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Bone May 2024Antiresorptive treatment is currently used in millions of patients with osteoporosis and cancer worldwide. Early studies of denosumab suggested a small signal in ovarian...
BACKGROUND
Antiresorptive treatment is currently used in millions of patients with osteoporosis and cancer worldwide. Early studies of denosumab suggested a small signal in ovarian cancer incidence and emerging data suggest that denosumab stimulates germ cell proliferation in the gonads. This study aims to determine the association between the use of denosumab and the risk of reproductive cancers compared with the use of alendronate.
RESEARCH DESIGN AND METHODS
Using a cohort study design, we used the Danish nationwide registries to identify a population of subjects ≥50 years of age during 2010-2017 who started denosumab after being on alendronate treatment for at least six months. The cohort was matched 1:2 with patients who had been treated with alendronate alone for at least six months. The risk of reproductive cancers and the risk difference between groups were estimated using the Longitudinal Targeted Maximum Likelihood Estimation (L-TMLE) method.
RESULTS
We identified 6054 Danish individuals who underwent treatment with denosumab. These individuals were matched with 12,108 receiving alendronate. The absolute risk of reproductive cancer was 1.05 % (95 % CI 0.75-1.34) after three years for denosumab users and was not different 0.03 % (-0.34-0.39) than for alendronate users. In supplemental analyses, there was no increased risk of non-reproductive cancers associated with the use of denosumab (risk difference of 0.54 % (-0.41-1.19). Analysis comparing denosumab users with the general population gave similar results.
CONCLUSION
There was no difference in the risk of cancer following treatment with denosumab compared to treatment with alendronate assessed after a short follow-up of 3 years.
Topics: Humans; Female; Alendronate; Denosumab; Bone Density Conservation Agents; Cohort Studies; Neoplasms; Osteoporosis, Postmenopausal
PubMed: 38395247
DOI: 10.1016/j.bone.2024.117053 -
Health Technology Assessment... Apr 2024Bisphosphonates are a class of medication commonly used to treat osteoporosis. Alendronate is recommended as the first-line treatment; however, long-term adherence (both...
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 ; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information.
Topics: Humans; Diphosphonates; Alendronate; Zoledronic Acid; Osteoporotic Fractures; Osteoporosis
PubMed: 38634483
DOI: 10.3310/WYPF0472 -
Advanced Science (Weinheim,... Aug 2023Precise detection of early osteolytic metastases is crucial for their treatment but remains challenging in the clinic because of the limited sensitivity and specificity...
Precise detection of early osteolytic metastases is crucial for their treatment but remains challenging in the clinic because of the limited sensitivity and specificity of traditional imaging techniques. Although fluorescence imaging offers attractive features for the diagnosis of osteolytic metastases, it is hampered by limited penetration depth. To address this issue, a fluoro-photoacoustic dual-modality imaging probe comprising a near-infrared dye caged by a cathepsin K (CTSK)-cleavable peptide sequence on one side and functionalized with osteophilic alendronate through a polyethylene glycol linker on the other side is reported. Through systematic in vitro and in vivo experiments, it is demonstrated that in response to CTSK, the probe generated both near-infrared fluorescent and photoacoustic signals from bone metastatic regions, thus offering a potential strategy for detecting deep-seated early osteolytic metastases.
Topics: Photoacoustic Techniques; Cathepsin K; Diagnostic Imaging
PubMed: 37341286
DOI: 10.1002/advs.202300217 -
Aging Clinical and Experimental Research Jan 2024Osteoporotic-related fractures represent an increasing burden to patients, health care systems and society.
BACKGROUND
Osteoporotic-related fractures represent an increasing burden to patients, health care systems and society.
AIMS
This study estimated cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) compared to relevant alternative strategies in US men and women aged 50 to 80 years at very high fracture risk (bone mineral density T-score ≤ - 2.5 and a recent fracture).
METHODS
A lifetime Markov-based microsimulation model was used to estimate healthcare costs and quality-adjusted life years (QALYs). Comparators were sequential treatment with unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Analyses were conducted based on initial fracture site (hip, vertebral, or any fracture) and treatment efficacy data (derived from clinical trials or a recent network meta-analysis).
RESULTS
From all analyses completed, sequential ABL/ALN demonstrated more QALYs for lower healthcare costs versus unbranded TPTD/ALN. No treatment was dominated (higher costs for less QALYs) versus ALN monotherapy. Sequential ABL/ALN resulted in favorable cost-effectiveness (at US threshold of $150,000/QALY) versus generic ALN monotherapy in men aged ≥ 50 years with any fracture type, women aged ≥ 65 years with any fracture type, and women aged ≥ 55 years having a hip or vertebral fracture.
DISCUSSION
Similar cost-effectiveness of sequential ABL/ALN versus unbranded TPTD/ALN, ALN monotherapy, and no treatment was observed in both US men and women at very high fracture risk, with a moderate improvement in cost-effectiveness in men versus women and in patients with a hip or vertebral fracture.
CONCLUSIONS
Sequential therapy with ABL/ALN was cost-effective in US men and women at very high risk of fractures.
Topics: Female; Humans; Male; Alendronate; Cost-Benefit Analysis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Spinal Fractures; Middle Aged; Aged; Aged, 80 and over
PubMed: 38289413
DOI: 10.1007/s40520-023-02682-7 -
Therapeutic Advances in Musculoskeletal... 2024Subjects with a fragility fracture have an increased risk of a new fracture and should receive effective strategies to prevent new events. The medium-term to long-term...
BACKGROUND
Subjects with a fragility fracture have an increased risk of a new fracture and should receive effective strategies to prevent new events. The medium-term to long-term strategy should be scheduled by considering the mechanisms of action in therapy and the estimated fracture risk.
OBJECTIVE
A systematic review was conducted to evaluate the sequential strategy in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines.
DESIGN
Systematic review and meta-analysis.
DATA SOURCES AND METHODS
PubMed, Embase, and the Cochrane Library were investigated up to February 2021 to update the search of a recent systematic review. Randomized clinical trials (RCTs) that analyzed the sequential therapy of antiresorptive, anabolic treatment, or placebo in patients with or at risk of a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using fixed-effects models. The primary outcome was the risk of refracture, while the secondary outcome was the bone mineral density (BMD) change.
RESULTS
In all, 17 RCTs, ranging from low to high quality, met our inclusion criteria. A significantly reduced risk of fracture was detected at (i) 12 or 24 months after the switch from romosozumab to denosumab placebo to denosumab; (ii) 30 months from teriparatide to bisphosphonates placebo to bisphosphonates; and (iii) 12 months from romosozumab to alendronate the only alendronate therapy (specifically for vertebral fractures). In general, at 2 years after the switch from anabolic to antiresorptive drugs, a weighted BMD was increased at the lumbar spine, total hip, and femoral neck site.
CONCLUSION
The Task Force formulated recommendations on sequential therapy, which is the first treatment with anabolic drugs or 'bone builders' in patients with very high or imminent risk of fracture.
PubMed: 38654732
DOI: 10.1177/1759720X241234584 -
Science Advances Apr 2024Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the...
Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the subchondral bone properties to OA development. We used parathyroid hormone (PTH) to modulate bone mass before OA initiation and alendronate (ALN) to inhibit bone remodeling during OA progression. We examined the spatiotemporal progression of joint damage by combining histopathological and transcriptomic analyses across joint tissues. The additive effect of PTH pretreatment before OA initiation and ALN treatment during OA progression most effectively attenuated load-induced OA pathology. Individually, PTH directly improved cartilage health and slowed the development of cartilage damage, whereas ALN primarily attenuated subchondral bone changes associated with OA progression. Joint damage reflected early transcriptomic changes. With both treatments, the structural changes were associated with early modulation of immunoregulation and immunoresponse pathways that may contribute to disease mechanisms. Overall, our results demonstrate the potential of subchondral bone-modifying therapies to slow the progression of OA.
Topics: Animals; Mice; Alendronate; Bone and Bones; Cartilage, Articular; Osteoarthritis; Parathyroid Hormone; Bone Remodeling; Weight-Bearing
PubMed: 38640238
DOI: 10.1126/sciadv.adk8402 -
RSC Advances Oct 2023The computational analysis of drug release from metal-organic frameworks (MOFs), specifically UiO-66, is the primary focus of this research. MOFs are recognized as...
The computational analysis of drug release from metal-organic frameworks (MOFs), specifically UiO-66, is the primary focus of this research. MOFs are recognized as nanocarriers due to their crystalline structure, porosity, and potential for added functionalities. The research examines the release patterns of three drugs: temozolomide, alendronate, and 5-fluorouracil, assessing various factors such as the drugs' distance from the UiO-66 centers, the interaction of drug functional groups with Zr metal ions, and the drug density throughout the nanocarrier. Findings reveal that 5-fluorouracil is located furthest from the UiO-66 center and exhibits the highest positive energy compared to the other drugs. Alendronate's density is observed to shift to the carrier surface, while 5-fluorouracil's density significantly decreases within the system. The drug density diminishes as the distance from the UiO-66 center of mass increases, suggesting a stronger positive interaction between the drugs and the nanocarrier. Moreover, Monte Carlo calculations were employed to load drugs onto the UiO-66 surface, leading to a substantial release of 5-fluorouracil from UiO-66. Quantum and Monte Carlo adsorption localization calculations were also conducted to gather data on the compounds' energy and geometry. This research underscores the potential of MOFs as nanocarriers for drug delivery and highlights the crucial role of temperature in regulating drug release from UiO-66. It provides insights into the complex dynamics of drug release and the factors influencing it, thereby emphasizing the promise of UiO-66 as a viable candidate for drug delivery. This work contributes to our understanding of UiO-66's role and sets the stage for improved performance optimization in the cancer treatment.
PubMed: 37920197
DOI: 10.1039/d3ra05587f -
Cellular and Molecular Biology... Oct 2023Sixty Sprague-Dawley female rats were randomly divided into sham-operated groups and five ovariectomy (OVX) subgroups. Rats subjected to sham and OVX were treated with...
Sixty Sprague-Dawley female rats were randomly divided into sham-operated groups and five ovariectomy (OVX) subgroups. Rats subjected to sham and OVX were treated with the vehicle, alendronate, and Zuogui Wan (ZGW) at the doses of low, medium and high lyophilized powder daily for 3 months, respectively. The gene or protein expression of NK1R, PPAR γ, and OSX were assayed by either quantitative polymerase chain reaction or Western blot analysis. The results showed that compared with the OVX group, ZGW could reduce the level of PPARγ and increase the levels of OSX and. Meanwhile, ZGW could prevent bone loss. In addition, we found ZGW upregulated for the NK1R mRNA or protein expression by promoting the expression level of transcription factor FoxO3 and increasing its binding to the NK1R promoter region -700/-200 sequence. These results suggest that the regulation of FoxO3 and NK1R played a role and contributed to the mechanism of ZGW underlying the increase in bone mass in the OVX rat model.
Topics: Animals; Female; Rats; Drugs, Chinese Herbal; Osteoporosis; Ovariectomy; Rats, Sprague-Dawley
PubMed: 37953564
DOI: 10.14715/cmb/2023.69.10.28 -
International Journal of Biological... Sep 2023Here, we fabricated a hybrid nanoparticle composed of polydopamine nanoparticles (pNPs), alendronate (Al) and genipin (GP) for cranial bone defect repair. Al was...
Here, we fabricated a hybrid nanoparticle composed of polydopamine nanoparticles (pNPs), alendronate (Al) and genipin (GP) for cranial bone defect repair. Al was crosslinked into pNPs via GP (Al@pNPs), after which hybrid nanoparticles were obtained. By embedding these Al@pNPs into the fibrin hydrogels, a multifunctional bone repair scaffold was fabricated (Al@pNPs/Fg). The Al@pNPs/Fg exhibited three synergistic effects on the bone microenvironment: i) enhanced ectomesenchymal stem cell (EMSC) osteogenic differentiation by activating the piezo 1 channel; ii) inhibited the formation and function of osteoclasts related to the NF-κB signaling pathways; and iii) promoted M2 polarization and anti-inflammatory factor expression under normal and simulated inflammatory conditions. Al@pNPs/Fg ultimately promoted cranial bone defect regeneration in an SD rat model. This simple and low-cost technology provides a new approach to constructing an efficient delivery system and has desirable biological properties, providing a tissue-committed niche for the repair of bone defects.
Topics: Rats; Animals; Osteogenesis; Tissue Scaffolds; Fibrin; Alendronate; Hydrogels; Rats, Sprague-Dawley; Bone Regeneration; Nanoparticles; Tissue Engineering
PubMed: 37524274
DOI: 10.1016/j.ijbiomac.2023.126072 -
MDM Policy & Practice 2023To conduct cost-utility analyses for Computed Tomography To Strength (CT2S), a novel osteoporosis screening service, compared with dual-energy X-ray absorptiometry...
Cost-Effectiveness Analysis of CT-Based Finite Element Modeling for Osteoporosis Screening in Secondary Fracture Prevention: An Early Health Technology Assessment in the Netherlands.
UNLABELLED
To conduct cost-utility analyses for Computed Tomography To Strength (CT2S), a novel osteoporosis screening service, compared with dual-energy X-ray absorptiometry (DXA), treat all without screening, and no screening methods for Dutch postmenopausal women referred to fracture liaison service (FLS). CT2S uses CT scans to generate femur models and simulate sideways fall scenarios for bone strength assessment. Early health technology assessment (HTA) was adopted to evaluate CT2S as a novel osteoporosis screening tool for secondary fracture prevention. We constructed a 2-dimensional simulation model considering 4 strategies (no screening, treat all without screening, DXA, CT2S) together with screening intervals (5 y, 2 y), treatments (oral alendronate, zoledronic acid), and discount rate scenarios among Dutch women in 3 age groups (60s, 70s, and 80s). Strategy comparisons were based on incremental cost-effectiveness ratios (ICERs), considering an ICER below €20,000 per QALY gained as cost-effective in the Netherlands. Under the base-case scenario, CT2S versus DXA had estimated ICERs of €41,200 and €14,083 per QALY gained for the 60s and 70s age groups, respectively. For the 80s age group, CT2S was more effective and less costly than DXA. Changing treatment from weekly oral alendronate to annual zoledronic acid substantially decreased CT2S versus DXA ICERs across all age groups. Setting the screening interval to 2 y increased CT2S versus DXA ICERs to €100,333, €55,571, and €15,750 per QALY gained for the 60s, 70s, and 80s age groups, respectively. In all simulated populations and scenarios, CT2S was cost-effective (in some cases dominant) compared with the treat all strategy and cost-saving (more effective and less costly) compared with no screening. CT2S was estimated to be potentially cost-effective in the 70s and 80s age groups considering the willingness-to-pay threshold of the Netherlands. This early HTA suggests CT2S as a potential novel osteoporosis screening tool for secondary fracture prevention.
HIGHLIGHTS
For postmenopausal Dutch women who have been referred to the FLS, direct access to CT2S may be cost-effective compared with DXA for age groups 70s and 80s, when considering the ICER threshold of the Netherlands. This study positions CT2S as a potential novel osteoporosis-screening tool for secondary fracture prevention in the clinical setting.A shorter screening interval of 2 y increases the effectiveness of both screening strategies, but the ICER of CT2S compared with DXA also increased substantially, which made CT2S no longer cost-effective for the 70s age group; however, it remains cost-effective for individuals in their 80s.Annual zoledronic acid treatment with better adherence may contribute to a lower cost-effectiveness ratio when comparing CT2S to DXA screening and the treat all strategies for all age groups.
PubMed: 37900721
DOI: 10.1177/23814683231202993