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Background Osteoporosis affects elderly patients of both sexes. It is characterized by an increased fracture risk due to defective remodeling of the bone microarchitecture. It affects in particular postmenopausal women due to their decreased levels of estrogen. Preclinical studies with animals demonstrated that loss of estrogen had a negative effect on bone healing and that increasing the estrogen level led to a better bone healing. We asked whether increasing the estrogen level in menopausal patients has a beneficial effect on bone mineral density (BMD) during callus formation after a bone fracture. Methods To investigate whether estrogen has a beneficial effect on callus BMD of postmenopausal patients, we performed a prospective double-blinded randomized study with 76 patients suffering from distal radius fractures. A total of 31 patients (71.13 years ±11.99) were treated with estrogen and 45 patients (75.62 years ±10.47) served as untreated controls. Calculated bone density as well as cortical bone density were determined by peripheral quantitative computed tomography (pQCT) prior to and 6 weeks after the surgery. Comparative measurements were performed at the fractured site and at the corresponding position of the non-fractured arm. Results We found that unlike with preclinical models, bone fracture healing of human patients was not improved in response to estrogen treatment. Furthermore, we observed no dependence between age-dependent bone tissue loss and constant callus formation in the patients . Conclusions Transdermally applied estrogen to postmenopausal women, which results in estrogen levels similar to the systemic level of premenopausal women, has no significant beneficial effect on callus BMD as measured by pQCT, as recently shown in preclinical animal models. Trial registration Low dose estrogen has no significant effect on bone fracture healing measured by pQCT in postmenopausal women, DRKS00019858 . Registered 25th November 2019 - Retrospectively registered. Trial registration number DRKS00019858 .

Summary This randomized and controlled study evaluated the effect of therapy with strontium ranelate on callus formation in wrist fractures and its incidence in wrist recovery. Radiographic healing, progression of clinical recovery, and callus quality with ultrasound were evaluated. No statistically significant benefit of therapy was found. Introduction Fracture prevention is the main goal of any therapy for osteoporosis. Various drugs used in osteoporosis treatment have the theoretical premises to promote fracture healing and osseointegration. In this study, the effect of strontium ranelate on callus formation in wrist fractures was evaluated and whether it could lead to clinically relevant modification of wrist recovery; having strontium ranelate osteoinductive properties, it could be used, if effective, as an adjunct in fracture healing for a faster and functionally better recovery and, at the same time, in starting proper therapy in osteoporotic patients with fragility fractures. Methods We considered only patients older than 60 years who had suffered wrist fracture and received nonoperative treatment with manual reduction of the fracture and cast for 35 days. Forty patients were included and randomly assigned to one of two groups: group A [patients treated with calcium (1200 mg/day) and vitamin D (800 IU/day)] and group B [patients treated with calcium (1200 mg/day) and vitamin D (800 IU/day) associated with strontium ranelate 2 g daily]. Radiographic healing was evaluated through the bone callus formation, cortical continuity, and density of the callus. A clinical evaluation using Castaing’s criteria was carried out 2 and 3 months following the fracture together with an ultrasound study of callus density and vessels. Results A parametric analysis of the X-ray data, clinical evaluation, and ultrasonography results showed that there were no statistically significant differences in the two groups ( p  > 0.05 for all data). Conclusion In analyzing the data obtained, we concluded that strontium ranelate administered in acute phase did not improve nor accelerate wrist fracture healing in our population.

There is an unmet need for improved, clinically relevant methods to longitudinally quantify bone healing during fracture care. Here we develop a smart bone plate to wirelessly monitor healing utilizing electrical impedance spectroscopy (EIS) to provide real-time data on tissue composition within the fracture callus. To validate our technology, we created a 1-mm rabbit tibial defect and fixed the bone with a standard veterinary plate modified with a custom-designed housing that included two impedance sensors capable of wireless transmission. Impedance magnitude and phase measurements were transmitted every 48 h for up to 10 weeks. Bone healing was assessed by X-ray, µCT, and histology. Our results indicated the sensors successfully incorporated into the fracture callus and did not impede repair. Electrical impedance, resistance, and reactance increased steadily from weeks 3 to 7—corresponding to the transition from hematoma to cartilage to bone within the fracture gap—then plateaued as the bone began to consolidate. These three electrical readings significantly correlated with traditional measurements of bone healing and successfully distinguished between union and not-healed fractures, with the strongest relationship found with impedance magnitude. These results suggest that our EIS smart bone plate can provide continuous and highly sensitive quantitative tissue measurements throughout the course of fracture healing to better guide personalized clinical care.

Longitudinal in vivo micro-computed tomography (micro-CT) is of interest to non-invasively capture the healing process of individual animals in preclinical fracture healing studies. However, it is not known whether longitudinal imaging itself has an impact on callus formation and remodeling. In this study, a scan group received weekly micro-CT measurements (week 0–6), whereas controls were only scanned post-operatively and at week 5 and 6. Registration of consecutive scans using a branching scheme (bridged vs. unbridged defect) combined with a two-threshold approach enabled assessment of localized bone turnover and mineralization kinetics relevant for monitoring callus remodeling. Weekly micro-CT application did not significantly change any of the assessed callus parameters in the defect and periosteal volumes. This was supported by histomorphometry showing only small amounts of cartilage residuals in both groups, indicating progression towards the end of the healing period. Also, immunohistochemical staining of Sclerostin, previously associated with mediating adverse radiation effects on bone, did not reveal differences between groups. The established longitudinal in vivo micro-CT-based approach allows monitoring of healing phases in mouse femur defect models without significant effects of anesthesia, handling and radiation on callus properties. Therefore, this study supports application of longitudinal in vivo micro-CT for healing-phase-specific monitoring of fracture repair in mice.

Background Fracture healing is commonly evaluated through physical examination and radiographic results. However, these methods rely on the surgeons’ subjective experience, without including the objective biomechanical properties of the bony callus. This paper presents an innovative method for measuring the callus stiffness in vivo to evaluate fracture healing, further instructing surgeons to remove external fixator safely. Methods A novel dynamic axial load-share ratio (D-LS) index and its associated measuring system was introduced, including the system’s composition (hexapod and insole modules), theoretical model, and method for D-LS measurement. From Jan 2022 to May 2024, 36 patients with tibial shaft fracture treated by Taylor Spatial Frame were evaluated in this prospective study. Once the patient had reached clinical bone healing conditions, the in vivo D-LS measurement was conducted. The patients’ demographic data, clinical outcomes, particularly D-LS value and refracture rate were recorded. Results At a mean follow-up of 16.50 ± 5.79 months, a total of 36 patients completed the final follow-up. Fixators were removed with an average of 24.81 ± 4.51 weeks. The result of hexapod module’s precision examination were maximum errors of 3.72 N, 3.31 N and 2.68 N in x -, y - and z -axis, respectively. The measuring process took an average system installation time of 15.42 ± 4.88 min. Two patients (5.56%) reported fracture site pain. Each patient’s D-LS was determined after three rounds of measurement. The average D-LS value was 15.58 ± 2.77% (range, 9.60–20.52%). None of the 36 patients reported refracture at the last follow-up. Conclusions The novel D-LS measurement system can measure the dynamic forces of lower limb for patients with external fixator in vivo. An objective biomechanical indicator of the regenerate callus was provided by the D-LS. The D-LS measurement is a complement to standard radiological assessment only after radiologically confirmed bone union. Measuring the D-LS in vivo could indicate whether the callus healing is sufficient in external fixation, and 15.6% (average) was recommended as a reference D-LS value for safe fixator removal.

We present a computational model that integrates mechanobiological regulations, angiogenesis simulations and models natural callus development to simulate bone fracture healing in rodents. The model inputs include atomic force microscopy values and micro-computed tomography on the first-day post osteotomy, which, combined with detailed finite element modeling, enables scrutinizing mechanical and biological interactions in early bone healing and throughout the healing process. The model detailed mesenchymal stem cell migration patterns, which are essential for tissue transformation and vascularization during healing, indicating the vital role of blood supply in the healing process. The model predicted bone healing in rodents ( n  = 48) over 21 days, matching daily tissue development with histological evidence. The developed computational model successfully predicts tissue formation rates and stiffness, reflecting physiological callus growth, and offers a method to simulate the healing process, potentially extending to humans in the future.

Background The current mainstay of orthopaedic pain control is opioid analgesics but there are few studies in the literature evaluating the effects of opioids on bone healing. Questions/purposes The purpose of this study was to use a rat fracture model to evaluate the effects of opioid administration on osseous union in the acute (4 weeks) and subacute (8 weeks) setting in an operatively stabilized fracture. We asked the following question: does morphine administration alter (1) fracture callus strength; (2) callus volume and formation; and (3) morphology and early remodeling to final osseous union? Methods A 0.4-mm femoral osteotomy gap was created in 50 Sprague-Dawley rats using an established model. Postoperatively, rats were randomized to control versus morphine-treated study groups. Equal numbers of rats from each group were euthanized at 4 weeks and 8 weeks postoperatively. Three-point bend biomechanical testing was performed to evaluate postoperative callus strength. Micro-CT scans and histological analyses were used to evaluate postoperative callus volume and formation, morphology, and features of early remodeling. Results Biomechanical testing identified a statistically significant (p = 0.048) reduction in callus strength in morphine-treated animals 8 weeks postoperatively compared with controls. Radiographic and histological analysis showed delayed callus maturation and lack of remodeling in the morphine group compared with control animals at 8 weeks. Micro-CT analysis expressed remodeling and resorption as a decrease in callus volume over the two time points. The control group had significant levels of resorption decreasing 29% (p = 0.023) over the 4-week to 8-week time interval. Morphine administration inhibited callus resorption and remodeling with only a 13% decrease (p = 0.393) in callus volume comparing these time points. The callus inhibition associated with morphine administration was not as evident in the acute, 4-week time setting. Conclusions Morphine administration inhibited callus strength in this animal model. This finding is likely consistent with the observation that the callus and healing bone appear to have a decreased rate of maturation and remodeling seen at 8 weeks. Clinical Relevance This study identifies that administration of an opioid pain medication leads to weaker callus and impedes callus maturation compared with controls. These findings may provide the impetus to alter our current orthopaedic analgesic gold standard toward more multimodal and opioid-limiting pain control regimens.

Background Nonsmokers may be affected by environmental tobacco smoke (secondhand smoke), but the effects of such exposure on fracture healing have not been well studied. Questions/purposes To explore the possible effects of passive inhalation of tobacco smoke on the healing of a diaphyseal fracture in femurs of rats. We hypothesized that secondhand exposure to tobacco smoke adversely affects fracture healing. Methods A mid-diaphyseal fracture was created in the femur of 41 female Wistar rats and fixed with an intramedullary metallic pin; 14 rats were excluded (nine for inadequate fractures and five for K wire extrusion). Tobacco exposure was provided by a smoking machine on a daily basis of four cigarettes a day. Each cigarette yielded 10 mg tar and 0.8 mg nicotine, and was puffed by alternating injections of fresh air for 30 seconds and smoke air for 15 seconds. The smoke exposure was previously adjusted to provide serum levels of cotinine similar to human secondhand tobacco exposure. Cotinine is a predominant catabolite of nicotine that is used as a biological biomarker for exposure to tobacco smoke. In one group (n = 11), the animals were intermittently exposed to tobacco smoke before sustaining the fracture but not afterward. In another group (n = 7), the exposure occurred before and after the fracture. The control group (n = 9) was sham-exposed before and after the fracture. We evaluated the specimens 28 days after bone fracture. The callus quality was measured by dual-energy x-ray absorptiometry (bone mineral density [BMD], bone mineral content [BMC], and callus area), μCT (callus volume and woven bone fraction), and mechanical bending (maximum force and stiffness). Results Tobacco exposure resulted in delayed bone callus formation, which is represented by decreased BMD (Control: 0.302 ± 0.008 g/cm 2 vs Preexposed: 0.199 ± 0.008 g/cm 2 and Pre- and Postexposed: 0.146 ± 0.009 g/cm 2 ; mean difference = 0.103 g/cm 2 , 95% CI, 0.094–0.112 g/cm 2 and mean difference = 0.156 g/cm 2 , 95% CI, 0.147–0.167 g/cm 2 ; p < 0.01), BMC (Control: 0.133 ± 0.005 g vs Preexposed: 0.085 ± 0.0034 g and Pre- and Postexposed: 0.048 ± 0.003 g; mean difference = 0.048 g, 95% CI, 0.045–0.052 g and mean difference = 0.085 g, 95% CI, 0.088–0.090 g; p < 0.01), callus volume (Control: 7.656 ± 1.963 mm 3 vs Preexposed: 17.952 ± 1.600 mm 3 and Pre- and Postexposed: 40.410 ± 3.340 mm 3 ; mean difference = −10.30 mm 3 , 95% CI, −14.12 to 6.471 mm 3 and mean difference, −32.75 mm 3 , 95% CI, −36.58 to 28.93 mm 3 ; p < 0.01), woven bone fraction (Control: 42.076 ± 3.877% vs Preexposed: 16.655 ± 3.021% and Pre- and Postexposed: 8.015 ± 1.565%, mean difference = 0.103%, 95% CI, 0.094–0.112% and mean difference = 0.156%, 95% CI, 0.147–0.166%; p < 0.01), maximum force (Control: 427.122 ± 63.952 N.mm vs Preexposed: 149.230 ± 67.189 N.mm and Pre- and Postexposed: 123.130 ± 38.206 N.mm, mean difference = 277.9 N.mm, 95% CI, 201.1–354.7 N.mm and mean difference = 304 N.mm, 95% CI, 213.2–394.8 N.mm; p < 0.01) and stiffness (Control: 491.397 ± 96.444 N.mm/mm vs Preexposed: 73.157 ± 36.511 N.mm/mm and Pre- and Postexposed: 154.049 ± 134.939 N.mm/mm, mean difference = 418.2 N.mm/mm, 95% CI, 306.3–530.1 N.mm/mm and mean difference = 337.3 N.mm/mm, 95% CI, 188.8–485.9 N.mm/mm; p < 0. 01). Conclusions Rats exposed to tobacco smoke showed delayed fracture healing and callus that was characterized by decreased maturity, density, and mechanical resistance, which was confirmed by all assessment methods of this study. Such effects were more evident when animals were exposed to tobacco smoke before and after the fracture. Future studies should be done in human passive smokers to confirm or refute our findings on fracture callus formation. Clinical Relevance The potential hazardous effects of secondhand smoke on fracture healing in rodents should stimulate future clinical studies in human passive smokers.

Collagen is a ubiquitous protein present in regenerating bone tissues that experiences multiple biological phenomena during distraction osteogenesis until the deposition of phosphate crystals. This work combines fluorescence techniques and mathematical modeling to shed light on the mechano-structural processes behind the maturation and accommodation-to-mineralization of the callus tissue. Ovine metatarsal bone calluses were analyzed through confocal images at different stages of the early distraction osteogenesis process, quantifying the fiber orientation distribution and mean intensity as fiber density measure. Likewise, a mathematical model based on the experimental data was defined to micromechanically characterize the apparent stiffening of the tissue within the distracted callus. A reorganization of the fibers around the distraction axis and increased fiber density were found as the bone fragments were gradually separated. Given the degree of significance between the mathematical model and previous in vivo data, reorganization, densification, and bundle maturation phenomena seem to explain the apparent mechanical maturation observed in the tissue theoretically.

SummaryOvariectomized (OVX) rats with type 2 diabetes mellitus (T2DM) with femur fracture received vehicle, insulin, or insulin plus parathyroid hormone (PTH) treatment for 2 and 3 weeks. Radiography, histomorphometry, histology, and immunohistochemistry in callus were evaluated.IntroductionReports about effects of PTH plus insulin on callus formation of osteoporotic fracture with T2DM were limited. This study was designed to investigate the effects of the combination of PTH and insulin on fracture healing in OVX rats with T2DM.MethodsTwo-month-old female rats were randomly divided into five groups: normal fracture (F), OVX fracture (OF), T2DM + OVX fracture (DOF), insulin-treated (2–4 u/daylight, 4–6 u/night, DOFI), and treated with insulin and PTH (50 μg/kg/day, 5 days/week, DOFIP). A closed mid-shaft fracture was established in the right femurs of all rats after 6 weeks of OVX. Rats were euthanized at 2 and 3 weeks post-fracture according to the time schedule, respectively.ResultsThe administration of insulin alone or insulin combined with PTH significantly increased mineralized bone volume fraction (BV/TV) and connectivity density (Conn.D) compared with those of the DOF group at 3 weeks post-fracture and also increased cartilaginous callus area ratio in the DOFI and DOFIP groups at 2 weeks and bony callus area ratio in the DOFIP groups at both the 2 and 3 weeks post-fracture.ConclusionsOVX rats with T2DM exhibited a marked delay in the fracture healing process; insulin treatment ameliorated these effects, and the healing process was enhanced following treatment with a combination of insulin and PTH.