Network Meta-Analysis of Pharmacological Agents for Osteoporosis Treatment and Fracture Prevention.

BACKGROUND AND OBJECTIVE: Osteoporosis afflicts a large number of populations in the world and is featured by systemic impairment of bone mass and strength which may further trigger an increase in the risk of fragile fractures. This network meta-analysis (NMA) is designed to distinguish therapies more preferable than others with respect to efficacy and safety. METHODS: We searched the medical literature for relevant studies systematically. Both direct and indirect evidence were synthesized to compare the efficacy, described by odds ratios (OR) and 95% credible intervals (CrI). Moreover, the surface under cumulative ranking curve was calculated to rank probabilities with respect to clinical outcomes. The new non-vertebral fractures, hip and wrist fractures, and adverse events were evaluated in this NMA. RESULTS: Patients treated by alendronate, denosumab, teriparatide were associated with a reduced risk of new non-vertebral fractures compared to those treated by placebo. Alendronate, denosumab and zoledronic acid had better efficacy in preventing hip fractures. With respect to wrist fractures prevention, no significant difference was observed. Zoledronic acid exhibited significantly increased risk of adverse events than placebo, alendronate, denosumab, and raloxifene. According to SUCRA, teriparatide ranked highest in new non-vertebral fractures prevention, etidronate and denosumab balanced safety and efficacy well. CONCLUSION: In summary, teriparatide appeared to be the most efficacious drug for preventing new non-vertebral fractures, while etidronate and denosumab were preferable for balancing safety and efficacy well.

Osteoclast-derived miR-23a-5p-containing exosomes inhibit osteogenic differentiation by regulating Runx2.

BACKGROUND: Some microRNAs (miRNAs) are involved in osteogenic differentiation. In recent years, increasing evidences have revealed that exosomes contain specific miRNAs. However, the effect and mechanism of miR-23a-5p-containing exosomes in osteoblast remain largely unclear. METHODS: We extracted exosomes from RANKL-induced RAW 264.7 cells, and identified exosomes via transmission electron microscopy, western blot and flow cytometry analysis. In addition, exosome secretion was inhibited by GW4869 and Rab27a siRNAs. miR-23a-5p expression was analyzed by qRT-PCR, and the related protein levels were examined by western blot assay. Furthermore, the number and distribution of osteoclasts were detected by TRAP staining, and early osteogenesis was evaluated by ALP staining. Combination of YAP1 and Runx2 was verified by Co-IP assay, and the regulation of miR-23a-5p and Runx2 was measured by dual luciferase reporter assay. RESULTS: We successfully extracted exosomes from RANKL-induced RAW 264.7 cells, and successfully verified exosomes morphology. We also indicated that miR-23a-5p was highly expressed in exosomes from RANKL-induced RAW 264.7 cells, and osteoclast-derived miR-23a-5p-containing exosomes inhibited osteoblast activity, while its inhibition weakened osteoclasts. In mechanism, we demonstrated that Runx2 was a target gene of miR-23a-5p, YAP interacted with Runx2, and YAP or Runx2 inhibited MT1DP expression. In addition, we proved that knockdown of MT1DP facilitated osteogenic differentiation by regulating FoxA1 and Runx2. CONCLUSIONS: We demonstrated that osteoclast-derived miR-23a-5p-containing exosomes could efficiently suppress osteogenic differentiation by inhibiting Runx2 and promoting YAP1-mediated MT1DP. Therefore, we suggested miR-23a-5p in exosomes might provide a novel mechanism for osteoblast function.

Lower-limb valgus deformity associated with developmental hip dysplasia.

BACKGROUND: Treating developmental dysplasia of the hip is often challenging. The difficulties include not only the hip surgery itself but also the treatment of the associated lower-limb valgus deformity. However, there have been very few studies on such deformity in patients with developmental hip dysplasia. In this study, we investigated the prevalence and severity of lower-limb valgus deformity, along with the relationship between the severity of valgus deformity and mechanical alterations of the hip or the ipsilateral knee. METHODS: Two hundred and six affected lower limbs of 116 adult patients with untreated developmental dysplasia of the hip were included in the study, grouped according to the severity of hip dysplasia. Each study participant's radiographs were measured to quantitatively evaluate the mechanical axis deviation of the lower limb, and further to evaluate the prevalence and severity of the lower-limb valgus deformity. Some mechanical alterations of the hip and the ipsilateral knee were also measured on the radiographs. RESULTS: Of the affected lower limbs, 14.1% had valgus deformities. Study participants with Crowe type III hip dysplasia had the most severe deformity and the highest prevalence of deformity. Severity of valgus deformity had a strong positive correlation with the lateral migration of the femoral head but not with the superior migration. A decreased lateral distal femoral angle contributed to the lower-limb valgus deformity, and the lateral distal femoral angle had a strong negative correlation with the severity of valgus deformity. CONCLUSIONS: Hip dysplasia is commonly associated with lower-limb valgus deformity, and the severity of the lower-limb valgus deformity is mostly affected by lateral migration but not superior migration of the femoral head. The valgus deformity may originate mainly in the distal femur, in addition to the hip joint itself. These findings can be taken into account when planning to treat the patients with hip dysplasia.