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.

Assessment of Quality of Life in Postmenopausal Women with Early Breast Cancer Participating in the PACT Trial: The Impact of Additional Patient Information Material Packages and Patient Compliance.

BACKGROUND: Breast cancer patients' self-understanding of their disease can impact their quality of life (QoL); the relationship between compliance and QoL is poorly understood. PATIENTS AND METHODS: The Patient's Anastrozole Compliance to Therapy (PACT) program, a prospective, randomized study, investigated the effect of additional patient information material (IM) packages on compliance with adjuvant aromatase inhibitor (AI) therapy in postmenopausal women with hormone receptor-positive early breast cancer. The QoL subanalysis presented here examined the impact of IM packages on QoL and the association between QoL and compliance. European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-BR23 questionnaires were completed at baseline, 12 and 24 months, or study termination to assess health-related QoL and disease-related symptoms. RESULTS: Of the 4,844 patients randomized to standard therapy or standard therapy + IM packages (1:1), 4,253 were available for QoL analysis. No difference in QoL was observed between groups at baseline. IM packages did not have a statistically significant impact on patient QoL at the 12- or 24-month follow-up. Compliant patients experienced improvement in multiple items across the QLQ-C30 and QLQ-BR23 scales at 12 months. However, those results should be interpreted carefully due to limitations in the statistical analyses. CONCLUSIONS: Provision of IM packages did not influence patients' QoL or satisfaction with care during AI therapy. Compliant patients appear to experience improved QoL compared to noncompliant patients, perhaps indicating a more self-empowered perception of their condition.

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.

Early identification and intervention matters: A comprehensive review of current evidence and recommendations for the monitoring of bone health in patients with cancer.

Bone metastases are common in patients with advanced solid tumors, and many individuals experience debilitating skeletal-related events (SREs; e.g. pathologic fracture, hypercalcemia, radiotherapy or surgery to bone, and spinal cord compression). These events substantially affect disease outcomes, including survival and quality of life, and healthcare systems. Plain radiography is the most widely used imaging modality for the detection of bone metastases; skeletal scintigraphy, computed tomography, positron emission tomography and magnetic resonance imaging offer greater sensitivity but their use in routine practice is restricted by high costs and limited availability. Biomarkers of bone turnover may also have a role in the early detection of bone metastases and can provide valuable prognostic information on disease progression. SREs can be delayed or prevented using agents such as the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor, denosumab, and bisphosphonates. Painful bone metastases can be treated with radiofrequency ablation, radiotherapy, or radionuclides such as radium-223 dichloride, which has been shown to delay the onset of SREs in men with castration-resistant prostate cancer. Close monitoring of bone health in patients with advanced cancer may lead to early identification of individuals with bone metastases who could benefit from early intervention to prevent SREs. This review examines current guideline recommendations for assessing and monitoring bone health in patients with advanced cancer, use of biomarkers and treatment of patients with bone metastases. The emerging evidence for the potential survival benefit conferred by early intervention with denosumab and bisphosphonates is also discussed, together with best practice recommendations.

[The calcium debate--strong bones at the expense of cardiovascular health?]. / Calcium: Knochenschutz auf Kosten der Gefässe?

Ensuring an adequate intake of calcium--by means of supplements, if necessary--is a well-established approach in prevention and therapy of osteoporosis. However, in the meantime concerns have been voiced doubting the safety of calcium supplements. The discussion commenced when a new evaluation of the Auckland calcium intervention study revealed a higher rate of myocardial infarction after administration of calcium, compared to placebo. Two meta-analyses on the cardiovascular risk of calcium supplements supported these findings. Nevertheless, these results are still discussed contentiously. Doubts were increased by the fact that neither a reevaluation of the WHI calcium vitamin D study, nor a current meta-analysis could identify calcium as a cardiovascular risk factor. Against this background the present article analyses the controversial data with respect to the well-known "Hill-criteria" of causality, including consistency of data, magnitude of association, dose-response relationship and biological plausibility.

Age-related differences in persistence in women with breast cancer treated with tamoxifen or aromatase inhibitors in Germany.

AIMS: To study age-related persistence in postmenopausal women with endocrine-responsive breast cancer treated with tamoxifen (TAM) and aromatase inhibitors (AI). METHODS: Data on 29,245 patients diagnosed with metastatic or non-metastatic breast cancer (BC) and initially treated with TAM or AI between 2004 and 2013 were included. The primary outcome measure was the age-dependent rate of discontinuation of endocrine treatment within 5years after initiation. Discontinuation of therapy was defined as a period of at least 90days without treatment. A multivariate Cox regression model was created to determine the influence of age on the risk of discontinuation. Health insurance type (private/statutory), type of care (gynecological/general), region (West/East Germany), concomitant diagnoses (depression, osteoporosis, and diabetes), and Charlson Comorbidity Score were included as covariates. RESULTS: The mean ages of the women in the <70 and ≥70 groups were 55.9 (SD: 9.7) and 77.4 (SD: 5.4) years, respectively. Within 5years after treatment initiation, 88.8% of women <70 of age and 82% of women ≥70 years of age had terminated treatment (p-value<0.001). Patients aged ≥70 exhibited a lower risk of treatment discontinuation than patients aged <70 (HR=0.75, 95% CI: 0.66-0.85). Furthermore, gynecological practices, disease management programs, and high Charlson scores increased persistence. CONCLUSIONS: Overall, the present study indicates that persistence rates are low in both women with BC aged <70 and those aged ≥70 years. We also found that younger women with BC are at a higher risk of treatment discontinuation than older women.

Gender differences in persistency to bisphosphonates in patients with metastatic breast and prostate cancer.

BACKGROUND: Bisphosphonates (BIS) treatment is a standard of care in metastatic bone disease (MBD) and regular intake is of upmost importance to ensure the effectiveness. The aim of this study was to investigate gender specific differences in persistence with BIS in MBD for the first time in this regard. PATIENTS AND METHODS: Out of the original database of 16 million patients, we extracted first-time metastatic cancer related BIS prescriptions from January 2001 to December 2011 in patients diagnosed with MBD following breast cancer (BC) or prostate cancer (PC). Patients were matched (1 : 1) in accordance to age. For persistence analyses, 1,007 patients with metastatic BC and PC were available. RESULTS: After 1 year of follow-up, 35.3% of BC and 26.6% of PC patients treated with BIS discontinued their treatment (p < 0.001). The differences were irrespective of increased refill gaps and route of BIS administration. The multivariate hazard ratios of the Cox regression models for 1-year risk of BIS discontinuation (adjusting for multiple variables) showed no increased risk for treatment discontinuation for BC vs. PC patients (HR: 0.87; 95% CI: 0.65 - 1.17). The use of co-medications decreased, regional and insurance aspects increased the risk of treatment discontinuation (HR of 0.88, 1.50, and 1.42). CONCLUSIONS: Although apparent in the primary analysis, we found no significant difference in the gender specific persistency after 12 months of first BIS treatment in MBD. Only co-medication, geographical and insurance aspects were associated with differences in discontinuation rates. Further studies are needed to investigate this clinically important relationship.

Adherence in tamoxifen therapy after conversion to a rebate pharmaceutical in breast cancer patients in Germany.

BACKGROUND: The aim of this study was to investigate the risk of therapy discontinuation in breast cancer patients treated with tamoxifen with and without conversion to a rebate pharmaceutical (tamoxifen) and to analyze the negative consequences of rebate contracts on the compliance of breast cancer patients among gynecologist and general practitioner practices in Germany. METHODS: This retrospective analysis was performed using the IMS Disease Analyzer® database. Women with a diagnosis of breast cancer and first time prescription of tamoxifen in the time from January 2008 until December 2011 were selected. Main outcome measure was the incident the hormone treatment discontinuation rates within 3 years after index date. Treatment discontinuation of tamoxifen was defined as 90 days without this or alternative hormonal therapy (aromatase inhibitors) during that time. RESULTS: In total, 3,620 patients were included in the persistence analysis. 1,712 (47.3%) patients were converted to a rebate product. Within 3 years of follow-up, the discontinuation rates increased to 51.5% for switched patients and 46.3% for patients without switch (p < 0.01). Hazard ratios for 3-year risk of tamoxifen therapy discontinuation were adjusted for age, sex, gynecologist care, patient and physician's residency, baseline co-morbidities (osteoporosis, diabetes, depression and thrombosis, side effects). These analyses comprised a significantly increased risk for treatment discontinuation for patients who were switched to a rebate pharmaceutical compared to patients without conversion to a rebate pharmaceutical (HR: 1.27, CI: 1.05 - 1.53, p = 0.014). CONCLUSIONS: This analysis underlines an association between the initiation of rebate contracts and a negative impact on the compliance of breast cancer patients on an adjuvant hormonal treatment The impact of rebate contracts on the health of patients and the health care costs should be evaluated in further therapeutic fields through additional research projects. *both authors contributed equally to the manuscript.

The epidemiology of osteoporosis--Bone Evaluation Study (BEST): an analysis of routine health insurance data.

BACKGROUND: Osteoporosis is a widespread disease of the skeleton that becomes more common with advancing age. Its prevalence is still inadequately documented. The goal of this study is to determine how common osteoporosis is in Germany. METHODS: The routine billing data of a large statutory health insurance carrier in Germany (the TK company) from the years 2006 to 2009 were anonymized and retrospectively analyzed. Insurees aged 50 and above with osteoporosis were identified either from their bearing the diagnosis of osteoporosis or of osteoporosis-related fractures, or from their having received prescription medication for osteoporosis. The prevalence and incidence of osteoporosis and the frequency of osteoporotic fractures were calculated for TK insurees and extrapolated to the overall German population. RESULTS: The prevalence of osteoporosis among persons aged 50 and above, as revealed by diagnoses of osteoporosis or osteoporotic fractures, or by the prescription of medication for osteoporosis, was found to be 14% (240,657 of 1.7 million insurees) in the year 2009; the sex-specific prevalence was 24% in women and 6% in men. An extrapolation of these figures implies that 6.3 million persons in Germany have osteoporosis. The incidence of osteoporosis in the same age group, as revealed by a diagnosis of osteoporosis or prescription of medication for osteoporosis, was found to be 2.1% per year, with 104,528 insurees having an index event for osteoporosis (initial diagnosis of osteoporosis or first prescription of a medication for osteoporosis). An extrapolation of this figure implies that 885,000 persons newly develop osteoporosis in Germany each year. Over the period of observation, 52% of the affected persons (total, 172,473 persons) sustained fractures, many of which were multiple. CONCLUSION: Osteoporosis is still common in Germany. The large number of insurees with single and multiple fractures implies that the treatment of this disease in Germany needs to be improved.

Cost comparison of outpatient treatment with granulocyte colony-stimulating factors (G-CSF) in Germany.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSF), are available for prevention of neutropenia and reduction of its complications in cytostatic chemotherapy. The purpose of this analysis was to determine the consumption rates for various G-CSF and to compare outpatient medication costs per patient and treatment cycle. METHODS: Prescription data of statutory health insurance members in Germany (IMS®LRx database) with G-CSF prescriptions between January 2008 and July 2010 were evaluated. A period of observation of at least 6 months prior to and after the G-CSF prescription was required. RESULTS: Prescription data of 8,726 patients treated with original filgrastim, 4,240 with biosimilar filgrastim, 6,456 with lenograstim, and 9,939 with pegfilgrastim were analyzed. The regression model showed statistically significant costreducing effects per cycle for treatment with lenograstim compared with non-lenograstim (-0.47 vs. original filgrastim; -0.15 vs. biosimilar filgrastim; -1.04 vs. pegfilgrastim; each p < 0.0001). This result has been adjusted for patient age, gender, number of injections, and prescribing specialist group. CONCLUSIONS: Treatment with the original preparation lenograstim is significantly cheaper compared to the other two original drugs and biosimilar. The costs of G-CSF treatment with the original preparation lenograstim and the filgrastim biosimilars are in a similar range, but with a significantly lower cost for lenograstim. Compared to their reference product the biosimilars thus show a cost advantage.

Cost-effectiveness analysis of anastrozole versus tamoxifen in adjuvant therapy for early-stage breast cancer - a health-economic analysis based on the 100-month analysis of the ATAC trial and the German health system.

BACKGROUND: In the 'Arimidex', Tamoxifen Alone or in Combination (ATAC) trial, the aromatase inhibitor (AI) anastrozole had a significantly better efficacy and safety profile than tamoxifen as initial adjuvant therapy for hormone receptor-positive (HR+) early breast cancer (EBC) in postmenopausal patients. To compare the combined long-term clinical and economic benefits, we carried out a cost-effectiveness analysis (CEA) of anastrozole versus tamoxifen based on the data of the 100month analysis of the ATAC trial from the perspective of the German public health insurance. PATIENTS AND METHODS: A Markov model with a 25-year time horizon was developed using the 100-month analysis of the ATAC trial as well as data obtained from published literature and expert opinion. RESULTS: Adjuvant treatment of EBC with anastrozole achieved an additional 0.32 quality-adjusted life-years (QALYs) gained per patient compared with tamoxifen, at an additional cost of D 6819 per patient. Thus, the incremental cost effectiveness of anastrozole versus tamoxifen at 25 years was D 21,069 ($30,717) per QALY gained. CONCLUSIONS: This is the first CEA of an AI that is based on extended follow-up data, taking into account the carryover effect of anastrozole, which maintains the efficacy benefits beyond therapy completion after 5 years. Adjuvant treatment with anastrozole for postmenopausal women with HR+ EBC is a cost-effective alternative to tamoxifen.