Strontium Ranelate Retards Disc Degradation and Improves Endplate and Bone Microarchitecture in Ovariectomized Rats with Lumbar Fusion Induced – Adjacent Segment Disc Degeneration

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

BackgroundIntervertebral disc (IVD) degeneration and pathological changes in the spinal cord are major causes of back pain. In addition to its well-established anti-resorptive effect on bone, calcitonin (CT) potentially exerts protective effects on IVD degeneration in ovariectomized rats. However, possible therapeutic effects of CT on lumbar fusion-induced adjacent-segment disc degeneration (ASDD) have not been investigated yet. In this study, we examined the effects of CT on IVD degeneration adjacent to a lumbar fusion in ovariectomized rats.MethodsPosterolateral lumbar fusion (PLF) at L4–5 was performed 4 weeks after ovariectomy (OVX) or sham surgery in female Sprague–Dawley rats. Following PLF + OVX, rats received either salmon CT (OVX + PLF + sCT, 16 IU/Kg/2d) or vehicle (OVX + PLF + V) treatment for 12 weeks; the remaining rats were divided into Sham + V, OVX + V, and PLF + V groups. Fusion status was analyzed by manual palpation and radiography. Adjacent segment disc was assessed by histological, histomorphometric, immunohistochemical analysis. L6 vertebrae microstructures were evaluated by micro-computed tomography.ResultsHistological analysis showed more severe ASDD occurred in OVX + PLF + V rats compared with the OVX + V or PLF + V groups. CT treatment suppressed the score for ASDD, increased disc height, and decreased the area of endplate calcification. Immunohistochemical staining demonstrated that CT decreased the expression of collagen type-I, matrix metalloproteinase-13, and a disintegrin and metalloproteinase with thrombospondin motifs-4, whereas it increased the expression of collagen type-II and aggrecan in the disc. Micro-computed tomography indicated that CT increased bone mass and improved the microstructure of the L6 vertebrae.ConclusionsThese results suggest that CT can prevent ASDD, induce beneficial changes in IVD metabolism, and inhibit deterioration of the trabecular microarchitecture of vertebrae in osteoporotic rats with lumbar fusion.

Strontium ranelate: A physiological approach for optimizing bone formation and resorption

The influence of vertebral augmentation on adjacent intervertebral discs remains controversial. The purpose of this study is to evaluate the effect of bone cement distribution on adjacent disc degeneration after vertebral augmentation for osteoporotic vertebral compression fractures (OVCFs). Patients with single level OVCF and upper endplate injury who underwent vertebral augmentation were enrolled. The patients were divided into four groups: Group A: bone cement contacted both the cranial and the distal endplates; Group B: bone cement only contacted the cranial endplate; Group C: bone cement only contacted the distal endplate; and Group D: bone cement contacted neither the cranial nor the distal endplates. The cranial discs of the fractured vertebrae were defined as adjacent discs and the upper discs proximally to the adjacent discs were defined as control discs. Degenerative disc change (DDC) was defined as a deteriorated postoperative Pfirrmann score compared with the preoperative score on MR images. The number of DDC cases and the disc heights were analyzed among the groups. A total of 184 patients with an average follow-up time of 28.6 months were included. The number of DDC cases in the adjacent discs was significantly higher than in the control discs in groups A (p < 0.001), B (p = 0.002), and D (p = 0.028), whereas the difference in group C was not statistically significant (p = 0.237). The incidence of adjacent disc degeneration was significantly higher in group A than that in group C (p = 0.06). The adjacent disc heights decreased significantly in groups A, B, and D (p < 0.001, p < 0.001, and p = 0.012, respectively), but did not decrease significantly in group C (p = 0.079). However, no statistical differences were detected among the four groups with respect to the preoperative adjacent disc height, follow-up adjacent disc height, preoperative control disc height, or follow-up control disc height. Bone cement distribution influences adjacent disc degeneration after vertebral augmentation in OVCFs. Cement distribution proximal to the injured endplate can accelerate adjacent disc degeneration, and cement in contact with both the cranial and distal endplates can induce a higher incidence of adjacent disc degeneration.

Effect on the microcirculatory bed of the bony tissue is one of promising approaches to treatment of osteoporosis.&#x0D; Aim. To study anti-osteoporotic properties of endothelioprotectors: L-arginine, L-norvaline and rosuvastatin.&#x0D; Materials and Methods. Osteoprotective properties of L-arginine, L-norvaline and rosuvastatin, and also of a reference drug– strontium ranelate – were studied on 152 female rats of Wistar line using a model of hypoestrogen-induced osteoporosis. Anti-osteoporotic and endothelioprotective effect of the drugs were evaluated by laser dopplerflowmetry (LDF) of the proximal metaphysis of the femoral bone, morphometry of trabeculae of bone, and also by calculation of the coefficient of endothelial dysfunction.&#x0D; Results. LDF showed that maximal increase in microcirculation of the proximal metaphysis of the femoral bone, in comparison with animals with untreated osteoporosis (61.52±3.74 perfusion units, PU) was achieved with L-norvaline (115.25±5.36 PU, p&lt;0.001) and rosuvastatin (106.57±5.22 PU, p&lt;0.001), less expressed effect was demonstrated by L-arginine (98.10±4.48 PU, p&lt;0.001) and a reference drug – strontium ranelate (86.49±4.99 PU). A similar tendency was observed in morphometry of trabeculae of bone: in the group with untreated osteoporosis the diameter of trabeculae was 61.68±1.24 µm, in the group with use fL-norvaline – 91.86±1.8 µm (p&lt;0.001), in the group with use of L-arginine – 86.64±1.39 µm (p&lt;0.001) and in the group with use of strontium ranelate – 89.08±1.09 µm.&#x0D; Conclusion. L-arginine and L-norvaline and also rosuvastatin possess the property of improving a morphofunctional condition of bone tissue and may be recommended for further preclinical study.

BackgroundCartilage 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.MethodsBone 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.ResultsLow 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 β-catenin, significantly promoted chondrogenesis, and SrR did not suppress this effect, while LiCl, an agonist of β-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 β-catenin by SrR-loaded GelMA than the other treatments.ConclusionSrR could promote BMSCs chondrogenic differentiation by inhibiting the Wnt/β-catenin signaling pathway and accelerate cartilage regeneration in rat femoral condyle defects.

OBJECTIVE: To explore the effect of physical exercise (EXE), strontium ranelate (SR), or their combination on bone status in ovariectomized (OVX) rats. DESIGN: Sixty female Wistar rats were randomized to one of five groups: sham (Sh), OVX (O), OVX+EXE (OE), OVX+SR (OSR), and OVX+EXE+SR (OESR). Animals in EXE groups were subjected to 10 drops per day (45 cm in height); rats in SR groups received 625 mg/kg/day of SR, 5 days/week for 8 weeks. Bone mineral density (BMD) and bone mineral content (BMC, dual-energy X-ray absorptiometry (DXA)), mechanical strength of the left femur (three-point bending test), and femur microarchitecture of (micro-computed tomography imaging, microCT) analyses were performed to characterize biomechanical and trabecular/cortical structure. Bone remodeling, osteocyte apoptosis, and lipid content were evaluated by ELISA and immunofluorescence tests. RESULTS: In OVX rats, whole-body BMD, trabecular parameters, and osteocalcin (OCN) levels decreased, while weight, lean/fat mass, osteocyte apoptosis, and lipid content all increased. EXE after ovariectomy improved BMD and BMC, trabecular parameters, cross-sectional area (CSA), moment of inertia, and OCN levels while decreasing osteocyte apoptosis and lipid content. SR treatment increased BMD and BMC, trabecular parameters, CSA, stiffness, OCN, and alkaline phosphatase (ALP) levels. Furthermore, fat mass, N-telopeptide (NTX) level, osteocyte apoptosis, and lipid content significantly decreased. The combination of both EXE and SR improved bone parameters compared with EXE or SR alone. CONCLUSION: EXE and SR had positive and synergistic effects on bone formation and resorption.

In monkeys, long-term strontium ranelate administration results in a dose-dependent bone strontium uptake (mainly into newly formed bone) that preserves the degree of mineralization of bone and the bone mineral at the crystal level, showing its safety at bone mineral level. Strontium ranelate simultaneously increases bone formation and decreases bone resorption, leading to prevention of bone loss and increase in bone mass and bone strength in normal and ovariectomized rats. This study investigated the interactions of stable strontium (Sr) with bone mineral in monkeys after long-term strontium ranelate treatment and after a period of treatment withdrawal. Iliac bone was obtained from untreated monkeys, monkeys at the end of a 52-week strontium ranelate administration (200, 500, 1250 mg/kg/day orally), and in parallel groups 10 weeks after the end of strontium ranelate administration (same three doses; n = 3-7). Sr uptake and distribution in bone mineral were quantified by X-ray microanalysis, changes at the crystal level by X-ray diffraction, and the degree of mineralization of bone (DMB) by quantitative microradiography. After strontium ranelate administration, dose-dependent Sr uptake occurred into cortical and cancellous bone, with higher content (1.6 times) in new than in old bone. This Sr uptake decreased (50%) 10 weeks after treatment withdrawal; the decrease occurred almost exclusively in new bone. At the end of strontium ranelate treatment and after its withdrawal, a preservation of crystal characteristics was observed, suggesting that Sr was only faintly linked to crystals by ionic substitution and of DMB. These results show the absence of a deleterious effect of long-term strontium ranelate treatment on bone mineralization, confirming the histomorphometric observations made in postmenopausal osteoporotic women treated with strontium ranelate.

Strontium ranelate: New insights into its dual mode of action

Subjects affected by thalassemia major (TM) often have reduced bone mass and increased fracture risk. Strontium ranelate (SrR) is an effective treatment for postmenopausal and male osteoporosis. To date, no data exist on the use of SrR in the treatment of TM-related osteoporosis. Our aim was to evaluate the effects of SrR on bone mineral density (BMD), bone turnover markers and inhibitors of Wnt signaling (sclerostin and DKK-1). Twenty-four TM osteoporotic women were randomized to receive daily SrR 2g or placebo in addition to calcium carbonate (1,000mg) and vitamin D (800IU). BMD at the lumbar spine and femoral neck, bone turnover markers (C-terminal telopeptide of procollagen type I [CTX], bone-specific alkaline phosphatase [BSAP]) and insulin-like growth factor-1 (IGF-1), sclerostin and DKK-1 were assessed at baseline and after 24months. Back pain was measured by visual analog scale (VAS) every 6 months. After 24months, TM women treated with SrR had increased their spine BMD values in comparison to baseline (p<0.05). Moreover, they also exhibited a reduction of CTX and sclerostin levels (but not DKK-1) and exhibited an increase of BSAP and IGF-1 (p<0.05); however, no significant changes were observed in the placebo group. In the SrR group, a reduction of back pain was observed after 18months in comparison to baseline (p<0.05) and after 24months in comparison to placebo (p<0.05). Our study reports for the first time the effects of SrR in the treatment of TM-related osteoporosis. SrR treatment improved BMD and normalized bone turnover markers, as well as lowering sclerostin serum levels.

Small birth size is associated with reduced adult bone mass. We determined if antenatal betamethasone exposure, birth weight, or prematurity affects peak bone mass in 174 adults. Antenatal betamethasone exposure did not. Lower birth weight and prematurity predicted reduced adult height. Slower fetal growth rather than prematurity predicted lower bone mass, but this lower bone mass was appropriate for reduced adult height. Small size at birth is reported to be associated with lower bone mass in adulthood. However, previous studies have not distinguished the relative contributions of length of gestation and fetal growth to size at birth. Fetal exposure to excess glucocorticoids has been proposed as a core mechanism underlying the associations between birth size and later disease risk. Antenatal glucocorticoids are given to pregnant women at risk for preterm delivery for the prevention of neonatal respiratory distress syndrome in their infants. We determined the relationship of antenatal exposure to betamethasone, birth weight, and prematurity to peak bone mass and femoral geometry in the adult survivors of the first randomized trial of antenatal glucocorticoids. We studied 174 young adults (mean age, 31 years) whose mothers participated in a randomized trial of antenatal betamethasone. Mothers received two doses of intramuscular betamethasone or placebo 24 h apart. Two thirds of participants were born preterm (<37 weeks gestation). We measured indices of bone mass and size and derived estimates of volumetric density and bone geometry from DXA assessments of the lumbar spine, femur, and total body. There were no differences between betamethasone-exposed and placebo-exposed groups in any of the lumbar spine, femur, or total body DXA measures. There was no effect of antenatal betamethasone on adult height, although leg length was increased relative to trunk length (p = 0.002). A lighter birth weight (p <or = 0.001) and lower gestational age (p = 0.013) were associated with shorter stature (height Z scores) at age 31 years. Prematurity had no effect on peak bone mass or femoral geometry. However, lower birth weight, independent of gestational age, was associated with lower later bone mass (p < 0.001 for lumbar spine and total body, p = 0.003 for femoral neck BMC). These effects on bone mass were related to bone size and not to estimates of volumetric density. In the femur, lower birth weight, independent of gestational age, was associated with narrowing of the upper shaft and narrow neck regions. Antenatal betamethasone exposure does not affect peak bone mass or femoral geometry in adulthood. Birth weight and prematurity predict adult height, but it is slower fetal growth, rather than prematurity, that predicts lower peak bone mass. The lower peak bone mass in those born small is appropriate for their adult height.

BackgroundPrevious clinical studies reported that thoracolumbar vertebral fractures (VFs) associated with high energy spine trauma cause adjacent intervertebral disc (IVD) degeneration; however, the effect of non-traumatic VFs on the progression of adjacent disc degeneration remains to be determined. The purpose of this study was to examine the association between non-traumatic VFs and degenerative changes of adjacent IVDs.MethodsNinety-eight consecutive patients undergoing spinal surgery were included in this study. VFs were semi-quantitatively evaluated by lateral lumbar radiography. Five hundred eighty-eight vertebral bodies (from T12 to L5) and 486 discs (from T12/L1 to L4/L5) were analyzed. The degree of IVD degeneration was evaluated by magnetic resonance imaging (MRI) and classified into two groups according to Pfirrmann’s classification. Grades I, II and III were defined as the early stage of IVD degeneration and Grades IV and V as the advanced stage. Intradiscal vacuum phenomena (VPs) were evaluated by computed tomography. Adjacent IVDs were categorized according to the locations of VFs (superior, inferior, and bilateral). Associations between the presence of VFs and the extent of IVD degeneration or the presence of VPs were statistically analyzed.ResultsIVDs adjacent to VFs were identified in 115 IVDs (31.1% of total; superior: 11.4%, bilateral: 8.6%, inferior: 11.1%). The presence of VFs was significantly associated with MRI grades of adjacent IVD degeneration (P < 0.01) and the prevalence of VPs within adjacent IVDs (P < 0.01). From logistic regression analysis, age, disc level, and VFs were independent related factors for disc degeneration (P < 0.05).ConclusionThis study showed that VFs were an independent related factor for adjacent disc degeneration and occurrence of intradiscal VPs. VFs may affect the micro-environment of adjacent IVDs, leading to disc degeneration and disc rupture.

Twenty-one 3.5-month-old female Sprague-Dawley rats were randomly assigned to three groups: BTX group, in which each rat received a single intramuscular injection of 2 U of Clostridium botulinum toxin (BTX) in the quadriceps femoris muscle of the right hind limb; BTX + SR group, in which each rat received a BTX injection and a dose of strontium ranelate (dose level of 625 mg/kg/day); and the control group. All the rats were killed at 9 weeks post-treatment. It was showed that BTX-induced rats a rapid loss of body weight in the first 3 weeks, after which their body weight showed a slow increase similar to that observed in the control rats. The net body weight loss was mainly attributed to muscle atrophy. BTX caused remarkable bone degradation in either the trabecular bone or the cortical bone of the disuse femur. The deteriorations in the bone mass and bone microstructure were locally limited and could be prevented by strontium ranelate treatment. Biomechanical analysis showed that strontium ranelate treatment improved the mechanical performance of the tibia in BTX-treated rats. It was showed that a clinical-corresponding dose of strontium ranelate could prevent bone loss in long-term immobilized rats.

Oestrogen deficiency increases the rate of bone remodelling which, in association with a negative remodelling balance (resorption exceeding formation), results in impaired bone architecture, mass and strength. Current anti-osteoporotic drugs act on bone remodelling by inhibiting bone resorption or by promoting its formation. An alternative therapeutic approach is based on the concept of inducing opposite effects on bone resorption and formation. One therapeutic agent, strontium ranelate, was shown to induce opposite effects on bone resorption and formation in pre-clinical studies and to reduce fracture risk in postmenopausal osteoporotic patients. How strontium ranelate acts to improve bone strength in humans remains a matter of debate, however. This review of the most recent pre-clinical and clinical studies is a critical analysis of strontium ranelate's action on bone resorption and formation and how it increases bone mass, microarchitecture and strength in postmenopausal osteoporotic women.

To investigate the biomechanical affect of percutaneous transforaminal endoscopic discectomy(PTED) on adjacent segments with different degrees of degeneration and related risk of adjacent segment diseases (ASD) caused by this operation. A healthy male adult volunteer was selected, and the lumbosacral vertebra image data was obtained by CT scan, and the external contour of the bone structure was reconstructed. On this basis, the external contour of the bone structure was fitted by using the smooth curve in 3D-CAD software, and the complete three-dimensional finite element modelof the non degenerate L3-S1 segment and the degenerative models of the L3-L4 and L5-S1 segment were drawn forward. In L4, L5 segment simulating PTED surgery through the removal of right part of articular process and nucleus pulposus and anulus fibrosus. After PTED was simulated in the L4-L5 segment and the risk of ASD has been evaluated by six changes of biomechanical indicators in flexion, extension, left and right lateral bending, left and right axial rotation conditions. In the finite element model without adjacent segmental disc degeneration, the annulus fibrosus von Mises stress and intradiscal pressure of the PTED model showed only a slight increase under most stress conditions, and a slight decrease in a few conditions, and there was no significant change trend before and after surgery. In the original degenerated adjacent segment disc model, the biomechanical indicators related to disc degeneration in the pre- and post-PTED model showed significant deterioration, leading to an increased risk of potential adjacent spondylopathy. PTED surgery will not lead to the significant deterioration of postoperative biomechanical environment of non-degeneration adjacent intervertebral discs, and the original degeneration of adjacent intervertebral discs is a important risk factor for ASD.