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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 -
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 -
The Journal of Clinical Endocrinology... Apr 2024Current clinical guidelines recommend a drug holiday after extended use of oral bisphosphonates. However, no studies have investigated the impact of drug holidays before...
CONTEXT
Current clinical guidelines recommend a drug holiday after extended use of oral bisphosphonates. However, no studies have investigated the impact of drug holidays before hip fractures on post-fracture mortality.
OBJECTIVE
To investigate the effect of drug holiday on post-fracture mortality in patients with extended use of oral bisphosphonates.
DESIGN
Retrospective population-based cohort study.
SETTING
All patients with hip fractures in Victoria, Australia from 2014-18.
PATIENTS
Patients adherent to oral alendronate or risedronate for ≥5 years prior to hip fracture.
INTERVENTION(S)
Group-based trajectory modelling categorized patients into different bisphosphonate usage after 5-year good adherence.
MAIN OUTCOME MEASURE(S)
Post-fracture mortality.
RESULTS
We identified 365 patients with good adherence (medication possession ratio ≥80%) to oral alendronate/risedronate for ≥5 years. Most patients (69%) continued to use oral bisphosphonates till admission for hip fracture; 17% had discontinued for one year and 14% had discontinued for two years. Post-fracture mortality was higher in patients who had discontinued risedronate for one year (Hazard ratio [HR] 2.37, 95% confidence interval [CI] 1.24-4.53) and two years (HR 3.08, 95% CI 1.48-6.41) prior to hip fracture. No increase or decrease in post-fracture mortality was observed in patients who had discontinued alendronate for one year (HR 0.59, 95% CI 0.29-1.18) or two years (HR 1.05, 95% CI 0.57-1.93) prior to hip fracture.
CONCLUSIONS
Post-fracture mortality is higher in people who discontinue risedronate, but not alendronate, for 1 or 2 years after being adherent to treatment for at least 5 years. The type of bisphosphonate may be a factor to consider when planning drug holidays.
PubMed: 38630464
DOI: 10.1210/clinem/dgae272 -
PloS One 2024Pretargeting, which is the separation of target accumulation and the administration of a secondary imaging agent into two sequential steps, offers the potential to...
Pretargeting, which is the separation of target accumulation and the administration of a secondary imaging agent into two sequential steps, offers the potential to improve image contrast and reduce radiation burden for nuclear imaging. In recent years, the tetrazine ligation has emerged as a promising approach to facilitate covalent pretargeted imaging due to its unprecedented kinetics and bioorthogonality. Pretargeted bone imaging with TCO-modified alendronic acid (Aln-TCO) is an attractive model that allows the evaluation of tetrazines in healthy animals without the need for complex disease models or targeting regimens. Recent structure-activity relationship studies of tetrazines evaluated important parameters for the design of potent tetrazine-radiotracers for pretargeted imaging. However, limited information is available for 99mTc-labeled tetrazines. In this study, four tetrazines intended for labeling with fac-[99mTc(OH2)3 (CO)3]+ were synthesized and evaluated using an Aln-TCO mouse model. 3,6-bis(2-pyridyl)-1,2,4,5-Tz without additional linker showed higher pretargeted bone uptake and less background activity compared to the same scaffold with a PEG8 linker or 3-phenyl-1,2,4,5-Tz-based compounds. Additionally, improved bone/blood ratios were observed in pretargeted animals compared to animals receiving directly labeled Aln-TCO. The results of this study implicate 3,6-bis(2-pyridyl)-1,2,4,5-Tz as a promising scaffold for potential 99mTc-labeled tetrazines.
Topics: Animals; Mice; Tomography, X-Ray Computed; Tomography, Emission-Computed, Single-Photon; Heterocyclic Compounds; Cell Line, Tumor; Radiopharmaceuticals; Positron-Emission Tomography
PubMed: 38626058
DOI: 10.1371/journal.pone.0300466 -
BMC Nephrology Apr 2024In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function,...
Increased risk of hypocalcemia with decreased kidney function in patients prescribed bisphosphonates based on real-world data from the MID-NET in Japan: a new-user cohort study.
BACKGROUND
In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function, despite warning against use of BPs in such patients in the package insert (PI) of Japan. The purpose of this study was to investigate the safety of BPs in patients with decreased kidney function.
METHODS
The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00 mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group).
RESULTS
A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90 mL/min/1.73m), 7,613 (52.32%) with mild (60 ≤ eGFR < 90 mL/min/1.73m), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60 mL/min/1.73m), and 418 (2.87%) with severe kidney function (eGFR < 30 mL/min/1.73m). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30 days during the follow-up period.
CONCLUSIONS
These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.
Topics: Humans; Cohort Studies; Hypocalcemia; Japan; Diphosphonates; Kidney
PubMed: 38622507
DOI: 10.1186/s12882-024-03553-7 -
Journal of Oral Biosciences Jun 2024Toll-like receptors (TLRs) recognize whole cells or components of microorganisms. Alendronate (ALN) is an anti-bone-resorptive drug that has inflammatory side effects....
Synergistic effect of Toll-like receptor 2 ligands and alendronate on proinflammatory cytokine production in mouse macrophage-like RAW-ASC cells is accompanied by upregulation of MyD88 expression.
OBJECTIVES
Toll-like receptors (TLRs) recognize whole cells or components of microorganisms. Alendronate (ALN) is an anti-bone-resorptive drug that has inflammatory side effects. The aim in this study was to examine whether ALN augments TLR2 ligand-induced proinflammatory cytokine production using mouse macrophage-like RAW264.7 cells transfected with murine apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) gene (hereafter, referred to as "RAW-ASC cells").
METHODS
RAW-ASC cells were pretreated with or without ALN and then incubated with or without TLR2 ligands. The levels of secreted mouse IL-1α, IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in culture supernatants and the activation of activator protein-1 (AP-1) or nuclear factor-κB (NF-κB) were measured using enzyme-linked immunosorbent assay (ELISA). The expressions of myeloid differentiation factor 88 (MyD88), caspase-11, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), ASC, NF-κB p65, and actin were analyzed via Western blotting. TLR2 expression was analyzed using flow cytometry.
RESULTS
ALN substantially upregulated the PamCSK-induced release of IL-1α, IL-1β, IL-6, and TNF-α and MyD88 expression in RAW-ASC cells. ST-2825, a MyD88 inhibitor, inhibited the ALN-augmented release of these cytokines. Pretreatment with ALN augmented PamCSK-induced NF-κB activation in RAW-ASC cells and upregulated AP-1 activation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein and ALN synergically upregulated the release of IL-1α, IL-1β, IL-6 and TNF-α in RAW-ASC cells.
CONCLUSIONS
Our findings suggest that ALN augments TLR2 ligand-induced proinflammatory cytokine production via the upregulation of MyD88 expression, and this augmentation is accompanied by the activation of NF-κB and AP-1 in RAW-ASC cells.
Topics: Animals; Alendronate; Mice; Toll-Like Receptor 2; Myeloid Differentiation Factor 88; Up-Regulation; Cytokines; Macrophages; RAW 264.7 Cells; Enzyme-Linked Immunosorbent Assay; Ligands; NF-kappa B; Tumor Necrosis Factor-alpha; Drug Synergism
PubMed: 38614429
DOI: 10.1016/j.job.2024.04.003 -
The Journal of Clinical Endocrinology... Apr 2024We previously reported that sequential teriparatide followed by denosumab substantially increases BMD in premenopausal idiopathic osteoporosis (PremenIOP).
CONTEXT
We previously reported that sequential teriparatide followed by denosumab substantially increases BMD in premenopausal idiopathic osteoporosis (PremenIOP).
OBJECTIVE
To determine whether administration of bisphosphonates after denosumab cessation is associated with stable BMD in PremenIOP.
DESIGN
Open-label extension study.
PARTICIPANTS
24 PremenIOP Teriparatide-Denosumab Study participants.
INTERVENTIONS
Oral alendronate (ALN), 70mg weekly, or IV zoledronic acid (ZOL), 5mg once (patient choice), was administered 7 months (M) after final denosumab dose.
OUTCOMES
BMD by DXA and serum C-telopeptide (CTX) q6M; vertebral fracture assessment (VFA) and HR-pQCT q12M.
RESULTS
24 women with PremenIOP (aged 43 ± 8 years), severely affected with low trauma adult fractures (range 0-12; 9 with vertebral fractures) and/or very low BMD, had large BMD increases on sequential teriparatide-denosumab (spine: 25 ± 9%; total hip: 11 ± 6%). During the Bisphosphonate Extension, mean BMD and CTX changes in the entire group were small and not statistically significant at 6 or 12M.Women choosing ZOL (n = 6) versus ALN (n = 18) did not differ by baseline age, BMI, fractures, BMD, or CTX. On ZOL, there were small LSBMD declines and CTX increases, particularly between 6M and 12M, while greater stability was observed on ALN.Changes in BMD and CTX did not differ by duration of denosumab (36M vs <36M) or between 20 women who remained premenopausal and 4 who transitioned into menopause. Higher pre-teriparatide CTX, likely reflecting baseline remodeling status, predicted more spine and hip bone loss. No new vertebral (clinical or VFA screening) or non-vertebral fractures occurred.
CONCLUSION
BMD remained stable in women with PremenIOP who received bisphosphonates after sequential teriparatide-denosumab therapy.
PubMed: 38605469
DOI: 10.1210/clinem/dgae240 -
Journal of Pharmacy & Bioallied Sciences Feb 2024To assess the role of bisphosphonate on osteotomy site and implant surface.
OBJECTIVES
To assess the role of bisphosphonate on osteotomy site and implant surface.
MATERIALS AND METHODS
Twenty patients with adequate width and height of edentulous space and a single missing posterior tooth between the ages of 25 and 55 were incorporated in this research. Ten participants received implant therapy alone; the other ten patients received implant therapy and bisphosphonate application to osteotomy site and the implant surface.
RESULT
Changes in the crestal bone level were seen in both the study and control groups. At 1 year, crestal bone loss was less in the bisphosphonate-treated group than in the control group.
CONCLUSION
The quantity of crestal bone loss was reduced when bisphosphonate (sodium alendronate) was applied locally near the implant and osteotomy site.
PubMed: 38595363
DOI: 10.4103/jpbs.jpbs_426_23 -
Cureus Mar 2024Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant genetic disorder characterized by congenital great toe malformations and progressive ectopic...
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant genetic disorder characterized by congenital great toe malformations and progressive ectopic ossification. We report a typical case of FOP in a 22-year-old female patient presenting with limited movement of the left knee joint, which began following trauma in 2019. Clinical examination revealed a large mass behind the left knee, bilateral great toe deformities, and no palpable superficial lymph nodes, without systemic pain or other discomfort. Imaging and genetic testing further supported the diagnosis of FOP, demonstrating high-density ossification within soft tissues and a mutation in the gene. Treatment involved a combination of methylprednisolone and alendronate sodium vitamin D3 tablets, which yielded some therapeutic efficacy. The discussion emphasizes clinical diagnosis, pathogenesis, and treatment strategies for FOP, including injury prevention, rehabilitation exercises, and pharmacological interventions. Despite the lack of definitive treatment options, timely diagnosis and comprehensive management can effectively alleviate symptoms and improve the quality of life for affected individuals.
PubMed: 38576636
DOI: 10.7759/cureus.55528