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Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years., Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up., Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Abstract: This narrative review analyzes the customization of menopause hormone therapy (MHT) for osteoporosis prevention and treatment in the context of the patients' age and menopausal age. In short, MHT is indicated in most women suffering from menopause before the age of 45 years except for breast cancer survivors. These women should be treated with MHT until the age of 50 years. For women who have entered menopause at around the age of 50 years, risks associated with MHT are low, and MHT is a safe option, provided there is an indication for it. We suggest that pursuing MHT entails different risks than initiating it, after the age of 60 years. In both cases, advantages and risks should be evaluated. We suggest using risk calculators to assess the magnitude of these risks and choosing regimens that entail the lowest breast and thrombosis risks., Competing Interests: Conflicts of Interest and Source of Funding: S.R. declares to have received funding from Abbott, Pfizer, Will, Gedeon Richter, MSD, Amgen, UCB Bayer, Mithra, Viatris for either research grants, speakers bureau, or advisory board participation. The other authors have no significant relationships with, or financial interest in, any commercial companies., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Postmenopausal breast cancer survivors (PBCS) are at increased risk of bone loss and fractures due to age-related decline of estrogen, and this risk is compounded by aromatase inhibitor cancer therapy. Several patient-level targetable risk factors can mitigate osteoporosis risk; however, adequate health behavior and risk perception in this population are underreported. The goal of this study was to evaluate osteoporosis knowledge and beliefs and assess their association with engagement in osteoporosis preventive behaviors among PBCS., Methods: In this cross-sectional descriptive study, early stage I-IIIA PBCS (ages 55-86 years) completed the Facts on Osteoporosis Quiz, Osteoporosis Health Beliefs Scale, and Osteoporosis Preventive Behaviors questionnaires. Participants who were non-English speaking or declined to participate were excluded. Clinical and sociodemographic information were obtained from chart review and baseline questionnaire, respectively. Fisher's exact test, Student t-test, and Wilcoxon Mann-Whitney tests were used where appropriate to assess the association between knowledge and beliefs with engagement in osteoporosis preventive behaviors., Results: The mean participant age was 66.1 years with 20% self-reporting as non-Hispanic White, 40% non-Hispanic Black, 27% Hispanic, and 13% other. Approximately 83% of the cohort had estrogen receptor positive breast cancer and received a bone density scan within the last six years. Osteoporosis knowledge (10.5 ± 3.4), seriousness (14.9 ± 3.8), and susceptibility (14.0 ± 3.5) mean scores were low among PBCS. Most PBCS (75%) were adherent to calcium and vitamin D supplements, but only 47% reported engagement in strength-training exercises. Married/partnered, higher osteoporosis knowledge and health motivation scores were associated with strength-training exercise. After adjustment for marital status and osteoporosis knowledge, only health motivation score remained significantly associated with strength-training exercise (OR 5.56, 95% CI 1.35-22.93)., Conclusions: PBCS are highly motivated to keep a healthy lifestyle despite limited osteoporosis knowledge, perceived risk, and susceptibility. However, < 50% participated in strength-training exercise. Our findings suggest that oncologic care should include osteoporosis and fracture prevention strategies, directed at encouraging cancer survivors to increase their engagement in osteoporosis preventive behaviors, particularly strength-training exercises., (© 2021. The Author(s).)

Purpose of Review: The goal of the review is to assess the appropriateness of menopausal hormone therapy (MHT) for the primary prevention of bone loss in women at elevated risk in the early years after menopause., Recent Findings: Estrogen alone or combined with progestin to protect the uterus from cancer significantly reduces the risk of osteoporosis-related fractures. MHT increases type 1 collagen production and osteoblast survival and maintains the equilibrium between bone resorption and bone formation by modulating osteoblast/osteocyte and T cell regulation of osteoclasts. Estrogens have positive effects on muscle and cartilage. Estrogen, but not antiresorptive therapies, can attenuate the inflammatory bone-microenvironment associated with estrogen deficiency. However, already on second year of administration, MHT is associated with excess breast cancer risk, increasing steadily with duration of use. MHT should be considered in women with premature estrogen deficiency and increased risk of bone loss and osteoporotic fractures. However, MHT use for the prevention of bone loss is hindered by increase in breast cancer risk even in women younger than 60 years old or who are within 10 years of menopause onset.

With declining mortality rates, the number of breast cancer survivors is increasing. Ongoing care after breast cancer treatment is often provided by primary care physicians. This care includes surveillance for cancer recurrence with a history and physical examination every three to six months for the first three years after treatment, every six to 12 months for two more years, and annually thereafter. Mammography is performed annually. Magnetic resonance imaging of the breast is not indicated unless patients are at high risk of recurrence, such as having a hereditary cancer syndrome. Many breast cancer survivors experience long-term sequelae from the disease or treatment. Premature menopause with hot flashes can occur and is managed with pharmacologic and nonpharmacologic treatments. Vaginal dryness is treated with vaginal lubricants and gels. Because cardiotoxicity from chemotherapy is possible, clinicians should be alert for this complication and perform echocardiography if appropriate. Impaired cognition after chemotherapy is also common; treatment includes cognitive rehabilitation therapy. Patients with treatment-induced menopause develop decreased bone density and should receive dual energy x-ray absorptiometry and pharmacologic and nonpharmacologic therapies. Others experience lymphedema, often best managed with weight loss and complex decongestive therapy. Some women develop chronic pain, which is treated by addressing psychological factors and with appropriate pharmacologic therapy.

Background: Cancer treatment-induced bone loss is an important long-term effect among breast cancer survivors. Little is known, however, about the pattern of bone loss and the factors associated with it., Objective: The aim of this study was to examine annual bone health changes and factors associated with bone loss for 3 years after diagnosis among women with breast cancer., Methods: Ninety-nine newly diagnosed women with breast cancer (mean age, 51.1 years) were enrolled in a prospective longitudinal study. Bone mineral density (BMD) was measured with dual-energy x-ray absorptiometry at baseline and yearly for 3 years., Results: During the 3-year follow-up, the proportion of women who had osteopenia or osteoporosis increased from 33.3% to 62.5%. The BMD of the participants significantly decreased 6.8% in the lumbar spine, 4.6% in the femur neck, and 3.5% in the total hip, with bone loss the greatest in the first year. In multiple linear regression analysis, chemotherapy was significantly associated with bone loss at all sites, and premenopausal status at diagnosis was significantly related to bone loss at the lumbar spine. We found no significant relationship between health behavior status and BMD change at any site., Conclusion: Women newly diagnosed with breast cancer can lose up to 6.8% of BMD during a 3-year follow-up. Chemotherapy and premenopausal status are important risk factors for bone loss., Implications for Practice: Identification of premenopausal women at diagnosis and monitoring BMD before and after chemotherapy are key for promoting bone health in women with breast cancer.

Objective: To evaluate risk factors for low bone mineral density (BMD) in postmenopausal breast cancer survivors compared with postmenopausal women without breast cancer (controls)., Method: In this study, 112 breast cancer survivors were compared to 224 women (controls). Inclusion criteria were amenorrhea ≥12 months, age 45-75 years, treated for breast cancer, and metastasis-free for at least 5 years. The control group consisted of women without breast cancer, matched by age and menopause status (in a proportion of 1: 2 as sample calculation). The risk factors for low BMD (osteopenia/osteoporosis) were assessed by interview. BMD was measured by dual-energy X-ray absorptiometry in the lumbar spine (L1-L4) and femoral neck. Logistic regression models (odds ratio, OR) were used to identify factors associated with low BMD., Results: The mean (standard deviation) age of breast cancer survivors was 61.3 (9.7) years, with a mean follow-up of 10.2 (3.9) years. These women had a higher incidence of osteopenia (45.1%) and osteoporosis (22.3%) in the femoral neck than controls (39.3% and 9.0%, respectively) (p = 0.0005). Lumbar spine BMD did not differ between groups (p = 0.332). Univariate analysis adjusted for age and time since menopause revealed that chemotherapy (OR 6.90; 95% confidence interval (CI) 5.57-9.77) was associated with a higher risk of low BMD. Contrarily, regular physical exercise (OR 0.24; 95% CI 0.06-0.98) and a body mass index ≥30 kg/m 2 (OR 0.09; 95% CI 0.02-0.37) reduced the risk among breast cancer survivors., Conclusion: Postmenopausal breast cancer survivors had a higher incidence of osteopenia and osteoporosis in the femoral neck than women without breast cancer. A history of chemotherapy was a risk factor for low BMD, whereas regular physical activity and high body mass index reduced the risk among breast cancer survivors.

Postmenopausal women with breast cancer on aromatase inhibitor (AI) treatment are at increased risk of bone mineral density loss, which may lead to minimal trauma fractures. We examined the cost-effectiveness of dual energy X-ray absorptiometry (DXA) with antiresorptive (AR) therapy compared with fracture risk assessment, lifestyle advice, and vitamin supplementation. We used a hypothetical Markov cohort model of lifetime duration for 60-year-old women with early stage breast cancer receiving AIs. The data to inform the model came from medical literature, epidemiological reports, and costing data sets. Two eligibility scenarios for AR therapy were considered: (A) osteoporosis and (B) osteopenia or osteoporosis. The main outcomes were incremental cost per quality-adjusted life years gained and cumulative fractures per 1000 women, calculated relative to the comparator. Key aspects of the model were explored in sensitivity analyses. Due to relatively low effectiveness gains, the outcomes were primarily driven by the costs. The incremental cost per quality-adjusted life year gained was A$47,556 and A$253,000 for scenarios A and B, respectively. The numbers of fractures avoided were 56 and 77 per 1000 women, respectively. The results were most sensitive to the initial probability of osteoporosis, baseline risk of fracture, and cohort starting age. Compared with risk assessment and lifestyle advice only, a DXA scan followed by an AR treatment is potentially cost-effective for women aged 60 and over undergoing AI therapy for early breast cancer. However, the number of fractures averted through this intervention is small.

Breast cancer, as the most common malignancy in women, remains a major public health issue despite countless advances across decades. Endocrine therapy is the cornerstone of treatment of the hormone-sensitive subtype of breast cancer. The use of aromatase inhibitors (AIs) in the postmenopausal women has extended the survival beyond that of Tamoxifen, but harbors a subset of side effects, most notably accelerated bone loss. This, however, does not occur in all women undergoing treatment. It is vital to identify susceptible patients early, to limit such events, employ early treatment thereof, or alter drug therapy. International trials on AIs, predominantly performed in North American and European females, provide little information on what to expect in women in developing countries. Here, surgeons often prescribe and manage endocrine therapy. The prescribing surgeon should be aware of the adverse effect of the endocrine therapy and be able to attend to side effects. This review highlights clinical and biochemical factors associated with decrease in bone mineral density in an, as yet, unidentified subgroup of postmenopausal women. In the era of personalized medical care, appropriate management of bone health by surgeons based on these factors becomes increasingly important.

Introduction: The SCAN breast cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines regarding the optimal time-point for initiation of bisphosphonates when using adjuvant aromatase inhibitors (AIs) and provide a consensus for their role in modifying clinical breast cancer outcomes., Materials and Methods: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting., Results: Six international guidelines were evaluated-those developed by the National Cancer Comprehensive Network (2015), the European Society of Medical Oncology (2014), the National Institute for Clinical Evidence (2012), the Scottish Intercollegiate Guidelines Network (2013), the British Columbia Cancer Agency (2013) and the treatment algorithm based on the National Osteoporosis Foundation guidelines (2006). Recommendations on the use of bisphosphonates in postmenopausal women initiating adjuvant AIs in breast cancer to preserve bone health and the use of adjuvant bisphosphonates to improve breast cancer outcomes were developed., Conclusion: These adapted guidelines form the SCAN Guidelines on the use of adjuvant bisphosphonates to influence breast cancer outcomes and maintenance of bone health when on AIs.

Breast cancer is the most commonly diagnosed cancer among women, but despite survival rates improvement, it is still the second major cause of cancer related death. In postmenopausal women with estrogen receptor (ER) dependent breast cancer, hormone therapy is an option, either by direct inhibition of ER using tamoxifen or by aromatase inhibition, resulting in decreased estrogen production. In this paper these two endocrine therapy approaches are compared in terms of their impact on bone health. Guidance for the prevention of bone loss and occurrence of fractures in postmenopausal women receiving AIs is also proposed. Despite intervention strategies to maintain bone health in AI-treated patients are not well established, recommendations by international societies to identify women with high risk of fracture and advice on the preventive anti-fracture therapy are exposed. Finally, available therapeutic options for management of bone loss in patients receiving AIs are presented. The search strategy for this literature review was conducted by using the key words "aromatase inhibitor*" and "bone loss" OR "aromatase inhibitor*" and "osteoporosis" in the MEDLINE/PubMed database. Nowadays, hormone-responsive breast cancer in postmenopausal women is preferably being treated with AIs instead of tamoxifen, due to clear benefits in disease-free survival and reduced recurrence. AIs have an advantageous side effect profile compared to tamoxifen, however all AIs have detrimental long-term effects on bone, due to nearly complete depletion of estrogens, resulting in increased bone loss and increased risk of fracture. Current recommendations state that all women treated with AIs should be evaluated for their fracture risk prior to initiation of AI-treatment, taking in consideration individual bone mineral density and several risk factors. The thresholds to introduce preventive therapy and drugs proposed differ among the available recommendations. Lifestyle modifications and adequate calcium and vitamin D supplementation have been documented to have good impact in long-term bone health. Additionally, bisphosphonates are the first therapeutic option for AI induced bone loss and should be continued as long as AI-treatment is maintained, being iv zoledronic acid 4 mg every 6 months the best tolerated option.

Background: Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results., Methods: A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of <-2.0 or fracture., Results: The incidence of a 5% decrease in the total lumbar spine bone mineral density at 5 years was 10.2% in the upfront treatment arm versus 41.2% in the delayed treatment arm (P<.0001). A total of 41 patients in the delayed treatment arm were eventually started on ZA. With the exception of increased NCI Common Toxicity Criteria (CTC) grade 1/2 elevated creatinine and fever in the patients treated on the upfront arm and cerebrovascular ischemia among those in the delayed treatment arm, there were no significant differences observed between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront treatment arm (2 vs 8 cumulative cases), although this difference was not found to be statistically significant. Bone fractures occurred in 24 patients in the upfront treatment arm versus 25 patients in the delayed treatment arm., Conclusions: Immediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms., (© 2015 American Cancer Society.)

Unlabelled: Bone mineral density (BMD) measurement can vary depending upon anatomical site, machine, and normative values used. This analysis compared different BMD endpoints in two clinical trials. Trial results differed across endpoints. Future clinical trials should consider inclusion of multiple endpoints in sensitivity analysis to ensure sound overall study conclusions., Introduction: Methodological issues hamper efficacy assessment of osteoporosis prevention agents in cancer survivors. Osteoporosis diagnosis can vary depending upon which bone mineral density (BMD) anatomical site and machine is used and which set of normative values are applied. This analysis compared different endpoints for osteoporosis treatment efficacy assessment in two clinical studies., Methods: Data from North Central Cancer Treatment Group phase III clinical trials N02C1 and N03CC (Alliance) were employed involving 774 patients each comparing two treatments for osteoporosis prevention. Endpoints for three anatomical sites included raw BMD score (RawBMD); raw machine-based, sample-standardized, and reference population-standardized T scores (RawT, TSamp, TRef); and standard normal percentile corresponding to the reference population-standardized T score (TPerc). For each, treatment arm comparison was carried out using three statistical tests using change and percentage change from baseline (CB, %CB) at 1 year., Results: Baseline correlations among endpoints ranged from 0.79 to 1.00. RawBMD and TPerc produced more statistically significant results (14 and 19 each out of 36 tests) compared to RawT (11/36), TSamp (8/36), and TRef (7/36). Spine produced the most statistically significant results (26/60) relative to femoral neck (20/60) and total hip (13/60). Lastly, CB resulted in 44 statistically significant results out of 90 tests, whereas %CB resulted in only 15 significant results., Conclusions: Treatment comparisons and interpretations were different across endpoints and anatomical sites. Transforming via sample statistics provided similar results as transforming via reference or machine-based norms. However, RawBMD and TPerc may be more sensitive to change as clinical trial endpoints.

Unlabelled: In postmenopausal women with low bone mass and hormone-receptor-positive breast cancer on an aromatase inhibitor, risedronate maintained skeletal health assessed by bone density and turnover markers. Women with the greatest decreases in bone turnover markers at 12 months had the greatest increases in bone density at 24 months., Introduction: Aromatase inhibitors (AIs), adjuvant endocrine therapy for postmenopausal women with hormone-receptor-positive breast cancer, are associated with bone loss and fractures. Our objectives were to determine if (1) oral bisphosphonate therapy can prevent bone loss in women on an AI and (2) early changes in bone turnover markers (BTM) can predict later changes in bone mineral density (BMD)., Methods: We conducted a 2-year double-blind, placebo-controlled, randomized trial in 109 postmenopausal women with low bone mass on an AI (anastrozole, letrozole, or exemestane) for hormone-receptor-positive breast cancer. Participants were randomized to once weekly risedronate 35 mg or placebo, and all received calcium plus vitamin D. The main outcome measures included BMD, BTM [carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type 1 procollagen (P1NP)], and safety., Results: Eighty-seven percent completed 24 months. BMD increased more in the active treatment group compared to placebo with an adjusted difference at 24 months of 3.9 ± 0.7 percentage points at the spine and 3.2 ± 0.5 percentage points at the hip (both p < 0.05). The adjusted difference between the active treatment and placebo groups were 0.09 ± 0.04 nmol/LBCE for CTX and 23.3 ± 4.8 μg/mL for P1NP (both p < 0.05). Women with greater 12-month decreases in CTX and P1NP in the active treatment group had a greater 24-month increase in spinal BMD (p < 0.05). The oral therapy was safe and well tolerated., Conclusion: In postmenopausal women with low bone mass and breast cancer on an AI, the oral bisphosphonate risedronate maintained skeletal health.

Breast cancer and osteoporosis are common conditions affecting women, particularly following menopause. With increasing breast cancer incidence, effects of therapies and decreasing mortality, issues relating to the preservation of bone health with breast cancer therapy have become a priority. Contributing factors to bone loss and fractures in women with breast cancer include tumor effects, estrogen deprivation secondary to breast cancer therapies (chemotherapy, ovarian ablation or aromatase inhibitors), natural menopause and secondary causes of bone loss, typically from concurrently prescribed medications. Management of osteoporosis and other survivorship care is complex, and a multi-disciplinary approach is recommended with assessment of risk factors for bone loss, optimization of bone health through lifestyle approaches and pharmacological interventions based on evidence-based algorithms. This review examines the pathophysiology of bone loss and gives guidelines for the management of bone disease in women with breast cancer.

SERMs represent a diverse group of molecules with varying levels of estrogenic agonist and antagonist activity in target tissues. SERMs have a long regulatory approval history and have been studied for a variety of therapeutic indications. The clinical effects of SERMs have been evaluated in a large number of phase 3 clinical trials. Many of the available SERMs have proved to be effective as chemo-preventive agents and treatments for breast cancer and a number are useful for the prevention and treatment of osteoporosis. The endometrial effect of SERMs has been a key differentiator in clinical practice and a major hurdle for regulatory approval. The effect of SERMs in the vagina also represents a major distinction among different SERMs. This review summarized key clinical finding of SERMs in different target tissues., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Treatment with bisphosphonates in women with breast cancer and established bone metastasis delays further skeletal-related events. Evidence is emerging that bisphosphonates are beneficial for secondary prevention of bone metastasis. The study aimed to estimate the effect of oral bisphosphonates for treatment or prevention of osteoporosis on development of bone metastasis in a population of women with breast cancer., Methods: A historical cohort of 21664 women diagnosed with breast cancer was created from health administrative data in Quebec, Canada. The primary outcome was time to develop bone metastasis; exposure was bisphosphonate use prediagnosis, postdiagnosis, both, or neither and a cumulative index of drug exposure. The sample was stratified according to stage (0-II or III) at time of diagnosis. Cox proportional hazards tested the effect of bisphosphonate use on time to develop bone metastases., Results: Taking bisphosphonates postdiagnosis of breast cancer only or continuing bisphosphonates started prior to diagnosis after diagnosis was associated with a reduction in risk of bone metastasis from 45% to 28% in women with local disease at diagnosis. In women with regional disease, postdiagnosis bisphosphonate use, with or without prediagnosis use, reduced risk by almost 50%. A statistically significant dose-response trend was observed relating increased use to lower risk (slope = 0.94, 95% confidence interval = 0.90 to 0.99). Bisphosphonates were also associated with a decreased risk of all-cause mortality similar to that of the development of bone metastasis., Conclusion: Low-dose oral bisphosphonates administered for prevention or treatment of postmenopausal osteoporosis were associated with lower risk of skeletal metastasis in patients with early- or more advanced-stage breast cancer., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: The efficacy of bisphosphonates (BPs) in treating bone loss associated with cancer therapies has been demonstrated in completed studies and ongoing clinical trials. The aim of this study was to investigate the evidence for BP use in treatment of bone loss in postmenopausal, early breast cancer (EBC) patients scheduled to receive aromatase inhibitors (AI)., Methods: A comprehensive search for relative articles published until December 2013 was performed. The outcomes included the percentage and absolute change in lumbar spine (LS) and total hip (TH) bone mineral density (BMD). Before pooled meta-analysis, the studies were evaluated for publication bias and heterogeneity. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated. We also performed subgroup and sensitivity analyses., Results: A total of 11 trials contributed to the analysis. BP was shown to be efficacious in increasing BMD at the LS and TH. WMD in BMD absolute change was 0.21 g/cm(2) (95% CI, 0.13-0.28) at the LS and 0.27 g/cm(2) (95% CI, 0.02-0.12) at the TH. WMD in BMD percentage change was 5.42 (95% CI, 4.37-6.48) at the LS and 3.03 (95% CI, 2.01-4.01) at the TH. Subgroup analysis revealed that age difference, interventional duration, types of interventions and BP types were associated with variable effects on BMD at the LS and TH., Conclusions: BPs may protect against bone loss in postmenopausal women with EBC receiving adjuvant AI treatment., (Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.)

Background: Breast cancer is the most frequently diagnosed cancer in women in the United States. Approximately 70% of breast cancers are diagnosed in postmenopausal women. Major clinical trials and experimental studies showed that aromatase inhibitors are effective against postmenopausal breast cancer. Despite their effectiveness in reducing tumor recurrence, aromatase inhibitors have adverse effects on the cardiovascular system and increase osteoporosis and bone fractures. Our study is aimed at investigating the role of natural steroid hormones on serum cardiovascular and bone resorption markers in an established mouse model mimicking postmenopausal breast cancer., Methods: Ovariectomized nude mice were transplanted with MCF-7 breast cancer cells constitutively expressing aromatase. The mice were treated with different combinations and doses of steroids, [estrogen (25 pg, 40 pg, 100 pg), progesterone (6 ng) and testosterone (50 ng)] along with dehydroepiandrostenedione (100 ug). Serum levels of HDL, LDL/VLDL, free and total cholesterol, total and bone specific alkaline phosphatase and triglycerides were analyzed after 5, 10 and 15 months., Results: Free cholesterol and LDL/VLDL levels in serum were reduced in groups mimicking estrous cycle and menstrual cycle hormones treatment. HDL cholesterol was increased in all the hormone treated groups except the estrous cycle-mimicking group. Bone specific alkaline phosphatase was decreased in menstrual cycle levels of estrogen and progesterone treatment., Conclusions: All together our results show that use of natural hormones in appropriate combinations have beneficial effects on cardiac and bone toxicity, along with better tumor reduction than current treatments.

Unlabelled: Our randomized controlled trial in prematurely menopausal breast cancer survivors showed that impact + resistance training prevented increases in percentage of body fat compared with controls and also improved BMD at the hip and prevented BMD loss at the spine among exercise-trained women who were menopausal for >1 year., Introduction: Cancer treatment-related menopause worsens bone health and body composition in breast cancer survivors (BCS). We investigated whether impact + resistance training could improve bone mineral density (BMD), reduce bone turnover, build muscle, and decrease fat mass in BCS with premature menopause., Methods: We conducted a randomized controlled trial in 71 BCS (mean age, 46.5 years) within 5 years of treatment-related menopause. Women were randomly assigned to one of two groups: (1) impact + resistance training (prevent osteoporosis with impact + resistance (POWIR)) or (2) exercise placebo (FLEX) 3×/week for 1 year. Outcomes were hip and spine BMD (in grams per square centimeter) and body composition (percent body fat (%BF) and lean and fat mass (in kilograms)) by DXA and bone turnover markers (serum osteocalcin (in nanograms per milliliter) and urinary deoxypryrodinoline (in nanomoles per milliliter)., Results: There were no significant group × time interactions for bone outcomes when using an intent-to-treat approach on the full sample. In analyses restricted to BCS who were menopausal for ≥1 year, POWIR increased BMD at the hip and slowed BMD loss at the spine compared with FLEX (femoral neck-POWIR, 0.004 ± 0.093 g/cm(2) vs. FLEX, -0.010 ± 0.089 g/cm(2); p < 0.01; spine-POWIR, -0.003 ± 0.114 g/cm(2) vs. FLEX, -0.020 ± 0.110 g/cm(2); p = 0.03). POWIR prevented increases in %BF (POWIR, 0.01 % vs. FLEX, 1.3 %; p < 0.04). Women with attendance to POWIR at ≥64 % had better improvements in %BF than women attending less often (p < 0.03)., Conclusion: Impact + resistance training may effectively combat bone loss and worsening body composition from premature menopause in BCS.

Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with postmenopausal women's health, including hormone responsive cancer and osteoporosis. Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or prevent and treat breast cancer. The search for the 'ideal' SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic potential of these compounds can be obtained. In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.

Aromatase Inhibitors are anti-estrogen agents that have proven efficacy for adjuvant therapy of estrogen receptor positive breast cancer primarily in post menopausal women with estrogen receptor positive breast cancer but increase the risk of cancer therapy induced bone loss (CTIBL). Recent studies have shown the potential benefit of bisphosphonate therapy to play a dual role in the management of breast cancer. These studies provide evidence that bisphosphonate therapy in conjunction with aromatase inhibitors (AI), not only decreases the risk of osteoporosis but, in addition, may improve survival from breast cancer.

Background/aim: Raloxifene is the first selective estrogen receptor modulator that has been approved for the treatment and prevention of osteoporosis in postmenopausal women in Europe and in the US. Although raloxifene reduces the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer, it is approved in that indication in the US but not in the EU. The aim was to characterize the clinical profiles of postmenopausal women expected to benefit most from therapy with raloxifene based on published scientific evidence to date., Methods: Key individual patient characteristics relevant to the prescription of raloxifene in daily practice were defined by a board of Swiss experts in the fields of menopause and metabolic bone diseases and linked to published scientific evidence. Consensus was reached about translating these insights into daily practice., Results: Through estrogen agonistic effects on bone, raloxifene reduces biochemical markers of bone turnover to premenopausal levels, increases bone mineral density (BMD) at the lumbar spine, proximal femur, and total body, and reduces vertebral fracture risk in women with osteopenia or osteoporosis with and without prevalent vertebral fracture. Through estrogen antagonistic effects on breast tissue, raloxifene reduces the risk of invasive estrogen-receptor positive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. Finally, raloxifene increases the incidence of hot flushes, the risk of venous thromboembolic events, and the risk of fatal stroke in postmenopausal women at increased risk for coronary heart disease. Postmenopausal women in whom the use of raloxifene is considered can be categorized in a 2 × 2 matrix reflecting their bone status (osteopenic or osteoporotic based on their BMD T-score by dual energy X-ray absorptiometry) and their breast cancer risk (low or high based on the modified Gail model). Women at high risk of breast cancer should be considered for treatment with raloxifene., Conclusion: Postmenopausal women between 50 and 70 years of age without climacteric symptoms with either osteopenia or osteoporosis should be evaluated with regard to their breast cancer risk and considered for treatment with raloxifene within the framework of its contraindications and precautions.

Unlabelled: Aromatase inhibitors (AIs) are widely used in women with breast cancer, but they are known to increase bone loss and risk of fractures. Based on available evidence and recommendations, an ESCEO working group proposes specific guidance for the prevention of AIs-induced bone loss and fragility fractures., Introduction: Aromatase inhibitors (AIs) are now the standard treatment for hormone receptor-positive breast cancer. However, deleterious effects of AIs on bone health have been reported. An ESCEO working group proposes guidance for the prevention of bone loss and fragility fractures in post-menopausal women with breast cancer receiving AIs., Methods: A panel of experts addressed the issue of skeletal effects of AIs and effectiveness of antifracture therapies for the prevention of AI-induced bone loss and fractures. Recommendations by national and international organizations, and experts' opinions on this topic were evaluated., Results: All aromatase inhibitors are associated with negative effects on the skeleton, resulting in bone loss and increased risk of fragility fractures. Current guidelines suggest approaches that differ both in terms of drugs proposed for fracture prevention and duration of treatment., Conclusion: The ESCEO working group recommends that all AI-treated women should be evaluated for fracture risk. Besides general recommendations, zoledronic acid 4 mg i.v. every 6 months, denosumab s.c., or possibly oral bisphosphonates should be administered for the entire period of AI treatment to all osteoporotic women (T-score hip/spine <-2.5 or ≥ 1 prevalent fragility fracture), to women aged ≥ 75 irrespective of BMD, and to patients with T-score <-1.5 + ≥ 1 clinical risk factor or T-score <-1.0 + ≥ 2 clinical risk factors. Alternatively, therapy could be considered in patients with a FRAX-determined 10-year hip fracture probability ≥ 3%.

Background: Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting., Methods: Overall, 602 postmenopausal women with early, hormone receptor-positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months) for 5 years. The primary endpoint was the change in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary endpoints included changes in LS BMD, total hip BMD, and bone turnover markers at 2, 3, and 5 years; fracture incidence at 3 years; and time to disease recurrence., Results: At month 61, the adjusted mean difference in LS and total hip BMDs between the upfront and delayed groups was 8.9% and 6.7%, respectively (P < .0001, for both). Approximately 25% of delayed patients received zoledronic acid by month 61. Only 1 patient experienced grade 4 renal dysfunction; no confirmed cases of osteonecrosis of the jaw were reported. Fracture rates (upfront, 28 [9.3%]; delayed, 33 [11%]; P = .3803) and Kaplan-Meier disease recurrence rates (upfront, 9.8 [95% confidence interval (CI), 6.0-10.3]; delayed, 10.5 [95% CI, 6.6-14.4]; P = .6283) were similar at month 61., Conclusions: Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal women with early BC receiving letrozole for 5 years, and long-term coadministration of letrozole and zoledronic acid is well tolerated., (Copyright © 2011 American Cancer Society.)

Background: Letrozole is a proven and effective adjuvant therapy in postmenopausal women with hormone receptor-positive (HR(+)) early breast cancer (EBC). As with other aromatase inhibitors (AIs), long-term letrozole administration is associated with decreased bone mineral density (BMD) and increased fracture risk. This study compared potential bone-protecting effects of immediate vs. delayed administration of zoledronic acid (ZOL) in patients with EBC receiving adjuvant letrozole., Patients and Methods: Patients with HR(+) EBC in whom adjuvant letrozole treatment was initiated (2.5 mg/day for 5 years) were randomized to immediate ZOL treatment (immediate ZOL) or delayed ZOL treatment (delayed ZOL) (both at 4 mg every 6 months). Patients in the delayed ZOL group received ZOL only for a BMD T-score that decreased to < -2.0 (lumbar spine [LS] or total hip [TH]) or for fracture. The primary endpoint was percentage change in the LS BMD at month 12. Patients were stratified by established or recent postmenopausal status, baseline T-scores, and adjuvant chemotherapy history., Results: At 12 months, the LS BMD increased in the immediate ZOL group (+2.72%) but decreased in the delayed ZOL group (-2.71%); the absolute difference between groups was significant (5.43%; P < .0001). Across all subgroups, patients receiving immediate ZOL had significantly increased LS and TH BMD vs. those who received delayed ZOL (P < .0001). Differences in fracture incidence or disease recurrence could not be ascertained because of early data cutoff and low incidence of events. Adverse events were generally mild, transient, and consistent with the known safety profiles of both agents., Conclusion: Immediate ZOL administration effectively prevented BMD loss and increased BMD in postmenopausal women with HR(+) EBC receiving adjuvant letrozole, regardless of BMD status at baseline., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The aim of the present study was to investigate the health risks of excess body weight in the light of its protective effects on bone fragility., Methods: Femoral neck and lumbar spine dual X-ray absorptiometry was performed for 1970 Finnish women with a mean baseline age of 58.8 years (range 53.1-65.7 years) in 1994 and 2004. Women were categorized according to baseline BMI into normal <25 kg/m2, overweight 25-29.9 kg/m(2) and obese ≥30 kg/m(2). Weight change (kg) was categorized into tertiles. Co-morbidities, not allowed to be present at baseline, was based on self-reports. Osteoporosis was defined as femoral neck or spinal (L2-L4) T-score <-2.5 SD at 10-year follow-up or <-2.0 SD+low trauma energy follow-up fracture. Uni- and multivariate logistic regression models were used to estimate the 10-year risk of incident health disorders. Adjustment for age, number of diseases, alcohol intake and smoking was used in the multivariate models., Results: Obesity (Ob) and overweight (Ow) were related with higher 10-year risk of hypertension (OR=2.6 (Ob)/OR=1.7 (Ow), p<0.001), coronary artery disease (OR=1.6, p<0.05/OR=1.2, p=NS), diabetes (OR=11.7/OR=5.3, p<0.001), osteoarthritis (OR=1.4, p<0.05/OR=1.1, p=NS), chronic back pain (OR=1.6, p=0.007/OR=1.2, p=NS) and poor self-rated health (OR=2.4, p<0.05/OR=1.5, p=NS) and lower risk of osteoporosis (OR=0.13/OR=0.28, p<0.001). Weight change of less than +1 kg was associated 1.8 and 2.6 times lower 10-year risk of having hypertension and breast cancer than weight change over 6.2 kg. Among obese women the absolute risk increase of hypertension was 17%, of diabetes 12%, and absolute risk reduction of osteoporosis 14% in comparison to BMI <25 kg/m(2)., Conclusions: Health related risks of high BMI outweigh its protective effects on bone. Weight gain increases the risk hypertension and breast cancer., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Bone mineral density (BMD)-based guidelines for bone-directed therapy in women with early breast cancer (EBC) appear inadequate for averting fractures, particularly during aromatase inhibitor (AI) therapy. Therefore, an algorithm was developed to better assess risk and direct treatment (Hadji P, Body JJ, Aapro MS et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol 2008; 19: 1407-1416). Here, we provide updated guidance on pharmacologic interventions to prevent/treat aromatase inhibitor-associated bone loss (AIBL)., Design: Systematic literature review identified recent advances in preventing/treating AIBL. Individual agents were assessed based on trial size, design, follow-up, and safety., Results: Fracture risk factors in patients with EBC remain unchanged (Hadji P, Body JJ, Aapro MS et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol 2008; 19: 1407-1416). The World Health Organization Fracture Risk Assessment Tool algorithm includes fracture risk factors plus BMD but does not adequately address AIBL effects. Several antiresorptives can prevent/treat AIBL. However, concerns regarding compliance and long-term efficacy/safety remain. Overall, evidence is strongest for twice-yearly zoledronic acid (ZOL), and recent advances support additional anticancer benefits from ZOL., Conclusions: All patients initiating AIs need advice regarding exercise, calcium/vitamin D supplements, baseline BMD monitoring (when available), and bone-directed therapy if T-score <-2.0 or at least two fracture risk factors were observed. Patients with T-score > -2.0 and no risk factors should be managed based on BMD loss during years 1-2. Unsatisfactory compliance/decreasing BMD after 12-24 months on oral bisphosphonates should trigger a switch to i.v. bisphosphonate.

A new analysis from the Women's Health Initiative included data on breast cancer incidence over a 11-year period from the randomized trial of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) and a subsequent observational follow-up. The conclusions were that CEE/MPA use was associated with an increase in both breast cancer incidence and mortality. We have concerns over the validity of their statistical analyses, as adjustments for baseline characteristics or for multiple comparisons demonstrate no significant differences in incidence between those allocated to CEE/MPA or placebo. We suspect that the apparent increase in mortality is the result of surveillance and detection bias rather than a true cause and effect. Even if such an effect were true, mortality from breast cancer would still be a very rare event. We also question the clinical relevance and applicability of their findings. The data over the 11 years show no increased risk of breast cancer with CEE/MPA in women who had not previously used hormone replacement therapy (HRT), and the vast majority of women on HRT would not be prior users at initiation. It should be remembered that women using CEE alone showed a significant decrease in breast cancer risk in the WHI trial and follow-up. Even if combined estrogen?progestogen HRT did cause an increase in breast cancer risk, and this is not proven, the magnitude of that risk is small, and less than that risk seen with many lifestyle factors. HRT is a benefit, not a risk, for those women requiring it.

Objective: The aim of this study was to examine the utilization of mammography and bone mineral density (BMD) screenings and factors associated with compliance according to the recommended clinical practice guidelines., Methods: Mammography and BMD were assessed using employer's administrative claims data for eligible women identified between January 2004 and December 2006. Women were categorized into five cohorts based on mammography- and BMD-recommended screening guidelines. Logistic regression modeling was used to examine the covariates associated with compliance., Results: Mammography and BMD screening utilization were low in relation to recommendations, with 21%, 27%, and 16% of women complying with mammography, age-motivated BMD, and fracture-motivated BMD screening guidelines, respectively. BMD screening use (odds ratio [OR], 7.19; 95% CI, 7.08-7.31) was associated with compliance in the mammogram cohort. Mammogram use was associated with compliance in both the age-motivated BMD cohort (OR, 6.01; 95% CI, 5.28-6.85) and the fracture-motivated BMD cohort (OR, 2.20; 95% CI, 2.07-2.33). Having a Papanicolaou test was strongly associated with compliance in the combined mammogram plus age-motivated BMD cohort (OR, 16.83; 95% CI, 14.01-20.22) and the combined mammogram plus fracture-motivated BMD cohort (OR, 10.46; 95% CI 9.26-11.81)., Conclusions: Postmenopausal women with employer-sponsored health insurance had low utilization of mammography and BMD screening relative to clinical guidelines. Use of other health screening services was associated with compliance with guidelines. Methods to improve adherence to mammography and BMD screening guidelines should be explored, which could possibly leverage the increased likelihood that women who receive one screening service will receive another.

Introduction: Raloxifene, a non-steroidal selective estrogen receptor modulator (SERM), offers a new dimension for the treatment and prevention of osteoporosis and risk reduction of invasive breast cancer in postmenopausal populations at high risk. Both osteoporosis and breast cancer are important public health issues for postmenopausal women. It is well known that estrogen and estrogen receptors play an important role in the pathogenesis of both diseases. Initially, hormone replacement therapy (HRT) was used for the purpose of preventing and treating postmenopausal osteoporosis. However, HRT significantly contributed to an increase in breast cancer risk. The SERM, raloxifene, is used for the prevention and for the treatment of postmenopausal osteoporosis and reducing the risk of invasive breast cancer in postmenopausal women., Areas Covered: This article reviews the emerging evidence of the efficacy of raloxifene in postmenopausal women, summarizes the results and places in perspective their therapeutic uses for women having either a high risk of osteoporosis or breast cancer. Emerging clinical evidence suggests bisphosphonates, currently used as drugs for the treatment of osteoporosis, may also reduce breast cancer risk. The status of other SERMs and bisphosphonates are included for completeness. A Medline search of raloxifene, osteoporosis, breast cancer and SERMs was used to derive a database of 355 references., Expert Opinion: Readers will understand the value of raloxifene to prevent osteoporosis and breast cancer in postmenopausal women. Although most women do not require pharmacotherapy for menopausal symptoms, many are severely affected by osteoporosis or breast cancer at and beyond menopause and, for such women, pharmacologic intervention is important if they are to retain an acceptable quality of life. It is reasonable to use raloxifene or bisphosphonate as an appropriate drug that targets symptom-free postmenopausal women for treatment and prevention of osteoporosis but raloxifene is proven to reduce the incidence of invasive breast cancer.

Arzoxifene is a selective estrogen receptor modulator (SERM) that has been shown to be more potent in preclinical testing than currently available agents. Its effects on clinical outcomes are not known. In a randomized, blinded trial, women aged 60 to 85 years with osteoporosis, defined as a femoral neck or lumbar spine bone mineral density T-score of -2.5 or less or a vertebral fracture, and women with low bone mass, defined as a bone density T-score of -1.0 or less and above -2.5, were assigned to arzoxifene 20 mg or placebo daily. The primary endpoints were new vertebral fracture in those with osteoporosis and invasive breast cancer in the overall population. After 3 years, the cumulative incidence of vertebral fractures in patients with osteoporosis was 2.3% lower in the arzoxifene group than in the placebo group, a 41% relative risk reduction [95% confidence interval (CI) 0.45-0.77, p < .001]. In the overall population, the cumulative incidence of invasive breast cancer over 4 years was reduced by 1.3%, with a 56% relative reduction in risk (hazard ratio = 0.44, 95% CI 0.26-0.76, p < .001); there was no significant decrease in nonvertebral fracture risk. Arzoxifene increased the cumulative incidence of venous thromboembolic events by 0.7%, with a 2.3-fold relative increase (95% CI 1.5-3.7). Like other SERMs, arzoxifene decreased vertebral fractures and invasive breast cancer while the risk of venous thromboembolic events increased., (Copyright © 2011 American Society for Bone and Mineral Research.)

Objective: This study reports the efficacy and safety of zoledronic acid (ZOL) in preventing bone loss in postmenopausal patients receiving an aromatase inhibitor (AI) following tamoxifen., Methods: Postmenopausal patients with stage I-III hormone receptor-positive breast cancer who received tamoxifen for 2.5-3 years were randomized to receive letrozole (2.5 mg/day) with (n = 47) or without (n = 43) ZOL (4 mg i.v. every 6 months) for 2 years. The primary endpoint was percent change from baseline in lumbar spine (LS) bone mineral density (BMD) up to 60 months., Results: Ninety patients (86 evaluable) with a median age of 59 years (42.9-83.6), 50/86 of whom had previously been treated with chemotherapy, were followed for a median time of 41.4 months. While the control group showed a significant decrease in LS T-score (p = 0.0005), the ZOL group presented an increase over time (p = 0.0143). Change over time in LS T-score was significantly different between groups, favoring ZOL (p < 0.0001 at 24 and 48 months). No fractures, renal dysfunction or osteonecrosis of the jaw were reported. The toxicity profile was similar to those previously reported for each drug., Conclusion: The addition of ZOL to letrozole was safe and efficacious in maintaining LS BMD in postmenopausal patients with hormone receptor-positive breast cancer and who were receiving letrozole following 2.5-3 years of tamoxifen., (Copyright © 2011 S. Karger AG, Basel.)

Background: Currently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, lasofoxifene was shown to reduce the risk of estrogen receptor-positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor-negative [ER-]) and ER+ invasive breast cancer are unknown., Methods: Postmenopausal women (n = 8556) aged 59-80 years with low bone density and normal mammograms were randomly assigned to two doses of lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case-control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone-binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided., Results: Breast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; P(interaction) = .04)., Conclusion: A 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.

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.)

The results of recent large clinical trials have led physicians and patients to question the safety of menopausal hormone therapy. In the past, physicians prescribed hormone therapy in an attempt to improve overall health and prevent cardiac disease. Hormone therapy appears to increase the risk of breast cancer when used for more than three to five years; therefore, regulatory agencies now advise that physicians prescribe it only to treat menopausal symptoms such as hot flashes and vaginal atrophy, with the smallest effective dosage and for the shortest possible duration. Although estrogen is the most effective treatment for hot flashes, alternatives such as venlafaxine and gabapentin are effective for some patients. Herbal formulations such as dong quai, ginseng, kava, and dietary soy, among others, do not appear to benefit patients more than placebo. In contrast to systemic estrogen therapy, topical estrogen therapy for vulvovaginal atrophy is more appealing for certain patients because it does not require the addition of a progestogen for endometrial protection. Some have advocated selective estrogen reuptake modulators as alternatives to hormone therapy for the prevention of menopausal osteoporosis. The decision to use either therapy depends on clinical presentation and a thorough evaluation of the risks and benefits, because both have potential detrimental health effects and both are linked to an increased risk of venous thromboembolism.

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objectives: The purpose of this review is to summarize the effectiveness of select vitamins, minerals and trace elements in postmenopausal women for their effects on bone health, cardiovascular health, breast cancer, cognition and vasomotor symptoms., Methods: Review of the relevant literature and results from recent clinical studies, as well as critical analyses of published systematic reviews and meta-analyses were obtained from PubMed and Cochrane Library of Reviews. Vitamin A, the B vitamins, vitamin C, calcium, vitamin D, vitamin E, vitamin K, magnesium, selenium and zinc were selected for review. In circumstances where the vitamin, mineral or trace element has not been studied for a given condition, no information was provided., Results and Discussion: All vitamins, minerals and trace elements play an important role in maintaining health and wellbeing among menopausal women. Adequate dietary intake is essential and supplementation should be considered in women with documented malabsorption syndromes or deficiencies. Based on a review of the literature, supplementation with vitamin C, D, K and calcium can also be recommended for proper maintenance of bone health. The only supplement studied for vasomotor symptoms was vitamin E and this vitamin lacked clinical support. Supplementation in healthy postmenopausal women with vitamins and minerals in diet or pill forms cannot be recommended currently for any other indications., (Published by Elsevier Ireland Ltd.)

Background: Aromatase inhibitors are used as adjuvant therapy for breast cancer (BC) and are associated with accelerated bone loss. Zoledronic acid (ZOL) prevents aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women with BC. This analysis assessed the cost-effectiveness of ZOL for prevention of fractures in postmenopausal women with BC., Materials and Methods: A Markov model was developed to project lifetime incidence of fractures, quality-adjusted life years (QALY), and costs as a function of bone mineral density (BMD) for women with early-stage BC receiving letrozole alone or with ZOL. Two strategies of ZOL therapy were compared with no treatment: starting ZOL treatment only when BMD levels decreased ('delayed ZOL') and starting ZOL simultaneously with letrozole therapy ('upfront ZOL')., Results: Delayed ZOL therapy was estimated to cost 16,069 pounds per QALY, when compared with not administering bisphosphonates for AIBL prevention. The corresponding cost per QALY gained for upfront ZOL versus no treatment was estimated at 21,973 pounds. The cost-effectiveness ratio for upfront versus delayed therapy was estimated at 24,868 pounds per QALY gained., Conclusion: Both delayed and upfront therapy with ZOL for the prevention of AIBL and fractures in BC patients in the UK appear to result in highly acceptable cost-effectiveness ratios.

The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)-approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05-1.47) and for noninvasive disease, 1.22 (95% CI, 0.95-1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36-0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12-0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60-0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer., (2010 AACR.)