Economic evaluation of four treatment strategies for postmenopausal patients with osteoporosis and a recent fracture in mainland China: a cost-effectiveness analysis.

Postmenopausal patients with osteoporosis who have a recent fracture are at very high risk of fracture, and this study finds that stratified treatment based on fracture risk would be a cost-effective treatment option for this population. PURPOSE: To evaluate the cost-effectiveness of four anti-osteoporosis medications (denosumab, zoledronate, teriparatide, and alendronate) for postmenopausal osteoporotic women in mainland China, using a stratified treatment strategy recommended by the American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE). METHODS: A microsimulation Markov model was used to compare the cost-effectiveness of the four treatments in postmenopausal osteoporotic patients of different ages (65, 70, 75, and 80 years), with a recent fracture from the Chinese healthcare perspective. The primary outcome was the incremental cost-effectiveness ratio (ICER), which represent the incremental cost per quality-adjusted life-year (QALY) obtained. One-way deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) were performed to assess the robustness of model findings. RESULTS: Alendronate was dominated by denosumab-to-alendronate and zoledronate at all ages examined, indicating that the costs of the two drugs were lower, but QALYs was greater. However, teriparatide-to-alendronate yielded an ICER of $76,432.07/ QALY, compared with alendronate at age 65, which exceeded the pre-determined willingness-to-pay threshold of $37,653/ QALY. The results were similar at other ages. The DSA showed that the most sensitive parameters were drug efficacy for vertebral and wrist fractures, the relative risk of vertebral fractures, and the persistence of the drugs. The PSA showed that zoledronate had a 100% probability of being the most cost-effective treatment, with a willingness-to-pay threshold of $37,653/ QALY. CONCLUSION: Stratified treatment based on very high fracture risk is more cost-effective than conventional pills in mainland China. Among the stratified treatments, zoledronate is the optimal option.

Cost-Effectiveness of Sequential Abaloparatide/Alendronate in Men at High Risk of Fractures in the United States.

BACKGROUND AND OBJECTIVES: Abaloparatide (ABL) significantly increases bone mineral density in men with osteoporosis similar to what was reported in postmenopausal women with osteoporosis. The cost effectiveness of sequential treatment with ABL followed by alendronate (ALN) in men at high fracture risk was compared to relevant alternative treatments. METHODS: A Markov-based microsimulation model based on a lifetime US healthcare decision maker perspective was developed to evaluate the cost (expressed in US$2021) per quality-adjusted life-years (QALYs) gained of sequential ABL/ALN. Comparators were sequential treatment unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Discount rates of 3% were used. Consistent with practice guidelines, patients received 18 months of ABL or TPTD followed by ALN for 5 years, or 5 years of ALN monotherapy. Analyses were conducted in high-risk men aged over 50 years defined as having a bone mineral density T-score ≤-2.5 and a recent fracture. Time-specific risk of subsequent fracture after a recent fracture, incremental costs up to 5 years following fractures, real-world medication adherence, and mostly US men-specific data were included in the model. One-way and probabilistic sensitivity analyses were conducted to assess the robustness of results. RESULTS: Over the full age range, sequential ABL/ALN led to more QALYs for lower costs than sequential unbranded TPTD/ALN, while no treatment was dominated (more QALYs, lower costs) by ALN monotherapy. The costs per QALY gained of sequential ABL/ALN were lower than the US threshold of US$150,000 versus generic ALN monotherapy. The probabilities that sequential ABL/ALN was cost effective compared to ALN monotherapy were estimated at 51% in men aged 50 years and between 88 and 90% in those aged ≥ 60 years. CONCLUSIONS: Sequential therapy using ABL/ALN may be cost effective compared with generic ALN monotherapy in US men aged ≥ 50 years at high fracture risk, especially in those aged ≥ 60 years. Unbranded TPTD/ALN and no treatment were dominated interventions (less QALY, more costs) compared with ABL/ALN or ALN monotherapy.

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.

Cost-effectiveness analysis of five drugs for treating postmenopausal women in the United States with osteoporosis and a very high fracture risk.

PURPOSE: Five strategies were recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) guidelines for the treatment of postmenopausal osteoporosis (PMO) patients with a very high fracture risk. We aimed to assess their cost-effectiveness in the United States (US). METHODS: A microsimulation Markov model was created to compare the cost-effectiveness of five treatment strategies, including zoledronate, denosumab, abaloparatide, teriparatide, and romosozumab in PMO patients with a recent fracture from the healthcare perspective of the US. The data used in the model were obtained from published studies or online resources. Base-case analysis, one-way deterministic sensitivity analysis (DSA) and probability sensitivity analysis (PSA) were conducted for 65-, 70-, 75-, and 80-year-old patients. RESULTS: In base case, at 65 years, zoledronate was the cheapest strategy. The incremental cost-effectiveness ratios (ICER, which represent incremental costs per QALY gained) of denosumab, teriparatide, abaloparatide, and romosozumab against zoledronate were $13,020/QALY (quality-adjusted years), $477,331 /QALY, $176,287/QALY, and $98,953/QALY, respectively. Under a willing-to-pay (WTP, which means the highest price a consumer will pay for one unit of a good of service) threshold of $150,000/QALY, denosumab and romosozumab were cost-effective against zoledronate. The PSA results showed that denosumab was the most cost-effective option with WTP thresholds of $50,000/QALY, $100,000/QALY and $150,000/QALY. The results were similar in other age groups. The DSA results indicated that the most common parameters that have important influence on the outcome were drug persistence, incidence of adverse events, the efficacy of drugs on hip fractures and the cost of the drug. CONCLUSION AND RELEVANCE: Among PMO patients with a very high fracture risk in the US, zoledronate is the cheapest strategy and denosumab is the most cost-effective choice among these five strategies.

Cost-utility Analysis of Neoadjuvant Teriparatide Therapy in Osteopenic Patients Undergoing Adult Spinal Deformity Surgery.

STUDY DESIGN: A cost-utility analysis study. OBJECTIVE: This study aims to evaluate the cost-utility of neoadjuvant teriparatide therapy in osteopenic patients undergoing adult spinal deformity (ASD) surgery. SUMMARY OF BACKGROUND DATA: There is increasing evidence supporting preoperative use of anabolic agents such as teriparatide for preoperative optimization of ASD patients with poor bone density. However, such treatments are associated with added costs. To our knowledge, the cost-utility of teriparatide in osteopenic patients undergoing ASD surgery has not been established. MATERIALS AND METHODS: A decision-analysis model was developed for a hypothetical 68-year-old female patient with osteopenia ( T score <-1.0) undergoing a T11 to pelvis instrumented spinal fusion for ASD. A comprehensive literature review was conducted to create estimates for event probabilities, costs, and quality adjusted life years at each node. Key model assumptions were that administration of a 4-month preoperative teriparatide course reduced 2-year postoperative reoperation rates [for pseudarthrosis from 5% to 2.5% and for proximal junctional failure (PJF) from 15% to 5%]. Monte Carlo simulations were used to calculate the mean incremental cost utility ratio and incremental net monetary benefits. One-way sensitivity analysis was used to estimate the contribution of individual parameters to uncertainty in the model. RESULTS: Teriparatide was the favored strategy in 82% of the iterations. The mean incremental cost utility ratio for the teriparatide strategy was negative (higher net benefit, lower net cost), and lower than the willingness-to-pay threshold of $50,000 per quality adjusted life year. Teriparatide use was associated with a mean incremental net monetary benefit of $3,948. One-way sensitivity analysis demonstrated that the factors with the greatest impact on the model were the incidence of PJF in the no teriparatide group, the duration and monthly cost of treatment, and the cost of reoperation due to PJF. CONCLUSIONS: Neoadjuvant teriparatide is a cost-effective strategy to reduce postoperative complications in patients with osteopenia undergoing ASD surgery.

Denosumabe e teriparatida para o tratamento indivíduos com osteoporose grave e falha terapêutica aos medicamentos disponíveis no Sistema Único de Saúde / Denosumab and teriparatide for the treatment of individuals with severe osteoporosis and therapeutic failure to the drugs available in the Unified Health System

INTRODUÇÃO: A osteoporose, doença que aumenta da fragilidade óssea e suscetibilidade à fratura, afeta cerca de 200 milhões de pessoas no mundo. No geral, a prevalência de osteoporose em estudos brasileiros varia de 6% a 33% dependendo da população e outras variáveis avaliadas. Entre os indivíduos com osteoporose, aqueles que apresentaram fratura osteoporótica têm duas vezes o risco para nova fratura. Para evitar novas fraturas, o tratamento preconizado deve incluir estratégias medicamentosas e não medicamentosas. Entre as medicamentosas, suplementação de cálcio e colecalciferol, alendronato, risedronato, pamidronato, raloxifeno, calcitonina e estrógenos conjugados são opções disponíveis no Protocolo Clínico de Diretrizes Terapêuticas (PCDT) de Osteoporose do Sistema Único de Saúde (SUS). Apesar da disponibilidade de tratamentos, estima-se que 25% dos pacientes continuam a apresentar falha terapêutica aos tratamentos disponíveis. Nesse contexto, as diretrizes clínicas nacionais e internacionais de sociedade médicas, recomendam o uso de denosumabe ou teriparatida a pacientes com osteoporose grave e falha terapêutica aos medicamentos disponíveis no SUS (alendronato, pamidronato, raloxifeno e risedronato). Entretanto, há incerteza se os benefícios identificados para população em tratamento de primeira linha, principal população incluída nos estudos, são sustentados em população com osteoporose grave e falha terapêutica em vigência de tratamento; e se a escolha, por estas opções terapêuticas, pode valer a pena e ser viável economicamente para o SUS. Assim, o objetivo do presente relatório é analisar as evidências científicas sobre eficácia, efetividade, segurança, bem como evidências econômicas do denosumabe e da teriparatida para o tratamento de pacientes com osteoporose grave com falha terapêutica aos medicamentos disponíveis no SUS (alendronato, pamidronato, raloxifeno e risedronato). TECNOLOGIAS: Denosumabe (Prolia®) e teriparatida (Fortéo®). PERGUNTA: Os medicamentos denosumabe e

Cost-Effectiveness of Sequential Teriparatide/Zoledronic Acid Compared With Zoledronic Acid Monotherapy for Postmenopausal Osteoporotic Women in China.

Objective: We aimed to assess the cost-effectiveness of sequential teriparatide/zoledronic acid relative to zoledronic acid monotherapy for postmenopausal osteoporotic women in China. Methods: A previously validated Markov microsimulation model was updated to examine the cost-effectiveness of daily subcutaneous teriparatide for 2 years followed by annual intravenous zoledronic acid for 3 years (sequential teriparatide/zoledronic acid), compared with zoledronic acid monotherapy for 3 years in Chinese women with postmenopausal osteoporosis at ages 65, 70, 75, and 80 from the health care payer perspective. Results: The incremental cost-effectiveness ratios (ICERs) (US dollars [$] per quality-adjusted life-year [QALY]) of sequential teriparatide/zoledronic acid vs. zoledronic acid monotherapy was $173,223/QALY at age 65 years, which was much higher than the pre-determined willingness-to-pay (WTP) threshold of $ 31,512/QALY, and the results were similar at other ages. In one-way sensitivity analyses, the two most impactful parameters were the cost of teriparatide and the residual effects of the medications included in this study. Sequential teriparatide/zoledronic acid became cost-effective at age 80 with the cost of teriparatide reduced by 50%. Without the residual effect, the ICER increased to $257,982/QALY. Probabilistic sensitivity analyses shown that the probabilities of zoledronic acid monotherapy being cost-effective were 100% at a WTP of $31,512/QALY. Conclusions: Among Chinese women with postmenopausal osteoporosis, sequential teriparatide/zoledronic acid was not cost-effective unless the cost of teriparatide was reduced by 50% only for the participants over 80 years.

Patterns of Teriparatide and Sequential Antiresorptive Agent Treatment Among Elderly Female Medicare Beneficiaries.

The 2020 American Association of Clinical Endocrinologists guidelines for assessing osteoporosis among postmenopausal women stratified postmenopausal women with osteoporosis to "high" and "very-high" fracture risk categories and recommended anabolic agents as initial therapy followed by an antiresorptive agent. Switching the order can blunt the effect of anabolic agents, and failing to follow with an antiresorptive can lead to loss of bone generated by the anabolic agent. It would be helpful to understand the real-world prescribing patterns of anabolic agents. Using the 2010-2015 Medicare 100% osteoporosis database, we assessed patient profiles, teriparatide prescribers, persistence of teriparatide therapy, and antiresorptive agent use after teriparatide discontinuation among elderly women who initiated teriparatide from 2011 to 2013. This study included 14,786 patients. In the year before teriparatide initiation, 30.0% of them had a fracture, 67.6% had a dual energy x-ray absorptiometry scan, 74.4% had a diagnosis of osteoporosis, and 47.9% used antiresorptive agents (non-naïve teriparatide users). Among those who had fractures, 49.4% initiated teriparatide within 3 months postfracture. Teriparatide was prescribed for 37% of users by primary care doctors, 19% by rheumatologists, 13% by endocrinologists, and 7.0% by orthopedists. Median time of teriparatide use was 7.2 months. After teriparatide discontinuation, 40.8% switched to antiresorptive agents (31.9% among naïve teriparatide users, 50.5% among non-naïve users). Among switchers, 42.5% switched within 60 days, 50.5% switched to denosumab, and 31.6% switched to oral bisphosphonates. This study of real-world prescribing data found that about half of teriparatide users switched from an antiresorptive agent, and less than half switched to antiresorptive agents after teriparatide discontinuation. Persistence of teriparatide use was suboptimal. In the management of postmenopausal osteoporosis, increasing the persistence of teriparatide use and improving the appropriate treatment sequence of anabolic and antiresorptive drugs are critical to maximizing gains in bone mass, providing the greatest protection against fractures. © 2021 American Society for Bone and Mineral Research (ASBMR).

Cost effectiveness of romosozumab versus teriparatide for severe postmenopausal osteoporosis in Japan.

This study assessed the cost effectiveness of romosozumab versus teriparatide, both sequenced to alendronate, for the treatment of severe postmenopausal osteoporosis in Japan, using bone mineral density (BMD) efficacy data. Results show that romosozumab/alendronate produces greater health benefits at a lower cost than teriparatide/alendronate. INTRODUCTION: This study aims to assess the cost effectiveness of romosozumab versus teriparatide, both sequenced to alendronate, for the treatment of severe postmenopausal osteoporosis in Japanese women previously treated with bisphosphonates. METHODS: A Markov model was used to assess the relative cost effectiveness of 1 year of romosozumab versus 2 years of teriparatide, both sequenced to alendronate for a total treatment duration of 5 years. Outcomes for a cohort of women with a mean age of 78 years, a T-score ≤-2.5 and a previous fragility fracture were simulated over a lifetime horizon. The analysis was conducted from the perspective of the Japanese healthcare system and used a discount rate of 2% per annum. To inform relative fracture incidence, the bone mineral density (BMD) advantage of romosozumab over teriparatide was translated into relative risks of fracture, using relationships provided by a meta-regression of osteoporosis therapy trials. Outcomes were assessed in terms of lifetime costs (2020 US dollars) and quality-adjusted life years (QALYs). RESULTS: Base case results showed that, compared with teriparatide/alendronate, romosozumab/alendronate reduced costs by $5134 per patient and yielded 0.045 additional QALYs. Scenario analyses and probabilistic sensitivity analysis confirmed that results are robust to uncertainty in model assumptions and inputs. CONCLUSION: Results show that romosozumab/alendronate produces greater health benefits at a lower total cost than teriparatide/alendronate.

Comparative effectiveness of denosumab, teriparatide, and zoledronic acid among frail older adults: a retrospective cohort study.

The comparative effects of zoledronic acid, denosumab, and teriparatide for preventing hip fractures in frail older adults, especially those in nursing homes, were unknown. We found that denosumab and zoledronic acid may be as effective as teriparatide for hip fracture prevention in nursing home residents. INTRODUCTION: Several non-oral drugs exist for osteoporosis treatment, including zoledronic acid (ZA), denosumab, and teriparatide. Little data exist on the comparative effectiveness of these drugs for hip fracture prevention in frail older adults. We examined their comparative effectiveness in one of the frailest segments of the US population-nursing home (NH) residents. METHODS: We conducted a national retrospective cohort study of NH residents aged ≥ 65 years using 2012 to 2016 national US Minimum Data Set clinical assessment data and linked Medicare claims. New parenteral ZA, denosumab, and teriparatide use was assessed via Medicare Parts B and D; hip fracture outcomes via Part A; and 125 covariates for confounding adjustment via several datasets. We used inverse probability weighted (IPW) competing risk regression models to compare hip fracture risk between groups with teriparatide as the reference. RESULTS: The study cohort (N = 2019) included 1046 denosumab, 578 teriparatide, and 395 ZA initiators. Mean age was 85 years, 90% were female, and 68% had at least moderate functional impairment. Seventy-two residents (3.6%) had a hip fracture and 1100 (54.5%) died over a mean follow-up of 1.5 years. Compared to teriparatide use, denosumab use was associated with a 46% lower risk of hip fracture (HR 0.54, 95% CI 0.29-1.00) and no difference was observed for ZA (HR 0.70, 95% CI 0.26-1.85). CONCLUSIONS: Denosumab and ZA may be as effective as teriparatide for hip fracture prevention in frail older adults. Given their lower cost and easier administration, denosumab and ZA are likely preferable non-oral treatments for most frail, older adults.

Eficácia e segurança da Teriparatida comparada aos bifosfonados orais e Raloxifeno para prevenção de fraturas em osteoporose: revisão rápida de evidências / Effectiveness, safety and cost-effectiveness of Teriparatide compared to oral biposphonates or Raloxifene for osteoporotic fracture prevention: rapid review of evidence

Tecnologia: Teriparatida, comparada a bifosfonados orais ou Raloxifeno. Indicação: prevenção de fraturas em pessoas com osteoporose. Pergunta: A Teriparatida é mais eficaz e segura que os bifosfonados orais ou o Raloxifeno para tratamento da osteoporose e prevenção de fraturas secundárias à osteoporose? Métodos: Levantamento bibliográfico foi realizado na base de dados PUBMED, seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta Assessing the Methodological Quality of Systematic Reviews version 2 (AMSTAR-2). Resultados: Foram selecionadas 2 revisões sistemáticas, que atendiam aos critérios de inclusão. Conclusão: Para a população em geral com osteoporose, a Teriparatida evita mais fraturas vertebrais que o Alendronato de sódio ou Risedronato de sódio, mas efeito similar para fraturas não vertebrais. Teriparatida previne mais fraturas vertebrais e não vertebrais que Raloxifeno. Teriparatida tem maior efeito sobre a massa óssea corporal que o Risedronato de sódio e o Raloxifeno, mas tem efeito similar ao Alendronato de sódio. Na população masculina com osteoporose, a terapia com bifosfonados orais é mais eficaz que suplementação nutricional ou placebo para prevenir fraturas. Já o tratamento com Teriparatida não é mais eficaz que a suplementação nutricional ou placebo

Teriparatide compared to oral bisphosphonates or Raloxifene. Indication: prevention of fractures in people with osteoporosis. Question: Is Teriparatide more effective and safer than oral bisphosphonates or Raloxifene for treating osteoporosis and preventing fractures secondary to osteoporosis? Methods: Bibliographic survey was carried out in the PUBMED database, following predefined search strategies. Evaluation of the methodological quality of systematic reviews was carried out using the tool Assessing the Methodological Quality of Systematic Reviews version 2 (AMSTAR-2). Results: Two systematic reviews were selected, which met the inclusion criteria. Conclusion: For the general population with osteoporosis, Teriparatide prevents more vertebral fractures than Alendronate or Risedronate sodium, but has similar effect for non-vertebral fractures. Teriparatide prevents more vertebral and non-vertebral fractures than Raloxifene. Teriparatide has a greater effect on body bone mass than Risedronate sodium and Raloxifene, but it has a similar effect to Alendronate sodium. In the male population with osteoporosis, oral bisphosphonates is more effective than nutritional supplementation or placebo to prevent fractures. Treatment with teriparatide is no more effective than nutritional supplementation or placebo

Characterizing patients initiating abaloparatide, teriparatide, or denosumab in a real-world setting: a US linked claims and EMR database analysis.

We characterized patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) in a real-world clinical setting from a large medical and pharmacy claims database. Differences were noted in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use for patients initiating ABL and TPTD compared with those receiving DMAB. INTRODUCTION: To characterize patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) treatment in a real-world clinical setting. METHODS: Patients aged ≥ 18 years initiating ABL, TPTD, or DMAB between May 1, 2017, and September 24, 2018 (without receiving the same drug in the previous 12 months), were identified using the OM1 Data Cloud, which contains medical and pharmacy claims from approximately 200 million US patients. The index date was the date of initial prescription or dispensing for ABL, TPTD, or DMAB during the study period. RESULTS: During the study period, 2666 patients initiated ABL, 9210 TPTD, and 116,718 DMAB. Mean age (standard deviation) was 69.2 (10.6) years for the ABL cohort, 68.6 (11.3) for TPTD, and 72.1 (10.2) for DMAB (P < 0.001; ABL vs DMAB). Proportionally more patients initiating ABL were female (95.2% ABL, 86.9% TPTD, and 91.3% DMAB, P < 0.001 ABL vs TPTD or DMAB). Nearly twice as many patients initiating ABL (19.1%) and TPTD (18.8%) had a previous pathologic/fragility fracture vs DMAB (9.6%; P < 0.001 ABL vs DMAB). Fewer patients initiating ABL (36.3%) or TPTD (39.7%) had Charlson comorbidity index of ≥ 2 vs DMAB (48.4%; P < 0.001 ABL vs DMAB). Before initiating ABL, TPTD, or DMAB, 44.3%, 33.8%, and 33.9% of patients had prior osteoporosis treatment, respectively. Bisphosphonate use was more common before initiating ABL (19.2%) or TPTD (19.6%), than before initiating DMAB (16.6%; P < 0.001 ABL vs DMAB). CONCLUSIONS: Patients initiating ABL and TPTD differed in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use compared with those initiating DMAB.

Denosumab, raloxifene, romosozumab and teriparatide to prevent osteoporotic fragility fractures: a systematic review and economic evaluation.

BACKGROUND: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. OBJECTIVES: The objectives were to evaluate the clinical effectiveness, safety and cost-effectiveness of non-bisphosphonates {denosumab [Prolia®; Amgen Inc., Thousand Oaks, CA, USA], raloxifene [Evista®; Daiichi Sankyo Company, Ltd, Tokyo, Japan], romosozumab [Evenity®; Union Chimique Belge (UCB) S.A. (Brussels, Belgium) and Amgen Inc.] and teriparatide [Forsteo®; Eli Lilly and Company, Indianapolis, IN, USA]}, compared with each other, bisphosphonates or no treatment, for the prevention of fragility fracture. DATA SOURCES: For the clinical effectiveness review, nine electronic databases (including MEDLINE, EMBASE and the World Health Organization International Clinical Trials Registry Platform) were searched up to July 2018. REVIEW METHODS: A systematic review and network meta-analysis of fracture and femoral neck bone mineral density were conducted. A review of published economic analyses was undertaken and a model previously used to evaluate bisphosphonates was adapted. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years for a simulated cohort of patients with heterogeneous characteristics. This was done for each non-bisphosphonate treatment, a strategy of no treatment, and the five bisphosphonate treatments previously evaluated. The model was populated with effectiveness evidence from the systematic review and network meta-analysis. All other parameters were estimated from published sources. An NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net monetary benefit was estimated using non-parametric regression. A probabilistic sensitivity analysis and scenario analyses were used to assess uncertainty. RESULTS: Fifty-two randomised controlled trials of non-bisphosphonates were included in the clinical effectiveness systematic review and an additional 51 randomised controlled trials of bisphosphonates were included in the network meta-analysis. All treatments had beneficial effects compared with placebo for vertebral, non-vertebral and hip fractures, with hazard ratios varying from 0.23 to 0.94, depending on treatment and fracture type. The effects on vertebral fractures and the percentage change in bone mineral density were statistically significant for all treatments. The rate of serious adverse events varied across trials (0-33%), with most between-group differences not being statistically significant for comparisons with placebo/no active treatment, non-bisphosphonates or bisphosphonates. The incremental cost-effectiveness ratios were > £20,000 per quality-adjusted life-year for all non-bisphosphonate interventions compared with no treatment across the range of QFracture and FRAX scores expected in the population eligible for fracture risk assessment. The incremental cost-effectiveness ratio for denosumab may fall below £30,000 per quality-adjusted life-year at very high levels of risk or for high-risk patients with specific characteristics. Raloxifene was dominated by no treatment (resulted in fewer quality-adjusted life-years) in most risk categories. LIMITATIONS: The incremental cost-effectiveness ratios are uncertain for very high-risk patients. CONCLUSIONS: Non-bisphosphonates are effective in preventing fragility fractures, but the incremental cost-effectiveness ratios are generally greater than the commonly applied threshold of £20,000-30,000 per quality-adjusted life-year. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018107651. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 29. See the NIHR Journals Library website for further project information.

BACKGROUND: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture, known as low-level (or 'low-energy') trauma. Some people are at particularly high risk of fragility fractures. The first treatment used is often a bisphosphonate, but non-bisphosphonate treatments are alternatives. AIMS: We aimed to determine how effective non-bisphosphonates {denosumab [Prolia®; Amgen Inc., Thousand Oaks, CA, USA], raloxifene [Evista®; Daiichi Sankyo Company, Ltd, Tokyo, Japan], romosozumab [Evenity®; Union Chimique Belge (UCB) S.A. (Brussels, Belgium) and Amgen Inc.] and teriparatide [Forsteo®; Eli Lilly and Company, Indianapolis, IN, USA]} are at preventing fractures, whether or not treatment has any risks for patients and whether or not the clinical benefits are achieved at a reasonable cost. METHODS: We have systematically identified and examined trials that assessed the clinical effects of non-bisphosphonates. For each clinical outcome, we have combined data from multiple trials to estimate the clinical effectiveness of each non-bisphosphonate treatment. We combined data from published sources in an economic model to estimate lifetime costs and clinical benefits for each non-bisphosphonate and compared these with the estimated costs and clinical outcomes for untreated patients and patients treated with bisphosphonates. RESULTS: All non-bisphosphonates reduced the risk of vertebral fractures compared with no treatment. For fractures at the hip or at any non-vertebral site, all of the non-bisphosphonates reduced the average number of fractures, but, for some non-bisphosphonates, we could not exclude the possibility that this was a chance finding. The chance of patients experiencing serious side effects was generally similar regardless of whether patients took non-bisphosphonates, bisphosphonates or placebo (a dummy pill). Blood clots were more common in patients taking raloxifene than in those taking placebo, but these were still a rare outcome (fewer than 1 in 100). The benefits of denosumab, teriparatide and romosozumab are few compared with their costs. For raloxifene, the risks generally outweigh the benefits. Treatment with bisphosphonates is likely to represent better value for money than treatment with non-bisphosphonates.

Treatment options for glucocorticoid-induced osteoporosis.

INTRODUCTION: Glucocorticoid (GC) induced osteoporosis (GIOP) is the most common form of secondary osteoporosis. It develops in a dose and time dependent manner, due to a rapid and transient increase in bone resorption, followed by the inhibition of bone formation. AREAS COVERED: In this review, the authors summarize the pathophysiology of GIOP and give discussion to the clinical management of patients taking GCs, focusing on the currently available drugs that have antiresorptive or anabolic activity on bone. EXPERT OPINION: Despite the widespread use of GCs and their well-established detrimental skeletal effects, GIOP remains an under-diagnosed and under-treated condition. Indeed, the clinical management of GIOP is still debated, so that the recent guidelines differ in their indications for pharmacological intervention. Either bone mineral density (BMD) or algorithms such as FRAX do not completely account for the remarkable and rapid increase in fracture risk of most GC-treated patients. Moreover, while oral bisphosphonates remain the most used and cost-effective option, the potential increased benefits of more potent antiresorptive agents (e.g. denosumab and zoledronate) or anabolic compounds (e.g. teriparatide) warrant further investigation. Despite the above limitations, the assessment of fracture risk is recommended for all individuals committed to receiving oral GCs for 3 months or longer.

Effects of teriparatide versus percutaneous vertebroplasty on pain relief, quality of life and cost-effectiveness in postmenopausal females with acute osteoporotic vertebral compression fracture: A prospective cohort study.

BACKGROUND: Osteoporotic vertebral compression fracture (OVCF) is a common disease in senior patients. Conservative treatments (usual care) and percutaneous vertebroplasty (PVP) are typically applied to treat OVCFs; however, their efficacies are not fully satisfactory. While Teriparatide (TPTD) is effective in both anti-osteoporosis and bone healing, whether TPTD could be applied as a conservative treatment for acute OVCFs remains unclear. METHODS: This investigation represents a real-world prospective cohort study, where 60 postmenopausal women (≥55 years old) with acute OVCFs were equally assigned to a TPTD conservative group or PVP (plus alendronate) group based on the patient's choice. TPTD (20 µg, s.c., once daily) or alendronate (70 mg, p.o., once weekly) were administrated together with 0.6 mg Caltrate and 500 iu Vitamin D3 per day. A health survey (SF-36) was conducted at 0-, 1- and 3-months post-treatment. Back pain and the Oswestry Disability Index (ODI) were measured at 0-week, 1-week, 1-month and 3-months after treatment, while the direct medical cost was analyzed at the end of the third month. RESULTS: Both treatments with TPTD and PVP significantly and similarly improved the patients' health quality, with reduced visual analogue and ODI scores at the end of the first and third months. PVP was more effective in reducing pain at the early time point (1 week, p < 0.05). 24 of 27 patients who were rescanned with magnetic resonance imaging in the TPTD group showed bone healing. The mid-vertebral height was increased by PVP (p < 0.05) but not by TPTD. The cost of TPTD treatment was 21,868.61 ±â€¯167.05 RMB per capita, while the cost for PVP treatment was 33,265.95 ±â€¯1491.11 RMB per capita (p < 0.05). CONCLUSION: TPTD conservative treatment obtained similar therapeutic effects but cost less than PVP in terms of treating acute OVCF.

Teriparatida en osteoporosis refractaria a bifosfonatos y alto riesgo de fractura / Teriparatide in osteoporosis refractory to bisphosphonates and high risk of fracture

CONTEXTO CLÍNICO: La Organización Mundial de la Salud (OMS) define a la osteoporosis como una enfermedad caracterizada por la disminución de la masa ósea y el deterioro de la microarquitectura del tejido óseo, que incrementa la fragilidad del esqueleto, con el consecuente aumento del riesgo de fractura. En base a la densidad mineral ósea, la OMS define osteoporosis a un T-score menor a -2,5 en columna lumbar, fémur o cuello femoral (Anexo III). Afecta a la población a nivel mundial, estimando que del 30 al 50% de las mujeres posmenopáusicas se ven afectadas por una baja densidad mineral ósea (DMO) y el 20% de los hombres mayores de 50 años. Según criterios de la Organización Mundial de la Salud, en la Argentina sólo una de cada cuatro mujeres mayores de 50 años presenta densitometría normal, dos tienen osteopenia y una osteoporosis. La proyección para el año 2025 según datos nacionales, estima que habrá 3,3 millones de mujeres posmenopáusicas con osteopenia y 1,65 millones con osteoporosis en la Argentina. El gasto asociado a la osteoporosis se desprende del costo directo del tratamiento de una fractura de cadera (3.800 dólares estadounidenses en el año 2010), y los de tratar una fractura vertebral (163 dólares estadounidenses en el año 2010); por lo tanto, los costos anuales de las consecuencias de la baja densidad mineral ósea en la Argentina son de aproximadamente 192 millones de dólares estadounidenses (año 2010). TECNOLOGÍA: La hormona paratiroidea endógena es la reguladora principal del metabolismo del calcio y del fósforo en el hueso y el riñón.9 Teriparatida es el fragmento activo de la hormona paratiroidea humana endógena. Es un agente formador de hueso que se utiliza para el tratamiento de la osteoporosis. Produce un aumento de la aposición de hueso nuevo en las superficies óseas trabecular y cortical al estimular en mayor medida la actividad osteoblástica sobre la actividad osteoclástica. Los eventos adversos más frecuentes son: anemia, hipercolesterolemia, depresión, mareos, cefalea, síncope, vértigo, palpitaciones, hipotensión, disnea. Con menor frecuencia puede presentarse hipercalcemia, hiperuricemia, taquicardia. Los estudios en ratas indican un aumento en la incidencia de osteosarcoma con la administración a largo plazo de teriparatida. Por lo cual no se debe exceder el tiempo recomendado de tratamiento de 24 meses. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de teriparatida para osteoporosis refractaria a bifosfonatos en pacientes con alto riesgo de fractura. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron dos ECAs, dos RS con MA, diez GPC, dos ETS, dos evaluaciones económicas y 12 informes de políticas de cobertura de teriparatida en osteoporosis refractaria a bifosfonatos y alto riesgo de fractura. CONCLUSIONES: Evidencia de alta calidad muestra que teriparatida en comparación a risedronato disminuye el riesgo de fractura vertebral en pacientes posmenopáusicas con osteoporosis y alto riesgo de fractura. Evidencia de moderada calidad sugiere que teriparatida en pacientes con osteoporosis refractaria en al menos un bifosfonato se asociaría a un menor riesgo de fractura vertebral y no vertebral en comparación a bifosfonatos o denosumab; no obstante, presentaría un menor beneficio que denosumab en la reducción del riesgo de fractura en cadera. El mayor beneficio obtenido con teriparatida se observa en pacientes muy seleccionados, con un muy alto riesgo de fractura o presencia de fracturas previas, T score < -3,5 y falla a dos líneas previas de bifosfonatos. Existe consenso parcial entre las guías de práctica clínica relevadas en recomendar su utilización en pacientes con osteoporosis y muy alto riesgo de fractura, principalmente vertebrales, que han fallado o no toleran los bifosfonatos; y en pacientes con osteoporosis secundaria a glucocorticoides. La mayoría de las políticas de cobertura relevadas cubren el uso de teriparatida en pacientes con diagnóstico de osteoporosis y alto riesgo de fractura que no hayan respondido adecuadamente a los bifosfonatos, es decir, pacientes añosos con antecedente de fracturas osteoporóticas, consumo de glucocorticoides y un T-score inferior a -3. No se encontraron estudios de costo-efectividad de teriparatida en Argentina. Dentro de las evaluaciones de tecnologías sanitarias consultadas Colombia y Perú no lo consideran costo-efectivo. No obstante, las evaluaciones realizadas en Europa y Brasil concluyen que teriparatida es costo-efectiva cuando se utiliza en pacientes muy seleccionados, es decir, en pacientes con osteoporosis y muy elevado riesgo de fractura que han fallado a una terapia previa con bifosfonatos.

Status quo of osteoporosis treatment in Japan disclosed by the National Database of Health Insurance Claims and Specific Health Checkups: too late in treatment initiation and too few in treated patients?

For the first time ever, the details of osteoporotic treatment were unveiled through the big data published by the government of Japan. The number of patients being treated is low and treatment start is late, especially in men. Our data are useful for education to not only patients but also doctors. PURPOSE: To analyze the current status and trend of osteoporosis treatment in Japan by analyzing the data on main drugs for osteoporosis disclosed in the National Database open data. METHODS: We used the National Database open data released by the Ministry of Health, Labour and Welfare in September 2018. Data on bisphosphonates, denosumab, and teriparatide were extracted to calculate the number of patients treated with these drugs based on the number of prescriptions filed. Using these prescription numbers, the proportion of patients treated with bisphosphonates, denosumab, or teriparatide among osteoporosis patients was calculated. Further, the data on the incidence of hip fractures were employed to validate the appropriateness of the timing of treatment initiation to osteoporosis patients in Japan. RESULTS: The number of patients in men administered bisphosphonates, denosumab, or teriparatide was about one tenth of that in women. The proportion of osteoporosis patients in men treated with bisphosphonates, denosumab, or teriparatide was highest in age group over 80 years at 19.4%. The proportion of osteoporosis patients in women treated with bisphosphonates, denosumab, or teriparatide was highest in age group 70-79 years at 23.7%. The incidence of hip fractures increases sharply over 80 years of age in both genders. CONCLUSION: Our findings suggested that osteoporosis treatment should be initiated in younger age, especially in men, in order to avoid osteoporotic fractures in Japan.

Debería usarse Denosumab para la prevención y tratamiento de fracturas osteoporóticas en la mujer postmenopáusica? / Should Denosumab be used for the prevention and treatment of osteoporotic fractures in postmenopausal women?

CONTEXTO: La osteoporosis es un trastorno esquelético caracterizado por resistencia óssea comprometida, predisposición pacientes a un mayor riesgo de fractura. La prevalência aumenta del 6% de las mujeres de edad 50 a 59 años a más del 40% de las mujeres de edad 80 años y mayores.1 Consecuencias de mantener una fractura puede ser grave e incluir un aumento riesgo de fracturas posteriores, hospitalización o institucionalización, disminución de la calidad de vida, y mortalidad prematura, con una carga relacionada com el sistema de salud. DESCRIPCIÓN DE LA TECNOLOGÍA: El denosumab es un anticuerpo monoclonal que inhibe la resorción ósea producida por los osteoclastos. Fue comercializado en 2010 para el tratamiento de la osteoporosis. En estos años se han identificado varios efectos adversos potencialmente graves: predisposición a infecciones, cáncer, reacciones de hipersensibilidad, transtornos autoinmunes, e incremento de la incidencia de múltiples fracturas vertebrales espontáneas al suspender el tratamiento. En este número revisamos estas novedades. TECNOLOGÍAS ALTERNATIVAS: Los agentes antirresortivos como los bifosfonatos orales son el estándar tratamiento para la osteoporosis posmenopáusica, en conjunto con medidas no farmacológicas y sobre todo el énfasis en la prevención de las caídas. Otras opciones de tratamiento incluyen un bisfosfonatos intravenoso (ácido zoledrónico), un agente formador de hueso (teriparatida) y un modulador selectivo del receptor de estrógeno (raloxifeno). MÉTODOS: Se realizó una búsqueda bibliográfica utilizando las siguientes bases de datos bibliográficas: MEDLINE, EMBASE, The Cochrane Library, y PubMed. Aplicaron filtros metodológicos para evaluaciones de tecnología sanitaria, estudios económicos, revisiones sistemáticas, metanálisis, y ensayos controlados aleatorios (ECA). La búsqueda también se limitó a Idioma en Inglés y humanos. Se excluyeron los resúmenes de congresos en los resultados de búsqueda. Se identificó la literatura gris (literatura que no se publica comercialmente) fue identificado mediante la búsqueda de secciones relevantes de la Lista de verificación de Grey Matters (http://www.cadth.ca/en/resources/grey-matters). Google y otros motores de búsqueda de internet fueron se utiliza para buscar en la web adicional materiales Estas búsquedas se complementaron con revisar las bibliografías de documentos clave y a través de contactos con expertos apropiados. ESTRATEGIA DE BÚSQUEDA: Se realizó una búsqueda con última fecha 26/08/2019 en diversas bases de datos, incluidas PubMed y Embase, así como la biblioteca Cochrane, ClinicalTrials.gov y bases de datos de revisiones sistematicas Epistemonikos. La búsqueda sólo incluyó documentos escrito en ingles y espanol. RESULTADOS: Denosumab comparado con placebo para pacientes con osteoporosis. El riesgo en el grupo de intervención (y su intervalo de confianza del 95%) se basa en el riesgo asumido en el grupo de comparación y en el efecto relativo de la intervención (y su intervalo de confianza del 95%). Eficacia frente a bifosfonatos: comparaciones directas. Se evalúa el perfil de evidencia GRADE donde se evidencia el metaanálisis entre cuatro ECA 5-8 que comprendieron 2071 participantes con un rango de seguimiento de 12 a 24 meses y compararon el uso de Denosumab con bifosfonatos orales (Alendronato,Etidronato). Existe incertidumbre en el efecto de denosumab sobre el riesgo de fracturas en comparación con bifosfonatos. La certeza em la evidencia va desde BAJA A MUY BAJA considerando la presencia de imprecisión muy seria y el potencial riesgo de sesgo de publicación. Eficacia frente a bifosfonatos: comparaciones indirectas. No se han encontrado en la literatura comparaciones directas entre Denosumab y otros fármacos distintos. Esta recomendación de cobertura otorga más peso a la incertidumbre en la eficacia comparada con bifosfonatos, al potencial impacto presupuestario de su uso y la potencial reducción de la equidad; que a la preferencia de los pacientes respecto de la forma de administración de las drogas para osteoporosis.

Cost-effectiveness of sequential treatment with abaloparatide vs. teriparatide for United States women at increased risk of fracture.

OBJECTIVES: There is emerging evidence supporting sequential therapy with an osteoanabolic followed by an antiresorptive in patients at high-risk of fragility fractures. This study assessed the cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) [(ABL/ALN)] compared with teriparatide (TPTD) followed by ALN (TPTD/ALN). METHODS: A previously validated Markov microsimulation model was adapted to estimate the cost-effectiveness of sequential ABL/ALN compared with sequential TPTD/ALN and no treatment with a lifetime horizon from the US payer perspective. Patients were assumed to receive ABL or TPTD for 18 months followed by 5 years of ALN in line with clinical recommendations. The effects of ABL on fracture risk were derived from the ACTIVExtend trial. The effects of TPTD were assumed to be maintained during subsequent ALN treatment, consistent with ACTIVExtend findings for ABL. Evaluation was completed for patients, aged 50-80 years with a BMD T-score ≤ -3.5 or with a T-score between -2.5 and -3.5 and a history of ≥ one osteoporotic fracture. RESULTS: In all simulated populations, sequential ABL/ALN therapy was dominant (lower costs, higher QALYs) compared with sequential TPTD/ALN therapy, resulting from the improved efficacy and lower drug price of ABL. Probabilistic sensitivity analyses suggested that ABL/ALN was dominant in at least 99% of the simulations. Compared to no treatment, the cost per QALY gained of ABL/ALN was always below $130,000. CONCLUSIONS: Sequential ABL/ALN therapy is a cost-effective (dominant) strategy compared with sequential TPTD/ALN therapy for the treatment of US women at increased risk of fractures.

Current Understanding of Epidemiology, Pathophysiology, and Management of Atypical Femur Fractures.

PURPOSE OF REVIEW: To summarize reports published since the 2013 American Society of Bone and Mineral Research Task Force Report on atypical femoral fractures (AFF). RECENT FINDINGS: The absolute incidence of AFFs remains low. AFFs are primarily associated with prolonged bisphosphonate (BP) exposure, but have also been reported in unexposed patients and those receiving denosumab for osteoporosis and metastatic bone disease. Asians may be more susceptible to AFFs. Lateral femoral bowing and varus hip geometry, which increase loading forces on the lateral femoral cortex, may increase AFF risk. Altered bone material properties associated with BP therapy may predispose to AFFs by permitting initiation and increasing propagation of micro-cracks. Relevant genetic mutations have been reported in patients with AFFs. Single X-ray absorptiometry femur scans permit early detection of incomplete and/or asymptomatic AFFs. Orthopedists recommend intramedullary rods for complete AFFs and for incomplete, radiologically advanced AFFs associated with pain and/or marrow edema on MRI. Teriparatide may advance AFF healing but few data support its efficacy. Greater understanding of biological and genetic predisposition to AFF may allow characterization of individual risk prior to initiating osteoporosis therapy and help allay fear in those at low risk for this complication, which remains rare in comparison to the osteoporotic fractures prevented by antiresorptive therapy.