Osteolysis is an osteolytic lesion featured by enhanced osteoclast formation and potent bone erosion. Lacking of effective regimen for treatment of the pathological process highlights the importance of identifying agents that can suppress the differentiation and function of osteoclast. Artemether is a natural compound derived from Artemisia annua L. and it is popularized for the treatment of malaria. In present study, we demonstrated that artemether could suppress RANKL-induced osteoclastogenesis and expression of osteoclast marker genes such as tartrate-resistant acid phosphatase, cathepsin K, matrix metalloproteinase 9, nuclear factor of activated T-cell cytoplasmic 1, and dendritic cell-specific transmembrane protein. It inhibited the osteoclastic bone resorption in a dose-dependent manner in vitro. Furthermore, artemether attenuated RANKL-induced MAPKs (ERK, JNK, p-38) activity. In addition, we have showed that artemether was able to mitigate bone erosion in a murine model of LPS-induced inflammatory bone loss. Taken together, these findings suggest that artemether reduces inflammatory bone loss via inhibition of MAPKs activation during osteoclast differentiation, and it might be a potential candidate for the treatment of osteoclast-related disorders.

Although antibiotic-loaded bone cement (ALBC) is used as a drug delivery vehicle to decrease infection rates, the varied clinical effect of the antibiotic release remains controversial. The objective of this study is to investigate the enhancement of continuous wave ultrasound (CWU) on vancomycin release and antimicrobial efficacy of ALBC in vitro and in vivo. We measured vancomycin concentrations after a 0.5-h exposure of CWU. The results showed that CWU increased the drug elution by 2.57-27.44% when compared with the controls in vitro. Ultrasonic intensity and vancomycin load both had a significant effect on the cumulative drug elution at 10.5 h, with a significant interaction between each other. We also implanted ALBC specimens into hip joints of sixteen New Zealand White female rabbits after inoculations of Staphylococcus aureus around primary implants for 30 days. Vancomycin concentrations in the hip cavity and urinary elimination of vancomycin were both measured after intermittent exposures of CWU. The results showed that CWU increased local Tmax by 47.6 microg/mL and urinary elimination of vancomycin by 109.56 microg, but failed to prolong local T>MIC. On day 30 after the implantation, assessment in clinical performance, radiology, bacteriology, and histology all showed a tendency of decreased bacterial vitality and relieved inflammation in the infected hip treated by CWU. This study suggested that CWU could effectively enhance vancomycin release and antimicrobial efficacy of ALBC, which may be of clinical significance for treating prosthesis-related infections.

This study sought to investigate the effect of delayed pulsed-wave ultrasound with low frequency on drug release from and the antimicrobial efficacy of vancomycin-loaded acrylic bone cement in vivo and the possible mechanism of this effect. After the implantation of cement and the inoculation of Staphylococcus aureus into the bilateral hips of rabbits, ultrasound (average intensity, 300 mW/cm 2 ; frequency, 46.5 kHz; on/off ratio, 20 min/10 min) was applied to animals in the normal ultrasound group (UG 0-12 ) from 0 through 12 h after surgery and to those in the delayed-ultrasound group (UG 12-24 ) from 12 through 24 h after surgery. The control group (CG) was not exposed to ultrasound. Based on vancomycin concentrations in left hip cavities at projected time intervals, the amount of time during which the local drug concentration exceeded the MIC (T >MIC ) in UG 12-24 was significantly prolonged compared with that in either CG or UG 0-12 , and the ratios between the areas under the concentration-time curves over 24 h and the MIC for UG 0-12 and UG 12-24 were both increased compared with that for CG. The greatest reductions in bacterial densities in both right hip aspirates and right femoral tissues at 48 h were achieved with UG 12-24 . Local hemorrhage in rabbits of UG 0-12 during the 12-h insonation was more severe than that in rabbits of UG 12-24 . Of four variables, the T >MIC and the bioacoustic effect were both identified as parameters predictive of the enhancement of the antimicrobial efficacy of cement by ultrasound. Sustained concentrations above the MIC replaced early high maximum concentrations and long-term subtherapeutic release of the drug, provided that ultrasound was not applied until local hemorrhage was relieved. The enhancement of the antimicrobial efficacy of cement by ultrasound may be attributed to the prolonged T >MIC and the bioacoustic effect caused by ultrasound.Of the patients worldwide undergoing total joint replacement per year, approximately 0.3 to 2.2% develop prosthesis-related infections resulting in devastating surgical failure (23,25). Antibiotic-loaded bone cement is the treatment of choice because of its high local dose and low systemic toxicity compared with those of intravenous antibiotics (23,25). However, it is sometimes deficient in antimicrobial efficacy (21). Many authors have attributed this defect to the incomplete release of the antibiotic from the cement (4,5,6,8,20,23,24). The matrix of polymethylmethacrylate is, to a large extent, impermeable to antibiotics. Not only is the bioavailability of the antibiotic decreased, but the prolonged exposure to the antibiotic also allows selective bacterial resistance to occur (20).Recently, low-frequency ultrasound has been found to enhance the release of gentamicin from cement (4, 8). Two possible mechanisms behind this phenomenon include acoustic streaming and an accelerated rate of mass transfer as a result of stable cavitation and the ultrasonic pressure wave. Also, such enhanced release of gentamicin may contribute to a d...

BackgroundTo examine whole-body vibration (WBV) effect on bone mineral density (BMD) and fall prevention in postmenopausal women, we performed a meta-analysis and systematic review of prospective randomized controlled trials (RCTs) comparing change in BMD of the femoral neck and lumbar spine and related factors of falls between WBV group and control group.MethodsEMBASE, PubMed, Cochrane Central Register of Controlled Trials, ISI Web of Science, and China National Knowledge Infrastructure (CNKI) were searched up to April 2015; search strategy was used as follows: (vibration) AND (osteoporo* OR muscle* OR bone mineral density OR BMD). All prospective randomized controlled trials comparing related factors of falls and BMD change in the femoral neck and lumbar spine between WBV group and control group were retrieved.ResultsEight of 3599 studies with 1014 patients were included, 477 in the WBV group, and 537 in the control group. We found that there was no significant difference in all magnitude groups of the femoral neck (N = 936, WMD: 0.00 (–0.00, 0.01); p = 0.18). A statistical significance showed in the all magnitude groups (N = 1014, WMD: 0.01 (0.00, 0.01); p = 0.01) and low-magnitude group (N = 838, WMD: 0.01 (0.00, 0.01); p = 0.007) of the lumbar spine. No significant difference was found in high-magnitude group of the lumbar spine (N = 176, WMD: 0.00 (−0.01, 0.02); p = 0.47), low-magnitude group (N = 838, WMD: 0.00 (−0.00, 0.00); p = 0.92) and high-magnitude group (N = 98, WMD: 0.02 (−0.00, 0.05); p = 0.06) of the femoral neck. All the studies provided data of related factors of falls such as strength of the lower limb, balance, and fall rate reported effectiveness of WBV therapy. In addition, no complication was reported.ConclusionsLow-magnitude whole-body vibration therapy can provide a significant improvement in reducing bone loss in the lumbar spine in postmenopausal women. Moreover, whole-body vibration can be used as an intervention for fall prevention.

Postmenopausal osteoporosis is initiated by estrogen withdrawal and is characterized mainly by over‐activated osteoclastic bone resorption. Targeting TNF receptor‐associated factor 6 (TRAF6) or its downstream signaling pathways to modulate osteoclast formation and function is an appealing strategy for osteoclast‐related disorders. In the present study, we determined the effect of tomatidine, a steroidal alkaloid derived from Solanaceae, on the formation and function of receptor activator of NF‐κB (RANK) ligand‐induced osteoclasts and the underlying mechanism. Tomatidine inhibited osteoclast formation in a dose‐dependent manner and decreased the expression of osteoclast marker genes. Actin ring formation and osteoclastic bone resorption were attenuated in the presence of tomatidine in vitro. Eight weeks after ovariectomy, tomatidine prevented estrogen deficiency‐induced bone loss and restored the mechanical properties of the femur. At the molecular level, tomatidine abrogated phosphorylation of c‐Jun N‐terminal kinase (JNK)/p38, NF‐κB, and protein kinase B (Akt) pathway proteins by suppressing RANK expression, inhibiting the binding of TRAF6 to RANK, and downregulating the osteoclastogenesis marker‐related protein expression. In summary, these data demonstrated that tomatidine attenuated osteoclast formation and function by modulating multiple TRAF6‐mediated pathways. Therefore, tomatidine could be a novel candidate for the treatment of osteoclast‐related disorders, including osteoporosis.—Hu, B., Sun, X., Yang, Y., Ying, Z., Meng, J., Zhou, C., Jiang, G., Li, S., Wu, F., Zhao, X., Zhu, H., Wu, H., Cai, X., Shi, Z., Yan, S. Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency‐induced bone mass loss by modulating TRAF6‐mediated signaling. FASEB J. 33,2574–2586 (2019). http://www.fasebj.org