Liver function in postmenopausal women on estrogen-androgen hormone replacement therapy: a meta-analysis of eight clinical trials.

OBJECTIVE: To compare hepatic biochemical changes of a combined estrogen-androgen preparation with that of estrogen alone in postmenopausal women. DESIGN: Hepatic biochemical values from 511 surgical and 130 nonsurgically menopausal women being treated with hormone replacement therapy were pooled from eight similarly designed studies performed between March 1988 and January 1996 comparing esterified estrogen-methyl-testosterone preparations with esterified estrogen, conjugated equine estrogens, and placebo controls. The eight studies in this meta-analysis were controlled, randomized, multicenter, double-blind with identical or similar treatment arms. For hepatic biochemistry parameters, raw data summaries and mean changes from baseline values with standard error (SE) were evaluated for the dosages and treatment groups at various time periods throughout the studies. RESULTS: Eight controlled trials involving 641 surgically and nonsurgically menopausal women were included. Changes from the pretreatment baseline values of liver function were compared at 1, 3, 6, 12, 18, and 24 months of therapy. No patients demonstrated hepatotoxicity or clinically significant elevation of liver biochemistry values. None of the liver biochemistry changes measured in these studies were of clinical significance, nor were there biochemical differences between estrogen therapy alone compared with combined esterified estrogen-methyltestosterone preparation when administered to postmenopausal women during a period of up to 24 months. CONCLUSIONS: Combined esterified estrogen-methyltestosterone therapy (in doses of 0.625 mg esterified estrogen + 1.25 mg methyltestosterone or 1.25 mg esterified estrogen + 2.5 mg methyltestosterone) was found to be safe regarding hepatic function in postmenopausal women during the course of 24 months in eight controlled clinical trials.     

Effects of lasofoxifene on bone in surgically postmenopausal cynomolgus monkeys

OBJECTIVE: The purpose of this study was to evaluate the effects on bone of two doses of the selective estrogen receptor modulator lasofoxifene in surgically postmenopausal cynomolgus monkeys for 24 months. The primary endpoint of this study was biomechanical testing of animals treated for 2 years. DESIGN: The design of the study was a five-group (sham-ovariectomy, ovariectomy, conjugated [0.02 mg/kg], and two doses of lasofoxifene [1.0 and 5.0 mg/kg]), parallel arm design, with the treatments lasting for 24 months. Bone biomarker and estradiol data were collected at baseline and 3, 6, 12, 18, and 24 months after surgery. Vertebral bone mineral density was determined at baseline and every 6 months after ovariectomy. Hip bone density was determined at baseline and 12 and 24 months postovariectomy. Iliac bone biopsies were collected at 7 months, and the second lumbar vertebra and left femur were collected at 24 months after initiation of treatment for histomorphometric examination. The third lumbar vertebra and right femur were tested for mechanical strength after 24 months of treatment. RESULTS: Lasofoxifene and conjugated estrogens prevented ovariectomy-induced increases in serum alkaline phosphatase and CrossLaps and resulted in increased vertebral (all three treatments) and hip (conjugated estrogens and high-dose lasofoxifene only) bone mineral density, although both doses of lasofoxifene exceeded the doses projected to be used in women. In the 7-month iliac biopsy specimens, both doses of lasofoxifene reduced bone turnover rates. These histomorphometric changes were not present in either the vertebral or femoral compartments measured after 24 months of treatment. Lasofoxifene-treated animals did not differ from ovariectomized controls in mechanical strength testing of either the third lumbar vertebra or right femur. CONCLUSIONS: Lasofoxifene prevented ovariectomy-induced increased bone turnover and loss of bone mineral density without having a detrimental effect on bone strength.     

The effect of low-dose conjugated equine estrogens and cyclic MPA on bone density

OBJECTIVE: to compare the effect of 0.3 and 0.625 mg conjugated equine estrogens on bone mineral density (BMD) in a private practice setting. METHODS: postmenopausal women interested in hormone replacement therapy were prescribed either 0.3 or 0.625 mg conjugated equine estrogens daily with 10 mg medroxyprogesterone acetate days 1-12 of the month. All women were given calcium citrate 1000 mg/day and vitamin D 400 IU/day. DEXA bone mineral density studies of the spine and hip were performed at baseline and 1 year. RESULTS: there was no significant difference in BMD at the spine, the trochanter or the femoral neck compared with baseline in either the 0.625 or 0.3 mg group. The mean percent increase in BMD for the 0.3 versus 0.625 mg group was: spine 2.6 versus 3.8%, femoral neck 1.8 versus 1.5%, and trochanter 0.5 versus 2.6%. CONCLUSION: both the 0.625 mg dose and the 0.3 mg dose of conjugated equine estrogens preserved BMD at the spine and hip over one year in early postmenopausal women who were also given cyclic medroxyprogesterone acetate, calcium citrate and vitamin D.     

Effect of low-dose transdermal E2/NETA on the reduction of postmenopausal bone loss in women

OBJECTIVE: To assess the efficacy of a continuous-combined transdermal patch (estradiol/ norethisterone acetate [E(2)/NETA] 25/125; Estragest TTS, Novartis, Basel, Switzerland) in the reduction of bone loss in postmenopausal women. DESIGN: In a 96-week, double-blind, randomized, multicenter, parallel study, 124 healthy women with an intact uterus more than 4 years after menopause received either transdermal continuous-combined E(2)/NETA (0.025/0.125 mg/day) or placebo patch for 24 treatment cycles; diet was normalized for calcium intake. Lumbar spine bone mineral density (BMD) ranged from 0.969 to 0.805 g/cm2 with a mean annual BMD decrement ranging from 3% to 8% within the last 24 months. BMD at lumbar spine L(2)-L(4) (postero-anterior) and femur were assessed by dual energy x-ray absorptiometry after 6, 12, and 24 cycles. Efficacy variables included measurement of biochemical markers of bone turnover (3, 6, 12, and 24 months). RESULTS: BMD at lumbar spine was significantly higher at all time points in the E(2)/NETA group than in the placebo group (P < 0.0001). Significant increases in BMD (P < 0.0008) from baseline were observed at all sites after 24 months in the E(2)/NETA group compared with placebo, which demonstrated a decrease from baseline. At endpoint, statistically significant decrements in the values of bone remodeling markers were observed (P < 0.05) with E(2)/NETA. CONCLUSIONS: E(2)/NETA 25/125 Estragest TTS was more effective than placebo in reducing the activation frequency of bone remodeling and in preventing bone loss at the spine and hip. Effects on the hip were similar to those observed for higher doses of estrogen.     

Changes in the serum levels of osteoprotegerin and soluble receptor activator for nuclear factor kappaB ligand after estrogen-progestogen therapy and their relationships with changes in bone mass in postmenopausal women

OBJECTIVE: To investigate changes in the serum levels of osteoprotegerin (OPG) and soluble receptor activator for nuclear factor kappaB ligand (sRANKL) after estrogen plus progestogen therapy (EPT) and to determine their relationships with changes in bone mineral density (BMD) and bone turnover markers in postmenopausal women. DESIGN: Serum levels of OPG, sRANKL, and bone turnover markers, such as osteocalcin and type I C-telopeptide breakdown products, parathyroid hormone, calcitonin, calcium, and phosphorus, and BMD at the lumbar spine and proximal femur were measured in 297 postmenopausal Korean women. In all, 143 women were treated with sequential EPT for 1 year. RESULTS: Before EPT, serum OPG and sRANKL levels and RANKL/OPG ratios were not related to BMD at the lumbar spine and proximal femur, except for a negative correlation (r = -0.13, P < 0.05) between serum OPG and BMD at the trochanter. Of the bone markers, serum parathyroid hormone alone correlated negatively with serum OPG (r = -0.19, P < 0.005) and positively with serum sRANKL (r = 0.23, P < 0.001) and sRANKL/OPG ratios (r = 0.28, P < 0.001). After 6 months of EPT, serum OPG and sRANKL levels were unchanged, but sRANKL/OPG ratios and serum levels of bone turnover markers, such as osteocalcin, type I C-telopeptide breakdown products, and phosphorus decreased significantly. The 1-year change in BMD at the lumbar spine and proximal femur after EPT was not found to be correlated with basal levels of serum OPG, sRANKL, and sRANKL/OPG ratios and their changes at 6 months after EPT. After 6 months of EPT, changes in all bone markers were not associated with changes in circulating OPG, sRANKL levels, and sRANKL/OPG ratios. CONCLUSIONS: After EPT, sRANKL/OPG ratios in the circulation decreased, but changes in this OPG-sRANKL system have no association with changes in any bone marker or BMD. The OPG-sRANKL system in the circulation might be involved in reduced bone resorption after EPT, but does not seem to be clinically useful for predicting BMD or bone turnover status and bone response after hormone therapy.     

Does calcium supplementation prevent postmenopausal bone loss? A double-blind, controlled clinical study

During a two-year study, we examined the effect of calcium supplementation on postmenopausal bone loss in 43 women in the early postmenopausal period who were assigned to one of three treatment groups: percutaneous 17 beta-estradiol (combined with progesterone during the second year), oral calcium (2000 mg daily), and placebo. All participants were examined every three months. Bone mineral content in the forearm (measured by single-photon absorptiometry) and in the entire body and spine (measured by dual-photon absorptiometry) remained constant in the estrogen-treated group but decreased significantly in the groups receiving calcium and placebo. In the calcium-treated group, we observed a tendency toward a slowed loss of compact bone (in the proximal forearm and total skeleton) as compared with the placebo group, while the rate of loss of trabecular bone (the distal forearm and spine) was the same as in the placebo group. Our preliminary data suggest that calcium supplementation in the dosage we used is not as effective as estrogen therapy for the prevention of early postmenopausal bone loss. Calcium supplementation may have had a minor effect on the loss of cortical bone, but it had no effect on the trabecular bone.     

Prevention of postmenopausal bone loss by pulsed estrogen therapy: comparison with transdermal route

OBJECTIVE: To compare the efficacy of pulsed estrogen therapy following intranasal 17beta-estradiol (E2) (S21400) with patch E2 in preventing postmenopausal bone loss and on bone turnover. METHODS: In this multinational open study, 361 postmenopausal women aged 51.5 (S.D. 4.6) years were treated with S21400 300 microg per day or patch E2 (delivering 50 microg per day), two patches per week, for 56 weeks. Bone mineral density (BMD) was assessed at the spine and hip using dual X-ray absorptiometry at baseline and week 56 (W56). Bone turnover markers (osteocalcin, bone alkaline phosphatase, urinary type I collagen C-telopeptides) were measured at baseline and weeks 12, 28 and 56. RESULTS: Spine and hip bone mineral density significantly increased in both groups (P < 0.001 versus baseline). Mean (S.D.) percent increases were 2.1 (3.0) at the spine (both groups), and 1.2 (2.4) and 1.1 (2.2) at the hip in the S21400 and patch E2 groups, respectively. Bone mineral density also significantly increased (P < 0.001 versus baseline) in osteopenic patients following S21400 and patch E2: 3.1 (3.5) and 2.4 (3.5) at the spine, and 2.0 (2.6) and 1.2 (2.7) at the hip, respectively. Bone metabolism was normalized at week 56 with a significant decrease (P < 0.001) from baseline in all markers: 56% and 53% for type I collagen C-telopeptides, and 24% and 25% for osteocalcin in the S21400 and patch E2 groups, respectively. CONCLUSION: Pulsed estrogen therapy was as effective in normalizing bone turnover and preventing postmenopausal bone loss as a reservoir patch.     

Raloxifene lowers serum lipoprotein(A) in healthy postmenopausal women: a randomized, double-blind, placebo-controlled comparison with conjugated equine estrogens.

OBJECTIVE: Long-term postmenopausal estrogen replacement therapy lowers the risk of osteoporotic fractures and coronary artery disease but increases the risk of endometrial cancer and probably breast cancer. Raloxifene, a nonsteroidal estrogen receptor ligand, seems to have a tissue-specific antiestrogenic action on endometrium and breast and the desired estrogenic action on bone and lipid metabolism. The purpose of this study was to investigate the effects of 24-month treatment with orally administered raloxifene in two doses (60 mg and 150 mg daily) and conjugated equine estrogens in a standard oral dose (0.625 mg daily) on serum lipoprotein(a) [Lp(a)], an independent risk factor for coronary artery disease, in healthy postmenopausal women who had undergone hysterectomy. DESIGN: A randomized, double-blind, placebo-controlled study was performed with 56 women. RESULTS: In the placebo group serum Lp(a) levels did not change throughout the study. After 6 months, serum Lp(a) was significantly reduced versus baseline in the raloxifene 150 (-17%; p = 0.003) and conjugated equine estrogens (-26%; p = 0.003) groups, but this reduction was significantly different from placebo only in the conjugated equine estrogens group. At 12 and 24 months, serum Lp(a) levels were significantly lowered versus baseline in all active treatment groups. However, these reductions were significantly different from placebo only in the raloxifene 150 and conjugated equine estrogens groups. After 24 months, serum Lp(a) was reduced versus baseline with 30% (p = 0.001) in the raloxifene 150 group and 35% (p = 0.001) in the conjugated equine estrogens group. CONCLUSIONS: Long term raloxifene treatment significantly lowers serum Lp(a) levels in postmenopausal women and thus might reduce the risk of coronary artery disease.     

Influence of pattern of menopausal transition on the amount of trabecular bone loss. Results from a 6-year prospective longitudinal study

INTRODUCTION: Bone density is lower in postmenopausal than in premenopausal women. Recent findings have suggested that accelerated bone loss already begins before menopause. Despite numerous cross-sectional studies on menopause-related bone density, longitudinal data on perimenopausal bone density changes are scarce. This study sought to characterize the dynamics of changes leading to postmenopausal osteopenia and to possibly find the time point at which accelerated bone loss begins. METHODS: We prospectively followed 34 pre-, peri- and early postmenopausal women without prior external hormone use, measuring their lumbar spine trabecular bone density with quantitative computer tomography at 0, 2 and 6 years. The analysis of the changes over time was done in a tri-parted fashion, since menopausal status changed variably for individual subjects: we grouped the participants according to their currently valid menopausal classification for prospective (baseline classification), interim (2 years) and retrospective (6-year classification) analysis. RESULTS: Six different patterns of menopausal transition were identified in our sample. Bone loss in the groups not reaching postmenopause during 6 years of observation was >50% of the maximum bone loss observed during the study period. Invariably for all analyses, the perimenopausal phase with estrogen levels still adequate was associated with the greatest reduction of trabecular bone mineral density, reaching 6.3% loss annually in the lumbar spine. By comparison, the average rate of loss was slower in the early postmenopause; total bone loss differed by pattern of menopausal transition (one-way ANOVA p<0.05). CONCLUSION: The presented data for the first time show the perimenopausal course of trabecular bone loss (as measured by QCT of the lumbar spine). Acceleration of bone loss during perimenopause reached half-maximal values of the total bone loss measured around menopause, despite adequate serum estradiol levels.     

Relation of the estrogen receptor alpha gene microsatellite polymorphism to bone mineral density and the susceptibility to osteoporosis in postmenopausal Chinese women in Taiwan.

OBJECTIVE: Osteoporosis is a common disorder with a strong genetic component. Our aim was to investigate the correlation of the estrogen receptor alpha gene microsatellite polymorphism (TA dinucleotide repeat polymorphism 5' upstream of exon 1) with bone mineral density and their relationship to osteoporosis. METHODS: We determined the estrogen receptor alpha gene microsatellite polymorphism using polymerase chain reaction-based microsatellite analysis in postmenopausal Chinese women in Taiwan. Bone mineral density of the lumbar spine and proximal femur were measured using dual-energy X-ray absorptiometry. RESULTS: The ERalpha genotype was classified into '12' through '27' according to the number of TA dinucleotide repeats they contained, as a 'signpost'. After adjustment for potential confounding factors including age, height, and weight, subjects with genotype 18+ (n=4) had lower bone mineral density values and a 54.5 times greater risk for osteoporosis when compared with subjects with genotype 18- (n=170) at the lumbar spine. This should be interpreted with caution because of the small number of subjects with the unfavorable genotype 18+. According to mean number of TA dinucleotide repeats, women with a high number of repeats (TA > or =20) (n=38) had the lowest bone mineral density and a 6.1 times greater risk for osteoporosis than women with a low number of repeats (TA < or =15) (n=61) at the femoral neck, after adjustment for potential confounding factors such as age, height, and weight. CONCLUSION: The present study suggests that the estrogen receptor alpha gene microsatellite polymorphism may be a candidate genetic marker for risk of osteoporosis in postmenopausal Chinese women in Taiwan.     

A prospective,randomized, placebo-controlled study of the dose effect of oral estradiol on bone mineral density in postmenopausal Chinese women

OBJECTIVES: One of the long-term consequences of estrogen deficiency in postmenopausal women is an increased risk of osteoporosis. Fractures of the hip and lumbar spine are associated with considerable morbidity and mortality. Estrogen replacement therapy reduces the risk of osteoporosis, but there is no clear agreement on the most appropriate doses to be used. The aim of this study was to compare changes in bone mineral density (BMD) measurements using conventional and lower dose estradiol. METHODS: A prospective, randomized, placebo-controlled 12-month study of the effect of 1 and 2 mg estradiol on BMD in 152 hysterectomized postmenopausal Chinese women with no contraindication to the use of estrogen replacement therapy. RESULTS: Over 12 months, spinal BMD in placebo treated patients decreased by a mean of 2% from baseline (-0.02+/-0.03 g/cm(2)) while it increased by 2% in the 1 mg (0.02+/-0.03 g/cm(2)) and 3% in the 2 mg group (0.03+/-0.03 g/cm(2)). Mean changes in BMD over 12 months in the hip were -0.02+/-0.02 g/cm(2) (-2%), 0.01+/-0.02 g/cm(2) (+1%) and 0.01+/-0.03 g/cm(2) (+1%) in the placebo, 1 and 2 mg estradiol groups, respectively (P<0.05). Relative to placebo, increases in BMD in both 1 and 2 mg groups were statistically significant for both spine and hip (P<0.05). However, there was no significant difference in the increase in BMD between the 1 and 2 mg doses for either lumbar spine or hip (P=0.82, 0.53, respectively). CONCLUSION: The results of our study show that a 1 mg dose of oral estradiol is effective in preventing bone loss in postmenopausal Chinese women.     

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss.     

Long-term compliance with estrogen replacement therapy in surgical postmenopausal women: benefits to bone and analysis of factors associated with discontinuation

OBJECTIVE: To evaluate prospectively the effects of long-term estrogen replacement therapy (ERT) on bone density in surgical postmenopausal women treated for 5 years with two different modalities and to determine the factors associated with discontinuation of ERT. DESIGN: We included in the present study 165 women (mean age, 46.8 +/- 4.6 years) who had undergone surgical menopause. ERT was prescribed immediately after surgery, and bone mineral density was measured at the lumbar spine before the women entered the study and at 12, 24, 36, 48, and 60 months after being included. Treated patients were assigned at random to one of two groups. The first group received conjugated equine estrogens 0.625 mg/day continuously, and the second group received transdermal 17beta-estradiol 50 mg/day continuously. Treated groups were compared with a nontreated control group. RESULTS: Our data showed that although ERT clearly protected against bone loss in women who had experienced surgical menopause, only one third of the treated patients continued ERT at the end of follow-up. The main reason for discontinuation was fear of cancer (36.1 % of cases). In addition, no differences were observed between oral and transdermal groups of treatment. CONCLUSIONS: Long-term ERT may have a protective effect against bone loss in surgically postmenopausal women; however, two thirds of treated patients discontinued therapy after 5 years and 43% of them presented a negative balance on bone mass in one or more bone density assessments. For this reason, enhancing compliance and monitoring treatment are mandatory.     

Denosumab

Denosumab is a fully human monoclonal IgG(2) antibody that binds to receptor activator of nuclear factor-κB ligand (RANKL) and inhibits bone resorption due to RANKL-mediated osteoclastogenesis. In Europe, subcutaneous denosumab is indicated for cancer treatment-induced bone loss in men with prostate cancer and in postmenopausal women with breast cancer. In a large (n= 1468), well designed, multinational, phase III trial in adult patients with prostate cancer who were receiving androgen-deprivation therapy, bone mineral density (BMD) at the lumbar spine was significantly improved from baseline after 24 (primary endpoint) and 36 months of treatment with subcutaneous denosumab (60 mg once every 6 months), relative to that with placebo. Moreover, the risk of new vertebral fracture was significantly reduced by 62% in the denosumab group compared with the placebo group. In breast cancer patients receiving aromatase inhibitor therapy (n =252), subcutaneous denosumab (60 mg once every 6 months) significantly improved BMD at the lumbar spine from baseline after 12 (primary endpoint) and 24 months of treatment relative to placebo in a pivotal phase III trial. There were significant improvements in BMD at all skeletal sites, including the lumbar spine, total hip, and femoral neck, after 24 and 36 months' denosumab treatment in prostate cancer patients and after 12 and 24 months' treatment in breast cancer patients. In general, these improvements occurred irrespective of baseline characteristics, including age, duration of hormone ablation therapy, and baseline BMD. Denosumab treatment was generally well tolerated for up to 24 months in breast cancer patients and for up to 36 months in prostate cancer patients.     

Cytokine changes in postmenopausal women treated with estrogens: a placebo-controlled study

PROBLEM: Hormone replacement therapy (HRT) is being increasingly used in postmenopausal women. Sex steroids are known to affect the immune system in several ways, although this is mainly based on clinical observations and experimental studies. METHOD OF STUDY: We studied the in vivo effects of transdermal estrogens (50 microg 17 beta-Estradiol/24 hr) on cytokine production in postmenopausal women. A total of 17 women were randomized to either placebo (n = 7) or active estrogen therapy (n = 10) for 14 weeks, with addition of oral medoxyprogesterone acetate 10 mg daily during the last 2 weeks in both groups. Secretion of the cytokines IFN-gamma, IL-4, IL-10 and IL-6 in blood mononuclear cells was determined, spontaneously and after stimulation with common vaccination antigens and mitogen, using the cell ELISA technique. RESULTS: IL-6 production after stimulation with purified protein derivate (PPD) decreased in the estrogen treated group (P < 0.01). Mitogen-induced IL-6 production was reduced in the estrogen treated group in contrast to an increase in the placebo group, leading to a significant difference (P < 0.01) between the groups after 12 weeks of treatment. This difference was eliminated after an addition of progestagens for 2 weeks. No significant changes were noted for IFN-gamma, IL-4 or IL-10 in relation to estrogen or placebo treatment. CONCLUSIONS: In the present controlled study, the main in vivo effect of estrogens was a decrease in IL-6 production, indicating a possible beneficial effect of estrogen therapy.     

Medroxyprogesterone acetate with Zoladex for long-term treatment of fibroids: effects on bone density and patient acceptability

A randomized trial was carried out to investigate the effect of 12 months administration of the gonadotrophin-releasing hormone agonist (GnRHa) Zoladex in combination with either placebo or medroxyprogesterone acetate (MPA) from the third month. Bone density, markers of bone resorption, symptoms and uterine volume were monitored in 24 women with symptomatic fibroids or menstrual problems. A total of 21 women were recruited to act as controls for the assessment of bone parameters. Vasomotor side-effects were reduced significantly in the MPA-treated group. The reduction in uterine volume in women with fibroids was not impaired by the addition of MPA. The bone markers osteocalcin and alkaline phosphatase were assessed in plasma, and the cross-links pyridinoline and deoxypyridinoline measured in urine. Changes in these markers are reported which suggest increases in bone resorption during the period of observation. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry at the spine and forearm. The net reduction in BMD at the spine in the treated groups was 4.30 +/- 0.59% at 6 months and 7.50 +/- 0.78% at 1 year, with no change in the control group. No change was seen in forearm BMD. No protective effect was observed when MPA was added. At 1 year after the completion of treatment, BMD remained significantly below baseline, and this has implications for the prolonged use of GnRHa.      

Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis

Although fluoride increases bone mass, the newly formed bone may have reduced strength. To assess the effect of fluoride treatment on the fracture rate in osteoporosis, we conducted a four-year prospective clinical trial in 202 postmenopausal women with osteoporosis and vertebral fractures who were randomly assigned to receive sodium fluoride (75 mg per day) or placebo. All received a calcium supplement (1500 mg per day). Sixty-six women in the fluoride group and 69 women in the placebo group completed the trial. As compared with the placebo group, the treatment group had increases in median bone mineral density of 35 percent (P less than 0.0001) in the lumbar spine (predominantly cancellous bone), 12 percent (P less than 0.0001) in the femoral neck, and 10 percent (P less than 0.0001) in the femoral trochanter (sites of mixed cortical and cancellous bone), but the bone mineral density decreased by 4 percent (P less than 0.02) in the shaft of the radius (predominantly cortical bone). The number of new vertebral fractures was similar in the treatment and placebo groups (163 and 136, respectively; P not significant), but the number of nonvertebral fractures was higher in the treatment group (72 vs. 24; P less than 0.01). Fifty-four women in the fluoride group and 24 in the placebo group had side effects sufficiently severe to warrant dose reduction; the major side effects were gastrointestinal symptoms and lower-extremity pain. We conclude that fluoride therapy increases cancellous but decreases cortical bone mineral density and increases skeletal fragility. Thus, under the conditions of this study, the fluoride-calcium regimen was not effective treatment for postmenopausal osteoporosis.     

Effects of tibolone on bone quality in ovariectomized monkeys

OBJECTIVE: The purpose of this report is to examine the effects of two doses of tibolone on bone quality (bone biomarkers, bone density, and bone strength) in ovariectomized cynomolgus monkeys fed high-fat diets. DESIGN: Ovariectomized cynomolgus monkeys were randomized into one of five treatment groups: placebo-treated control, tibolone (0.2 mg/kg/day), tibolone (0.05 mg/kg/day), conjugated equine estrogens (Premarin, 0.042 mg/kg/day), and conjugated equine estrogens plus medroxyprogesterone acetate (0.042 and 0.167 mg/kg/day, respectively). Bone quality was assessed by determining bone strength and density in vertebrae and femora collected after 24 months of treatment. RESULTS: Monkeys treated for 24 months with tibolone had increased bone mineral density in the distal femur and improved biomechanical properties in the midshaft femur compared with placebo-treated ovariectomized monkeys, as did monkeys treated with conjugated equine estrogens with or without medroxyprogesterone acetate. No treatment effects were seen in lumbar vertebra bone density or strength. There was no significant difference between tibolone and estrogen on biomechanical properties of the femur. CONCLUSION: These data show that tibolone is comparable to conjugated equine estrogens with or without medroxyprogesterone acetate in decreasing bone turnover and increasing bone strength in ovariectomized monkeys.     

Changes in bone markers after once-weekly low-dose alendronate in postmenopausal women with moderate bone loss

BACKGROUND: High bone turnover, with bone resorption exceeding bone formation, is a major mechanism of postmenopausal osteoporosis. Therefore, inhibition of bone resorption is a rational approach for the prevention of bone loss. The objective of the current study was to determine the short-term efficacy of once-weekly low-dose alendronate in the prevention of bone loss, via bone turnover markers, in early postmenopausal Korean women with moderate bone loss. METHODS: This study involved a 12-week, randomized, double-blind clinical trial that compared the effects of placebo with alendronate 20mg once weekly. All subjects received supplemental calcium 600 mg and vitamin D 400IU daily. We recruited 63 postmenopausal women (ranging from 50 to 65 years of age) with the lowest lumbar spine bone mineral density (BMD) at least 2.0 S.D. below the mean value for young healthy adults. BMD was measured at baseline and serum alkaline phosphatase (ALP), osteocalcin, C-terminal telopeptide of type I collagen (CTX), and osteoprotegerin (OPG) were measured at baseline and 12 weeks after treatment. RESULTS: We randomly assigned 63 women to either placebo or alencronate 20 mg once a week for 3 months. Forty-nine women continued and completed all 3 months. After 3 months, bone resorption markers were significantly decreased in the alendronate group than in the placebo group: CTX -47.2% vs. 15% (p<0.01), ALP 1.6% vs. 25.9% (p=0.01), osteocalcin -29.2% vs. -13.6 (p=0.06). Women who received alendronate showed similar results to those who received placebo with regard to adverse events. CONCLUSION: Once-weekly low-dose alendronate may be a cost-effective and safe method of suppressing bone turnover in early postmenopausal women with moderate bone loss.     

Trimegestone in a low-dose, continuous-combined hormone therapy regimen prevents bone loss in osteopenic postmenopausal women

OBJECTIVE: To determine the efficacy of estrogen + progestogen therapy with 1 mg 17beta-estradiol and 0.125 mg trimegestone in the prevention of postmenopausal osteoporosis. DESIGN: For this study, 360 healthy, postmenopausal women with osteopenia [lumbar spine bone mineral density (BMD) between -1.0 and -2.5 SD of the premenopausal mean value] were enrolled in a 2-year prospective, randomized study, and 70% completed. Treatments were 1 mg 17beta-estradiol + 0.125 mg trimegestone (n = 179) or placebo (n = 181), given as daily oral therapy. All received a daily supplement of 500 mg calcium and 400 IU vitamin D. BMD measurements at the lumbar spine, total hip, and femoral neck as well as blood and urinary biochemical markers of bone turnover (serum osteocalcin), serum bone-specific alkaline phosphatase, serum CrossLaps, and urinary CrossLaps took place regularly. RESULTS: BMD increases relative to placebo were 6.3%, 3.9%, and 3.8% at the lumbar spine, total hip, and femoral neck, respectively (all P < 0.001). The biochemical markers of bone turnover were suppressed accordingly. Serum CrossLaps and urinary CrossLaps decreased rapidly, by 52% and 54%, respectively, whereas serum osteocalcin and serum bone-specific alkaline phosphatase revealed a more retarded decrease of 40% and 33%, respectively. Of the women receiving hormone therapy, 75% had amenorrhea from the first cycle, and 5% withdrew prematurely due to metrorrhagia or mastalgia. CONCLUSION: This new estrogen + progestogen therapy is efficient in increasing BMD in an osteopenic postmenopausal population. Furthermore, it is well tolerated, with few adverse events and an early bleeding control, which is likely to improve compliance to the treatment over the long term.