-
British Journal of Clinical Pharmacology Aug 2023Despite 2 h of daily exercise training, muscle wasting and bone loss are still present after 6-month missions to the international space station. Some crew members... (Review)
Review
Despite 2 h of daily exercise training, muscle wasting and bone loss are still present after 6-month missions to the international space station. Some crew members lose bone much faster than others. In preparation for missions to the Moon and Mars, space agencies are therefore reviewing their countermeasure portfolios. Here, we discuss the potential of current pharmacological strategies. Bone loss in space is fuelled by bone resorption. Alendronate, an oral bisphosphonate, reduced bone losses in experimental bed rest and space. However, gastrointestinal side effects precluded its further utilization in space. Zoledronate (a potent bisphosphonate), denosumab (RANKL antagonist) and romosozumab (sclerostin antagonist) are all administered via injection. They effectively suppress bone resorption and are routinely prescribed against osteoporosis. Their serious adverse effects, namely, osteonecrosis of the jaw and atypical femur fractures occur very rarely when the usage is limited to 1 or 2 years. Hence, utilization of one of these compounds may outweigh the bone risks of space travelling, in particular in those with high bone resorption rates. Muscle wasting in space is likely due to hampered muscle protein synthesis. Even though this might theoretically be countered by the synthesis-boosting effects of anabolic steroids, the practical grounds for such recommendation are currently weak. Moreover, they reveal their full potential only when combined with an anabolic exercise stimulus, for example, via strength training. It therefore seems that a combination of exercise and pharmacological countermeasures should be considered for musculoskeletal health on the way to the Moon and Mars and back.
PubMed: 37559171
DOI: 10.1111/bcp.15877 -
Calcified Tissue International Nov 2023Buffered and effervescent alendronate (ALN-EFF) increases gastric pH and is reported to decrease the risk of gastrointestinal side effects compared to conventional... (Randomized Controlled Trial)
Randomized Controlled Trial
Buffered and effervescent alendronate (ALN-EFF) increases gastric pH and is reported to decrease the risk of gastrointestinal side effects compared to conventional formulations of alendronate (ALN). The clinical effectiveness of ALN-EFF, however, has not been investigated. This study aims to investigate if ALN-EFF is non-inferior to ALN in suppressing bone turnover markers (BTM). We conducted a 16-week prospective, randomized, open-label study comprising 64 postmenopausal women with BMD T-score < -1 naïve to osteoporosis treatment. Participants were randomized 1:1 to ALN or ALN-EFF. We collected blood samples at 0, 4, 8, and 16 weeks. Non-inferiority margin was determined as 12% (80% of efficacy retained), and an SD of 15% on change in CTx. CTx decreased by 58.2% ± 24.1% in the ALN group and by 46.9% ± 23.3% (CI - 38.42:- 55.35) in the ALN-EFF group (p = 0.08). The non-inferiority limit was 46.6%. With ALN-EFF the CI crosses the non-inferiority limit thus the test for non-inferiority was indeterminate. PINP decreased by 45.7 ± 22.6% in the ALN group and by 35.1 ± 20.7% in the ALN-EFF group (p = 0.07). Changes over time in the BTMs were not significantly different between the groups, p > 0.10 for both CTx and PINP. There was no difference in frequency of AEs or compliance between the two groups, but rate of discontinuation was lower with ALN-EFF. In conclusion, suppression of BTMs was not significantly different between the groups but formal non-inferiority could not be established.
Topics: Female; Humans; Alendronate; Osteoporosis, Postmenopausal; Prospective Studies; Bone Density; Bone Remodeling; Bone Density Conservation Agents
PubMed: 37803182
DOI: 10.1007/s00223-023-01140-w -
Frontiers in Immunology 2023Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure...
Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
Topics: Humans; HIV Infections; HIV-1; Virus Activation; Virus Latency; Alendronate; HIV Seropositivity
PubMed: 37744358
DOI: 10.3389/fimmu.2023.1219250 -
Journal of Bone and Mineral Research :... May 2024Although clinical trials have shown that denosumab significantly increases bone mineral density at key skeletal sites more than oral bisphosphonates, evidence is lacking...
Although clinical trials have shown that denosumab significantly increases bone mineral density at key skeletal sites more than oral bisphosphonates, evidence is lacking from head-to-head randomized trials evaluating fracture outcomes. This retrospective cohort study uses administrative claims data from Medicare fee-for service beneficiaries to evaluate the comparative effectiveness of denosumab versus alendronate in reducing fracture risk among women with postmenopausal osteoporosis (PMO) in the US. Women with PMO ≥ 66 years of age with no prior history of osteoporosis treatment, who initiated denosumab (n = 89 115) or alendronate (n = 389 536) from 2012 to 2018, were followed from treatment initiation until the first of a specific fracture outcome, treatment discontinuation or switch, end of study (December 31, 2019), or other censoring criteria. A doubly robust inverse-probability of treatment and censoring weighted function was used to estimate the risk ratio associated with the use of denosumab compared with alendronate for hip, nonvertebral (NV; includes hip, humerus, pelvis, radius/ulna, other femur), non-hip nonvertebral (NHNV), hospitalized vertebral (HV), and major osteoporotic (MOP; consisting of NV and HV) fractures. Overall, denosumab reduced the risk of MOP by 39%, hip by 36%, NV by 43%, NHNV by 50%, and HV fractures by 30% compared with alendronate. Denosumab reduced the risk of MOP fractures by 9% at year 1, 12% at year 2, 18% at year 3, and 31% at year 5. An increase in the magnitude of fracture risk reduction with increasing duration of exposure was also observed for other NV fracture outcomes. In this cohort of almost half-a-million treatment-naive women with PMO, we observed clinically significant reductions in the risk of MOP, hip, NV, NHNV, and HV fractures for patients on denosumab compared with alendronate. Patients who remained on denosumab for longer periods of time experienced greater reductions in fracture risk.
PubMed: 38753892
DOI: 10.1093/jbmr/zjae079 -
BMC Musculoskeletal Disorders Sep 2023Bisphosphonate medications, including alendronate, ibandronate and risedronate administered orally and zoledronate, administered intravenously, are commonly prescribed...
BACKGROUND
Bisphosphonate medications, including alendronate, ibandronate and risedronate administered orally and zoledronate, administered intravenously, are commonly prescribed for the treatment of osteoporosis based on evidence that, correctly taken, bisphosphonates can improve bone strength and lead to a reduction in the risk of fragility fractures. However, it is currently unclear how decisions to select between bisphosphonate regimens, including intravenous regimen, are made in practice and how clinicians support patients with different treatments.
METHODS
This was an interpretivist qualitative study. 23 semi-structured telephone interviews were conducted with a sample of general practitioners (GPs), secondary care clinicians, specialist experts as well as those providing and leading novel treatments including participants from a community intravenous (IV) zoledronate service. Data analysis was undertaken through a process of iterative categorisation.
RESULTS
The results report clinicians varying experiences of making treatment choices, as well as wider aspects of osteoporosis care. Secondary care and specialist clinicians conveyed some confidence in making treatment choices including on selecting IV treatment. This was aided by access to diagnostic testing and medication expertise. In contrast GPs reported a number of challenges in prescribing bisphosphonate medications for osteoporosis and uncertainty about treatment choice. Results also highlight how administering IV zoledronate was seen as an opportunity to engage in broader care practices.
CONCLUSION
Approaches to making treatment decisions and supporting patients when prescribing bisphosphonates for osteoporosis vary in practice. This study points to the need to co-ordinate osteoporosis treatment and care across different care providers.
Topics: Humans; Female; Zoledronic Acid; Osteoporosis; Diphosphonates; Ibandronic Acid; Alendronate; Bone Density Conservation Agents; Osteoporosis, Postmenopausal
PubMed: 37770860
DOI: 10.1186/s12891-023-06865-1 -
Archives of Osteoporosis Mar 2024This retrospective study compared the efficacy of anabolic agents (romosozumab and teriparatide) with that of alendronate in preventing subsequent vertebral body...
UNLABELLED
This retrospective study compared the efficacy of anabolic agents (romosozumab and teriparatide) with that of alendronate in preventing subsequent vertebral body fractures (SVBFs) after balloon kyphoplasty (BKP). All anabolic agents significantly reduced SVBFs. Romosozumab was most effective in increasing bone mineral density (BMD) and completely suppressed distant vertebral body fractures.
INTRODUCTION
To determine optimal anti-osteoporosis medications, we compared romosozumab and teriparatide to alendronate as a control from perioperative BKP to the 1st postoperative year for treatment and secondary fracture prevention in osteoporosis.
METHODS
A total of 603 patients who underwent initial BKP for osteoporotic vertebral fractures were evaluated and categorized into five groups based on drug administration: romosozumab (group R, 155 patients), twice-weekly teriparatide (group TW, 48), weekly teriparatide (group W, 151), daily teriparatide (group D, 138), and alendronate (control) (group C, 111). The 1-year incidence of SVBFs, BMD change rate, and probability of requiring BKP were compared among the groups.
RESULTS
SVBF incidence was 3.9%, 6.5%, 8.3%, 6.0%, and 14.4% in groups R, D, TW, W, and C, respectively, with all other groups exhibiting significantly lower rates than group C. The groups that administered the anabolic agents had a notably lower incidence of distant fractures than group C. Compared with group C, group R showed significantly higher BMD change rates in lumbar vertebral bodies at 4, 8, and 12 months and group D at 12 months. Anabolic agent groups exhibited significantly higher improvement rates than group C after conservative treatment alone.
CONCLUSION
The anabolic agents were found to be more effective at reducing the incidence of SVBF (especially distant vertebral fractures) than alendronate. These agents decreased the rate of repeat BKP even after the occurrence of a fracture. Overall, the use of an anabolic agent for the treatment of osteoporosis after BKP is better than the use of alendronate, even when treatment is initiated in the perioperative stage.
Topics: Humans; Vertebral Body; Kyphoplasty; Teriparatide; Alendronate; Retrospective Studies; Anabolic Agents; Osteoporosis; Osteoporotic Fractures; Bone Density; Spinal Fractures; Fractures, Compression; Bone Density Conservation Agents
PubMed: 38512565
DOI: 10.1007/s11657-024-01374-7 -
Biomaterials Advances Sep 2024Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution...
Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution is bone-homing and selective-active targeting of anticancer loaded-nanovectors. Herein, ivermectin (IVM) and methyl dihydrojasmonate (MDJ)-loaded nanostructured lipid carriers (IVM-NLC) were formulated then dually decorated by lactoferrin (Lf) and alendronate (Aln) to optimize (Aln/Lf/IVM-NLC) for active-targeting and bone-homing potential, respectively. Aln/Lf/IVM-NLC (1 mg) revealed nano-size (73.67 ± 0.06 nm), low-PDI (0.43 ± 0.06), sustained-release of IVM (62.75 % at 140-h) and MDJ (78.7 % at 48-h). Aln/Lf/IVM-NLC afforded substantial antileukemic-cytotoxicity on K562-cells (4.29-fold lower IC), higher cellular uptake and nuclear fragmentation than IVM-NLC with acceptable cytocompatibility on oral-epithelial-cells (as normal cells). Aln/Lf/IVM-NLC effectively upregulated caspase-3 and BAX (4.53 and 15.9-fold higher than IVM-NLC, respectively). Bone homing studies verified higher hydroxyapatite affinity of Aln/Lf/IVM-NLC (1 mg; 22.88 ± 0.01 % at 3-h) and higher metaphyseal-binding (1.5-fold increase) than untargeted-NLC. Moreover, Aln/Lf/IVM-NLC-1 mg secured 1.35-fold higher in vivo bone localization than untargeted-NLC, with lower off-target distribution. Ex-vivo hemocompatibility and in-vivo biocompatibility of Aln/Lf/IVM-NLC (1 mg/mL) were established, with pronounced amelioration of hepatic and renal toxicity compared to higher Aln doses. The innovative Aln/Lf/IVM-NLC could serve as a promising nanovector for bone-homing, active-targeted leukemia therapy.
Topics: Humans; Animals; Drug Carriers; Lactoferrin; Alendronate; Ivermectin; K562 Cells; Nanoparticles; Mice; Antineoplastic Agents; Bone and Bones; Lipids; Apoptosis
PubMed: 38875802
DOI: 10.1016/j.bioadv.2024.213924 -
Hormones (Athens, Greece) Jun 2024Menopausal hormone therapy (MHT) has consistently shown a bone protective effect by reducing the risk of vertebral, non-vertebral, and hip fractures in postmenopausal... (Review)
Review
OBJECTIVE
Menopausal hormone therapy (MHT) has consistently shown a bone protective effect by reducing the risk of vertebral, non-vertebral, and hip fractures in postmenopausal women regardless of baseline fracture risk. However, the optimal sequential treatment after MHT discontinuation has not been determined. This systematic review aimed to obtain the best evidence regarding the effect of antiresorptive or osteoanabolic treatment on bone mineral density (BMD) and/or fracture risk following MHT.
METHODS
A comprehensive search was conducted in the PubMed, Scopus, and Cochrane databases up to October 31, 2023. Randomized-controlled trials (RCTs) and observational studies conducted in postmenopausal women were included.
RESULTS
After the exclusion of duplicates, 717 studies were identified. Two were eligible for qualitative analysis, one RCT and one retrospective cohort study. The RCT showed that alendronate 10 mg/day for 12 months further increased lumbar spine (LS) BMD by 2.3% following MHT and maintained femoral neck (FN) BMD in postmenopausal women (n = 144). It also decreased bone anabolic and resorption markers by 47 and 36%, respectively. In the retrospective study (n = 34), raloxifene 60 mg/day increased both LS and FN BMD at 12 months by 3 and 2.9%, respectively. No fractures were reported.
CONCLUSIONS
Antiresorptive therapy with either a bisphosphonate (i.e., alendronate) or raloxifene could be considered a sequential antiosteoporosis therapy after MHT withdrawal since they have been shown in studies to further increase BMD. However, no safe conclusions can be drawn from the existing literature.
Topics: Humans; Female; Bone Density Conservation Agents; Osteoporosis, Postmenopausal; Bone Density; Estrogen Replacement Therapy
PubMed: 38236381
DOI: 10.1007/s42000-024-00526-1 -
Archives of Oral Biology Nov 2023To assess sodium alendronate as a local adjunctive therapy for treating experimental periodontitis in male rats treated with chemotherapy.
OBJECTIVES
To assess sodium alendronate as a local adjunctive therapy for treating experimental periodontitis in male rats treated with chemotherapy.
DESIGN
One-hundred-eighty male rats were randomly divided into two groups (n = 90) based on the systemic treatments: PSS, physiological saline solution; and 5-Fluorouracil, and then, subdivided into three subgroups (n = 30): NT, no treatment; scaling and root planing; and sodium alendronate. Treatments were performed 7 days after induction of experimental periodontitis. Specimens were collected at 14, 22, and 37 days after induction. Alveolar bone level, percentage of bone in the furcation, percentage of non-vital bone in the furcation, histopathologic features, and immunolabeling pattern for tartrate-resistant acid phosphatase (TRAP) and osteocalcin (OCN) were evaluated.
RESULTS
The lowest amount of alveolar bone and highest amount of non-vital bone was found in group 5-Fluorouracil when no treatment was performed. In animals receiving 5-Flurouracil and subjected to periodontal treatment, adjunctive sodium alendronate resulted in higher percentage of bone in the furcation and higher alveolar bone loss, when compared with scaling and root planing alone. Better structural and cellularity patterns were found in the periodontal tissues when sodium alendronate was used, regardless of systemic treatment. Higher TRAP-expression was found when no treatment was performed. Sodium alendronate didn't affect the immunolabeling pattern of osteocalcin in the presence of 5-Fluorouracil.
CONCLUSION
Adjunctive therapy with local sodium alendronate prevented alveolar bone loss and improved the histopathological features of the periodontal tissues following scaling and root planing in male rats with experimental periodontitis receiving anticancer chemotherapy with 5-Fluorouracil.
Topics: Rats; Male; Animals; Alendronate; Alveolar Bone Loss; Rats, Wistar; Dental Scaling; Osteocalcin; Periodontitis; Fluorouracil; Sodium
PubMed: 37633028
DOI: 10.1016/j.archoralbio.2023.105794 -
Toxicology and Applied Pharmacology Oct 2023Alendronate, a nitrogen-containing bisphosphonate, has reported long-term clinical success in the management of distinct bone-related conditions, particularly in the...
Alendronate, a nitrogen-containing bisphosphonate, has reported long-term clinical success in the management of distinct bone-related conditions, particularly in the modulation of post-menopausal osteoporosis. Nonetheless, whether the inhibitory activity over osteoclastic cells' functionality is widely acknowledged, contradictory evidence arises from the assessment of alendronate activity over osteoblastic populations. This may be of particular relevance in situations in which bone formation exceeds bone resorption, with further emphasis on embryonic development, since alendronate can cross the placental barrier and alendronate-based therapies are being extended into women of reproductive age. Accordingly, the present study aims to assess the effects of alendronate, at distinct concentrations (1.5EM to 1.5EM) on bone tissue development, within a translational animal model - the embryonic chicken development model. Embryos, at the beginning of osteogenesis (day 7) were exposed to different alendronate concentrations for 4 days. Embryos were following characterized for skeletal development by histomorphometric analysis upon histochemical staining, microtomographic analysis, and gene expression assessment of genes related to osteoclastogenic/osteoclastic and osteoblastogenic/osteogenic differentiation, as well as to the immuno-inflammatory activation. The findings revealed that exposure to alendronate had a dose-dependent impact on skeletal growth and mineralization. This effect was evidenced by diminished bone volume and reduced bone surface parameters, with the 1.5EM concentration leading to a remarkable reduction of over 50%. Additionally, a decreased osteoclastogenic/osteoclastic gene expression was verified, associated with a diminished osteoblastogenic/osteogenic program - within the 30-50% range for 1.5E-7 M, supporting the diminished bone formation process. An increased inflammatory activation may contribute, at least in part, to the attained outcomes. Overall present findings suggest a negative influence of alendronate on the embryonic bone development process in a dose-dependent manner, highlighting the potential risk of alendronate use during embryonic development.
Topics: Female; Pregnancy; Animals; Chick Embryo; Alendronate; Osteogenesis; Chickens; Placenta; Embryonic Development
PubMed: 37652309
DOI: 10.1016/j.taap.2023.116673