Oral daily PTH(1-34) tablets (EB613) in postmenopausal women with low BMD or osteoporosis: a randomized, placebo-controlled, six-month, phase 2 study.

Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered parathyroid hormone (PTH) tablet on serum markers of bone formation [N-terminal propeptide of Type I procollagen (PINP) and osteocalcin (OC)] and bone resorption [crosslinked C-telopeptide (CTX)], bone mineral density (BMD) and safety in postmenopausal women with low BMD or osteoporosis. In this 6-month, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3 and 6 months and BMD of lumbar spine, total hip and femoral neck was measured at 6 months. Biochemical marker changes were dose dependent with minimal or no effect at the two lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 month after oral PTH initiation (p < 0.0001), remained elevated through 3 months and were back to baseline at 6 months. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 months respectively (both p ≤ 0.02). At 6 months, 2.5 mg tablets increased mean BMD vs placebo of the lumbar spine by 2.7%, total hip by 1.8%, and femoral neck by 2.8% (all p ≤ 0.01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

Despite the superior benefits of bone building (anabolic) agents and guidelines supporting their use, these medications are used in a minority of patients for whom they are appropriate, in part because they require daily or monthly injections, which limit patient acceptance. An oral anabolic tablet has potential to address this substantial treatment gap. In this double-blind, placebo controlled, dose-finding randomized study, 161 postmenopausal women with low bone mineral density or osteoporosis were treated with varying doses of the active part of parathyroid hormone [PTH(1-34)] or placebo given in daily oral tablets for 6 months. The highest oral PTH tablet dose (2.5 mg), produced an increase in markers of bone formation while simultaneously decreasing the markers of bone breakdown. Significant gains in bone mineral density of the spine and hip were observed at the end of the 6-month study and there were no significant safety concerns. The 2.5 mg oral PTH tablet dose was well tolerated when patients were instructed to titrate up to the full dose. We conclude that this PTH tablet might be the first effective orally administered bone building medication and should be studied further in treatment of women with osteoporosis.

DXA assessment and fracture prevention in hormone positive breast cancer patients after treatment initiation with aromatase inhibitors: A registry-based cohort study.

Background: Several guidelines have been proposed to prevent aromatase inhibitors induced bone loss (AIBL), but there is scarce data on their endorsement in clinical practice. Aim: To assess bone health evaluation and fracture prevention in postmenopausal women with estrogen receptor (ER)-positive breast cancer after aromatase inhibitors (AI) initiation. Methods: An historical cohort analysis based on data from the cancer and osteoporosis Maccabi Health Services (MHS) registries from Jan 1st 2009 to Dec 31st 2020. Cases of estrogen receptor (ER)-positive breast cancer were extracted. Index date was set as the first aromatase inhibitors (AI) purchase. Variables such as age, BMI, smoking history, alcohol use, rheumatoid arthritis, diabetes, glucocorticosteroid use, previous fractures, BMD T-scores and purchases of AI and anti-resorptive agents were collected. Age under 50, previous cancer, prior major osteoporotic fractures and prior anti-resorptive treatment were exclusion criteria. Kaplan-Meier curves were generated to assess the time to outcomes. Multivariable Cox's proportional hazards survival model was performed. Results: A total of 8617 women initiating AI were eligible. The median follow up was 6.1 years. The mean (SD) age at index was 62.8 (9.2), the mean (SD) BMI was 29.1 (5.6). The mean (SD) T-score was -1.3 (1.2) at the lumbar spine, -1.5 (0.9) at the femoral neck and -1.0 (1.0) at the total hip. Twenty percent had type 2 diabetes, 8.1 % were active smokers, 3.8% had rheumatoid arthritis and 1.2% were exposed to glucocorticoids.A total of 37% and 53% underwent a DXA scan at 1 and 2 years from AI initiation, and 12% and 17% were prescribed an anti-resorptive agent at 1 and 2 years from index. Advanced age was associated with a higher rate of evaluation and treatment, while obesity and diabetes were associated with a lower rate. The cumulative incidence of a major osteoporotic fracture was 8.8 and 15.8 % at 5 and 10 years, respectively. Conclusions: Despite the excess risk of fractures, bone health assessment and preventive treatment are still partial and postponed in breast cancer AI treated patients. Strategies to ensure appropriate care are needed.

Lower incidence of hip fractures among elderly Ethiopian immigrants to Israel: first assessment from the Israel National Trauma Registry (INTR) 2011-2020.

The incidence hip fractures (HF) among Ethiopian immigrants is unknown. In Israel, the incidence of HF among Ethiopian immigrants aged ≥ 50 years between 2011 and 2020 was lower than in the general Israeli population, but possibly on the rise. These data should be confirmed in other countries where the Ethiopian diaspora has settled. PURPOSE: The incidence of osteoporotic fractures in the aging Ethiopian population that immigrated to Western countries has not been reported. This study sought to provide a first assessment of the incidence of hip fractures in Ethiopian immigrants in Israel, as a proxy for osteoporosis in this population. METHODS: This is an epidemiologic study of the incidence of hip fractures (HF) in people aged ≥ 50 years in Israel, between 2011 and 2020. Data were extracted from the Israel National Trauma Registry (INTR). Annual age-adjusted HF incidence rates (IR), and standardized incidence ratios (SIR) among Ethiopian-born (EB) relative to non-EB subjects (others) were computed. RESULTS: During the study period, among subjects age ≥ 50 in the INTR, only 20.1% of the EB suffered a HF, in contrast to 32.3% of subjects from other origins (P < 0.0001). Although EB subjects were generally younger than their non-EB counterparts, the age at which they sustained a HF was similar: 80.45 ± 11.7 years for EB vs. 79.44 ± 10.32 years, P = 0.19. EB men were more likely to sustain a HF, as they represented 41.8% of all HF in their respective group, in comparison with 33.6% for others (P = 0.02). Annual IR of HF were lower for EB subjects throughout the study. Despite an initial rise in the SIR, these were also lower for most of the period. CONCLUSIONS: In Israel, EB subjects ≥ 50 years still enjoy protection from HF. Our data require confirmation from other Western countries where the Ethiopian diaspora is aging. If a secular upward trend is observed, contributing risk factors should be identified to enable preventative measures.

Quantitative MR Analysis of Changes in the Radius Bone Marrow in Osteoporosis.

Purpose: This pilot study aimed to explore the feasibility of scanning the human distal radius bone marrow in vivo to detect osteoporosis-related changes using magnetic resonance and evaluate whether the radius may serve as an accessible probing site for osteoporosis. This may lead in the future to the use of affordable means such as low-field MRI scanners for the monitoring of disease progression. Methods: A clinical trial was performed using a 3T MR scanner, including 26 women assigned into three study groups: healthy-premenopausal (n = 7; mean age 48.6 ± 3.5 years), healthy-postmenopausal (n = 10; mean age 54.5 ± 5.6 years), and osteoporotic-postmenopausal (n = 9; mean age 61.3 ± 5.6 years). Marrow fat composition was evaluated using T2 maps, a two-compartment model of T1, and a Dixon pulse sequence. Results: The osteoporotic group exhibited higher fat content than the other two groups and lower T2 values than the healthy-premenopausal group. Conclusions: Osteoporosis-related changes in the composition of the distal radius bone marrow may be detected in vivo using MRI protocols. The scanning protocols chosen here can later be repeated using low-field MRI scanners, thus offering the potential for early detection and treatment monitoring, using an accessible, affordable means that may be applied in small clinics. This trial is registered with MOH_2018-05-23_002247, NCT03742362.

Validation of a multi-frequency bioelectrical impedance analysis device for the assessment of body composition in older adults with type 2 diabetes.

BACKGROUND: Aging and type 2 diabetes (T2DM) are associated with an increased risk of sarcopenia. Diagnosis of sarcopenia is commonly done using dual-energy X-ray absorptiometry (DXA) in specialized settings. Another available method for assessing body composition is direct segmental multi-frequency bioelectrical impedance analysis (DSMF-BIA). Here, we examine the accuracy of a DSMF-BIA (InBody-770) for assessing body composition in older adults with T2DM when compared to DXA. METHODS: Eighty-four obese/overweight older adults (49 women, 71 ± 5 years) with T2DM who were recruited for the CEV-65 study and had both DSMF-BIA and DXA assessments at baseline were included. The analysis included Bland-Altman plots and intra class correlation coefficients. Sub-analyses were performed according to gender and following 10 weeks of interventions (diet, circuit training, and Empagliflozin). RESULTS: The leg lean mass results according to DSMF-BIA and DXA were 14.76 ± 3.62 kg and 15.19 ± 3.52 kg, respectively, with no difference between devices according to Bland-Altman analyses (p = 0.353). Assessment of appendicular skeletal mass index did not differ between DSMF-BIA and DXA (7.43 vs. 7.47 kg/m2; p = 0.84; ICC = 0.965, p < 0.0001; mean difference -0.068, p = 0.595). Gender and treatment interventions did not modify the accuracy of the DSMF-BIA when compared to DXA. CONCLUSIONS: In older adults with T2DM the degree of agreement between DSMF-BIA and DXA, was high, supporting the use of DSMF-BIA to measure muscle mass.

Development and efficacy of a computerized decision support system for osteoporosis management in the community.

Computerized alerts for primary care physicians, provided during visits of patients who met treatment guidelines based on their electronic medical records, are an efficient method to raise awareness to many otherwise missed cases, especially after fracture. PURPOSE: Measure the efficacy of an automated real-time alert which was developed to assist osteoporosis management in the community. METHODS: The study population included treatment naïve patients with T-score ≤ - 2.5 or hip or vertebral fracture in a 2 million member Israeli health fund. On each ambulatory visit to a primary care physician or endocrinologist, a pop-up screen reminded the caregiver to consider treatment initiation. A follow-up "smart-set" screen conveniently gathered links to common actions (namely, (a) issue first line therapy prescription, (b) referral to nutritionist consultation, (c) laboratory tests relevant for osteoporosis, and (d) printing an information page for the patient). Time till treatment initiation was compared between the 3 years prior to and following the intervention. RESULTS: Within 2 years since alert activation, a total of n = 21,070 cases were alerted, 52% of which were long standing cases: untreated for over 6 months since the event. During this period, a total of 30% initiated treatment purchases. As compared with the 3 years prior to the intervention, time till treatment initiation decreased following the intervention with HR = 1.05, 1.94, 1.29 (p values = 0.020, < 0.001, 0.005) for T-score, hip, and vertebral cases respectively. Initiation rates within 6 months increased from 52.0 to 59.8%, from 12.3 to 27.7%, and from 17.4 to 27.1% among T-score, hip, and vertebral cases, respectively (p value < 0.001). Male sex, nursing home residence, having diabetes or a cardiovascular disease and age younger than 60 or older than 80 were associated with lower treatment rates. CONCLUSIONS: A computerized decision support system can efficiently raise attention to many otherwise missed high-risk osteoporotic cases, particularly those after fractures.

Association between abdominal obesity and fragility fractures among elderly Israeli women.

BACKGROUND: Obesity has been traditionally viewed as a protective factor for fractures. Recent studies have challenged this concept, particularly regarding abdominal obesity. We aimed to investigate the association between abdominal obesity, body mass index (BMI) and fragility fractures prevalence in a sample of community-dwelling elderly Israeli women. METHODS: The data in this cross-sectional study were based on 'Mabat Zahav'-a survey of a nationally representative sample of elderly Israelis. The study population included 669 women. Data on fragility fractures site and circumstances were self-reported, and height, weight, waist and calf circumferences were measured. Waist circumference (WC) variable was divided into tertiles: < 88 cm, 88-99 cm and > 99 cm. RESULTS: Sixty-five women reported fragility fractures (14 hip fractures, 18 vertebral fractures and 39 wrist fractures). Mean age was 73.9 ± 5.9 years, mean BMI was 29.9 ± 5 kg/m2 and mean WC was 93.9 ± 12 cm. While BMI was not associated with osteoporotic fractures, abdominal obesity (WC > 88 cm) was positively associated with fragility fractures, independently of age, smoking, physical activity [middle and high WC tertiles {3.15 (95% CI 1.41-7.02), 2.78 (95% CI 1.05-7.31), respectively}]. CONCLUSIONS: Among this sample of elderly women, abdominal obesity was positively associated with fragility fractures, independently of age, smoking, physical activity and BMI. Waist circumference, an easily measured anthropometric indicator, may be useful for assessing the risk of fragility fractures in elderly women, particularly among those with normal or high BMI-a vast population which has been traditionally considered as having lower fracture risk.

Fracture incidence after denosumab discontinuation: Real-world data from a large healthcare provider.

BACKGROUND: Vertebral fractures (VF) upon Denosumab (DMAB) discontinuation were first described as a distinct phenomenon in 2015, yet the magnitude of this event remains undetermined. OBJECTIVES: To estimate fracture risk after DMAB discontinuation, in a real-world setting. METHODS: The computerized database of a 2.3-million members' state-mandated health organization was utilized to detect osteoporotic patients with at least two DMAB dispenses. Treatment discontinuation was defined as a refill gap of 3 months or more, while the discontinuation date was defined as an anticipated missed purchase date. Fractures were identified by an osteoporosis registry and individually adjudicated by an expert's review. Fractures occurring within one year from discontinuation among DMAB discontinuers (DD) and from the 2nd year of treatment onwards for persistent users (PU) were included. RESULTS: A total of 1500 DD (92% females, mean ±â€¯SD age = 71.8 ±â€¯9.5y), and 1610 PU (91%, 71.7 ±â€¯8.8) were identified. At baseline, the groups were comparable in fracture- history, bisphosphonate exposure, smoking, and bone density. Multiple VF occurred in 12 (0.8%) DD vs. 2 (0.1%) PU (p = 0.006). The overall rate of fractures per 100 patient-years of follow-up was significantly higher in DD than PU (RR 3.2, 95% CI 2.2-4.8), as well as the rate of VF (RR 4.7, 95% CI 2.3-9.6) and multiple VF (RR 14.6, 95% CI 3.3-65.3, effect size 1.06). CONCLUSIONS: Patients who discontinue DMAB are at greater risk of major OP fractures than those who persist with treatment. Same is true for clinical multiple vertebral fractures, yet the incidence of the latter was low. These findings demonstrate a need for greater awareness and thoughtful management of DMAB discontinuation.

The association between adherence with oral bisphosphonates and the risk of breast cancer in post-menopausal women.

BACKGROUND: Several observational studies have suggested a protective effect of oral bisphosphonates (BP) on the risk of breast cancer, but no such association has been seen in randomized control trials. The role of oral BP in breast cancer prevention remains unclear. AIM: To investigate the association between different levels of BP exposure and breast cancer incidence in a cohort of osteoporotic post-menopausal women. SUBJECTS AND METHODS: This historical prospective study was conducted using the computerized databases of Maccabi Healthcare Services (MHS) in Israel. Included in the study were osteopenic and osteoporotic women aged 55-75 years who started BP therapy between 1998 and 2012. The subjects were enrolled in MHS for at least 3 years before therapy initiation, and had a minimum follow-up of 5 years in MHS. Women with a previous cancer, and women treated with selective estrogen receptor modulators (SERMs) were excluded. BP exposure was expressed in quintiles of proportion of days covered (PDC) with BP during follow-up period and cancer incidence was ascertained by the Israel National Tumor Registry. Person-years of follow-up began on January 1st, 1998 and ended at the date of cancer diagnosis, death, or December 31st, 2012, whichever occurred first. RESULTS: A total of 11,717 patients (mean age = 66.87 ±â€¯4.38) were eligible for the analysis. During a total of 130,252 person-years of follow-up, (mean 7.2 years) 173 incident cases of breast cancer were diagnosed. Compared to women with a PDC with BP of 20% or lower, the adjusted hazard ratio for breast cancer were HR = 0.81 (95%CI: 0.48-1.39), HR = 0.82 (95%CI: 0.50-1.33), HR = 0.72 (95%CI:0.45-1.15) and HR = 1.14 (95%CI:0.76-1.70) among women with 20-40%, 40-60%, 60%-80%, and 80% or higher, PDC, respectively. CONCLUSION: In this study, we did not find a significant association between oral BP therapy for osteoporosis and the risk of breast cancer in postmenopausal women. The discrepancy between our results and the reports of such an association in observational studies might originate from an indication bias.

Exposure to alendronate is associated with a lower risk of bone metastases in osteoporotic women with early breast cancer.

BACKGROUND: Bisphosphonate (BP) treatment to prevent bone loss in breast cancer patients is already well established. However, data on the association between oral BP exposure before cancer diagnosis and disease outcomes in patients with early breast cancer are still scarce. Limited information is available on alendronate, the most common oral agent for the treatment of post-menopausal osteoporosis, regarding the association with bone metastases. AIM: To examine the association between oral bisphosphonate exposure before cancer diagnosis and the risk of bone metastases in osteoporotic women diagnosed with early breast cancer. SUBJECTS AND METHODS: This historical cohort study was conducted at the oncology division at Tel Aviv Medical Center. The study population included post-menopausal women with early breast cancer, diagnosed between 2002 and 2012. Data on cancer characteristics, diagnosis of osteoporosis, prior bisphosphonate exposure and outcome were collected from medical files. RESULTS: Among 297 osteoporotic women identified, 145 (49%) were treated with bisphosphonates (alendronate in 90% of the cases) before cancer diagnosis. BP-treated women were significantly older than the BP-naïve ones (67.9 years vs 64.6 years, p = 0.01), but comparable in risk factors and disease characteristics. Over a mean follow up of 5.6 years, nine cases of bone metastases were identified, eight of them among BP-naïve patient (cumulative incidence of 9.9%) and one among BP-treated patients (0.7%). In a multivariable Cox's proportional hazards survival model the use of BP prior to cancer diagnosis was associated with a hazard ratio of 0.04 (95%CI:0.004-0.403, p = 0.006) for bone metastasis. The HR remained similar after further adjustment for tumor stage and cancer therapy. CONCLUSIONS: History of alendronate use is associated with a lower likelihood of bone metastases in postmenopausal women with early breast cancer. Oral bisphosphonate treatment could be sufficient for reducing the risk of bone metastases.

Vertebral Fractures Following Denosumab Discontinuation in Patients with Prolonged Exposure to Bisphosphonates.

Denosumab (DMAB) efficacy for treatment of osteoporosis was demonstrated in a pivotal trial with a reduction in vertebral and hip fractures during 3 years, and fracture risk reduction was sustained up to 10 years in an extension study. DMAB causes potent yet reversible inhibition of bone resorption. Bone density declines rapidly upon discontinuation and bone turnover markers increase above baseline in a rebound fashion. Spontaneous multiple vertebral fractures after DMAB discontinuation were recently reported. Prior treatment with bisphosphonates (BP) was postulated to decrease the risk for this alarming phenomenon. We aimed to describe our experience of fractures following DMAB withdrawal with special attention to past history of osteoporosis treatment. A phone survey of physicians engaged in bone metabolism from nine hospitals in Israel was performed. Clinical data of the patients presenting with vertebral fractures upon DMAB discontinuation were summarized and compared to the previously published cases. Nine elderly (74.2 ± 5.3 years) female patients were identified. Most patients had a prolonged prior exposure to BP (7.4 ± 3.2 years). All but one sustained osteoporotic fractures prior to DMAB initiation and their FRAX scores were high. Thirty-six vertebral fractures were identified in nine patients. Eight patients presented with multiple fractures, and most fractures were spontaneous. In line with the previous reports, the timing and severity of the fractures raise concern of DMAB discontinuation effect. Prolonged BP exposure in most of our patients challenges the protective effect hypothesis. Care providers, patients, and regulatory authorities should be aware of the possible risk of DMAB treatment interruption.

Adherence With Bisphosphonates and Long-Term Risk of Hip Fractures: A Nested Case-Control Study Using Real-World Data.

BACKGROUND: Hip fracture is a major complication of osteoporosis. Bisphosphonate medication is the mainstay of treatment for osteoporosis. However, concerns have been raised regarding the effectiveness of bisphosphonates in reducing hip fracture risk after long-term use, particularly among patients with suboptimal adherence. OBJECTIVE: To examine the association between adherence with bisphosphonate therapy and long-term risk of hip fracture. METHODS: Included in the present nested case-control study were osteoporotic women (n = 14 357) who initiated bisphosphonate therapy in 2000-2010 and were retrospectively followed for incident hip fracture through November 2014. Within this cohort, each case of primary hip fractures was individually matched to 3 controls without a primary hip fracture. Proportion of follow-up days covered (PDC) with bisphosphonates was calculated from bisphosphonate purchases. Adherence was categorized into the following groups: purchase of 1 or 2 months' supply (reference group), at least 3 months' supply to PDC ≤20%, PDC >20% to ≤80%, PDC >80% to ≤100%. RESULTS: Included in the analysis were 426 case-control groups with a mean age (SD) of 73.7 years (7.9). Compared with the reference group, PDC of 80% to 100% with bisphosphonates was associated with a significant reduction in hip fracture risk for patients with 8 to 15 years of follow-up (OR = 0.39; 95% CI = 0.18-0.87). Among patients with a follow-up of up to 3 years, OR was 0.58 (95% CI = 0.31-1.06). CONCLUSIONS: Adherence with bisphosphonates among osteoporotic patients is associated with lower risk of hip fracture, with no indication of diminished effectiveness with long-term use.

Role of Side Effects, Physician Involvement, and Patient Perception in Non-Adherence with Oral Bisphosphonates.

INTRODUCTION: The benefits of osteoporosis therapy are compromised by low adherence, thus requiring a better understanding of its barriers and unmet needs. The objective of this study was to assess reasons for non-adherence with oral bisphosphonates among osteoporotic women. METHODS: A cross-sectional patient survey of women who initiated therapy with risedronate or alendronate between the years 2010 and 2012 were non-adherent [Medication Possession Ratio (MPR) <70%] or switched therapy within the first year. Survey participants were identified using Maccabi Health Services computerized database. Patients who gave informed consent completed a 20-min telephonic survey, assessing reasons for discontinuation or switching, including physician involvement, side effects, administration regimen, perceptions of bone health, and medications' efficacy. RESULTS: The study population included 493 females (mean age = 66 ± 7) of whom 40% discontinued all anti-osteoporotic therapy (mean MPR = 19%), 9% remained on initial therapy (mean MPR = 47%), and 51% switched therapy (mean MPR = 62%). Family history, fracture history, socioeconomic status, and index drug class and frequency were similar in all groups. The most common reasons for switching or discontinuation of the first-line therapy were gastrointestinal side effects, such as heartburn, acid reflux or other (40.0%), and physician recommendation (26.7%). The major reasons for complete discontinuation of therapy were side effects (26.9%) and physician recommendation (20.0%). Perceived low importance was more commonly mentioned than high cost of medication (14% vs. 3%). CONCLUSION: Our findings highlight the importance of low tolerability to non-adherence with osteoporosis therapy and underlines poor patients' awareness and sub-optimal physicians' involvement in conveying the importance of this therapy. FUNDING: Merck & Co Inc.

Cost and Consequences of Nonadherence With Oral Bisphosphonate Therapy: Findings From a Real-World Data Analysis.

BACKGROUND: Adherence to osteoporosis treatment remains poor despite available treatments and physician and patient education. This study aims to determine the effect of low adherence in real-world data. OBJECTIVE: To examine the association between adherence with oral bisphosphonate therapy and fracture risk as well as health care resource utilization. METHODS: Women included in this retrospective analysis were 55 years or older and had started oral bisphosphonate therapy between 2005 and 2011 in a large not-for-profit health care center in Israel. Adherence to therapy was measured by the medication possession ratio (MPR) during the first year from therapy initiation. Patients with MPR lower than 70% were considered nonadherent. Study outcomes were osteoporotic fracture events and health care utilization (including physician visits and hospitalizations) during the second year from therapy initiation. RESULTS: Among the 17 770 women included in the analysis (mean age = 66.5 years; SD = ±8.3 years), 48.9% were nonadherent to therapy during the first year of treatment. Osteoporotic fracture risks during the second year among adherent and nonadherent patients were 2.1% and 2.5%, respectively (P = 0.1). When analysis was limited to patients 75 years or older, nonadherence with bisphosphonates was associated with an adjusted odds ratio of 1.49 (95% CI = 1.08-2.04) for osteoporotic fractures compared with adherent patients. Nonadherent patients had 13.4% higher medical costs than their adherent counterparts among patients 75 years and older (P = 0.002). CONCLUSIONS: In patients 75 years and older, nonadherence with oral bisphosphonates can be associated with significantly greater short-term risk of osteoporotic fractures and higher utilization of health care services.

Cortisol response and desire to binge following psychological stress: comparison between obese subjects with and without binge eating disorder.

While stress and negative affect are known to precede "emotional eating", this relationship is not fully understood. The objective of this study was to explore the relationship between induced psychological stress, hypothalamic-pituitary-adrenal (HPA) axis activity, and eating behavior in binge eating disorder (BED). The Trier Social Stress Test (TSST) was applied in obese participants with (n=8) and without BED (n=8), and normal weight controls (n=8). Psychological characteristics, eating-related symptoms, and cortisol secretion were assessed. Baseline stress, anxiety and cortisol measures were similar in all groups. At baseline desire to binge was significantly higher among the BED group. While the TSST induced an increase in cortisol levels, a blunted cortisol response was observed in the BED group. In the BED group, a positive correlation was found between cortisol (area under the curve) levels during the TSST and the change in VAS scores for desire to binge. Post-TSST desire to binge and sweet craving were significantly higher in the BED group and correlated positively with stress, anxiety, and cortisol response in the BED group only. These results suggest chronic down-regulation of the HPA axis in participants with BED, and a relationship between psychological stress, the acute activation of the HPA axis, and food craving.

Testosterone is a strong correlate of ghrelin levels in men and postmenopausal women.

BACKGROUND/AIMS: The secretion and regulation of several hormones such as leptin and growth hormone (GH) is sexually dimorphic. Gender effects on ghrelin, a hormone involved in the regulation of GH secretion and appetite control, are controversial. Our aim was to study the relationship between plasma ghrelin and serum sex steroid hormone concentrations. METHODS: Forty-five subjects (19 men, 12 premenopausal and 14 postmenopausal women) were evaluated at the Institute of Endocrinology and Metabolism, Tel Aviv Sourasky Medical Center, Israel. After an overnight fast, blood samples were collected for measurements of ghrelin, testosterone, bioavailable testosterone (BT) and estradiol. Statistical analysis was performed with adjustments for age and body mass index. Results are given as mean +/- standard deviation. RESULTS: Ghrelin levels were significantly higher in women (510 +/- 489 pg/ml) than in men (319 +/- 237 pg/ml; p = 0.02). There was a positive correlation between ghrelin and both total testosterone (r = 0.5, p = 0.039) and BT (r = 0.719, p = 0.0011) in male subjects. In premenopausal women, no significant correlations were found between ghrelin and testosterone or BT (r = -0.39, p = 0.2). In contrast, ghrelin strongly and positively correlated with total testosterone (r = 0.7, p = 0.01) and BT (r = 0.821, p = 0.001) in postmenopausal women. Estradiol and ghrelin were positively correlated in the group as a whole (r = 0.356, p = 0.019), but not significantly when analyzed separately by gender. CONCLUSIONS: Circulating ghrelin in humans is sexually dimorphic. Testosterone correlates positively with ghrelin levels in men and postmenopausal women.

Serum cortisol levels in patients admitted to the department of medicine: Prognostic correlations and effects of age, infection, and comorbidity.

BACKGROUND: In contrast to healthy adults or critically ill patients, data on serum cortisol levels in noncritically ill patients admitted to general internal medicine wards has not been well characterized. We aimed to describe the distribution and range of serum cortisol levels in patients admitted to the department of medicine, to discover whether old age, severe infections, or comorbidity induced a blunted hypothalamic-pituitary-adrenal (HPA) response and whether initial serum cortisol value had a prognostic significance. METHODS: Morning (8 am) serum cortisol level together with epidemiologic, clinical, and laboratory data were analyzed for 252 consecutive adult (age > or = 18 yrs) patients admitted to the department of internal medicine during a 6-weeks period. RESULTS: The mean serum cortisol level (541 +/- 268 nmol/L) was within the normal range. Only one patient had a low serum cortisol level of 72 nmol/L, whereas the majority of patients had either normal (80%) or increased (19%) serum cortisol levels. Older age, sepsis, prolonged duration of fever, higher comorbidity score, and higher serum creatinine level were each associated with significantly higher serum cortisol level. In addition, a higher serum cortisol level was significantly related to longer hospitalization and higher in-hospital mortality rate. CONCLUSIONS: Serum cortisol level positively correlated with age, disease severity, and outcome. All admitted patients, except one, had normal to high serum cortisol. Whether this increased cortisol level is an adequate HPA response or less than required for the disease-induced stress should be investigated in further studies.