Bone Formation Rate Research Articles

Hypobaric hypoxia deteriorates bone mass and strength in mice.

Mountaineers at high altitude are at increased risk of acute mountain sickness as well as high altitude pulmonary and cerebral edema. A densitometric study in mountaineers has suggested that expeditions at high altitude decrease bone mineral density. Surprisingly, the in vivo skeletal effects of hypobaric hypoxia are largely unknown, and have not been studied using advanced contemporary methods to assess bone microstructure. Eighty-four 22-week-old female mice were divided into seven groups with 12 mice in each group: 1. Baseline; 2. Normobaric, 4weeks; 3. Hypobaric hypoxia, 4weeks; 4. Normobaric, 8weeks; 5. Hypobaric hypoxia, 8weeks; 6. Normobaric, 12weeks; and 7. Hypobaric hypoxia, 12weeks. Hypobaric hypoxia mice were housed in hypobaric chambers at an ambient pressure of 500mbar (5500m altitude), while normobaric mice were housed at sea level atmospheric pressure for 4, 8, or 12weeks, respectively. Hypobaric hypoxia had a profound impact on femoral cortical bone and L4 trabecular bone, while the effect on femoral trabecular bone was less pronounced. Hypobaric hypoxia reduced the bone strength of the femoral mid-diaphysis and L4 at all time-points. At femoral cortical bone, hypobaric hypoxia reduced bone formation through fewer mineralizing surfaces and lower bone formation rate after 2weeks. In addition, bone strength decreased, and C-terminal telopeptide of type I collagen (CTX-I) increased independently of the duration of exposure to simulated high altitude. At L4, hypobaric hypoxia resulted in a substantial reduction in bone volume fraction, trabecular thickness, and trabecular number after 4weeks of exposure. Hypobaric hypoxia reduced bone strength and femoral bone mass, while femoral trabecular bone was much less affected, indicating the skeletal response to hypobaric hypoxia differ between cortical and trabecular bone. These findings provide initial preclinical support for future clinical studies in mountaineers to assess bone status and bone strength after exposure to prolonged high altitude exposure.

Sclerostin antibody improves phosphate metabolism hormones, bone formation rates, and bone mass in adult Hyp mice.

X-linked hypophosphatemia (XLH) is caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX). Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23), impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily by osteocytes, suppresses bone formation by antagonizing canonical Wnt-signaling and is reported to be elevated in XLH patients. Our previous study reported that a monoclonal antibody to sclerostin (Scl-Ab) decreases FGF23 and increases phosphate and bone mass in growing Hyp mice (XLH murine model). In the current study, we investigated the efficacy of Scl-Ab in treating XLH pathophysiology in adult Hyp mice that are past the period of rapid skeletal growth (12 and 20-weeks old). We hypothesized that Scl-Ab would not only increase bone formation, bone strength and bone mass, but would also normalize phosphate regulating hormones, FGF23, parathyroid hormone (PTH), and vitamin 1,25(OH)2D. Scl-Ab treatment increased cortical area, trabecular bone volume fraction, trabecular bone formation rate, and the bending moment in both sexes of both age groups. Scl-Ab treatment suppressed circulating levels of intact FGF23 and c-term FGF23 in treated male and female wild-type and Hyp mice of both age groups and improved both vitamin 1,25(OH)2D and PTH. Scl-Ab treated Hyp mice also showed evidence of increased renal expression of the sodium-phosphate co-transporter, NPT2a, specifically in the female Hyp mice. Our study suggests that Scl-Ab treatment can improve several skeletal and metabolic pathologies associated with XLH, further establishes the role of sclerostin in the regulation of FGF23 and provides evidence that Scl-Ab can improve phosphate regulation by targeting the bone-renal axis.

Acceleration of Bone Regeneration Induced by a Soft-Callus Mimetic Material.

Clinical implementation of endochondral bone regeneration (EBR) would benefit from the engineering of devitalized cartilaginous constructs of allogeneic origins. Nevertheless, development of effective devitalization strategies that preserves extracellular matrix (ECM) is still challenging. The aim of this study is to investigate EBR induced by devitalized, soft callus‐mimetic spheroids. To challenge the translatability of this approach, the constructs are generated using an allogeneic cell source. Neo‐bone formation is evaluated in an immunocompetent rat model, subcutaneously and in a critical size femur defect. Living spheroids are used as controls. Also, the effect of spheroid maturation towards hypertrophy is evaluated. The devitalization procedure successfully induces cell death without affecting ECM composition or bioactivity. In vivo, a larger amount of neo‐bone formation is observed for the devitalized chondrogenic group both ectopically and orthotopically. In the femur defect, accelerated bone regeneration is observed in the devitalized chondrogenic group, where defect bridging is observed 4 weeks post‐implantation. The authors' results show, for the first time, a dramatic increase in the rate of bone formation induced by devitalized soft callus‐mimetics. These findings pave the way for the development of a new generation of allogeneic, “off‐the‐shelf” products for EBR, which are suitable for the treatment of every patient.

Анализ вероятности возникновения периимплантной инфекции и ее последствия при внешней транспедикулярной фиксации позвоночника

The main purpose of spinal fixation is to provide conditions for vertebral fusion at the level of injury. Bone fusion is associated with many factors including stability of injured segment, restoration of the anterior support column, condition of the bone tissue and other aspects. The timing of bone formation can be affected by soft tissue inflammation at the site of the rods of the external fixation system. Peri-implant infection is reported to occur in 0.7-20 % of cases with external transpedicular fixation. The timing of the complication and the dependence of the frequency of the occurrence on the patient's treatment strategy are debatable. Another topical issue is the study of the consequences of peri-implant infection with the need to establish the validity of the assumption about the effect of peri-implant infection on the rate of bone formation using a clinical model. This would allow the findings to be used for new methods of treatment considering the risk of possible complications, giving preference to low-traumatic semi-closed methods of spine fixation. Nevertheless, external transpedicular fixation is practical for open spinal injury or significant vertebral displacement with the need of significant reduction efforts to be applied. The purpose was to explore the effect of soft tissue inflammation on the timing of bone formation with spinal fusion surgery using different surgical methods of treatment of uncomplicated spinal fractures. Material and methods The review included 111 patients with uncomplicated fractures of the lower thoracic and lumbar spine. Based on a retrospective analysis the participants were assigned to three groups depending on the presence/absence of peri-implant infection and the timing of the occurrence: 81 patients experienced no complications, 16 had serous-purulent inflammation of soft tissues at the site of the rods of the external fixation device that developed on average after 20 days with 14 patients seen with pin tract infection after 2 months of anterior fusion surgery and failed bone formation. Results Peri-implant infection rate was found to be higher with external fixation (14.4 %) than that with anterior fusion surgery (12.6 %). The complication rate was 1.85 times less with one-stage surgical treatment as compared to two-stage treatment. Peri-implant infection developed later (after 21‑63 days) with one-stage treatment as compared with two-stage procedure (after 12-24 days). Infection associated with the external fixation led to increase in timing of bone formation by 6-7 %, by 2-4 weeks on average. Bone formation failed in 35 % of cases (p < 0.0002) due to peri-implant inflammation caused by Staphylococcus aureus, as the common pathogen and the bacteria detected resulted in ineffective antibacterial therapy. Immunological parameters (IgM and haptoglobin) were quantified to assess the risk of peri-implant infection. Discussion Peri-implant infection rate associated with external transpedicular fixation was shown to be comparable with the previously obtained data. Sharply defined notions were reported earlier to differentiate between infectious peri-implant osteolysis and mechanical loosening. We compared the data on the duration of bone formation and the timing of peri-implant infection and developed a model that with high sensitivity (73 %) and specificity (100 %) allowed description of cases with impaired osteogenesis. Changes in some immunological parameters (immunoglobulins, acute-phase proteins) were shown to affect both bone formation and stability of bone fixation.

Recombinant Human Bone Morphogenic Protein-2 Immobilized Fabrication of Magnesium Functionalized Injectable Hydrogels for Controlled-Delivery and Osteogenic Differentiation of Rat Bone Marrow-Derived Mesenchymal Stem Cells in Femoral Head Necrosis Repair

Femoral head necrosis (FHN) is a clinically progressive disease that leads to overwhelming complications without an effective therapeutic approach. In recent decades, transplantation of mesenchymal stem cells (MSCs) has played a promising role in the treatment of FHN in the initial stage; however, the success rate is still low because of unsuitable cell carriers and abridged osteogenic differentiation of the transplanted MSCs. Biopolymeric-derived hydrogels have been extensively applied as effective cell carriers and drug vesicles; they provide the most promising contributions in the fields of tissue engineering and regenerative medicine. However, the clinical potential of hydrogels may be limited because of inappropriate gelation, swelling, mechanical characteristics, toxicity in the cross-linking process, and self-healing ability. Naturally, gelated commercial hydrogels are not suitable for cell injection and infiltration because of their static network structure. In this study, we designed a novel thermogelling injectable hydrogel using natural silk fibroin-blended chitosan (CS) incorporated with magnesium (Mg) substitutes to improve physical cross-linking, stability, and cell osteogenic compatibility. The presented observations demonstrate that the developed injectable hydrogels can facilitate the controlled delivery of immobilized recombinant human bone morphogenic protein-2 (rhBMP-2) and rat bone marrow-derived MSCs (rBMSCs) with greater cell encapsulation efficiency, compatibility, and osteogenic differentiation. In addition, outcomes of in vivo animal studies established promising osteoinductive, bone mineral density, and bone formation rate after implantation of the injectable hydrogel scaffolds. Therefore, the developed hydrogels have great potential for clinical applications of FHN therapy.

Inching Closer to the End of the Debate Between Fixed Versus Mobile-Bearing Total Ankle Arthroplasty: Commentary on an article by M. Assal, MD, et al.: "Three-Year Rates of Reoperation and Revision Following Mobile Versus Fixed-Bearing Total Ankle Arthroplasty. A Cohort of 302 Patients Treated with 2 Implants of Similar Design".

Commentary The study by Assal et al. presents an interesting perspective on fixed versus mobile-bearing prostheses in total ankle arthroplasty (TAA) because the study utilizes similarly designed prostheses from the same manufacturer, with all surgical procedures performed by 1 of 2 surgeons. The Salto (integra) prosthesis was designed by French surgeons in 1997, showing good initial results with short- and mid-term follow-up studies1,2. This prosthesis has a 3-component design with a mobile-bearing spacer. The Salto Talaris (integra) was introduced to the U.S. market in 2006 and to the European market in 2012. There were minor design changes between the Salto and the Salto Talaris, mainly to accommodate a fixed bearing on the tibial component of the latter prosthesis in order to allow 510(k) approval by the Food and Drug Administration in the U.S. Over the years, there have been multiple studies discussing the short- and mid-term outcomes of either the Salto or the Salto Talaris, with prostheses showing acceptable if not excellent results3-5. The debate regarding fixed versus mobile-bearing prostheses has been ongoing for many years. The concept of a mobile-bearing prosthesis was introduced with the theoretical advantage of having better-conforming articular surfaces and lower contact stress, with the dissipation of stress over a more consistent area of the joint. Another theoretical advantage was the self-correction and positioning of the polyethylene spacer, reducing wear and stress on the spacer itself. However, the majority of studies have not confirmed these theoretical advantages and in fact have suggested that the use of a mobile-bearing prosthesis leads to a higher rate of complications in the first year postoperatively6. In a 2014 study retrospectively comparing the use of fixed versus mobile-bearing prostheses with a minimum follow-up of 2 years, Gaudot et al. reported that mobile-bearing prostheses had higher rates of radiolucent lines (40%) and cyst formation (24%) compared with fixed-bearing prostheses (12% and 3%, respectively)7. One strength of the study by Assal et al. was that it included 2 relatively large cohorts, with 131 fixed-bearing TAAs and 171 mobile-bearing TAAs. The mobile-bearing procedures were performed in the earlier half of the study period. As a result, 1 theoretical concern was regarding the surgical experience of the surgeons over time; however, the surgeons had been performing mobile-bearing TAAs since 2000, with the study period beginning in 2004, so they were adequately experienced with the procedure by the outset of the study. The authors also reported that the complication rate in the mobile-bearing group was stable throughout the study period and did not decrease with time. The most important conclusion of this study was that the rate of revision was 3 times higher among mobile-bearing compared with fixed-bearing prostheses. Most concerning was that most of the reported failures of mobile-bearing TAAs were because of cyst formation and gutter impingement due to heterotopic bone formation, with these prostheses showing higher rates of heterotopic bone formation in the medial and lateral gutters. There were several questions that went unanswered in the study by Assal et al and that should be addressed in future studies. What caused the increased rate of lysis, cysts, hypertrophic bone, and failure among mobile-bearing TAAs? One possible explanation is the smaller spacer utilized in the mobile-bearing implant, which increases the load per square inch of the polyethylene insert, contributing to greater wear. Was there a higher rate of backside wear between the polyethylene insert and the tibial baseplate among mobile-bearing TAAs? This effect could cause an excess of problematic polyethylene debris. Was there potential for edge-loading between the polyethylene spacer and the tibial component if the overall alignment was not reasonably accurate? Along with these questions, the greatest shortcoming of the study was that it was not a prospective, randomized trial, but instead was essentially a comparison of the results of 2 longitudinal studies. However, 1 strength was that the study utilized 2 prostheses with similar designs from the same manufacturer, which will be of substantial value if the trial can continue to longer-term follow-ups. The debate regarding fixed versus mobile-bearing prostheses will continue, but the study by Assal et al. provided an interesting window into the potential shortcomings of mobile-bearing TAAs. I congratulate the authors on an excellent paper.

Implant Placement With Graftless Sinus Floor Elevation via the Lateral Approach: A Case Series With 4 Years Post-Loading Radiographical Outcomes and Implant Survival Rate.

The purpose of the present study was to evaluate the radiographical outcomes, survival rate, and amount of bone formation around implants placed during graftless lateral sinus lift approach (GLSLA). Five patients (6 sinus augmentations) were consecutively treated with GLSLA. After Schneiderian membrane elevation and implant insertion, only blood clot was left to fill the new sinus compartment. After 4 months of healing, implants were functionally loaded. in all cases, samples were taken for biopsy at the time of second-stage surgery. The radiographical marginal bone variations and apical bone gain were assessed using cone beam- computed tomography taken 4 months after the surgery (at crown insertion) and after 4 years of loading. A total of 14 implants were placed in a mean initial residual bone height of 3.1 mm (range 1.64 mm). No failure was recorded, and all the implants were successfully loaded yielding a 100% survival rate. Vital bone formation was 33% according to the histomorphometry data. Four years after loading the mean radiographic bone remodeling was 1.3 mm. The mean ridge height was 7.6 mm and the mean apical bone gain amounted for 3.8mm. Within the limitations of this study, the placement of dental implants in conjunction with GLSLA seems to be feasible and accompanied by high implant survival rate.

Iron deficiency and high-intensity running interval training do not impact femoral or tibial bone in young female rats.

In the USA, as many as 20 % of recruits sustain stress fractures during basic training. In addition, approximately one-third of female recruits develop Fe deficiency upon completion of training. Fe is a cofactor in bone collagen formation and vitamin D activation, thus we hypothesised Fe deficiency may be contributing to altered bone microarchitecture and mechanics during 12-weeks of increased mechanical loading. Three-week old female Sprague Dawley rats were assigned to one of four groups: Fe-adequate sedentary, Fe-deficient sedentary, Fe-adequate exercise and Fe-deficient exercise. Exercise consisted of high-intensity treadmill running (54 min 3×/week). After 12-weeks, serum bone turnover markers, femoral geometry and microarchitecture, mechanical properties and fracture toughnessand tibiae mineral composition and morphometry were measured. Fe deficiency increased the bone resorption markers C-terminal telopeptide type I collagen and tartate-resistant acid phosphatase 5b (TRAcP 5b). In exercised rats, Fe deficiency further increased bone TRAcP 5b, while in Fe-adequate rats, exercise increased the bone formation marker procollagen type I N-terminal propeptide. In the femur, exercise increased cortical thickness and maximum load. In the tibia, Fe deficiency increased the rate of bone formation, mineral apposition and Zn content. These data show that the femur and tibia structure and mechanical properties are not negatively impacted by Fe deficiency despite a decrease in tibiae Fe content and increase in serum bone resorption markers during 12-weeks of high-intensity running in young growing female rats.

Current Concepts of Surface Topography of Implants: A Review

AbstractBoth the rate of osseointegration and its extent depend upon the characteristics of the implant surface.1 2 3 4 5 Depending on the surface of the implant determination of implant–bone contact area, the rate of bone formation around the implant can be done.6 Hence, the implant surface plays an important part in multiple ways in the osseointegration process.

Mechanical loading alleviated the inhibition of β2-adrenergic receptor agonist terbutaline on bone regeneration.

The long-term use of adrenergic medication in treating various conditions, such as asthma, increases the chances of bone fracture. Dynamic mechanical loading at a specific time is a method for improving bone quality and promoting healing. Therefore, we hypothesized that precisely controlling the mechanical environment can contribute to the alleviation of the negative effects of chronic treatment with the common asthma drug terbutaline, which is a β2-adrenergic receptor agonist that facilitates bone homeostasis and defect repair through its anabolic effect on osteogenic cells. Our in vitro results showed that terbutaline can directly inhibit osteogenesis by impairing osteogenic differentiation and mineralization. Chronic treatment in vivo was simulated by administering terbutaline to C57BL/6J mice for 4weeks before bone defect surgery and mechanical loading. We utilized a stabilized tibial defect model, which allowed the application of anabolic mechanical loading. During homeostasis, chronic terbutaline treatment reduced the bone formation rate, the fracture toughness of long bones, and the concentrations of bone formation markers in the sera. During defect repair, terbutaline decreased the bone volume, type H vessel, and total blood vessel volume. Terbutaline treatment reduced the number of osteogenic cells. Periostin, which was secreted mainly by Prrx1+ osteoprogenitors and F4/80+ macrophages, was inhibited by treating the bone defect with terbutaline. Interestingly, controlled mechanical loading facilitated the recovery of bone volume and periostin expression and the number of osteogenic cells within the defect. In conclusion, mechanical loading can rescue negative effects on new bone accrual and repair induced by chronic terbutaline treatment.

Smad2 and Smad3 expressed in skeletal muscle promote immobilization-induced bone atrophy in mice

Skeletal muscle is known to regulate bone homeostasis through muscle-bone interaction, although factors that control this activity remain unclear. Here, we newly established Smad3-flox mice, and then generated skeletal muscle-specific Smad2/Smad3 double conditional knockout mice (DcKO) by crossing Smad3-flox with skeletal muscle-specific Ckmm Cre and Smad2-flox mice. We show that immobilization-induced gastrocnemius muscle atrophy occurring due to sciatic nerve denervation was partially but significantly inhibited in DcKO mice, suggesting that skeletal muscle cell-intrinsic Smad2/3 is required for immobilization-induced muscle atrophy. Also, tibial bone atrophy seen after sciatic nerve denervation was partially but significantly inhibited in DcKO mice. Bone formation rate in wild-type mouse tibia was significantly inhibited by immobilization, but inhibition was abrogated in DcKO mice. We propose that skeletal muscle regulates immobilization-induced bone atrophy via Smad2/3, and Smad2/3 represent potential therapeutic targets to prevent both immobilization-induced bone and muscle atrophy.

In premenopausal women with idiopathic osteoporosis, lower bone formation rate is associated with higher body fat and higher IGF-1.

Premenopausal women with idiopathic osteoporosis (IOP) have marked deficits in bone microarchitecture but variable bone remodeling. We previously reported that those with low tissue-level bone formation rate (BFR) are less responsive to teriparatide and have higher serum IGF-1, a hormone anabolic for osteoblasts and other tissues. The IGF-1 data were unexpected because IGF-1 is low in other forms of low turnover osteoporosis-leading us to hypothesize that IGF-1 relationships are paradoxical in IOP. This study aimed to determine whether IOP womenwith low BFR have higher IGF-1 and paradoxical IGF-1 relationships in skeletal and non-skeletal tissues, and whether IGF-1 and the related measures predict teriparatide response. This research is an ancillary study to a24month clinical trial of teriparatide for IOP. Baseline assessments were related to trial outcomes: BMD, bone remodeling. Premenopausal women with IOP(n = 34); bone remodeling status wasdefined by baseline cancellous BFR/BS on bone biopsy. Serum IGF-1 parameters, compartmental adiposity (DXA, CT, MRI), serum hormones, and cardiovascular-risk-markers related to fat distribution. As seen in other populations, lower BFR was associated with higher body fat and poorer teriparatide response. However, in contrast to observations in other populations, low BFR, higher body fat, and poorer teriparatide response were all related to higher IGF-1: IGF-1 Z-score was inversely related to BFR at all bone surfaces (r = - 0.39 to - 0.46; p < 0.05), directly related to central fat (p = 0.05) and leptin (p = 0.03). IGF-1 inversely related to 24month hip BMD %change (r = - 0.46; p = 0.01). Paradoxical IGF-1 relationships suggest that abnormal or atypical regulation of bone and fat may contribute to osteoporosis mechanisms in premenopausal IOP.

Pulsed electromagnetic field therapy alters early healing in a rat model of rotator cuff injury and repair: Potential mechanisms.

Rotator cuff repair failure remains common due to poor tendon healing, particularly at the enthesis. We previously showed that pulsed electromagnetic field (PEMF) therapy improved the mechanical properties of the rat supraspinatus tendon postoperatively. However, little is known about the mechanisms behind PEMF-dependent contributions to improved healing in this injury model. The objective of this study was to determine the influence of PEMF treatment on tendon gene expression and cell composition, as well as bone microarchitecture and dynamic bone metabolism during early stages of healing. We hypothesized that PEMF treatment would amplify tendon-healing related signaling pathways while mitigating inflammation and improve bone metabolism at the repair site. Rats underwent rotator cuff injury and repair followed by assignment to either control (non-PEMF) or PEMF treatment groups. Gene and protein expression as well as tendon and bone histological assessments were performed 3, 7, 14, 21, and 28 days after injury. Gene expression data demonstrated an upregulation in the bone morphogenetic protein 2 signaling pathway and increases in pro-osteogenic genes at the insertion, supporting important processes to re-establish the tendon-bone interface. PEMF also downregulated genes related to a fibrotic healing response. Anti-inflammatory effects were demonstrated by both gene expression and macrophage phenotype. PEMF significantly increased the rate of kinetic bone formation directly adjacent to the tendon enthesis as well as the number of cuboidal surface osteoblasts (active osteoblasts) in the humeral head. This study has provided insight into how PEMF affects cellular and molecular processes in the supraspinatus tendon and adjacent bone after injury and repair.

Low bone turnover is associated with plain X-ray vascular calcification in predialysis patients.

BackgroundVascular calcification (VC) is a common finding in chronic kidney disease (CKD) patients and predicts subsequent cardiovascular morbidity and mortality in this population. Vascular calcification is linked to disordered mineral metabolism and has been associated with bone histomorphometry changes in CKD. However, data on predialysis patients is scarce.MethodsA cross-sectional study was conducted on a cohort of 56 CKD patients not yet on dialysis, who underwent a transiliac bone biopsy for histomorphometric evaluation after double tetracycline labeling. Patients had no previous exposure to calcium salts, vitamin D agents, steroids or bisphosphonates. Vascular calcification was assessed at the time of biopsy, using Kauppila (plain X-ray of the lateral lumbar spine) and Adragão (plain X-ray of the pelvis and hands) scores.ResultsVascular calcification was seen in two-thirds of the cohort. Subjects with VC were more likely to be male and have diabetes, and had significantly higher sclerostin and osteoprotegerin circulating levels than those without VC. The histomorphometric analysis showed that bone formation rate was significantly lower in VC compared to non-VC patients. In the multivariable logistic regression analysis, bone formation rate was independently associated with the presence of VC.ConclusionsVascular calcification is highly prevalent in predialysis patients, especially in those with diabetes. The independent association between bone formation rate and VC provides evidence of an important interaction between bone and vessel in CKD. Our results suggest that low bone turnover is a non-traditional risk factor for cardiovascular disease in predialysis patients.

Correlation Analysis of Adverse Reactions of Antiosteoporosis Drugs by Different Mechanisms with Bone Turnover and Vitamin D.

Objective The risk factors for the most common adverse reactions of two types of antiosteoporosis drugs in the first treatment of postmenopausal osteoporosis were analyzed to investigate the relationship between the occurrence of adverse reactions and different bone transition states and vitamin D levels. Methods A total of 381 postmenopausal women who were diagnosed with osteoporosis in the Osteoporosis Clinic of Ningxia Medical University General Hospital from January 2017 to June 2020 were enrolled. A telephone follow-up survey was conducted on the mentioned subjects. According to the survey results, the mentioned subjects were selected according to their first use of antiosteoporosis drugs. They were divided into zoledronic acid and teriparatide acetate groups. The subjects in the two groups were divided into two groups according to the presence or absence of adverse reactions after medication and according to vitamin D level and P1NP level, and the correlation between the two factors and the occurrence of adverse reactions was analyzed. Results Among the 307 patients treated with zoledronic acid for antiosteoporosis, 99 patients developed acute phase adverse reactions (APR+), accounting for 32.2% of the total subjects. 56.7 percent of the subjects had vitamin D deficiency. The 25(OH)D level of the APR + subjects was 16.75 ± 9.20 ng/mL, significantly lower than that of the APR− patients (23.68 ± 10.67 ng/mL). Serological P1NP level in APR+ patients was 73.95 ± 34.50 ng/ml, significantly higher than that of APR− patients with 55.80 ± 36.91 ng/ml. Musculoskeletal symptoms were observed in 14 of the 74 subjects treated with teriparatide acetate, accounting for 18.9% of the total subjects. The 25(OH)D level was deficient in 59.5% of the subjects. The 25(OH)D level of the subjects with musculoskeletal symptoms was 15.96 ± 8.17 ng/ml, while that of the subjects without musculoskeletal symptoms was 20.86 ± 8.52 ng/ml, which showed no statistical significance. The reason was considered to be related to the small sample size included in the study. The P1NP level of subjects with musculoskeletal symptoms was 96.85 ± 58.52 ng/ml, significantly higher than the P1NP level of subjects without musculoskeletal symptoms (55.28 ± 27.87 ng/ml). Conclusions The 25(OH)D level in vivo was negatively correlated with the acute phase adverse reactions after the first infusion of zoledronic acid. When the rate of bone formation is increased and osteoblasts are active, the risk of acute phase adverse reactions is increased with the use of zoledronic acid as antiosteoporosis therapy. There was no significant correlation between 25(OH)D levels and musculoskeletal symptoms after teriparatide acetate treatment of osteoporosis. When the rate of bone formation is increased and osteoblasts are active, the risk of adverse reactions to musculoskeletal symptoms is increased with antiosteoporosis treatment with teriparatide acetate.

Evaluation of osteogenic potential of Cissus quadrangularis on mandibular alveolar ridge distraction

BackgroundThis randomized clinical trial was designed to evaluate osteogenic potential of Cissus quadrangularis in alveolar distraction to facilitate implant installation.Material and methodsTwenty patients with atrophic ridge were treated by alveolar distraction. After completing distractor activation, patients were randomly divided into two equal groups according to administered drug (placebo and Cissus quadrangularis group). After a consolidation period, distractors were removed and implants were inserted. Clinical evaluation was done to assess wound healing, and distractor and implant stability. Histological evaluation was performed at time of implant insertion. Radiographic evaluation was performed to assess bone volume and density after distraction, as well as, density and bone loss around implant.ResultsRadiographic and histological results showed that bone formation and maturation of study group were faster than that of control group. There was a significant increased bone density in distracted area and around implant in study group than control group. A significant bone loss at end of consolidation period, and around implant at end of the study was reported in control group than study group.ConclusionCissus quadrangularis administration during the consolidation period is associated with increased osteogenic potential of distracted bone. The histological and radiographic findings of current study proved that Cissus quadrangularis not only enhances rate of new bone formation, but also bone density to withstand the biomechanical requirements of implant placement in a shorter time.Trial registrationThis study was retrospectively registered on www.ClinicalTrial.gov: NCT04669795-17\\12\\2020.

NMUR1 in the NMU-Mediated Regulation of Bone Remodeling.

Neuromedin-U (NMU) is an evolutionarily conserved peptide that regulates varying physiologic effects including blood pressure, stress and allergic responses, metabolic and feeding behavior, pain perception, and neuroendocrine functions. Recently, several lines of investigation implicate NMU in regulating bone remodeling. For instance, global loss of NMU expression in male and female mice leads to high bone mass due to elevated bone formation rate with no alteration in bone resorption rate or observable defect in skeletal patterning. Additionally, NMU treatment regulates the activity of osteoblasts in vitro. The downstream pathway utilized by NMU to carry out these effects is unknown as NMU signals via two G-protein-coupled receptors (GPCRs), NMU receptor 1 (NMUR1), and NMU receptor 2 (NMUR2), and both are expressed in the postnatal skeleton. Here, we sought to address this open question and build a better understanding of the downstream pathway utilized by NMU. Our approach involved the knockdown of Nmur1 in MC3T3-E1 cells in vitro and a global knockout of Nmur1 in vivo. We detail specific cell signaling events (e.g., mTOR phosphorylation) that are deficient in the absence of NMUR1 expression yet trabecular bone volume in femora and tibiae of 12-week-old male Nmur1 knockout mice are unchanged, compared to controls. These results suggest that NMUR1 is required for NMU-dependent signaling in MC3T3-E1 cells, but it is not required for the NMU-mediated effects on bone remodeling in vivo. Future studies examining the role of NMUR2 are required to determine the downstream pathway utilized by NMU to regulate bone remodeling in vivo.

Epo/EpoR signaling in osteoprogenitor cells is essential for bone homeostasis and Epo-induced bone loss

High erythropoietin (Epo) levels are detrimental to bone health in adult organisms. Adult mice receiving high doses of Epo lose bone mass due to suppressed bone formation and increased bone resorption. In humans, high serum Epo levels are linked to fractures in elderly men. Our earlier studies indicated that Epo modulates osteoblast activity; however, direct evidence that Epo acts via its receptor (EpoR) on osteoblasts in vivo is still missing. Here, we created mice lacking EpoR in osteoprogenitor cells to specifically address this gap. Deletion of EpoR in osteoprogenitors (EpoR:Osx-cre, cKO) starting at 5 weeks of age did not alter red blood cell parameters but increased vertebral bone volume by 25% in 12-week-old female mice. This was associated with low bone turnover. Histological (osteoblast number, bone formation rate) and serum (P1NP, osteocalcin) bone formation parameters were all reduced, as were the number of osteoclasts and TRAP serum level. Differentiation of osteoblast precursors isolated from cKO versus control mice resulted in lower expression of osteoblast marker genes including Runx2, Alp, and Col1a1 on day 21, whereas the mineralization capacity was similar. Moreover, the RANKL/OPG ratio, which determines the osteoclast-supporting potential of osteoblasts, was substantially decreased by 50%. Similarly, coculturing cKO osteoblasts with control or cKO osteoclast precursors produced significantly fewer osteoclasts than coculture with control osteoblasts. Finally, exposing female mice to Epo pumps (10 U·d−1) for 4 weeks resulted in trabecular bone loss (−25%) and increased osteoclast numbers (1.7-fold) in control mice only, not in cKO mice. Our data show that EpoR in osteoprogenitors is essential in regulating osteoblast function and osteoblast-mediated osteoclastogenesis via the RANKL/OPG axis. Thus, osteogenic Epo/EpoR signaling controls bone mass maintenance and contributes to Epo-induced bone loss.

Osteoblastic glucocorticoid signaling exacerbates high-fat-diet- induced bone loss and obesity

Chronic high-fat diet (HFD) consumption not only promotes obesity and insulin resistance, but also causes bone loss through mechanisms that are not well understood. Here, we fed wild-type CD-1 mice either chow or a HFD (43% of energy from fat) for 18 weeks; HFD-fed mice exhibited decreased trabecular volume (−28%) and cortical thickness (−14%) compared to chow-fed mice. In HFD-fed mice, bone loss was due to reduced bone formation and mineral apposition, without obvious effects on bone resorption. HFD feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network (LCN). In mice fed HFD, skeletal glucocorticoid signaling was activated relative to chow-fed mice, independent of serum corticosterone concentrations. We therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss, using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice). In HSD2OB/OCY-tg mice, bone formation and mineral apposition rates were not suppressed by HFD, and bone loss was significantly attenuated. Interestingly, in HSD2OB/OCY-tg mice fed HFD, both Wnt signaling (less sclerostin induction, increased β-catenin expression) and glucose uptake were significantly increased, relative to diet- and genotype-matched controls. The osteocyte LCN remained intact in HFD-fed HSD2OB/OCY-tg mice. When fed a HFD, HSD2OB/OCY-tg mice also increased their energy expenditure and were protected against obesity, insulin resistance, and dyslipidemia. Therefore, glucocorticoid signaling in osteoblasts and osteocytes contributes to the suppression of bone formation in HFD-fed mice. Skeletal glucocorticoid signaling is also an important determinant of glucose uptake in bone, which influences the whole-body metabolic response to HFD.

Combining Bone Collagen Matrix with hUC-MSCs for Application to Alveolar Process Cleft in a Rabbit Model.

Most materials used clinically for filling severe bone defects either cannot induce bone re-generation or exhibit low bone conversion, therefore, their therapeutic effects are limited. Human umbilical cord mesenchymal stem cells (hUC-MSCs) exhibit good osteoinduction. However, the mechanism by which combining a heterogeneous bone collagen matrix with hUC-MSCs to repair the bone defects of alveolar process clefts remains unclear. A rabbit alveolar process cleft model was established by removing the bone tissue from the left maxillary bone. Forty-eight young Japanese white rabbits (JWRs) were divided into normal, control, material and MSCs groups. An equal volume of a bone collagen matrix alone or combined with hUC-MSCs was implanted in the defect. X-ray, micro-focus computerized tomography (micro-CT), blood analysis, histochemical staining and TUNEL were used to detect the newly formed bone in the defect area at 3 and 6months after the surgery. The bone formation rate obtained from the skull tissue in MSCs group was significantly higher than that in control group at 3months (P < 0.01) and 6months (P < 0.05) after the surgery. The apoptosis rate in the MSCs group was significantly higher at 3months after the surgery (P < 0.05) and lower at 6months after the surgery (P < 0.01) than those in the normal group. Combining bone collagen matrix with hUC-MSCs promoted the new bone regeneration in the rabbit alveolar process cleft model through promoting osteoblasts formations and chondrocyte growth, and inducing type I collagen formation and BMP-2 generation.