Bisphosphonates for prevention of postmenopausal osteoporosis

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 Bone loss resumed at a normal postmenopausal rate when treatment was withdrawn.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).     

Tibolone for prevention and treatment of postmenopausal osteoporosis

Tibolone has been widely accepted as remedy for vasomotor symptoms and for prevention of bone loss. Studies over the past 25 years have documented its effects on bone mineral density in younger and older women. Tibolone reduces bone turnover substantially (about the same amount as hormone therapy). Increases in bone mineral density (BMD) accompany this reduction in bone turnover, but like all other antiresorptive therapies, reduction in fracture risk (i.e. 50%) is always greater than would be predicted from BMD change. Finally, as with hormone therapies, dosage reductions have been prompted by new evidence of low dosage efficacy and concern over dose-related side effects. Solid evidence has now emerged from large, dose-ranging studies that the 1.25mg tibolone dosage is adequate for preservation of BMD and for reduction of fracture risk. Now that fracture efficacy has been added to the list of tibolone's documented bone benefits, physicians must consider this in the overall risks and benefits of its use.     

Oral hormone therapy with 17beta-estradiol and 17beta-estradiol in combination with norethindrone acetate in the prevention of bone loss in early postmenopausal women: dose-dependent effects

OBJECTIVE: A 2-year multicenter, double-blind, randomized, placebo-controlled study examined the efficacy and safety of different doses of 17beta-estradiol (E(2)) alone and continuous-combined oral formulations of E(2) and norethindrone acetate (NETA) versus placebo in the prevention of bone loss in newly menopausal women. DESIGN: Patients were randomized to one of seven groups: placebo, E(2) 0.25 mg, E2 0.5 mg, E(2) 1 mg, E(2) 1 mg/NETA 0.25 mg, E(2) 1 mg/NETA 0.5 mg, or E(2) 2 mg/NETA 1 mg. Treatment was a once-daily tablet taken for 26 months. The primary efficacy endpoint was the change in bone mineral density (BMD) at the lumbar spine, measured by dual-energy x-ray absorptiometry, at screening and at 13, 19, and 26 months. BMD changes at the femoral neck and trochanter were also assessed. Biochemical markers of bone metabolism were measured at baseline, and at 3, 6, 13, 19, and 26 months. Histological diagnoses of endometrial samples were tabulated for each treatment group. RESULTS: A total of 327 women were randomized and 189 women completed the 2-year trial. BMD at the lumbar spine decreased 2.3% in the placebo group. The lowest dose of unopposed E(2) prevented bone loss at the spine and hip. Significant increases in spine BMD compared with placebo occurred in all groups of treatment with E(2) and were more pronounced in the combination groups. Compared with placebo, women receiving active treatment experienced greater reductions in bone resorption markers. The effects were evident by 6 months and generally remained stable thereafter. Adverse events, primarily associated with the endometrium, were the most common reasons for discontinuation. CONCLUSIONS: There is a dose-dependent effect of E(2) on BMD. The addition of NETA seems to enhance the response in BMD observed with E(2). Low doses of E(2) (1 mg and lower) can be considered for the prevention of osteoporosis, while titrating the hormone dose to individual patient's needs.     

Percutaneous 17beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women

OBJECTIVE: To determine the efficacy and tolerability of two strengths of percutaneous 17beta-estradiol in a hydroalcoholic gel and placebo in controlling vasomotor symptoms of menopause. DESIGN: A total of 221 postmenopausal women were assigned randomly to treatment with percutaneous 17beta-estradiol gel 1.25 g (containing 0.75 mg of estradiol) or 2.5 g (containing 1.5 mg of estradiol) or placebo gel applied once daily for 12 weeks. The primary efficacy variable was the mean change from baseline in the frequency of moderate/severe hot flushes. In addition, the mean changes from baseline in the frequency and severity of all hot flushes were assessed. Safety and tolerability were evaluated from endometrial biopsy, adverse events, and laboratory tests. RESULTS: A significant reduction (P < 0.05) in the mean frequency of moderate-to-severe hot flushes and mean frequency and severity of all hot flushes was observed with both 17beta-estradiol gel groups compared with placebo. The mean number of moderate-to-severe hot flushes at the end of the study with 17beta-estradiol gel 2.5 g, 17beta-estradiol gel 1.25 g, and placebo gel was 2.0, 2.8 and 5.2, respectively. The overall incidence of adverse events was not significantly different among groups, though a higher incidence of estrogen-related adverse events was reported with the 17beta-estradiol gel 2.5-g dose. CONCLUSIONS: 17beta-estradiol gel was effective and well tolerated for alleviating moderate-to-severe hot flushes in postmenopausal women. Therapy may be initiated with the 1.25-g dose with an increase to the 2.5-g dose if needed.     

Acute administration of 17beta-estradiol improves endothelium-dependent vasodilation in postmenopausal women

Objectives: Estrogen’s effect on endothelial function in postmenopausal women with mild hypertension but no other cardiovascular risk factors remains unclear. This study investigated the effect of an acutely administered therapeutic/low dose of 17β-estradiol on vasodilation in this patient population. Methods: Forearm blood flow (FBF) was measured in seven white, hypertensive (blood pressure 144 ± 8/93 ± 5 mmHg), postmenopausal (mean age: 54.4 ± 5 years) women at baseline and during the intra-brachial infusion of increasing doses of acetylcholine (ACh; 0.75, 5, and 15 μg/100 mL tissue/min) and sodium nitroprusside (NP; 1, 2, and 4 μg/100 mL tissue/min). These measurements were obtained both before and after the sublingual administration of 17β-estradiol. Eight normotensive women (blood pressure 115 ± 8/76 ± 5 mmHg) with otherwise similar characteristics served as controls (mean age: 55.8 ± 5 years). Exclusion criteria included medications or any condition that could alter endothelial function. Results: Before estradiol administration, FBF values at baseline and after all doses of ACh and NP were similar between groups. Acutely administered 17β-estradiol significantly improved the FBF response to ACh in both the normotensive (maximal response: 17.6 ± 5 versus 22.5 ± 7 mL/min/100 mL) and hypertensive (11 ± 4 versus 16 ± 6; 12 ± 4 versus 17 ± 5 and 14 ± 3 versus 20 ± 7 mL/min/100 mL) groups. It also altered the NP dose–response curve in the both groups. Conclusion: 17β-estradiol improved vasodilatory responses in mildly hypertensive postmenopausal women without other risk factors for cardiovascular disease.     

Efficacy of ipriflavone in the prevention and treatment of postmenopausal osteoporosis

The efficacy of ipriflavone was investigated in a 1-year double-blind, placebo-controlled, parallel group clinical trial. Ninety-one postmenopausal women completed the study, 41 received ipriflavone and 50 placebo treatment. After six months the bone mineral density of the L2–L4 vertebral region increased in the ipriflavone-treated group (0.015 g/cm²), whereas it decreased in the placebo-treated group. The differences between the treatment groups were statistically significant. Our results support the efficacy of ipriflavone in the treatment of postmenopausal osteoporosis. Since the positive effect was more pronounced after 6 months, the possibility of an intermittent ipriflavone treatment might be taken into consideration in the future.     

金雀异黄素防治绝经后骨质疏松症机制的研究进展

大豆制品中所含的植物雌激素金雀异黄素，作为一种天然的选择性雌激素受体调节剂，具有雌激素样作用而无雌激素样副作用，已成为取代传统激素替代疗法的热门研发对象。金雀异黄素防治绝经后骨质疏松的机制可能涉及到多种途径，包括ER受体途径，局部细胞因子途径，旁分泌激素途径，OPG/RANK/RANKL途径等。     

Novel enzyme immunoassay for 17 beta-estradiol.

A novel approach to the enzyme immunoassay of analytes is presented and illustrated by demonstration of an estradiol assay. The assay depends on the competitive binding of estradiol and estradiol-DNP conjugate to immobilized anti-estradiol. The amount of estradiol-DNP bound is inversely proportional to the amount of free estradiol, and is measured through the use of peroxidase-labeled anti-DNP antibodies. The assay gives a dose-response curve from 10 pg/tube to 450 pg/tube and shows satisfactory correlation with radioimmunoassay.     

A prospective randomized comparative study of the effects of intranasal and transdermal 17 beta-estradiol on postmenopausal symptoms and vaginal cytology

CONTEXT: Investigating the adverse effects of oral hormone replacement therapy (HRT), the clinical effectiveness of alternative combinations and route of administrations. AIM: To compare the effects of intranasal and transdermal 17 beta-estradiol combined with vaginal progesterone on vasomotor symptoms and vaginal cytology. SETTINGS AND DESIGN: A 12-week, prospective, randomized comparative study was conducted between July 2005 and September 2006. MATERIALS AND METHODS: Eighty postmenopausal women aged between 42-57 years, who had scores of > or =1.7 on the menopause rating scale-I (MRS-I) items "1-6", were randomly assigned to receive intranasal (300 microg/day, n =40) or transdermal (50 microg/day, n =40) 17 beta-estradiol continuously. All patients also received a vaginal progesterone gel twice weekly. Vasomotor symptoms were evaluated at weeks 0, 4, 8 and 12. Vaginal maturation index (VMI) was evaluated at weeks 0 and 12 of the study. STATISTICAL ANALYSES: The Mann-Whitney U and the Wilcoxon tests were used. P < 0.05 was regarded as significant. RESULTS: Thirty-two women in the intranasal and 29 women in the transdermal group completed the study. The total score of the MRS, the sum-scores of Factor 1 "HOT FLUSHES" and Factor 2 "PSYCHE" significantly decreased in both groups at week 4. Factor 3 "ATROPHY" scores significantly decreased only in the transdermal group at week 12. The VMI showed no changes within and between the two groups at the end of the study. CONCLUSION: Intranasal and transdermal 17beta-estradiol combined with vaginal progesterone gel as a continuous HRT caused a similar decrease in vasomotor symptoms but did not have any significant effect on VMI after 12 weeks of treatment in this study population.     

Changes in lipid and lipoprotein profile in postmenopausal women receiving low-dose combinations of 17beta-estradiol and norethisterone acetate

OBJECTIVE: To evaluate the modification of lipid and lipoprotein by use of low doses of continuous-combined formulations of 17beta-estradiol (E ) and norethisterone acetate (NETA) in healthy postmenopausal women. DESIGN: The study was designed as a double-blind, randomized, placebo-controlled trial. A total of 120 healthy postmenopausal women were randomized to one of three treatment arms: (1) placebo group ( = 40); (2) E /NETA 0.25-mg group-subjects receiving oral continuous-combined E 1 mg and NETA 0.25 mg ( = 40); (3) E /NETA 0.5-mg group-women who were treated with E 1 mg and NETA 0.5 mg ( = 40). The duration of study was 12 months. Plasma levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL) cholesterol, triglycerides, lipoprotein(a), apolipoprotein A and apolipoprotein B were determined on four occasions (i.e., baseline, 3-, 6-, and 12-month visits). RESULTS: There were no differences in the baseline characteristics among the three groups. A total of 102 women completed the study, resulting in a compliance rate of 85%. There was a significant reduction of total cholesterol, LDL cholesterol, and lipoprotein(a) in both combined groups when compared with placebo. The level of apolipoprotein B declined significantly only in the E /NETA 0.25-mg group. Decrements were observed within 3 months of treatment and maintained thereafter. No significant changes were found in triglycerides, VLDL cholesterol, HDL cholesterol, apolipoprotein A, and LDL/HDL ratio. Between the two active combined groups, no statistically significant differences were noted. CONCLUSION: Favorable changes in lipids and lipoproteins were associated with the low dose of E /NETA combinations. These effects may contribute to the reduction or prevention of atherogenesis in postmenopausal women.     

Histomorphometric classification of postmenopausal osteoporosis: implications for the management of osteoporosis.

AIMS--To define and group static and dynamic iliac crest histomorphometric parameters in women with established osteoporosis. METHODS--Iliac crest biopsy specimens from 146 white women were sectioned undecalcified and examined using image analysis. RESULTS--Five distinct groups were defined on the basis of histomorphometric changes in cell function: group 1, decreased osteoblastic and osteoclastic activity; group 2, decreased osteoblastic and increased osteoclastic activity; group 3, increased osteoblastic and osteoclastic activity; group 4, no bone surface cell activity; and group 5, apparently normal osteoblastic and osteoclastic activity. CONCLUSIONS--Five distinct subgroups of patients with postmenopausal osteoporosis can be defined based on changes in bone cell function. Defining cellular dysfunction in this way may be important for tailoring treatment regimens to the needs of individual patients.     

Oral 17beta-estradiol (1 mg) continuously combined with dydrogesterone improves the serum lipid profile of postmenopausal women

OBJECTIVE: To investigate the effects of 1 mg 17beta-estradiol continuously combined with 2.5, 5, 10, or 20 mg dydrogesterone on the serum lipid profile of postmenopausal women. DESIGN: Serum lipid profile was measured in two 1-year studies performed in healthy, nonhysterectomized, postmenopausal women. One study (n = 182) had an open design and investigated oral 17beta-estradiol 1 mg daily continuously combined with dydrogesterone 2.5 mg daily; the other study (n = 326) had a double-blind, randomized design and investigated oral 17beta-estradiol 1 mg daily continuously combined with dydrogesterone at doses of 5, 10, or 20 mg daily. RESULTS: With all four dosages of dydrogesterone, serum total and low-density lipoprotein cholesterol were significantly reduced (-4.6% to -7.6% and -6.3% to -11.6%, respectively), whereas high-density lipoprotein cholesterol was significantly increased (+4.3% to +7.4%). Serum apolipoprotein A1 and B also improved significantly, reflecting the favorable changes in high-density lipoprotein and low-density lipoprotein cholesterol, as did lipoprotein(a). CONCLUSION: Oral 17beta-estradiol 1 mg daily continuously combined with dydrogesterone 2.5 to 20 mg daily has beneficial effects on serum lipid profile in postmenopausal women.     

伊班膦酸钠治疗绝经妇女骨质疏松的Meta分析

BACKGROUND: Alendronate has a marked enhancing effect on bone mineral density. Ibandronate is the newest (the third generation) bisphosphonates. Evidence-based medicine data on the therapeutic effects of both two drugs remain lacking because of different administration routes and time. OBJECTIVE: To compare the therapeutic effects of ibandronate and alendronate on postmenopausal osteoporosis. METHODS: A computer-based online search was conducted in CNKI, PubMed, CECDB, BMA, VIP, CQVIP, CBM, EMbase, ASP, The Cochrane Library, and EMCC databases from August 1999 to August 2015 to screen the relevant randomized controlled trials. Meta-analysis was performed using Stata/SE version 12.0 software by extracting data from the relevant articles. RESULTS AND CONCLUSION: A total of 10 randomized controlled trials involving 725 patients (ibandronate and alendronate for 379 and 346 patients, respectively) were included. The meta-analysis results showed that bone mineral density was significantly increased (P=0.174, I2= 29.4%, WMD=0.03, 95%CI (0.01-0.04)) at 6 months after treatment and incidence rate of fracture was significantly decreased (P=5.810, I2=0%, OR=0.32, 95%CI: (0.10-1.00)) during 1-year treatment with ibandronate compared with alendronate treatment. However, no significant differences were found between two drug treatments in lumbar spine bone mineral density at 1 year after treatment and the incidence rate of fracture during 6-month treatment. Six-month treatment of ibandronate can improve bone mineral density and reduce the incidence rate of fracture of patients with postmenopausal osteoporosis. 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Effects of intranasal 17beta-estradiol administration on serum bioactive interleukin-6 and C-reactive protein levels in healthy postmenopausal women

OBJECTIVE: Oral estrogen increases the levels of C-reactive protein (CRP), which is an independent risk factor for coronary heart disease in healthy individuals. The aim of our study was to investigate the effects of intranasal 17beta-estradiol (E2) on serum CRP and its most potent stimulant, interleukin-6 in healthy postmenopausal women. DESIGN: Thirty-six healthy postmenopausal women (45-54 y) were enrolled. According to their individual preferences, they were assigned to intranasal (n = 10), transdermal (n = 14), or oral (n = 12) continuous E2 treatment with a sequential progestin (10-14 d in a 28-d cycle). Blood samples were drawn at baseline and after 3, 6, and 12 months during the estrogen-only phase to adjust for the progestin effect. RESULTS: In women taking intranasal or transdermal E2, there were no significant changes in median serum CRP levels during the 12-month treatment period. In women taking oral E2 preparations, serum median CRP levels were significantly higher compared to baseline after 6 and 12 months of the therapy (P < 0.05). Conversely, serum median bioactive interleukin-6 levels were significantly lower after 6 and 12 months in women taking E2 intranasally or orally and after 12 months in women taking E2 transdermally (P < 0.05). CONCLUSIONS: The results of our study show that intranasal, similarly to transdermal, E2 administration does not increase serum CRP levels in postmenopausal women. They also support the hypothesis that CRP increase during oral estrogen treatment is not mediated by the enhancement of interleukin-6 production by the immune cells but is rather caused by the hepatic first-pass metabolism effect.     

The immune system and postmenopausal osteoporosis

In the last decay investigators have paid attention to the relation between immune system, estrogen deficiency and bone loss; some of the pathways have been clarified whereas others remain an unexplained challenge. This review summarizes the evidence that links immune cells, estrogen loss, and osteoclast formation and activity.     

The role of physical activity in the prevention of osteoporosis in postmenopausal women—An update

Context and objective

Osteoporosis causes an increase in bone fragility. Its clinical significance mainly refers to (hip) fractures secondary to (low or moderate) trauma. In Europe and North America about 6% of men and 21% of women aged 50–84 years are classified to have osteoporosis. Although it is well accepted that exercise is essential for the management of osteoporosis, the exact role of physical activity in the primary and secondary prevention of osteoporotic fractures is still controversial.

Methods

The MEDLINE database and reference lists of selected publications were systematically searched for randomized controlled trials and prospective cohort studies, respectively, published since January 2000 regarding the association of physical activity and osteoporosis in postmenopausal women.

Results

Two prospective cohort studies indicate the clinical relevance of this association by showing an inverse relationship between physical activity and the risk of hip fracture. There is convincing evidence that physical activity effectively slows bone loss in postmenopausal women in a dose-dependent manner. Exercise programs may increase bone mineral density.

Conclusion

In order to maximize the goals of public health most effective, individually adapted, intense, high impact exercise programs are needed. However, they may be complicated to communicate and adherence on the population level may be hard to achieve. These programs must be weighed against popular and applicable existing programs (e.g. aerobic classes, Tai Chi, and walking) which appear to be easier to adhere to but appear to be less effective in the prevention of osteoporotic fractures in the individual postmenopausal women.