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Aerospace Medicine and Human Performance May 2023Prolonged exposure to microgravity is associated with a significant reduction in bone density, exposing astronauts to renal calculi in flight and osteoporotic fractures... (Review)
Review
Prolonged exposure to microgravity is associated with a significant reduction in bone density, exposing astronauts to renal calculi in flight and osteoporotic fractures on return to Earth. While physical countermeasures and bisphosphonates may reduce demineralization, additional therapies are needed for future interplanetary missions. This literature review aims to understand the current background pertaining to denosumab (a monoclonal antibody therapy used in osteoporosis) and its potential use for long duration spaceflight. A literature review was conducted using the following keywords: "osteoporosis"; "osteopaenia"; "microgravity"; "space flight"; "bed rest"; "denosumab"; "alendronate"; "bisphosphonates"; and "countermeasures". Additional articles were identified through references. Included for discussion were 48 articles, including systemic reviews, clinical trials, practice guidelines, and textbooks. No previous bed rest or in-flight studies regarding denosumab were identified. In osteoporosis, denosumab is superior to alendronate in maintaining bone density with a lower rate of side-effects. Emerging evidence in reduced biomechanical loading state suggests denosumab improves bone density and decreases fracture risk. Concerns exists over vertebral fracture risk following discontinuation. The dosing regimen of denosumab offers practical advantages over bisphosphonates. Existing spaceflight studies with alendronate serve as a template for a study with denosumab and allow for a direct comparison of efficacy and safety. Denosumab has numerous potential advantages as a countermeasure to microgravity-induced osteopenia when compared to alendronate, including: improved efficacy; fewer side-effects: better tolerability; and a convenient dosing regimen. Two further studies are proposed to determine in-flight efficacy and the suitability of monoclonal antibody therapy in the spaceflight environment.
Topics: Humans; Bone Density Conservation Agents; Diphosphonates; Alendronate; Osteoporotic Fractures; Space Flight; Antibodies, Monoclonal; Bone Diseases, Metabolic
PubMed: 37069761
DOI: 10.3357/AMHP.6053.2023 -
Orthodontics & Craniofacial Research Aug 2017To evaluate orthodontic tooth movement (OTM) in rats treated with two types of bisphosphonates (BPs), alendronate sodium (A) and zoledronic acid (Z).
OBJECTIVE
To evaluate orthodontic tooth movement (OTM) in rats treated with two types of bisphosphonates (BPs), alendronate sodium (A) and zoledronic acid (Z).
DESIGN
In all, 15 male Wistar rats were randomly divided into three groups. Group OTM+A: orthodontic tooth movement and subcutaneous administration of alendronate sodium (2.5 mg/kg); Group OTM+Z: orthodontic tooth movement and subcutaneous administration of zoledronic acid (0.02 mg/kg), and Group OTM: orthodontic tooth movement and subcutaneous injection of saline. The BPs were administered once a day during 25 days before OTM started and during 10 days of OTM. The left upper first molar was moved with a stainless-steel closed coil spring which delivered an initial force of 0.4N. OTM was measured with a digital caliper comparing the moved and the contralateral side. The histomorphometric analysis counted the number of osteoclasts, inflammatory cells, blood vessels and fibroblasts (n/10 m ) in periodontal ligament (PDL) of the distobuccal root.
RESULTS
A reduction of 58.3% of OTM was found in Group OTM+A and 99.6% in Group OTM+Z, when compared with Group OTM. There was a significant decrease of osteoclasts and inflammatory cells in BP-treated groups. Blood vessels and fibroblastic cells decreased mainly in Group OTM+Z.
CONCLUSION
Alendronate sodium and zoledronic acid have similar effects on the periodontal tissue during orthodontic treatment in rats. Especially, zoledronic acid can affect orthodontic tooth movement.
Topics: Alendronate; Animals; Bone Density; Bone Remodeling; Diphosphonates; Imidazoles; Male; Rats; Rats, Wistar; Tooth Movement Techniques; Zoledronic Acid
PubMed: 28653350
DOI: 10.1111/ocr.12192 -
Osteoporosis International : a Journal... Jun 2020
Topics: Alendronate; Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Female; Humans; Osteoporosis, Postmenopausal; Treatment Outcome
PubMed: 32246168
DOI: 10.1007/s00198-020-05379-z -
ACS Biomaterials Science & Engineering Dec 2023The development of magnesium-derived biomaterials is one of the most promising research in bone tissue engineering, and related strategies have been extensively used for...
The development of magnesium-derived biomaterials is one of the most promising research in bone tissue engineering, and related strategies have been extensively used for tendon, skull, cartilage, and bone regeneration. Also, alendronate, a well-recognized drug for osteoporosis treatment, has recently attracted a great deal of attention for bone repair. However, rapid corrosion of Mg and low systemic bioavailability of alendronate are the main limitations hampering their full exploitation. In this work, by means of physical and chemical cross-linking conjugating magnesium-metal-organic frameworks (Mg-MOFs) and bone-targeting alendronate to biocompatible gelatin scaffolds, a facile method is developed for the preparation of organic/inorganic nanocomposite gel scaffolds. The results affirmed that the nanocomposite gel scaffolds possessed excellent biocompatibility, continuous slow release of Mg and alendronate, strong bone affinity, and bone regeneration. It is noteworthy that the continuous slow release of Mg and alendronate could induce the macrophage switch to the M2 phenotype and promote osteogenic differentiation in the early stage, resulting in improved bone regeneration during implanting the scaffolds into the distal femoral. In summary, Mg-MOFs-loaded alendronate-modified gelatin gel scaffolds have been developed, exhibiting great potential for bone regenerative.
Topics: Diphosphonates; Osteogenesis; Alendronate; Magnesium; Gelatin; Nanogels; Tissue Scaffolds; Bone Regeneration
PubMed: 37942941
DOI: 10.1021/acsbiomaterials.3c01080 -
Arteriosclerosis, Thrombosis, and... Jul 2019Osteoporosis and cardiovascular diseases are major public health issues. Bone and cardiovascular remodeling share multiple biological markers and pathways. Medical... (Review)
Review
Osteoporosis and cardiovascular diseases are major public health issues. Bone and cardiovascular remodeling share multiple biological markers and pathways. Medical intervention, such as using romosozumab, an antisclerostin antibody, improves the clinical outcome of osteoporosis. However, blocking sclerostin leads to Wnt (wingless/integrated) activation and participation in the cardiovascular remodeling process, which could potentially lead to adverse events. Based on the opposing roles of bisphosphonates and the Wnt pathway on endothelial dysfunction, lipid accumulation and calcification of the vessel walls, the combination of romosozumab and bisphosphonates could be a new therapeutic approach to reducing the risks of adverse cardiovascular events in romosozumab receivers. Visual Overview- An online visual overview is available for this article.
Topics: Adaptor Proteins, Signal Transducing; Alendronate; Antibodies, Monoclonal; Cardiovascular Diseases; Humans; Osteoporosis; Wnt Signaling Pathway
PubMed: 31242037
DOI: 10.1161/ATVBAHA.119.312371 -
BMJ Open Dec 2015Concerns have been raised about a possible link between bisphosphonate use, and in particular alendronate, and upper gastrointestinal (UGI) cancer. A number of... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Concerns have been raised about a possible link between bisphosphonate use, and in particular alendronate, and upper gastrointestinal (UGI) cancer. A number of epidemiological studies have been published with conflicting results. We conducted a systematic review and meta-analysis of observational studies, to determine the risk of esophageal and gastric cancer in users of bisphosphonates compared with non-users.
DESIGN
We searched PubMed, MEDLINE, EMBASE, Web of Knowledge and Cochrane Database of Systematic Reviews for studies investigating bisphosphonates and esophageal or gastric cancer. We calculated pooled ORs and 95% CIs for the risk of esophageal or gastric cancer in bisphosphonate users compared with non-users. We performed a sensitivity analysis of alendronate as this was the most common single drug studied and is also the most widely used in clinical practice.
RESULTS
11 studies (from 10 papers) examining bisphosphonate exposure and UGI cancer (gastric and esophageal), met our inclusion criteria. All studies were retrospective, 6/11 (55%) case-control and 5/11(45%) cohort, and carried out using data from 5 longitudinal clinical databases. Combining 5 studies (1 from each database), we found no increased risk, OR 1.11 (95% CI 0.97 to 1.27) of esophageal cancer in bisphosphonate users compared with non-users and no increased risk of gastric cancer in bisphosphonate users, OR 0.96 (95% CI 0.82 to 1.12).
CONCLUSION
This is the fourth and most detailed meta-analysis on this topic. We have not identified any compelling evidence for a significantly raised risk of esophageal cancer or gastric cancer in male and female patients prescribed bisphosphonates.
Topics: Alendronate; Bone Density Conservation Agents; Diphosphonates; Esophageal Neoplasms; Humans; Stomach Neoplasms
PubMed: 26644118
DOI: 10.1136/bmjopen-2014-007133 -
The Veterinary Clinics of North... Mar 2017Hypercalcemia in cats is recognized with increased frequency, especially idiopathic hypercalcemia, which is the most common cause. Idiopathic hypercalcemia seems to be... (Review)
Review
Hypercalcemia in cats is recognized with increased frequency, especially idiopathic hypercalcemia, which is the most common cause. Idiopathic hypercalcemia seems to be unique to the cat, not occurring in the dog as a specific syndrome. There are many causes of hypercalcemia, and diagnosis relies on evaluation of clinical signs, physical examination, diagnostic imaging, serum biochemistry, urinalysis, and evaluation of calcium metabolic hormones. With an accurate diagnosis, treatment options can be tailored to the individual.
Topics: Alendronate; Animals; Bone Density Conservation Agents; Calcium; Cat Diseases; Cats; Diagnosis, Differential; Glucocorticoids; Hydroxycholecalciferols; Hypercalcemia; Specimen Handling
PubMed: 27988049
DOI: 10.1016/j.cvsm.2016.09.004 -
Aging Clinical and Experimental Research Nov 2022Oral bisphosphonates are a key intervention in the treatment of osteoporosis and in reducing the risk of fragility fractures. Their use is supported by over 3 decades of... (Review)
Review
Oral bisphosphonates are a key intervention in the treatment of osteoporosis and in reducing the risk of fragility fractures. Their use is supported by over 3 decades of evidence; however, patient adherence to oral bisphosphonates remains poor in part due to complex dosing instructions and adverse events, including upper gastrointestinal symptoms. This problem has led to the development of novel oral bisphosphonate formulations. Buffered, effervescent alendronate is dissolved in water and so seeks to reduce upper gastro-intestinal adverse events, and gastro-resistant risedronate aims to reduce the complexity of dosing procedure (e.g. fasting prior to consumption) whilst still maintaining the efficacy of fracture risk reduction. Clinical trials and real-world data have been employed to demonstrate some benefits in terms of reduced upper gastro-intestinal adverse events, adherence, persistence and health economic outcomes. This report describes the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores where oral bisphosphonates sit in current clinical practice guidelines, review their risk-benefit profile and the consequences of poor adherence before exploring novel oral bisphosphonate formulations and their potential clinical and health economic impact. Further research is required but there are signs that these novel, oral bisphosphonate formulations may lead to improved tolerance of oral bisphosphonates and thus, improved adherence and fracture outcomes.
Topics: Humans; Osteoporosis; Diphosphonates; Fractures, Bone; Risedronic Acid; Alendronate
PubMed: 36331798
DOI: 10.1007/s40520-022-02272-z -
Bone Jul 2022Despite their ability to reduce fracture-risk and increase Bone Mineral Density (BMD) in osteoporotic women, bisphosphonates are reported to reduce formation of new...
Despite their ability to reduce fracture-risk and increase Bone Mineral Density (BMD) in osteoporotic women, bisphosphonates are reported to reduce formation of new bone. Reduced bone formation has been suggested to lead to accumulation of microfractures and contribute to rare side effects in cortical bone such as atypical femur fractures. However, most studies are limited to trabecular bone. In this study, the cortical bone remodeling in human iliac bone specimens of 65 non-treated and 24 alendronate-treated osteoporotic women was investigated using a new histomorphometric classification of intracortical pores. The study showed that only 12.4 ± 11% of the cortical pore area reflected quiescent pores/osteons in alendronate-treated patients versus 8.5 ± 5% in placebo, highlighting that new cortical remodeling events remain to be activated. The percent and size of eroded pores (events in resorption-reversal phase) remained unchanged, but their contribution to total pore area was 1.4-fold higher in alendronate versus placebo treated patients (66 ± 22% vs 48 ± 22%, p < 0.001). On the other hand, the mixed eroded-formative pores (events with mixed resorption-reversal-formation phases) was 2-fold lower in alendronate versus placebo treated patients (19 ± 14% vs 39 ± 23% of total pore area, p < 0.001), and formative pores (event in formation phase) was 2.2-fold lower in alendronate versus placebo treated patients (2.1 ± 2.4% vs 4.6 ± 3.6%, p < 0.01), and their contribution to total pore area was 2.4-fold lower (1.3 ± 2.1% vs 3.1 ± 4.4%, p < 0.05). Importantly, these differences between alendronate and placebo treated patients were significant in patients after 3 years of treatment, not after 2 years of treatment. Collectively, the results support that cortical remodeling events activated during alendronate treatment has a prolonged reversal-resorption phase with a delayed transition to formation, becoming increasingly evident after 3-years of treatment. A potential contributor to atypical femur fractures associated with long-term bisphosphonate treatment.
Topics: Alendronate; Bone Density; Bone Remodeling; Bone and Bones; Cortical Bone; Diphosphonates; Female; Humans
PubMed: 35413490
DOI: 10.1016/j.bone.2022.116419 -
Journal of Clinical Pharmacology Apr 2023This systematic review and meta-analysis aimed to reveal the efficacy and safety of zoledronic acid compared with alendronate in patients with primary osteoporosis. The... (Meta-Analysis)
Meta-Analysis
This systematic review and meta-analysis aimed to reveal the efficacy and safety of zoledronic acid compared with alendronate in patients with primary osteoporosis. The PubMed, Embase, and the Cochrane Library databases were searched from the establishment of each database to April 2022 for comparative studies on the topic, including randomized controlled trials (RCTs) and cohort studies, and 2 authors individually extracted information and data concerning study design, baseline characteristics, bone mineral density (BMD), bone turnover markers, and adverse events (AEs). We identified 8 eligible trials, including 1863 participants. Pooled estimates demonstrated that, compared with alendronate, zoledronic acid showed no significant difference in increasing the BMD of the lumbar spine after 1 year (SMD = -0.03, 95%CI -0.15 to 0.09, I = 0.41%) or after 2 years (SMD = 0.16, 95%CI -0.12 to 0.43, I = 63%), and the BMD of the total hip after 1 year (SMD = -0.08, 95%CI -0.31 to 0.14, I = 64%) or after 2 years (SMD = 0.05, 95%CI -0.21 to 0.32, I = 61%). No significant difference in improving bone turnover markers, including serum C-terminal cross-linking telopeptide of type-1 collagen, urine N-terminal cross-linking telopeptide of type-1 collagen, and serum procollagen type-1 N-terminal propeptide, were found, whereas significantly higher total AE rates (RR = 2.27, 95%CI 1.60 to 3.21, I = 75%) were recorded within 3 days of infusion, but some lower AE rates, particularly of gastrointestinal AEs (RR = 0.6, 95%CI 0.44 to 0.83, I = 37%), were noted after 3 days of infusion. Compared with alendronate, zoledronic acid has achieved comparable therapeutic results in the treatment of primary osteoporosis in increasing BMD and reducing bone turnover marker levels. Zoledronic acid showed a better safety profile than alendronate with long-term use, especially with regards to gastrointestinal-related AEs.
Topics: Humans; Female; Alendronate; Zoledronic Acid; Diphosphonates; Bone Density Conservation Agents; Bone Density; Osteoporosis; Osteoporosis, Postmenopausal
PubMed: 36433675
DOI: 10.1002/jcph.2181