Influence of Various Strontium Formulations (Ranelate, Citrate, and Chloride) on Bone Mineral Density, Morphology, and Microarchitecture: A Comparative Study in an Ovariectomized Female Mouse Model of Osteoporosis.

Osteoporosis stands out as a prevalent skeletal ailment, prompting exploration into potential treatments, including dietary strontium ion supplements. This study assessed the efficacy of supplementation of three strontium forms-strontium citrate (SrC), strontium ranelate (SrR), and strontium chloride (SrCl)-for enhancing bone structure in 50 female SWISS mice, aged seven weeks. In total, 40 mice underwent ovariectomy, while 10 underwent sham ovariectomy. Ovariectomized (OVX) mice were randomly assigned to the following groups: OVX (no supplementation), OVX + SrR, OVX + SrC, and OVX + SrCl, at concentrations equivalent to the molar amount of strontium. After 16 weeks, micro-CT examined trabeculae and cortical bones, and whole-bone strontium content was determined. Results confirm strontium administration increased bone tissue mineral density (TMD) and Sr content, with SrC exhibiting the weakest effect. Femur morphometry showed limited Sr impact, especially in the OVX + SrC group. This research highlights strontium's potential in bone health, emphasizing variations in efficacy among its forms.

Apatite/Chitosan Composites Formed by Cold Sintering for Drug Delivery and Bone Tissue Engineering Applications.

In the biomedical field, nanocrystalline hydroxyapatite is still one of the most attractive candidates as a bone substitute material due to its analogies with native bone mineral features regarding chemical composition, bioactivity and osteoconductivity. Ion substitution and low crystallinity are also fundamental characteristics of bone apatite, making it metastable, bioresorbable and reactive. In the present work, biomimetic apatite and apatite/chitosan composites were produced by dissolution-precipitation synthesis, using mussel shells as a calcium biogenic source. With an eye on possible bone reconstruction and drug delivery applications, apatite/chitosan composites were loaded with strontium ranelate, an antiosteoporotic drug. Due to the metastability and temperature sensitivity of the produced composites, sintering could be carried out by conventional methods, and therefore, cold sintering was selected for the densification of the materials. The composites were consolidated up to ~90% relative density by applying a uniaxial pressure up to 1.5 GPa at room temperature for 10 min. Both the synthesised powders and cold-sintered samples were characterised from a physical and chemical point of view to demonstrate the effective production of biomimetic apatite/chitosan composites from mussel shells and exclude possible structural changes after sintering. Preliminary in vitro tests were also performed, which revealed a sustained release of strontium ranelate for about 19 days and no cytotoxicity towards human osteoblastic-like cells (MG63) exposed up to 72 h to the drug-containing composite extract.

Strontium ranelate retards disc degradation and improves endplate and bone micro-architecture in ovariectomized rats with lumbar fusion induced - Adjacent segment disc degeneration.

Objectives: Adjacent segment disc degeneration (ASDD) is one of the long-term sequelae of spinal fusion, which is more susceptible with osteoporosis. As an anti-osteoporosis drug, strontium ranelate (SR) has been reported to not only regulate bone metabolism but also cartilage matrix formation. However, it is not yet clear whether SR has a reversal or delaying effect on fusion-induced ASDD in a model of osteoporosis. Materials and methods: Fifth three-month-old female Sprague-Dawley rats that underwent L4-L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after bilateral ovariectomy (OVX) surgery. Animals were administered vehicle (V) or SR (900 mg/kg/d) orally for 12 weeks post-PLF as follows: Sham+V, OVX + V, PLF + V, OVX + PLF + V, and OVX + PLF + SR. Manual palpation and X-ray were used to evaluate the state of lumbar fusion. Adjacent-segment disc was assessed by histological (VG staining and Scoring), histomorphometry (Disc Height, MVD, Calcification rate and Vascular Bud rate), immunohistochemical (Col-II, Aggrecan, MMP-13, ADAMTS-4 and Caspase-3), and mRNA analysis (Col-I, Col-II, Aggrecan, MMP-13 and ADAMTS-4). Adjacent L6 vertebrae microstructures were evaluated by microcomputed tomography. Results: Manual palpation and radiographs showed clear evidence of the fused segment's immobility. After 12 weeks of PLF surgery, a fusion-induced ASDD model was established. Low bone mass caused by ovariectomy can significantly exacerbate ASDD progression. SR exerted a protective effect on adjacent segment intervertebral disc with the underlying mechanism possibly being associated with preserving bone mass to prevent spinal instability, maintaining the functional integrity of endplate vascular microstructure, and regulating matrix metabolism in the nucleus pulposus and annulus fibrosus. Discussion: Anti-osteoporosis medication SR treatments not only maintain bone mass and prevent fractures, but early intervention could also potentially delay degenerative conditions linked to osteoporosis. Taken together, our results suggested that SR might be a promising approach for the intervention of fusion-induced ASDD with osteoporosis.

Evaluating the effect of strontium ranelate and photobiomodulation on cementogenic and osteogenic differentiation of buccal fat pad-derived stem cells: An in vitro study.

This study aimed to analyze the impact of strontium ranelate (Str), photobiomodulation (PBM), or their combination of the proliferation, osteogenic differentiation, and cementogenic differentiation of buccal fat pad-derived stem cells. BFPdSCs were exposed to one of the following interventions: (1) PBM (660 nm), (2) PBM (660 nm) + Str, (3) PBM (880 nm), (4) PBM (880 nm) + Str, (5) Str. All study groups had significantly higher osteogenic differentiation than the control group (p < 0.05), and no significant difference existed between the 660 and 808 nm groups (p = 0.97). Compared to the Str group, 660 nm and 880 nm group samples had significantly lower osteogenic differentiation (p < 0.0001), while other groups did not show a significant difference. Regarding cementogenic differentiation, the 660 nm group showed higher values than the 808 nm group (p < 0.01). Compared with the Str group, 660 nm, 660 nm + Str, and 808 nm + Str groups showed significantly higher gene expression (p < 0.05). In the case of osteogenic differentiation, although photobiomodulation alone had a lower inducing effect than strontium ranelate, combining 808 nm diode lasers and strontium ranelate may provide the best results. Moreover, using a 660 nm diode laser and exposing stem cells to strontium ranelate can be the most effective approach to induce cementogenic differentiation.

Guided bone regeneration of calcium phosphate-coated and strontium ranelate-doped titanium mesh in a rat calvarial defect model.

PURPOSE: When applied alone, titanium (Ti) mesh may not effectively block the penetration of soft tissues, resulting in insufficient new bone formation. This study aimed to confer bioactivity and improve bone regeneration by doping calcium phosphate (CaP) precipitation and strontium (Sr) ranelate onto a TiO2 nanotube (TNT) layer on the surface of a Ti mesh. METHODS: The TNT layer was obtained by anodizing on the Ti mesh, and CaP was formed by cyclic pre-calcification. The final specimens were produced by doping with Sr ranelate. The surface properties of the modified Ti mesh were investigated using high-resolution field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray diffraction. To evaluate the effects of surface treatment on cell viability, osteoblasts were cultured for 1-3 days, and their absorbance was subsequently measured. In an in vivo experiment, critical-size defects were created in rat calvaria (Ф=8 mm). After 5 weeks, the rats were sacrificed (n=4 per group) and bone blocks were taken for micro-computed tomography and histological analysis. RESULTS: After immersing the Sr ranelate-doped Ti mesh in simulated body fluid, the protrusions observed in the initial stage of hydroxyapatite were precipitated as a dense structure. On day 3 of osteoblast culture, cell viability was significantly higher on the pre-calcified Sr ranelate-doped Ti mesh surface than on the untreated Ti mesh surface (P<0.05). In the in vivo experiment, a bony bridge formed between the surrounding basal bone and the new bone under the Sr ranelate-doped Ti mesh implanted in a rat calvarial defect, closing the defect. New bone mineral density (0.91±0.003 g/mm3) and bone volume (29.35±2.082 mm3) significantly increased compared to the other groups (P<0.05). CONCLUSIONS: Cyclic pre-calcification of a Ti mesh with a uniform TNT layer increased bioactivity, and subsequent doping with Sr ranelate effectively improved bone regeneration in bone defects.

Osteogenic effect of magnesium oxychloride cement modified with phytic acid and loaded with strontium ranelate.

BACKGROUND: Magnesium oxychloride cement has good mechanical properties, but poor water resistance. METHODS: Phytic acid, which can form chelate with Mg2+, was used to modify magnesium oxychloride cement, and the effects of phytic acid on the strength, in vitro degradation and biological activity of magnesium oxychloride cement were studied. Based on the preparation of phytic acid modified magnesium oxychloride cement with good water resistance and biological activity, osteoporosis treatment strontium ranelate was loaded on phytic acid- magnesium oxychloride cement, strontium ranelate/phytic acid-magnesium oxychloride cement was prepared. RESULTS: It was found that the compressive strength of 1.25 wt% phytic acid-magnesium oxychloride cement after soaking in SBF for 28 d could reach 40.5 ± 2.0 MPa, 13.33% higher than that of the control group (when phytic acid was 0 wt%), and the mass loss rate of all ages was lower than that of the control group. The water resistance of magnesium oxychloride cement was effectively improved by phytic acid. After loading with strontium ranelate, the water resistance of 1.25 wt% phytic acid-magnesium oxychloride cement was improved. Cell experiments showed that strontium ranelate could effectively promote cell proliferation and improve the expression of osteoblast-related proteins. When strontium ranelate/phytic acid-magnesium oxychloride cement samples were implanted subcutaneously in rats for 4 w, no obvious inflammatory response was observed, and the material was tightly bound to the surrounding tissues. When bone cement was implanted into rat femur for 4 w, the bone cement was gradually wrapped and absorbed by new bone tissue, which grew from the outside to the inside, indicating that the bone cement containing strontium ranelate/phytic acid-magnesium oxychloride cement had excellent bone-forming ability. CONCLUSIONS: In conclusion, the results indicated that strontium ranelate/phytic acid-magnesium oxychloride cement composite bone cement had a potential application prospect in clinical bone repair.

Role of Calcitonin and Strontium Ranelate in Osteoporosis.

Background: Both Strontium Ranelate (SR) and Calcitonin (CT) can be used to treat osteoporosis. Calcitonin was actually one of the very initial medicines used to treat osteoporosis, especially in postmenopausal cases. However, the fracture prevention effect of Calcitonin is only proven to be in vertebrae and that too with nasal route only. When comparing Calcitonin with other conventional medications in treating osteoporosis, Calcitonin has got no additional advantages. Strontium Ranelate has got double effect, i.e., less bone resorption and more bone formation. Therefore, it can lead to an increase in bone mass significantly. Strontium Ranelate has been proven to decrease the risk of non-vertebral fractures as well as vertebral fractures. Conclusion: Both Calcitonin and Strontium Ranelate are used only as a second-line therapy for the treatment of osteoporosis and not as first-line therapy, mainly because of their safety concern and also because they do not provide any advantages compared to other therapy for the treatment of osteoporosis.

Strontium Ranelate Ameliorates Intervertebral Disc Degeneration via Regulating TGF-ß1/NF-κB Axis.

Intervertebral disc degeneration (IVDD) is a prevalent and debilitating condition characterized by chronic back pain and reduced quality of life. Strontium ranelate (SRR) is a compound traditionally used for treating osteoporosis via activating TGF-ß1 signaling pathway. Recent studies have proved the anti-inflammatory effect of SRR on chondrocytes. Although the exact mechanism of IVDD remains unclear, accumulating evidences have emphasized the involvement of multifactorial pathogenesis including inflammation, oxidative stress damage, and etc. However, the biological effect of SRR on IVDD and its molecular mechanism has not been investigated. Firstly, this study proved the decreased expression of Transforming Growth Factor-beta 1(TGF-ß1) in degenerated human intervertebral disc tissues. Subsequently, we confirmed for the first time that SRR could promote cell proliferation, mitigate inflammation and oxidative stress in human nucleus pulposus cells in vitro via increasing the expression of TGF-ß1 and suppressing the Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB) pathway. The molecular docking result proved the interaction between SRR and TGF-ß1 protein. To further verify this interaction, gain- and loss- of function experiments were conducted. We discovered that both TGF-ß1 knockdown and overexpression influenced the activation of the NF-κB pathway. Taken together, SRR could mitigate IL-1ß induced-cell dysfunction in human nucleus pulposus cells by regulating TGF-ß1/NF-κB axis in vitro. Finally, the in vivo therapeutic effect of SRR on IVDD was confirmed. Our findings may contribute to the understanding of the complex interplay between inflammation and degenerative processes in the intervertebral disc and provide valuable insights into the development of targeted treatment-based therapeutics for IVDD.

Strontium ranelate enriched Ruminococcus albus in the gut microbiome of Sprague-Dawley rats with postmenopausal osteoporosis.

BACKGROUND: Gut microbiome is critical to our human health and is related to postmenopausal osteoporosis (PMO). Strontium ranelate (SrR) is an anti-osteoporosis oral drug that can promote osteoblast formation and inhibit osteoclast formation. However, the effect of SrR on gut microbiome has been rarely studied. Therefore, we investigated the effect of oral SrR on gut microbiome and metabolic profiles. RESULTS: In this study, we used ovariectomized (OVX) Sprague-Dawley rats to construct a PMO model and applied oral SrR for 6 weeks. The relative abundance of intestinal microbiome was investigated by 16S rRNA metagenomic sequencing. Ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to analyze changes in metabolites of intestinal contents. Results demonstrated that 6-week oral SrR alleviated osteoporosis and significantly changed the composition of the gut microbiome and metabolic profiles of OVX rats. Ruminococcus, Akkermansia and Oscillospira were significantly enriched in the gut of OVX rats after 6-week oral SrR. Especially, the species R. albus showed the greatest importance by a random forest classifier between OVX and OVX_Sr group. The enrichment of R. albus in the gut was positively correlated with bone mineral density and the accumulation of lycopene and glutaric acid, which also significantly elevated after oral SrR. CONCLUSIONS: We discovered that oral SrR can improve bone health while stimulate the accumulation of gut microbe R. albus and metabolites (lycopene and glutaric acid). The results suggested possible connections between oral SrR and the gut-bone axis, which may provide new insight into the treatment/prevention of osteoporosis.

Effect of strontium ranelate and cerium oxide addition in the diet on bone quality and expression level of osteocalcin and alkaline phosphatase genes in broiler chicken.

BACKGROUND: In the modern broiler industry, leg and gait disorders are considerable problems. Fast-growing broilers are especially susceptible to bone abnormalities, causing major problems for broiler producers. Strontium ranelate (SrR) has been used successfully for the treatment of osteoporosis in humans. In addition, cerium oxide (CeO) is an anti-stress agent applied in the biological system. METHODS: This study was conducted to investigate the effect of SrR, CeO, and their combinations on tibia quality in broilers. A total of 384 one-day-old Ross chicks were divided into six treatments, with four replicates per treatment (16 birds per replicate). The control group was fed a standard diet, and other groups were fed SrR at levels 450, 900 mg/kg feed, CeO at levels 300 and 600 mg/kg feed and a combination of 450 SrR + 300 CeO mg/kg feed. Bone mineral density (BMD), bone mineral content (BMC), bone strength (BS), tibia area, tibia weight, bone Length, bone diameter, minerals in tibia bone of male broilers, alkaline phosphatase gene (ALP) and osteocalcin gene (OC) in male broilers were analysed. RESULTS: The results showed that the addition of SrR and CeO had no significant influence (p > 0.01) on BMD, BMC, BS, bone weight, bone length and bone diameter. While there was a significant interaction between sex and treatments, especially in the combination group, BS in females significantly (p < 0.01) increased compared to the control group. Generally, females were found to be more responsive to treatments than males. Significant increases in gene expression were noticed in OC with the addition of low levels of SrR and CeO and mixed group compared to the control. The gene expression of ALP was increased significantly only in a combination group compared to the control group. CONCLUSION: It is concluded that SrR and CeO can be used as beneficial additives in the feed to improve the tibia quality of broilers.

Strontium Ranelate Inhibits Osteoclastogenesis through NF-κB-Pathway-Dependent Autophagy.

Strontium ranelate (SR) is a pharmaceutical agent used for the prevention and treatment of osteoporosis and fragility fracture. However, little attention has been paid to the effect of SR on alveolar bone remodeling during orthodontic tooth movement and its underlying mechanism. Here, we investigated the influence of SR on orthodontic tooth movement and tooth resorption in Sprague-Dawley rats and the relationship between the nuclear factor-kappa B (NF-κB) pathway, autophagy, and osteoclastogenesis after the administration of SR in vitro and in vivo. In this study, it was found that SR reduced the expression of autophagy-related proteins at the pressure side of the first molars during orthodontic tooth movement. Similarly, the expression of these autophagy-related proteins and the size and number of autophagosomes were downregulated by SR in vitro. The results also showed that SR reduced the number of osteoclasts and suppressed orthodontic tooth movement and root resorption in rats, which could be partially restored using rapamycin, an autophagy inducer. Autophagy was attenuated after pre-osteoclasts were treated with Bay 11-7082, an NF-κB pathway inhibitor, while SR reduced the expression of the proteins central to the NF-κB pathway. Collectively, this study revealed that SR might suppress osteoclastogenesis through NF-κB-pathway-dependent autophagy, resulting in the inhibition of orthodontic tooth movement and root resorption in rats, which might offer a new insight into the treatment of malocclusion and bone metabolic diseases.

Strontium Ranelate and Strontium Chloride Supplementation Influence on Bone Microarchitecture and Bone Turnover Markers-A Preliminary Study.

Despite strontium ranelate use in osteoporosis management being one of the promising concepts in disease treatment, there is no clear evidence that strontium organic compounds are more effective than inorganic ones. The aim of this study was to compare strontium chlorate and strontium ranelate influence on the mice bone microarchitecture. We investigated whether strontium chlorate (7.532 mmol/L) and strontium ranelate (7.78 mmol/L) solutions fed to healthy SWISS growing mice (n = 42) had an influence on the percent of bone volume (BV/TV), trabecular thickness (Tb.Th), number of trabeculae (Tb.N), and separation between each trabecula (Tb.Sp) in the chosen ROI (region of interest) in the distal metaphysis of the left femurs. The cortical bone surface was examined close to the ROI proximal scan. There was an increase in each examined parameter compared with the control group. There were no statistical differences between strontium ranelate and strontium chlorate parameters. Our study indicates that organic and inorganic strontium compounds similarly affect the bone microarchitecture and strength.

Calcium Phosphate/Hyaluronic Acid Composite Hydrogels for Local Antiosteoporotic Drug Delivery.

Despite the bone ability of self-regeneration, large bone defects require surgical intervention. Likewise, when it comes to osteoporotic bone fractures, new approaches should be considered a supportive mechanism for the surgery. In recent years, more and more attention has been attracted to advanced drug delivery systems for local osteoporosis treatment, combining appropriate biomaterials with antiosteoporotic drugs, allowing simultaneously to regenerate the bone and locally treat the osteoporosis. Within the current research, hyaluronic acid/strontium ranelate (HA/SrRan), HA/calcium phosphate nanoparticles (HA/CaP NPs), and HA/CaP NPs/SrRan hydrogels were prepared. The effect of CaP and SrRan presence in the composites on the swelling behavior, gel fraction, molecular structure, microstructure, and SrRan and Sr2+ release, as well as in vitro cell viability was evaluated. Obtained results revealed that the route of CaP nanoparticle incorporation into the HA matrix had a significant effect on the hydrogel gel fraction, rheological properties, swelling behavior, and microstructure. Nevertheless, it had a negligible effect on the release kinetics of SrRan and Sr2+. The highest cell (3T3) viability (>80%) was observed for HA hydrogels, with and without SrRan. Moreover, the positive effect of SrRan on 3T3 cells was also demonstrated, showing a significant increase (up to 50%) in cell viability if the used concentrations of SrRan were in the range of 0.05-0.2 µg/ml.

Enfoques terapéuticos de la osteoporosis / Therapeutic approaches to osteoporosis

La finalidad del tratamiento de la osteoporosis es la prevención primaria y secundaria de fracturas. Las indicaciones para las intervenciones terapéuticas en la osteoporosis deben derivarse de la determinación del riesgo absoluto de fractura, que tiene en cuenta la evaluación de los factores de riesgo y la densidad ósea. El propósito de este estudio es comentar algunos enfoques terapéuticos empleados en la osteoporosis, destacando el mecanismo de acción del ranelato de estroncio que aumenta la formación de hueso y disminuye la resorción. La causa más común de osteoporosis en las mujeres es la disminución de los niveles de estrógeno durante la menopausia, lo que lleva a un aumento significativo en el recambio de masa ósea y el consiguiente desequilibrio entre la formación y reabsorción ósea con un aumento de la pérdida ósea y el deterioro de la estructura y fuerza óseas. El ranelato de estroncio sigue siendo una opción farmacológica eficaz y viable en la prevención de las fracturas vertebrales y del cuello femoral en mujeres posmenopáusicas y hombres adultos con osteoporosis, en cuanto a indicaciones, contraindicaciones y una cuidadosa evaluación de sus efectos y riesgos. Representa una alternativa a los medicamentos antirresortivos en caso de contraindicación, intolerancia o fracaso(AU)

The purpose of the treatment of osteoporosis is the primary and secondary prevention of fractures. The indications for therapeutic interventions in osteoporosis should be derived from the determination of the absolute risk of fracture, which takes into account the evaluation of risk factors and bone density. To comment on some therapeutic approaches used in osteoporosis, highlighting the mechanism of action of strontium ranelate that increases bone formation and reduces resorption. The most common cause of osteoporosis in women is the decrease in estrogen levels during menopause, which leads to a significant increase in the turnover of bone mass and the consequent imbalance between bone formation and resorption with an increase in bone loss and deterioration of bone structure and strength. Strontium ranelate continues to be an effective and viable pharmacological option in the prevention of vertebral and femoral neck fractures in postmenopausal women and adult men with osteoporosis, in terms of indications, contraindications and a careful evaluation of its effects and risks. It represents an alternative to antiresorptive drugs in case of contraindication, intolerance or failure(AU)

Strontium Functionalization of Biomaterials for Bone Tissue Engineering Purposes: A Biological Point of View.

Strontium (Sr) is a trace element taken with nutrition and found in bone in close connection to native hydroxyapatite. Sr is involved in a dual mechanism of coupling the stimulation of bone formation with the inhibition of bone resorption, as reported in the literature. Interest in studying Sr has increased in the last decades due to the development of strontium ranelate (SrRan), an orally active agent acting as an anti-osteoporosis drug. However, the use of SrRan was subjected to some limitations starting from 2014 due to its negative side effects on the cardiac safety of patients. In this scenario, an interesting perspective for the administration of Sr is the introduction of Sr ions in biomaterials for bone tissue engineering (BTE) applications. This strategy has attracted attention thanks to its positive effects on bone formation, alongside the reduction of osteoclast activity, proven by in vitro and in vivo studies. The purpose of this review is to go through the classes of biomaterials most commonly used in BTE and functionalized with Sr, i.e., calcium phosphate ceramics, bioactive glasses, metal-based materials, and polymers. The works discussed in this review were selected as representative for each type of the above-mentioned categories, and the biological evaluation in vitro and/or in vivo was the main criterion for selection. The encouraging results collected from the in vitro and in vivo biological evaluations are outlined to highlight the potential applications of materials' functionalization with Sr as an osteopromoting dopant in BTE.

The anti-inflammation effect of strontium ranelate on rat chondrocytes with or without IL-1ß in vitro.

Temporomandibular joint osteoarthritis (TMJ-OA) is a common disease with a high level of inflammation in the joint micro-environment and cartilage degradation. Anti-inflammation and cartilage regeneration are the key therapies for TMJ-OA, but currently, there are no novel medicines or treatments that can control its pathogenic progression. Strontium ranelate (SrR) is an anti-osteoporosis drug and is now considered a promising anti-OA drug, but the anti-inflammatory effect of SrR remains to be elucidated. In the present study, the anti-inflammatory effect of SrR in a normal or high IL-1ß environment was observed. Cell viability under the treatment of SrR was tested using Cell Counting Kit-8. Toluidine blue staining, immunofluorescence staining, hydroxyproline assay, PCR assay and western blotting were used to detect the expression of collagen (Col)II, proteoglycans (PG) and aggrecan as a reflection of extracellular matrix synthesis and MMP-9,13 hydroxyproline was used as an inflammation indicator. IL-1ß of 10 ng/ml was added to the culture medium as inflammation environment and the tests of those biomarkers were done again. Then, the changes in ß-catenin were also studied by immunofluorescence staining, PCR assay and western blotting to explore the possible involvement of the Wnt/ß-catenin pathway. The results showed a significant inhibition of MMP-9, MMP-13, ß-catenin and promotion of Col-II, PG and aggrecan in normal chondrocytes. The presence of IL-1ß markedly upregulated the expression of MMP-9, MMP-13 and ß-catenin while suppressing Col-II and PG and SrR partially reversed this trend. In conclusion, SrR decreased MMPs but promoted Col-II, aggrecan and PG synthesis in rat chondrocytes with or without the presence of IL-1ß and SrR attenuated the IL-1ß-induced increase in ß-catenin, thus reducing the inflammatory reaction.

Strontium ranelate improves post-extraction socket healing in rats submitted to the administration of bisphosphonates.

The aim of this study was to evaluate the effect of strontium ranelate (Sr) on post-extraction socket healing in rats submitted to the administration of bisphosphonates. Sixty rats were submitted to the tooth extraction of the first lower molar after 60 days of the daily administration of saline solution (SS) or alendronate (ALN). Then, the animals were allocated into six groups namely CTR: administration of SS during the whole experiment, ALN: administration of ALN during the whole experiment, ALN/SS: application of SS for 30 days after extraction in animals previously treated with ALN, ALN/Sr: application of Sr for 30 days after extraction in animals previously treated with ALN, ALN/S60: ALN therapy interruption 30 days before the extraction followed by the application of SS for 60 days, and ALN/Sr60: ALN therapy interruption 30 days before the tooth extraction followed by the application of Sr for 60 days. The healing of the post-extraction sockets was evaluated by microCT and histomorphometry. The use of ALN induced partial bone necrosis, inflammatory infiltration, and a delay in soft tissue healing; the use of Sr improved the connective tissue organization. Sr has subtle positive effects on the post-extraction healing in animals submitted to the administration of bisphosphonate.

Facilitated and Controlled Strontium Ranelate Delivery Using GCS-HA Nanocarriers Embedded into PEGDA Coupled with Decortication Driven Spinal Regeneration.

BACKGROUND AND PURPOSE: Strontium ranelate (SrR) is an oral pharmaceutical agent for osteoporosis. In recent years, numerous unwanted side effects of oral SrR have been revealed. Therefore, its clinical administration and applications are limited. Hereby, this study aims to develop, formulate, and characterize an effective SrR carrier system for spinal bone regeneration. METHODS: Herein, glycol chitosan with hyaluronic acid (HA)-based nanoformulation was used to encapsulate SrR nanoparticles (SrRNPs) through electrostatic interaction. Afterward, the poly(ethylene glycol) diacrylate (PEGDA)-based hydrogels were used to encapsulate pre-synthesized SrRNPs (SrRNPs-H). The scanning electron microscope (SEM), TEM, rheometer, Fourier-transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS) were used to characterize prepared formulations. The rabbit osteoblast and a rat spinal decortication models were used to evaluate and assess the developed formulation biocompatibility and therapeutic efficacy. RESULTS: In vitro and in vivo studies for cytotoxicity and bone regeneration were conducted. The cell viability test showed that SrRNPs exerted no cytotoxic effects in osteoblast in vitro. Furthermore, in vivo analysis for new bone regeneration mechanism was carried out on rat decortication models. Radiographical and histological analysis suggested a higher level of bone regeneration in the SrRNPs-H-implanted groups than in the other experimental groups. CONCLUSION: Local administration of the newly developed formulated SrR could be a promising alternative therapy to enhance bone regeneration in bone-defect sites in future clinical applications.

Strontium ranelate promotes chondrogenesis through inhibition of the Wnt/ß-catenin pathway.

BACKGROUND: Cartilage regeneration is a key step in functional reconstruction for temporomandibular joint osteoarthritis (TMJ-OA) but is a difficult issue to address. Strontium ranelate (SrR) is an antiosteoporosis drug that has been proven to affect OA in recent years, but its effect on chondrogenesis and the underlying mechanism are still unclear. METHODS: Bone mesenchymal stem cells (BMSCs) from Sprague-Dawley (SD) rats were induced in chondrogenic differentiation medium with or without SrR, XAV-939, and LiCl. CCK-8 assays were used to examine cell proliferation, and alcian blue staining, toluidine blue staining, immunofluorescence, and PCR analysis were performed. Western blot (WB) analyses were used to assess chondrogenic differentiation of the cells. For an in vivo study, 30 male SD rats with cartilage defects on both femoral condyles were used. The defect sites were not filled, filled with silica nanosphere plus gelatine-methacryloyl (GelMA), or filled with SrR-loaded silica nanosphere plus GelMA. After 3 months of healing, paraffin sections were made, and toluidine blue staining, safranin O/fast green staining, and immunofluorescent or immunohistochemical staining were performed for histological evaluation. The data were analyzed by SPSS 26.0 software. RESULTS: Low concentrations of SrR did not inhibit cell proliferation, and the cells treated with SrR (0.25 mmol/L) showed stronger chondrogenesis than the control. XAV-939, an inhibitor of ß-catenin, significantly promoted chondrogenesis, and SrR did not suppress this effect, while LiCl, an agonist of ß-catenin, strongly suppressed chondrogenesis, and SrR reversed this inhibitory effect. In vivo study showed a significantly better cartilage regeneration and a lower activation level of ß-catenin by SrR-loaded GelMA than the other treatments. CONCLUSION: SrR could promote BMSCs chondrogenic differentiation by inhibiting the Wnt/ß-catenin signaling pathway and accelerate cartilage regeneration in rat femoral condyle defects.

Controlled SrR Delivery by the Incorporation of Mg Particles on Biodegradable PLA-Based Composites.

Among several ions playing a vital role in the body, Sr2+ and Mg2+ are involved in the mechanism of bone formation, making them especially useful for bone tissue engineering applications. Recently, polylactic acid (PLA)/Mg composites have emerged as a promising family of biomaterials due to their inherent biocompatibility and biodegradability properties. In these composites, polymer and bio-metal have a synergetic effect-while the PLA inhibits the Mg fast reactivity, Mg provides bioactivity to the inert polymer buffering the medium pH during degradation. Meanwhile, the typical form of administrating Sr2+ to patients is through the medication strontium ranelate (SrR), which increases the bone mineral density. Following this interesting research line, a new group of composites, which integrates Mg particles and SrR charged onto halloysite nanotubes (HNT) in a polymeric matrix, was proposed. PLA/Mg/SrR-HNT composites have been processed following a colloidal route, obtaining homogenous composites granulated and film-shaped. The drug delivery profile was evaluated in terms of in vitro lixiviation/dissolution paying special attention to the synergism of both ions release. The combination of two of the most reported ions involved in bone regeneration in the composite biomaterial may generate extra interest in bone healing applications.