Trajectories and prognostic factors for recovery after hip fracture: a longitudinal cohort study.

PURPOSE: The aim of this study was to determine recovery trajectories and prognostic factors for poor recovery in frail and non-frail patients after hip fracture. METHODS: Patients with a hip fracture aged 65 years and older admitted to a hospital in the Netherlands from August 2015 to November 2016 were asked to complete questionnaires at one week and one, three, six, 12, and 24 months after injury. The questionnaires included the ICEpop CAPability measure for older people, Health Utility Index, and the Hospital Anxiety Depression Scale. Latent class trajectory analysis was used to determine trajectories of recovery. Patient and injury characteristics for favourable and unfavourable outcome were compared with logistic regression. RESULTS: In total, 696 patients were included of which 367 (53%) patients were frail. Overall, recovery trajectories in frail patients were worse compared to trajectories in non-frail patients. In frail patients, poor recovery was significantly associated with dementia. Lower age was a prognostic factor for good recovery. Immobility, loneliness and weight loss were prognostic for respectively poor capability and symptoms of anxiety and depression. In non-frail patients, recovery after hip fracture was associated with loneliness and the type of hip fracture. CONCLUSION: Although frailty is associated with poor recovery in older patients with hip fracture, a large proportion of frail patients show good recovery. Loneliness determines poor recovery with anxiety and depressive symptoms. TRAIL REGISTRATION: ClinicalTrials.gov identifier: NCT02508675 (July 27, 2015).

Culturing periprosthetic tissue in blood culture bottles results in isolation of additional microorganisms.

Despite low sensitivity, culture of periprosthetic tissue (PPT) specimens on agars and in broths has traditionally been used for the detection of causative microorganisms in patients suspected for prosthetic joint infection (PJI). The aim of this study was to evaluate the added diagnostic value of culturing PPT in blood culture bottles (BCB) over the conventional combination of standard agar and broth alone. This prospective cohort study was conducted over a 12-month period and included consecutive patients undergoing revision arthroplasty. Overall, 113 episodes from 90 subjects were studied; 45 subjects (50.0%) met the Infectious Diseases Society of America (IDSA) criteria for PJI, of whom the majority (75.6%) had an acute infection. Sensitivity and specificity of culture were assessed using IDSA criteria for PJI as gold standard. Although the increase in sensitivity from 84.44 (CI 70.54; 93.51) to 93.33% (81.73; 98.60) was not significant, added diagnostic value of culturing PPT in BCBs was demonstrated by the significantly higher number of detected pathogens in culture sets with BCBs compared to culture without BCBs (61 pathogens in conventional set versus 89 when BCBs were included for 57 PJI episodes, P = <0.0001). In 17 (29.8%) episodes, microorganisms were cultured from BCBs only, and in 9 (52.9%) of these episodes, virulent pathogens were found. This study demonstrates that PPT culture in BCBs leads to isolation of additional microorganisms, both virulent and low-virulent, which were not cultured with use of agars and broths alone. Isolation of additional causative microorganisms has serious consequences for the treatment strategy in PJI.

Health status after periprosthetic proximal femoral fractures.

Aims: Periprosthetic proximal femoral fractures (PFFs) are a major complication after total hip arthroplasty (THA). Health status after PFF is not specifically investigated. The aim of this study is to evaluate the health status pattern over two years after sustaining a PFF. Methods: A cohort of patients with PFF after THA was derived from the Brabant Injury Outcomes Surveillance (BIOS) study. The BIOS study, a prospective, observational, multicentre follow-up cohort study, was conducted to obtain data by questionnaires pre-injury and at one week, and one, three, six, 12, and 24 months after trauma. Primary outcome measures were the EuroQol five-dimension three-level questionnaire (EQ-5D-3L), the Health Utility Index 2 (HUI2), and the Health Utility Index 3 (HUI3). Secondary outcome measures were general measurements such as duration of hospital stay and mortality. Results: A total of 70 patients with a PFF were included. EQ-5D utility scores were significantly lower on all timepoints except at six months' follow-up compared to pre-injury. EuroQol visual analogue scale (EQ-VAS) scores at one month's follow-up were significantly lower compared to pre-injury. The percentage of reported problems at two years was higher for all dimensions except anxiety/depression when compared to pre-injury. The mean EQ-5D utility score was 0.26 higher in males compared to females (95% confidence interval (CI) 0.01 to 0.42; p = 0.003). The mean EQ-VAS score for males was 8.9 points higher when compared to females over all timepoints (95% CI 1.2 to 16.7; p = 0.027). Mortality was 10% after two years' follow-up. Conclusion: PFF patients are a frail population with substantial functional impairment at baseline. Post-injury, they have a significant and clinically relevant lower health status two years after trauma when compared to pre-injury. Health status improves the most between one and three months after injury. Two years after PFF, more patients experience problems in mobility, self-care, usual activities, and pain/discomfort than pre-injury.

Low-magnitude whole body vibration does not affect bone mass but does affect weight in ovariectomized rats.

Mechanical loading has stimulating effects on bone architecture, which can potentially be used as a therapy for osteoporosis. We investigated the skeletal changes in the tibia of ovariectomized rats during treatment with whole body vibration (WBV). Different low-magnitude WBV treatment protocols were tested in a pilot experiment using ovariectomized rats with loading schemes of 2 × 8 min/day, 5 days/week (n = 2 rats per protocol). Bone volume and architecture were evaluated during a 10 week follow-up using in-vivo microcomputed tomography scanning. The loading protocol in which a 45 Hz sine wave was applied at 2 Hz with an acceleration of 0.5g showed an anabolic effect on bone and was therefore further analyzed in two groups of animals (n = 6 each group) with WBV starting directly after or 3 weeks after ovariectomy and compared to a control (non-WBV) group at 0, 3, 6 and 10 weeks' follow-up. In the follow-up experiment the WBV stimulus did not significantly affect trabecular volume fraction or cortical bone volume in any of the treatment groups during the 10 week follow-up. WBV did reduce weight gain that was induced as a consequence of ovariectomy. We could not demonstrate any significant effects of WBV on bone loss as a consequence of ovariectomy in rats; however, the weight gain that normally results after ovariectomy was partly prevented. Treatment with WBV was not able to prevent bone loss during induced osteoporosis.

Systemic treatment with pulsed electromagnetic fields do not affect bone microarchitecture in osteoporotic rats.

PURPOSE: Pulsed electromagnetic fields (PEMF) are currently used in the treatment of spinal fusions and non-unions. There are indications that PEMF might also be effective in the treatment of osteoporosis. In this study we examined whether whole-body PEMF treatment affects the bone microarchitecture in an osteoporotic rat model. METHODS: Twenty-week-old female rats were ovariectomised (n=20). Four different PEMF treatment protocols based on previous experimental studies and based on clinically used PEMF signals were examined (2 h/day, 5 days/week). A control group did not receive PEMF. At zero, three and six weeks cancellous and cortical bone architectural changes at the proximal tibia were evaluated using in vivo microCT scanning. RESULTS: PEMF treatment did not induce any changes in cancellous or cortical bone compared to untreated controls. CONCLUSIONS: Although previous studies have shown strong effects of PEMF in osteoporosis we were unable to demonstrate this in any of the treatment protocols. Using in vivo microCT scanning we were able to identify small bone changes in time. Subtle differences in the experimental set-up might explain the differences in study outcomes in the literature. Since PEMF treatment is safe, future experimental studies on the effect of PEMF on bone can better be performed directly on humans, eliminating the potential translation issues between animals and humans. In this study we found no support for the use of PEMF in the treatment of osteoporosis.

Stimulation of osteogenic differentiation in human osteoprogenitor cells by pulsed electromagnetic fields: an in vitro study.

BACKGROUND: Although pulsed electromagnetic field (PEMF) stimulation may be clinically beneficial during fracture healing and for a wide range of bone disorders, there is still debate on its working mechanism. Mesenchymal stem cells are likely mediators facilitating the observed clinical effects of PEMF. Here, we performed in vitro experiments to investigate the effect of PEMF stimulation on human bone marrow-derived stromal cell (BMSC) metabolism and, specifically, whether PEMF can stimulate their osteogenic differentiation. METHODS: BMSCs derived from four different donors were cultured in osteogenic medium, with the PEMF treated group being continuously exposed to a 15 Hz, 1 Gauss EM field, consisting of 5-millisecond bursts with 5-microsecond pulses. On culture day 1, 5, 9, and 14, cells were collected for biochemical analysis (DNA amount, alkaline phosphatase activity, calcium deposition), expression of various osteoblast-relevant genes and activation of extracellular signal-regulated kinase (ERK) signaling. Differences between treated and control groups were analyzed using the Wilcoxon signed rank test, and considered significant when p < 0.05. RESULTS: Biochemical analysis revealed significant, differentiation stage-dependent, PEMF-induced differences: PEMF increased mineralization at day 9 and 14, without altering alkaline phosphatase activity. Cell proliferation, as measured by DNA amounts, was not affected by PEMF until day 14. Here, DNA content stagnated in PEMF treated group, resulting in less DNA compared to control.Quantitative RT-PCR revealed that during early culture, up to day 9, PEMF treatment increased mRNA levels of bone morphogenetic protein 2, transforming growth factor-beta 1, osteoprotegerin, matrix metalloproteinase-1 and -3, osteocalcin, and bone sialoprotein. In contrast, receptor activator of NF-κB ligand expression was primarily stimulated on day 14. ERK1/2 phosphorylation was not affected by PEMF stimulation. CONCLUSIONS: PEMF exposure of differentiating human BMSCs enhanced mineralization and seemed to induce differentiation at the expense of proliferation. The osteogenic stimulus of PEMF was confirmed by the up-regulation of several osteogenic marker genes in the PEMF treated group, which preceded the deposition of mineral itself. These findings indicate that PEMF can directly stimulate osteoprogenitor cells towards osteogenic differentiation. This supports the theory that PEMF treatment may recruit these cells to facilitate an osteogenic response in vivo.

Extracorporeal Shock Wave Treatment for Delayed Union and Nonunion Fractures: A Systematic Review.

OBJECTIVES: Nonunions after bone fractures are usually treated surgically with risk of infections and failure of osteosynthesis. A noninvasive alternative is extracorporeal shock wave treatment (ESWT), which potentially stimulates bone regeneration. Therefore this review investigates whether ESWT is an effective and safe treatment for delayed unions and nonunions. DATA SOURCES: Embase.com, MEDLINE ovid, Cochrane, Web of Science, PubMed publisher, and Google Scholar were systematically searched. STUDY SELECTION: Inclusion criteria included studies with patients with delayed union or nonunion treated with ESWT; inclusion of ≥10 patients; and follow-up period ≥6 weeks. DATA EXTRACTION: Assessment for risk of bias was conducted by 2 authors using the Cochrane tool. Union rates and adverse events were extracted from the studies. DATA SYNTHESIS: Two RCTs and 28 nonrandomized studies were included. One RCT was assessed at medium risk of bias and reported similar union rates between ESWT-treated patients (71%) and surgery-treated patients (74%). The remaining 29 studies were at high risk of bias due to poor description of randomization (n = 1), nonrandomized allocation to control groups (n = 2), or absence of control groups (n = 26). The average union rate after ESWT in delayed unions was 86%, in nonunions 73%, and in nonunions after surgery 81%. Only minor adverse events were reported after ESWT. CONCLUSIONS: ESWT seems to be effective for the treatment of delayed unions and nonunions. However, the quality of most studies is poor. Therefore, we strongly encourage conducting well-designed RCTs to prove the effectiveness of ESWT and potentially improve the treatment of nonunions because ESWT might be as effective as surgery but safer. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Effect of unfocused extracorporeal shockwave therapy on bone mineral content of twelve distal forearms of postmenopausal women: a clinical pilot study.

Extracorporeal shockwave therapy showed a pronounced effect on bone mass in previous animal studies. We showed in this pilot study that a single treatment with unfocused shockwave therapy in unselected patients does not show side effects. Although our study did not show any effect of shockwave on BMD, the limited sample size does not definitively exclude this and a study with 174 subjects per group would be needed to show an effect size of 0.3 with a power of 80%. PURPOSE: Unfocused extracorporeal shockwave therapy might stimulate bone formation to reduce the fracture risk. In this study, we assessed the safety of unfocused extracorporeal shockwave therapy and its effects on bone mass. METHODS: A clinical pilot study with twelve female patients free of bone disease undergoing elective surgery of the lower extremity or elective spinal surgery under general anesthesia received 3.000 electrohydraulic-generated unfocused extracorporeal shockwaves (energy flux density 0.3 mJ/mm2) to one distal forearm. The contralateral forearm served as a control. We examined the effect on bone mass with the use of repeated dual energy X-ray absorptiometry measurements and we measured patient discomfort around the therapy. RESULTS: No difference in bone mineral content and density was measured 6 and 12 weeks after therapy. shockwave therapy occasionally caused transient erythema or mild hematoma, but no discomfort in daily life or (late) adverse events. CONCLUSIONS: Unfocused extracorporeal shockwave therapy is a safe treatment, but no increase in bone mass on the forearm was found at 0.3 mJ/mm2 energy flux density. In this study, we were not able to demonstrate that a single treatment with unfocused shockwave therapy in unselected patients had any effect in terms of bone mineral density (BMD) or bone mineral content (BMC). A power analysis indicated that 174 patients per group are required to show an effect size of 0.3 with a power of 80%.

Unfocused shockwaves for osteoinduction in bone substitutes in rat cortical bone defects.

Bone substitutes are frequently used in clinical practice but often exhibit limited osteoinductivity. We hypothesized that unfocused shockwaves enhance the osteoinductivity of bone substitutes and improve osteointegration and angiogenesis. Three different bone substitutes, namely porous tricalcium phosphate, porous hydroxyapatite and porous titanium alloy, were implanted in a critical size (i.e. 6-mm) femoral defect in rats. The femora were treated twice with 1500 shockwaves at 2 and 4 weeks after surgery and compared with non-treated controls. The net volume of de novo bone in the defect was measured by microCT-scanning during 11-weeks follow-up. Bone ingrowth and angiogenesis in the bone substitutes was examined at 5 and 11 weeks using histology. It was shown that hydroxyapatite and titanium both had an increase of bone ingrowth with more bone in the shockwave group compared to the control group, whereas resorption was seen in tricalcium phosphate bone substitutes over time and this was insensitive to shockwave treatment. In conclusion, hydroxyapatite and titanium bone substitutes favour from shockwave treatment, whereas tricalcium phosphate does not. This study shows that osteoinduction and osteointegration of bone substitutes can be influenced with unfocused shockwave therapy, but among other factors depend on the type of bone substitute, likely reflecting its mechanical and biological properties.

Optimization of screw fixation in rat bone with extracorporeal shock waves.

Screw fixation in osteoporotic patients is becoming an increasing problem in orthopaedic surgery as deterioration of cortical and cancellous bone hamper biomechanical stability and screw fixation. This might result in delayed weight-bearing or failure of instrumentation. We hypothesized that local peri-operative shock wave treatment can optimize osseointegration and subsequent screw fixation. In eight female Wistar rats, two cancellous and two cortical bone screws were implanted in both femora and tibiae. Immediately after implantation, 3.000 unfocused extracorporeal shock waves (energy flux density 0.3 mJ/mm2 ) were applied to one side. The other side served as non-treated internal control. Evaluation of osseointegration was performed after 4 weeks with the use of microCT scanning, histology with fluorochrome labeling, and pull-out tests of the screws. Four weeks after extracorporeal shock wave treatment, treated legs exhibited increased bone formation and screw fixation around cortical screws as compared to the control legs. This was corroborated by an increased pull-out of the shock wave treated cortical screws. The cancellous bone screws appeared not to be sensitive for shock wave treatment. Formation of neocortices after shock wave therapy was observed in three of eight animals. Furthermore, de novo bone formation in the bone marrow was observed in some animals. The current study showed bone formation and improved screw fixation as a result of shock wave therapy. New bone was also formed at locations remote from the screws, hence, not contributing to screw fixation. Further, research is warranted to make shock wave therapy tailor-made for fracture fixation. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:76-84, 2018.

Unfocused extracorporeal shock waves induce anabolic effects in osteoporotic rats.

Unfocused extracorporeal shock waves (UESW) have been shown to have an anabolic effect on bone mass. Therefore we investigated the effects of UESW on bone in osteoporotic rats with and without anti-resorptive treatment. Twenty-week-old rats were ovariectomized (n = 27). One group was treated with saline and another group with Alendronate (ALN) 2.4 µg/kg, 3×/week. UESW were applied 2 weeks after ovariectomy. Thousand UESW were applied to one hind leg, the contra-lateral hind leg was not treated and served as control. With the use of in vivo micro-CT scanning it was shown that in saline treated rats trabecular bone volume fraction (BV/TV) was higher at 2 weeks follow-up in UESW treated legs compared to control legs. However, at 4 and 10 weeks no difference was found. In ALN treated animals UESW led to a pronounced anabolic response resulting in an increase in BV/TV at all time-points. Furthermore, UESW resulted in increased cortical volume (CtV), higher trabecular connectivity and, more plate-like and thicker trabeculae. Biomechanical testing showed that UESW lead to a higher maximum force before failure and higher stiffness in all treatment groups. With histology abundant areas of intramembranous bone formation along the periosteal cortex and within the bone marrow were observed. In conclusion this study shows promising results for the use of UESW in the treatment of osteoporosis, especially when this treatment is combined with an anti-resorptive treatment.

Selective laser melting-produced porous titanium scaffolds regenerate bone in critical size cortical bone defects.

Porous titanium scaffolds have good mechanical properties that make them an interesting bone substitute material for large bone defects. These scaffolds can be produced with selective laser melting, which has the advantage of tailoring the structure's architecture. Reducing the strut size reduces the stiffness of the structure and may have a positive effect on bone formation. Two scaffolds with struts of 120-µm (titanium-120) or 230-µm (titanium-230) were studied in a load-bearing critical femoral bone defect in rats. The defect was stabilized with an internal plate and treated with titanium-120, titanium-230, or left empty. In vivo micro-CT scans at 4, 8, and 12 weeks showed more bone in the defects treated with scaffolds. Finally, 18.4 ± 7.1 mm(3) (titanium-120, p = 0.015) and 18.7 ± 8.0 mm(3) (titanium-230, p = 0.012) of bone was formed in those defects, significantly more than in the empty defects (5.8 ± 5.1 mm(3) ). Bending tests on the excised femurs after 12 weeks showed that the fusion strength reached 62% (titanium-120) and 45% (titanium-230) of the intact contralateral femurs, but there was no significant difference between the two scaffolds. This study showed that in addition to adequate mechanical support, porous titanium scaffolds facilitate bone formation, which results in high mechanical integrity of the treated large bone defects.

Unfocused extracorporeal shock wave therapy as potential treatment for osteoporosis.

Extracorporeal shock wave therapy (ESWT) influences the differentiation of bone marrow stroma cells towards osteoprogenitors and increases the expression of several growth factors. To assess whether unfocused ESWT might serve as a treatment for osteoporosis, we examined the bone architecture dynamics of ESWT-treated and untreated rat tibiae using in vivo micro-computed tomography (CT) scanning. In addition, the effects of ESWT on fracture healing, using a bilateral fibula osteotomy, were examined. Unilateral unfocused ESWT with 2,000 pulses and an energy flux density of 0.16 mJ/mm(2) was applied to the hind leg of ovariectomized and sham-ovariectomized rats. A single treatment with unfocused ESWT resulted in a higher trabecular bone volume fraction (BV/TV) in the proximal tibia of the sham-ovariectomized animals. Three weeks after ESWT, BV/TV was 110% of baseline BV/TV in treated legs versus 101% in untreated contralateral control legs (p = 0.001) and 105% of baseline BV/TV versus 95% at 7 weeks after ESWT (p = 0.0004). In ovariectomized rats, shock wave treatment resulted in a diminished bone loss. At 7 weeks, the BV/TV of the treated legs was 50% of baseline BV/TV, whereas in untreated control legs this was 35% (p = 0.0004). ESWT did not influence acute fracture healing. This study shows that bone microarchitecture can be affected by unfocused shock waves, and indicates that unfocused ESWT might be useful for the treatment of osteopenia and osteoporosis.

Chondrogenic priming of human bone marrow stromal cells: a better route to bone repair?

The use of bioengineered cell constructs for the treatment of bone defects has received much attention of late. Often, bone marrow stromal cells (BMSCs) are used that are in vitro-stimulated toward the osteogenic lineage, aiming at intramembranous bone formation. The success of this approach has been disappointing. A major concern with these constructs is core degradation and necrosis caused by lack of vascularization. We hypothesized that stimulation of cells toward the endochondral ossification process would be more successful. In this study, we tested how in vitro priming of human BMSCs (hBMSCs) along osteogenic and chondrogenic lineages influences survival and osteogenesis in vivo. Scaffolds that were pre-cultured on chondrogenic culture medium showed collagen type II and collagen type X production. Moreover, vessel ingrowth was observed. Priming along the osteogenic lineage led to a mineralized matrix of poor quality, with few surviving cells and no vascularization. We further characterized this process in vitro using pellet cultures. In vitro, pellets cultured in chondrogenic medium showed progressive production of collagen type II and collagen type X. In the culture medium of these chondrogenic cultured pellets, vascular endothelial growth factor (VEGF) release was observed at days 14, 21, and 35. When pellets were switched to culture medium containing beta-glycerophosphate, independent of the presence or absence of transforming growth factor beta (TGF-beta), mineralization was observed with a concomitant reduction in VEGF and matrix metalloproteinase (MMP) release. By showing that VEGF and MMPs are produced in chondrogenically differentiated hBMSCs in vitro, we demonstrated that these cells produce factors that are known to be important for the induction of vascularization of the matrix. Inducing mineralization in this endochondral process does, however, severely diminish these capacities. Taken together, these data suggest that optimizing chondrogenic priming of hBMSCs may further improve vessel invasion in bioengineered constructs, thus leading to an alternative and superior approach to bone repair.