Context: Established bone turnover markers do not reflect fracture risk in idiopathic male and premenopausal osteoporosis and the role of microRNAs (miRNAs) in these patients is currently unclear. miRNAs are a class of small non-coding RNAs that regulate gene expression and bone tissue homeostasis. They are considered a new class of endocrine regulators with promising potential as biomarkers. Objective: Evaluation of circulating miRNA signatures in male and female subjects with idiopathic and postmenopausal osteoporotic low-traumatic fractures. Design, Setting, and Patients: This was a case-control study of cross-sectional design of 36 patients with prevalent low-traumatic fractures and 39 control subjects Main Outcome Measures: One hundred eighty-seven miRNAs were quantified in serum by qPCR, compared between groups and correlated with established bone turnover markers. Results: Significant differences in serum levels of circulating miRNAs were identified in all three subgroups (46 in premenopausal, 52 in postmenopausal, 55 in male). A set of 19 miRNAs was consistently regulated in all three subgroups. Eight miRNAs [miR-152-3p, miR-30e-5p, miR-140-5p, miR-324-3p, miR-19b-3p, miR-335-5p, miR-19a-3p, miR-550a-3p] were excellent discriminators of patients with low-traumatic fractures, regardless of age and sex, with area under the curve values > 0.9. The 11 remaining miRNAs showed area under the curve values between 0.81 and 0.89. Correlation analysis identified significant correlations between miR-29b-3p and P1NP, and miR-365-5p and iPTH, TRAP5b, P1NP and Osteocalcin, as well as BMDL1–L4 and miR-19b-3p, miR-324-3p, miR-532-5p, and miR-93-5p. Conclusions: Specific serum miRNA profiles are strongly related to bone pathologies. Therefore miRNAs might be directly linked to bone tissue homeostasis. In particular, miR-29b-3p has previously been reported as regulator of osteogenic differentiation and could serve as a novel marker of bone turnover in osteoporotic patients as a member of a miRNA signature.

The assessment of bone quality and the prediction of fracture risk in idiopathic osteoporosis (IOP) are complex prospects as bone mineral density (BMD) and bone turnover markers (BTM) do not indicate fracture-risk. MicroRNAs (miRNAs) are promising new biomarkers for bone diseases, but the current understanding of the biological information contained in the variability of miRNAs is limited. Here, we investigated the association between serum-levels of 19 miRNA biomarkers of idiopathic osteoporosis to bone microstructure and bone histomorphometry based upon bone biopsies and µCT (9.3 μm) scans from 36 patients. Four miRNAs were found to be correlated to bone microarchitecture and seven miRNAs to dynamic histomorphometry (p < 0.05). Three miRNAs, namely, miR-29b-3p, miR-324-3p, and miR-550a-3p showed significant correlations to histomorphometric parameters of bone formation as well as microstructure parameters. miR-29b-3p and miR-324-p were found to be reduced in patients undergoing anti-resorptive therapy. This is the first study to report that serum levels of bone-related miRNAs might be surrogates of dynamic histomorphometry and potentially reveal changes in bone microstructure. Although these findings enhance the potential value of circulating miRNAs as bone biomarkers, further experimental studies are required to qualify the clinical utility of miRNAs to reflect dynamic changes in bone formation and microstructure.

Extracorporeal shockwave therapy is a treatment modality, originally introduced into the clinic as lithotripsie, which has also been successfully used in the last two decades in the non-invasive treatment of delayed or non-healing fractures. Initially, the mechanism of action was attributed to microfracture-induced repair, but intensive basic research has now shown that the shockwave generates its effect in tissue via mechanotransduction. Numerous signal transduction pathways have already been demonstrated, which in their entirety trigger an endogenous regeneration process via cell proliferation, migration and differentiation. Clinically, these shockwave-conveyed biological signals support healing of acute, delayed and non-union fractures. The attainable outcome is comparable to surgery but avoiding an open approach with associated potential complications. These advantageous properties with a clearly positive cost-benefit ratio make shockwave therapy a first line treatment in delayed and non-union fractures.

Background: Zoledronic acid improves bone microarchitecture and biomechanical properties after chronic rotator cuff repair (RCR) in rats. Besides the positive effects of zoledronic acid on bone mineral density and bone microarchitecture, bisphosphonates have positive effects on skeletal muscle function. Purposes/Hypothesis: The purposes of this study were to (1) longitudinally evaluate circulating bone- and muscle-specific serum micro-ribonucleic acids (miRNAs) and (2) investigate supraspinatus muscle tissue after tenotomy and delayed RCR in a rat model. It was hypothesized that zoledronic acid would improve muscle regeneration after chronic RCR in rats. Study design: Controlled laboratory study. Methods: A total of 34 male Sprague-Dawley rats underwent unilateral (left) supraspinatus tenotomy (time point 1) with delayed transosseous RCR after 3 weeks (time point 2). All rats were sacrificed 8 weeks after RCR (time point 3). Animals were randomly assigned to 2 groups. One day after RCR, the control group was given 1 mL of subcutaneous saline solution, and the intervention group was treated with a subcutaneous single-dose of 100 µg/kg body weight of zoledronic acid. All 34 study animals underwent miRNA analysis at all 3 time points. In 4 animals of each group, histological analyses as well as gene expression analyses were conducted. Results: Circulating miRNAs showed significantly different expressions between both study groups. In the control group, a significant downregulation was observed for muscle-specific miR-1-3p ( P = .004), miR-133a-3p ( P < .001), and miR-133b ( P < .001). Histological analyses showed significantly higher rates of regenerating myofibers on the operated side (left) of both study groups compared with the nonoperated side (right; P = .002). On the nonoperated side, significantly higher rates of regenerating myofibers were observed in the intervention group compared with the control group ( P = .031). The myofiber cross-sectional area revealed significantly smaller myofibers on both sides within the intervention group compared with both sides of the control group ( P < .001). Within the intervention group, significantly higher expression levels of muscle development/regeneration marker genes embryonal Myosin heavy chain ( P = .017) and neonatal Myosin heavy chain ( P = .016) were observed on the nonoperated side compared with the operated side. Conclusion: An adjuvant single-dose of zoledronic acid after RCR in a chronic defect model in rats led to significant differences in bone- and muscle-specific miRNA levels. Therefore, miR-1-3p, miR-133a-3p, and miR-133b might be used as biomarkers for muscle regeneration after RCR. Clinical Relevance: Adjuvant treatment with zoledronic acid may improve muscle regeneration after chronic RCR in humans, thus counteracting fatty muscle infiltration and atrophy.