The use of extracorporeal shock wave therapy for the treatment of bone marrow oedema - a systematic review and meta-analysis.

BACKGROUND: Extracorporeal shock wave therapy (ESWT) has been used for various pathologies associated with bone marrow oedema (BME). However, it is still not clear whether ESWT may be favourable in the treatment of BME. Therefore, the aim of this systematic review was to assess the efficacy of ESWT for the treatment of BME. METHODS: MEDLINE was searched for relevant literature with no time constraints. Both randomized and non-randomized trials were included. Case reports and conference abstracts were excluded. Titles and abstracts were screened and full-text articles of included studies were retrieved. Data on the effect of ESWT on pain, function, and the BME area on magnet resonance imaging were extracted. RESULTS: Pain, function, and magnet resonance imaging results all improved across the studies - regardless of whether it was a randomized or non-randomized study. This effect was consistent across multiple pathologies such as osteonecrosis of the femoral head, BME associated with knee osteoarthritis, Kienböck's disease, and osteitis pubis. The meta-analysis showed that pain (after 1 month: weighted mean difference (WMD) = - 2.23, 95% CI - 2.58 to - 1.88, P < 0.0001; after 3-6 month: WMD = - 1.72, 95% CI - 2.52 to - 0.92, P < 0.00001) and function (after 1 month: WMD = - 1.59, 95% CI - 2.04 to - 1.14, P < 0.0001; after 3-6 month: WMD = - 2.06, 95% CI - 3.16 to - 0.96, P = 0.0002; after ≥ 12 month: WMD = - 1.20, 95% CI - 1.83 to - 0.56, P = 0.0002) was reduced in terms of ESWT treatment compared to a control group. CONCLUSIONS: Based on the available evidence, ESWT may be an adequate option for conservative therapy in pathologies involving BME. TRIAL REGISTRATION: PROSPERO, CRD42021201719 . Registered 23 December 2020.

Prospective biomechanical analysis of donor-site morbidity after fibula free flap.

PURPOSE: The fibula free flap (FFF) is a standard method for osseous reconstruction. The purpose of this study was to investigate functional deficits after harvesting a free fibula flap. MATERIAL AND METHODS: We designed and implemented a prospective clinical cohort study. The study sample consisted of patients undergoing mandible resection and reconstruction with a fibula free flap. The primary endpoint was the time-dependent difference in maximum peak power per body mass (MPP). In addition, balance ability, American Orthopedic Foot and Ankle Society (AOFAS) score, sensory limitations, general surgical complications, and the range of motion were recorded. RESULTS: A total of 27 patients were examined pre- and postoperatively (8 months on average). MPP and balance ability were significantly reduced (p < 0.001) postoperatively. Furthermore, a deficit in dorsal extension and a considerable reduction of the AOFAS score were recorded. For the primary outcome, there were no significant predictors on multivariate analysis. CONCLUSIONS: Our results indicate a postoperative reduction of lower limb performance with a relevant impact on everyday activities, equivalent to the average loss of 7 life years of a healthy, fit individual. However, these data do not challenge the value of this commonly used microvascular graft. Future efforts should focus on the development of strategies to minimize the associated donor-site morbidity.

Prospective biomechanical evaluation of donor site morbidity after radial forearm free flap.

Although the radial forearm free flap (RFF) is a commonly-used microvascular flap for orofacial reconstruction, we are aware of few prospective biomechanical studies of the donor site. We have therefore evaluated the donor site morbidity biomechanically of 30 consecutive RFF for orofacial reconstruction preoperatively and three months postoperatively. This included the Mayo wrist score, the Disabilities of the Arm, Shoulder and Hand (DASH) score, grip strength, followed by tip pinch, key pinch, palmar pinch, and range of movement of the wrist. Primary defects were all closed with local full-thickness skin grafts from the donor site forearm, thereby circumventing the need for a second defect. Postoperative functional results showed that there was a reduction in hand strength measured by (grip strength: -24.1%, in tip pinch: -23.3%, in key pinch: -16.5, and in palmar pinch: -19.3%); and wrist movement measured by extension (active=14.3% / passive= -11.5%) and flexion = -14.8% / -8.9%), and radial (-9.8% / -9.8%) and ulnar (-11.0% / -9.3%) abduction. The Mayo wrist score was reduced by 9.4 points (-12.9%) and the DASH score increased by 16.1 points (+35.5%) compared with the same forearm preoperatively. The local skin graft resulted in a robust wound cover with a good functional result. Our results show that the reduction in hand strength and wrist movement after harvest of a RFF is objectively evaluable, and did not reflect the subjectively noticed extent and restrictions in activities of daily living. Use of a local skin graft avoids a second donor site and the disadvantages of a split-thickness skin graft.

Superior performance of cone beam tomography in detecting a calcaneus fracture.

Cone beam computed tomography is a state-of-the-art imaging tool, initially developed for dental and maxillofacial application. With its high resolution and low radiation dose, cone beam tomography has been expanding its application fields, for example, to diagnosis of traumata and fractures in the head and neck area. In this study, we demonstrate superior and satisfactory performance of cone beam tomography for the imaging of a calcaneus fracture in comparison to conventional X-ray and computed tomography.

Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells.

The cytosolic protein Sharpin is a component of the linear ubiquitin chain assembly complex, which regulates NF-κB signaling in response to specific ligands, such as TNF-α. Its inactivating mutation in chronic proliferative dermatitis mutation (Cpdm) mice causes multiorgan inflammation, yet this phenotype is not transferable into wild-type mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, and that this osteopenia is corrected by Tnf deletion. Because the cellular mechanism underlying this pathology, however, was still undefined, we performed a thorough skeletal phenotyping of Cpdm mice on the basis of nondecalcified histology and cellular and dynamic histomorphometry. We show that the trabecular and cortical osteopenia in Cpdm mice is solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. Consistently, Cpdm primary calvarial cells display reduced osteogenic capacity ex vivo, and the same was observed with CD11b(-) bone marrow cells. Unexpectedly, short-term treatment of these cultures with TNF-α did not reveal an impaired molecular response in the absence of Sharpin. Instead, genome-wide and gene-specific expression analyses revealed that Cpdm mesenchymal cells display increased responsiveness toward TNF-α-induced expression of specific cytokines, such as CXCL5, IL-1ß, and IL-6. Therefore, our data not only demonstrate that the skeletal defects of Cpdm mice are specifically caused by impaired differentiation of osteoprogenitor cells, they also suggest that increased cytokine expression in mesenchymal bone marrow cells contributes to the inflammatory phenotype of Cpdm mice.

The Protein Tyrosine Phosphatase Rptpζ Suppresses Osteosarcoma Development in Trp53-Heterozygous Mice.

Osteosarcoma (OS), a highly aggressive primary bone tumor, belongs to the most common solid tumors in growing children. Since specific molecular targets for OS treatment remain to be identified, surgical resection combined with multimodal (neo-)adjuvant chemotherapy is still the only way to help respective individuals. We have previously identified the protein tyrosine phosphatase Rptpζ as a marker of terminally differentiated osteoblasts, which negatively regulates their proliferation in vitro. Here we have addressed the question if Rptpζ can function as a tumor suppressor protein inhibiting OS development in vivo. We therefore analyzed the skeletal phenotype of mice lacking Ptprz1, the gene encoding Rptpζ on a tumor-prone genetic background, i.e. Trp53-heterozygosity. By screening a large number of 52 week old Trp53-heterozygous mice by contact radiography we found that Ptprz1-deficiency significantly enhanced OS development with 19% of the mice being affected. The tumors in Ptprz1-deficient Trp53-heterozygous mice were present in different locations (spine, long bones, ribs), and their OS nature was confirmed by undecalcified histology. Likewise, cell lines derived from the tumors were able to undergo osteogenic differentiation ex vivo. A comparison between Ptprz1-heterozygous and Ptprz1-deficient cultures further revealed that the latter ones displayed increased proliferation, a higher abundance of tyrosine-phosphorylated proteins and resistance towards the influence of the growth factor Midkine. Our findings underscore the relevance of Rptpζ as an attenuator of proliferation in differentiated osteoblasts and raise the possibility that activating Rptpζ-dependent signaling could specifically target osteoblastic tumor cells.

Metaphyseal bone formation induced by a new injectable ß-TCP-based bone substitute: a controlled study in rabbits.

PURPOSE: Adequate filling of bone defects still poses a challenge in every day clinical work. As many bone defects are irregularly shaped the need for appropriate scaffolds reaching the complete defect surface are great. The purpose of this pre-clinical pilot study was to investigate the handling, biocompatibility, biodegradation and osteoconductivity of a new pasty bone substitute (pure phase ß-TCP, hyaluronic acid, methylcellulose) in bone tissue. METHODS: In an unilateral tibial defect model the peri-implant and bone tissue response to the new pasty bone substitute was tested in New Zealand white rabbits for up to 24 weeks compared to empty controls. Analysis included HR-pQCT scans, histomorphometric evaluation and quantification of vascularization of un-decalcified histological slices. RESULTS: After 1 week the experimental group presented significantly higher new bone volume fraction (p = 0.021) primarily consisting of immature bone matrix and higher vessel density compared to controls (p = 0.013). After 4 weeks bone formation was not significantly different to controls but was distributed more evenly throughout the defect. Bone matrix was now mineralized and trabeculae were thicker than in controls (p = 0.002) indicating faster intramedullary bone maturation. Controls presented extensive periosteal bone formation, major fibrous tissue influx and high vascularization. After 12 and 24 weeks there was no new bone detectable. There were no severe signs of inflammation at all time points. CONCLUSION: The substitute showed an early induction of bone formation. It promoted accelerated intramedullary bone repair and maturation and prevented periosteal bone formation indicating its potential use for reconstructive surgery of bone defects.

Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II.

Mucolipidosis type II (MLII) is a severe multi-systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock-in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro-osteoclastogenic cytokine interleukin-6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature.

Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin.

Although Wnt signaling is considered a key regulatory pathway for bone formation, inactivation of ß-catenin in osteoblasts does not affect their activity but rather causes increased osteoclastogenesis due to insufficient production of osteoprotegerin (Opg). By monitoring the expression pattern of all known genes encoding Wnt receptors in mouse tissues and bone cells we identified Frizzled 8 (Fzd8) as a candidate regulator of bone remodeling. Fzd8-deficient mice displayed osteopenia with normal bone formation and increased osteoclastogenesis, but this phenotype was not associated with impaired Wnt signaling or Opg production by osteoblasts. The deduced direct negative influence of canonical Wnt signaling on osteoclastogenesis was confirmed in vitro and through the generation of mice lacking ß-catenin in the osteoclast lineage. Here, we observed increased bone resorption despite normal Opg production and a resistance to the anti-osteoclastogenic effect of Wnt3a. These results demonstrate that Fzd8 and ß-catenin negatively regulate osteoclast differentiation independent of osteoblasts and that canonical Wnt signaling controls bone resorption by two different mechanisms.

Long-term donor-site morbidity after microsurgical fibular graft: is there a difference between the medial approach and the lateral approach?

PURPOSE: Microvascular fibula harvesting for osseous reconstruction is a valuable aid in maxillofacial surgery. We assessed whether the lateral and the medial harvesting techniques differed with respect to long-term donor-site morbidity. MATERIALS AND METHODS: We conducted a retrospective cohort study of patients who had undergone free fibula harvesting at the University Medical Center Hamburg-Eppendorf, Hamburg, Germany, between 1987 and 2008. The primary predictor variable was the surgical approach. The primary and secondary outcome variables were the American Orthopaedic Foot & Ankle Society score and the result of the Short Form 36 Health Survey on quality of life, respectively. Other variables were age, gender, harvest length, operation time, and specific impairments and surgical complications. Statistical analysis was performed with SPSS, version 14.0 (SPSS, Chicago, IL); P < .05 was considered significant. RESULTS: The 42 patients had a mean age of 55.5 years. The mean follow-up period was 81 months (range, 7-174 months). In the medial group, the mean American Orthopaedic Foot & Ankle Society score was 94.4 points and the total number of impairments was 34, as compared with 85.6 points and 46 impairments, respectively, in the lateral group. This tendency for less morbidity with the medial approach was only found in female patients. The Short Form 36 scores were not statistically different between the 2 surgical approaches. CONCLUSIONS: The medial approach led to less functional impairment of the foot and ankle. Our results support the medial approach as a viable alternative, especially in women, but only in cases when a skin paddle is not necessary.

Comparison of 2D and 3D navigation techniques for percutaneous screw insertion into the scaphoid: results of an experimental cadaver study.

Navigation in hand surgery is still in the process of development. Initial studies have demonstrated the feasibility of 2D and 3D navigation for the palmar approach in scaphoid fractures, but a comparison of the possibilities of 2D and 3D navigation for the dorsal approach is still lacking. The aim of the present work was to test navigation for the dorsal approach in the scaphoid using cadaver bones. After development of a special radiolucent resting splint for the dorsal approach, we performed 2D- and 3D-navigated scaphoid osteosynthesis in 12 fresh-frozen cadaver forearms using a headless compression screw (Synthes). The operation time, radiation time, number of trials for screw insertion, and screw positions were analyzed. In six 2D-navigated screw osteosyntheses, we found two false positions with an average radiation time of 5 ± 2 seconds. Using 3D navigation, we detected one false position. A false position indicates divergence from the ideal line of the axis of the scaphoid but without penetration of the cortex. The initial scan clearly increased overall radiation time in the 3D-navigated group, and for both navigation procedures operating time was longer than in our clinical experience without navigation. Nonetheless, 2D and 3D navigation for non-dislocated scaphoid fractures is feasible, and navigation might reduce the risk of choosing an incorrect screw length, thereby possibly avoiding injury to the subtending cortex. The 3D navigation is more difficult to interpret than 2D fluoroscopic navigation but shows greater precision. Overall, navigation is costly, and the moderate advantages it offers for osteosynthesis of scaphoid fractures must be considered critically in comparisons with conventional operating techniques.

Telomerase-deficient mice exhibit bone loss owing to defects in osteoblasts and increased osteoclastogenesis by inflammatory microenvironment.

Telomere shortening owing to telomerase deficiency leads to accelerated senescence of human skeletal (mesenchymal) stem cells (MSCs) in vitro, whereas overexpression leads to telomere elongation, extended life span, and enhanced bone formation. To study the role of telomere shortening in vivo, we studied the phenotype of telomerase-deficient mice (Terc(-/-)). Terc(-/-) mice exhibited accelerated age-related bone loss starting at 3 months of age and during 12 months of follow-up revealed by dual-energy X-ray absorptiometric (DXA) scanning and by micro-computed tomography (µCT). Bone histomorphometry revealed decreased mineralized surface and bone-formation rate as well as increased osteoclast number and size in Terc(-/-) mice. Also, serum total deoxypyridinoline (tDPD) was increased in Terc(-/-) mice. MSCs and osteoprogenitors isolated from Terc(-/-) mice exhibited intrinsic defects with reduced proliferating cell number and impaired osteogenic differentiation capacity. In addition, the Terc(-/-) -MSC cultures accumulated a larger proportion of senescent ß-galactosidase(+) cells and cells exhibiting DNA damage. Microarray analysis of Terc(-/-) bone revealed significant overexpression of a large number of proinflammatory genes involved in osteoclast (OC) differentiation. Consistently, serum obtained from Terc(-/-) mice enhanced OC formation of wild-type bone marrow cultures. Our data demonstrate two mechanisms for age-related bone loss caused by telomerase deficiency: intrinsic osteoblastic defects and creation of a proinflammatory osteoclast-activating microenvironment. Thus telomerization of MSCs may provide a novel approach for abolishing age-related bone loss.

Factors influencing the accuracy of iliosacral screw placement in trauma patients.

Correct placement of iliosacral screws remains a surgical challenge. The aim of this retrospective study was to identify parameters which impact the accuracy of this technically demanding procedure. Eighty-two patients with vertically unstable pelvic injuries treated with a total of 147 iliosacral screws were included. Assessment of postoperative CT scans revealed screw misplacement in 13 cases (8%), of which six occurred following insertion of two unilateral screws into S1. Six screw misplacements occurred in patients with dislocation injuries of the posterior pelvis. Comparison of a navigated and the standard technique revealed a decreased screw misplacement rate in the navigated group (15% standard vs. 3% navigation, p < 0.05). In addition, the malposition rate was influenced by the surgeon's individual experience (20% for low vs. 3.9% for high volume surgeons, p < 0.05). Overall, the accuracy of iliosacral screw placement depends on the number of screws inserted into S1 and the extent of dislocation. In experienced hands, the use of navigation represents a helpful tool to improve the placement accuracy.

The role of calcitonin and alpha-calcitonin gene-related peptide in bone formation.

The Calca gene encodes two polypeptides, calcitonin (CT) and alpha-calcitonin gene-related peptide (alpha-CGRP), generated through alternative splicing. While CT, a hormone mainly produced by thyroidal C cells, has been described as a major regulator of bone resorption, alpha-CGRP, a neuropeptide expressed in the cells of the central and peripheral nervous system, is mostly known as a regulator of vascular tone. Surprisingly, the generation and skeletal analyses of two mouse deficiency models has recently uncovered a physiological function for both peptides in the regulation of bone formation. In the first model, where the replacement of exons 2-5 of the Calca gene resulted in the combined deficiency of CT and alpha-CGRP, an increased bone formation rate (BFR) was observed, whereas decreased BFR was found in the second model, where the introduction of a translational termination codon into exon 5 of the Calca gene resulted in the specific absence of alpha-CGRP.

Fhl2 deficiency results in osteopenia due to decreased activity of osteoblasts.

Osteoporosis is one of the major health problems today, yet little is known about the loss of bone mass caused by reduced activity of the bone-forming osteoblasts. Here we show that mice deficient for the transcriptional cofactor four and a half LIM domains 2 (Fhl2) exhibit a dramatic decrease of bone mass in both genders. Osteopenia is caused by a reduced bone formation rate that is solely due to the diminished activity of Fhl2-deficient osteoblasts, while their number remains unchanged. The number and activity of the bone-resorbing cells, the osteoclasts, is not altered. Enforced expression of Fhl2 in differentiated osteoblasts boosts mineralization in cell culture and, importantly, enhances bone formation in transgenic animals. Fhl2 increases the transcriptional activity of runt-related transcription factor 2 (Runx2), a key regulator of osteoblast function, and both proteins interact in vitro and in vivo. In summary, we present Fhl2-deficient mice as a unique model for osteopenia due to decreased osteoblast activity. Our data offer a novel concept to fight osteoporosis by modulating the anabolic activity of osteoblasts via Fhl2.

Decreased bone formation and osteopenia in mice lacking alpha-calcitonin gene-related peptide.

UNLABELLED: We recently described an unexpected high bone mass phenotype in mice lacking the Calca gene that encodes CT and alphaCGRP. Here we show that mice specifically lacking alphaCGRP expression display an osteopenia caused by a decreased bone formation. These results show that alphaCGRP is a physiological activator of bone formation and that the high bone mass phenotype of the Calca-deficient mice is caused by the absence of CT. INTRODUCTION: Calcitonin (CT) and alpha-calcitonin gene-related peptide (alphaCGRP) are two polypeptides without completely defined physiologic functions that are both derived from the Calca gene by alternative splicing. We have recently described an unexpected high bone mass phenotype in mice carrying a targeted deletion of the Calca gene. To uncover whether this phenotype is caused by the absence of CT or by the absence of alphaCGRP, we analyzed a mouse model, where the production of alphaCGRP is selectively abolished. MATERIALS AND METHODS: Bones from Calca(-/-) mice, alphaCGRP(-/-) mice, and their corresponding wildtype controls were analyzed using radiography, muCT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring the urinary collagen degradation products. CT expression was determined using radioimmunoassay and RT-PCR. Immunohistochemistry was performed using an anti-CGRP antibody on decalcified bone sections. RESULTS: Unlike the Calca-deficient mice, the alphaCGRP-deficient mice do not display a high bone mass phenotype. In contrast, they develop an osteopenia that is caused by a reduced bone formation rate. Serum levels and thyroid expression of CT are not elevated in alphaCGRP-deficient mice. While CGRP expression is detectable in neuronal cell close to trabecular bone structures, the components of the CGRP receptor are expressed in differentiated osteoblast cultures. CONCLUSION: The discrepancy between the bone phenotypes of Calca(-/-) mice and alphaCGRP(-/-) mice show that the high bone mass phenotype of the Calca(-/-) mice is caused by the absence of CT. The osteopenia observed in the alphaCGRP(-/-) mice that have normal levels of CT further show that alphaCGRP is a physiologic activator of bone formation.

Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene.

Calcitonin (CT) is a known inhibitor of bone resorption. Calcitonin gene-related peptide-alpha (CGRPalpha), produced by alternative RNA processing of the CT/CGRP gene, has no clearly defined role in bone. To better understand the physiologic role of the CT/CGRP gene we created a mouse in which the coding sequences for both CT and CGRPalpha were deleted by homologous recombination. The CT/CGRP(-/-) knockout (KO) mice procreated normally, there were no identifiable developmental defects at birth, and they had normal baseline calcium-related chemistry values. However, KO animals were more responsive to exogenous human parathyroid hormone as evidenced by a greater increase of the serum calcium concentration and urine deoxypyridinoline crosslinks, an effect reversed by CT and mediated by a greater increase in bone resorption than in controls. Surprisingly, KO mice have significantly greater trabecular bone volume and a 1.5- to 2-fold increase in bone formation at 1 and 3 months of age. This effect appears to be mediated by increased bone formation. In addition, KO mice maintain bone mass following ovariectomy, whereas wild-type mice lose approximately one-third of their bone mass over 2 months. These findings argue for dual roles for CT/CGRP gene products: prevention of bone resorption in hypercalcemic states and a regulatory role in bone formation.