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Journal of Nanobiotechnology Oct 2022Glucocorticoids (GCs) overuse is associated with decreased bone mass and osseous vasculature destruction, leading to severe osteoporosis. Platelet lysates (PL) as a pool...
BACKGROUND
Glucocorticoids (GCs) overuse is associated with decreased bone mass and osseous vasculature destruction, leading to severe osteoporosis. Platelet lysates (PL) as a pool of growth factors (GFs) were widely used in local bone repair by its potent pro-regeneration and pro-angiogenesis. However, it is still seldom applied for treating systemic osteopathia due to the lack of a suitable delivery strategy. The non-targeted distribution of GFs might cause tumorigenesis in other organs.
RESULTS
In this study, PL-derived exosomes (PL-exo) were isolated to enrich the platelet-derived GFs, followed by conjugating with alendronate (ALN) grafted PEGylated phospholipid (DSPE-PEG-ALN) to establish a bone-targeting PL-exo (PL-exo-ALN). The in vitro hydroxyapatite binding affinity and in vivo bone targeting aggregation of PL-exo were significantly enhanced after ALN modification. Besides directly modulating the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs), respectively, PL-exo-ALN also facilitate their coupling under GCs' stimulation. Additionally, intravenous injection of PL-exo-ALN could successfully rescue GCs induced osteoporosis (GIOP) in vivo.
CONCLUSIONS
PL-exo-ALN may be utilized as a novel nanoplatform for precise infusion of GFs to bone sites and exerts promising therapeutic potential for GIOP.
Topics: Humans; Exosomes; Glucocorticoids; Mesenchymal Stem Cells; Osteogenesis; Osteoporosis; Alendronate
PubMed: 36310171
DOI: 10.1186/s12951-022-01400-1 -
Scientific Reports Jul 2023Atypical femur fracture (AFF) is a rare but catastrophic adverse event first reported in the long-term use of alendronate, one of the most commonly used drugs for...
Atypical femur fracture (AFF) is a rare but catastrophic adverse event first reported in the long-term use of alendronate, one of the most commonly used drugs for osteoporosis currently. However, further evidence is needed to learn more regarding other common anti-osteoporosis drugs and the risk for AFF. In this study, reports of AFF were identified from Food and Drug Administration Adverse Event Reporting System database. Disproportionality analyses were performed to examine the reporting odds ratio (ROR), information component (IC) and adjusted ROR (adj. ROR) signals for AFF for common anti-osteoporosis drugs. A total of 1692 unique AFF reports were identified. The disproportionality signals (the lower bound of 95% confidence interval > 1 for ROR and adjusted ROR, and > 0 for IC) were detected for alendronate, denosumab, pamidronate, risedronate, zoledronate, ibandronate, and teriparatide while no signal was detected for raloxifene, abaloparatide, and romosozumab. When restricted in patients with osteoporosis, the disproportionality signals were still detected for alendronate, pamidronate, risedronate, denosumab, and ibandronate. Our results suggest that alendronate has the largest risk signal, while the risks varied among different bisphosphonates. In addition, denosumab was found statistically associated with AFF in both the entire database and patients with osteoporosis.
Topics: Humans; Alendronate; Bone Density Conservation Agents; Risedronic Acid; Denosumab; Ibandronic Acid; Pharmaceutical Preparations; Pamidronate; Osteoporosis; Diphosphonates; Femur
PubMed: 37407650
DOI: 10.1038/s41598-023-37944-x -
Advanced Healthcare Materials Jun 2023Osteoporosis is a degenerative bone disease resulting from bone homeostasis imbalance regulated by osteoblasts and osteoclasts. Treating osteoporotic bone defects tends...
Osteoporosis is a degenerative bone disease resulting from bone homeostasis imbalance regulated by osteoblasts and osteoclasts. Treating osteoporotic bone defects tends to be more difficult due to suppressed osteogenic differentiation, hyperactive osteoclastogenesis, and impaired angiogenesis. Hence, a drug carrier system composed of gelatin-coated hollow mesoporous silica nanoparticles (HMSNs/GM) loaded with pro-osteogenic parathyroid (PTH) and anti-osteoclastogenic alendronate (ALN) is constructed and compounded into calcium magnesium phosphate cement (MCPC). The spatial-temporal release of ions and drugs, controllable degradation rate, and abundant pore structure of MCPC composites enhance osteoporotic bone regeneration in ovariectomized rats by accelerating vascularization, promoting osteogenic differentiation and mineralization, and inhibiting osteoclastogenesis and bone resorption. The MCPC/HMSNs@ALN-PTH/GM demonstrates a synergistic threefold effect on osteogenesis, osteoclastogenesis, and angiogenesis. It improves the osteoporotic pathophysiological microenvironment and promotes osteoporotic vascularized bone defect regeneration, holding huge potential for other functional biomaterials design and clinical management.
Topics: Rats; Animals; Osteogenesis; Bone Regeneration; Osteoporosis; Osteoclasts; Biocompatible Materials; Alendronate
PubMed: 36780559
DOI: 10.1002/adhm.202203099 -
JAMA Jun 2024
Topics: Humans; Fractures, Bone; United States; United States Food and Drug Administration; Alendronate; Bone Density Conservation Agents; Hip Fractures; Bone Remodeling; Fractures, Spontaneous; Drug Approval; Drug Labeling
PubMed: 38748439
DOI: 10.1001/jama.2024.6077 -
Journal of Investigative Medicine : the... Oct 2023This study conducted a meta-analysis to analyze the efficacy and safety of osteoporosis medications in kidney transplant recipients and patients with chronic kidney... (Meta-Analysis)
Meta-Analysis Review
This study conducted a meta-analysis to analyze the efficacy and safety of osteoporosis medications in kidney transplant recipients and patients with chronic kidney disease (CKD). PubMed, Embase, the Cochrane Central Register of Controlled Trials were searched from the date of their inception through October 21, 2022. We performed a meta-analysis of the efficacy and safety of osteoporosis medications in adult patients with stage 3-5 CKD or kidney transplant recipients enrolled in randomized clinical trials (RCTs). We calculated the standard mean deviations with 95% confidence intervals (CI) for bone mineral density (BMD) and T scores after 6 and 12 months treatment, pooled odds ratio and 95% CI for fracture risk, and summarized adverse events. The inclusion criteria were met by 27 studies. Out of this, 19 studies were included for the meta-analysis. In stage 3-4 CKD patients, alendronate increased lumbar spine BMD. In patients at stage 5 CKD and undergoing hemodialysis, alendronate and raloxifene increased lumbar spine BMD. After 6 months, the BMD of kidney transplant recipients was seen to be significantly increased; however, there was no difference after 12 months, and the risk of fracture did not reduce. Thus, there is no evidence that these medications reduce the risk of fracture, and their effect on BMD and fracture remains unproven. These medications may increase the incidence of adverse events and their safety needs to be further evaluated. Therefore, we cannot draw a definitive conclusion about the efficacy and safety of osteoporosis medications in the above group of patients.
Topics: Adult; Humans; Alendronate; Bone Density Conservation Agents; Diphosphonates; Kidney Transplantation; Osteoporosis; Bone Density; Fractures, Bone; Renal Insufficiency, Chronic; Kidney Failure, Chronic
PubMed: 37387531
DOI: 10.1177/10815589231184215 -
The American Journal of Sports Medicine Jun 2023Mechanical loading and alendronate (ALN) can be used as noninvasive physical therapy methods for osteoarthritis (OA). However, the timing and efficacy for treatments are...
BACKGROUND
Mechanical loading and alendronate (ALN) can be used as noninvasive physical therapy methods for osteoarthritis (OA). However, the timing and efficacy for treatments are unknown.
PURPOSE
To determine whether the timing of mechanical loading and ALN influences the pathobiological changes of OA.
STUDY DESIGN
Controlled laboratory study.
METHODS
Mice with OA induced by anterior cruciate ligament transection were subjected to early (1-3 weeks) or late (5-7 weeks) axial compressive dynamic load or intraperitoneal injection of ALN. Changes in gait were analyzed using gait analysis system, pathobiological changes in subchondral bone, cartilage, osteophyte, and synovitis were assessed using micro-computed tomography, tartrate-resistant acid phosphatase staining, pathologic section staining, and immunohistochemistry at 1, 2, 4, and 8 weeks.
RESULTS
At 1, 2, and 4 weeks, the OA limb had lower mean footprint pressure intensity, lower bone volume per tissue volume (BV/TV) in the subchondral bone, and more osteoclasts. At 4 weeks, the early loading, ALN, and load + ALN treatments induced less cartilage destruction, with a corresponding reduction in Osteoarthritis Research Society International score and increased hyaline cartilage thickness. The treatments also resulted in fewer osteoclasts and higher BV/TV and bone mineral density of subchondral bone and suppressed inflammation and interleukin 1β- and tumor necrosis factor α-positive cells in synovium. At 8 weeks, early loading or load + ALN improved the mean footprint pressure intensity and knee flexion. At 8 weeks, early load + ALN had a synergistic effect on protecting hyaline cartilage and proteoglycans. Footprint pressure intensity and cartilage destruction were worse in late loading limbs, and no differences in BV/TV, bone mineral density, osteophyte formation, and synovium inflammation were found between the late load, ALN, and load + ALN groups and the anterior cruciate ligament transection group.
CONCLUSION
Dynamic axial mechanical loading or ALN in the early stages of knee trauma protected against OA by suppressing subchondral bone remodeling. However, late loading promoted cartilage degeneration in advanced OA, indicating that reduced loading should be performed in the late stages of OA to avoid the acceleration of OA.
CLINICAL RELEVANCE
Early low-level functional exercise or antiosteoporotic drugs could clearly slow or prevent the progression of early OA. For patients with mild to severe OA, loading reduction via brace protection or maintenance of joint stability via early ligament reconstruction surgery may ameliorate OA exacerbation.
Topics: Mice; Animals; Osteophyte; X-Ray Microtomography; Cartilage, Articular; Osteoarthritis; Alendronate; Bone Remodeling; Inflammation; Disease Models, Animal
PubMed: 37103335
DOI: 10.1177/03635465231164644 -
Bone Nov 2022The balance between osteoclastic bone resorption and osteoblastic bone formation is ultimately responsible for maintaining a structural and functional skeleton. Despite... (Review)
Review
The balance between osteoclastic bone resorption and osteoblastic bone formation is ultimately responsible for maintaining a structural and functional skeleton. Despite their strength, bones do break and the main cause of fractures are trauma and decreased bone mineral density as a result of aging and/or pathology that weakens the bone's microarchitecture and subsequently, its material properties. Osteoporosis is a disease marked by increased osteoclast activity and decreased osteoblastic activity tipping the remodeling balance in favor of bone resorption and can be caused by aging, glucocorticoids, disuse and estrogen-deficiency. Ultimately, this leads to brittle and weaker bones which become more prone to trauma or stress-induced fractures. The current treatment for preventing and treating osteoporotic fractures is the use of antiresorptive drugs such as bisphosphonates (BPs) and denosumab, but unfortunately, their long-term use, especially with alendronate and ibandronate, has been associated with increased risk of atypical femoral fractures (AFFs); femoral diaphyseal fractures distal to the lesser trochanter but proximal to the supracondylar flare. The purpose of this review is to examine the information that exists in the literature examining the effects of BPs on fracture repair of long bones in rodent (rat and mouse) models. The focus on rodents stems from the scientific community's unresolved need to develop small animal models to examine the molecular, cellular, tissue and biomechanical mechanisms responsible for the development of AFFs and how best they can be treated.
Topics: Alendronate; Animals; Bone Density Conservation Agents; Bone Resorption; Denosumab; Diphosphonates; Estrogens; Femoral Fractures; Fractures, Stress; Glucocorticoids; Ibandronic Acid; Mice; Rats; Rodentia
PubMed: 36041726
DOI: 10.1016/j.bone.2022.116542 -
The Cochrane Database of Systematic... May 2023Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue leading to increased bone fragility. In people with... (Review)
Review
BACKGROUND
Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue leading to increased bone fragility. In people with beta-thalassaemia, osteoporosis represents an important cause of morbidity and is due to a number of factors. First, ineffective erythropoiesis causes bone marrow expansion, leading to reduced trabecular bone tissue with cortical thinning. Second, excessive iron loading causes endocrine dysfunction, leading to increased bone turnover. Lastly, disease complications can result in physical inactivity, with a subsequent reduction in optimal bone mineralization. Treatments for osteoporosis in people with beta-thalassaemia include bisphosphonates (e.g. clodronate, pamidronate, alendronate; with or without hormone replacement therapy (HRT)), calcitonin, calcium, zinc supplementation, hydroxyurea, and HRT alone (for preventing hypogonadism). Denosumab, a fully human monoclonal antibody, inhibits bone resorption and increases bone mineral density (BMD). Finally, strontium ranelate simultaneously promotes bone formation and inhibits bone resorption, thus contributing to a net gain in BMD, increased bone strength, and reduced fracture risk. This is an update of a previously published Cochrane Review.
OBJECTIVES
To review the evidence on the efficacy and safety of treatment for osteoporosis in people with beta-thalassaemia.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which includes references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of most recent search: 4 August 2022.
SELECTION CRITERIA
Randomized controlled trials (RCTs) in people with beta-thalassaemia with: a BMD Z score below -2 standard deviations (SDs) for children aged under 15 years, adult males (aged 15 to 50 years) and premenopausal females aged over 15 years; or a BMD T score below -2.5 SDs for postmenopausal females and males aged over 50 years.
DATA COLLECTION AND ANALYSIS
Two review authors assessed the eligibility and risk of bias of the included RCTs, and extracted and analysed data. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included six RCTs (298 participants). Active interventions included bisphosphonates (3 trials, 169 participants), zinc supplementation (1 trial, 42 participants), denosumab (1 trial, 63 participants), and strontium ranelate (1 trial, 24 participants). The certainty of the evidence ranged from moderate to very low and was downgraded mainly due to concerns surrounding imprecision (low participant numbers), but also risk of bias issues related to randomization, allocation concealment, and blinding. Bisphosphonates versus placebo or no treatment Two RCTs compared bisphosphonates to placebo or no treatment. After two years, one trial (25 participants) found that alendronate and clodronate may increase BMD Z score compared to placebo at the femoral neck (mean difference (MD) 0.40, 95% confidence interval (CI) 0.22 to 0.58) and the lumbar spine (MD 0.14, 95% CI 0.05 to 0.23). One trial (118 participants) reported that neridronate compared to no treatment may increase BMD at the lumbar spine and total hip at six and 12 months; for the femoral neck, the study found increased BMD in the neridronate group at 12 months only. All results were of very low-certainty. There were no major adverse effects of treatment. Participants in the neridronate group reported less back pain; we considered this representative of improved quality of life (QoL), though the certainty of the evidence was very low. One participant in the neridronate trial (116 participants) sustained multiple fractures as a result of a traffic accident. No trials reported BMD at the wrist or mobility. Different doses of bisphosphonate compared One 12-month trial (26 participants) assessed different doses of pamidronate (60 mg versus 30 mg) and found a difference in BMD Z score favouring the 60 mg dose at the lumbar spine (MD 0.43, 95% CI 0.10 to 0.76) and forearm (MD 0.87, 95% CI 0.23 to 1.51), but no difference at the femoral neck (very low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment. Zinc versus placebo One trial (42 participants) showed zinc supplementation probably increased BMD Z score compared to placebo at the lumbar spine after 12 months (MD 0.15, 95% CI 0.10 to 0.20; 37 participants) and 18 months (MD 0.34, 95% CI 0.28 to 0.40; 32 participants); the same was true for BMD at the hip after 12 months (MD 0.15, 95% CI 0.11 to 0.19; 37 participants) and 18 months (MD 0.26, 95% CI 0.21 to 0.31; 32 participants). The evidence for these results was of moderate certainty. The trial did not report BMD at the wrist, fracture incidence, mobility, QoL, or adverse effects of treatment. Denosumab versus placebo Based on one trial (63 participants), we are unsure about the effect of denosumab on BMD Z score at the lumbar spine, femoral neck, and wrist joint after 12 months compared to placebo (low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment, but the investigators reported a reduction in bone pain measured on a visual analogue scale in the denosumab group after 12 months of treatment compared to placebo (MD -2.40 cm, 95% CI -3.80 to -1.00). Strontium ranelate One trial (24 participants) only narratively reported an increase in BMD Z score at the lumbar spine in the intervention group and no corresponding change in the control group (very low-certainty evidence). This trial also found a reduction in back pain measured on a visual analogue scale after 24 months in the strontium ranelate group compared to the placebo group (MD -0.70 cm (95% CI -1.30 to -0.10); we considered this measure representative of improved quality of life.
AUTHORS' CONCLUSIONS
Bisphosphonates may increase BMD at the femoral neck, lumbar spine, and forearm compared to placebo after two years' therapy. Zinc supplementation probably increases BMD at the lumbar spine and hip after 12 months. Denosumab may make little or no difference to BMD, and we are uncertain about the effect of strontium on BMD. We recommend further long-term RCTs on different bisphosphonates and zinc supplementation therapies in people with beta-thalassaemia-associated osteoporosis.
Topics: Adult; Child; Female; Male; Humans; Middle Aged; beta-Thalassemia; Alendronate; Pamidronate; Clodronic Acid; Denosumab; Osteoporosis; Diphosphonates; Fractures, Bone
PubMed: 37159055
DOI: 10.1002/14651858.CD010429.pub3 -
Heliyon Sep 2023Bisphosphonates are known to induce a severe adverse effect known as medication-related osteonecrosis of the jaw (MRONJ). Previous studies have proven the impact of...
OBJECTIVES
Bisphosphonates are known to induce a severe adverse effect known as medication-related osteonecrosis of the jaw (MRONJ). Previous studies have proven the impact of bisphosphonates on microperfusion; therefore, this study aimed to investigate alendronate-induced microcirculatory reactions in the calvarial periosteum of rats.
STUDY DESIGN
Bone chambers were implanted into 48 Lewis rats. Microhemodynamics, inflammatory parameters, functional capillary density and defect healing were examined after alendronate treatment for two and six weeks using repetitive intravital fluorescence microscopy for two weeks.
RESULTS
Microhemodynamics remained unchanged. In alendronate-treated rats, inflammation was slightly increased, functional capillary density was significantly reduced (day 10: controls 100.45 ± 5.38 cm/cm, two weeks alendronate treatment 44.77 ± 3.55 cm/cm, six weeks alendronate treatment 27.54 ± 2.23 cm/cm) and defect healing was decelerated. The changes in functional capillary density and defect healing were dose-dependent.
CONCLUSION
The bisphosphonate alendronate has a significant negative impact on periosteal microperfusion in vivo. This could be a promising target for the treatment of MRONJ.
PubMed: 37681156
DOI: 10.1016/j.heliyon.2023.e19468 -
Minerva Endocrinologica Dec 2019Several formulations of vitamin D and alendronate are available for the treatment of osteoporosis. The objective of this study was to examine efficacy and safety of...
BACKGROUND
Several formulations of vitamin D and alendronate are available for the treatment of osteoporosis. The objective of this study was to examine efficacy and safety of calcifediol (25(OH)D) compared to cholecalciferol (vitamin D3) and also the relationship between different formulations of alendronate and adverse reactions.
METHODS
We observed a population of women diagnosed with postmenopausal osteoporosis or osteopenia treated with alendronate 70 mg weekly associated to vitamin D3 or 25(OH)D at monthly total dose of 625 µg. Data collected both at baseline (T0) and at follow-up after at least 12 months of therapy (T1) were: demographic characteristics, BMI, full medical history, lumbar T-score, femur T-score, calcium, osteocalcin, alkaline phosphatase, PTH and vitamin D blood level.
RESULTS
A total of 362 patients were enrolled in the study. Alendronate 70 mg + calcifediol (A+25(OH)D) group consisted of 202 patients while 160 patients were treated with alendronate 70 mg + cholecalciferol (A+D3). In the A+25(OH)D group, we observed a significant increase in lumbar T-score value (0.26±0.35 vs. 0.13±0.3) and serum vitamin D (20.64±20.71 vs. 6.07±7.61 ng/mL) levels compared to the A+D3 group (P<0.05). The lowest incidence of gastrointestinal adverse reactions was observed among patients taking alendronate 70 mg in drinkable solution form (P<0.05).
CONCLUSIONS
Alendronate 70 mg with calcifediol gives a better outcome in the treatment of osteoporosis according to lumbar T-score and vitamin D serum level observed at one-year follow-up compared to alendronate 70 mg with cholecalciferol. Both vitamin D formulations did not show to cause hypercalcemia in this study. Alendronate 70 mg in drinkable solution form is also associated with lowest incidence of gastrointestinal adverse reactions.
Topics: Aged; Alendronate; Alkaline Phosphatase; Bone Density; Bone Density Conservation Agents; Calcifediol; Calcium; Cholecalciferol; Drug Therapy, Combination; Exercise; Female; Femur; Humans; Lumbar Vertebrae; Middle Aged; Osteocalcin; Osteoporosis, Postmenopausal; Parathyroid Hormone; Phosphorus; Retrospective Studies; Vitamin D
PubMed: 31971357
DOI: 10.23736/S0391-1977.19.03052-9