss resumed at a normal postmenopausal rate promptly after withdrawal of alendronate in early postmenopausal women consistent with a substantial underlying natural bone loss during early menopause. Oral ibandronate increased bone mass at all skeletal regions in elderly postmenopausal women with low bone mass, and 2.5 mg ibandronate per day was the lowest dose with this effect. The results are indicative of ibandronate as an option for secondary prevention of postmenopausal osteoporosis, but longer-term phase III trials should be performed before ibandronate can be recommended for this indication. The study showed that 2.5 mg ibandronate per day was efficient for prevention of bone loss and increment in bone mass in a population of women at particular risk of osteoporosis because of low bone mass. There were no differences between 2.5 mg ibandronate per day and placebo in terms of side effects, including complaints from the gastrointestinal tract, and ibandronate appeared safe for longer-term use in this dosing. Bone loss resumed at a normal postmenopausal rate when treatment was withdrawn. The response in bone mass and biochemical markers indicated that 2.5 mg ibandronate per day is equivalent to 10 mg alendronate per day in postmenopausal women. Our studies of two recently developed biochemical markers, urine CTX and serum total OC, showed that bone turnover was lowest in the premenopausal period, where these biochemical markers furthermore revealed a negative association with bone mass. It indicated that increased bone turnover contributes to a small premenopausal bone loss and resulting lowered bone mass. In consistence, a small premenopausal bone loss was observed in some regions of the hip. The biochemical markers increased at the time of menopause, consistent with initiation of the postmenopausal bone loss, and became gradually more negatively associated with bone mass as time past the menopause increased. The biochemical markers were furthermore higher in postmenopausal women with low bone mass, consistent with the characterization of postmenopausal osteoporosis as a condition with increased bone turnover. Our results consistently indicated a central role of increased bone turnover for development of low bone mass and osteoporosis. It is, however, also important to stress that the associations between biochemical markers and bone mass were too weak to allow for a valid individual estimation of bone mass based on biochemical markers. In contrast, the biochemical markers were shown as valid tools for monitoring and prediction of treatment effect of bisphosphonates. CTX, NTX, and total OC revealed the best performance characteristics in this respect. Six months after start of treatment, the level of suppression of these biochemical markers of bone resorption and formation accurately reflected the size of the 1-2 year response in bone mass in groups of women treated with bisphosphonate. This was a clear advance over bone densitometry, which has a precision error in the area of the anticipated yearly bone mass response during bisphosphonate therapy. The relationship was consistent during treatment with alendronate or ibandronate and in younger or elderly postmenopausal women. In individual patients, cut-off values of an about 40% decrease in urine CTX or NTX and an about 20% decrease in total OC validly predicted long-term prevention of bone loss. The sensitivity of prediction was high, but the specificity low. This implicated that the biochemical markers could be used as an exact method to detect "responders" to therapy, whereas "non-responders" to bisphosphonate treatment should be detected with bone densitometry in patients who do not reveal a decrease below the cut-off value in the biochemical marker during treatment. However, before such approach can be generally recommended the cut-off values of the biochemical markers should be validated in future clinical trials of bisphosphonate. Postmenopausal osteoporosis develops slowly over many years and mainly becomes a significant individual and socio-economic health problem 1-3 decades after the menopause. Prevention of postmenopausal osteoporosis by bisphosphonates is therefore likely to imply a treatment regimen of at least a decade, as presently recommended for HRT (Consensus Development Statement 1997). However, future cost-effectiveness studies should reveal when bisphosphonate treatment should ideally be initiated. Our studies showed that the bisphosphonates were effective over the range from general recommendation (recently postmenopausal women with normal bone mass) to a reservation for women at particular risk of osteoporosis (elderly women, thin women, or women with osteopenia). Presently available biochemical markers could be used for groupwise and individual monitoring and prediction of treatment response. Most presently available biochemical markers, however, have the drawback of a low specificity. Recent studies of CTX measured in serum are promising, and indicate that this new biochemical marker might have overcome these drawbacks due to a pronounced response to treatment and a low long-term biological variation (Christgau et al. 1998b, Rosen et al. 1998, and 2000).
BACKGROUND: Treatment with estrogen causes increased release of nitric oxide and this appears to be an important mechanism involved in the cardioprotective effect of estrogen. Previous studies have clearly shown that estrogen has an acute vasodilatory effect. Recently, abnormality of flow mediated endothelial dilation, which is defined as an endothelial dysfunction, has been proposed as an early manifestation of atherogenesis. However, its effect in type 2 diabetes is unknown. Stimulus-provoked endothelium dependent dilatation, using high-resolution external vascular ultrasound, is a useful method in the measurement of endothelial function. The main advantages of this method are that it is completely non-invasive, accurate and reproducible. This classical method for the measurement of endothelial dysfunction, utilizing non-invasive, high-resolution ultrasonography, has some limitations especially in terms of reproducibility. To improve the accuracy and reproducibility of this method, measurements made for this study involved the use of an additional attachment. This device was an ultrasound probe that was attached to the arm of patient. In addition, this study evaluated not only a change in diameter in terms of flow mediated vasodilation, but also initial and peak response times during this test. The aims of this study are: (1) to evaluate the flow mediated peak vasoreactivity (FMD), the lag time from base line to initiation of vasodilation (IRT) and the peak response of endothelial dependent vasodilation in a control group and in young diabetic patients; and (2) to evaluate the effect of estrogen treatment on flow mediated vasodilation in postmenopausal women with diabetes. METHOD: Measurements were taken for flow mediated vasodilation (endothelial dependent vasodilation: FMD), endothelial independent vasodilation (EID) and lag time from base line to initial reaction of FMD. The aforementioned non-invasive method and attachment were used. Subjects for the experiment were 12 young people with diabetes (six male and six female, mean age 26.3) and 12 age-matched healthy controls (six male and six female, mean age 25.6). In addition, measurements were taken for FMD, EID and lag time in the brachial artery before and after estrogen supplementation (Premarin 0.625 mg for 7 days). Subjects for the experiment were 16 normal postmenopausal women and 18 age-matched postmenopausal women with type 2 diabetes. RESULT: There is no significant difference in BMI (body mass index), mean age, or blood pressure between the control group and the young diabetic group. There were no differences in age, total and LDL cholesterol levels or body mass index between the groups of postmenopausal women (P<0.05). However, the HDL cholesterol level was found to be significantly lower in postmenopausal women with diabetes than in normal postmenopausal women (respectively, a mean+/-SD; 38.95+/-11.96 mg/dl vs. 52.20+/-9.55 mg/dl, P<0.05). The FMD of young diabetic patients is slightly lower than that of age-matched young healthy controls (healthy control: 8.9+/-2.7%, young diabetic patients: 6.3+/-2.1%, P<0.05). There was no difference in endothelial independent vasodilation between the control group and the young diabetic group. The IRT of FMD was significantly shorter in the healthy control group than in the young diabetic group (healthy control: 20.4+/-2.8 s, diabetic group: 29.5+/-5.4 s, P<0.0001). In contrast, the IRT of EID was no different between the two groups. The IRT of FMD showed a significant negative correlation with FMD (r=-0.61, P<0.01) and a significant negative correlation with high-density lipoprotein (HDL) cholesterol (r=-0.68, P<0.0001). The basal endothelium dependent vascular reactivity was significantly decreased in postmenopausal women with diabetes compared with normal postmenopausal women (8.0+/-3.9 vs. 13.7+/-6.2%, P<0.05). Estrogen supplementation increased endothelium dependent vasodilation not only in postmenopausal women with diabetes (from 8.0+/-3.9 to 15.1+/-4.0%, P<0.05) but also in normal postmenopausal women (from 13.7+/-6.2 to 20.1+/-4.7%, P<0.05). In contrast, the responses to sublingual nitroglycerin were comparable between postmenopausal women with diabetes (from 21.1+/-6.0 to 22.1+/-4.1%, P>0.05) and normal postmenopausal women (from 25.8+/-7.8 to 25.2+/-4.5%, P>0.05), both before and after estrogen supplementation. CONCLUSION: These findings indicate that in addition to the percentage change in FMD, lag time from base line to initial response time (IRT) of FMD is a good indicator for evaluation of endothelial dysfunction. Also, this new parameter may be a more sensitive parameter for differentiation between the diseased state and the normal state of the endothelium than percentage changes in FMD. In terms of postmenopausal women, endothelial dysfunction was prominent in women with diabetes and was significantly improved by estrogen but not reversed. These results suggest that other factors in addition to estrogen deficiency play a role in endothelial dysfunction in postmenopausal women with diabetes mellitus.
It is currently believed that the postmenopausal ovary remains a gonadotropin-driven, androgen-producing gland. However, the adrenal contribution to circulating androgen levels may explain some conflicting results previously reported. In addition, the steroidogenic potential and gonadotropin responsiveness of the postmenopausal ovary have not been recently reassessed. Plasma T, bioavailable T, free T, androstenedione (Adione), and dehydroepiandrosterone sulfate levels were measured in postmenopausal or ovariectomized women with complete adrenal insufficiency, compared with women with intact adrenals. A stimulation human chorionic gonadotropin test (on d 0, 3, and 6) was performed in postmenopausal women with adrenal insufficiency. Dexamethasone was administered for 4 d in postmenopausal women with intact adrenals. Intraovarian T and androstenedione were also measured in homogenates of ovarian tissue from postmenopausal women. Immunocytochemistry was performed on postmenopausal ovaries and premenopausal controls to detect the presence of steroidogenic enzymes (P-450 aromatase, P-450 SCC, 3beta HSD, and P-450 C17) and gonadotropin receptors. Plasma androgen levels were below or close to the limit of the assay in all women with adrenal insufficiency. They were similar in postmenopausal and oophorectomized women with normal adrenals. No hormonal changes were observed after human chorionic gonadotropin injections in women with adrenal insufficiency. In contrast, a dramatic decrease of all steroids was observed after dexamethasone administration in postmenopausal women with intact adrenals. Intraovarian T and androstenedione levels were negligible in postmenopausal ovarian tissue. P-450 aromatase was absent from the 17 ovaries studied, and the enzymes for androgen biosynthesis were either absent (n = 13) or present in very low amounts (n = 4). In all the postmenopausal ovaries, FSH and LH receptors were completely absent. In the absence of adrenal steroids, postmenopausal women have no circulating androgens. This result is consistent with the immunocytochemical studies showing the almost constantly absent steroidogenic enzymes and LH receptors in the postmenopausal ovary. Thus, the climacteric ovary is not a critical source of androgens. The arrest of androgen secretion after menopause may impact significantly on women's health.
UNLABELLED: Decreased bone mineral density (BMD) with age is an increasing health problem, especially for postmenopausal women. Multiple factors have been reported to affect BMD including both genetic and environmental factors such as calcium intake and physical activity. For Thailand, people residing in different regions may differ in BMD due to these factors. However, there is a paucity of data concerning this issue. The objectives of this study were to identify the lifestyle factors which may influence BMD and to investigate the association between BMD and these factors in postmenopausal women who have been living in Bangkok and other provinces in Thailand. Subjects consisted of 466 postmenopausal women aged 46-90 years including 236 Bangkokians (116 early postmenopausals and 120 late postmenopausals) and 230 non-Bangkokians (134 early postmenopausals and 96 late postmenopausals). All were healthy and ambulatory. BMD was measured by dual energy X-ray absorptiometry (DEXA, Expert XL). Calcium intake was assessed by food-frequency questionnaire. Data were expressed by mean + /- SEM. There were 22 per cent (n=52), 5.9 per cent (n=14), and 4.2 per cent (n=10) of postmenopausal Bangkokians while 13.9 per cent (n=32), 4.3 per cent (n=10), and 2.2 per cent (n=5) of postmenopausal non-Bangkokians who had low BMD at spine, femoral neck, and at both sites, respectively. Spine BMD (SPBMD) and femoral neck BMD (FNBMD) increased significantly across the quartiles of calcium intake in both groups of subjects (P<0.05) and a significant difference was found between the lowest and the highest quartiles of calcium intake (P<0.05). Moreover, BMD at both regions was shown to be correlated with calcium intake, exercise and sunlight exposure in these subjects (P<0.001). Further analysis revealed higher BMD at spine (0.992 + 0.02 vs 0.945 +/- 0.02 g/cm2, P<0.05) and at femur (0.780 +/- 0.01 vs 0.740 +/- 0.01 g/cm2, P<0.05), calcium intake (348.9 +/- 12.7 vs 316.3 +/- 8.0 mg/day, P<0.05), exercise (2.8 +/- 0.1 vs 2.4 +/- 0.1 h/wk, P<0.001) and sunlight exposure (2.9 +/- 0.06 vs 1.9 +/- 0.04 h/day, P<0.001) were found in late postmenopausal women in other provinces than their counterparts in Bangkok. Nevertheless, no significant difference of BMD at both sites, calcium intake and exercise was found in the early postmenopausal groups of these two areas. CONCLUSIONS: There were significant differences in BMD and lifestyle factors between late postmenopausal women in Bangkok and other provinces. Environmental factors especially calcium intake, exercise and sunlight exposure, may influence BMD in late postmenopausal Thai women.
During the late 1970s, there was a dramatic reduction in postmenopausal estrogen use in the United States, which may have reflected concern over a well-publicized postmenopausal estrogen-endometrial cancer link. The authors studied 310 postmenopausal women in a defined population over the period 1974-1981 to evaluate whether hysterectomy and certain other characteristics predicted change in postmenopausal estrogen use status during this period and, as a secondary issue, whether women who subsequently began postmenopausal estrogen use had different characteristics prior to use, an important question in the evaluation of the relation of postmenopausal estrogen use to morbidity and mortality from cancer, cardiovascular disease, or other diseases in observational studies. The only strong predictor of whether postmenopausal estrogen use would be discontinued was the presence of an intact uterus. Women who discontinued postmenopausal estrogen use were also somewhat older and heavier than those who continued, but were otherwise quite similar on a wide range of variables, including risk factors for and the presence of various chronic diseases. Similarly, the absence of a uterus was the only strong predictor of the initiation of postmenopausal estrogen use. Thus, concern about a possible postmenopausal estrogen-endometrial cancer link appeared to have been the major determinant of change in postmenopausal estrogen use in this time period. In the secondary analysis, variables other than hysterectomy did not discriminate between women who initiated postmenopausal estrogen use versus those who did not report use of postmenopausal estrogens, suggesting that a broad range of other characteristics was not a priori different in these two groups.
Hormone replacement therapy (HRT) with ovarian hormones is an important therapeutic modality for postmenopausal women. However, a negative side effect of HRT is an increased risk of breast cancer. Surgical induction of menopause by ovariectomy (OVX) in mice is an experimental model that may provide insights into the effects of hormone replacement therapy on the human breast. We have developed a mouse model of early and late postmenopausal states to investigate the effects of HRT on the normal mammary gland. The purpose of this study was to determine if HRT-induced proliferation was due to the direct action of the hormones on the mammary gland, or mediated systemically by hormones or growth factors produced elsewhere in the body. Estrogen (E) or E plus the synthetic progestin, R5020, were implanted directly into the mammary glands of early (1 week post OVX) and late (5 week post OVX) postmenopausal mice instead of administration by injection. We report that responses of early and late postmenopausal mice to implanted hormones were the same as those observed previously with systemically administered hormones. Implanted E conferred an enhanced proliferative response in the late postmenopausal gland characterized morphologically by enlarged duct ends. E+R5020 implants induced similar degrees of cell proliferation in both postmenopausal states but the morphological responses differed. Ductal sidebranching was observed in early postmenopausal mice, whereas duct end enlargement was observed in late postmenopausal mice. The differences in morphological response to E+R5020 in 5 week post OVX were associated with an inability of E to induce progesterone receptors (PR) in the late postmenopausal gland. The responses of the late postmenopausal glands to E and E+P were very similar to that observed previously in immature pubertal glands in ovary-intact mice. In pubertal mice, PR cannot be induced by E unless the mammary gland is pre-treated with EGF-containing implants. Similarly, herein pre-treatment of the late postmenopausal mammary gland with EGF-containing implants restored PR induction by E. Thus, EGF may determine the sensitivity of the mammary gland to E and E+P in late postmenopause and at puberty.
AIM: Modern understanding of the etiology of postmenopausal osteoporosis is based on the imbalance between bone resorption and formation due to estrogen deficiency, which may take several forms and combinations of decreased and/or increased activity of both or one cell type. Studies of postmenopausal osteoporosis have pointed to the existence of heterogeneity in the remodeling imbalance. Bone histology analyzed in a group of women with established postmenopausal osteoporosis undergoing bone biopsy is part of the diagnostic procedure. Data were compared and grouped according to the published histomorphometric classification of postmenopausal osteoporosis. METHODS: The study included 43 postmenopausal women aged 44-71 years with osteoporosis established by densitometry of the lumbar spine and hip. Secondary causes of osteoporosis were ruled out. Full thickness transiliacai bone biopsy specimens were obtained after double labeling regime with oxytetracycline (Geomycin, Pliva). Biopsy specimens were processed for undecalcified embedding in resin and sections stained by Goldner trichrome and toluidine blue, or used for fluorescence microscopy. A grid attached to the microscope eyepiece was used for histomorphometry. The following parameters were assessed according to the recommendations of the American Society for Bone and Mineral Research: bone volume (BV/TV, %), osteoid surface (OS/BS, %), osteoblast surface (Ob. S/BS, %), osteoid volume (OV/BV, %), osteoid thickness (O. Th, m), osteoclast surface (Oc. S/BS, %), mineral apposition rate (MAR, m/day). Thus obtained data were compared to published reference data for normal healthy population and also expressed as z-scores (the number of standard deviations by which the value differs from the mean of the normal age and sex matched controls). The study was approved by the hospital ethics committee. All patients signed an informed consent to take part in the clinical study. DISCUSSION: Histomorphometric analysis of bone biopsy demonstrated that on an average bone resorption, i.e. osteoclast surface, was considerably increased and osteoid volume moderately increased. The remaining histomorphometric parameters studied were generally normal for age and sex as compared to the published reference data. Increased osteoclast surface in 65% of patients indicated that bone loss was an active and prevailing process in these postmenopausal women, which was considerably more pronounced than in the normal age-matched population. Results of the histomorphometric analysis were categorized according to the published classification of postmenopausal osteoporosis. The percentage of patients in each group differed from literature data, most probably due to the sample size and choice. None of the patients had histomorphometric features of reduced osteoblastic and osteoclastic activity, but in 37% of postmenopausal women osteoclastic activity was increased while osteoblastic activity was normal, a feature not described in the original histomorphometric classification of postmenopausal osteoporosis. CONCLUSIONS: Histomorphometric analysis of bone biopsy in women with postmenopausal osteoporosis revealed bone resorption as a predominant finding. Different groups were recognized based on the diversity of bone cell activity. The difference in the frequencies in study groups, and observation of a distinct group not included in the histomorphometric classification of postmenopausal osteoporosis probably resulted from sample size and nonspecific population traits. Histomorphometric analysis of bone in postmenopausal osteoporosis is an important contribution to better understanding of this most common bone disorder.