Bisphosphonate alternative regimens for the prevention of osteoporotic fragility fractures: BLAST-OFF, a mixed-methods study.

Background: Bisphosphonates are a class of medication commonly used to treat osteoporosis. Alendronate is recommended as the first-line treatment; however, long-term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates are available, which can be given intravenously and have been shown to improve long-term adherence. However, the most clinically effective and cost-effective alternative bisphosphonate regimen remains unclear. What is the most cost-effective bisphosphonate in clinical trials may not be the most cost-effective or acceptable to patients in everyday clinical practice. Objectives: 1. Explore patient, clinician and stakeholder views, experiences and preferences of alendronate compared to alternative bisphosphonates. 2. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates, and estimate the value of further research into their benefits. 3. Undertake stakeholder/consensus engagement to identify important research questions and further rank research priorities. Methods: The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: • Stage 1A - we elicited patient and healthcare experiences to understand their preferences of bisphosphonates for the treatment of osteoporosis. This was undertaken by performing a systematic review and framework synthesis of qualitative studies, followed by semistructured qualitative interviews with participants. • Stage 1B - we updated and expanded the existing Health Technology Assessment systematic review and clinical and cost-effectiveness model, incorporating a more comprehensive review of treatment efficacy, safety, side effects, compliance and long-term persistence. • Stage 2 - we identified and ranked further research questions that need to be answered about the effectiveness and acceptability of bisphosphonates. Results: Patients and healthcare professionals identified a number of challenges in adhering to bisphosphonate medication, balancing the potential for long-term risk reduction against the work involved in adhering to oral alendronate. Intravenous zoledronate treatment was generally more acceptable, with such regimens perceived to be more straightforward to engage in, although a portion of patients taking alendronate were satisfied with their current treatment. Intravenous zoledronate was found to be the most effective, with higher adherence rates compared to the other bisphosphonates, for reducing the risk of fragility fracture. However, oral bisphosphonates are more cost-effective than intravenous zoledronate due to the high cost of zoledronate administration in hospital. The importance of including patients and healthcare professionals when setting research priorities is recognised. Important areas for research were related to patient factors influencing treatment selection and effectiveness, how to optimise long-term care and the cost-effectiveness of delivering zoledronate in an alternative, non-hospital setting. Conclusions: Intravenous zoledronate treatment was generally more acceptable to patients and found to be the most effective bisphosphonate and with greater adherence; however, the cost-effectiveness relative to oral alendronate is limited by its higher zoledronate hospital administration costs. Future work: Further research is needed to support people to make decisions influencing treatment selection, effectiveness and optimal long-term care, together with the clinical and cost-effectiveness of intravenous zoledronate administered in a non-hospital (community) setting. Limitations: Lack of clarity and limitations in the many studies included in the systematic review may have under-interpreted some of the findings relating to effects of bisphosphonates. Trial registration: This trial is registered as ISRCTN10491361. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127550) and is published in full in Health Technology Assessment; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information.

Bisphosphonates are drug treatments commonly used to treat osteoporosis. Alendronate is the most used and is taken by mouth, weekly at a specific time of the week, which can be challenging. Less than one in four people continue this treatment beyond 2 years. Alternative bisphosphonates are available, which vary in frequency and how they are administered. The most acceptable and best value-for-money regimen is unclear. Our aim was to determine how effective alternative bisphosphonates are compared to alendronate at preventing fractures and whether reduction in fracture risk was achieved at a reasonable financial cost, but acceptable to patients. The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: Stage 1A: a review of the published evidence on patients' and doctors' views, experiences and preferences regarding different bisphosphonate treatment regimens, followed by interviews with patients and healthcare professionals. Stage 1B: an update of an existing study on how effective bisphosphonates are in preventing fragility fractures caused by osteoporosis and whether they are good value for money. Stage 2: identification of questions that need to be answered about the effectiveness and acceptability of bisphosphonate treatments. Taking bisphosphonate medication often involves quite a lot of effort by patients, particularly when taking alendronate tablets. A yearly infusion of zoledronate treatment was more acceptable, easier to engage with and the most effective treatment compared to alendronate. However, the cost of administering zoledronate in hospital made alendronate better value for money. Bisphosphonates are effective in reducing the risk of fracture, but 'continuing with treatment', particularly alendronate tablets, remains a challenge. A yearly infusion of zoledronate offers an acceptable and effective treatment, but further research is needed to support patients and healthcare professionals in making decisions about the various treatments, benefits and cost savings of administering zoledronate outside of hospital and in the community.

Cost-Effectiveness Analysis of Denosumab in the Prevention of Skeletal-Related Events Among Patients With Breast Cancer With Bone Metastasis in India.

PURPOSE: Denosumab is clinically superior to zoledronic acid (ZA) for preventing and delaying time to first and subsequent skeletal-related events (SREs) among patients with breast cancer (BC) with bone metastases. We evaluated the cost and health benefits of denosumab and ZA (once every 4 weeks and once every 12 weeks) among four different molecular subtypes of BC with bone metastases in India. MATERIALS AND METHODS: A Markov model was developed in Microsoft Excel to estimate lifetime health consequences and resulting costs among cohort of 1,000 patients with BC with bone metastasis, for three intervention scenarios, namely denosumab (once every 4 weeks), ZA (once every 4 weeks), and ZA (once every 12 weeks). The health outcomes were measured in terms of SREs averted and quality-adjusted life-years (QALYs) gained. The cost of each intervention scenario was measured using both the health system and the patient's perspectives. Indirect costs because of lost productivity were not included. The future costs and outcomes were discounted at the standard rate of 3%. RESULTS: Over a lifetime, the incremental number of SREs averted with use of denosumab once every 4 weeks (compared with ZA once every 4 weeks and once every 12 weeks) among patients with luminal A, luminal B, human epidermal growth factor receptor 2-enriched, and triple negative breast cancer were estimated as 0.39, 0.26, 0.25, and 0.19, respectively. The number of QALYs lived were slightly higher in the denosumab arm (1.45-2.80) compared with ZA once every 4 weeks and once every 12 weeks arms (1.44-2.78). However, denosumab once every 4 weeks was not found to be a cost-effective alternative for either of the four molecular subtypes of breast cancer. ZA once every 12 weeks was found to be a cost-effective option with an average cost-effectiveness ratio ranging between ₹68,254 and ₹73,636. CONCLUSION: ZA once every 12 weeks is the cost-effective treatment option for BC with bone metastases in India. The present study findings hold significance for standard treatment guidelines under India's government-funded health insurance program.

The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis.

Background: Clinical guidelines commonly recommend preventative treatments for people above a risk threshold. Therefore, decision-makers must have faith in risk prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing to account for direct treatment disutility (i.e. the hassle of taking treatments). We explored these issues using two case studies: primary prevention of cardiovascular disease using statins and osteoporotic fracture using bisphosphonates. Objectives: Externally validate three risk prediction tools [QRISK®3, QRISK®-Lifetime, QFracture-2012 (ClinRisk Ltd, Leeds, UK)]; derive and internally validate new risk prediction tools for cardiovascular disease [competing mortality risk model with Charlson Comorbidity Index (CRISK-CCI)] and fracture (CFracture), accounting for competing-cause death; quantify direct treatment disutility for statins and bisphosphonates; and examine the effect of competing risks and direct treatment disutility on the cost-effectiveness of preventative treatments. Design, participants, main outcome measures, data sources: Discrimination and calibration of risk prediction models (Clinical Practice Research Datalink participants: aged 25-84 years for cardiovascular disease and aged 30-99 years for fractures); direct treatment disutility was elicited in online stated-preference surveys (people with/people without experience of statins/bisphosphonates); costs and quality-adjusted life-years were determined from decision-analytic modelling (updated models used in National Institute for Health and Care Excellence decision-making). Results: CRISK-CCI has excellent discrimination, similar to that of QRISK3 (Harrell's c = 0.864 vs. 0.865, respectively, for women; and 0.819 vs. 0.834, respectively, for men). CRISK-CCI has systematically better calibration, although both models overpredict in high-risk subgroups. People recommended for treatment (10-year risk of ≥ 10%) are younger when using QRISK-Lifetime than when using QRISK3, and have fewer observed events in a 10-year follow-up (4.0% vs. 11.9%, respectively, for women; and 4.3% vs. 10.8%, respectively, for men). QFracture-2012 underpredicts fractures, owing to under-ascertainment of events in its derivation. However, there is major overprediction among people aged 85-99 years and/or with multiple long-term conditions. CFracture is better calibrated, although it also overpredicts among older people. In a time trade-off exercise (n = 879), statins exhibited direct treatment disutility of 0.034; for bisphosphonates, it was greater, at 0.067. Inconvenience also influenced preferences in best-worst scaling (n = 631). Updated cost-effectiveness analysis generates more quality-adjusted life-years among people with below-average cardiovascular risk and fewer among people with above-average risk. If people experience disutility when taking statins, the cardiovascular risk threshold at which benefits outweigh harms rises with age (≥ 8% 10-year risk at 40 years of age; ≥ 38% 10-year risk at 80 years of age). Assuming that everyone experiences population-average direct treatment disutility with oral bisphosphonates, treatment is net harmful at all levels of risk. Limitations: Treating data as missing at random is a strong assumption in risk prediction model derivation. Disentangling the effect of statins from secular trends in cardiovascular disease in the previous two decades is challenging. Validating lifetime risk prediction is impossible without using very historical data. Respondents to our stated-preference survey may not be representative of the population. There is no consensus on which direct treatment disutilities should be used for cost-effectiveness analyses. Not all the inputs to the cost-effectiveness models could be updated. Conclusions: Ignoring competing mortality in risk prediction overestimates the risk of cardiovascular events and fracture, especially among older people and those with multimorbidity. Adjustment for competing risk does not meaningfully alter cost-effectiveness of these preventative interventions, but direct treatment disutility is measurable and has the potential to alter the balance of benefits and harms. We argue that this is best addressed in individual-level shared decision-making. Study registration: This study is registered as PROSPERO CRD42021249959. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/12/22) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 4. See the NIHR Funding and Awards website for further award information.

Before offering a medicine to prevent disease, prescribers must expect it to do more good than harm. This balance depends on how likely it is that the person will develop the disease we want to prevent. But people might first die for other reasons. We call this a 'competing risk'. In most cases, the mathematical tools we use to estimate the chance of developing a disease do not account for competing risks. Another problem is that, when weighing up the benefits and harms of medicines, we ignore the hassle they cause patients, even when they do not cause side effects. We used two examples: statins to prevent heart disease and bisphosphonates to prevent fractures. First, we assessed if existing tools get predictions wrong by not accounting for competing risks. We found that they exaggerate the chance of heart attacks and strokes. However, the exaggeration is greatest among people who would clearly benefit from preventative treatment. So it may not change treatment decisions much. The fracture prediction tool we studied was very inaccurate, exaggerating risk among older people, but underestimating risk among younger people. We made a new fracture risk prediction tool. It gave better predictions, but it was still inaccurate for people aged > 85 years and those with several health problems. Next, we asked people questions designed to put a number on the hassle that statins and bisphosphonates cause. Most people thought that taking either is inconvenient, but the hassle factor for bisphosphonates is bigger. Finally, we updated the mathematical models that the National Institute for Health and Care Excellence used when recommending statins and bisphosphonates. We worked out if competing risks and the hassle of taking medicines make a difference to results. Statins remain a good idea for almost everyone, unless they really hate the idea of taking them. But bisphosphonates would do more harm than good for anyone who agrees with the hassle factor we found.

Descriptive assessment of 54 cases with complex regional pain syndrome in lower limbs.

INTRODUCTION: Complex regional pain syndrome (CRPS), also known as Sudeck syndrome, is a chronic painful condition usually affecting the limbs after trauma or surgery. Its presentation is heterogeneous and its physiopathology, diagnosis and treatment remain controversial. The objective of this study was to analyze a group of patients with this rare syndrome, describing in detail the results of the dual energy X-ray absorptiometry (DXA) and the response to bisphosphonate treatment. METHOD: We retrospectively analyzed 54 patients with CRPS, taking into account their demographic features, inciting events and diagnostic tests. As regards treatment, we analyzed the results and adverse events of the use of bisphosphonates Results: We found a female predominance (74%), with 55 ± 13 years. The most common inciting event was trauma (59%), followed by surgery. The difference in bone mineral density between the affected limb and the healthy one was 12 to 15%. Forty-four patients were treated with bisphosphonates (pamidronate, ibandronate, zoledronic acid) and showed a clinical improvement, mainly in terms of pain intensity. Only six patients presented with adverse events, like pseudoflu syndrome and acute phase symptoms. CONCLUSION: In our cohort, lower limbs CRPS predominantly affects middle aged women. DXA scans are tests used to quantify bone loss and the response to treatment. The use of bisphosphonates is an interesting therapeutic option to improve clinical symptoms in most patients. Future prospective randomized studies will be needed to confirm our results.

Introducción: El síndrome doloroso regional complejo (SDRC), también conocido como síndrome de Sudeck, es una enfermedad dolorosa crónica que generalmente afecta a las extremidades luego de un trauma o cirugía. Su presentación es heterogénea y existen controversias sobre su fisiopatología, adecuado diagnóstico y tratamiento. El objetivo de este trabajo es describir un grupo de pacientes con SDRC en miembros inferiores, describiendo los resultados de la densitometría mineral ósea (DMO) y la respuesta al tratamiento con bifosfonatos. Método: Analizamos retrospectivamente 54 pacientes con SDRC, teniendo en cuenta características demográficas, factores desencadenantes y estudios diagnósticos. En relación al tratamiento, analizamos los resultados y efectos adversos del uso de bifosfonatos. Resultados: Encontramos un predominio femenino (74%), con una edad de 55 ± 13 años. Los factores desencadenantes más comunes fueron los traumatismos (59%) y la cirugía. La diferencia de densidad mineral ósea entre el miembro comprometido y el sano fue 12 a 15%. En los 44 pacientes fueron tratados con bifosfonatos (pamidronato, ibandronato y ácido zoledrónico), su uso se asoció a mejoría clínica, especialmente del dolor. Seis pacientes tuvieron efectos adversos como sindrome pseudogripal y síntomas de fase aguda. Conclusión: En nuestra población, el SDRC de miembros inferiores predomina en mujeres de edad media. La DMO es un método que permite cuantificar la pérdida ósea y la respuesta al tratamiento. Los bifosfonatos son una buena opción terapéutica para el control de síntomas. Son necesarios futuros estudios de naturaleza prospectiva y aleatorizada para confirmar nuestros resultados.

Bone turnover markers for assessment of anti-resorptive effect in clinical practice: A good idea meets the problem of measurement uncertainty.

OBJECTIVES: Bone turnover markers (BTM) are measures for understanding the effect of anti-resorptives upon osteoclast activity. Post-hoc trial data suggests reduction in BTM of 40% may represent a target for defining appropriate response to therapy. We modeled clinical application of this target threshold in an individual patient setting where assay measurement uncertainty and biological variation are included. DESIGN: Using serum C-telo-peptide (ß-CTX), we constructed hypothetical scenarios of ß-CTX measurement pre and post bisphosphonate therapy. Using typical ß-CTX assay characteristics (analytical coefficient of variation, CV 5.0%) and published intra-individual ß-CTX data for post-menopausal women (CV 18.0%), we calculated the post-therapy ß-CTX that must be seen on single repeat measure for 95% confidence that the observed result was ≥40% below baseline. Sensitivity analyses considered greater and lesser variations in the combined sources of variation. RESULTS: The one-tailed 95% reference change value for any detectable therapeutic decrease in ß-CTX was 22%. However, to have 95% confidence of having achieved a reduction ≥40%, an observed ß-CTX decrease of ≥56% is required. Larger decreases are needed for scenarios of greater analytical or intra-individual variation. CONCLUSIONS: Although population data suggest a ß-CTX decrease of 40% is commensurate with adequate therapeutic response to anti-resorptives, application to an individual patient where measurement and natural variation are present is problematic. ß-CTX decreases much >40% are required to be confident of having achieved the optimal treatment response. It is uncertain whether this is a legitimate change to be expected in all individual patients and therefore clinical application of this threshold is uncertain.

No Increased Risk of Nonunion with Bisphosphonate Use in a Medicare Claims Cohort Following Operatively Treated Long-Bone Fractures.

BACKGROUND: The diagnosis of a fragility fracture represents an important intervention event for the initiation of medical osteoporosis treatments. However, it is unclear if osteoporosis medications increase the risk of nonunion if administered in the setting of acute fracture. The purpose of the present study was to investigate whether bisphosphonates or selective estrogen receptor modulators/hormone replacement therapy (SERM/HRT) are associated with nonunion following fracture in a Medicare population. METHODS: A retrospective analysis of Medicare claims from 2016 to 2019 was performed to identify patients ≥65 years of age who had a surgically treated long-bone fracture as identified with Current Procedural Terminology (CPT) codes and International Classification of Diseases, 10th Revision (ICD-10) codes. Successive claims were linked for each beneficiary through 1 year following the fracture to determine fracture union status. Multivariable logistic regression models were specified to identify the association between medications and fracture union status while controlling for age, sex, race, Charlson Comorbidity Index (CCI), and fracture type. RESULTS: Of the 111,343 included fractures, 10,452 (9.4%) were associated with a diagnosis of nonunion within 1 year. The nonunion group was younger (79.8 ± 8.3 versus 80.6 ± 8.4 years; p < 0.001), more likely to be White (92.4% versus 90.9%; p < 0.001), and more likely to have a CCI of ≥2 (50.9% versus 49.4%; p < 0.001). Bisphosphonate use was more common in the nonunion group (12.2% versus 11.4%; p = 0.017). When controlling for race, age, sex, and CCI, neither bisphosphonates (OR, 1.06 [95% CI, 0.99 to 1.12]; p = 0.101) nor SERM/HRT (OR, 1.13 [0.93 to 1.36]; p = 0.218) were associated with nonunion. Bisphosphonate use within 90 days post-fracture was not significantly associated with nonunion (OR, 0.94 [95% CI, 0.86 to 1.03]; p = 0.175), and the timing of medication administration did not influence fracture union status. CONCLUSIONS: The rate of nonunion after operatively treated long-bone fractures was 9.4%. In this cohort, use of a bisphosphonate or SERM/HRT was not associated with fracture union status at 1 year. Orthopaedic surgeons should not withhold or delay initiating medical therapies for osteoporosis in the setting of acute fracture out of concern for nonunion. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Adjuvant treatment of surgically treated bone metastasis patients: association with hospital characteristics and trends over time.

Patients with metastatic disease of the bone (MDB) often require surgical stabilization; however, there is not widespread consensus on subsequent adjuvant management. This study aimed to characterize utilization of perioperative adjuvant treatment among MDB patients. We identified 9413 surgically treated MDB patients with primary (breast, kidney, lung, prostate, or multiple myeloma) cancer from Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for receipt of chemotherapy, radiation, and bisphosphonates, respectively, in the adjuvant setting (90 days before or after surgery) by hospital characteristics-medical school affiliation, surgery volume, and Commission on Cancer (CoC) accreditation. Trends in treatment utilization by year of surgery were assessed via bar charts and Chi-square tests for trend. Patients surgically treated at major medical schools or high-volume facilities (compared to no medical school affiliation and low volume) had significantly higher odds of receiving radiation and chemotherapy, independent of patient and tumor characteristics (OR (95% CI); medical school: radiation 1.33 (1.19-1.49), chemotherapy 1.15 (1.02-1.30); and high volume: radiation 1.22 (1.11-1.34), chemotherapy 1.11 (1.02-1.22)). Patients surgically treated at CoC-accredited institutions, compared to non-accredited, had significantly higher odds of receiving radiation and bisphosphonates [radiation 1.24 (1.13-1.36); bisphosphonates 1.15 (1.04-1.28)]. Use of chemotherapy and bisphosphonates increased while radiation use declined over the study period from 1991 to 2014. Medical school affiliation, hospital volume, and CoC accreditation are associated with receipt of adjuvant treatment to prevent or manage pathologic fractures in MDB patients. Further investigation is needed to determine whether these associations reflect delivery of optimal care.

Cost Effectiveness Analyses of Interventions for Osteoporosis in Men: A Systematic Literature Review.

BACKGROUND: Osteoporosis is often considered to be a disease of women. Over the last few years, owing to the increasing clinical and economic burden, the awareness and imperative for identifying and managing osteoporosis in men have increased substantially. With the approval of agents to treat men with osteoporosis, more economic evaluations have been conducted to assess the potential economic benefits of these interventions. Despite this concern, there is no specific overview of cost-effectiveness analyses for the treatment of osteoporosis in men. OBJECTIVES: This study aims (1) to systematically review economic evaluations of interventions for osteoporosis in men; (2) to critically appraise the quality of included studies and the source of model input data; and (3) to investigate the comparability of results for studies including both men and women. METHODS: A literature search mainly using MEDLINE (via Ovid) and Embase databases was undertaken to identify original articles published between 1 January, 2000 and 30 June, 2022. Studies that assessed the cost effectiveness of interventions for osteoporosis in men were included. The Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases and the International Osteoporosis Foundation osteoporosis-specific guideline was used to assess the quality of design, conduct, and reporting of included studies. RESULTS: Of 2973 articles identified, 25 studies fulfilled the inclusion criteria, classified into economic evaluations of active drugs (n = 8) or nutritional supplements (n = 4), intervention thresholds (n = 5), screening strategies (n = 6), and post-fracture care programs (n = 2). Most studies were conducted in European countries (n = 15), followed by North America (n = 9). Bisphosphonates (namely alendronate) and nutritional supplements were shown to be generally cost effective compared with no treatment in men over 60 years of age with osteoporosis or prior fractures. Two other studies suggested that denosumab was cost effective in men aged 75 years and older with osteoporosis compared with bisphosphates and teriparatide. Intervention thresholds at which bisphosphonates were found to be cost effective varied among studies with a 10-year probability of a major osteoporotic fracture that ranged from 8.9 to 34.2% for different age categories. A few studies suggested cost effectiveness of screening strategies and post-fracture care programs in men. Similar findings regarding the cost effectiveness of drugs and intervention thresholds in women and men were captured, with slightly greater incremental cost-effectiveness ratios in men. The quality of the studies included had an average score of 18.8 out of 25 (range 13-23.5). Hip fracture incidence and mortality risk were mainly derived from studies in men, while fracture cost, treatment efficacy, and disutility were commonly derived from studies in women or studies combining both sexes. CONCLUSIONS: Anti-osteoporosis drugs and nutritional supplements are generally cost effective in men with osteoporosis. Screening strategies and post-fracture care programs also showed economic benefits for men. Cost-effectiveness and intervention thresholds were generally similar in studies conducted in both men and women, with slightly greater incremental cost-effectiveness ratios in men.

A systematic review of cost­effectiveness analyses of sequential treatment for osteoporosis.

Sequential treatment of osteoporosis has been increasingly mentioned in recent years. However, the corresponding systematic review has not been reported. This study aims to systematically review and assess all full-text pharmacoeconomic studies of sequential treatment for osteoporosis. A comprehensive literature search was performed using PubMed, EMBASE (Ovid), CNKI, and Wanfang Database to identify original articles, published before June 17, 2022. The quality of included articles was evaluated by the updated Consolidated Health Economic Evaluation Reporting Standards (CHEERS 2022) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases International Osteoporosis Foundation (ESCEO-IOF). In general, ten articles were included in this review. For the comparison between sequential treatment and bisphosphonate monotherapy, more than 75% of studies demonstrated the sequential treatment was cost-effective or dominant, with the exception of sequential treatment involving teriparatide. When the comparisons occurred between the two sequential treatment groups, the sequential treatments associated with either abaloparatide or romosozumab were cost-effective or dominant compared to the sequential treatment involving teriparatide. Several major key drivers of cost-effectiveness included drug cost, medication persistence and adherence, drug effect on fracture risk, offset effect, time horizon, and baseline fracture risk. The most of studies were identified as high quality in CHEERS (2022) and ESCEO-IOF. The cost-effectiveness of sequential treatment for osteoporosis is influenced by multiple factors. Generally, the sequential treatments involving abaloparatide, romosozumab, denosumab, and bisphosphonates may be considered as the preferred option for osteoporosis with high fracture risk, while the sequential treatment with teriparatide was not a cost-effectiveness strategy. The ESCEO-IOF and CHEER (2022) increase the transparency, comparability, extrapolation, and quality of research, engage patients and the general public in research on health services and policies, and help improve the quality of health technology assessment.

Real-world effectiveness of anti-osteoporosis medications for the prevention of incident hip and clinical vertebral fractures in patients on long-term glucocorticoid therapy: A nationwide health insurance claims database study in Japan.

PURPOSE: Early initiation of anti-osteoporosis medications (AOMs) is recommended for patients on long-term glucocorticoid (GC) therapy. This study aimed to clarify the real-world effectiveness of AOMs against incident hip and vertebral fractures in patients undergoing GC therapy using the nationwide health insurance claims database of Japan (NDBJ). METHODS: Patients aged ≥50 years who were prescribed GC (≥5 mg/day prednisolone or equivalent) for ≥90 days and who were followed up regarding AOM prescription and hip and clinical vertebral fracture incidences for the subsequent 1080 days between 2012 and 2018 were selected from NDBJ. Associations of AOMs prescribed within 90 days since GC therapy initiation with hip or vertebral fracture risk were evaluated by Cox proportional hazards regression using propensity score inverse probability weighting (IPW) for receiving any AOM or individual AOMs. RESULTS: In total, 96,475 women and 98,385 men were included in the analysis; 38.0 % of women and 27.6 % of men received AOMs. Patients who received any AOM and those who received bisphosphonates or denosumab had a significantly lower risk of hip and clinical vertebral fractures than those who received no AOM in both sexes after propensity score IPW. Teriparatide was associated with an increased risk of both fractures in women and an increased risk of clinical vertebral fractures in men. Selection biases such as confounding by indication might have caused an underestimation of AOMs' protective effects. CONCLUSIONS: Bisphosphonates and denosumab were associated with a lower fracture incidence in patients on long-term GC therapy in real-world settings.

Establishment and assessment of rodent models of medication-related osteonecrosis of the jaw (MRONJ).

Medication-related osteonecrosis of the jaw (MRONJ) is primarily associated with administering antiresorptive or antiangiogenic drugs. Despite significant research on MRONJ, its pathogenesis and effective treatments are still not fully understood. Animal models can be used to simulate the pathophysiological features of MRONJ, serving as standardized in vivo experimental platforms to explore the pathogenesis and therapies of MRONJ. Rodent models exhibit excellent effectiveness and high reproducibility in mimicking human MRONJ, but classical methods cannot achieve a complete replica of the pathogenesis of MRONJ. Modified rodent models have been reported with improvements for better mimicking of MRONJ onset in clinic. This review summarizes representative classical and modified rodent models of MRONJ created through various combinations of systemic drug induction and local stimulation and discusses their effectiveness and efficiency. Currently, there is a lack of a unified assessment system for MRONJ models, which hinders a standard definition of MRONJ-like lesions in rodents. Therefore, this review comprehensively summarizes assessment systems based on published peer-review articles, including new approaches in gross observation, histological assessments, radiographic assessments, and serological assessments. This review can serve as a reference for model establishment and evaluation in future preclinical studies on MRONJ.

A systematic review and meta-analysis on impact of suboptimal use of antidepressants, bisphosphonates, and statins on healthcare resource utilisation and healthcare cost.

BACKGROUND: Depression, osteoporosis, and cardiovascular disease impose a heavy economic burden on society. Understanding economic impacts of suboptimal use of medication due to nonadherence and non-persistence (non-MAP) for these conditions is important for clinical practice and health policy-making. OBJECTIVE: This systematic literature review aims to assess the impact of non-MAP to antidepressants, bisphosphonates and statins on healthcare resource utilisation and healthcare cost (HRUHC), and to assess how these impacts differ across medication classes. METHODS: A systematic literature review and an aggregate meta-analysis were performed. Using the search protocol developed, PubMed, Cochrane Library, ClinicalTrials.gov, JSTOR and EconLit were searched for articles that explored the relationship between non-MAP and HRUHC (i.e., use of hospital, visit to healthcare service providers other than hospital, and healthcare cost components including medical cost and pharmacy cost) published from November 2004 to April 2021. Inverse-variance meta-analysis was used to assess the relationship between non-MAP and HRUHC when reported for at least two different populations. RESULTS: Screening 1,123 articles left 10, seven and 13 articles on antidepressants, bisphosphonates, and statins, respectively. Of those, 27 were rated of good quality, three fair and none poor using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. In general, non-MAP was positively associated with HRUHC for all three medication classes and most prominently for bisphosphonates, although the relationships differed across HRUHC components and medication classes. The meta-analysis found that non-MAP was associated with increased hospital cost (26%, p = 0.02), outpatient cost (10%, p = 0.01), and total medical cost excluding pharmacy cost (12%, p<0.00001) for antidepressants, and increased total healthcare cost (3%, p = 0.07) for bisphosphonates. CONCLUSIONS: This systematic literature review is the first to compare the impact of non-MAP on HRUHC across medications for three prevalent conditions, depression, osteoporosis and cardiovascular disease. Positive relationships between non-MAP and HRUHC highlight inefficiencies within the healthcare system related to non-MAP, suggesting a need to reduce non-MAP in a cost-effective way.

Prevalence and patterns of anti-osteoporotic drug use based on 2019 real-world nationwide data in Greece.

We used the Greek nationwide database to capture individuals on anti-osteoporotic treatment during 2019. From the estimated number of 683,679 osteoporotic individuals, only 42% were receiving treatment, with the total annual cost being almost one-tenth of the total cost of fractures. The treatment gap was significantly higher in males than in females. INTRODUCTION: Based on the 2019 European scorecard (SCOPE), osteoporosis is diagnosed in an estimated 683,679 individuals in Greece, with the direct cost of incident fractures being €694.7 million, although further relevant real-world data are scarce. METHODS: The e-Government Center for Social Security Services prescription database, which covers almost 100% of the Greek population, was used to capture all individuals on anti-osteoporotic treatment during 2019. RESULTS: A total of 288,983 among 8,641,341 people, corresponding to 3.3% of the total adult Greek population, had filled at least one anti-osteoporotic prescription (6.0% and 0.36% for females and males, respectively). Prevalence of anti-osteoporotic treatment increased with age, from 0.15% in those younger than 50 to 8.6% in those older than 70 years. Oral bisphosphonates were more frequently prescribed (58.8%), followed by denosumab (39.4%). Alendronate was more frequently prescribed in males and in people younger than 60 years. Denosumab was more frequently prescribed in females and in people older than 60 years. Selective estrogen-receptor modulators, teriparatide, and parenteral bisphosphonates accounted for 1.1%, 1.0%, and 0.02% of all prescriptions, respectively. Orthopedic surgeons (39.6%), endocrinologists (19.6%), general practitioners (19%), and rheumatologists (9.3%) prescribed the vast majority of anti-osteoporotic regimens, with significant differences in prescription patterns. The annual cost of treatment per patient increased significantly with age, being on average €323.33. CONCLUSIONS: Less than half of the estimated number of individuals with osteoporosis in 2019 in Greece received treatment, with the total annual cost being far less than the estimated cost of incident-fragility fractures. The impact of this undertreatment on related health care costs merits further investigation.

One changing and challenging scenario: the treatment of cancer patients with bone metastases by bisphosphonates and denosumab, the cost-benefit evaluation of different options, and the risk of medication-related osteonecrosis of the jaw (MRONJ).

Antiresorptive drugs (bisphosphonates and denosumab) have become the cornerstone of medical supportive treatment of bone metastases in solid cancer patients. In the beginning, the choice of available antiresorptive agents was limited to bisphosphonates and the treatment options restricted principally to monthly pamidronate and monthly zoledronic acid. Introduction of new antiresorptive therapies (monthly denosumab) and schedules (zoledronic acid every 3 months, upfront or after initial period of monthly infusion) in the last decade increased the range of available options, thus challenging treatment decision making. Direct and indirect costs of very different treatment options are difficult to interpret in a global cost-benefit analysis. In addition, awareness of the increased risk of medication-related osteonecrosis of the jaw (MRONJ) in bone metastatic cancer patients receiving long-term antiresorptive medications is likely to influence therapy choice in the real-life scenario. We discuss the possible threat of MRONJ risk underestimation and the need for long-term risk stratification of patients based on actuarial data, the role of bisphosphonates and denosumab in that scenario, and the emerging role of surgical therapy to successfully cure MRONJ, in the light of the improved quality of life and survival of patients with bone metastases from solid cancers.

MRI in the Diagnosis and Treatment Response Assessment of Chronic Nonbacterial Osteomyelitis in Children and Adolescents.

PURPOSE OF REVIEW: To explain the central role of magnetic resonance imaging (MRI) in the diagnosis and follow-up of chronic nonbacterial osteomyelitis (CNO) in children and adolescents, centering on practical technical aspects and salient diagnostic features. RECENT FINDINGS: In the absence of conclusive clinical features and widely accepted laboratory tests, including validated disease biomarkers, MRI (whether targeted or covering the entire body) currently plays an indispensable role in the diagnosis and therapy response assessment of CNO. Whole-body MRI, which is the reference imaging standard for CNO, can be limited to a short tau inversion recovery (STIR) coronal image set covering the entire body and a STIR sagittal set covering the spine, an approximately 30-min examination with no need for intravenous contrast or diffusion-weighted imaging. The hallmark of CNO is periphyseal (metaphyseal and/or epi-/apophyseal) osteitis, identified as bright foci on STIR, with or without inflammation of the adjacent periosteum and surrounding soft tissue. Response to bisphosphonate treatment for CNO has some unique MRI findings that should not be mistaken for residual or relapsing disease. Diagnostic features and treatment response characteristics of MRI in pediatric CNO are discussed, also describing the techniques used, pitfalls encountered, and differential diagnostic possibilities considered during daily practice.

Utility of PINP to monitor osteoporosis treatment in primary care, the POSE study (PINP and Osteoporosis in Sheffield Evaluation).

PURPOSE: In Sheffield (UK), we introduced the PINP monitoring algorithm for the management of osteoporosis treatment delivered in primary care. Our aims were to evaluate whether this algorithm was associated with better osteoporosis outcomes and was cost-effective compared to standard care. METHODS: Inclusion criteria were referral from Sheffield GPs, BMD scans performed between 2012 and 2013 and a report advising initiation of oral bisphosphonate and PINP monitoring. 906 patients were identified and retrospectively divided into Group A (intention to monitor, with baseline PINP, n = 588) and Group B (no intention to monitor, without baseline PINP, n = 318). The model described by Davis and colleagues was used to extrapolate life-time costs and quality-adjusted life-years (QALYs). RESULTS: No differences were found in baseline characteristics between groups (age, gender, BMI, BMD and major risk factors for fractures). More patients in Group A started oral treatment (77.4% vs 49.1%; p < 0.001), but there were no differences between groups in the presence of a gap in treatment >3 months or in treatment duration. Patients in Group A were more likely to have follow-up DXA scan at 4-6 years from baseline (46.9% vs 29.2%; p < 0.000) and had a greater increase in total hip BMD (+2.74% vs + 0.42%; p value = 0.003). Fewer new fractures occurred in Group A but this was not statistically significant, but the numbers of fractures were small. Patients in Group A were more likely to change management (p = 0.005) including switching to zoledronate (p = 0.03). The PINP measurement and increased prescribing in Group A resulted in increases in both costs (£30.19) and QALYs (0.0039) relative to Group B, giving an incremental cost effectiveness ratio (ICER) of £7660 in the probabilistic sensitivity analysis. CONCLUSIONS: Patients monitored with PINP are more likely to start oral bisphosphonate treatment, switch to zoledronate, have follow-up DXA scans and a greater increase of hip BMD. PINP monitoring has the potential to be cost-effective in a UK NHS setting given that interventions with an ICER under £20,000 are generally considered to be cost-effective.

Cost-effectiveness of 3 versus 6 years of zoledronic acid treatment before bisphosphonate holiday for women with osteoporosis.

We evaluated the cost-effectiveness of recurrent periods of 3 versus 6 years of zoledronic acid treatment prior to 3-year bisphosphonate holidays for US postmenopausal women with osteoporosis and femoral neck BMD T-scores between - 2.5 and - 3.5. We found that cycles of 3 years of treatment followed by holidays is likely to be the more cost-effective option. INTRODUCTION: We compared the effectiveness and cost-effectiveness of cycles of 3 years versus 6 years of zoledronic acid treatment prior to 3-year bisphosphonate holidays for US postmenopausal women with osteoporosis. METHODS: We developed an individual-level state-transition microsimulation cost-effectiveness model to compare treatment strategies over the lifetime of recurrent periods of 3 years of zoledronic acid followed by 3-year holidays (zoledronic acid 3/3), recurrent periods of 6 years of zoledronic acid followed by 3-year holidays (zoledronic acid 6/3), and no zoledronic acid treatment for women with osteoporosis and femoral neck BMD T-scores between - 2.5 and - 3.5. RESULTS: Base-case analysis and all key parameter sensitivity analysis findings for every treatment initiation age evaluated (50, 60, 70, and 80) revealed that zoledronic acid 3/3 was consistently the most cost-effective strategy, assuming a willingness-to-pay of $100,000 per quality-adjusted life-year (QALY). In general, the zoledronic acid 3/3 and 6/3 strategies were relatively close in effectiveness (QALYs) over the lifetime; however, lifetime direct health care costs were on average approximately $2000 lower for the 3/3 strategy. Probabilistic sensitivity analysis results revealed that the zoledronic acid 3/3 strategy was favored in greater than 70% of the iterations for a willingness-to-pay threshold of $100,000/QALY for all treatment initiation ages evaluated. CONCLUSIONS: After 3 years of zoledronic acid treatment for postmenopausal women with osteoporosis and femoral neck BMD T-scores between - 2.5 and - 3.5, taking 3-year holidays before restarting another treatment cycle is likely to be more cost-effective over the lifetime than cycles of 6 years of treatment prior to 3-year holidays.

Patterns of oral bisphosphonate deprescribing in older nursing home residents with dementia.

In a national sample of Medicare nursing home residents with dementia treated with bisphosphonates, 20% had bisphosphonates deprescribed. Residents with clinical characteristics representing decreased likelihood for long-term benefit were more likely to have bisphosphonates deprescribed. Future studies are needed to evaluate outcomes of deprescribing bisphosphonates in this population. INTRODUCTION: To determine incidence of deprescribing bisphosphonates among nursing home (NH) residents with dementia and identify factors associated with deprescribing. METHODS: 2015-2016 Medicare claims, Part D prescriptions, Minimum Data Set (MDS) 3.0, and Nursing Home Compare for non-skilled NH residents aged 65 + with dementia and prescriptions for oral bisphosphonates overlapping the first 14 days of the stay. Our primary definition for deprescribing was a 90-day gap in medication supply; we also explored the reliability of different deprescribing definitions (30-, 90-, 180-day gaps). We estimated associations of NH, provider, and resident characteristics with deprescribing bisphosphonates using competing risks regression models. RESULTS: Most NH residents with dementia treated with bisphosphonates (n = 5312) were ≥ 80 years old (72%), white (81%), and female (90%); about half were dependent for transfers (50%) or mobility (45%). Using a 90-day gap in supply, the 180-day cumulative incidence of deprescribing bisphosphonates was 14.8%. This increased to 32.1% using a 30-day gap and decreased to 11.7% using a 180-day gap. Factors associated with increased likelihood for bisphosphonate deprescribing were age ≥ 90 years, newly admitted (vs. prevalent stay), dependent for mobility, swallowing difficulty, > 1 hospitalization in the prior year, CCRC facility, and nurse practitioner primary provider (vs. physician). Cancer and western geographic region were associated with reduced likelihood for deprescribing. CONCLUSION: In a national sample of NH residents with dementia, bisphosphonate deprescribing was uncommon, and associated with clinical characteristics signifying poor prognosis and decreased likelihood for long-term benefit. Future studies should evaluate clinical outcomes of deprescribing bisphosphonates in this population.

Fracture rates and economic outcomes in patients with osteoporosis prescribed risedronate gastro-resistant versus other oral bisphosphonates: a claims data analysis.

Patients with osteoporosis prescribed risedronate gastro-resistant had a lower incidence of fractures versus those prescribed other oral bisphosphonates. Administration of risedronate gastric-resistant does not require fasting, and this more convenient dosing administration may explain its improved efficacy. PURPOSE: Up to half of patients do not follow complex dosing instructions of immediate-release bisphosphonates used for the prevention of osteoporotic fractures, which can result in suboptimal effectiveness. Risedronate gastro-resistant (GR) offers a more convenient dosing option by eliminating the need for fasting. This study compares fracture rates and outcomes between osteoporosis women treated with risedronate GR (GR cohort) versus other oral bisphosphonates (other cohort). METHODS: Claims from women with osteoporosis in the USA were analyzed. Patients were classified into the two cohorts based on the first oral bisphosphonate observed (index date) and matched 1:1 based on patient characteristics. Patients were observed for ≥ 2 years following the index date. Fracture rates, health care resource utilization and costs, and treatment persistence were compared. RESULTS: In total, 2,726 patients were selected in each cohort (median age: 60.0 years). The incidence of fractures was lower in the GR versus the other cohort for any fracture sites (incidence rate ratio, 95% CI: 0.83, 0.70-0.97) and spine fractures (0.71, 0.54-0.95), although the respective rate of medication discontinuation at 2 years was 80.5% and 74.4%. Time to first fracture was delayed for the GR cohort, reaching statistical significance after 36 months. The GR cohort incurred fewer hospitalizations (incidence rate per 1,000 patient-years: GR = 106.74; other = 124.20, p < 0.05) translating into lower hospitalization costs per patient per year (GR = $3,611; other = $4,603, p < 0.05). CONCLUSIONS: Patients prescribed risedronate GR versus other bisphosphonates had a lower incidence of fractures, which may be explained by the fact that the GR formulation is absorbed even when taken with food.

Treatment patterns and long-term persistence with osteoporosis therapies in women with Medicare fee-for-service (FFS) coverage.

Osteoporosis, a chronic disease, requires long-term therapy. In Medicare-insured women, denosumab persistence was higher than oral bisphosphonate persistence over up to 3 years of follow-up. Longer-term persistence was higher among women who persisted in the first year of therapy. INTRODUCTION: Osteoporosis, a chronic, progressive disease, requires long-term therapy; this study assessed long-term persistence with anti-resorptive therapies in postmenopausal women. METHODS: This retrospective cohort study used administrative claims for women with data in the 100% Medicare osteoporosis sample who initiated (index date) denosumab, oral/intravenous (IV) bisphosphonate, or raloxifene between 2011 and 2014 and who had ≥ 1 year (zoledronic acid: 14 months) of pre-initiation medical/pharmacy coverage (baseline). Persistence was assessed from index date through end of continuous coverage, post-index evidence of censoring events (e.g., incident cancer), death, or end of study (December 31, 2015). RESULTS: The study included 318,419 oral bisphosphonate users (78% alendronate), 145,056 denosumab users, 48,066 IV bisphosphonate users, and 31,400 raloxifene users; mean age ranged from 75.5 years (raloxifene) to 78.5 years (denosumab). In women with at least 36 months of follow-up (denosumab N = 25,107; oral bisphosphonates N = 79,710), more denosumab than oral bisphosphonate initiators were persistent at 1 year (73% vs. 39%), 2 years (50% vs. 25%), and 3 years (38% vs. 17%). Persistence decreased over time for all treatment groups, with denosumab users having the highest persistence in every follow-up time interval at or after 18 months. Women using denosumab, oral bisphosphonates, or raloxifene who persisted in a given year were more likely to remain persistent through the subsequent year. CONCLUSIONS: Denosumab users persisted longer with therapy than women using other anti-resorptive medications, including oral bisphosphonates. Early persistence may predict long-term persistence. Overall persistence with osteoporosis medications is suboptimal and may impact fracture risk. Efforts to improve first year persistence are needed.