Combination of strontium chloride and photobiomodulation in the control of tooth sensitivity post-bleaching: A split-mouth randomized clinical trial.

OBJECTIVE: This split-mouth randomized controlled clinical trial assessed the effect of 10% strontium chloride in combination with photobiomodulation (PBM) for the control of tooth sensitivity (TS) post-bleaching. METHODS: The upper/lower, right and left quadrants of fifty volunteers were randomized and allocated to four groups (n = 25): PLACEBO-placebo gel + simulation of PBM; Placebo + PBM; STRONTIUM-10% strontium chloride + simulation of PBM; and PBM + STRONTIUM-10% strontium chloride + PBM. All groups received tooth bleaching treatment with 35% hydrogen peroxide. For the PBM treatment, the laser tip was positioned in the apical and cervical regions of the teeth bleached in the respective hemi-arch. The laser system was operated in continuous mode, using 1.7 J of energy. A dose of 60 J/cm2 was applied to each point for 16 seconds under 808 nm near-infrared light (100mW of power), with a point area of 0.028 cm2. TS was assessed during a 21-day follow-up, using the modified visual analogue scale. RESULTS: In the intragroup assessment, the Friedman test indicated that PBM + STRONTIUM promoted the greatest reduction in TS after the second week of treatment (p ≤ 0.05). The Wilcoxon-Mann-Whitney test indicated that the groups Placebo + PBM, STRONTIUM, and STRONTIUM + PBM did not differ statistically (p ≥ 0.05) in the first and third weeks of treatment The group PLACEBO exhibited the greatest TS in the first three days after each bleaching session. CONCLUSION: The combination of 10% strontium chloride with PBM was effective in reducing post-bleaching TS; however, the combination of 10% strontium chloride with PBM was effective in reducing post-bleaching TS; however, it did not differ from the individual use of Placebo + PBM or STRONTIUM groups assessed after 21 days of follow-up.

A bioceramic scaffold composed of strontium-doped three-dimensional hydroxyapatite whiskers for enhanced bone regeneration in osteoporotic defects.

Reconstruction of osteoporotic bone defects is a clinical problem that continues to inspire the design of new materials. Methods: In this work, bioceramics composed of strontium (Sr)-doped hydroxyapatite (HA) whiskers or pure HA whiskers were successfully fabricated by hydrothermal treatment and respectively named SrWCP and WCP. Both bioceramics had similar three-dimensional (3D) porous structures and mechanical strengths, but the SrWCP bioceramic was capable of releasing Sr under physiological conditions. In an osteoporotic rat metaphyseal femoral bone defect model, both bioceramic scaffolds were implanted, and another group that received WCP plus strontium ranelate drug administration (Sr-Ran+WCP) was studied for comparison. Results: At week 1 post-implantation, osteogenesis coupled blood vessels were found to be more common in the SrWCP and Sr-Ran+WCP groups, with substantial vascular-like structures. After 12 weeks of implantation, comparable to the Sr-Ran+WCP group, the SrWCP group showed induction of more new bone formation within the defect as well as at the implant-bone gap region than that of the WCP group. Both the SrWCP and Sr-Ran+WCP groups yielded a beneficial effect on the surrounding trabecular bone microstructure to resist osteoporosis-induced progressive bone loss. While an abnormally high blood Sr ion concentration was found in the Sr-Ran+WCP group, SrWCP showed little adverse effect. Conclusion: Our results collectively suggest that the SrWCP bioceramic can be a safe bone substitute for the treatment of osteoporotic bone defects, as it promotes local bone regeneration and implant osseointegration to a level that strontium ranelate can achieve.

Cylindrical Layered Bone Scaffolds with Anisotropic Mechanical Properties as Potential Drug Delivery Systems.

3D cylindrical layered scaffolds with anisotropic mechanical properties were prepared according to a new and simple method, which involves gelatin foaming, deposition of foamed strips, in situ crosslinking, strip rolling and lyophilization. Different genipin concentrations were tested in order to obtain strips with different crosslinking degrees and a tunable stability in biological environment. Before lyophilization, the strips were curled in a concentric structure to generate anisotropic spiral-cylindrical scaffolds. The scaffolds displayed significantly higher values of stress at break and of the Young modulus in compression along the longitudinal than the transverse direction. Further improvement of the mechanical properties was achieved by adding strontium-substituted hydroxyapatite (Sr-HA) to the scaffold composition and by increasing genipin concentration. Moreover, composition modulated also water uptake ability and degradation behavior. The scaffolds showed a sustained strontium release, suggesting possible applications for the local treatment of abnormally high bone resorption. This study demonstrates that assembly of layers of different composition can be used as a tool to obtain scaffolds with modulated properties, which can be loaded with drugs or biologically active molecules providing properties tailored upon the needs.

Squamous Cell Carcinoma Biomarker Sensing on a Strontium Oxide-Modified Interdigitated Electrode Surface for the Diagnosis of Cervical Cancer.

Cervical cancer is a life-threatening complication, appearing as the uncontrolled growth of abnormal cells in the lining of the cervix. Every year, increasing numbers of cervical cancer cases are reported worldwide. Different identification strategies were proposed to detect cervical cancer at the earlier stages using various biomarkers. Squamous cell carcinoma antigen (SCC-Ag) is one of the potential biomarkers for this diagnosis. Nanomaterial-based detection systems were shown to be efficient with different clinical biomarkers. In this study, we have demonstrated strontium oxide-modified interdigitated electrode (IDE) fabrication by the sol-gel method and characterized by scanning electron microscopy and high-power microscopy. Analysis of the bare devices indicated the reproducibility with the fabrication, and further pH scouting on the device revealed that the reliability of the working pH ranges from 3 to 9. The sensing surface was tested to detect SCC-Ag against its specific antibody; the detection limit was found to be 10 pM, and the sensitivity was in the range between 1 and 10 pM as calculated by 3σ. The specificity experiment was carried out using major proteins from human serum, such as albumin and globulin. SCC-Ag was shown to be selectively detected on the strontium oxide-modified IDE surface.

The synergistic effect of strontium-substituted hydroxyapatite and microRNA-21 on improving bone remodeling and osseointegration.

Surgical failure, mainly caused by loosening implants, causes great mental and physical trauma to patients. As the population ages, improving the physicochemical properties of implants to achieve favourable osseointegration will continue to be the focus of future research. Herein, we fabricated a titanium (Ti)-based SrHA/miR-21 composite coating that was generated by hydrothermal deposition of SrHA followed by miR-21 nanocapsule immobilisation. Both SrHA nanoparticles with good superhydrophilicity and miR-21 nanocapsules with uniform sizes were distributed evenly on the surface of Ti. In vitro experiments revealed that the composite coating was beneficial for osteoblast proliferation, differentiation and mineralization. In vivo evaluations demonstrated that this coating could not only promote the expression of the angiogenic factor CD31 but also enhance the expression of osteoblastic genes to facilitate angio-osteogenesis. In addition, the composite coating also showed a decreased RANKL expression compared with the miR-21 coating. As a result, the SrHA/miR-21 composite coating promoted new bone formation and mineralization and thus enhanced osseointegration and bone-implant bonding strength. Therefore, this method provides a new strategy for bone repair.

The effects of mometasone furoate and strontium chloride in a rat model of allergic rhinitis.

Neurogenic inflammation plays a role in the pathophysiology of allergic rhinitis. Highly effective in reducing the sensory irritation caused by some substances, strontium salts directly affect C-type nerve fibers. The aim of this study was to compare the efficacy of mometasone furoate and strontium chloride on early-phase symptoms in a rat model of allergic rhinitis. Wistar albino rats (n = 24) were randomly divided into three groups: the mometasone group, receiving 1 µg mometasone furoate (2 µl/site); the strontium 3% group, receiving 3% strontium chloride (2 µl/site); and the strontium 5% group, receiving 5% strontium chloride (2 µl/site). To induce significant nasal symptoms of allergic rhinitis, 5 µmol of histamine dihydrochloride (HDC) (2 µl/site) was administered. Symptoms of allergic rhinitis were recorded as frequencies of sneezing and nasal rubbing during a 15-minute interval. On days 1 and 2, respectively, 0.9% sodium chloride (NaCl) (2 µl/site to each nasal cavity) and HDC were administered in all of the study groups. On days 3 and 4, the study drugs were administered 10 and 30 minutes before the administration of HDC. On day 5, the study drugs were administered 10 minutes after the administration of HDC. The results of the present study revealed that when strontium chloride or mometasone furoate was administered 30 minutes before the onset of symptoms, a significant decrease was observed in sneezing and nasal rubbing. The number of sneezing occurrences was significantly lower and the number of nasal rubbing occurrences was higher in the strontium 3% group compared to the groups in which mometasone furoate and 5% strontium chloride were administered after onset of symptoms. Recent studies have investigated the efficacy and safety of strontium chloride nasal drops compared with common pharmacologic treatments of allergic rhinitis. These studies have revealed that allergic rhinitis can be successfully and safely treated with strontium-chloride-containing products, thus offering a potential new treatment strategy.

Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers.

OBJECTIVE: The aim of this study was to comparatively evaluate the efficacy of strontium-89 chloride (89 SrCl2) in treating bone metastasis-associated pain in patients with lung, breast, or prostate cancer. MATERIALS AND METHODS: The 126 patients with lung cancer included 88, 16, 15, 4, and 3 patients with adenocarcinoma, squamous cell carcinoma, nonsmall cell carcinoma, mixed carcinoma, and small cell carcinoma, respectively, and the control group consisted of patients with breast (71 patients) or prostate cancer (49 patients) who underwent 89 SrCl2 treatment during the same period. The treatment dose of 89 SrCl2 was 2.22 MBq/kg. RESULTS: The efficacy rate of treatment in the lung cancer group was 75.4%, compared to 95.0% in the control group. Approximately 67% of patients with lung cancer and bone metastases and 47% of control patients exhibited mild-to-moderate reductions of leukocyte and platelet counts 4 weeks after 89 SrCl2 treatment. CONCLUSIONS: 89 SrCl2 can safely and effectively relieve bone pain caused by bone metastasis from lung cancer. However, its efficacy was lower in patients with lung cancer with bone metastasis than in those with breast or prostate cancer with bone metastasis, and its effects on the peripheral hemogram were also significantly stronger in the lung cancer group.

A synergetic biomineralization strategy for immobilizing strontium during calcification of the coccolithophore Emiliania huxleyi.

The coccolithophore species Emiliania huxleyi has one of the most global distributions in the modern oceans. They are characteristically covered with calcite scales called coccoliths. In this study, stable strontium immobilization during the calcification process was investigated to indirectly assess a proposed bioremediation approach for removing Sr2+ contamination from marine environments. Results indicate that E. huxleyi has high Sr2+ tolerance and removal efficiency in response to Sr2+ stress ranging from 5.6 to 105.6 ppm. Sr2+ immobilization during E. huxleyi calcification indicates a concentration-dependent synergistic mechanism. At lower concentrations of Sr2+ (25.6 ppm), Sr2+ is incorporated into coccoliths through competitive supply between Sr2+ and Ca2+. In addition, calcite productivity decreases with increased Sr2+ removal efficiency due to crystallographic transformation of coccoliths from hydrated calcite into aragonite at 55.6 ppm Sr2+. Further formation of strontianite at 105.6 ppm Sr2+ is due to precipitation of Sr2+ on the edge of the rims and radial arrays of the coccoliths. Our study implies that coccolithophores are capable of significant removal of Sr2+ from the marine environment.

Injectable simvastatin gel for minimally invasive periosteal distraction: In vitro and in vivo studies in rat.

OBJECTIVES: To evaluate whether the subperiosteal injection of simvastatin (SIM) with a novel in situ gel-forming system, SrHA/Alg (strontium hydroxyapatite/alginate), can stimulate vertical bone augmentation in a rat calvarial model. MATERIAL AND METHODS: The SrHA/Alg solution was synthesized and combined with different doses of SIM (0.01, 0.02, 0.1, and 0.2 mg) to form the following groups: (1) SrHA/Alg only, (2) SrHA/Alg/0.01, (3) SrHA/Alg/0.02, (4) SrHA/Alg/0.1, and (5) SrHA/Alg/0.2. The SIM release pattern was analyzed, and rat primary periosteum-derived cell (PDC) responses were investigated. Twenty male Wistar rats were enrolled in the calvarial subperiosteal injection experiment with each animal receiving a 200-µl single subperiosteal injection of SrHA/Alg with different amounts of SIM (0, 0.01, 0.02, and 0.1 mg) incorporated (n = 5). The 0.2 mg dose group was not tested in vivo due to the severe toxicity found in vitro. The new bone formation was assessed histologically and radiologically at 8 weeks. RESULTS: The slow release of SIM was confirmed, and PDC viability decreased in the SrHA/Alg/0.2 group. Alkaline phosphatase positive areas and mineralization areas were significantly greater in the SrHA/Alg/0.01 and SrHA/Alg/0.02 groups (p < .05). The mRNA expression level of Runx2 significantly increased in the SrHA/Alg/SIM-0.02 group by day 7 (p < .05) and significantly higher levels of VEGF were found in the SrHA/Alg/0.01 and SrHA/Alg/0.02 groups at different time points (p < .05). In vivo, no prominent clinical sign of inflammation was observed, and the most significant bone gain was shown in the SrHA/Alg/0.02 group (p < .05). The osteoclast formation within the newly formed bone area was reduced in the SrHA/Alg/0.1 group (p < .05). CONCLUSIONS: When combined with SrHA/Alg system, the 0.02 mg SIM seemed to be the optimal dose to stimulate subperiosteal bone formation without inducing inflammation. This combination may hold potential therapeutic benefits for clinical bone augmentation in a minimally invasive manner.

Histopathological evaluation of the effect of locally administered strontium on healing time in mandibular fractures: An experimental study.

BACKGROUND: Mandibular fractures are the most common facial fractures. They can be treated by conservative techniques or by surgery. The authors hypothesized that the application of a single local dose of strontium chloride would accelerate the healing of subcondylar mandibular fractures, shorten the recovery time and prevent complications. OBJECTIVES: The aim of the present pilot study was to evaluate the effects of a single local dose of strontium chloride on the healing of subcondylar mandibular fractures in rats. MATERIAL AND METHODS: This randomized experimental study was carried out on 24 male Wistar albino rats. The rats were randomly divided into 3 groups: experimental group 1, receiving 3% strontium chloride; experimental group 2, receiving 5% strontium chloride; and the control group. A full thickness surgical osteotomy was created in the subcondylar area. A single dose of strontium solution (0.3 cc/site) was administered locally by injection on the bone surfaces of the fracture line created. Nothing was administered to the control group. The mandibles were dissected on postoperative day 21. The fractured hemimandibles were submitted to histopathological examination. RESULTS: The median bone fracture healing score was 9 (range: 7-9) in experimental group 1; 8 (range: 7-10) in experimental group 2; and 7.50 (range: 7-8) in the control group. When the groups were compared in terms of bone healing scores, there was a statistically significant difference between experimental group 1 and the control group (p < 0.05). CONCLUSIONS: This study is the first to show that local strontium may have positive effects on the healing of subcondylar mandibular fractures. In the authors' opinion, 3% strontium was beneficial for accelerating facial skeleton consolidation and bone regeneration in rat subcondylar mandibular fractures. This treatment procedure may be combined with closed fracture treatment or a conservative approach.

Efecto del ranelato de estroncio sobre la densidad mineral ósea en hombres con osteoporosis / Effect of strontium ranelate on bone mineral density in men with osteoporosis

La osteoporosis afecta al 6-7% de la población masculina. Es alta la proporción de pacientes con fracturas sin diagnóstico previo de esta enfermedad. La mortalidad luego de una fractura es mayor en hombres que en población femenina; a pesar de esto, la mayoría de los pacientes no reciben tratamiento. Los fármacos aprobados, en nuestro medio, para tratar la osteoporosis masculina son: bifosfonatos, teriparatida y ranelato de estroncio. El objetivo de este estudio fue evaluar el efecto del ranelato de estroncio sobre la densidad mineral ósea en hombres después de 1 año de tratamiento. Se incluyeron los registros de 20 hombres de 67,8±3,0 años, tratados con ranelato de estroncio (2 g/día) durante 1 año. Todos los pacientes presentaban un T-score inferior a -2,5 en cadera o columna vertebral o un T-score inferior a -2,0 y factores de riesgo de fractura. No hubo modificación de parámetros de laboratorio luego del tratamiento (calcemia, calciuria, fósforo sérico, parathormona, 25(OH)vitamina D, fosfatasa alcalina y desoxipiridinolina) en relación a los basales. Luego del tratamiento con ranelato de estroncio se observó incremento de la densidad mineral ósea en columna lumbar: 0,953±0,029 versus 0,997±0,030 g/cm2 (p=0,0068), cuello femoral: 0,734±0,013 versus 0,764±0,016 g/cm2 (p=0,0084) y cadera total: 0,821±0,02 versus 0,834±0,02 g/cm2 (p=0,0419). Conclusión: el tratamiento con ranelato de estroncio produjo un incremento significativo de la densidad mineral ósea en columna lumbar y fémur proximal en hombres con osteoporosis. (AU)

Osteoporosis affects 6-7% of the male population. The proportion of patients with fragility fractures but without diagnosis of the disease is high. Mortality after hip fracture is higher in men than in women; in spite of this, most patients are left without treatment for osteoporosis. Drugs approved, for the treatment of osteoporosis in our country are bisphosphonates, teriparatide, and strontium ranelate (SrR). The objective of this study was to evaluate the effect of SrR on axial BMD in men after one year of treatment. We obtained pertinent data from medical registries of 20 men aged 67,8±3,0 years, treated with oral SrR (2 g/day) for 12 months. All patients had a T-score below -2,5 at the hip or the lumbar spine, or a T-score below -2,0 and one or more risk factors for fracture. The levels of serum calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, or PTH, or urinary calcium and desoxipyridinoline remained unchanged following SrR administration. After treatment with SrR there were significant increases in BMD at the lumbar spine: 0,953±0,029 versus 0,997±0,030 g/cm2 (p=0,0068), femoral neck: 0,734±0,013 versus 0,764±0,016 g/cm2 (p=0.0084), and total hip: 0,821±0,02 versus 0,834±0,02 g/cm2 (p=0,0419). Conclusion: in osteoporotic men, treatment with SrR significantly increases BMD in the lumbar spine and the proximal femur. (AU)

Strontium chloride hexahydrate as a candidate molecule for long-term treatment of allergic rhinitis.

BACKGROUND & OBJECTIVES: Neurogenic inflammation plays a role in the pathophysiology of allergic rhinitis (AR). Strontium salts are highly effective in reducing the sensory irritation. This study was aimed to investigate the efficacy of strontium chloride (SC) on AR symptoms based on the duration of SC use before the symptoms begin. METHODS: Wistar albino rats (n=18) were randomly divided into three groups: Group 1, received 1µg mometasone furoate (MF); Group 2, three per cent SC; and Group 3 received five per cent SC (2 µl/site). Drugs were administered to the each nasal cavity for three weeks every morning. On the days 7, 14 and 21, histamine dihydrochloride (HD) 5 µmol (2 µl/site) was administered and the frequencies of nasal rubbing and sneezing were counted for 15 min. RESULTS: After 7, 14 and 21 day medication period, the groups were compared in terms of the frequency of sneezing and nasal rubbing following HD. There was a significant difference among the groups in terms of the frequency of sneezing on the day 7 (PPInterpretation & conclusions: Our results showed that three and five per cent SC were less effective than MF for sneezing during the first week, but the efficiency was equal to that of MF after the first 14 days. Long-term use of SC was as effective as MF on nasal rubbing. SC can be as effective as MF on both sneezing and nasal rubbing on regular use over three weeks.

Sr2+ has low efficiency in regulating spontaneous release at the Calyx of Held synapses.

It has been known that Ca2+ plays an essential role in mediating different modes of neurotransmitter release via different sensing mechanisms. Synaptotagmin 1, 2, and 9 were found to act as the Ca2+ sensors for synchronous release and synaptotagmin 7 and Doc-2 were proposed as the Ca2+ sensors for asynchronous release. Comparatively, the Ca2+ sensor for spontaneous release remains a mystery. At the Calyx of Held synapse, the Ca2+ sensor for spontaneous release was found not identical to the sensor for synchronous release, synaptotagmin 2. As Ca2+ sensors have different sensitivity to Sr2+ and Ca2+ and induce significantly different rate of vesicle release, Sr2+ is traditionally used as a tool to examine the intrinsic properties of different Ca2+ sensors. Here, we employed cell-attached patch recording and presynaptic/postsynaptic whole-cell recording at the Calyx of Held synapses of synaptotagmin 2 knock-out mice to assay the Sr2+ and Ca2+ influx into the nerve terminal at resting potential and observed the effects of Ca2+ and Sr2+ on spontaneous neurotransmitter release. We found that the dwell time of single voltage gated Ca2+ channel opening increased around threefold for Sr2+ than Ca2+ with the channel conductance unchanged; the divalent cation sensing machinery in regulating spontaneous release has much lower sensitivity to Sr2+ than Ca2+ . Thus, our study reveals some of the intrinsic properties of Ca2+ sensor(s) of spontaneous transmitter release and provided an insight into the underlying mechanisms.

Strontium release from Sr2+-loaded bone cements and dispersion in healthy and osteoporotic rat bone.

Drug functionalization of biomaterials is a modern and popular approach in biomaterials research. Amongst others this concept is used for the functionalization of bone implants to locally stimulate the bone healing process. For example strontium ions (Sr2+) are administered in osteoporosis therapy to stimulate bone growth and have recently been integrated into bone cements. Based on results of different analytical experiments we developed a two-phase model for the transport of therapeutically active Sr2+-ions in bone in combination with Korsmeyer-Peppas kinetics for the Sr2+ release from bone cement. Data of cement dissolution experiments into water in combination with inductively coupled plasma mass spectrometry (ICP-MS) analysis account for dissolution kinetics following Noyes-Whitney rule. For dissolution in α-MEM cell culture media the process is kinetically hindered and can be described by Korsmeyer-Peppas kinetics. Time of flight secondary ion mass spectrometry (ToF-SIMS) was used to determine the Sr2+ diffusion coefficient in healthy and osteoporotic trabecular rat bone. Therefore, bone sections were dipped in aqueous Sr2+-solution by one side and the Sr2+-profile was measured by classical SIMS depth profiling. The Sr2+ mobility can be described by a simple diffusion model and we obtained diffusion coefficients of (2.28±2.97)⋅10-12cm2/s for healthy and of (1.55±0.93)⋅10-10cm2/s for osteoporotic bone. This finding can be explained by a different bone nanostructure, which was observed by focused ion beam scanning electron microscopy (FIB-SEM) and transmission electron microscopy (TEM). Finally, the time and spatially resolved drug transport was calculated by finite element method for the femur of healthy and osteoporotic rats. The obtained results were compared to mass images that were obtained from sections of in vivo experiments by ToF-SIMS. The simulated data fits quite well to experimental results. The successfully applied model for the description of drug dispersion can help to reduce the number of animal experiments in the future.

Injectable hybrid system for strontium local delivery promotes bone regeneration in a rat critical-sized defect model.

Strontium (Sr) has been described as having beneficial influence in bone strength and architecture. However, negative systemic effects have been reported on oral administration of Sr ranelate, leading to strict restrictions in clinical application. We hypothesized that local delivery of Sr improves osteogenesis without eliciting detrimental side effects. Therefore, the in vivo response to an injectable Sr-hybrid system composed of RGD-alginate hydrogel cross-linked in situ with Sr and reinforced with Sr-doped hydroxyapatite microspheres, was investigated. The system was injected in a critical-sized bone defect model and compared to a similar Sr-free material. Micro-CT results show a trend towards higher new bone formed in Sr-hybrid group and major histological differences were observed between groups. Higher cell invasion was detected at the center of the defect of Sr-hybrid group after 15 days with earlier bone formation. Higher material degradation with increase of collagen fibers and bone formation in the center of the defect after 60 days was observed as opposed to bone formation restricted to the periphery of the defect in the control. These histological findings support the evidence of an improved response with the Sr enriched material. Importantly, no alterations were observed in the Sr levels in systemic organs or serum.

Evaluación de la respuesta densitométrica en pacientes con osteoporosis posmenopáusica tratadas con ranelato de estroncio o denosumab / Densitometric response in postmenopausal osteoporosis treated with strontium ranelate or denosumab

Tanto el ranelato de estroncio (RSr) como el denosumab (Dmab) son eficaces en el tratamiento de la osteoporosis (OP) posmenopáusica (PM). El efecto de cada fármaco por separado sobre la densidad mineral ósea (DMO) ha sido estudiado recientemente. Con ambas drogas se observó, al año de tratamiento, un aumento significativo de la DMO en columna lumbar (CL), cuello femoral (CF) y cadera total (CT). En este trabajo comparamos la respuesta densitométrica al año de tratamiento con una y otra droga. Utilizamos los registros de 425 pacientes PMOP tratadas con Dmab y 441 tratadas con RSr. En cada paciente analizamos el porcentaje de cambio; se clasificaron como respondedoras aquellas que mostraron un cambio ≥3%. Adicionalmente se comparó la respuesta en pacientes no previamente tratadas con bifosfonatos (BF-naïve) en comparación con pacientes que habían recibido previamente un BF. Al analizar el grupo completo para Dmab, el porcentaje de pacientes respondedoras fue de 68,4% en CL, 63,3% en CF y 49,3% en CT. Por otro lado, en el grupo de pacientes tratadas con RSr, el porcentaje de respondedoras (53,8% en CL, 40,0% en CF y 35,6% en CT) fue estadísticamente menor. Cuando comparamos la respuesta entre las pacientes BF-naïve que recibieron RSr o Dmab, el Dmab indujo mayor respuesta en CL y CF que el grupo RSr, sin diferencias en CT. Cuando se analizaron los subgrupos BF-previo, las tratadas con Dmab mostraron mayor respuesta en todas las regiones. Conclusión: en pacientes con OP-PM, el tratamiento con Dmab produjo mayores incrementos densitométricos que el RSr, siendo el porcentaje de pacientes respondedoras mayor con Dmab que con RSr. (AU)

Both strontium ranelate (SrR) and denosumab (Dmab) are effective in the treatment of postmenopausal osteoporosis (PMOP). The effect of each drug on bone mineral density (BMD) has been studied separately by us. With both treatments, there was a significant increase after one year of treatment at the lumbar spine (LS) and hip. In this paper we compared the densitometric response after one year of treatment with both drugs used separately. We used the clinical records of 425 PM patients treated with Dmab and 441 treated with SrR. For each patient we analyzed the percentage of change; those who showed a change ≥3% were classified as responders. Additionally, the response was compared in patients not previously treated with bisphosphonates (BP-naïve) compared to patients who had previously received a BP. When analyzing the complete group for Dmab, the percentage of "responders" was 65.2% at the LS, 62.9% at the femoral neck (FN) and 47.4% at the total hip (TH). On the other hand, in the group of patients treated with SrR the percentage of responders (53.8% at the LS, 40.0% at the FN and 35.6% at the TH) was statistically lower. When comparing the response between in BF-naïve patients receiving RSr or Dmab, Dmab induced a greater response at the LS and FN than the RSr group, with no statistical differences at the TH. When the subgroups with prior BP treatment were analyzed, those treated with Dmab showed greater response in all regions. Conclusion: in patients with PMOP treatment with Dmab produced greater densitometric increments than SrR, and the percentage of responders was higher with Dmab than with SrR. (AU)

The combined effects of nanotopography and Sr ion for enhanced osteogenic activity of bone marrow mesenchymal stem cells (BMSCs).

Both surface topography and chemistry have a significant influence on the biological performance of orthopedic implant coatings. In our study, a surface modification strategy embodying bioactive trace element incorporation and nanotopography construction was employed to enhance the osteogenic activity of calcium silicate (Ca-Si) coatings. We developed strontium-loaded nanolayer on plasma sprayed Ca-Si (CS) coating via hydrothermal treatment which was denoted as Sr-NT-CS. The original CS coating and the CS coating modified with similar nanotopography (NT-CS) were studied in parallel. We investigated the cellular effects of surface topography and released Sr ion on the adhesion, proliferation, differentiation, and mineralization of BMSCs and the associated molecular mechanisms. The results indicated that the nanotopography activated integrin ß1, promoted the spread of BMSCs into a polygonal osteoblastic shape, and induced higher levels of collagen secretion. The Sr incorporation stimulated osteogenic differentiation and mineralization as indicated by the increases in ALP activity and mineralized nodules formation. The examination of gene expressions revealed that Sr ion exerted the effects by interacting with extracellular calcium sensitive receptor (CaSR), and combined with the nanotopographical cue for the up-regulation of osteogenic master transcription factor Runx2. The promoted Runx2 subsequently affected osteoblast (OB) marker genes (BMP-2, BSP, OPN, and OCN), thus driving BMSCs to differentiate into OBs. Moreover, the Sr incorporation inhibited osteoclastogenesis, as indicated by the down-regulation of interleukin-6 (IL-6) and the inhibition of RANKL/RANK system. Those results suggested that our developed Sr-NT-CS coating have combined the effects of nanotopography and Sr ion for enhanced osteogenic activity of BMSCs.

Setd2 is associated with strontium-induced bone regeneration.

Strontium Ranelate has been utilized as a preventative treatment option for osteoporosis with the release of Sr ions having a direct effect on preventing osteoclast activation and promoting osteoblast differentiation. Previously our group has prepared and characterized a porous Sr-mesoporous bioactive glass (Sr-MBG) scaffold demonstrating its ability to enhance new bone formation when compared to MBG alone. The goal of the present study was to elucidate the bone-inducing properties of Sr by utilizing RNA-seq on in vivo tissue samples to investigate potential target genes responsible for Sr-induced new bone formation. The results demonstrated an increased expression and affiliation of Setd2 in the Sr-MBG group when compared to MBG group alone. Immunofluorescent staining further demonstrated a localization of Setd2 and H3K36me3 in Runx2-positive cells in defects treated with Sr-MBG scaffolds. It was detected that specifically MAPK pathway was activated in MG63 stimulated by Sr. To verify the role of Setd2 in bone formation in the presence of SrCl2, Setd2 was knocked-down and overexpressed in MG63 with/without SrCl2 stimulation. The result showed that Setd2 plays a positive role in osteoblast differentiation which was enhanced by SrCl2. Furthermore, it was found that Setd2 regulated the activation of ERK, which set up a positive feedback in the osteoblast differentiation process. Based on these findings, it was shown that Setd2 has an active role in osteoblast differentiation. As a histone methylase, Setd2 may also turn to be an epigenetic target for new treatment options of osteoporosis. STATEMENT OF SIGNIFICANCE: Our research group recently demonstrated that the combination of MBG scaffolds with Sr, efficiently promoted bone regeneration in rat femoral defects even in severely compromised osteoporotic animals, however, the epigenetic mechanism by which Sr ions function to promote bone generation remains unclear. This study showed an increased expression and affiliation of Setd2 and H3K36me3. In vitro, the increased expression of Setd2 promoted osteoblastic differentiation of MG63 stimulated by SrCl2 in MAPK-dependent way, which activated ERK in turn leading to a positive feedback. Based on these findings, it was shown that Setd2 has an active role in osteoblast differentiation and may also turn to be an epigenetic target for new treatment options of osteoporosis and the development of novel bone regeneration scaffold.

Melatonin-micronutrients Osteopenia Treatment Study (MOTS): a translational study assessing melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7) on bone density, bone marker turnover and health related quality of life in postmenopausal osteopenic women following a one-year double-blind RCT and on osteoblast-osteoclast co-cultures.

This one-year double blind randomized control trial assessed the effects of nightly melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7; MSDK) on bone mineral density (BMD) and quality of life (QOL) in postmenopausal osteopenic women (ages 49-75). Compared to placebo, MSDK treatment increased BMD in lumbar spine (4.3%) and left femoral neck (2.2%), with an upward trend for total left hip (p=0.069). MSDK increased serum P1NP levels and reduced bone turnover (CTx:P1NP). Psychometric analyses indicated that mood and sleep quality improved for the MSDK group. MSDK-exposed human mesenchymal stem cells (hMSCs) and human peripheral blood monocytes (hPBMCs) plated in transwells or layered demonstrated increases in osteoblastogenesis, decreases in osteoclastogenesis, increases in OPG (TNFRSF11B) and decreases in RANKL (TNFSF11) levels. In transwell osteoblasts, MSDK increased pERK1/2 (MAPK1/MAPK3) and RUNX2 levels; decreased ERK5 (MAPK7); and did not affect the expression of NFκB (NFKB1) and ß1integrin (ITGB1). In layered osteoblasts, MSDK also decreased expression of the metabolic proteins PPARγ (PPARG) and GLUT4 (SLC2A4). In adipose-derived human MSCs, MSDK induced osteoblastogenesis. These findings provide both clinical and mechanistic support for the use of MSDK for the prevention or treatment of osteopenia, osteoporosis or other bone-related diseases.