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Bone vasculature influences osteogenesis and haematopoiesis in the bone microenviroment. Mechanical loading has been shown to stimulate the formation of osteogenesis-related type H vessels in an ovariectomy (OVX)-induced osteoporosis mouse model. To determine the loading-driven mechanism of angiogenesis and the formation of type H vessels in bone, we evaluated the roles of PI3K/Akt signaling and erythropoiesis in the bone marrow. The daily application of mechanical loading (1 N at 5 Hz for 6 min/day) for 2 weeks on OVX mice inhibited osteoclast activity, associated with an increase in the number of osteoblasts and trabecular volume ratio. Mechanical loading enhanced bone vasculature and vessel formation, as well as PI3K/Akt phosphorylation and erythropoiesis in the bone marrow. Notably, LY294002, an inhibitor of PI3K signaling, blocked the tube formation by endothelial progenitor cells, as well as their migration and wound healing. The conditioned medium, derived from erythroblasts, also promoted the function of HUVECs with elevated levels of VEGF, CD31, and Emcn. Collectively, this study demonstrates that mechanical loading prevents osteoporotic bone loss by promoting angiogenesis and type H vessel formation. This load-driven preventing effect is in part mediated by PI3K/Akt signaling and erythropoiesis in the bone marrow., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study reports the effects of a recreational team handball exercise programme (randomised controlled trial, RCT) on bone health, postural balance and body composition in inactive postmenopausal women without previous experience of the sport. Sixty-seven postmenopausal women (68.3 ± 6.2 years, stature 156.9 ± 5.8 cm, body mass 65.6 ± 9.6 kg, body fat 40.9 ± 5.9%, VO 2peak 25.2 ± 3.6 mL·min -1 ·kg -1 ) were randomised into team handball (THG, n = 41) and control (CG, n = 26) groups. During the 16-week intervention period, THG performed two to three 60-min training sessions per week, while CG continued with their habitual physical activity. Bone mineral density (BMD) and content (BMC), biochemical bone formation (osteocalcin (OC), procollagen type-1 amino-terminal propeptide (P1NP)) and resorption (carboxy-terminal type-1 collagen crosslinks (CTX)) markers, postural balance, body fat and lean mass were evaluated at baseline and post intervention. A time x group interaction (p ≤ 0.02) was shown for lumbar spine BMD (+1.5%) and BMC (+2.3%), P1NP (+37.6 ± 42.4%), OC (+41.9 ± 27.0%) and postural balance (-7 ± 37% falls), in favour of THG with no changes in CG. This RCT showed that short-term recreational team handball practice had an impact on bone turnover and was effective for improving bone health and postural balance in postmenopausal women without previous experience of the sport, hence potentially helping to reduce the risk of falls and fractures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Previous reviews have concluded that exercise has only modest effects on bone mineral density (BMD) in postmenopausal women. Despite the well-recognized strong positive relationship between load magnitude and bone response observed from animal research, the majority of human trials have examined the effects of only low to moderate intensity exercise on bone. We speculated that meta-analysing according to intensity may reveal a more potent exercise effect at higher intensity., Objectives: To determine the effects of low, moderate and high intensity exercise on BMD at the spine and hip in postmenopausal women., Methods: Electronic databases and reference lists were searched for RCTs that examined the effect of exercise compared to control on DXA-derived lumbar spine, femoral neck or total hip BMD in healthy postmenopausal women. Interventions were classified as low, moderate or high intensity and pooled based on classification. Mean differences (MD) were calculated using random effects models and a risk of bias analysis was undertaken. To determine the effect of different exercise types (resistance and impact training) on BMD outcomes, subgroup analyses for all intensity categories and outcomes were conducted. Separate meta-analyses were undertaken to examine the influence of adding exercise to a bone medication intervention and to examine exercise effects on fracture risk., Results: Fifty-three trials, testing 63 interventions (19 low, 40 moderate, 4 high intensity) were included. At the lumbar spine, high intensity exercise yielded greater BMD effects (MD = 0.031 g/cm 2 95% CI [0.012, 0.049], p = 0.002) than moderate (MD = 0.012 g/cm 2 95% CI [0.008, 0.017], p < 0.001) and low intensity (MD = 0.010 g/cm 2 95% CI [0.005, 0.015], p < 0.001). Low and moderate intensity exercise was equally effective at the femoral neck (low: 0.011 g/cm 2 95% CI [0.006, 0.016], p < 0.001; moderate: 0.011 g/cm 2 95% CI [0.007, 0.015], p < 0.001), but no effect of high-intensity exercise was observed. Moderate intensity exercise increased total hip BMD (0.008 g/cm 2 95% CI [0.004, 0.012], p < 0.001), but low intensity did not. There were insufficient data to meta-analyse the effect of high intensity exercise at the total hip. Resistance training, potentially in combination with impact training, appears to be the most effective osteogenic stimulus at the spine and hip. Findings from meta-regression analyses were not informative and no influence of exercise on medication efficacy was observed. Risk of bias was mainly low or unclear due to insufficient information reported., Conclusion: High intensity exercise is a more effective stimulus for lumbar spine BMD than low or moderate intensity, but not femoral neck BMD, however, the latter finding may be due to lack of power. While data from high-intensity exercise interventions are limited, the current comprehensive meta-analysis demonstrates the same positive relationship between load magnitude and bone response in humans that is observed in animal research. Findings have implications for optimal exercise prescription for osteoporosis in postmenopausal women., Study Registration: Registered on PROSPERO (CRD42018117254)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Due to older people's low sports participation rates, exercise frequency may be the most critical component for designing exercise protocols that address bone. The aims of the present article were to determine the independent effect of exercise frequency (ExFreq) and its corresponding changes on bone mineral density (BMD) and to identify the minimum effective dose that just relevantly affects bone. Based on the 16-year follow-up of the intense, consistently supervised Erlangen Fitness and Osteoporosis Prevention-Study, ExFreq was retrospectively determined in the exercise-group of 55 initially early-postmenopausal females with osteopenia. Linear mixed-effect regression analysis was conducted to determine the independent effect of ExFreq on BMD changes at lumbar spine and total hip. Minimum effective dose of ExFreq based on BMD changes less than the 90% quantile of the sedentary control-group (n=43). Cut-offs were determined after 4, 8, 12 and 16years using bootstrap with 5000 replications. After 16years, average ExFreq ranged between 1.02 and 2.96sessions/week (2.28±0.40sessions/week). ExFreq has an independent effect on LS-BMD (p<.001) and hip-BMD (p=.005) changes. Bootstrap analysis detected a minimum effective dose at about 2sessions/week/16years (cut-off LS-BMD: 2.11, 95% CI: 2.06-2.12; total hip-BMD: 2.22, 95% CI: 2.00-2.78sessions/week/16years). In summary, the minimum effective dose of exercise frequency that relevantly addresses BMD is quite high, at least compared with the low sport participation rate of older adults. This result might not be generalizable across all exercise types, protocols and cohorts, but it does indicate at least that even when applying high impact/high intensity programs, exercise frequency and its maintenance play a key role in bone adaptation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Periostin is preferentially expressed by the periosteum, which mainly covers the long bones. Therefore, the role of periostin in osteoporotic fracture (OF) may differ depending on bone type. We performed a case-control study to investigate whether periostin can serve as a predictor of OF risk, particularly after dividing OFs into non-vertebral and vertebral fractures., Methods: Among 532 consecutive postmenopausal women not taking any drug or without any disease that could affect bone metabolism, 133 cases with OF (i.e., non-vertebral and/or vertebral fractures) and 133 age- and body mass index-matched controls were enrolled. Non-vertebral (i.e., forearm, humerus, hip, and pelvis; n=81) and morphological vertebral (n=62) fractures were identified by an interviewer-assisted questionnaire and lateral thoracolumbar radiographs, respectively. Bone mineral density (BMD) and plasma periostin levels were also measured., Results: Plasma periostin was markedly higher in subjects with non-vertebral fracture than their controls even after adjustment for BMD and potential confounders (P=0.006). Each standard deviation increment of plasma periostin was associated with a multivariable-adjusted odds ratio of 1.59 for non-vertebral fracture. The odds for non-vertebral fracture were 2.48-fold higher in subjects in the highest periostin tertile compared with those in the lowest periostin tertile (95% confidence interval=1.10-5.61). However, associations between plasma periostin and vertebral fracture were not observed, regardless of the adjustment model used. Consistently, plasma periostin levels were inversely associated with proximal femur BMD (P=0.007 to 0.030) but not lumbar spine BMD. In subgroup analyses, plasma periostin had no correlation with the levels of classical bone turnover markers., Conclusions: Plasma periostin may be a potential biomarker of the risk of OF, especially in non-spinal skeletal sites, such as the limbs, rather than spine., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Yerba Mate (Ilex paraguariensis) tea consumption is higher in Argentina and other South American countries than those of coffee or tea (Camellia sinensis). The effects of Yerba Mate on bone health have not previously been explored. From a program for osteoporosis prevention and treatment, postmenopausal women who drank at least 1 L of Yerba Mate tea daily during 4 or more years (n=146) were identified, and matched by age and time since menopause with an equal number of women who did not drink Yerba Mate tea. Their bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and femoral neck. Yerba Mate drinkers had a 9.7% higher lumbar spine BMD (0.952 g/cm(2) versus 0.858 g/cm(2): p<0.0001) and a 6.2% higher femoral neck BMD (0.817 g/cm(2) versus 0.776 g/cm(2); p=0.0002). In multiple regression analysis, Yerba Mate drinking was the only factor, other than body mass index, which showed a positive correlation with BMD at both the lumbar spine (p<0.0001) and the femoral neck (p=0.0028). Results suggest a protective effect of chronic Yerba Mate consumption on bone., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: The National Osteoporosis Foundation (NOF) recommends considering treatment in women with a 20% or higher 10-year probability of a major fracture. However, raloxifene reduces both the risk of vertebral fractures and invasive breast cancer so that raloxifene treatment may be clinically appropriate and cost-effective in women who do not meet a 20% threshold risk. The aim of this study was to identify cost-effective scenarios of raloxifene treatment compared to no treatment in younger postmenopausal women at increased risk of invasive breast cancer and fracture risks below 20%., Method: A micro-simulation model populated with data specific to American Caucasian women was used to quantify the costs and benefits of 5-year raloxifene treatment. The population evaluated was selected based on 10-year major fracture probability as estimated with FRAX® being below 20% and 5-year invasive breast cancer risk as estimated with the Gail risk model ranging from 1% to 5%., Results: The cost per QALY gained ranged from US $22,000 in women age 55 with 5% invasive breast cancer risk and 15-19.9% fracture probability, to $110,000 in women age 55 with 1% invasive breast cancer risk and 5-9.9% fracture probability. Raloxifene was progressively cost-effective with increasing fracture risk and invasive breast cancer risk for a given age cohort. At lower fracture risk in combination with lower invasive breast cancer risk or when no preventive raloxifene effect on invasive breast cancer was assumed, the cost-effectiveness of raloxifene worsened markedly and was not cost-effective given a willingness-to-pay of US $50,000. At fracture risk of 15-19.9% raloxifene was cost-effective also in women at lower invasive breast cancer risk., Conclusions: Raloxifene is potentially cost-effective in cohorts of young postmenopausal women, who do not meet the suggested NOF 10-year fracture risk threshold. The cost-effectiveness is contingent on their 5-year invasive breast cancer risk. The result highlights the importance of considering a woman's full risk profile when considering anti-osteoporosis treatment., (Copyright © 2010. Published by Elsevier Inc.)

Introduction: Osteoporosis is a major health problem for postmenopausal women. Adjuvant hormonal therapy with aromatase inhibitors (AIs) in postmenopausal breast cancer patients further worsens bone loss. Bisphosphonates are able to prevent AI-induced bone loss, but limited data exists on their effect on bone structure. Our objectives were to (1) examine the impact of AIs and no-AIs on hip structural geometry (HSA) of chemotherapy-induced postmenopausal women, and (2) determine if oral bisphosphonates could affect these changes., Methods: This is a sub-analysis of a 2-year double-blind randomized trial of 67 women with nonmetastatic breast cancer, newly postmenopausal following chemotherapy (up to 8 years), who were randomized to risedronate, 35 mg once weekly (RIS) and placebo (PBO). Many women changed their cancer therapy from a no-AI to an AI during the trial. Outcomes were changes in Beck's HSA-derived BMD and structural parameters., Results: Eighteen women did not receive adjuvant hormone therapy, while 41 women received other therapy and 8 received AIs at baseline distributed similarly between RIS and PBO. Women on AIs and PBO were found to have the lowest BMD and indices. RIS improved BMD and several HSA indices at the intertrochanteric site in women regardless of their hormonal therapy, but most improvement was observed in women who were not on AIs (all p< or =0.05 except buckling ratio). Changes at the narrow neck and femoral shaft were similar., Conclusion: The use of AIs appears to lead to lower HSA-derived BMD and hip structural indices as compared to women on no or non-AI therapy in chemotherapy-induced postmenopausal breast cancer patients. Preventive therapy with once weekly oral risedronate maintains structural, skeletal integrity independently of the use of or type of adjuvant therapy.

Introduction: Monthly oral ibandronate has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with osteoporosis, but its efficacy has not been investigated in women with low bone mass. The objective of this study was to examine the efficacy and safety of monthly oral ibandronate (150 mg) treatment in postmenopausal women with low bone mass., Methods: This 1-year, double-blind, placebo-controlled, randomized study enrolled ambulatory postmenopausal women aged 45-60 years with baseline lumbar spine (LS) BMD T-score<-1.0 and >-2.5 and baseline T-score>-2.5 at the total hip, trochanter, and femoral neck (collectively defined as the proximal femur) and no prior vertebral or low-trauma osteoporotic fractures at baseline. Subjects received either 150 mg monthly oral ibandronate or placebo. All subjects received calcium and vitamin D supplements. The primary endpoint was the relative change from baseline (%) in mean LS BMD at 1 year (intent-to-treat population). Treatment groups were compared by means of a two-way ANOVA model which adjusted for independent factors including treatment group, baseline LS BMD T-score, and time since menopause. Responder analyses examined the percentage of participants with changes from baseline in LS BMD and proximal femur BMD>or=0%. Adverse events and safety laboratory parameters were monitored continuously., Results: A total of 77 women received monthly ibandronate and 83 women received placebo. Subjects treated with ibandronate achieved larger increases in LS BMD after 1 year compared with subjects receiving placebo (3.7% vs -0.4% [difference of 4.1%, p<0.0001]). After 3 months, median serum C-terminal telopeptide of type I collagen levels were reduced by >55% in the ibandronate group compared with approximately 4% in the placebo group. At 1 year, 88.2% of the participants treated with ibandronate achieved increases in LS BMD>or=0% compared with 38.6% of subjects receiving placebo. Treatment regimens were well tolerated in both the ibandronate-treated and placebo groups., Conclusion: Monthly ibandronate therapy prevents bone loss in postmenopausal women with low bone mass.

Whilst exercise is recommended for optimum bone health in adult women, there are few systematic reviews of the efficacy of walking as singular exercise therapy for postmenopausal bone loss. The aim of this study was to assess the effects of prescribed walking programmes on bone mineral density (BMD) at the hip and spine in postmenopausal women and to determine if effects are modified by variations in protocol design. We undertook a systematic review and meta-analysis of randomised (RCTs) and non-randomised controlled trials. Electronic bibliographic databases, key journals and reference lists of reviews and articles were searched to identify studies for inclusion. Randomised and non-randomised controlled trials assessing the effects of walking on lumbar spine, femoral neck and total hip BMD, measured by radiographic techniques, among sedentary postmenopausal women were eligible for inclusion. Two independent reviewers assessed studies for eligibility. Reported absolute BMD outcomes were combined in the analysis. Weighted mean differences (WMD) were calculated using a fixed and random-effects models. Heterogeneity among trials was examined using the Q statistic and I2 methods. Potential publication bias was assessed through funnel plot inspection. Assessment of trial quality was also performed using the widely used instrument devised by Jadad et al. [Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Cont Clin Trials 1996; 17:1-12]. Eight trials were eligible for inclusion. Treatment duration ranged from 6 to 24 months. All eight trials reported BMD data at the lumbar spine following walking interventions among postmenopausal women. Meta-analysis showed no significant change in BMD at this site [WMD (fixed-effect) 0.007 g/cm2 95% CI (-0.001 to 0.016); P=0.09)]. BMD data at the femoral neck were available from five trials among postmenopausal women. Results were inconsistent (I2=51.4%) in showing a positive effect of walking on BMD at this site [WMD (random-effects) 0.014 g/cm2 95% CI (0.000 to 0.028); P=0.05). Insufficient data were available for meta-analysis of the total hip site. Funnel plots showed some asymmetry for negative lumbar spine BMD outcomes. Trial quality scores ranged from 0 to 3 from the Jadad scale of 0 to 5. We conclude that regular walking has no significant effect on preservation of BMD at the spine in postmenopausal women, whilst significant positive effects at femoral neck are evident. However, diverse methodological and reporting discrepancies are apparent in the published trials on which these conclusions are based. Other forms of exercise that provide greater targeted skeletal loading may be required to preserve bone mineral density in this population.

Aromatase inhibitors have demonstrated their superiority to tamoxifen as adjuvant therapy for early breast cancer in postmenopausal women, but are associated with an increased risk of fractures. The aim of our study was to analyze bone loss, bone turnover and their determinants in postmenopausal women treated with anastrozole. We investigated bone loss and bone turnover markers (BTM) in a prospective open cohort study of 118 postmenopausal women treated with anastrozole for an early hormone-dependent breast cancer. Women without osteoporosis were not treated and compared with an age-matched control group of 114 healthy women. Osteoporotic patients (T-scoreor=6 courses) and a marked antiestrogenic response--defined by a level of 17beta-estradiol50% between baseline and 1 year--were associated with greater bone loss. In multivariate model, women in the highest quartile of bone loss at the spine (>5.6% at 1 year) and hip (>4.9%) had a marked antiestrogenic response with OR of 10.4 [95% C.I. 1.9-57.2] (p=0.007) and 5.7 [1.3-25] (p=0.024) respectively. Among patients in the surveillance group, those with a normal T-score at both sites (n=46) had also a significant bone loss at spine -3.3+/-0.5% [-4.3 to -2.3], p<0.0001 and at the hip -2.9+/-0.6% [-4.1 to -1.7] p<0.0001. In osteoporotic women treated simultaneously with anastrozole and risedronate, bone loss was prevented at hip, and increased at the spine (+4.1+/-0.9% [2.3 to 5.9], p=0.008), and BTM decreased (-24%, -39% for CTX, p=0.003 and 0.001 vs. changes in the untreated group). Anastrozole increases bone turnover and induces an accelerated bone loss that is significantly related to the suppression of 17beta-estradiol production induced by aromatase inhibitor. The bisphosphonate risedronate prevents anastrozole induced bone loss.

Context: Statins inhibit HMG-CoA reductase, preventing synthesis of mevalonate but also of isoprenoids, which affect osteoclast activity. Amino-bisphosphonates share this effect. In vitro and in vivo, statins show convincing anabolic and anti-resorptive bone effects. However, in a clinical meta-analysis (MA), they did not prevent hip fractures., Objective and Design: Our meta-analysis studied the impact of statins on bone mineral density (BMD) at various sites and compared the effects of lipophilic and more hydrophilic statins., Data Sources: Our PubMed and Embase queries using two keywords (statins, BMD) were updated to October 2006., Data Collection: Two readers independently collected BMDs from studies., Data Synthesis: Twenty-one studies, mostly observational (three randomized controlled trials and one pseudo-randomized study), were assessed. Two studies were excluded (no control groups). Three studies could not be analyzed. The sixteen studies analyzed mainly included postmenopausal osteopenic women (2971 patients under statins). Statins significantly increased BMD at total hip (TH) and femoral neck (FN). Effect sizes (ESs) were modest: 0.21 at TH (95% confidence interval [CI]: 0.16-0.25) and 0.20 at FN (CI: 0.08-0.28). Among women, statins acted similarly (ES: 0.20 for TH and 0.18 for FN; CI: 0.14-0.25 and 0.06-0.31 respectively); lipophilic statins (simvastatin, lovastatin) almost entirely caused this effect, at both TH (ES: 0.20; CI: 0.15-0.26) and FN (ES: 0.22; CI: 0.06-0.37)., Conclusion: Our findings of modest but statistically significant beneficial effects of statins on hip BMD should promote large double-blind randomized controlled trials on their bone effects, in view of their major beneficial cardiovascular effects with excellent safety profile.

We have previously shown that a single subcutaneous injection of glucagon-like peptide-2 (GLP-2) at 10 p.m. in postmenopausal women results in a dose-dependent decrease in the nocturnal serum and urine concentrations of fragments derived from the degradation of the C-terminal telopeptide region of collagen type I (s-CTX and u-CTX) and u-DPD, markers of bone resorption. In contrast, bone formation, as assessed by serum osteocalcin and procollagen type I N-terminal propeptide (PINP), appeared to be unaffected by treatment with exogenous GLP-2. These effects were further investigated in a 14-day study. The aim was to demonstrate that a parenteral formulation of GLP-2 is safe and well tolerated after repeated dosing in healthy postmenopausal women for 14 days. It was further investigated whether the effects on bone turnover markers were sustained throughout the study period. The study was a double-blind placebo-controlled trial with 60 postmenopausal women and 2 different doses of GLP-2 (1.6 mg and 3.2 mg GLP-2) against a saline control. The data for bone resorption revealed a similar reduction on Day 1 and Day 14, both based on time course and AUC. There were no signs of tachyphylaxis and no serious adverse reaction. Both GLP-2 doses resulted in similar and significant (p<0.001) reduction in bone resorption indicating that the maximum efficacious dose has been approached. Osteocalcin and PINP levels were unaffected at Day 1 and Day 14, suggesting a disassociation between bone resorption and bone formation during GLP-2 treatment.

We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to some extent explain why this polymorphism is associated with low BMD or fracture in some study populations and not in others. It would also indicate that fractures associated with the TT genotype could be preventable by vitamin B supplementation. We have, therefore, reviewed baseline food record data from our original study to determine if BMD and fracture associations with the MTHFR genotype depended on the intake of folate, riboflavin, or other members of the vitamin B complex, associated with homocysteine metabolism. We analyzed genotype, BMD, and dietary records from 1700 healthy postmenopausal women who participated in the DOPS study. For the assessment of fracture risk, we used longitudinal observations from 854 women in the control group who remained compliant with their initial allocation of no treatment. Riboflavin intake was significantly correlated with femoral neck (FN) BMD in women with the TT genotype (r = 0.24, P < 0.01). FN and lumbar spine (LS) BMD were only associated with the MTHFR genotype in the lowest quartile of riboflavin intake. At the FN, similar threshold effects were shown for folate, vitamin B12, and vitamin B6. Among these vitamin B complex members, stepwise regression analysis identified riboflavin as the only significant predictor of FN BMD in the TT genotype. In conclusion, we confirm reports that BMD in the MTHFR TT genotype is only significantly reduced in the lowest quartile of riboflavin, B12, B6, and folate intake, at least at the time of menopause. Vitamin B supplementation would only be expected to benefit BMD in about 2% of the population, i.e., those with the TT genotype and low vitamin B intake.

The deterioration of trabecular microarchitecture induced by elevated bone turnover is increasingly recognized as a factor in the pathogenesis of osteoporotic fractures. We investigated the effect of the reduction of turnover with risedronate on trabecular architecture in postmenopausal women with osteoporosis. Iliac crest bone biopsy specimens taken before and after 3 years of treatment from patients receiving risedronate 5 mg daily (n = 21) or placebo (n = 17) were analyzed using 3-D microcomputed tomography. We found a significant correlation between baseline bone turnover and bone loss in the placebo group, providing evidence that higher turnover induced higher bone loss leading to a greater degree of architectural degradation. When patients were classified into two groups based on baseline bone turnover (MS/BS less than or greater than the median value for the entire cohort), significant decreases in trabecular bone volume (BV/TV, P = 0.009) and trabecular thickness (Tb.Th*, P = 0.008) and an increase in marrow star volume (Ma.St.V, P = 0.008), a measure of trabecular porosity, were observed in the higher turnover (MS/BS> median) placebo-treated patients. The trabecular structure shifted from plates to rods as shown by an increase in structure model index (SMI, P = 0.028) and bone surface to bone volume ratio (BS/BV, P = 0.006). The changes from baseline in the lower turnover (MS/BS

Alendronate has been shown to reduce bone turnover and increase bone mass. However, little is known about the duration of the effect on bone after treatment withdrawal. The aim of this study was to investigate the long-term effects on bone mineral density (BMD) and bone turnover of various alendronate regimens after treatment withdrawal. In this study, we followed 203 postmenopausal women who previously participated in two alendronate randomized placebo-controlled trials. Daily oral treatment with various doses of alendronate (2.5-20 mg) were given for 2, 4, or 6 yr followed by no treatment for 7, 5, or 3 yr, respectively. Bone mineral density of the lumbar spine, hip, and forearm was measured by dual-energy x-ray absorptiometry. Biochemical markers of bone turnover were induced serum C-terminal telopeptides of type I collagen (CTX) and osteocalcin. Women who received alendronate (2.5-10 mg per day) for 2 yr had a 3.8% higher BMD compared to those receiving placebo when assessed 7 yr after withdrawal. The residual effect was proportionally larger in women who had received treatment for 4 (5.9%, P=0.02) or 6 yr (8.6%, P=0.002), respectively. However, the largest residual effect was found in women treated with alendronate 20 mg per day for 2 yr (9.7%, P=0.01 vs. placebo). The rate of bone loss after alendronate withdrawal was comparable to the bone loss observed in the placebo group. Bone markers tended to reverse back to normal levels, but were still affected even several years after withdrawal of treatment. This study has demonstrated that the efficacy of alendronate in preventing bone loss was proportional to the duration of treatment. The rate of bone loss after withdrawal of alendronate corresponded to the normal postmenopausal rate of bone loss. A residual effect on BMD was found up to 7 yr after treatment withdrawal.

The purpose of this cohort study was to focus on factors associated with bone mass and structure of lower limbs and physical performance after menopause. Eighty nonsmoking women with a mean age of 62.1 (SD 0.8) years participated in the study. They were classified into two groups by their use of hormone replacement therapy (HRT), either the current users (n = 43) or the never or discontinued users (n = 37). The tibial shaft and distal tibia were scanned with peripheral computed tomography. For the shaft region, the bone mineral content (BMC, g), cortical density (CoD, g/cm(3)), cortical area (CoA, mm(2)), and section modulus (BSI, mm(3)) were determined. For the distal part, the evaluated variables were BMC, total area (ToA), ratio of cortical to total area (CoA/ToA), trabecular density (TrD, g/mm(3)), cortical thickness, BSI, and buckling ratio. Isometric and dynamic muscle strength of the leg extensors, agility and postural sway, and cardiorespiratory capacity (VO(2max)) were measured. Unadjusted values for all bone variables were slightly higher among the HRT users compared to nonusers, with the exception of TrD with no difference. After controlling for body weight, the mean differences (95% confidence interval) remained significant for CoD of the tibial shaft and BSI of the distal tibia, the mean between-group differences being 1.5% (0.4 to 2.5%) and 23.0% (7.1 to 41.3%), respectively. Underlying the greater bending strength, HRT users had thicker cortices and a greater ratio of CoA/ToA. No differences existed between the two study groups for lower limb isometric or dynamic power, cardiorespiratory capacity, or postural balance or sway. HRT may offer protection against bone loss and maintain bone strength, although its ability to improve physical performance is not evident.

Achievement of higher peak bone mass early in life may play a critical role against postmenopausal bone loss. Bone mineral density (BMD) of the spine, femoral neck, greater trochanter, Ward's triangle, and spine bone mineral content (BMC) and bone surface area (BSA) were assessed by dual energy x-ray absorptiometry in 300 healthy females (age 6-32 years). Bone measurements were described by using nonlinear models with age, weight, height, or dietary calcium intake as the explanatory variables. At the spine, femoral neck, greater trochanter, and Ward's triangle, the highest BMD level was observed at 23.0 +/- 1.4, 18.5 +/- 1.6, 14.2 +/- 2.0, and 15.8 +/- 2.1 years, respectively. The age of attaining peak spine BMC and BSA cannot be estimated, as significant increases in these two measures were observed through this age group. Age, weight, and height were all significant predictors of all these bone measurements. Weight was a stronger predictor than age for all sites. Dietary calcium intake was not a significant predictor for any of these bone measurements. We conclude that age of attaining peak bone mass at the hip is younger than at the spine, and BMC and BSA at the spine continue to increase through the early thirties in females.

Since effective prevention and treatment of osteoporosis demands a high degree of long-term compliance, optimization of the dosing regimen in terms of efficacy and convenience of drug intake is a critical issue of oral bisphosphonate treatment. The purpose of the present study was to investigate whether the efficacy of the treatment with oral ibandronate, 2.5 mg daily, can be maintained if changing the postdose fast from 60 to 30 min. This was a 48-week, multicenter, open-label, randomized, parallel-group noninferiority study. Subjects were postmenopausal women 55-80 years old with lumbar spine (L1-L4) bone mineral density (BMD) corresponding to a T score < or =2.5. Women were randomly assigned to take 2.5 mg ibandronate exactly 30 or 60 min before breakfast. Lumbar spine and proximal femur (trochanter, femoral neck, total hip) BMD were measured by dual energy X-ray absorptiometry; serum osteocalcin and creatinine-corrected urinary C-telopeptide of type I collagen (u-CTX/Cr) excretion were measured by ELISA. After 48 weeks of treatment, the relative increase in lumbar spine BMD from baseline in the 30-min fast group was lower than that in the 60-min fast group (3.07% versus 4.95%, one-sided 97.5% CI = -2.89%) such that the prespecified noninferiority criteria were not met. The mean relative increases in BMD at the trochanter (3.04% versus 4.36%), femoral neck (1.82% versus 2.19%), and total hip (2.35% versus 3.21%) in the 30-min fast group were also lower than those in the 60-min fast group. Less suppression of the markers of bone turnover (u-CTX/Cr, -48.5% vs -61.8%; serum osteocalcin, -34.8% vs 43.8%) was observed in the 30-min compared with the 60-min group. In conclusion, if reducing the postdose fasting interval, dose-increase compensation would likely to be required to maintain efficacy of oral ibandronate treatment. Another potential solution for improving the convenience with bisphosphonate treatment is expected from weekly or monthly dosing regimens currently under clinical investigations.

Calcitonin is a powerful inhibitor of osteoclast activity that exerts a rapid, transient, and reversible inhibition of bone resorption. Prolonged administration of parenteral calcitonin, by injections of 100 IU every 1 or 2 days, can prevent postmenopausal or postovariectomy bone loss, and is also able to increase trabecular bone mass among patients presenting an established osteoporosis. Prolonged treatment with calcitonin injections is, however, difficult to maintain over the long run. In addition to the ease of administration compared with the injectable forms, nasal calcitonin is much better tolerated, the side effects being rare and generally negligible. A prolonged administration of 200 IU intranasal calcitonin acutely inhibits parameters of bone resorption and can increase lumbar spine bone mineral density (BMD) by 1.7%-3.3% after 1 year. Lower doses also appear to be efficient to prevent early postmenopausal bone loss, but the data are conflictual. The results are more consistent in patients who already suffer from established osteoporosis. The increase in lumbar spine BMD is in the order of 1%-2% after 1 year with 200 IU daily. A therapeutic benefit of calcitonin at the level of the cortical bone has been less well demonstrated than for the trabecular bone. As for other antiosteoporotic therapies, the effect of calcitonin on the reduction of fracture risk has been examined less than the beneficial effect on trabecular bone mass. Currently, there is still no prospective, placebo-controlled study with a sufficient number of patients that demonstrates that long-term parenteral calcitonin administration reduces the risk of osteoporotic fractures. The efficacy of nasal calcitonin treatment to reduce vertebral fracture rate has been best examined in the PROOF (Prevent Recurrence of Osteoporotic Fractures) study. This was a prospective 5-year, placebo-controlled, dose-response study of nasal calcitonin (100, 200, or 400 IU daily). The increase in lumbar spine BMD was modest but significant and not clearly dose dependent, as was the reduction in bone turnover. The relative risk of developing new vertebral fractures was reduced by 33% at the end of the study in the 200-IU dose group (relative risk = 0.67, 95% CI 0.47-0.97, p = 0.03). There was also a nonsignificant reduction in the risk of hip fracture in this dose group. The doses of 100 and 400 IU of calcitonin also reduced the vertebral fracture risk, but the difference did not reach the classical level of statistical significance. A possible effect of calcitonin to enhance bone quality, which cannot be assessed by routinely available methods, is currently being investigated in a prospective placebo-controlled trial that could provide a rational explanation for these effects of calcitonin on the reduction in the vertebral fracture rate without much increase in bone mass or a marked reduction in bone turnover.

We examined the association between continuous leisure-time physical activity and the change in bone mineral density (BMD) and bone mineral content (BMC) in a population-based random sample of 1873 peri- and postmenopausal women. Leisure-time physical activities were registered with self-administered questionnaires in 1989 and 1994, and with an assisted questionnaire in 1995-1997. BMD and BMC were measured from lumbar vertebrae L2-4 and left femoral neck using dual-energy X-ray absorptiometry (DXA) in 1989-1991 and 1994-1997. During the average 5.6 year follow-up, annual loss of lumbar BMC was 124 mg (311 vs. 435 mg, p = 0.036) and annual loss of lumbar BMD was 1.22 mg/cm(2) (4.15 vs. 5.37 mg/cm(2), p = 0.21) smaller among women with regular (at least 1 h each week) weight-bearing leisure-time exercise compared with sedentary women. The advantage was even larger in women with walking or jogging as their only regular weight-bearing leisure-time exercise; that is, their annual loss of lumbar BMC was 180 mg (272 vs. 452 mg, p = 0.022), and annual loss of lumbar BMD was 2.78 mg/cm(2) (2.96 vs. 5.74 mg/cm(2), p = 0.029) smaller than in sedentary women. Continuous leisure-time physical activity did not have any association with loss of BMC or BMD in the femoral neck Physical activity during 12 months before the last bone densitometry was not associated with loss of BMC or BMD at any site. Our results suggest that regular weight-bearing exercise diminishes lumbar bone loss, but might be ineffective in the prevention of femoral osteoporosis among peri- and early postmenopausal women.

Levormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), has been evaluated for its effects on bone in cynomolgus monkeys (Macaca fascicularis). Adult female monkeys were imported from Indonesia and randomized into six groups of 25-28 animals each (n = 158). Animals in one group were sham ovariectomized (sham) and received vehicle. Animals in the remaining five groups were ovariectomized and received either vehicle (ovx); 17beta-estradiol at 0.016 mg/kg (est); or levormeloxifene at 0.5 (L1), 1 (L2), or 5 (L3) mg/kg. Lumbar spine and whole body bone mass were measured by dual-energy X-ray absorptiometry (DXA) pretreatment and at 6 and 12 months following the initiation of treatment. Bone mass at the femoral neck was measured by peripheral quantitative computed tomography (pQCT) at 0 and 12 months. Serum markers of bone turnover, including bone-specific alkaline phosphatase (BSAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), and urinary collagen C-terminal extension peptides (CrossLaps), were measured at 0, 6, and 12 months. Ovariectomy resulted in an increase in these markers; the increase was prevented by estradiol or levormeloxifene. Estradiol or levormeloxifene inhibited loss of lumbar spine bone mineral density (BMD) following ovariectomy compared with untreated monkeys (ovx -5.0%; sham -0.4%; est +0.2%; L1 -3.6%, L2 -2.0%, L3 -2.5%). Estradiol, but not levormeloxifene, prevented loss of BMD at the femoral neck (ovx -7.4%; sham -3.1%; est -3.6%; L1 -8.0%, L2 -6.5%, L3 -7.8%), and whole body bone mineral content (BMC) (ovx -7.6%; sham -1.9%, est -2.9%; L1 -6.2%, L2 -6.1%, L3 -6.7%). Bone loss at each site was correlated with bone turnover as measured by serum and urine biomarkers. There was no dose effect of levormeloxifene.

The objectives of the Hong Kong study are to investigate the efficacy of 10 mg alendronate in preventing bone loss at the hip and spine in osteoporotic Chinese women. One hundred osteoporotic Chinese women, aged 60-79 years, were randomized to receive 10 mg of alendronate or placebo, with 500 mg elemental calcium. Bone mineral density (BMD) at the spine and hip were measured at baseline, 6 months, and 12 months. Seventy-eight subjects completed the study. The alendronate-treated group gained more bone at both the spine (p < 0.01) and femoral neck (p < 0.001), with a mean difference (+/-SE) of 2.4% (+/-0.86%) at the spine and 3.98% (+/-0.95%) at the femoral neck. Of the 100 patients, 6 subjects in the alendronate group and 5 subjects in the placebo group had mild gastrointestinal symptoms. We conclude that alendronate (10 mg) was effective in preventing bone loss in postmenopausal osteoporotic Chinese women.

In clinical practice, a large proportion of patients have bone mass values for which a therapeutic intervention is considered necessary, but the accepted aim might be the sole preservation or marginal increases of the actual bone mass. These goals might be achieved with lower or intermittent doses of a powerful agent for the purpose of fewer side effects and improved compliance. The aim of this study was to assess the effects of two intermittent alendronate regimens in the treatment of postmenopausal osteoporosis. One hundred twenty-four postmenopausal women (age range 52-75 years, at least 7 years since last menopause) with a bone mineral density (BMD) at either the femoral neck or lumbar spine of 2 SD below the mean values of young healthy individuals, and without a history of previous osteoporotic fracture, were randomly assigned either to calcium/vitamin D supplements, alone or associated with two different intermittent oral alendronate regimens: 20 mg once a week (weekly alendronate group) or 10 mg daily (orally) for 1 month out of 3 (cyclical alendronate group). After 1 year, in both groups given intermittent alendronate, we observed significant increases in BMD at both the spine (+2.2 +/- 2.6 and +2.5 +/- 2.9) and femoral neck (+1.6 +/- 4.8 and +1.5 +/- 2.2) for the weekly and cyclical regimens, respectively. This was associated with a significant diminution of both serum bone-specific alkaline phosphatase and urinary N-telopeptides of collagen type I excretion. In the patients in the control group BMD decreased significantly at the lumbar spine, with a slight decline of serum bone-specific alkaline phosphatase. Compliance with treatment and drug tolerability were good in both alendronate groups. In conclusion, intermittent alendronate administration at cumulative doses (and costs) three times lower than those currently recommended for osteoporosis treatment is very well accepted, and is able to significantly increase BMD at the spine and femoral neck and to decrease the markers of bone turnover. These regimens can be clinically useful in the long-term treatment of postmenopausal osteoporosis without prevalent osteoporotic fractures, particularly in women with lower compliance for continuous administration.

The cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6 induce osteoclast formation and may contribute to the development of postmenopausal osteoporosis. Cross-sectional studies have suggested that both IL-1 and IL-1ra secretion increase on estrogen withdrawal, and that postmenopausal osteoporosis is associated with an inadequate increase in monocyte IL-1ra secretion with age. We measured cytokine mRNA (IL-1beta, IL-1ra, IL-6, and TNF-alpha) directly in bone biopsies from early postmenopausal women to determine if a lower compensatory increase in IL-1ra mRNA could be demonstrated in women with rapid bone loss after the menopause. Biopsies were obtained from 23 early postmenopausal women (mean age 53.9 years) who participated in a randomized study of hormone replacement therapy (HRT) and risk factors for osteoporosis. Bone mineral density was assessed by duel energy X-ray absorptiometry at 0, 1, 2, and 5 years. Women in the control group were recruited to the biopsy study based on their observed rate of bone loss (upper or lower tertile). Consent was also obtained from 11 participants receiving HRT. Biopsies were taken at 2 years, frozen in nitrogen, and homogenized. Cytokine mRNA was measured by competitive reverse transcriptase polymerase chain reaction. The IL-1ra/IL-1beta mRNA slope for the slow-loss group was steeper (deltaF = 23.3, p < 0.01) than that observed in the fast-loss group, indicating that slower bone loss was associated with higher IL-1ra mRNA levels relative to IL-1beta. During HRT, the IL-1beta mRNA level was inversely correlated with serum estradiol (log r2 = 0.77, p < 0.01), and women with a serum estradiol below 200 pmol/L during HRT had IL-1beta, mRNA levels identical to the control group. In contrast, IL-1ra mRNA was independent of serum estradiol. Histomorphometric analysis revealed weak correlations between IL-1beta mRNA and activation frequency (r2 = 0.26, p = 0.06) and between IL-1ra and volume referent bone resorption rate (r2 = 0.19, p = 0.11). TNF-alpha was not associated with the bone loss rates or with serum estradiol, and only three samples were positive for IL-6 mRNA. The findings support the hypothesis that IL-1beta production within bone increases with declining estrogen levels, and that an increase in II-1ra protects against accelerated bone loss.

This international, randomized, double-blind, placebo-controlled, parallel group, dose-ranging trial was designed to determine the efficacy of 2 years of therapy with a new matrix transdermal 17beta-estradiol (Menorest) in preventing bone loss in early postmenopausal women, and to identify an appropriate dose. Two hundred ninety-two ambulatory women with natural or surgical menopause for 1-6 years were randomized to receive patches delivering 17beta-estradiol 50, 75, or 100 microg/day twice weekly for 25 days per 28 day cycle (with dydrogesterone 10 mg twice daily from days 11 to 24) or placebo, for 24 months. The primary outcome measure was the percentage change from baseline in lumbar spine bone mineral density (BMD) at 2 years. Secondary endpoints were percentage changes from baseline in three sites of proximal femur BMD and total body BMD, and in biochemical bone turnover markers. At 2 years, the difference from placebo in percentage change from baseline of L1-4 spine BMD was 6.2%, 7.6%, and 7.8% in the 50, 75, and 100 microg/day groups, respectively. Lumbar spine bone increased in 65.5%, 76.8%, and 81.0% of patients in the respective active treatment groups, compared with 4.9% on placebo. BMD increased significantly relative to placebo in the femoral neck, trochanter, total hip, and total body. Serum osteocalcin, bone alkaline phosphatase and urinary type I collagen C-telopeptide decreased significantly and dose dependently in 17beta-estradiol patients vs. placebo. For example, at 2 years, the difference between placebo and the 50 microg/day group, expressed in percentage change from baseline, was 3.25% at the femoral neck, 3.92% at the trochanter, 3.52% for total hip, and 2.40% for the total body. Breast pain and skin reactions were more common in the actively treated groups, but tolerability was generally good. Therefore, after 2 years, 17beta-estradiol was well-tolerated and highly effective at doses of between 50 and 100 microg/day in preventing bone loss and reducing bone turnover in early postmenopausal women. The dose of 50 microg/day, the lowest dose tested, is a suitable dose. There was little clinical benefit of increasing the dosage from 75 to 100 microg/day.

Data from the Danish cohort (n = 67) of a multicenter trial of oral alendronate in the prevention of postmenopausal osteoporosis were used to evaluate the capacity of the biochemical markers to predict changes in bone mineral density (BMD). A panel of markers were measured: serum N-terminal midfragment osteocalcin (N-MID OC); serum total osteocalcin (total OC); bone-specific alkaline phosphatase (BSAP); serum and urine C-telopeptides of type I collagen (sCL and uCL); urine N-telopeptide crosslinks of type I collagen (NTX); and deoxypyridinoline (dPyr). The correlation between change from baseline at months 3-12 in total OC, N-MID OC, sCL, uCL, and NTX and 2 year response in spine BMD ranged from r = -0.45 to r = -0.78 (p < 0.001), and from r = -0.38 to r = 0.10 (n.s. to p < 0.002) for BSAP and dPyr. Sensitivity and specificity were used to assess the accuracy of change from baseline at month 6 in the biochemical markers for predicting prevention of bone loss in the spine over 2 years. The cutpoints used were a 30% (N-MID OC) or 50% (all other markers) decrease from baseline. Sensitivity levels were 82% (N-MID OC), 98% (total OC), 78% (sCL and NTX), and 89% (uCL). Specificities were 91% (N-MID OC), 59% (total OC), 100% (sCL), 71% (uCL), and 84% (NTX). Positive predictive values were 95% (N-MID OC), 82% (total OC), 100% (sCL), 87% (uCL), and 90% (NTX). In comparison, the predictive capacities of change from baseline at year 2 in hip BMD in predicting prevention of bone loss at the spine were similar: sensitivity, 82%; specificity, 55%; and positive predictive value, 79%. In conclusion, short-term changes in biochemical markers were valid predictors of long-term changes in BMD. Short-term changes in the sensitive biochemical markers revealed a predictive capacity similar to bone densitometry at the hip measured over 2 years. The sensitive biochemical markers offered a fast and valid alternative to bone densitometry for monitoring of alendronate treatment.

The purpose of this study was to determine the effects of oral estrogen replacement therapy with conjugated equine estrogens (CEE), alone or in combination with continuous medroxyprogesterone acetate (MPA), on lumbar spine bone mineral content (BMC) and density (BMD) and on serum chemistries in ovariectomized cynomolgus monkeys when therapy is initiated following a 2 year hypoestrogenic period. Study design was done in the form of a randomized, placebo-controlled, nonhuman primate paraclinical trial. Monkeys were subjects in an experiment designed to study the effects of a lipid-lowering diet combined with hormone replacement therapy on atherosclerosis. Initially, they were ovariectomized and fed a high-fat diet for 24 months. They were then were allocated to three treatment groups by stratified randomization and were fed a diet containing reduced dietary fat for an additional 28 months. Treatment groups consisted of: (1) an untreated group (ovx, n = 24); (2) a CEE-treated group (CEE, n = 19); and (3) a CEE plus continuous MPA group (CEE + MPA, n = 20). Lumbar spine BMC and BMD values were measured by dual-energy x-ray absorptiometry at baseline and 4, 10, 16, 22, and 28 months of treatment. Serum chemistries were relevant to bone metabolism at 22 and 28 months. Rates of gain in BMC and BMD were greater (p < 0.05) in hormone-supplemented animals (groups 2 and 3) than in untreated ovx animals during the first 16 months of treatment, resulting in increased BMC and BMD measurements in these groups. Serum markers of bone metabolism were significantly lower (p < 0.05) in the hormone-treated groups (groups 2 and 3) compared with ovx animals after 22 and 28 months of treatment, indicating reductions in bone turnover rate. Oral estrogen replacement with CEE at doses similar to those taken by women leads to significantly increased BMC and BMD in monkeys, even when therapy is begun 2 years after ovariectomy. Most of the increase occurred during the first 16 months of treatment. The addition of MPA to the CEE regimen provided no additional benefit.

This study was designed to assess the effects of exercise training (Tr) following an etidronate treatment (E) on bone mineral density (BMD) of the femur and trabecular bone of the tibia in ovariectomized (ovx) rats. Female Wistar rats were ovariectomized (ovx) or sham-operated (sham) at 15 weeks of age and divided into five experimental groups: sham; ovx; ovx + E; ovx + Tr; ovx + E + Tr. Etidronate treatment of 5 mg/kg, 5 days/week was administered for 2 weeks and exercised on a treadmill for 30 m/min, 60 min/day, 5 days/week for 10 weeks. BMD of the femur and the trabecular bone area of the proximal tibia were significantly (p < 0.05) higher in E and/or Tr compared to ovx groups. However, the cortical region was not affected significantly by ovariectomy. The area partially filled with the trabecular bone at the constant width was observed only in the E rats. The number of osteoclasts in E group was significantly lower (p < 0.05) than in the ovx and ovx + Tr groups. The ovx + Tr rats had a higher number of osteoblasts (p < 0.05) than the ovx and ovx + E groups. There was a significant interaction between ovx + Tr and ovx + E on BMD in the proximal region of the femur (p < 0.05) and trabecular bone area of the tibia (p < 0.001). These results suggest that the etidronate treatment for 2 weeks beforehand influenced the effects of subsequent exercise training on maintaining the BMD in the proximal femur and the trabecular bone area of the tibia.

Prostaglandins have been reported to mediate the effects of ovariectomy on bone loss. We studied the effect of naproxen, an inhibitor of production of prostaglandins, on ovariectomy-induced bone loss. One hundred forty female Wistar rats 4.5 months of age were divided into groups of baseline, sham operation (sham), sham treated with naproxen at 10 mg/kg per day (in food), and ovariectomy treated with naproxen or estrogen as intramuscular injection of estradiol at 0.2 mg/kg body weight per week. They were killed 3, 6, and 9 months postsurgery. Bone mineral density (BMD) of the lumbar spine (L1-4), femoral neck, midshaft, and distal metaphysis was determined using dual-energy X-ray absorptiometry (DXA) in vitro. The compressive test of the L1 vertebral body and torsional test of the left femur were performed. The right femoral neck and femoral midshaft were processed undecalcified for determining cross-sectional moments of inertia. Naproxen treatment partially prevented ovariectomy-induced loss or less gain in BMD, in a significant manner, in the femoral neck cortical area, and also in L1 compressive strength and stiffness. Estrogen fully prevented these ovariectomy-induced effects. Naproxen showed no effect on ovariectomy-induced improvement in femoral torsional strength and stiffness and cross-sectional moments of inertia. No statistically significant difference was found between naproxen-treated sham rats and untreated sham rats. The data suggest that naproxen partially prevents ovariectomy-induced osteopenia.

The effects of progestins on bone loss in female oophorectomized (ovx) rats were evaluated. One-year-old Sprague-Dawley rats were divided into eight groups: (1) beginning controls (control); (2) sham-operated controls (sham); (3) ovx; (4) ovx treated with estrogen (ovx + E); (5) ovx treated with progesterone (ovx + P); (6) ovx treated with estrogen and progesterone (ovx + E + P); (7) sham group treated with estrogen (sham + E); and (8) sham group treated with progesterone (sham + P). Immediately after surgery, the rats in the hormone injected groups were subcutaneously (s.c.) injected daily for 15 weeks with estrogen (17-beta-estradiol, 0.01 mg/kg in ethanol), or progesterone (4-pregnene-3,20-dione, 0.1 mg/kg in ethanol), or both. At the end of 15 weeks, the bone mineral density (BMD) and bone histomorphometry of the rats' lumbar vertebrae and serological parameters were measured. In the sham, ovx, and ovx + P groups, treatment with progesterone alone did not maintain the BMD in the lumbar vertebrae, but in the ovx + E and ovx + E + P, sham + E, and sham + P groups, progesterone did not inhibit the action of estrogen in the aged ovx rat model. BMD in the sham + P group was significantly higher than in the sham group (270.8+/-10.8 mg/cm2 versus 253.6+/-10.2 mg/cm2; p < 0.01). Bone histomorphometry revealed that bone volume (BV/TV) increased more in the ovx + E + P group than in the ovx + E group and more in the sham + P group than in the sham group, but not significantly. The ovx + E, ovx + E + P, sham + E, and sham + P groups showed no significant differences in the bone formation and resorption parameters, but the bone formation variables tended to increase in the ovx + E + P and sham + P groups. We concluded that progesterone alone cannot prevent bone loss or the increase in turnover after ovx and that estrogen, not progesterone, accounted for all of the bone activity in this study. It seems doubtful that progesterone inhibits the action of estrogen, and in fact may have a beneficial effect on bone metabolism.

The aim of this study was to determine whether the higher vertebral bone mass in women receiving hormone replacement therapy (HRT) is confined to the trabecular rich vertebral body rather than the predominantly cortical posterior processes, and to determine whether the protective effect of HRT at the proximal femur, a predominantly cortical site, is less than at the spine. Bone mass (g) of the third lumbar vertebra (total, vertebral body and posterior processes, measured by lateral scanning), and bone mineral density (g/cm2) of the femoral neck, Ward's triangle, and trochanter were measured using dual X-ray absorptiometry in a cross-sectional study of 71 women receiving HRT for 5.7 +/- 0.4 years (mean +/- SEM), ranging from 1 to 21 years, 69 age-matched controls, and 42 premenopausal controls aged 20 to 40 years. Relative to untreated postmenopausal controls, total bone mass of the third lumbar vertebra (body plus posterior processes) by postero-anterior (PA) scanning was 0.4 +/- 0.1 SD or 9.6 +/- 3.0% higher in HRT treated women (p < 0.01). By lateral scanning, total bone mass was higher than age-matched controls (z score 0.4 +/- 0.1 SD or 11.2 +/- 3.4%, p < 0.01). This difference was confined to the vertebral body (z score 0.6 +/- 0.1 SD, p < 0.001), which was 17.1 +/- 3.3% higher than in age-matched controls (p < 0.001). Bone mass of the posterior processes was no higher [z score 0.1 +/- 0.1, not significant (NS)]. The deficit at the vertebral body in HRT-treated women, relative to premenopausal controls, was half the deficit at the vertebral body in untreated postmenopausal women (t score -0.7 +/- 0.1 vs. -1.4 +/- 0.1 SD, respectively; p < 0.001) but no less at the posterior processes (t score -1.6 +/- 0.2 vs. -1.9 +/- 0.2 SD, respectively; NS). Similarly, the deficit in the vertebral body in the HRT treated group was half the deficit at their posterior processes (t score -0.7 +/- 0.1 SD vs. -1.6 +/- 0.2, respectively; p < 0.001). In HRT-treated women, bone mass diminished significantly with age at the posterior processes (r = -0.31, p < 0.01), but not at the vertebral body (r = -0.21, p = 0.07). Bone mass diminished significantly with age at the vertebral body and posterior processes in untreated women (r = -0.55, p < 0.001; r = -0.45, p < 0.001, respectively). Bone density (g/cm2) diminished at all femoral sites with advancing age in HRT-treated women. A protective effect was seen at the femoral neck and Ward's triangle, but not trochanter (z score 0.2 +/- 0.1, p = 0.06; 0.3 +/- 0.1, p < 0.05; 0.0 +/- 0.1, NS, respectively). In conclusion, the protective effect of HRT against bone loss at the vertebral body, the site of fracture in osteoporosis, may be underestimated by PA scanning. The greater benefit at the vertebral body, and more modest effect at the proximal femur, suggests that HRT may be a more effective means of reducing the risk of spine than hip fractures.

The association between sports participation during adolescence and peri- and postmenopausal bone mineral density (BMD) was examined among 2025 women aged 48-58 years. Adolescent recreational and competitive sporting activities were registered with a self-administered questionnaire. Altogether, 881 (43.5%) women stated that they had taken part in sports during their adolescence. BMD was measured using dual X-ray absorptiometry (DXA) in lumbar vertebrae 2-4 and the left femoral neck. The unadjusted BMD was 2.4% higher (p = 0.001) and the adjusted BMD was 1.4% higher in the spine (p = 0.015 after adjusting for age, weight, time from menopause to densitometry, and duration of estrogen replacement therapy) among women who had taken part in sports during their adolescence compared to women who had been inactive. There was no significant difference in femoral neck BMD between these groups. The results of this population-based study suggest that intense recreational physical activity in adolescence could play some role in preventing axial osteoporosis in later life.

Hyperthyroidism increases bone turnover and induces bone loss. This study examines the effect of thyroid hormone excess on two biochemical markers of bone turnover (hydroxyproline and bone alkaline phosphatase) as well as on bone mineral content (BMC) and bone mineral density (BMD). The possible protective role of dimethyl-APD (olpadronate, OLP), on both suppression of bone turnover and bone mineral loss in ovariectomized (ovx) rats, was also studied. Female Sprague-Dawley rats, were assigned to five groups of eight rats each: sham, ovx, ovx OLP treated (0.3 mg/kg per week), ovx T4 treated (250 micrograms/kg per day), and ovx T4-OLP rats. Rats were killed after 5 weeks of treatment. At the end of the study, blood samples were analyzed for serum calcium, phosphorus, T4, total and bone alkaline phosphatase (ALP and b-ALP), and urinary samples for hydroxyproline/creatinine ratio (HOProl/creat). Moreover, total BMC, BMD, and scanned area were determined by DXA. Ovx T4-OLP-treated rats presented higher values of b-ALP than ovx T4-treated, ovx, and sham rats (p < 0.05). Ovx increased HOProl/creat excretion compared with sham (p < 0.05), but it was similar compared with ovx T4-treated rats. OLP treatment reduced HOProl/creat excretion in both ovx T4-treated (p < 0.05) and ovx rats (p < 0.05). The final BMC in ovx was lower than in the sham group, but the difference was not statistically significant (p < 0.08). The lowest BMC was observed in ovx T4 rats (p < 0.05). When final BMC was expressed per body weight (BMC/W), ovx rats presented a significantly lower BMC/W than sham rats (p < 0.05). Ovx OLP rats had BMC/W levels higher than ovx (p < 0.005), ovx T4 (p < 0.01), and ovx T4-OLP rats (p < 0.01). The ovx group had a final BMD lower than sham animals (p < 0.05), but not significantly different than the ovx T4 rats. BMC and BMD of OLP ovx rats, whether they received T4 or not, was similar to the sham group. The highest final BMD was observed in the ovx T4-OLP group. In summary, the prevention of an increase in HOProl excretion accompanied by the fact that final BMD and BMC in OLP-treated animals were comparable to sham control rats may reflect that OLP administration could inhibit bone resorption in both T4-treated or -untreated rats. Although further studies are necessary, these findings may have clinical relevance in estrogen-depleted patients to whom medical management other than the reduction of T4 administration would be desirable.

We examined the effects of nandrolone decanoate (25 mg im every 3 weeks) on bone mass, serum biomarkers, and bone histomorphometric endpoints in 52 female cynomolgus macaques randomized into four treatment groups: (1) sham-ovariectomized (sham); (2) ovariectomized + placebo for 2 years (ovx); (3) ovx + nandrolone decanoate for 2 years (Nan); and (4) ovx + nandrolone decanoate beginning 1 year after ovx (dNan). Serum alkaline phosphatase (ALP), osteocalcin, and tartrate-resistant acid phosphatase (TRAP) were assayed every 3 months, and X-ray densitometry of the lumbar spine was done every 6 months. Fluorochrome-labeled iliac biopsies collected at baseline and 1 year, and lumbar vertebrae and midshaft femur collected at 2 years, were evaluated histomorphometrically. Body weight increased over 50% with administration of nandrolone. After 2 years, ovx animals had lower spinal BMC and BMD than all other groups. Ovx animals also had higher bone turnover rates than all other groups, as indicated by higher levels of the serum and urine biomarkers, and by at least twofold higher label-based bone formation rates in the femur diaphysis and in both cancellous and cortical bone of the ilium and vertebral bodies. Nandrolone-treated animals had similar serum estradiol levels as the sham animals, presumably due to conversion of endogenous or exogenous androgens. The effects of nandrolone on bone in this experiment are consistent with estradiol action and may be attributable to the increased serum estradiol. Despite >50% higher body weight, nandrolone-treated, ovariectomized animals did not have higher bone mass than sham animals.

Interleukin (IL)-1 is a potent inducer of bone resorption, and an increased secretion of the IL-1 agonists IL-1 alpha and IL-1 beta relative to the IL-1 receptor antagonist (IL-1ra) has been proposed as a mechanism leading to post-menopausal osteoporosis. T-lymphocytes are capable of secreting bone resorptive cytokines and have also been linked with bone metabolism and the development of osteoporosis. Cytokine secretion from whole blood cell cultures was compared between two randomized groups of healthy early post-menopausal women (mean age 52.5 yrs, N = 91) and lymphocyte subsets were quantitated by flow cytometry. One group received cyclic estrogen-gestagen replacement therapy (ERT) while the other group was untreated. In spite of a significant bone maintaining effect of ERT, the basal and LPS-stimulated secretion of IL-1 alpha, IL-1 beta, and IL-1ra was identical in the two groups. There was no association between cytokine release and bone mass or loss assessed over 2 yrs. The only exception was a weak estrogen-independent correlation between basal IL-1ra secretion and bone loss (r = -0.21, p < 0.05). Flow cytometry did not confirm a relationship between CD4/CD8 T-cell ratios and bone density or loss, and there was no effect of ERT on lymphocyte subsets. The number of CD3+ CD56+ T-cells showed a highly significant negative correlation with femoral and lumbar bone density in untreated women (r = -0.42, p < 0.01) similar to that found in patients with established osteoporosis, indicating that these adherent mononuclear cells may be important in the pathophysiology of post-menopausal bone loss. The possibility that IL-1ra acts as an independent bone-sparing factor unrelated to estrogen withdrawal warrants further investigation. In conclusion, ERT maintains bone without affecting the release of the IL-1 family of cytokines in whole blood cultures.

Hormone replacement therapy (HRT) has been the method of choice for the prevention of postmenopausal osteoporosis since the early 1990s. Although a number of routes of administration are now available, HRT is still predominantly administered orally. In the United States, HRT formulations traditionally comprise conjugated equine estrogens. In Europe, however, HRT preparations tend to be based on 17 beta-estradiol, a natural human estrogen. Furthermore, distinct patterns of HRT use are apparent based on the age of the woman receiving it. Current recommendations are that early postmenopausal women (in their early 50s) receive sequential combined estrogen/progestogen therapy with continued monthly bleeds, while in women who are at least 1 year postmenopausal, continuous combined HRT, which leads to endometrial atrophy and cessation of monthly bleeding, is preferred. Clinical experience to date clearly demonstrates that long-term HRT unequivocally increases bone mass and reduces the risk of fractures in postmenopausal women, with no significant differences between sequential and continuous combined prescribing regimens. Data demonstrating that antiestrogens such as tamoxifen may preserve bone mass have led to the initiation of large-scale trials to determine the potential clinical utility of such agents for the prevention of osteoporosis in postmenopausal women. Nonhormonal therapeutic approaches are now also available, most notably bisphosphonates and vitamin D analogs. At present, however, traditional HRT remains the regimen of choice for the prevention of postmenopausal osteoporosis, given its additional beneficial effects on acute menopausal symptoms, as well as on the cardiovascular system and brain.

The effect of short-term estradiol treatment, administered from the time of ovariectomy, on increased bone turnover and subsequent bone loss was studied in the rat. Adult female Sprague-Dawley rats were ovariectomized and administered daily subcutaneous (s.c.) injections of 17 beta-estradiol at 8 micrograms/ kg per day (Low) and 20 micrograms/kg per day (High) or vehicle alone (Veh). Femoral trabecular bone volume (BV/TV) and trabecular number (Tb.N) in the distal femur were transiently increased at 6 days postoperation in a dose-dependent manner following estradiol administration [mean +/- SEM: BV/TV (%), day 0, 6.6 +/- 0.2; day 6, Veh 7.8 +/- 0.4, Low 10.2 +/- 2.2, High 12.8 +/- 1.7 (p < 0.05); Tb.N (/mm), day 0, 2.30 +/- 0.24; day 6, Veh 2.89 +/- 0.33, Low 3.4 +/- 0.7, High 4.39 +/- 0.34 (p < 0.05)]. Estradiol prevented the ovariectomy-induced decrease in BV/TV and Tb.N between 9 and 15 days observed in Veh rats. Both serum alkaline phosphatase and urine hydroxyproline excretion were maintained at preoperative levels or lower from day 6 postoperation with high dose estradiol. Serum osteocalcin, however, rose above preoperative levels with estradiol at days 6 and 9, but returned to these values on days 15 and 21 postoperation. These results suggest that estradiol, administered from the time of ovariectomy, immediately suppressed markers associated with osteoblast proliferation/matrix synthesis and bone resorption. Mineralization does not appear to be so rapidly suppressed by estradiol with relatively high levels immediately following administration, resulting in a transient increase in trabecular bone volume and trabecular number.

The present article describes the results from a phase II dose finding study of the effect of ibandronate, a new, third generation bisphosphonate, in postmenopausal osteoporosis. One hundred and eighty postmenopausal, white women, at least 10 years past a natural menopause, with osteopenia defined as a bone mineral density (BMD) in the distal forearm at least 1.5 SD below the premenopausal mean, entered and 141 (78%) completed a 12 months randomized, double-blind, placebo-controlled study. The women received 0.25, 0.5, 1.0, 2.5, or 5.0 mg ibandronate daily or placebo. All women received a daily calcium supplementation of 1000 mg Ca2+. Bone mass and biochemical markers of bone turnover were measured every 3 months throughout the study period. The average changes in bone mass showed positive outcome in all regions in the groups receiving ibandronate 2.5 and 5.0 mg. The responses in the two groups were not significantly different, although there was a tendency toward a higher response in bone mass in the group receiving ibandronate 2.5 mg, where the increase in BMD was 4.6 +/- 3.1% (SD) in the spine (p < 0.001), 1.3 +/- 3.0% (SD) to 3.5 +/- 5.3% (SD) in the different regions of the proximal femur (p < 0.03 to p < 0.002), and 2.0 +/- 1.9% (SD) in total body bone mineral content (BMC) (p < 0.001). There was no significant changes in bone mass in the group receiving calcium (placebo) and ibandronate 0.25 mg. Dose-related responses were found in all biochemical markers of bone turnover. In average, serum osteocalcin decreased 13 +/- 14% (SD) (placebo) and 35 +/- 14% (SD) (5.0 mg). Urinary excretions of breakdown products of type I collagen decreased 35 +/- 21% (SD) (placebo) and 78 +/- 28% (SD) (5.0 mg), p < 0.001 in all groups. In conclusion, the results suggest that ibandronate treatment increases bone mass in all skeletal regions in a dose dependent manner with 2.5 mg being the most effective dose. Ibandronate treatment reduces bone turnover to premenopausal levels and is well tolerated.

There is a persuasive rationale from the use of hormone replacement therapy (HRT) at the time of the menopause, but there are a number of factors which limit its widespread application for osteoporosis. These relate partly to the long-term efficacy of HRT when given for a finite duration at the time of the menopause, and long-term prospective studies are warranted to address this issue. In addition, there are problems in the acceptability of, and long-term compliance with, many HRT regimens. A further difficulty relates to the logic of targeting women at risk from osteoporosis at the time of the menopause when the benefits and risks of HRT are largely extraskeletal. There may be a case for targeting HRT much later in life provided that HRT regimens can be made acceptable to such patients. Finally, the importance of the menopause to the problems of osteoporosis has been overemphasized, and other factors are important in determining the geographic variation in hip fracture risk as well as the increase in age- and gender-specific incidence that has occurred in many countries. The causes from this are unknown, but are clearly not related to gonadal status, because these phenomena are observed both in men and in women. A plausible hypothesis is the differences in physical activity between communities and the decrease in physical activity within communities. It will be important to determine the etiology of these phenomena so that logical preventive strategies can be developed.

The present randomized, double-blind, placebo-controlled, 2-year study is the first to evaluate the effect of 1.25 and 2.5 mg tibolone daily oral administration on trabecular and cortical bone loss in early postmenopausal women. Ninety-four healthy, normal weight, nonsmoking women participated 1-3 years following spontaneous menopause. Twenty-three subjects were randomized to the placebo group, 36 to the 1.25 mg/day tibolone group, and 35 to the 2.5 mg/day tibolone group. Bone density was assessed at 6 month intervals. Spinal trabecular bone density (BD) was measured with quantitative computed tomography. Phalangeal cortical BD was measured by radiographic absorptiometry. The 2-year change vs. baseline in the placebo group for trabecular BD was -6.4% (95% confidence interval -8.1 to -4.7). Cortical BD did not change significantly. At 24 months both tibolone groups showed a statistically significantly higher trabecular [9.4% (6.6-12.2) for the 1.25 mg group and 14.7% (11.8-17.5%) for the 2.5 mg group] and phalangeal BD [4.4% (1.5-7.4) for the 1.25 mg group and 6.8% (3.8-9.8) for the 2.5 mg group] as compared to the placebo group. After 2 years of tibolone in both regimes, trabecular and phalangeal BD was significantly higher as compared to pretreatment values. At 24 months the 2.5 mg group showed a significantly higher trabecular (p < 0.001) but not phalangeal (p = 0.064) BD compared to the 1.25 mg group. Tibolone prevents early postmenopausal bone loss by inducing an increase in trabecular and phalangeal BD.

The objective of this study was to determine whether intranasal salmon calcitonin prevents physiological bone loss at perimenopause. A double-blind study of 120 perimenopausal women without present or past disease or medication that could affect bone metabolism were studied. The subjects were randomized in two groups and provided with nasal spray bottles containing either placebo (excipient only) or active compound (excipient plus 50 international units (IU) salmon calcitonin per dose). Subjects took one puff from the nasal spray in each nostril every morning. All subjects took one soluble tablet of calcium (1000 mg) per day. Serum biochemistry, dual-energy X-ray absorptiometry of lumbar spine and proximal femur, quantitative computed tomography of lumbar spine, and single photon attenuation of forearm were used to evaluate bone mineral density (BMD). There were no differences in demographic characteristics or hormone status at entry. No fractures were recorded during the study period. Serum calcium increased and serum dihydroxyvitamin D and osteocalcin decreased in both groups. There was no difference in biochemical parameters between the groups. The BMD of upper femur did not change during the study, but it was decreased in the lumbar spine in both groups. The mineral content of distal radius increased in both groups. In conclusion, nasal salmon calcitonin, 100 IU daily, has no protective effect on bone mass and does not modify bone metabolism at perimenopause.

Bone mineral density of the distal forearm decreases with age in women, and this results in an increased risk of forearm fractures. Men have no increase in risk of forearm fractures with age because they have a higher peak bone mass at this site and less of a decrease in bone mineral density with ageing. Bone loss from the forearm slows in women after the age of 65 years in women and this may account for the plateau in forearm fracture rate after this age. Women with forearm fractures have twice the expected risk of vertebral and hip fractures. Forearm fractures before the age of 60 years are associated with an increase in the risk of vertebral fractures. Forearm fractures after the age of 70 years are associated with an increased risk of hip fractures. Thus, women presenting with forearm fractures are a good target population for the prevention of osteoporosis.

There is increasing evidence that load-bearing is an important, if not the most important, functional influence on bone mass and architecture. Load-bearing most probably exerts its influence through the dynamic strains engendered in the bone tissue. Mechanically adaptive bone modeling and remodeling can be regarded as a homeostatic mechanism regulating functional bone strains at each location throughout the skeleton. Because most long bones are loaded in a certain amount of bending normal function, strains vary across the bones' cross-section. Both the longitudinal curvature and cross-sectional shape of a number of bones engender strains during functional loading rather than reduce them. Bone's adaptive response to load-bearing therefore results in functional strains which are neither uniform in distribution nor minimal in magnitude. Not all aspects of bone's strain environment are equally effective as influences on bone architecture. Unusual strain distributions, high strains, and high strain rates seem to be particularly osteogenic. The osteogenic response which follows exposure to such strains appears to saturate after only a few loading cycles. This is consistent with adaptive bone (re)modeling being sensitive to strain "errors," which are not repeated frequently, rather than the repetitious strain cycles engendered during normal predominant activities. Exercise regimens designed to control bone architecture can usefully capitalize on this feature of the adaptive (re)modeling response. Each exercise session need not be prolonged but should include as many novel strain distributions as possible, preferably involving high peak strains and strain rates. To maintain any level of bone mass requires a continued, loading-related osteoregulatory stimulus. Exposure to appropriate load-bearing exercise needs therefore to be repeated, probably at daily or alternate-daily intervals. In short-term experiments in rat bones, estrogen amplifies the osteogenic response to a single period of loading. The features of postmenopausal bone loss are consistent with the etiology of the condition being primarily withdrawal of estrogen's contribution to bone's mechanically adaptive response.

The purpose of this study was to determine the efficacy of droloxifene (DRO), an estrogen antagonist/agonist, in preventing ovariectomy (OVX)-induced lumbar vertebral cancellous bone loss and bone turnover in aged female rats. Fifty-three Sprague-Dawley female rats were OVX or sham-operated at 19 months of age, and divided into 6 groups: (I) sham-operated controls; (II) OVX vehicle controls; (III) OVX rats treated with E2 at 30 micrograms/kg/day; (IV)-(VI) OVX rats treated with DRO at either 2.5, 5, or 10 mg/kg p.o. daily. The treatment period was 8 weeks. Static and dynamic cancellous bone histomorphometric parameters were determined on 4 and 10 microns thick, undecalcified, double-fluorescent labeled sections of the fourth lumbar vertebral body. Changes in body weight, uterine weight, and total serum cholesterol were also determined. OVX for 8 weeks in 19-month-old female rats resulted in reduced trabecular bone volume (-18%) and trabecular width (-10%) and increased labeling perimeter (+52%), bone formation rate/bone surface referent (+60%), bone formation rate/bone volume referent (+77%), osteoclast number (+41%), and osteoclast perimeter (+41%). E2 treatment at 30 micrograms/kg/day for 8 weeks prevented OVX-induced cancellous bone loss and decreased bone resorption, bone formation, and bone turnover to the values of sham controls. DRO at 2.5-10 mg/kg/day completely prevented bone loss and bone turnover associated with estrogen deficiency. Osteoclast number and perimeter were significantly decreased in DRO-treated-OVX rats compared to both sham and OVX controls. Trabecular bone volume, trabecular width, labeling perimeter, bone formation rate/bone surface referent, and bone formation rate/bone volume referent showed no differences in DRO-treated OVX rats compared to those of E2-treated OVX rats and sham controls. These histomorphometric results indicated that DRO is an estrogen agonist on cancellous bone of lumbar vertebral bodies of aged, OVX rats. Further, E2 treatment prevented the OVX-induced increase in body weight gain and nonsignificantly reduced total serum cholesterol compared to OVX controls. Body weight gain and total serum cholesterol did not differ between OVX rats treated with E2 and sham controls. In OVX rats treated with DRO, body weight decreased significantly in a dose-response manner, and total serum cholesterol was significantly reduced by 65% to 70% compared to both sham and OVX controls. In addition, treatment with E2 increased uterine weight to the value of sham controls in OVX rats. However, DRO had no effect on uterine weight at either 2.5 or 10 mg/kg/day, while it only slightly but significantly increased uterine weight over OVX controls at 5 mg/kg/day. We conclude that DRO was efficacious in the prevention of lumbar vertebral cancellous bone loss and in the decline of total serum cholesterol but had no effect on uterine weight in the aged, OVX female rats. Our data suggest that DRO is a potentially useful agent for the prevention of vertebral bone loss leading to spinal fractures in postmenopausal women.

The recent FDA Guidelines For Preclinical and Clinical Evaluation of Agents Used in the Treatment or Prevention of Postmenopausal Osteoporosis (1994) delineate specific preclinical animal models to demonstrate the efficacy and safety of new, potential agents for osteoporosis therapy. The Guidelines recommend that agents be evaluated in two animal species, including the ovariectomized (OVX) rat and in a second non-rodent model. We have performed a series of studies to determine whether the recommended OVX rat models, endpoints, and study design adequately address the efficacy and safety of therapeutic agents for the treatment or prevention of osteoporosis. Our study results indicate that the rat OVX model mimics postmenopausal cancellous bone loss when examined over relatively short periods of time. These data illustrate that cancellous bone turnover increases following OVX and this increased bone turnover produces bone loss. Estrogen completely blocks the activation of bone turnover and bone loss. Thus, our data suggest that the rat OVX model in the proximal tibia, distal femur, and lumbar vertebrae mimics conditions in the postmenopausal woman and is suitable for the evaluation of potential therapeutic agents for the prevention of osteoporosis. However, when the duration of the studies extends to 12 months as suggested by the Guidelines, the indices of cancellous bone turnover return to the value of sham controls, although the trabecular bone volume remains lower than that of sham controls in OVX rats. Therefore, it is difficult to determine the effects of potential therapeutic agents on the bone turnover in estrogen deficient conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

We demonstrated previously that progesterone prevents ovariectomy-induced bone loss. RU 486 is a synthetic steroid with antiprogesterone activities in reproductive tissue. We used 12-week-old rats to evaluate effects of RU 486 in sham-operated rats and to compare medroxyprogesterone (MPA), RU 486, and medroxyprogesterone plus RU 486 combined treatment in ovariectomized rats. Ovariectomized rats were treated with MPA (60 mg/kg intramuscularly), RU 486 (10 mg/kg/day subcutaneously every 4 days), both, or vehicle. Sham-operated rats were treated with similar doses of RU 486 or vehicle. After 4 weeks of treatment the rats were sacrificed and bone histomorphometry was performed on proximal tibial metaphysis. Trabecular bone volume was lower (33.9 +/- 1.5% vs. 46.3 +/- 1.4%) and bone turnover was higher in ovariectomized than in sham-operated rats. The fraction of trabecular bone in OVX rats treated with MPA, RU 486, or both were 41.6 +/- 2.5%, 44.8 +/- 2.8%, and 38.4 +/- 1.4%, respectively. Medroxyprogesterone treatment tended to preserve bone mass by inhibiting the increased resorption indices while maintaining higher formation rates seen in ovariectomized rats. The effects of RU 486 were similar to those of medroxyprogesterone, suggesting an agonist-like effect. Medroxyprogesterone effects were attenuated when it was combined with RU 486, suggesting that RU 486 acted as a partial antagonist in the presence of exogenous progesterone. Bone parameters were less affected in sham-operated RU 486-treated rats, and there was no significant change in bone volume (43.2 +/- 1.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Both estrogen and calcium have been shown to be of benefit in reducing the incidence of osteoporosis in postmenopausal women. It has been suggested that estrogen promotes the intestinal absorption of calcium, and this effect may especially benefit postmenopausal women with a low dietary intake of calcium. The purpose of this study was to examine the effect of calcium supplementation on the bone mineral density (BMD) of postmenopausal women using estrogen replacement therapy. BMD measurements were made over 12 months in two groups of postmenopausal women, one having treatment with estrogen alone, and the second having estrogen and 1000 mg of supplemental calcium each day. There was no significant reduction in BMD between the two groups over the 12-month study period. Those in the group having supplemental calcium had a significant increase in BMD at the femoral neck (p = 0.023), but not in other areas of the femur nor in the lumbar spine. The results of this study suggest that the addition of supplemental calcium may improve the bone mass of postmenopausal women using estrogen who have a low dietary calcium intake. This benefit appears to be more pronounced in corticocancellous than in trabecular bone, and may therefore have a greater effect on the femoral neck than the lumbar spine.

To assess the long-term effect of vitamin D or calcium supplementation on the skeletal metabolism of aging laboratory rodents, 1.5-month-old female Wistar rats were fed with diets containing twice the concentration of vitamin D (group 2) and of calcium (group 3) as in the usual rat chow. Follow-up to 24 months of age did not show significant differences between the enriched-diet groups and the controls (group 1) in terms of the vertebral body weight and protein content. Significantly higher bone mineral contents were found in groups 2 and 3 than were found in controls, as revealed by an increased bone mineral density (BMD: +62%, group 2; +48%, group 3) and vertebral calcium content (+73%, group 2; +84%, group 3). The vertebral alkaline phosphatase enzymatic activity was significantly lower in the enriched diet groups than in controls (-47%, group 2; -45%, group 3). The ratio alkaline phosphatase/acid phosphatase activity was markedly reduced in groups 2 and 3 (-57% and -59%, respectively), which might indicate a diminished rate of bone turnover. The trabecular bone volume (BV/TV) decreased in all groups during senescence, being significantly elevated in group 3 as compared to controls. Vitamin D and calcium dietary supplementations increase the axial mineral bone content in laboratory rats and might reduce the bone turnover. Their influence on the trabecular bone volume has yet to be examined.

The effect on calcaneal bone loss of interrupting immobilization by daily periods of normal walking was investigated in adult female sheep. The left calcaneus of 28 sheep was protected from normal loading by placing an external fixator across the hock joint, from the tibia to the metatarsus. In vivo strain gauge recordings from 3 animals showed that, at a test location on the calcaneus, this resulted in a significant reduction in principal strain magnitude during walking at 1.5 m s-1 from a peak of -228 x 10(-6) before application of the fixator, to 71 x 10(-6) with the fixator in place. In addition to reducing peak strains during normal activity, the fixator also abolished the high magnitude transient strains (peak -1147 x 10(-6)) normally experienced when the sheep made sudden movements. Thirteen animals (group 1) had fixators applied, and were given no further treatment. In a further 6 animals (group 2), the fixator was removed for 20 min per day, during which they walked on a motorized treadmill at 1.5 m s-1. In the remaining 6 sheep (group 3), incomplete fixator bars were applied to allow uninterrupted joint movement. Over the 12-week period of the experiment, dual photon absorptiometric scans showed that the bone mineral content (BMC) of the calcanei of group 1 fell by 22%. In group 2, where immobilization was interrupted by daily walking, the BMC fell by 21%. In group 3, with incomplete bars, there was no significant reduction in BMC.(ABSTRACT TRUNCATED AT 250 WORDS)