Advances in exosome modulation of ferroptosis for the treatment of orthopedic diseases.

Current treatments for orthopaedic illnesses frequently result in poor prognosis, treatment failure, numerous relapses, and other unpleasant outcomes that have a significant impact on patients' quality of life. Cell-free therapy has emerged as one of the most promising options in recent decades for improving the status quo. As a result, using exosomes produced from various cells to modulate ferroptosis has been proposed as a therapeutic method for the condition. Exosomes are extracellular vesicles that secrete various bioactive chemicals that influence disease treatment and play a role in the genesis and progression of orthopaedic illnesses. Ferroptosis is a recently defined kind of controlled cell death typified by large iron ion buildup and lipid peroxidation. An increasing number of studies indicate that ferroptosis plays a significant role in orthopaedic illnesses. Exosomes, as intercellular information transfer channels, have been found to play a significant role in the regulation of ferroptosis processes. Furthermore, accumulating research suggests that exosomes can influence the course of many diseases by regulating ferroptosis in injured cells. In order to better understand the processes by which exosomes govern ferroptosis in the therapy of orthopaedic illnesses. This review discusses the biogenesis, secretion, and uptake of exosomes, as well as the mechanisms of ferroptosis and exosomes in the therapy of orthopaedic illnesses. It focuses on recent research advances and exosome mechanisms in regulating iron death for the therapy of orthopaedic illnesses. The present state of review conducted both domestically and internationally is elucidated and anticipated as a viable avenue for future therapy in the field of orthopaedics.

Comparison of rehabilitation outcomes between robot-assisted and freehand screw placement in treatment of femoral neck fractures: a systematic review and meta-analysis.

PURPOSE: To compare the postoperative rehabilitation of femoral neck fractures treated with robot-assisted nailing and freehand nailing. METHODS: We systematically searched the PubMed, EMBASE, Cochrane, China National Knowledge Infrastructure(CNKI), WanFang database, China Science and Technology Journal Database (VIP) and Web of Science databases to identify potentially eligible articles. Indispensable data such as the year of publication, country, study type, robot type, age, number of patients, sex distribution, study design, and outcome indicators were extracted. The outcome indicators of interest included healing rate, length of healing time, Harris score, operation time, frequency of X-ray fluoroscopy, frequency of guide pin insertion, and intraoperative blood loss. RevMan 5.4.1 was used for the meta-analysis. RESULTS: Fourteen studies with 908 participants were included in this meta-analysis. The results showed that in terms of healing rate (SMD = 2.75, 95% CI, 1.03 to 7.32, P = 0.04) and Harris score (SMD = 2.27, 95% CI, 0.79 to 3.75, P = 0.003), robot-assisted screw placement technique scores were higher than the traditional freehand technique. Additionally, operative time (SMD = -12.72, 95% CI, -19.74 to -5.70, P = 0.0004), healing time (SMD = -13.63, 95% CI, -20.18 to -7.08, P < 0.0001), frequency of X-ray fluoroscopy (SMD = - 13.64, 95% CI, - 18.32 to - 8.95, P < 0.00001), frequency of guide pin insertion (SMD = - 7.95, 95% CI, - 10.13 to - 5.76, P < 0.00001), and intraoperative blood loss (SMD = - 17.33, 95% CI, - 23.66 to - 11.00, P < 0.00001) were lower for patients who underwent robotic-assisted screw placement than those for patients who underwent the conventional freehand technique. CONCLUSION: Compared to the freehand nailing technique, robot-assisted nailing helps improve postoperative healing rates in patients with femoral neck fractures; shortens healing times; better restores hip function; reduces the number of intraoperative fluoroscopies, guides pin placements; reduces intraoperative bleeding; and increases perioperative safety.

Flushing effect of micro-bolus pulse injection and its potential impact on peripheral veins under hemostasis.

To explore the feasibility of using micro-bolus pulse injection method to reduce the dilution effect of pipeline on high concentration injection, and to understand low liquid volume bolus injection based on low injection speed. Using a programmable pulse injection pump, a 25-cm - long pipeline containing water-soluble fluorescent agent was flushed using different volumes of bolus, and the time spent for the complete disappearance of the fluorescent agent was recorded to evaluate the flushing efficiency. The finite element simulation of 2-phase flow was carried out using computational fluid dynamics (CFD) technology, and the difference of shear rate and pressure distribution in the vein of pulse injection and direct injection of bolus under hemostasis was compared and simulated. Micro-bolus pulse flushing has advantages in completing perfusion imaging applications, such as small volume imaging agent injection. Compared with non-pulse injection, the effective flushing volume decreases by 49.7%, the average injection speed decreases by 56%, and the maintenance time of high shear rate is shorter when using micro-bolus pulse injection. The impact of micro-bolus pulse injection on the vein can achieve the same or even lower negative effects as other injection methods after increasing the hemostatic distance to 100 mm. In the case of bolus injection requiring high concentration and small volume, such as for radiopharmaceutical dynamic imaging, the application of micro-bolus pulse injection is an effective way to overcome the dilution phenomenon of the imaging agent in the pipeline. During hemostasis, the micro-bolus pulse injection needs to control a longer hemostasis distance to reduce the potential impact on peripheral veins.

[Research progress in influence of microstructure on performance of triply-periodic minimal surface bone scaffolds].

Objective: To summarize the influence of microstructure on performance of triply-periodic minimal surface (TPMS) bone scaffolds. Methods: The relevant literature on the microstructure of TPMS bone scaffolds both domestically and internationally in recent years was widely reviewed, and the research progress in the imfluence of microstructure on the performance of bone scaffolds was summarized. Results: The microstructure characteristics of TPMS bone scaffolds, such as pore shape, porosity, pore size, curvature, specific surface area, and tortuosity, exert a profound influence on bone scaffold performance. By finely adjusting the above parameters, it becomes feasible to substantially optimize the structural mechanical characteristics of the scaffold, thereby effectively preempting the occurrence of stress shielding phenomena. Concurrently, the manipulation of these parameters can also optimize the scaffold's biological performance, facilitating cell adhesion, proliferation, and growth, while facilitating the ingrowth and permeation of bone tissue. Ultimately, the ideal bone fusion results will obtain. Conclusion: The microstructure significantly and substantially influences the performance of TPMS bone scaffolds. By deeply exploring the characteristics of these microstructure effects on the performance of bone scaffolds, the design of bone scaffolds can be further optimized to better match specific implantation regions.

[Research progress on the design of bone scaffolds with different single cell structures].

Objective: To review the research progress of design of bone scaffolds with different single cell structures. Methods: The related literature on the study of bone scaffolds with different single cell structures at home and abroad in recent years was extensively reviewed, and the research progress was summarized. Results: The single cell structure of bone scaffold can be divided into regular cell structure, irregular cell structure, cell structure designed based on topology optimization theory, and cell structure designed based on triply periodic minimal surface. Different single cell structures have different structural morphology and geometric characteristics, and the selection of single cell structure directly determines the mechanical properties and biological properties of bone scaffold. It is very important to choose a reasonable cell structure for bone scaffold to replace the original bone tissue. Conclusion: Bone scaffolds have been widely studied, but there are many kinds of bone scaffolds at present, and the optimization of single cell structure should be considered comprehensively, which is helpful to develop bone scaffolds with excellent performance and provide effective support for bone tissue.

Effects of genus Epimedium in the treatment of osteoarthritis and relevant signaling pathways.

Osteoarthritis (OA) is a common chronic degenerative joint disease in clinical practice with a high prevalence, especially in the elderly. Traditional Chinese Medicine (TCM) believes that OA belongs to the category of "Bi syndrome" and the "bone Bi syndrome". The etiology and pathogenesis lie in the deficiency of the liver and kidney, the deficiency of Qi and blood, and external exposure to wind, cold, and dampness. Epimedium is a yang-reinforcing herb in TCM, which can tonify the liver and kidney, strengthen muscles and bones, dispel wind, cold and dampness, and can treat both the symptoms and the root cause of "bone Bi syndrome". In addition, Epimedium contains a large number of ingredients. Through modern science and technology, more than 270 compounds have been found in Epimedium, among which flavonoids are the main active ingredients. Therefore, our study will review the effects and mechanisms of genus Epimedium in treating OA from two aspects: (1) Introduction of Epimedium and its main active ingredients; (2) Effects of Epimedium and its active ingredients in treating OA and relevant signaling pathways, in order to provide more ideas for OA treatment.

Surface modification techniques of titanium and titanium alloys for biomedical orthopaedics applications: A review.

Biomedical alloys have an important share in orthopedic applications. Among them, titanium and its titanium alloys are widely used as implant materials because of their excellent mechanical properties and non-cytotoxicity. However, its disadvantages such as its biological inertness and poor antibacterial properties inhibit its further development. Therefore, the surface properties of titanium are crucial in the implantation process and determine the success of the implant. The main purpose of this review is to provide a comprehensive and detailed description of the modification techniques used for the surface modification of titanium implants. In this paper, the corresponding technical methods are introduced systematically from four aspects: mechanical method, physical surface modification, chemical surface modification and electrochemical technique to understand the experimental mechanism of each modification technique, and the above methods can indeed improve the various properties of titanium and its alloys. With the increasing demand for implants in the future, the requirements for surface properties will also increase. Therefore, the development of new coating materials with higher performance by combining various advantages of existing modification technologies is the main trend of future research on surface modification of titanium alloys.

Comparison of short-term clinical outcomes between robot-assisted and freehand pedicle screw placement in spine surgery: a meta-analysis and systematic review.

STUDY DESIGN: Meta-analysis and systematic review. BACKGROUND: Robot-assisted pedicle screw placement technique offers greater accuracy than the traditional freehand screw placement technique. However, it is controversial whether there is a difference between the two procedures in terms of improved clinical outcomes. MATERIALS AND METHODS: We systematically searched PubMed, EMBASE, Cochrane, and Web of Science to identify potentially eligible articles. Indispensable data such as the year of publication, study type, age, number of patients, sex distribution, and outcomes were extracted. The outcome indicators of interest included Oswestry disability index (ODI), visual analog scale (VAS) score, operative time, intraoperative blood loss, and post-operative length of stay. RevMan 5.4.1 was used for the meta-analysis. RESULTS: A total of eight studies with 508 participants were included. Eight were related to ΔVAS, six were related to ΔODI, seven were related to operative time, five were related to intraoperative blood loss, and seven were related to the length of hospitalization. The results showed that, in terms of ΔVAS (95% CI, -1.20 to -0.36, P = 0.0003) and ΔODI (95% CI, -2.50 to -0.48, P = 0.004), robot-assisted pedicle screw placement technique scored higher than traditional freehand technique. Additionally, the intraoperative blood loss (95% CI, -140.34 to -10.94, P = 0.02) and the length of hospitalization (95% CI, -2.59 to -0.31, P = 0.01) for patients who underwent robotic-assisted pedicle screw placement were less than that of those who underwent the conventional freehand screw placement. No significant difference was found between robot-assisted techniques and conventional freehand techniques in pedicle screw placement in surgical time (95% CI, -2.24 to 26.32, P = 0.10). CONCLUSIONS: Robot-assisted technique helps improve short-term clinical outcomes, reduce intraoperative blood loss and patient suffering, and shorten recovery time compared to the freehand technique.

Pulse Electromagnetic Field for Treating Postmenopausal Osteoporosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Postmenopausal osteoporosis is a type of chronic disease with high morbidity and high economic burden. Due to the adverse effects of long-term drug therapy, physical therapy, such as pulsed electromagnetic fields (PEMF), is widely implemented in clinical practice. Therefore, we first conducted the meta-analysis on the efficacy and safety of PEMF in the treatment of postmenopausal osteoporosis. We searched eight databases to acquire potentially eligible studies. Outcome indicators include bone mineral density (BMD), visual analogue scale (VAS), biochemical markers of alkaline phosphatase (ALP), osteocalcin, bone-specific alkaline phosphatase (BSAP), type I collagen carboxy-terminal peptide (CTX), and adverse events. The results showed that a total of 19 studies (1303 patients) were retrieved from eight databases. Compared with conventional medications, PEMF combined with conventional medications significantly increased BMD of lumbar vertebra, femoral, Ward's triangle, bone-specific biochemical indicators of ALP, BSAP, and osteocalcin, and relieved pain. However, The incidence of adverse events was not statistically significant between PEMF combined with conventional medications and conventional medications alone. Compared with conventional medications, PEMF significantly increased the BMD of the femur and reduced the degree of pain, but there was no statistical difference in the BMD of the lumbar spine between PEMF and placebo. Except osteocalcin, BSAP, CTX, and ALP showed no significant difference. In view of its efficacy and safety, PEMF intervention can be considered as a potentially effective complementary therapy for postmenopausal women with osteoporosis. © 2022 Bioelectromagnetics Society.

The efficacy of perioperative gabapentin for the treatment of postoperative pain following total knee and hip arthroplasty: a meta-analysis.

BACKGROUND: Postoperative pain after total knee arthroplasty (TKA) and total hip arthroplasty (THA) influence patients' rehabilitation and life quality. Although gabapentin has been widely used for analgesia, its efficacy is still controversial in TKA and THA. This meta-analysis was performed to assess the efficacy and safety of gabapentin following TKA and THA. METHOD: Electronic databases including PubMed, EMBASE, Cochrane Central Register of Controlled Trials, MEDLINE, and ClinicalTrials.gov were comprehensively retrieved for randomized controlled trials from their inception to June 2019. A total of 7 studies, which compared the administration of gabapentin with that of placebo for the treatment of postoperative pain, were included in our meta-analysis. The meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULT: There was no difference in pain score at 24 (P = 0.87), 48 (P = 0.15), and 72 (P = 0.85) h associated with the use of gabapentin. Likewise, no difference in accumulative morphine consumption at 48 h following TKA or THA was found between gabapentin and placebo (DM = - 8.14, 95% CI - 18.55 to 2.28, P = 0.13). The incidence of opioid-related adverse effects, including nausea, pruritus, sedation, and dizziness, is no difference between gabapentin and placebo group. However, subgroup analysis indicated that gabapentin could reduce the incidence of pruritus after TKA (RR = 0.35, 95% CI 0.12 to 0.99, P = 0.05). CONCLUSION: Based on our meta-analysis, gabapentin did not decrease postoperative pain, cumulative morphine consumption, and the incidence of adverse effects after TKA and THA. There was not enough evidence to support the administrations of gabapentin for postoperative pain after TKA and THA.

Correction to: Finite element analysis of two cephalomedullary nails in treatment of elderly reverse obliquity intertrochanteric fractures: zimmer natural nail and proximal femoral nail antirotation-ΙΙ.

In the original publication of this article [1], Chinese text of the Figs. 3, 4, 5 has not been converted to English.

Biomechanical efficacy of four different dual screws fixations in treatment of talus neck fracture: a three-dimensional finite element analysis.

BACKGROUND: Current there are different screws fixation methods used for fixation of the talar neck fracture. However, the best method of screws internal fixation is still controversial. Few relevant studies have focused on this issue, especially by finite element analysis. The purpose of this study was to explore the mechanical stability of dual screws internal fixation methods with different approaches and the best biomechanical environment of the fracture section, so as to provide reliable mechanical evidence for the selection of clinical internal fixation. METHODS: The computed tomography (CT) image of the healthy adult male ankle joint was used for three-dimensional reconstruction of the ankle model. Talus neck fracture and screws were constructed by computer-aided design (CAD). Then, 3D model of talar neck fracture which fixed with antero-posterior (AP) parallel dual screws, antero-posterior (AP) cross dual screws, postero-anterior (PA) parallel dual screws, and postero-anterior (PA) cross dual screws were simulated. Finally, under the condition of 2400N vertical load, finite element analysis (FEA) were carried out to compare the outcome of the four different internal fixation methods. The results of Von Mises stress, displacement of four groups which contain talus fracture fragments and screws internal fixations were analyzed. RESULTS: Compared with the other three groups, postero-anterior (PA) parallel dual screws had better results in the stress peak, stress distribution, and displacement of talus and internal fixation. CONCLUSIONS: To sum up, the Von Mises stress of fracture section was the smallest, the stress distribution of screws were the most scattered, and the peak value was the smallest in posterior to anterior parallel double screws fixation, which was obviously better than that in the other three groups. When using screws internal fixation, the method of posterior to anterior screws fixation is better than that of anterior to posterior screws fixation, and the peak value and stress distribution of parallel double screws fixation is better than that of cross double screws fixation. Thus, for the talar neck fracture, the use of posterior to anterior parallel double screws fixation is recommended in clinical surgery.

Finite element analysis of two cephalomedullary nails in treatment of elderly reverse obliquity intertrochanteric fractures: zimmer natural nail and proximal femoral nail antirotation-ΙΙ.

BACKGROUND: More elderly patients are suffering from intertrochanteric fractures. However, the choice of internal fixation is still controversial, especially in the treatment of unstable intertrochanteric fracture; thus, previous implants continue to be improved, and new ones are being developed. The purpose of our study was to compare the biomechanical advantages between the zimmer natural nail (ZNN) and proximal femoral nail antirotation-II (PFNA-II) in the treatment of elderly reverse obliquity intertrochanteric fractures. METHODS: A three-dimensional finite element was applied for reverse obliquity intertrochanteric fracture models (AO31-A3.1) fixed with the ZNN or PFNA-II. The distribution, peak value and position of the von Mises stress and the displacement were the criteria for comparison between the two groups. RESULTS: The stresses of the internal fixation and femur in the ZNN model were smaller than those in the PFNA-II model, and the peak values of the two groups were 364.8 MPa and 171.8 MPa (ZNN) and 832.3 MPa and 1795.0 MPa (PFNA-II). The maximum amount of displacement of the two groups was similar, and their locations were the same, i.e., in the femoral head vertex (3.768 mm in the ZNN model and 3.713 mm in the PFNA-II model). CONCLUSIONS: The displacement in the two models was similar, but the stresses in the implant and bone were reduced with the ZNN. Therefore, the ZNN implant may provide biomechanical advantages over PFNA-II in reverse obliquity intertrochanteric fractures, as shown through the finite element analysis. These findings from our study may provide a reference for the perioperative selection of internal fixations.

Custom-made Prosthesis for Reconstruction after Radical Resection for Chondrosarcoma of Manubrium.

The clinical incidence of tumors in the manubrium is not high. Regardless of whether the tumor is primary or metastatic, the tumor should be completely removed as long as the patient is able to tolerate the surgery. This procedure can lead to sternal defects. Deciding on the method of defect reconstruction is a critical problem that clinicians face. In this , to reduce the limitations of the patient's upper body movement after surgery due to the inflexibility in the connections of the sternal prosthesis, we created a prosthesis using a computer-assisted design method and a 3-D technique, to completely preserve the agility of the sternum and maximize the patient's post-operational movement. The method used in the present study takes into consideration the individual's chest anatomy, sternum stress, and many other biological characteristics. Care is taken to measure the sternum size accurately, to provide personalized treatment, to accomplish precise results, and to reduce potential future damage. The patient's shoulder function was improved following the procedure.

The efficacy of dexamethasone on pain and recovery after total hip arthroplasty: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Total hip arthroplasty (THA) perioperative dexamethasone treatment is still a controversial subject. We write this systematic review and meta-analysis to evaluate the efficacy of dexamethasone on pain and recovery after THA. METHODS: Two researchers searched the relevant studies from Pubmed, Cochrane, and Embase. The research was reported according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Randomized controlled trials (RCTs) were included in our meta-analysis. At the same time, the assessment of the risk of bias was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions version. The pooled data are processed by software RevMan 5.3. RESULT: In accordance with inclusion and exclusion, 3 studies with 207 patients were eligible and accepted into this meta-analysis. For RCTs, the risk of bias was evaluated by Cochrane Collaboration tool. Only one study did not have detection bias. Our study demonstrated that the dexamethasone group was more effective than the placebo group in term of visual analogue scale (VAS) score at 24 hours (P < .001), 48 hours (P = .04); opioid consumption (P < .001); length of stay (LOS, P < .001); and postoperative nausea (P = .001). CONCLUSION: Dexamethasone not only reduces postoperative pain scores and postoperative opioids consumption within 48 hours, but also reduces postoperative vomiting and effectively reduces LOS. However, we still need large sample size and high quality studies to explore the relationship between complications and dose response to give the final conclusion.

Comparing intramedullary nailing and plate fixation for treating distal tibail fractures: A meta-analysis of randomized controlled trials.

BACKGROUND: Intramedullary nailing (IMN) and plate have been reported as two effective devices for treating distal extra-articular fractures. However, reports of complications after fractures with use of different tibial fixation techniques in literature are controversial. Thus, we performed a meta-analysis of randomized controlled trials (RCTs) to compare IMN with plate for evaluating the safety and efficacy. METHODS: The studies were searched from PubMed, Embase, Web of science and the Cochrane Central Register of Controlled Trials by two reviewers up to August 2017. The quality of RCTs was assessed by Cochrane Handbook. Data were extracted from studies and analyzed by Review Manager 5.3. 95% confidence interval (CI) and risk ratio (RR) were calculated for dichotomous data. RESULTS: Eight RCTs with 482 patients were included in the meta-analysis. We found no statistically significant differences between IMN and plate on union time (SMD = -0.20, 95%CI -0.58 to 0.18, P = 0.3), delayed or nonunion (RR = 1.19, 95%CI 0.66 to 2.14, P = 0.56) and malunion (RR = 1.63, 95%CI 1.01 to 2.65, P = 0.05). IMN group had shorter operative time (P < 0.0001) and radiation time (P < 0.0001), lower incidence of wound complications (P = 0.0003) and higher rate of knee pain (P < 0.0001) than the plate group. CONCLUSION: The meta-analysis showed that intramedullary nailing reduced the time of surgery and radiation and the risk of wound complications compared with plate fixation. Furthermore, union time and union complications were common following both treatments. Overall, intramedullary nailing is found to be taken priority for distal tibial metaphyseal fractures. More RCTs are required to support current evidence.

Bone Microarchitecture and Biomechanics of the Necrotic Femoral Head.

The mechanism behind osteonecrosis of the femoral head (ONFH) remains unclear. The aim of this study was to explore the pathogenesis of ONFH from a biomechanical standpoint to provide a theoretical basis for improved treatments. We compared the bone structure of fractured femoral heads with that of necrotic femoral heads by Micro-CT scanning and histological evaluation. In addition, we compared the biomechanical properties of each zone in fractured femoral heads with those in necrotic femoral heads by using biomechanical tests. Compared with fractured femoral heads, bone microarchitecture and bone morphometry in necrotic zone and sclerotic zone of necrotic femoral heads have altered markedly. In addition, the biomechanical properties of the necrotic zone in femoral heads weaken markedly, while those of the sclerotic zone strengthen. We hypothesize that discordance between bone structure and function of the femoral head may be involved in the pathogenesis of ONFH and that more attention should be paid to the prevention and treatment of such discordance.

TET3 Mediates Alterations in the Epigenetic Marker 5hmC and Akt pathway in Steroid-Associated Osteonecrosis.

Steroid-associated osteonecrosis (SAON) is one of the common complications of clinical glucocorticoid (GC) administration, with osteocyte apoptosis appearing as the primary histopathological lesion. However, the precise mechanism underlying SAON remains unknown. Epigenetic modification may be a major cause of SAON. Recently, cumulative research revealed that Ten-Eleven Translocation (TET) proteins can catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and then alter the epigenetic state of DNA. Here, we report that TET3-5hmC was upregulated in the femoral head tissues of SAON patients and MLO-Y4 cells with dexamethasone (Dex) treatment. Knockdown of TET3 in MLO-Y4 cells decreased 5hmC enrichment and rescued Dex-induced apoptosis. Meanwhile, the local intramedullary injection of TET3 siRNA in Sprague-Dawley rats abrogated GC-induced osteocyte apoptosis, histopathological changes, abnormal MRI signals, and bone microstructure declines in the femoral head in vivo. Moreover, a hydroxymethylated DNA immunoprecipitation (hMeDIP)-chip analysis of Dex-treated osteocytes revealed 456 different 5hmC-enriched genes. The Akt pathway was found to mediate the functional effect of Dex-induced dynamic 5hmC change; this was further verified in clinical samples. The loss of TET3 in MLO-Y4 cells abrogated Dex-induced Akt signaling pathway inhibition. Therefore, our data for the first time identify the effect of TET3-5hmC on the Akt pathway and the necessity of this signaling cascade in SAON, identifying a new potential therapeutic target. © 2016 American Society for Bone and Mineral Research.