A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Real-world evidence: new opportunities for osteoporosis research. Recommendations from a Working Group from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

This narrative review summarises the recommendations of a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) for the conduct and reporting of real-world evidence studies with a focus on osteoporosis research. PURPOSE: Vast amounts of data are routinely generated at every healthcare contact and activity, and there is increasing recognition that these real-world data can be analysed to generate scientific evidence. Real-world evidence (RWE) is increasingly used to delineate the natural history of disease, assess real-life drug effectiveness, understand adverse events and in health economic analysis. The aim of this work was to understand the benefits and limitations of this type of data and outline approaches to ensure that transparent and high-quality evidence is generated. METHODS: A ESCEO Working Group was convened in December 2022 to discuss the applicability of RWE to osteoporosis research and approaches to best practice. RESULTS: This narrative review summarises the agreed recommendations for the conduct and reporting of RWE studies with a focus on osteoporosis research. CONCLUSIONS: It is imperative that research using real-world data is conducted to the highest standards with close attention to limitations and biases of these data, and with transparency at all stages of study design, data acquisition and curation, analysis and reporting to increase the trustworthiness of RWE study findings.

Mean Bone Material Strength Index Values for Women are Lower Than Those for Men: Data from a Single Geographical Location.

Bone material strength index (BMSi) values are obtained using impact microindentation, which assesses the ability of bone to resist indentation. Differences in BMSi between men and women are unclear, and to date, BMSi sex differences have not been compared for individuals from the same population. Therefore, we compared BMSi values for men and women drawn from the same geographical location in Australia. Participants (n = 220) were from the Geelong Osteoporosis Study. BMSi was measured, following international published guidelines, using an OsteoProbe for participants at recent follow-up phases (women 2022-2023 and men 2016-2022). Women (n = 55) were age matched to men (n = 165) in a 1:3 ratio. A two-sample t test was used to determine the intergroup difference in mean BMSi. Linear regression was also performed, adjusting for weight and height. Median (IQR) ages for men and women were 67.0 (61.7-71.5) and 67.4 (62.0-71.2) years (p = 0.998). Men were heavier (81.0 ± 10.9 vs 71.0 ± 13.9 kg, p < 0.001) and taller (173.9 ± 6.4 vs 161.5 ± 7.5 cm, p < 0.001) than women. Mean (± SD) BMSi for women (75.7 ± 7.4) was lower than for men (82.8 ± 6.8) (p < 0.001). The difference persisted after adjustment for weight and height (mean ± SE: 76.5 ± 1.1 vs 82.5 ± 0.6, p < 0.001). Given the higher fracture risk observed for women, the higher mean BMSi values in men are consistent with cross sectional data suggesting this measure may be useful in fracture prediction.

Reference Intervals for Bone Impact Microindentation in Healthy Adults: A Multi-Centre International Study.

Impact microindentation (IMI) is a novel technique for assessing bone material strength index (BMSi) in vivo, by measuring the depth of a micron-sized, spherical tip into cortical bone that is then indexed to the depth of the tip into a reference material. The aim of this study was to define the reference intervals for men and women by evaluating healthy adults from the United States of America, Europe and Australia. Participants included community-based volunteers and participants drawn from clinical and population-based studies. BMSi was measured on the tibial diaphysis using an OsteoProbe in 479 healthy adults (197 male and 282 female, ages 25 to 98 years) across seven research centres, between 2011 and 2018. Associations between BMSi, age, sex and areal bone mineral density (BMD) were examined following an a posteriori method. Unitless BMSi values ranged from 48 to 101. The mean (± standard deviation) BMSi for men was 84.4 ± 6.9 and for women, 79.0 ± 9.1. Healthy reference intervals for BMSi were identified as 71.0 to 97.9 for men and 59.8 to 95.2 for women. This study provides healthy reference data that can be used to calculate T- and Z-scores for BMSi and assist in determining the utility of BMSi in fracture prediction. These data will be useful for positioning individuals within the population and for identifying those with BMSi at the extremes of the population.

Associations Between Aldosterone-Renin-Ratio and Bone Parameters Derived from Peripheral Quantitative Computed Tomography and Impact Microindentation in Men.

Components of the renin-angiotensin-aldosterone system (RAAS) are present on bone cells. One measure of RAAS activity, the aldosterone-renin-ratio (ARR), is used to screen for primary aldosteronism. Associations between ARR and bone mineral density are conflicting. This study investigated associations between ARR and peripheral quantitative computed tomography (pQCT) and impact microindentation (IMI). Male participants (n = 431) were from the Geelong Osteoporosis Study. "Likely" primary aldosteronism was defined as ARR ≥ 70 pmol/mIU. Another group, "possible" primary aldosteronism, was defined as either ARR ≥ 70 pmol/mIU or taking a medication that affects the RAAS, but not a beta blocker, and renin < 15 mU/L. Using pQCT, images at 4% and 66% of radial (n = 365) and tibial (n = 356) length were obtained. Using IMI measurements, bone material strength index (BMSi; n = 332) was determined. Associations between ARR or likely/possible primary aldosteronism and IMI or pQCT-derived bone parameters were tested using median regression. ARR and aldosterone values were not associated with any of the pQCT-derived bone variables in either unadjusted or adjusted analyses. Men with likely primary aldosteronism (n = 16), had lower adjusted total bone area (radial 66% site, - 12.5%). No associations were observed for men with possible primary aldosteronism (unadjusted or adjusted). No associations with BMSi were observed (p > 0.05). There were no associations between ARR or aldosterone and pQCT-derived bone parameters. Men with likely primary aldosteronism had lower bone area, suggesting clinically high levels of ARR may have a negative impact on bone health.

Risk factors for a second nonsimultaneous hip fracture in a prospective cohort study.

INTRODUCTION: The risk factors for a second nonsimultaneous hip fracture are unclear, and in general, it is empirically assumed that they are similar to those associated with the first hip fracture. We aimed to determine the incidence of a second hip fracture and define the characteristics of the patients sustaining the event in a prospective cohort study in a Spanish population. MATERIALS AND METHODS: We conducted a multicentric, prospective cohort study in a representative sample of 45 hospitals from 15 autonomic regions in Spain. In total, the study included 994 patients. One hundred and one patients presented a nonsimultaneous contralateral hip fracture, constituting the intervention group. The remaining 893 patients presenting with a hip fracture formed the control group. The main outcome measures of this study were sociodemographic characteristics of the patient, comorbid conditions, and baseline and postfracture clinical outcomes (inpatient complications and acute mortality). RESULTS: The key fracture risk factors were a history of fragility fractures, the need for assistance when walking outdoors and a history of falls. There were no associations between the groups in any of the common fragility risk factors, including rheumatoid arthritis, secondary osteoporosis, or steroid consumption. The results showed that patients suffering a nonsimultaneous hip fracture had an increased risk of mortality after discharge compared with the control group. CONCLUSION: A nonsimultaneous second hip fracture leads to a near-significant increase in four-month mortality. In our study, this fracture was associated with a history of falls, prior fragility fractures, and the need for a walking aid.

Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes.

Importance: Although tramadol is increasingly used to manage chronic noncancer pain, few safety studies have compared it with other opioids. Objective: To assess the associations of tramadol, compared with codeine, with mortality and other adverse clinical outcomes as used in outpatient settings. Design, Setting, and Participants: Retrospective, population-based, propensity score-matched cohort study using a primary care database with routinely collected medical records and pharmacy dispensations covering more than 80% of the population of Catalonia, Spain (≈6 million people). Patients 18 years or older with 1 or more year of available data and dispensation of tramadol or codeine (2007-2017) were included and followed up to December 31, 2017. Exposures: New prescription dispensation of tramadol or codeine (no dispensation in the previous year). Main Outcomes and Measures: Outcomes studied were all-cause mortality, cardiovascular events, fractures, constipation, delirium, falls, opioid abuse/dependence, and sleep disorders within 1 year after the first dispensation. Absolute rate differences (ARDs) and hazard ratios (HRs) with 95% confidence intervals were calculated using cause-specific Cox models. Results: Of the 1 093 064 patients with a tramadol or codeine dispensation during the study period (326 921 for tramadol, 762 492 for codeine, 3651 for both drugs concomitantly), a total of 368 960 patients (184 480 propensity score-matched pairs) were included after study exclusions and propensity score matching (mean age, 53.1 [SD, 16.1] years; 57.3% women). Compared with codeine, tramadol dispensation was significantly associated with a higher risk of all-cause mortality (incidence, 13.00 vs 5.61 per 1000 person-years; HR, 2.31 [95% CI, 2.08-2.56]; ARD, 7.37 [95% CI, 6.09-8.78] per 1000 person-years), cardiovascular events (incidence, 10.03 vs 8.67 per 1000 person-years; HR, 1.15 [95% CI, 1.05-1.27]; ARD, 1.36 [95% CI, 0.45-2.36] per 1000 person-years), and fractures (incidence, 12.26 vs 8.13 per 1000 person-years; HR, 1.50 [95% CI, 1.37-1.65]; ARD, 4.10 [95% CI, 3.02-5.29] per 1000 person-years). No significant difference was observed for the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders. Conclusions and Relevance: In this population-based cohort study, a new prescription dispensation of tramadol, compared with codeine, was significantly associated with a higher risk of subsequent all-cause mortality, cardiovascular events, and fractures, but there was no significant difference in the risk of constipation, delirium, falls, opioid abuse/dependence, or sleep disorders. The findings should be interpreted cautiously, given the potential for residual confounding.

Functional Analyses of Four CYP1A1 Missense Mutations Present in Patients with Atypical Femoral Fractures.

Osteoporosis is the most common metabolic bone disorder and nitrogen-containing bisphosphonates (BP) are a first line treatment for it. Yet, atypical femoral fractures (AFF), a rare adverse effect, may appear after prolonged BP administration. Given the low incidence of AFF, an underlying genetic cause that increases the susceptibility to these fractures is suspected. Previous studies uncovered rare CYP1A1 mutations in osteoporosis patients who suffered AFF after long-term BP treatment. CYP1A1 is involved in drug metabolism and steroid catabolism, making it an interesting candidate. However, a functional validation for the AFF-associated CYP1A1 mutations was lacking. Here we tested the enzymatic activity of four such CYP1A1 variants, by transfecting them into Saos-2 cells. We also tested the effect of commonly used BPs on the enzymatic activity of the CYP1A1 forms. We demonstrated that the p.Arg98Trp and p.Arg136His CYP1A1 variants have a significant negative effect on enzymatic activity. Moreover, all the BP treatments decreased CYP1A1 activity, although no specific interaction with CYP1A1 variants was found. Our results provide functional support to the hypothesis that an additive effect between CYP1A1 heterozygous mutations p.Arg98Trp and p.Arg136His, other rare mutations and long-term BP exposure might generate susceptibility to AFF.

Bone density, microarchitecture and tissue quality after 1 year of treatment with dolutegravir/abacavir/lamivudine.

BACKGROUND: Bone mineral density (BMD) decreases with ART initiation with a tenofovir disoproxil fumarate-containing regimen, although bone tissue quality increases. The impact of dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC)-based ART initiation on bone health parameters is not clear. OBJECTIVES: To study the impact of DTG/ABC/3TC-based therapy on bone health parameters in ART-naive individuals with HIV after 48 weeks of treatment. METHODS: An observational, prospective and analytical study of treatment-naive patients with HIV undergoing a DTG/ABC/3TC-based regimen at 48 week follow-up. Changes in bone strength parameters (BMD, bone microarchitecture and bone tissue quality) were assessed with non-parametric methods. RESULTS: Sixteen HIV-infected ART-naive patients starting DTG/ABC/3TC were included. BMD in the lumbar spine showed a significant decrease of -2.25% (P = 0.007) and -4.1% in the femoral neck (P = 0.007). Bone microarchitecture, as measured by trabecular bone score, also decreased significantly by -2.5% (P = 0.03). In contrast, bone quality [bone material strength index (BMi)], as measured by microindentation, significantly increased with respect to baseline after 48 weeks of treatment, showing better bone properties of +6.53% (P < 0.001). No significant changes were found in bone turnover markers. In addition, a positive significant correlation between the CD4/CD8 cell count ratio at baseline and changes in BMSi after 48 weeks of treatment was observed (Spearman's rho = 0.4974; P = 0.04). CONCLUSIONS: After a 48 week treatment with DTG/ABC/3TC-based ART, BMD and trabecular bone score decreased while bone tissue quality, as measured by microindentation, improved significantly. The state of the immune system at ART initiation is related to bone quality recovery. An overarching approach to assess bone toxicity in ART-treated patients is needed.

Bone tissue quality in patients with monoclonal gammopathy of uncertain significance.

INTRODUCTION: Monoclonal gammopathy of uncertain significance (MGUS) is highly prevalent in older adults and affects bone structure, with osteoporosis and increased risk of fractures in up to 14% of affected patients. Dual-energy X-ray absorptiometry (DXA), the standard technique for diagnosing osteoporosis, is ineffective to reveal microstructure and bone quality in this disease. MATERIALS AND METHODS: We conducted a cross-sectional study of patients with MGUS, recruited consecutively from the Hematology and Internal Medicine Departments of Hospital del Mar, Barcelona, between January 2011 and January 2018. Medical records, clinical results and spinal X-ray images were collected. Bone mineral density (BMD) at hip and spine was measured by DXA and Bone Material Strength index (BMSi) by impact microindentation on the tibial mid-shaft. RESULTS: Thirty-nine patients with MGUS and 65 age-matched controls without previous fractures were included. In the MGUS group, 11 (28.2%) patients had prevalent fractures, nearly half of them vertebral (n = 5, 45.45%). Compared to controls, MGUS patients had significantly lower BMSi, a mean (SD) of 70.72 (9.70) vs. 78.29 (8.70), p = 0.001, and lower spinal BMD values (0.900 [0.159] vs. 1.003 [0.168], respectively, p = 0.012), but no significant differences at femoral neck and total hip. No association was observed between BMSi and DXA. Bone remodeling markers (procollagen type-1 N propeptide, bone-alkaline phosphatase and C-terminal telopeptide of type I collagen) did not differ between the two groups. CONCLUSIONS: Spinal BMD and mechanical properties of bone tissue, as measured by impact microindentation, were impaired in patients with MGUS. These changes in bone tissue mechanical resistance were independent of DXA levels.

Assessment of early therapy discontinuation and health-related quality of life in breast cancer patients treated with aromatase inhibitors: B-ABLE cohort study.

PURPOSE: The most frequent adverse effects of aromatase inhibitors (AI) are arthralgia and bone loss induction. These reduce the quality of life of patients and their adherence to the treatment. This study evaluates the early AI cessation caused by AI intolerance, and the evolution of joint pain and health-related quality of life (HRQoL) during AI treatment until 1-year after AI completion. METHODS: Data of 910 women diagnosed with early breast cancer and candidates for AI were recruited in B-ABLE cohort. AI discontinuation was analyzed by survival analysis, including Kaplan-Meier estimation and Cox regression. Patients were distributed in three groups of the study according to previous tamoxifen (TAM) exposure and length of AI treatment: TAM-2yAI, TAM-3yAI, and 5yAI. Evolution of joint pain and HRQoL in osteoporosis was evaluated using Visual Analog Scale (VAS) and ECOS-16 tests, respectively, from baseline to 1-year after AI completion through repeated-measures ANOVA. RESULTS: Risk of AI discontinuation was increased in patients previously exposed to tamoxifen compared to non-exposed (adjusted HR 5.30 [95% CI 2.23 to 12.57]). VAS and ECOS-16 scores of TAM-2yAI and TAM-3yAI groups increased during AI treatment, mainly during the first 3-12 months. After 1-year from AI completion, values tend to decrease to baseline levels. In 5yAI group, VAS and ECOS-16 levels increased at three months, and VAS remained significantly higher at 1-year post-treatment. CONCLUSIONS: AI therapy increased joint pain and reduced HRQoL, mainly during the first year of treatment. Patients previously treated with tamoxifen experienced greater pain when they switched to AI therapy and had an excess risk of discontinuation during the first 12 months. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03811509. Registered 28 January 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03811509 .

Proof of Concept on Functionality Improvement of Mesenchymal Stem-Cells, in Postmenopausal Osteoporotic Women Treated with Teriparatide (PTH1-34), After Suffering Atypical Fractures.

Osteoporosis long-term treatment with nitrogen-containing bisphosphonates, has been associated with uncommon adverse effects, as atypical femoral fractures (AFF). Thus, treatment with teriparatide (TPTD; fragment of human parathyroid hormone; PTH1-34) has been proposed for such patients. Besides its anabolizing effect on bone, TPTD may affect stem-cell mobilization and expansion. Bone marrow mononuclear cells (BMMNC) were isolated from five women that had suffered AFF associated to bisphosphonate treatment, before and after 6 months of TPTD therapy. The presence of mesenchymal stromal cells (CD73, CD90 and CD105 positive cells), gene expression of NANOG, SOX2 and OCT4, proliferation, senescence and capacity to differentiate into osteoblasts and adipocytes were analyzed. After TPTD treatment, BMMNC positive cells for CD73, CD90 and CD105 increased from 6.5 to 37.5% (p < 0.05); NANOG, SOX2 and OCT4 were upregulated, being statistically significant for NANOG (p < 0.05), and cells increased proliferative capacity more than 50% at day 7 (p < 0.05). Senescence was reduced 2.5-fold (p < 0.05), increasing differentiation capacity into osteoblasts and adipocytes, with more than twice mineralization capacity of extracellular matrix or fat-droplet formation (p < 0.05), respectively. Results show that TPTD treatment caused BMMNC "rejuvenation", increasing the number of cells in a more undifferentiated stage, with higher differentiation potency. This effect may favor TPTD anabolic action on bone in such patients with AFF, increasing osteoblast precursor cells. Such response could also arise in other osteoporotic patients treated with TPTD, without previous AFF. Furthermore, our data suggest that TPTD effect on stromal cells may have clinical implications for bone-regenerative medicine. Further studies may deepen on this potential.

Radiofrequency echographic multi-spectrometry for the in-vivo assessment of bone strength: state of the art-outcomes of an expert consensus meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

PURPOSE: The purpose of this paper was to review the available approaches for bone strength assessment, osteoporosis diagnosis and fracture risk prediction, and to provide insights into radiofrequency echographic multi spectrometry (REMS), a non-ionizing axial skeleton technique. METHODS: A working group convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis met to review the current image-based methods for bone strength assessment and fracture risk estimation, and to discuss the clinical perspectives of REMS. RESULTS: Areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is the consolidated indicator for osteoporosis diagnosis and fracture risk assessment. A more reliable fracture risk estimation would actually require an improved assessment of bone strength, integrating also bone quality information. Several different approaches have been proposed, including additional DXA-based parameters, quantitative computed tomography, and quantitative ultrasound. Although each of them showed a somewhat improved clinical performance, none satisfied all the requirements for a widespread routine employment, which was typically hindered by unclear clinical usefulness, radiation doses, limited accessibility, or inapplicability to spine and hip, therefore leaving several clinical needs still unmet. REMS is a clinically available technology for osteoporosis diagnosis and fracture risk assessment through the estimation of BMD on the axial skeleton reference sites. Its automatic processing of unfiltered ultrasound signals provides accurate BMD values in view of fracture risk assessment. CONCLUSIONS: New approaches for improved bone strength and fracture risk estimations are needed for a better management of osteoporotic patients. In this context, REMS represents a valuable approach for osteoporosis diagnosis and fracture risk prediction.

Cortical and Trabecular Bone Analysis of Patients With High Bone Mass From the Barcelona Osteoporosis Cohort Using 3-Dimensional Dual-Energy X-ray Absorptiometry: A Case-Control Study.

High bone mass (HBM), a rare phenotype, can be detected by dual-energy X-ray absorptiometry (DXA) scanning. Measurements with peripheral quantitative computed tomography at the tibia have found increased trabecular bone mineral density and changes in cortical bone density and structure, all of which lead to increased bone strength. However, no studies on cortical and trabecular bone have been performed at the femur. The recently developed 3-dimensional (3D)-DXA software algorithm quantifies the trabecular and cortical volumetric bone mineral density (vBMD) and the anatomical distribution of cortical thickness using routine hip DXA scans. We analyzed the femurs of 15 women with HBM and 15 controls from the Barcelona Osteoporosis (BARCOS) cohort using the 3D-DXA technique. The mean vBMD of proximal femur was 29.7% higher in HBM cases than in controls for the integral bone, 41.3% higher for the trabecular bone, and 7.3% higher for the cortical bone (p < 0.001). No differences in bone size were detected between cases and controls. Patients with HBM had a thicker cortex and higher trabecular and cortical vBMDs, as measured by 3D-DXA at the femur and compared to controls; bone size was similar in both groups. To the best of our knowledge, this is the first description of trabecular and cortical characteristics of the hip in patients with HBM.

Romosozumab in postmenopausal women with low bone mineral density.

BACKGROUND: Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. METHODS: In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 µg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. RESULTS: All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. CONCLUSIONS: In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).

Patients' preferences for anti-osteoporosis drug treatment: a cross-European discrete choice experiment.

Objectives: To estimate the preferences of osteoporotic patients for medication attributes, and analyse data from seven European countries. Methods: A discrete choice experiment was conducted in Belgium, France, Ireland, the Netherlands, Spain, Switzerland and the UK. Patients were asked to choose repeatedly between two hypothetical unlabelled drug treatments (and an opt-out option) that varied with respect to four attributes: efficacy in reducing the risk of fracture, type of potential common side effects, and mode and frequency of administration. In those countries in which patients contribute to the cost of their treatment directly, a fifth attribute was added: out-of-pocket cost. A mixed logit panel model was used to estimate patients' preferences. Results: In total, 1124 patients completed the experiment, with a sample of between 98 and 257 patients per country. In all countries, patients preferred treatment with higher effectiveness, and 6-monthly subcutaneous injection was always preferred over weekly oral tablets. In five countries, patients also preferred a monthly oral tablet and yearly i.v. injections over weekly oral tablets. In the three countries where the out-of-pocket cost was included as an attribute, lower costs significantly contributed to the treatment preference. Between countries, there were statistically significant differences for 13 out of 42 attribute/level interactions. Conclusion: We found statistically significant differences in patients' preferences for anti-osteoporosis medications between countries, especially for the mode of administration. Our findings emphasized that international treatment recommendations should allow for local adaptation, and that understanding individual preferences is important if we want to improve the quality of clinical care for patients with osteoporosis.

Parathyroid Hormone-Related Protein Analogs as Osteoporosis Therapies.

The only bone anabolic agent currently available for osteoporosis treatment is parathyroid hormone (PTH)-either its N-terminal 1-34 fragment or the whole molecule of 1-84 aminoacids-whose intermittent administration stimulates new bone formation by targeting osteoblastogenesis and osteoblast survival. PTH-related protein (PTHrP) is an abundant factor in bone which shows N-terminal homology with PTH and thus exhibits high affinity for the same PTH type 1 receptor in osteoblasts. Therefore, it is not surprising that intermittently administered N-terminal PTHrP peptides induce bone anabolism in animals and humans. Furthermore, the C-terminal region of PTHrP also elicits osteogenic features in vitro in osteoblastic cells and in various animal models of osteoporosis. In this review, we discuss the current concepts about the cellular and molecular mechanisms whereby PTHrP may induce anabolic actions in bone. Pre-clinical studies and clinical data using N-terminal PTHrP analogs are also summarized, pointing to PTHrP as a promising alternative to current bone anabolic therapies.

Real-Life and RCT Participants: Alendronate Users Versus FITs' Trial Eligibility Criterion.

We aimed to characterize incident users of alendronate from Denmark and Spain, and investigate their eligibility for participation in the pivotal Fracture Intervention Trial (FIT). This is an international cross-sectional study, where the data were obtained from the SIDIAP database (Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària) from Catalonia (Spain) and the Danish Health Registries (DHR). This study included patients who were incident users of alendronate, ≥40 years old with no history of Paget's disease. Our measurements were the proportion of incident users of alendronate who were not eligible to participate in FIT. 14,316 and 21,221 subjects initiated alendronate in 2006-2007 (SIDIAP) and 2005-2006 (DHR), respectively. SIDIAP and DHR alendronate user cohorts had 2347 (16.4 %) and 5275 (24.9 %) subjects aged >80 years old, reported 9 (0.1 %) and 91 (0.4 %) diagnoses of myocardial infarction, 423 (3 %) and 368 (1.7 %) of erosive gastro-intestinal disease, 200 (1.4 %) and 1109 (5.2 %) of dyspepsia, and 349 (2.4 %) and 149 (0.7 %) of metabolic bone disease, all of which were exclusion criteria in FIT. Men [3818 (26.7 %) in SIDIAP and 3885 (18.3 %) in DHR] and glucocorticoid users [1229 (8.6 %) in SIDIAP and 4716 (22.2 %) in DHR] were also excluded from the FIT trial. Overall, 3447 (35.4 %) SIDIAP and 6228 (44.5 %) (when not considering men and glucocorticoid users) DHR of incident alendronate users would have been excluded from FIT. One in two real-life users of alendronate exhibited one or more clinical characteristics that would have led to them being excluded from the FIT trial.

Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammatory joint disorders: new insights from emerging data. An expert consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

PURPOSE: This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate. METHODS: This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized. RESULTS: The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects. DISCUSSION: Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation. CONCLUSIONS: Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach.