Cost-effectiveness of romosozumab for the treatment of postmenopausal women with osteoporosis at high risk of fracture in Belgium.

This study evaluated the cost-effectiveness of sequential treatment with romosozumab-to-alendronate compared to alendronate monotherapy and teriparatide-to-alendronate, in postmenopausal osteoporotic women from a Belgian healthcare perspective. Romosozumab-to-alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide-to-alendronate for osteoporotic women at high risk of fracture in Belgium. PURPOSE: This study aimed to evaluate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate compared to alendronate monotherapy and teriparatide followed by alendronate, in postmenopausal osteoporotic women at high risk of fracture, from a Belgian healthcare perspective. Romosozumab is reimbursed in Belgium since December 2021. METHODS: A Markov microsimulation model was used to evaluate the cost-effectiveness of romosozumab-to-alendronate compared to alendronate monotherapy and to teriparatide-to-alendronate over a lifetime horizon. Patients transition between five different health states every 6 months based on fracture risks or death. The model was populated with Belgium-specific epidemiological and cost data, where available. The fracture risk reduction of romosozumab treatment was collated from the ARCH study, and from a published network meta-analysis. Costs were included from a healthcare perspective (NIHDI). Cost-effectiveness was reported in terms of costs per quality-adjusted life year (QALY), reported in Euro (€) 2022. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed. RESULTS: Romosozumab-to-alendronate was associated with 0.12 additional QALYs at an additional cost of €2314 compared to alendronate monotherapy, resulting in an ICER of €19,978. Compared to teriparatide-to-alendronate, romosozumab-to-alendronate was found to be dominant, with higher QALYs and lower costs. The base-case results were robust to uncertainty in the input parameters when conducting the sensitivity analysis. CONCLUSION: Sequential treatment with romosozumab followed by alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide followed by alendronate for postmenopausal women with osteoporosis at high risk of fracture in Belgium.

Clinical and biological parameters associated with fracture recurrence according to fracture liaison service dataset.

This study describes the characteristics of 337 patients seen by the fracture liaison service of the Amiens University Hospital for at least two osteoporotic fractures between 2009 and 2019. Results showed that recurrent fracture occurs rapidly after the index fracture. Rheumatological and therapeutic managements are not sufficient, mainly because of cognitive disorders or patients' refusal. PURPOSE: The aim of this study was to describe the characteristics of patients taken in charge by a fracture liaison service and sustaining a recurrent osteoporotic fracture. METHODS: This was a retrospective and monocentric study based on the dataset of patients included in the FLS of the Department of Rheumatology of the Amiens University Hospital. To be included in the study cohort, patients must have had at least two consecutive osteoporotic fractures between January 2009 and December 2019. RESULTS: Three hundred thirty-seven patients were included. The mean age at index fracture was 77.3 ± 12.5 years. Eighty-four percent of the patients were women. 89.3% of the patients had a Charlson comorbidity index between 1 and 4. Nearly half of the patients had cognitive disorders. Femoral neck was the most frequent site for both index and recurrent fractures. Thirty-seven percent of patients benefited from a consultation in Rheumatology after their index fracture. The main reasons for the lack of follow-up were cognitive disorders and patient rejection. CONCLUSION: Our study showed that recurrent fracture occurs rapidly after the index fracture and that rheumatological and therapeutic managements are not sufficient, mainly because of cognitive disorders or patients' refusal impairing the patients to benefit from specialized management.

Imminent fall risk after fracture.

RATIONALE: Adults with a recent fracture have a high imminent risk of a subsequent fracture. We hypothesise that, like subsequent fracture risk, fall risk is also highest immediately after a fracture. This study aims to assess if fall risk is time-dependent in subjects with a recent fracture compared to subjects without a fracture. METHODS: This retrospective matched cohort study used data from the UK Clinical Practice Research Datalink GOLD. All subjects ≥50 years with a fracture between 1993 and 2015 were identified and matched one-to-one to fracture-free controls based on year of birth, sex and practice. The cumulative incidence and relative risk (RR) of a first fall was calculated at various time intervals, with mortality as competing risk. Subsequently, analyses were stratified according to age, sex and type of index fracture. RESULTS: A total of 624,460 subjects were included; 312,230 subjects with an index fracture, matched to 312,230 fracture-free controls (71% females, mean age 70 ± 12, mean follow-up 6.5 ± 5 years). The RR of falls was highest in the first year after fracture compared to fracture-free controls; males had a 3-fold and females a 2-fold higher risk. This imminent fall risk was present in all age and fracture types and declined over time. A concurrent imminent fracture and mortality risk were confirmed. CONCLUSION/DISCUSSION: This study demonstrates an imminent fall risk in the first years after a fracture in all age and fracture types. This underlines the need for early fall risk assessment and prevention strategies in 50+ adults with a recent fracture.

Cost-effectiveness of romosozumab for the treatment of postmenopausal women with severe osteoporosis at high risk of fracture in Sweden.

Romosozumab is a novel bone-building drug that reduces fracture risk. This health economic analysis indicates that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture. PURPOSE: To estimate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate ("romosozumab-to-alendronate") compared with alendronate alone in patients with severe osteoporosis at high risk of fracture in Sweden. METHODS: A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), for women treated with romosozumab-to-alendronate or alendronate alone. Patients aged 74 years with a recent major osteoporotic fracture (MOF) were followed from the start of treatment until the age of 100 years or death. Treatment with romosozumab for 12 months was followed by alendronate for up to 48 months or alendronate alone with a maximum treatment duration of 60 months. The analysis had a societal perspective. Efficacy of romosozumab and alendronate were derived from phase III randomized controlled trials. Resource use and unit costs were collected from the literature. Cost-effectiveness was estimated using incremental cost-effectiveness ratio (ICER) with QALYs as effectiveness measures. RESULTS: The base case analysis showed that sequential romosozumab-to-alendronate treatment was associated with 0.089 additional QALYs at an additional cost of €3002 compared to alendronate alone, resulting in an ICER of €33,732. At a Swedish reference willingness-to-pay per QALY of €60,000, romosozumab-to-alendronate had a 97.9% probability of being cost-effective against alendronate alone. The results were most sensitive to time horizon, persistence assumptions, patient age, and treatment efficacy. CONCLUSION: The results of this study indicate that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture.

A novel economic framework to assess the cost-effectiveness of bone-forming agents in the prevention of fractures in patients with osteoporosis.

A novel cost-effectiveness model framework was developed to incorporate the elevated fracture risk associated with a recent fracture and to allow sequential osteoporosis therapies to be evaluated. Treating patients with severe osteoporosis after a recent fracture with a bone-forming agent followed by antiresorptive therapy can be cost-effective compared with antiresorptive therapy alone. Incorporating these novel technical attributes in economic evaluations can support appropriate policy and reimbursement decision-making. PURPOSE: To develop a cost-effectiveness model accommodating increased fracture risk after a recent fracture and treatment sequencing. METHODS: A micro-simulation cost-utility model was developed to accommodate both treatment sequencing and increased risk with recent fracture. The risk of fracture was estimated and simulated using the FRAX® algorithms combined with Swedish registry data on imminent fracture relative risk. In the base-case cost-effectiveness analysis, a sequential treatment starting with a bone-forming agent for 12 months followed by an antiresorptive agent for 48 months initiated immediately after a major osteoporotic fracture (MOF) in a 70-year-old woman with a T-score of 2.5 or less was compared to an antiresorptive treatment alone for 60 months. The model was populated with data relevant for a UK population reflecting a personal social service perspective. RESULTS: The cost per additional quality-adjusted life year (QALY) gained in the base-case setting was estimated at £34,584. Sensitivity analyses revealed the sequential treatment to be cost-saving compared with administering a bone-forming treatment alone. Without simulating an elevated fracture risk immediately after a recent fracture, the cost per QALY changed from £34,584 to £62,184. CONCLUSION: Incorporating imminent fracture risk in economic evaluations has a significant impact on the cost-effectiveness when evaluating fracture prevention treatments in patients with osteoporosis who sustained a recent fracture. Bone-forming treatment followed by antiresorptive therapy can be cost-effective compared to antiresorptive therapy alone depending on treatment acquisition costs.

Fragility fracture identifies patients at imminent risk for subsequent fracture: real-world retrospective database study in Ontario, Canada.

BACKGROUND: The secondary fracture prevention gap in the osteoporosis field has been previously described as a 'crisis'. Closing this gap is increasingly important in the context of accumulating evidence showing that an incident fragility fracture is associated with an increased risk of subsequent fracture within 1-2 years, known as imminent fracture risk. The objective of this study was to use health services data to characterize the time between index fragility fractures occurring at different osteoporotic sites and subsequent fractures. METHODS: This retrospective observational study used de-identified health services data from the publicly funded healthcare system in Ontario, the largest province of Canada. Patients aged > 65 with an index fragility fracture occurring between 2011 and 2015 were identified from the ICES Data Repository using International Classification of Diseases (ICD)-10 codes. We examined median time to subsequent fragility fractures for osteoporotic fracture sites until the end of follow-up (2017). BMD assessment and use of osteoporosis therapies following index fracture were also characterized. RESULTS: Among 115,776 patients with an index fragility fracture, 17.8% incurred a second fragility fracture. Median time between index and second fracture occurring at any site was 555 days (interquartile range: 236-955). For each index fracture site examined, median time from index to second fracture was < 2 years. The proportion of patients with BMD assessment was 10.3% ≤1 year prior to and 16.4% ≤1 year post index fracture. The proportion of patients receiving osteoporosis therapy was 29.8% ≤1 year prior, 34.6% ≤1 year post, and 25.9% > 3 years post index fracture. CONCLUSIONS: This cohort of Canadian patients aged > 65 years who experienced a fragility fracture at any site are at imminent risk of experiencing subsequent fracture within the next 2 years and should be proactively assessed and treated.

[Do All Very Old Patients Benefit from Osteoporosis Drug Treatment?]

INTRODUCTION: Osteoanabolic osteoporosis drugs have become better available. The osteoanabolic therapeutic principle has a stronger, faster-onset fracture-reducing effect than the antiresorptive preparations. It has also been newly recognized that the significance of a first fragility fracture as a risk factor is time-dependent: the less time that has elapsed since the first fracture, the higher the resulting re-fracture risk. Patients older than 65 years whose index fragility fracture occurred less than two years before are therefore grouped in a separate "Imminent Fracture Risk" category. These innovations were implemented by updating the osteoporosis therapy guideline. According to this guideline, patients in the "Imminent Fracture Risk" category should be offered osteoporosis therapy as soon as possible, in order to avoid as many fractures as possible. We are critical of an overly strict implementation of this algorithm in very old fracture patients. Our own data indicate that more than 30 % of this subpopulation do not experience the effect of a newly started osteoporosis therapy. We advocate a clinically based indication for osteoporosis therapy. For this, we propose a "Question Surprise" modified for osteological purposes. "Would I be surprised if I had to treat the same patient for a fracture again in a year?" If the question is answered with "No," then that patient could be a candidate for specific osteoporosis treatment.

Is Orthotic Treatment Beneficial for Fresh Osteoporotic Vertebral Fractures? A Propensity Score Matching Study.

BACKGROUND CONTEXT: Orthotic treatment is a common option for the conservative treatment of osteoporotic vertebral fractures (OVF). However, there is insufficient evidence of its clinical benefit. PURPOSE: To investigate the effectiveness of orthotic treatment for OVF. STUDY DESIGN/SETTING: Retrospective cohort study with data from two prospective studies. PATIENT SAMPLE: This study included 160 patients with fresh OVF enrolled in 2012 and 2020 prospective cohort studies. OUTCOME MEASURES: The visual analog scale (VAS) score for low back pain was used for clinical outcomes, and radiographic parameters included the percent height of the vertebra and angular change of the vertebral body. Moreover, the occurrence of secondary vertebral fractures was followed-up over time. METHODS: The patients were divided into brace and no-brace groups and were matched according to propensity score for age, sex, anterior percent height at the initial examination, and presence of old OVFs. Hazard ratio for the cumulative incidence of secondary vertebral fractures with and without bracing were calculated and analyzed using the generalized Wilcoxon test. In addition, the brace group was divided into soft and rigid brace groups and compared with the no-brace group. RESULTS: Each group had 61 cases after propensity score matching. There were no significant differences in the VAS improvement for low back pain and the change in percent height of the anterior and posterior walls from initial examination to 6 months after injury (p = 0.87, p = 0.39 and p = 0.14, respectively, mixed-effect models). Meanwhile, the mean angular change of fractured vertebrae was 4.3° / 3.2° initially and 1.2° / 2.5° at 6 months (the brace group / no-brace group, respectively; p = 0.007, mixed-effect models). A significant difference was also observed between the rigid brace group and the no-brace group (p = 0.008, mixed effect models). The incidence of secondary vertebral fractures was 1.6% / 11.4% at 1 month, indicating a significant difference (the brace group / no-brace group, respectively; p = 0.028). The hazard ratio for the cumulative incidence of secondary fractures due to orthotic treatment was 0.47 (95% confidence interval 0.20-1.09, p = 0.054). CONCLUSIONS: Although orthotic treatment for fresh OVF did not relieve pain, it might contribute to the stabilization of the fractured vertebra, especially using a rigid brace. Moreover, it might influence a reduction of the imminent vertebral fracture risk immediately after the onset of OVF. CLASSIFICATIONS: Clinical study.

The why and how of sequential and combination therapy in osteoporosis. A review of the current evidence.

It is now well recognized that over the lifetime of a patient with osteoporosis, more than one medication will be needed to treat the disease and to decrease fracture risk. Though current gaps in osteoporosis therapy can be potentially mitigated with sequential and combination regimens, how to move seamlessly amongst the multiple treatments currently available for osteoporosis for sustained efficacy is still unclear. Data from recent studies show that an anabolic agent such as teriparatide or romosozumab followed by an antiresorptive affords maximal gain in BMD and possibly better and earlier fracture risk reduction compared to a regimen which follows the opposite sequence. Sequentially moving to a bisphosphonate such as alendronate from an anabolic agent such as abaloparatide has also been shown to preserve the fracture reduction benefits seen with the latter. This sequence of an anabolic agent followed by an antiresorptive should especially be considered in the high-risk patient with imminent fracture risk to rapidly reduce the risk of subsequent fractures. The data surrounding optimum timing of initiation of bisphosphonate therapy following denosumab discontinuation is still unclear. Though data suggests that combining a bisphosphonate with teriparatide does not provide substantial BMD gains compared to monotherapy, the concomitant administration of denosumab with teriparatide has been shown to significantly increase areal BMD as well as to increase volumetric BMD and estimated bone strength. This narrative review explores the available evidence regarding the various sequential and combination therapy approaches and the potential role they could play in better managing osteoporosis.

Fragility Fractures and Imminent Fracture Risk in the Spanish Population: A Retrospective Observational Cohort Study.

Fragility fractures constitute a major public health problem worldwide, causing important high morbidity and mortality rates. The aim was to present the epidemiology of fragility fractures and to assess the imminent risk of a subsequent fracture and mortality. This is a retrospective population-based cohort study (n = 1369) with a fragility fracture. We estimated the incidence rate of index fragility fractures and obtained information on the subsequent fractures and death during a follow-up of up to three years. We assessed the effect of age, sex, and skeletal site of index fracture as independent risk factors of further fractures and mortality. Incidence rate of index fragility fractures was 86.9/10,000 person-years, with highest rates for hip fractures in women aged ≥80 years. The risk of fracture was higher in subjects with a recent fracture (Relative Risk(RR), 1.80; p < 0.01). Higher age was an independent risk factor for further fracture events. Significant excess mortality was found in subjects aged ≥80 years and with a previous hip fracture (hazard ratio, 3.43 and 2.48, respectively). It is the first study in Spain to evaluate the incidence of major osteoporotic fractures, not only of the hip, and the rate of imminent fracture. Our results provide further evidence highlighting the need for early treatment.

Deterioration of Cortical and Trabecular Microstructure Identifies Women With Osteopenia or Normal Bone Mineral Density at Imminent and Long-Term Risk for Fragility Fracture: A Prospective Study.

More than 70% of women sustaining fractures have osteopenia or "normal" bone mineral density (BMD). These women remain undetected using the BMD threshold of -2.5 SD for osteoporosis. As microstructural deterioration increases bone fragility disproportionate to the bone loss producing osteopenia/normal BMD, we hypothesized that the structural fragility score (SFS) of ≥70 units, a measure capturing severe cortical and trabecular deterioration, will identify these women. Distal radial images were acquired using high-resolution peripheral quantitative tomography in postmenopausal French women, mean age 67 years (range 42-96 years); 1539 women were followed for 4 years (QUALYOR) and 561 women followed for 8 years (OFELY). Women with osteopenia or normal BMD accounted for ~80% of fractures. Women ≥70 years, 29.2% of the cohort, accounted for 39.2% to 61.5% of fractures depending on follow-up duration. Women having fractures had a higher SFS, lower BMD, and a higher fracture risk assessment score (FRAX) than women remaining fracture-free. In each BMD category (osteoporosis, osteopenia, normal BMD), fracture incidence was two to three times higher in women with SFS ≥70 than <70. In multivariable analyses, associations with fractures remained for BMD and SFS, not FRAX. BMD was no longer, or weakly, associated with fractures after accounting for SFS, whereas SFS remained associated with fracture after accounting for BMD. SFS detected two-to threefold more women having fractures than BMD or FRAX. SFS in women with osteopenia/normal BMD conferred an odds ratio for fracture of 2.69 to 5.19 for women of any age and 4.98 to 12.2 for women ≥70 years. Receiver-operator curve (ROC) analyses showed a significant area under the curve (AUC) for SFS, but not BMD or FRAX for the women ≥70 years of age. Targeting women aged ≥70 years with osteopenia indicated that treating 25% using SFS to allocate treatment conferred a cost-effectiveness ratio < USD $21,000/QALY saved. Quantifying microstructural deterioration complements BMD by identifying women without osteoporosis at imminent and longer-term fracture risk. © 2019 American Society for Bone and Mineral Research.

Secondary fracture prevention: Drug treatment, fall prevention and nutrition requirements.

In view of the high imminent risk for subsequent fractures, evaluation as early as possible after the fracture will result in early decisions about drug treatment, fall prevention and nutritional supplements. Drug treatment includes anti-resorptive and bone forming agents. Anti-resorptive therapy with broad spectrum fracture prevention and early anti-fracture effects are the first choice. In patients with multiple or severe VFs, the bone forming agent teriparatide should be considered. Adequate calcium and vitamin D are needed in all patients, together with appropriate nutrition, including adequate protein intake.

Fragility fractures and imminent fracture risk in Hong Kong: one of the cities with longest life expectancies.

INTRODUCTION: Imminent fracture risk, or fractures within 2 years of an initial fracture, is a pressing issue worldwide. Hong Kong is a city with one of the longest life expectancies. The concern of fragility fractures and the imminent risk of a subsequent fracture is becoming a top priority. The objective of this study was to present the epidemiology of incident fragility fractures of all public acute hospitals and the imminent risk of a subsequent fracture in Hong Kong. METHODOLOGY: This was a retrospective population-based analysis. Patient records from all acute hospitals in Hong Kong from 1 January 2004 to 31 December 2018 were retrieved for patients ≥ 50 years of age with hip, distal radius, or proximal humerus fractures. Secondary fractures and falls were identified in the subsequent 5 years. Post hoc analysis in recent 2013-2018 period was performed. Overall survival (re-fracture incidence) on age subgroups using Kaplan survival analysis and variables was compared using the log-rank test. Cox proportional hazard regressions, obtaining the hazard ratios (HR) and their respective 95% confidence intervals (CI), were used. RESULTS: There is an overall increasing trend of fragility fractures (hip, distal radius, proximal humerus) from 5596 in 2004 to 8465 in 2018. The average cumulative imminent risk of fractures from recent 5 years is 3.87% at 1 year and 6.50% at 2 years. 49.5% of the patients with a secondary fracture occurred within 2 years since the initial major fragility fracture. Post hoc analysis in recent 2013-2018 period (N = 7039) showed male patients were 1.21 times more likely to have further fractures with time (HR = 1.21 (1.02, 1.45), p = 0.03) compared with female patients. Patients over age 95 were 2.01 times higher than patients of age under 75 to have further fracture over time. CONCLUSIONS: Following an initial fracture, prompt treatment strategies should be adopted to avoid imminent risk of fractures. This window of opportunity in the first 2 years is a golden period to treat osteoporosis and prevent falls. Our post hoc analysis has shown that male patients and patients older than 95 are at even higher risk. Clinicians and allied healthcare professionals should be alert on these patients.

The why and how of sequential and combination therapy in osteoporosis. A review of the current evidence

ABSTRACT It is now well recognized that over the lifetime of a patient with osteoporosis, more than one medication will be needed to treat the disease and to decrease fracture risk. Though current gaps in osteoporosis therapy can be potentially mitigated with sequential and combination regimens, how to move seamlessly amongst the multiple treatments currently available for osteoporosis for sustained efficacy is still unclear. Data from recent studies show that an anabolic agent such as teriparatide or romosozumab followed by an antiresorptive affords maximal gain in BMD and possibly better and earlier fracture risk reduction compared to a regimen which follows the opposite sequence. Sequentially moving to a bisphosphonate such as alendronate from an anabolic agent such as abaloparatide has also been shown to preserve the fracture reduction benefits seen with the latter. This sequence of an anabolic agent followed by an antiresorptive should especially be considered in the high-risk patient with imminent fracture risk to rapidly reduce the risk of subsequent fractures. The data surrounding optimum timing of initiation of bisphosphonate therapy following denosumab discontinuation is still unclear. Though data suggests that combining a bisphosphonate with teriparatide does not provide substantial BMD gains compared to monotherapy, the concomitant administration of denosumab with teriparatide has been shown to significantly increase areal BMD as well as to increase volumetric BMD and estimated bone strength. This narrative review explores the available evidence regarding the various sequential and combination therapy approaches and the potential role they could play in better managing osteoporosis.