Bone Protection Research Articles

Pathogenetic treatment with strontium ranelate in women with postmenopausal osteoporosis

The possibility of recovering the functional status is now considered as an integral part of the development of new treatment strategies for chronic diseases, including osteoporosis (OP). The possibility to optimize the treatment of OP, by exerting a more physiological effect on bone and simultaneously reducing the increased bone resorption and formation, is highly urgent. The system of osteoprotegerin (OPG), receptor activator of nuclear factor-κ B and its ligand has been confirmed to play a central role in the regulation of bone metabolism. At the same time, there is strong evidence that OPG performs a key function in bone metabolism regulation, by suppressing the differentiation of osteoclasts (OC) and reducing their activity. The synthesis of OPG decreases with age in postmenopausal and glucocorticoid-induced OP. Thus, more effective bone protection needs to elevate the level of OPG, by stimulating its synthesis. Bivalos facilitates the replication of osteoblasts and the higher expression of OPG, resulting in a reduction in the differentiation and activity of OC. Thus, Bivalos positively uncouples the interrelated processes of bone metabolism. A combination of the bone-forming and antiresorptive effects of the agent leads to the recovery of bone balance in favor of bone formation. Strontium ranelate should be presently considered as a first-line safe and effective agent for the long-term treatment of women with postmenopausal OP.

Anti-IL-17A therapy protects against bone erosion in experimental models of rheumatoid arthritis

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine secreted by a subset of memory T cells and other innate immune cells. It is associated with rheumatoid arthritis (RA) due to IL-17A expression in RA synovial fluid. The severe bone erosive rat adjuvant-induced arthritis (rAIA) and mouse collagen-induced arthritis (mCIA) models were used to address the therapeutic efficacy of anti-IL-17A treatment with a focused investigation on bone protection. In the rAIA model, treatment with anti-IL-17A completely alleviated arthritis, lowered the level of receptor activator of NFκB ligand (RANKL), and inhibited structural damage to the bones. In the mCIA model, IL-17A neutralization coincident with arthritis development or in mice with established arthritis diminished joint swelling by inhibiting disease initiation and progression. Intriguingly, even the few joints that became outwardly severely inflamed in the presence of an anti-IL-17A antagonist had diminished joint histopathology scores compared to severely inflamed, control-treated mice. The bone-preserving property correlated with decreased RANKL message in severely inflamed paws of arthritic mice. These data identify IL-17A as a key factor in inflammation-mediated bone destruction and support anti-IL-17A therapy for the treatment of inflammatory bone diseases such as RA.

The effects of intravenous zoledronic acid in Chinese women with postmenopausal osteoporosis

The aim of this study was to assess the efficacy and safety of a once-yearly zoledronic acid treatment for Chinese women with postmenopausal osteoporosis in Taiwan and Hong Kong. This post hoc subpopulation analysis, from the Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly Pivotal Fracture Trial, enrolled 323 Chinese women with osteoporosis who were randomly given either annual infusions of zoledronic acid or placebo for 3 consecutive years. The incidence of fractures and changes in bone mineral density (BMD) were measured; adverse events (AEs) and tolerability were recorded and assessed. The results of this study at 36months demonstrate that there was a significantly reduced risk of morphometric vertebral fracture and clinical vertebral fracture in subjects treated with zoledronic acid (P<0.05). In addition, there were significant increases of BMD by 4.9%, 4.3%, and 7.0% in the total hip, femoral neck, and trochanter, respectively, in the zoledronic acid group compared with the placebo group (P<0.001 for all comparisons). The incidences of AEs were comparable between the two groups. Thus, once-yearly zoledronic acid treatment showed bone protection effects by reducing the risk of vertebral fracture and increasing BMD in Chinese women with postmenopausal osteoporosis.

Cannabinoid Receptors as Target for Treatment of Osteoporosis: A Tale of Two Therapies

The central nervous system plays an important role in regulating bone metabolism in health and in disease with a number of neurotransmitters been reported to influence bone cell activity through a central relay. In keeping with this, recent studies demonstrated that endocannabinoids and their receptors are involved in the pathogenesis of osteoporosis. The endocannabinoids anandamide and 2-arachidonylglycerol are found in the skeleton and numerous studies also showed that bone cells express the cannabinoid receptors CB1 and CB2 and the orphan receptor GPR55. Pharmacological and genetic inactivation of CB1, CB2 and GPR55 in adult mice suppress bone resorption, increase bone mass and protect against bone loss, suggesting that inverse agonists/antagonists of these receptors may serve as anti-resorptive agents. In the ageing skeleton however CB1 and CB2 receptors have a protective effect against age-dependent bone loss in both male and female mice. CB1 receptor deficiency in aged mice results in accelerated age-dependent osteoporosis due to marked increase in bone resorption and significant reduction in bone formation coupled to enhanced adipocyte accumulation in the bone marrow compartment. Similar acceleration of bone loss was also reported in CB2 deficient mice of similar age but found to be associated with enhanced bone turnover. This review summarises in vitro and in vivo findings relating to the influence of cannabinoid ligands on bone metabolism and argues in favour of the exploitation of cannabinoid receptors as targets for both anabolic and anti-resorptive therapy for treatment of complex multifaceted bone diseases such as osteoporosis.

170th ENMC International Workshop: Bone protection for corticosteroid treated Duchenne muscular dystrophy. 27–29 November 2009, Naarden, The Netherlands

The first ENMC workshop for bone protection in DMD patients treated with corticosteroids included 18 participants from Europe, USA and Canada. The participants were from diverse backgrounds including Paediatric Neurology, Endocrinology, Metabolic bone disease, Orthopaedics and Medical Physics. The objectives of the workshop were to discuss the problem of vertebral fractures with the following aims:

Protection of Trabecular Bone in Ovariectomized Rats by Turmeric (Curcuma longa L.) Is Dependent on Extract Composition

Extracts prepared from turmeric (Curcuma longa L., [Zingiberaceae]) containing bioactive phenolic curcuminoids were evaluated for bone-protective effects in a hypogonadal rat model of postmenopausal osteoporosis. Three-month female Sprague-Dawley rats were ovariectomized (OVX) and treated with a chemically complex turmeric fraction (41% curcuminoids by weight) or a curcuminoid-enriched turmeric fraction (94% curcuminoids by weight), both dosed at 60 mg/kg 3x per week, or vehicle alone. Effects of two months of treatment on OVX-induced bone loss were followed prospectively by serial assessment of bone mineral density (BMD) of the distal femur using dual-energy X-ray absorptiometry (DXA), while treatment effects on trabecular bone microarchitecture were assessed at two months by microcomputerized tomography (microCT). Chemically complex turmeric did not prevent bone loss, however, the curcuminoid-enriched turmeric prevented up to 50% of OVX-induced loss of trabecular bone and also preserved the number and connectedness of the strut-like trabeculae. These results suggest that turmeric may have bone-protective effects but that extract composition is a critical factor.

Regulatory T Cells Protect from Local and Systemic Bone Destruction in Arthritis

We previously demonstrated the suppressive effects of regulatory T cells (Treg cells) on osteoclast differentiation in vitro. In this article, we show that blood markers of bone resorption inversely correlate with the amount of circulating Treg cells in healthy controls and rheumatoid arthritis patients, further suggesting that Treg cells may control bone destruction in vivo. Indeed, bone marrow from Foxp3-transgenic (Foxp3tg) mice fully protected human TNF transgenic (hTNFtg) mice from TNF-alpha-induced bone destruction, whereas Foxp3-deficient bone marrow enhanced local and systemic bone loss. The same protective effect was also obtained by treating hTNFtg mice with the CD28 superagonist mAb (CD28 SA), which increased Treg cell numbers. In both models, bone protection by Treg cells was associated with reduced osteoclast numbers, resulting in less bone-resorbing activity. Reduced osteoclast numbers were not caused by an intrinsic defect in osteoclast differentiation because osteoclast precursors from hTNFtg/Foxp3tg chimeras responded normally to M-CSF and receptor activator of NF-kappaB ligand. Although a decrease in the clinical signs of arthritis was observed in Foxp3tg bone marrow-transferred and CD28 SA-treated hTNFtg mice, the bone-protective effect of Treg cells was independent of the suppression of inflammation, as demonstrated by the increased systemic bone density observed in wild-type mice treated with CD28 SA. This work demonstrated that increasing Treg cell numbers improved clinical signs of arthritis and suppressed local and systemic bone destruction. Thus, enhancing the activity of Treg cells would be beneficial for the treatment of inflammation-induced bone loss observed in rheumatoid arthritis.

Hormonal therapy with estradiol and testosterone implants: bone protection?

Objective. To assess bone mineral density (BMD) in postmenopausal women using estradiol and testosterone hormonal implants comparing to that of patients without hormonal therapy.Design of the study. Sixty-one patients were followed in prospective cohort study separated in Group 1, 34 women using implants and Group 2, 27 women without implants and BMD assessment through Dual energy X-ray absorptiometry was conducted in the beginning of follow-up and after 1 year.Results. The average lumbar spine BMD in Group 1 was 1.123 ± 0.16 kg/m2 and 1.144 ± 0.18 kg/m2 after 1 year, p = 0.39 and femur BMD was 0.922 ± 0.16 kg/m2 and 0.957 ± 0.12 kg/m2 after 1 year of treatment, p = 0.076. In Group 2, the initial lumbar spine BMD average was 1.064 ± 0.2 kg/m2 and after 1 year, 1.001 ± 0.23 kg/m2, p = 0.112 and femur BMD changed from 0.928 ± 0.14 kg/m2 to 0.881 ± 0.15 kg/m2 after 1 year, p = 0.046.Conclusion. BMD variance between the groups in the period of 1 year showed that the combination of estradiol and testosterone promoted bone protection in post menopausal women.

Secondary osteoporosis UPDATE. Pathophysiology and management of cancer treatment-induced bone loss/fractures

Patients with cancers such as breast or prostate cancer who have been treated with hormone deprivation therapies or anti-cancer agents for certain periods of time frequently manifest reduced bone mass or pathological fractures during their clinical course. These are likely due to an imbalance between osteoblastic bone formation and osteoclastic bone resorption resulting from hypogonadism. Bone should be carefully monitored in cancer patients who are going to continually receive adjuvant hormonal or anti-cancer therapies. Administration of anti-bone resorption agents such as bisphosphonates may be necessary to maintain bone mineral density and protect pathological fractures in these cancer patients.

Structural, cellular, and molecular evaluation of bone erosion in experimental models of rheumatoid arthritis: Assessment by μCT, histology, and serum biomarkers

Bone erosion is a clinical endpoint for various diseases including rheumatoid arthritis. In this paper, we used rodent arthritis models with severe bone erosion to examine the structural, cellular, and molecular aspects of the inflammation-driven bone resorption process. Our data show that bone loss is observed only in chronically, severely inflamed joints. The most severely affected anatomic sites were the metatarsal phalangeal joint and tarsal bones of the paw. The magnitude of the inflammation-driven bone erosion was dependent on both the duration of inflammatory response and the severity of the joint swelling response. The application of micro-computed tomography well demonstrated the therapeutic benefit of anti-IL-17A in protection of bones from erosion. Alterations in the cellular profile of the joint occurred prior to any major structural deterioration of the bone. Receptor activator for nuclear factor κB ligand, a potent inducer of osteoclast differentiation and bone resorption, was elevated in animals coincident with severe arthritis initiation. The experimental approaches and concepts outlined in this paper provide a valuable process to evaluate and quantify therapies that modulate rodent arthritis-associated bone-erosion models.

Higher protein weight loss diet does not affect bone mineral density (BMD) in a double‐blind RCT in postmenopausal women

In spite of longstanding theory that protein intakes above the RDA are harmful to bone, clinical trials have variably shown no influence or protection of bone with higher protein intakes during weight loss. Studies to date have failed to match intakes of calcium and vitamin D, leaving the independent effect of protein ambiguous.We prescribed a conventional, MyPyramid‐based energy restricted diet (1500 kcal/d) to 31 postmenopausal women (age 65±5y, BMI 33.8±4.9), then randomly assigned 50g/d of supplemental maltodextrin (CARB) or whey protein isolate (PRO) to be added as 25g doses to breakfast and lunch, for 0.8g/kg total protein in CARB and 1.4g/kg in PRO groups. All women received 1g Calcium and 800 IU Vitamin D as a daily multivitamin.After 6 mo, women lost (PRO, CARB) 9.8±6.7, 4.8±3.7% of baseline weight (p=0.06). Bone mineral density changed 2.4, 2.1% (p=0.70) for whole body, −0.8, 1.4% (p=0.13) for lumbar spine and −0.4 and −0.2% (p=0.84) for total hip.This double blind, randomized, controlled trial supports growing consensus that higher protein intakes are not harmful to bone in the context of adequate calcium and vitamin D intakes.Support: National Dairy Council &amp; Carraway Foundation

Methothrexate directly inhibits RANKL expression and osteoclast formation in very early arthritis

Methotrexate (MTX) is one of the most widely used therapies in rheumatoid arthritis (RA) due to its anti-inflammatory and potential bone protection effect. Bone biology is governed by the RANKL/RANK/OPG...

Anteromedial approach for shoulder arthroplasty: Current indications, complications, and results

The anteromedial approach to the shoulder with detachment of the anterior deltoid from its clavicular and anterior acromial origins is a method of enhancing exposure for difficult shoulder arthroplasty cases. The aim of this study is to describe the current frequency of use, indications, complications, and results of this approach. Between 2000 and 2003, 723 consecutive shoulder arthroplasties were performed. In 110 (15%) an anteromedial approach was used. Patient data; previous surgery; indications for surgery; pain, motion, and strength before and after surgery; complications; and the need for reoperation were assessed. This approach was used in 9.5% of primary cases and 39% of revision cases. Seventy percent had had previous surgery. For primary arthroplasty, the most frequent diagnoses were osteoarthritis and the sequelae of fractures. In revision cases the most common diagnoses were instability and glenoid loosening. The structural indications for the anteromedial approach were severe scarring, protection of a frail deltoid, improvement in rotator cuff or glenoid exposure, protection of osteopenic bone, or enhancement of exposure in oncologic cases or resections. Ninety patients had more than 2 years of follow-up. Pain improved after primary and revision arthroplasty. Motion only improved in primary arthroplasty. There was little change in strength. No proximal deltoid detachments or other approach-related complications were identified. The anteromedial approach is a reliable technique to improve surgical exposure in difficult shoulder arthroplasty cases. When performed adequately, it can be applied safely without anterior deltoid detachment or clinically evident major complications.

Effect of oral clodronate on bone mass, bone turnover and subsequent metastases in women with primary breast cancer

Breast cancer treatments have been associated with accelerated bone loss and increased osteoporosis risk. In a subgroup analysis of a randomised, double-blind, placebo-controlled study, we compared the changes in spine and total hip bone mineral density (BMD) and biochemical markers of bone turnover in women with primary breast cancer who had received standard therapy plus either oral clodronate 1600 mg/d ( n = 419) or placebo ( n = 432) for 2 years. After 2 years, spine BMD was 1.92% higher in patients who received clodronate instead of placebo ( P < 0.0001) and total hip BMD was 1.29% higher ( P = 0.002 versus placebo). Patients who received clodronate had a median 26% reduction in levels of serum N-terminal pro-peptide of type I procollagen (PINP) – a marker of bone turnover – after 2 years of therapy. This compares with a median 5% increase in patients who received placebo ( P < 0.0001). Effects on BMD, but not biochemical markers, persisted for up to 3 years post-treatment. Early changes in PINP were associated with changes in BMD and the likelihood of developing bone metastases. This study shows the use of oral clodronate during primary breast cancer treatment is associated with reduced bone turnover and protection against bone metastases.

Impact of Zoledronic Acid in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole: Z-FAST, ZO-FAST, and E-ZO-FAST.

Abstract Background: Aromatase inhibitors (AI) are accepted as adjuvant endocrine therapy for hormone receptor-positive (HR+) postmenopausal early breast cancer (EBC) with superior efficacy to tamoxifen. However, because of the increased bone loss associated with the use of AI, three international randomised studies Z-FAST, ZO-FAST and E-ZO-FAST were performed to evaluate the bone protective effects of zoledronic acid (ZOL). These studies showed that the bone mineral density (BMD) loss associated with AI therapy can effectively be prevented by ZOL. In addition, these studies included disease-free survival (DFS) as a secondary endpoint, although the studies were not powered to detect a difference between treatment arms. Following the results from ABCSG 12 indicating a powerful effect of ZOL in premenopausal women receiving endocrine therapy, exploratory analyses of the individual trials have been done. However, this is the first report of DFS outcome for all three studies.Materials and Methods: Across the three studies 2194 patients(pts) with HR+ EBC were randomised to either immediate ZOL 4mg every 6 months or delayed ZOL where bone protection was started if either the BMD T-score fell below &amp;lt; -2.0 SD or a non-traumatic fracture occurred. DFS was defined as time to first appearance of breast cancer recurrence or death from any cause. Pts in ZO-FAST and E-ZO-FAST, but not in Z-FAST, were followed for recurrence and survival after stopping study drug. DFS was summarized by the Kaplan-Meier method and compared between the two groups using the log-rank test, stratified by baseline BMD and adjuvant chemotherapy. A Gail-Simon test was performed to assess interactions between treatment and study on DFS.Results: Median follow up times for this analysis are 54, 48 and 36 months respectively for Z-FAST, ZO-FAST and E-ZO-FAST. The proportion of pts with a follow-up lag time of ≥ 6 months was 29.7% Z-FAST, 8.3% ZO-FAST and 8.7% E-ZO-FAST. The pt-years of time on study for both arms combined were calculated; Z-FAST 2709; ZO-FAST 4260 and E-ZO-FAST 1580. The percent of pts starting ZOL in the delayed ZOL arm was: Z-FAST 26%, ZO-FAST 25%, and E-ZO-FAST 17%. The Gail-Simon test was statistically significant for a quantitative interaction between studies (p-value 0.047). Therefore, combining the results was not considered statistically appropriate. Numbers of recurrences and individual trial hazard ratios are shown below.Table 1 No of PatientsImmediateDelayedHR (95% CI)p valueZ-FAST60222260.80 (0.45-1.41)NSZO-FAST106532530.59 (0.38-0.92)0.0176E-ZO-FAST52719111.76 (0.83-3.69)NS Conclusion: This exploratory analysis of DFS has several limitations: a small number of pt events, differences between trials in the method of collecting pt follow up data on DFS and length of median follow-up times, a wide range of pt-years on study, and a statistically significant interaction between studies, reflecting the heterogeneity of results. Also, the use of a ZOL delayed arm as active control limits a direct assessment to that of no ZOL. Additional analyses are planned when the studies are completed. Results from ongoing appropriately powered randomised studies are awaited to determine the true role of adjuvant ZOL in EBC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4082.

A retrospective study of the role of an occupational therapist in the cancer nutrition rehabilitation program

The purpose of the study was to determine how frequently each domain of activity was addressed and how frequently specific interventions were used by an occupational therapist (OT) with cancer patients who attended an 8-week Cancer Nutrition and Rehabilitation (CNR) program. Sixty-two patients with cancer were assessed. All received interventions by the OT within the CNR program. The following activity domains: (1) self-care, (2) productivity, and (3) leisure that were addressed during appointments with the OT were recorded following each visit. Seven categories of interventions were predetermined and their use was recorded using a checklist. Descriptive statistics were conducted and revealed that 36% of the therapist's time was spent assessing patients' functional capacity while 64% was spent providing interventions. The OT's interventions addressed leisure and exercise (54%), productive activities such as housework and paid employment (32%), and basic activities of daily living (14%). The frequency of specific interventions provided were as follows: 40% in teaching of energy conservation and activity management techniques, 33% in goal setting/support and counseling, 9% in cognitive retraining/stimulation, 6% in communication with community agencies, and 4% in teaching of joint and bone protection techniques, help with management of neuropathies, and education on scar management respectively. It is suggested that OTs practicing in oncology use a variety of interventions to better address productive and leisure activities. The data suggests that limitations in these areas were more prevalent than in self-care activities. Further study is needed to examine OT interventions in oncology.

Vitamin K function mediated by activation of steroid and xenobiotic receptor

Insufficient vitamin K nutrition is one of the risks for bone fracture. Vitamin K is clinically applied to osteoporosis treatment in Japan and Asian countries, as the administration has preventive effects on bone fracture. Recent studies have revealed that vitamin K functions as a ligand for Steroid and Xenobiotic Receptor (SXR), as well as a cofactor for gamma-carboxylase. In osteoblastic cells, several SXR responsive genes have been identified, including tsukushi, matrilin-2, CD14, and Msx2. Working together with gamma-carboxylated bone proteins, these SXR targets will function in the vitamin K-mediated bone protection. It has been also suggested that vitamin K could prevent or treat the hepatocellular carcinoma (HCC) in some clinical studies. SXR may also contribute to the vitamin K-dependent reduction of HCC.

The α-Isoform of p38 MAPK Specifically Regulates Arthritic Bone Loss

Pharmacological inhibitors have provided evidence for the key role of p38 MAPK in osteoclast differentiation and in inflammation-induced bone loss. However, these inhibitors block more than one of the four p38 isoforms, usually p38alpha and p38beta, and sometimes also other kinases such as JNK3. We show in this study that p38alpha is the main p38 isoenzyme expressed in the osteoclast precursors and in the mature osteoclasts. p38alpha as well as its downstream substrates were phosphorylated in osteoclast progenitors stimulated by TNF-alpha. Using Mx-cre-mediated conditional gene inactivation we demonstrated that mice lacking p38alpha were protected against TNF-alpha-induced bone destruction at the site of inflammation as well as against TNF-alpha-mediated systemic bone loss. The bone protection was associated to decreased osteoclast numbers in vivo as well as a decreased IL-1beta expression in the inflamed tissue and in the isolated monocytes. The phenotype was cell autonomous because, similarly to p38alpha-deficient cells, knockdown of p38alpha in monocytes resulted in a decreased osteoclast differentiation in vitro. It was not caused by major changes in RANKL-mediated ERK or JNK activation but rather associated to an increased NF-kappaB activation caused by a decrease in IkappaBalpha recovery. Thus, our data show that developing specific inhibitors of the alpha-isoenzyme of p38 would be beneficial for the treatment of inflammation-induced bone destruction as observed in rheumatoid arthritis.

IBD care in Europe: A comparative audit of the inpatient management of Crohn's disease and ulcerative colitis using the national UK IBD audit tool

Background and aims The National UK IBD audit tool is an electronic database created to improve the quality and safety of care for IBD patients by auditing individual patient care, service resources and organisation against national standards. We used the National UK IBD audit tool to compare the organisation and process of IBD care between services in Oxford (UK) and Milan (Italy), as a pilot study to evaluate its application outside national boundaries. Methods Clinical and demographic data of patients with CD and UC, consecutively admitted during a 2 month period, were collected and compared between the centres, to each other and to the UK IBD standards obtained by previous audit analyses performed in Oxford in 2006. Results 20 and 26 patients with UC were admitted in Oxford and Milan, as well as 21 and 20 patients with CD, respectively. Most admissions in Milan were planned admissions for moderately active treatment-refractory disease. No patient died. Oxford had a higher surgery rate. Endoscopy for UC consisted mainly of colonoscopy in Milan (92%) and flexible sigmoidoscopy in Oxford (64%). In CD, Oxford data revealed a higher use of immununomodulators and CT scan, compared with higher use of bowel ultrasound in Milan. CRP was the preferred biomarker of disease activity. The following areas did not reach the standards set for the 2006 UK IBD Audit: the lack in Milan of IBD specialist nurses and few dietitian visits, as well as little attention to heparin prophylaxis and abdominal radiography in UC. Both sites paid little attention to stool cultures and revealed a high rate of active smokers in CD and little attention to bone protection in steroids users. Since the 2006 audit in Oxford, improvements include IBD specialist nurse visits, dietitian visits, number of active smokers, stool samples, prophylactic heparin, bone protection and nutritional assessment. Conclusions Consistent procedural differences between Oxford and Milan identified by audits of both UC and CD could be resolved by organisational change, with an improvement in the service. The UK IBD audit tool is an easy instrument to assess the processes and outcomes of care delivery in IBD and can be applied also outside UK.

Prevalence and Impact of Vaginal Symptoms among Postmenopausal Women

Vulvovaginal atrophy (VVA) is reported by one-quarter to one-half of postmenopausal women. We evaluated the prevalence, inconvenience of, and issues surrounding hormone use for VVA symptoms in women who were current, past, and never users of menopausal hormone therapy (MHT), along with the relationship of sexual activity to VVA symptoms. An online survey was sent to 3,471 women >or=45 years old participating in a panel of approximately 43,000 U.S. adults maintained by Knowledge Networks. Respondents were stratified by MHT use (current, past, and never) and sexual activity (sexually active and not sexually active). Final respondent data underwent a poststratification process and Chi-square analysis of hormone use and VVA by sexual activity. Main Outcome Measures. Percent, calculated as the ratio of response over total responding for each survey question for all and stratified respondents. Forty-five percent (1,038/2,290) of respondents (age range 45-89 years; mean 60.7 years) were postmenopausal and currently or previously experienced VVA. Approximately 60% of past or never users of MHT reported vaginal symptoms; >90% found them bothersome. In comparison, 82% of current users reported VVA symptoms prior to use. 85% of all respondents were aware of safety issues associated with MHT. The prevalence and perceived severity of VVA symptoms were substantial but less frequent in nonsexually active women. Analysis of MHT use by past or current hormone use indicated a trend away from oral dosing and towards patch or vaginal hormones. Postmenopausal women have a high rate of VVA symptoms. Those who use MHT do so for multiple reasons-hot flashes, VVA, bone protection, dyspareunia-and most have concerns about long-term safety, despite the fact that the majority of MHT use was for >5 years. Safety concerns and lack of physician recommendation were major reasons for not using or discontinuing MHT.