Osteoporosis does not affect bone mineral density change in the proximal humerus or the functional outcome after open reduction and internal fixation of unilateral displaced 3- or 4-part fractures at 12-month follow-up.

BACKGROUND: The aim of this prospective study was to investigate bone mineral density (BMD) changes in the proximal humerus of the shoulder during a healing period of 12 months after displaced 3- or 4-part proximal humerus fractures treated with open reduction and internal fixation (ORIF) with an anatomic angular stable locking plate and the influence on fracture healing and functional outcomes. METHODS: In a prospective multicenter study, 36 patients (29F and 7M, age range: 38-83) with unilateral displaced 3- or 4-part proximal humerus fractures were included for ORIF. Dual-energy x-ray absorptiometry for osteoporosis status was employed. Postoperative and 6-week, 3-, 6-, and 12-month shoulder radiographs and dual-energy x-ray absorptiometry of the shoulder with BMD measures in 4 templated regions of interest (ROIs) were performed. Functional outcomes, Western Ontario Osteoarthritis of the Shoulder index, Constant score, visual analog scale pain (VAS), and 36-Item Short Form Survey, were collected. RESULTS: A total of 17 of 36 patients had osteoporosis. We found no differences in BMD changes, functional outcomes, radiology, or need for revision surgery between the osteoporosis and nonosteoporosis groups. The BMD values gradually declined from baseline to 3-month follow-up in all 4 ROIs of the operated shoulders. All 4 ROIs in the operated shoulder presented with a reduction in BMD at 3, 6, and 12 months compared with baseline, whereas no significant BMD changes were seen in the healthy shoulder during the study period. The functional outcomes displayed an increase in Constant score from 3 to 12 months, but a decrease in domains of the 36-Item Short Form Survey from preinjury to 12 months (physical functioning, general health, and bodily pain). Preinjury and 12-month Western Ontario Osteoarthritis of the Shoulder index, VAS pain at rest, and VAS pain at activity were comparable. CONCLUSION: BMD changes appeared swiftly in the proximal humerus, after the treatment of displaced 3- or 4-part fractures with ORIF, particularly affecting the proximal diaphysis of the humerus. Shoulder function was restored to preinjury levels for most of the patients. Osteoporosis may not be regarded as a contraindication for the treatment of displaced 3- or 4-part fractures with ORIF.

The rate of disuse osteopenia in admitted, non-weight-bearing patients.

Disuse osteopenia is a well-recognized consequence of prolonged physical inactivity, but its rate after orthopaedic injuries necessitating non-weight-bearing is not well studied. The purpose of this study was to estimate the rate of disuse osteopenia at the lumbar spine and proximal femur in patients with lower extremity trauma admitted to the hospital. We performed a retrospective chart review of patients with lower extremity trauma with a period of strict non-weight-bearing between completion of two computed tomography (CT) scans. The radiodensity of the proximal femur or lumbar vertebrae was measured from the earliest and latest available CT scans within the non-weight-bearing timeframe. The change in estimated bone mineral density (eBMD) was calculated as a proxy for disuse osteopenia. A total of 189,111 patients were screened, with 17 patients in the proximal femur group and 15 patients in the lumbar spine group meeting inclusion and exclusion criteria. The average rate of change in eBMD of the proximal femur was a decrease of 7.54 HU/day, 95% confidence interval (CI) [3.65, 11.43]. The average rate of change in eBMD of the lumbar spine was an increase of 1.45 HU/day, 95% CI [-3.15, 6.06]. In admitted, non-weight-bearing orthopaedic trauma patients, our novel study suggests that the proximal femur experiences disuse osteopenia during periods of non-weight-bearing, although this finding was not observed at the lumbar spine. The clinical significance of this data underscores the important consideration of disuse osteopenia by all physicians when caring for patients that may require non-weight-bearing restrictions.

Hawkins sign of the knee: Imaging appearance and clinical implication of an unusual pattern of disuse osteopenia.

Disuse osteopenia (DO) is a disorder due to reduced weight-bearing often following immobilization injuries. It is most commonly observed in the ankles and knees and is believed to be due primarily to increased bone reabsorption associated with disuse. Both traditional radiography and magnetic resonance (MR) imaging are useful in identifying abnormalities associated with DO. Specifically, linear subchondral osteopenia has been given the term "Hawkins sign" when seen in the talus, but this finding may also be seen elsewhere. When present, it not only is an indication of DO but also indicates the presence of sufficient vascular flow, and the unlikely development of avascular necrosis. We report a case of Hawkins sign of the knee demonstrated on radiography and MR and demonstrate the clinical importance of recognizing this sign, outside its usual setting, in assessing the prognosis of a healing fracture.

Development of Osteopenia During Distal Radius Fracture Recovery.

Purpose: To determine the degree of disuse osteopenia (DO) and factors associated with its development during treatment of distal radius fractures (DRFs). Methods: We retrospectively reviewed charts and radiographs of patients with DRFs treated with and without surgery at 2 health care systems. We defined DO as a >10% drop from initial to 6-week second metacarpal cortical percentage and 6-week absolute second metacarpal cortical percentage <60%. Bivariate analyses were performed to evaluate associations between treatment type, patient and fracture characteristics, and radiographic measurements with odds of developing DO. Significant associations were included in multivariable analyses, adjusting for patient and fracture characteristics. Results: Approximately 18% of 517 included patients met the criteria for development of DO (n = 93). Bivariate analysis showed that surgical treatment was associated with lower odds of developing DO, whereas advancing age was associated with increased odds. In adjusted multivariable models, only advancing age was associated with increased odds of developing DO. Conclusions: A fairly important proportion of patients with DRF develop hand DO 6 weeks after surgical or nonsurgical treatment. The clinical relevance of this finding is uncertain and requires further investigation. Type of study/level of evidence: Prognostic IV.

The Skeletal Cellular and Molecular Underpinning of the Murine Hindlimb Unloading Model.

Bone adaptation to spaceflight results in bone loss at weight bearing sites following the absence of the stimulus represented by ground force. The rodent hindlimb unloading model was designed to mimic the loss of mechanical loading experienced by astronauts in spaceflight to better understand the mechanisms causing this disuse-induced bone loss. The model has also been largely adopted to study disuse osteopenia and therefore to test drugs for its treatment. Loss of trabecular and cortical bone is observed in long bones of hindlimbs in tail-suspended rodents. Over the years, osteocytes have been shown to play a key role in sensing mechanical stress/stimulus via the ECM-integrin-cytoskeletal axis and to respond to it by regulating different cytokines such as SOST and RANKL. Colder experimental environments (~20-22°C) below thermoneutral temperatures (~28-32°C) exacerbate bone loss. Hence, it is important to consider the role of environmental temperatures on the experimental outcomes. We provide insights into the cellular and molecular pathways that have been shown to play a role in the hindlimb unloading and recommendations to minimize the effects of conditions that we refer to as confounding factors.

MSTN is a key mediator for low-intensity pulsed ultrasound preventing bone loss in hindlimb-suspended rats.

Low-intensity pulsed ultrasound (LIPUS) has been used to accelerate bone fracture healing. However, the issue whether LIPUS is effective in preventing osteoporosis has not been clarified, and if so, what possible mechanisms might be responsible. Myostatin (MSTN) is a negative regulator of muscle growth, and its absence will trigger a positive response to bone. In this study, we examined the effects of LIPUS on bone micro-structure, mechanical properties and damage healing of hindlimb-suspended rats, and investigated whether the inhibition of MSTN plays a role in this process. The rats were randomly divided into four groups: Normal control group (NC), Hind limb suspension group (HLS), Hind limb suspension and 80 mW/cm2 LIPUS irradiation group (HLS+ 80 mW/cm2), Hind limb suspension and 30 mW/cm2 LIPUS irradiation group (HLS+ 30 mW/cm2). The HLS+ 80 mW/cm2 rats were treated with LIPUS (1 MHz, 80 mW/cm2) and the HLS+ 30 mW/cm2 rats were treated with LIPUS (1 MHz, 30 mW/cm2) on the femur for 20 min/day for 28 days. MC3T3-E1 cells were respectively cultured with the serum of wild type mouse and MSTN knockout mouse at 1% concentration for 7 days. After 28 days, LIPUS effectively prevented the destruction of bone microstructure and the decline of mechanical properties, and promoted bone defect healing in the tail-suspended rats. In addition, LIPUS effectively reduced the MSTN content in the quadriceps and serum of the tail-suspended rats, inhibited its receptor and downstream signaling molecules and activated the Wnt signaling pathway in femurs. Growth of MC-3T3-E1 cell cultured with the serum of MSTN knockout mice was superior to that with wild mice serum on day 7. These results indicate that MSTN is a key mediator in LIPUS preventing bone loss caused by hindlimb-suspension.

Targeted silencing of miRNA-132-3p expression rescues disuse osteopenia by promoting mesenchymal stem cell osteogenic differentiation and osteogenesis in mice.

BACKGROUND: Skeletal unloading can induce severe disuse osteopenia that often occurs in spaceflight astronauts or in patients subjected to prolonged bed-rest or immobility. Previously, we revealed a mechano-sensitive factor, miRNA-132-3p, that is closely related to the osteoblast function. The aim of this study was to investigate whether miRNA-132-3p could be an effective target for treating disuse osteopenia. METHODS: The 2D-clinostat device and the hindlimb-unloaded (HU) model were used to copy the mechanical unloading condition at the cellular and animal levels, respectively. Mimics or inhibitors of miRNA-132-3p were used to interfere with the expression of miRNA-132-3p in bone marrow-derived mesenchymal stem cells (BMSCs) in vitro for analyzing the effects on osteogenic differentiation. The special in vivo antagonists of miRNA-132-3p was delivered to the bone formation regions of HU mice for treating disuse osteopenia by a bone-targeted (AspSerSer)6-cationic liposome system. The bone mass, microstructure, and strength of the hindlimb bone tissue were analyzed for evaluating the therapeutic effect in vivo. RESULTS: miRNA-132-3p expression was declined under normal conditions and increased under gravitational mechanical unloading conditions during osteogenic differentiation of BMSCs in vitro. The upregulation of miRNA-132-3p expression resulted in the inhibition of osteogenic differentiation, whereas the downregulation of miRNA-132-3p expression enhanced osteogenic differentiation. The inhibition of miRNA-132-3p expression was able to attenuate the negative effects of mechanical unloading on BMSC osteogenic differentiation. Most importantly, the targeted silencing of miRNA-132-3p expression in the bone tissues could effectively preserve bone mass, microstructure, and strength by promoting osteogenic differentiation and osteogenesis in HU mice. CONCLUSION: The overexpression of miRNA-132-3p induced by mechanical unloading is disadvantageous for BMSC osteogenic differentiation and osteogenesis. Targeted silencing of miRNA-132-3p expression presents a potential therapeutic target for the prevention and treatment of disuse osteoporosis.

Single pulsed electromagnetic field restores bone mass and microarchitecture in denervation/disuse osteopenic mice.

Pulsed electromagnetic fields (PEMFs) have been proposed to treat bone loss. However, time-consuming is the main complaint. A time-saving and effective treatment is of expectation. Previously, we showed a 3 min daily of single pulsed electromagnetic field (SPEMF) accelerated bone formation of long bone defect in mice. Here we compared the effect of SPEMF with PEMF for treating denervation/disuse osteopenic mice. Healthy mice were divided into 3 groups: intact mice (INT), INT + PEMF, and INT + SPEMF. Induced osteopenic mice were divided to osteopenia (IOP), IOP + PEMF, and IOP + SPEMF groups. The PEMF treated groups were subjected to daily 8 h PEMF(15 Hz, 18 G) exposure, while SPEMF treated groups were daily 3 min SPEMF(0.2 Hz, 1 T) exposure. BMD was evaluated every two weeks during the 12 weeks of treatment. Microarchitecture was evaluated on week 12. SPEMF significantly reversed bone loss in IOP mice as early as 6 weeks post-treatment, while PEMF reversed bone loss after 8 weeks. Bone volume was significantly increased in the IOP + PEMF and IOP + SPEMF group. Besides, bone volume and trabecular number of IOP + SPEMF mice were restored to the levels of INT mice in 12 weeks. Our finding suggests SPEMF increased BMD and restored microarchitecture of disuse osteopenic mice to healthy level.

Disuse osteopenia following leg fracture in postmenopausal women: Implications for HIP fracture risk and fracture liaison services.

INTRODUCTION: Disuse osteopenia is a known consequence of reduced weight-bearing and has been demonstrated at the hip following leg injury but has not been specifically studied in postmenopausal women. METHOD: Bilateral DXA (GE Lunar Prodigy) bone mineral density (BMD) measurements were taken at the neck of femur (NOF), total hip region (TH) and lumbar spine in postmenopausal female groups comprising controls (N = 43), new leg fractures (#<3wks) (N = 9), and participants who had sustained a leg fracture more than one year previously (#>1yr) (N = 24). #>1yr were assessed at a single visit and the remaining groups at intervals over twelve months. Weight-bearing, function, 3-day pedometer readings, and pain levels were also recorded. RESULTS: The #<3wks demonstrated significant (p < 0.05) losses in ipsilateral TH BMD at 6 weeks from baseline 0.927 ± 0.137 g/cm2, to 0.916 ± 0.151 g/cm2 improving to 0.946 ± 0.135 g/cm2 (n.s) at 12 months following gradual return to normal function and weight-bearing activity. The #>1yr scored significantly below controls in almost all key physical and functional outcomes demonstrating a long-term deficit in hip bone density on the ipsilateral side. CONCLUSION: The clinical significance of post-fracture reduction in hip BMD is a potential increased risk of hip fracture for a variable period that may be mitigated after return to normal function and weight-bearing. Improvement at 12 months in #<3wks is not consistent with #>1yr results indicating that long-term impairment in function and bone health may persist for some leg fracture patients. Unilateral bone loss could have implications for Fracture Liaison Services when assessing the requirement for medication post fracture.

Dynamic acoustic radiation force retains bone structural and mechanical integrity in a functional disuse osteopenia model.

Disuse osteopenia and bone loss have been extensively reported in long duration space mission and long term bed rest. The pathology of the bone loss is similar to osteoporosis but highly confined to weight bearing bones. The current anabolic and/or anti-resorptive drugs have systemic effects and are costly over extended time, with concerns of long term fracture risk. This study use Low Intensity Pulsed Ultrasound (LIPUS) as a non-invasive acoustic force and anabolic stimulus to countermeasure disuse induced bone loss. Four-month old C57BL/6 mice were randomized into five groups, 1) age-matched (AM), 2) non-suspended sham (NS), 3) non-suspended-LIPUS (NU), 4) suspended sham (SS), and 5) suspended-LIPUS (SU) groups. After four weeks of suspension, µCT analyses showed significant decreases in trabecular bone volume fraction (BV/TV) (-36%, p<0.005), bone tissue mineral density (TMD) (-3%, p<0.05), trabecular thickness (Tb.Th) (-12.5%, p<0.005), and increase in bone surface/bone volume (+BS/BV) (+16%, p<0.005), relative to age-matched (AM). The application of LIPUS for 20 min/day for 5 days/week, significantly increased TMD (+3%, p<0.05), Tb.Th (+6%, p<0.05), and decreased BS/BV (-10%, p<0.005), relative to suspension alone (SS) mice. Histomorphometry analyses showed a breakdown of bone microstructure under disuse conditions consist with µCT results. In comparison to SS mice, LIPUS treated bone showed increased structural integrity with increased bone formation rates at metaphysical endosteal and trabecular surfaces (+0.104±0.07 vs 0.031±0.30 µm(3)/µm(2)/day) relative to SS. Four-point bending mechanical tests of disused SS femurs showed reduced elastic modulus (-53%, p<0.05), yield (-33%, p<0.05) and ultimate strength (-45%, p<0.05) at the femoral diaphysis relative to AM bone. LIPUS stimulation mitigated the adverse effects of disuse on bone elastic modulus (+42%, p<0.05), yield strength (+29%, p<0.05), and ultimate strength (+39%, p<0.05) relative to SS femurs. LIPUS provides the essential mechanical stimulus to retain bone morphological and mechanical integrity in disuse conditions. This study demonstrates LIPUS potential as regional therapeutic agent to countermeasure disuse induced bone loss while maintaining bone's integrity.