In-hospital mortality of pelvic ring fractures in older adults now and then: A pelvic registry study.

AIM: With the predicted demographic change, the treatment of geriatric patients will become a major issue for health systems worldwide. The majority of pelvic ring fractures occur in older adults, and their treatment might be associated with a distinct mortality. Herein, we analyzed the data of 5665 patients with pelvic ring fractures aged ≥60 years included in the German Pelvic Trauma Registry from 1991 to 2013. METHODS: The data were collected prospectively, multicentrically in hospitals participating in the German Pelvic Trauma Registry. Demographic data were retrospectively analyzed, stratified for age, sex, type of injury, mode of therapy, injury severity score (ISS) and mortality. RESULTS: The overall mortality decreased over the 22-year study period from 9.3% to 3.8% (P < 0.05), whereas the median ISS significantly increased. During the observation period, mortality was higher in patients with type B and, particularly, type C fractures when compared with patients with type A fractures. Mortality rates of patients aged >80 years did not significantly differ from those aged >60 or >70 years. Male patients showed a significantly higher mortality compared with female patients, as well as a significantly higher median ISS. The mortality rate of patients with surgically-treated type C fractures decreased over the study period from 35.7% to 6.9% (P < 0.05). CONCLUSIONS: Over the past two decades, the mortality of older patients after pelvic ring fractures has significantly decreased. The higher overall mortality rate of male patients might mainly be accounted for by the relatively higher fraction of type C fractures and a higher ISS. Geriatr Gerontol Int 2019; 19: 24-29.

Pelvic ring fractures in the elderly now and then - a pelvic registry study.

OBJECTIVES: To analyze the changes in demographic data stratified for age, sex and type of injury of elderly patients suffering from pelvic ring fractures over a 22-year observation period. DESIGN/SETTING: Data has been collected prospectively, multi-centrically in hospitals participating in the German Pelvic Trauma Registry. PATIENTS: We analyzed the data of 5665 patients with an age ≥60years included in the German Pelvic Trauma Registry from 1991 to 2013. KEY RESULTS: Over the 22-year study period the frequency of type A fractures decreased significantly from 84.8% to 43.9%, while type C and, in particular, type B fractures significantly increased from 7.0% and 8.2% to 14.3% and 41.8%. In patients between 60 and 70 years of age the frequency of type B and C fractures was higher compared to patients >70years. The proportion of female patients, who represent the majority of the cohort (75%), was stable over the entire observation period. Interestingly, type A fractures were found more frequently in females, while type B and C fractures were found more frequently in males. CONCLUSIONS: With the predicted demographic change and a shift toward more severe injury patterns (type B and C pelvic fractures) in the elderly population, trauma departments will need to develop specific surgical concepts for geriatric patients with pelvic ring fractures.

Surgical treatment of pelvic ring fractures in the elderly now and then: a pelvic registry study.

BACKGROUND: With the demographic change, the treatment of elderly patients has become a major issue for health systems worldwide. AIMS: The aim of this study was to analyze the change in the rate of surgical treatment of pelvic ring fractures in patients with an age of ≥60 years over a 22-year period depending on fracture type, age and sex. METHODS: Data of 5665 patients with an age of ≥60 years, who were treated for pelvic ring fractures from 1991 to 2013 in one of 31 hospitals participating in the German Pelvic Trauma Registry, were included. The registry is divided into four time periods: t 1 = 1991-1993, t 2 = 1997-2000, t 3 = 2001-2008 and t 4 = 2009-2013. Data had been collected prospectively and was analyzed retrospectively, stratified for age and sex of the patients as well as type of fracture and mode of therapy (surgical vs. conservative). RESULTS: There was a significant increase (p < 0.05) in the overall rate of surgical treatment. Nonetheless, during all time periods patients with an age of >70 years were significantly less frequently surgically treated compared to 60- to 70-year-olds. Regardless of the fracture type, the rate of surgical treatment was significantly higher (p < 0.05) in male compared to female patients during t 1. While this difference persisted for type A and type B fractures, the frequency of surgical treatment of type C fractures approximated in males and females. CONCLUSIONS: The present data indicate that the rate of surgical treatment of pelvic ring fractures in elderly patients has significantly increased over the 22-year period. Nonetheless, older patients (>70 years) as well as female patients are still less frequently surgically treated.

A novel tool for continuous fracture aftercare - Clinical feasibility and first results of a new telemetric gait analysis insole.

Weight bearing after lower extremity fractures still remains a highly controversial issue. Even in ankle fractures, the most common lower extremity injury no standard aftercare protocol has been established. Average non weight bearing times range from 0 to 7 weeks, with standardised, radiological healing controls at fixed time intervals. Recent literature calls for patient-adapted aftercare protocols based on individual fracture and load scenarios. We show the clinical feasibility and first results of a new, insole embedded gait analysis tool for continuous monitoring of gait, load and activity. Ten patients were monitored with a new, independent gait analysis insole for up to 3 months postoperatively. Strict 20 kg partial weight bearing was ordered for 6 weeks. Overall activity, load spectrum, ground reaction forces, clinical scoring and general health data were recorded and correlated. Statistical analysis with power analysis, t-test and Spearman correlation was performed. Only one patient completely adhered to the set weight bearing limit. Average time in minutes over the limit was 374 min. Based on the parameters load, activity, gait time over 20 kg weight bearing and maximum ground reaction force high and low performers were defined after 3 weeks. Significant difference in time to painless full weight bearing between high and low performers was shown. Correlation analysis revealed a significant correlation between weight bearing and clinical scoring as well as pain (American Orthopaedic Foot and Ankle Society (AOFAS) Score rs=0.74; Olerud-Molander Score rs=0.93; VAS pain rs=-0.95). Early, continuous gait analysis is able to define aftercare performers with significant differences in time to full painless weight bearing where clinical or radiographic controls could not. Patient compliance to standardised weight bearing limits and protocols is low. Highly individual rehabilitation patterns were seen in all patients. Aftercare protocols should be adjusted to real-time patient conditions, rather than fixed intervals and limits. With a real-time measuring device high performers could be identified and influenced towards optimal healing conditions early, while low performers are recognised and missing healing influences could be corrected according to patient condition.

Predictors of mortality for complex fractures of the pelvic ring in the elderly: a twelve-year review from a German level I trauma center.

STUDY OBJECTIVE: To document mortality rate and predictors of mortality in elderly patients with complex pelvic fractures. METHODS: We reviewed a total of 84 subjects whose ages were above 70 years with complex pelvic fractures, admitted to our hospital from January 2001 to December 2012. A multivariate linear regression model was used to determine the predictors of mortality in the study population. The median age of the patients was 80.4 years (range 70-94 years). 65 of 84 (77%) patients were females. There were 72 Tile Type B fractures (86%) and 12 Type C fractures (14%). The most common associated injuries were thoracic, extremity and head injuries, with incidence of 13 (15%), 11 (13%), and 9 (11%), respectively. RESULTS: The mortality rate was 10% in our study population. The initial haemoglobin on admission (p<0.01), the presence of blood vessel injuries (p<0.01) and the number of PRBCs transfused within the first six hours after admission (p<0.01) independently predicted mortality in elderly patients with complex pelvic fractures. CONCLUSION: Although there is a downward trend in mortality in elderly patients with complex pelvic fractures, haemodynamic instability still has a significant impact on survival of those patients.

Pelvic fracture in multiple trauma: are we still up-to-date with massive fluid resuscitation?

Until today the mortality of complex pelvic trauma remains unacceptably high. On the one hand this could be attributed to a biological limit of the survivable trauma load, on the other hand side an ongoing inadequate treatment might be conceivable too. For the management of multiple trauma patients with life-threatening pelvic fractures, there is ongoing international debate on the adequate therapeutic strategy, e.g. arterial embolization or pelvic packing, as well as aggressive or restrained volume therapy. Whereas traditional pelvis-specific trauma algorithms still recommend massive fluid resuscitation, there is upcoming evidence that a restrained volume therapy in the preclinical setting may improve trauma outcomes. Less intravenous fluid administration may also reduce haemodilution and concomitant trauma-associated coagulopathy. After linking the data of the TraumaRegister DGU(®) and the German Pelvic Injury Register, for the first time, the initial fluid management for complex pelvic traumas as well as for different Tile/OTA types of pelvic ring fractures could be addressed. Unfortunately, the results could not answer the question of the adequate fluid resuscitation but confirmed the actuality of massive fluid resuscitation in the prehospital and emergency room setting. Low-volume resuscitation seems not yet accepted in practice in managing multiple trauma patients with pelvic fractures at least in Germany. Nevertheless, prevention of exsanguination and of complications like multiple organ dysfunction syndrome still poses a major challenge in the management of complex pelvic ring injuries. Even nowadays, fluid management for trauma, not only for pelvic fractures, remains a controversial area and further research is mandatory.

Endostatin inhibits Callus remodeling during fracture healing in mice.

Information on the impact of endogenous anti-angiogenic factors on bone repair is limited. The hypothesis of the present study was endostatin, an endogenous inhibitor of angiogenesis, disturbs fracture healing. We evaluated this hypothesis in a closed femoral fracture model studying two groups of mice, one that was treated by a daily injection of 10 µg recombinant endostatin subcutaneously (n = 38) and a second one that received the vehicle for control (n = 37). Histomorphometric analysis showed a significantly increased callus formation in endostatin-treated animals at 2 and 5 weeks post-fracture. This was associated with a significantly higher callus tissue fraction of cartilage and fibrous tissue at 2 weeks and a significantly higher fraction of bone at 5 weeks post-fracture. Biomechanical testing revealed a significantly higher torsional stiffness in the endostatin group at 2 weeks. For both groups, we could demonstrate the expression of the endostatin receptor unit integrin alpha5 in endothelial cells, osteoblasts, osteoclasts, and chondrocytes at 2 weeks. Immunohistochemical fluorescence staining of CD31 showed a lower number of blood vessels in endostatin-treated animals compared to controls. The results of the present study indicate endostatin promotes soft callus formation but inhibits callus remodeling during fracture healing most probably by an inhibition of angiogenesis.

Trauma registry record linkage: methodological approach to benefit from complementary data using the example of the German Pelvic Injury Register and the TraumaRegister DGU(®).

BACKGROUND: In Germany, hospitals can deliver data from patients with pelvic fractures selectively or twofold to two different trauma registries, i.e. the German Pelvic Injury Register (PIR) and the TraumaRegister DGU(®) (TR). Both registers are anonymous and differ in composition and content. We describe the methodological approach of linking these registries and reidentifying twofold documented patients. The aim of the approach is to create an intersection set that benefit from complementary data of each registry, respectively. Furthermore, the concordance of data entry of some clinical variables entered in both registries was evaluated. METHODS: PIR (4,323 patients) and TR (34,134 patients) data from 2004-2009 were linked together by using a specific match code including code of the trauma department, dates of admission and discharge, patient's age, and sex. Data entry concordance was evaluated using haemoglobin and blood pressure levels at emergency department arrival, Injury Severity Score (ISS), and mortality. RESULTS: Altogether, 420 patients were identified as documented in both data sets. Linkage rates for the intersection set were 15.7% for PIR and 44.4% for TR. Initial fluid management for different Tile/OTA types of pelvic ring fractures and the patient's posttraumatic course, including intensive care unit data, were now available for the PIR population. TR is benefiting from clinical use of the Tile/OTA classification and from correlation with the distinct entity "complex pelvic injury." Data entry verification showed high concordance for the ISS and mortality, whereas initial haemoglobin and blood pressure data showed significant differences, reflecting inconsistency at the data entry level. CONCLUSIONS: Individually, the PIR and the TR reflect a valid source for documenting injured patients, although the data reflect the emphasis of the particular registry. Linking the two registries enabled new insights into care of multiple-trauma patients with pelvic fractures even when linkage rates were poor. Future considerations and development of the registries should be done in close bilateral consultation with the aim of benefiting from complementary data and improving data concordance. It is also conceivable to integrate individual modules, e.g. a pelvic fracture module, into the TR likewise a modular system in the future.

What are predictors for patients' quality of life after pelvic ring fractures?

BACKGROUND: Data from literature on predictors for patients' quality of life after pelvic ring fractures are conflicting and based on small study populations. QUESTIONS/PURPOSES: We therefore evaluated predictors for health-related quality of life in patients with pelvic ring injuries at a minimum of 1 year postfracture. METHODS: We surveyed 172 patients of the German Pelvic Trauma Registry admitted to four medical centers between February 3, 2004, and May 11, 2011. The median age of the followup cohort was 47 years (range, 8-88 years); 69 of 172 (40%) patients were female. Patients were characterized by a median Injury Severity Score of 17. There were 31 Tile Type A fractures (18%), 77 Type B fractures (45%), and 64 Type C fractures (37%). The incidence of complex fractures and multiple traumas was 34 of 172 (20%) and 116 of 172 (67%), respectively. One hundred twenty-five (73%) patients were treated operatively. We obtained the EQ-5D™ score to assess patients' health-related quality of life. For the analysis of predictors for quality of life, a multivariate linear regression model was built. The median followup was 3 years (range, 1-6 years). RESULTS: The median EQ-5D™ score was 0.78 (interquartile limits, 0.63 and 1.00). Age, complex trauma, and surgery independently predicted the EQ-5D™ score. CONCLUSIONS: We conclude patients with higher age, complex trauma, and surgery had a higher likelihood for a reduced quality of life after pelvic ring injuries.

Delayed fracture healing in aged senescence-accelerated P6 mice.

BACKGROUND: Osteoporosis is characterized by poor bone quality. However, it is still controversially discussed whether osteoporosis compromises fracture healing. Herein, we studied whether the course of healing of a femur fracture is affected by osteoporosis or age. METHODS: Using the senescence-accelerated osteoporotic mouse, strain P6 (SAMP6), and a closed femur fracture model, we studied the process of fracture healing in 5- and 10-month-old animals, including biomechanical, histomorphometric, and protein biochemical analysis. RESULTS: In five-month-old osteoporotic SAMP6 mice, bending stiffness, callus size, and callus tissue distribution as well as the concentrations of the bone formation marker osteocalcin and the bone resorption markers tartrate-resistant acid phosphatase form 5b (TRAP) and deoxypyridinoline (DPD) did not differ from that of non-osteoporotic, senescence-resistant, strain 1 (SAMR1) controls. In contrast, femur fractures in 10-month-old SAMP6 mice showed a significantly reduced bending stiffness and an increased callus size compared to fractures in age-matched SAMR1 controls. This indicates a delayed fracture healing in advanced age SAMP6 mice. The delay of fracture healing was associated with higher concentrations of TRAP and DPD. Significant differences in osteocalcin concentrations were not found between SAMP6 animals and SAMR1 controls. CONCLUSION: In conclusion, the present study indicates that fracture healing in osteoporotic SAMP6 mice is not affected in five-month-old animals, but delayed in animals with an age of 10 months. This is most probably due to the increased osteoclast activity in advanced age SAMP6 animals.

Soft tissue fibroblasts from well healing and chronic human wounds show different rates of myofibroblasts in vitro.

Due to an increasing life expectancy in western countries, chronic wound treatment will be an emerging challenge in the next decades. Because therapies are improving slowly appropriate diagnostic tools enabling the early prediction of the healing success remain to be developed. We used a well-established in vitro assay in combination with the analysis of 27 cytokines to discriminate between fibroblasts from chronic (n = 6) and well healing (n = 8) human wounds. Proliferation and migration of the cells as well as their response to hypoxia and their behaviour in co-culture with microvascular endothelial cells were analyzed. Myofibroblast differentiation, a time-limited essential process of regular wound healing, was also quantified. Besides weaker proliferation and migration significantly higher rates of myofibroblasts were detected in chronic wounds. With respect to the cytokine release, there was a clear trend within the group of chronic wound fibroblasts, which were releasing interferon-γ, monocyte chemotactic protein-1, granulocyte-macrophage colony stimulating factor and basic fibroblast growth factor in higher amounts than fibroblasts from healing wounds. Although the overall response of both groups of fibroblasts to hypoxia and to the contact with endothelial cells was similar, especially chronic wound fibroblasts seemed to benefit from the endothelial interaction during hypoxia and displayed better migration characteristics. The study shows (1) that the assay can identify specific features of fibroblasts derived from different human wounds and (2) that wound fibroblasts are varying in their response to the chosen parameters. Thus, current therapeutic approaches and individual healing prediction might benefit from this assay.

Excess dietary methionine does not affect fracture healing in mice.

BACKGROUND: An elevated serum concentration of homocysteine (hyperhomocysteinemia) has been shown to disturb fracture healing. As the essential amino acid, methionine, is a precursor of homocysteine, we aimed to investigate whether excess methionine intake affects bone repair. MATERIAL/METHODS: We analyzed bone repair in 2 groups of mice. One group was fed a methionine-rich diet (n=13), and the second group received an equicaloric control diet without methionine supplementation (n=12). Using a closed femoral fracture model, bone repair was analyzed by histomorphometry and biomechanical testing at 4 weeks after fracture. Blood was sampled to measure serum concentrations of homocysteine, the bone formation marker osteocalcin, and the bone resorption marker collagen I C-terminal crosslaps RESULTS: Serum concentrations of homocysteine were significantly higher in the methionine group than in the control group, while serum markers of bone turnover did not differ significantly between the 2 groups. Histomorphometry revealed no significant differences in size and tissue composition of the callus between animals fed the methionine-enriched diet and those receiving the control diet. Accordingly, animals of the 2 groups showed a comparable bending stiffness of the healing bones. CONCLUSIONS: We conclude that excess methionine intake causes hyperhomocysteinemia, but does not affect fracture healing in mice.

Early detection of subclinical organ dysfunction by microdialysis of the rectus abdominis muscle in a porcine model of critical intra-abdominal hypertension.

The aim of this study was to evaluate microdialysis of the rectus abdominis muscle (RAM) for early detection of subclinical organ dysfunction in a porcine model of critical intra-abdominal hypertension (IAH). Microdialysis catheters for analyses of lactate, pyruvate, and glycerol levels were placed in cervical muscles (control), gastric and jejunal wall, liver, kidney, and RAM of 30 anesthetized mechanically ventilated pigs. Catheters for venous lactate and interleukin 6 samples were placed in the jugular, portal, and femoral vein. Intra-abdominal pressure (IAP) was increased to 20 mmHg (IAH20 group, n = 10) and 30 mmHg (IAH30, n = 10) for 6 h by controlled CO2 insufflation, whereas sham animals (n = 10) exhibited a physiological IAP. In contrast to 20 mmHg, an IAH of 30 mmHg induced pathophysiological alterations consistent with an abdominal compartment syndrome. Microdialysis showed significant increase in the lactate/pyruvate ratio in the RAM of the IAH20 group after 6 h. In the IAH30 group, the strongest increase in lactate/pyruvate ratio was detected in the RAM and less pronounced in the liver and gastric wall. Glycerol increased in the RAM only. After 6 h, there was a significant increase in venous interleukin 6 of the IAH30 group compared with baseline. Venous lactate was increased compared with baseline and shams in the femoral vein of the IAH30 group only. Intra-abdominal pressure-induced ischemic metabolic changes are detected more rapidly and pronounced by microdialysis of the RAM when compared with intra-abdominal organs. Thus, the RAM represents an important and easily accessible site for the early detection of subclinical organ dysfunction during critical IAH.

A new model to analyze metaphyseal bone healing in mice.

BACKGROUND: Despite the increasing clinical problems with metaphyseal fractures, most experimental studies investigate the healing of diaphyseal fractures. Although the mouse would be the preferable species to study the molecular and genetic aspects of metaphyseal fracture healing, a murine model does not exist yet. Using a special locking plate system, we herein introduce a new model, which allows the analysis of metaphyseal bone healing in mice. METHODS: In 24 CD-1 mice the distal metaphysis of the femur was osteotomized. After stabilization with the locking plate, bone repair was analyzed radiologically, biomechanically, and histologically after 2 (n=12) and 5 wk (n=12). Additionally, the stiffness of the bone-implant construct was tested biomechanically ex vivo. RESULTS: The torsional stiffness of the bone-implant construct was low compared with nonfractured control femora (0.23 ± 0.1 Nmm/°versus 1.78 ± 0.15 Nmm/°, P<0.05). The cause of failure was a pullout of the distal screw. At 2 wk after stabilization, radiological analysis showed that most bones were partly bridged. At 5 wk, all bones showed radiological union. Accordingly, biomechanical analyses revealed a significantly higher torsional stiffness after 5 wk compared with that after 2 wk. Successful healing was indicated by a torsional stiffness of 90% of the contralateral control femora. Histological analyses showed new woven bone bridging the osteotomy without external callus formation and in absence of any cartilaginous tissue, indicating intramembranous healing. CONCLUSION: With the model introduced herein we report, for the first time, successful metaphyseal bone repair in mice. The model may be used to obtain deeper insights into the molecular mechanisms of metaphyseal fracture healing.

What are predictors of mortality in patients with pelvic fractures?

BACKGROUND: Our knowledge of factors influencing mortality of patients with pelvic ring injuries and the impact of associated injuries is currently based on limited information. QUESTIONS/PURPOSES: We identified the (1) causes and time of death, (2) demography, and (3) pattern and severity of injuries in patients with pelvic ring fractures who did not survive. METHODS: We prospectively collected data on 5340 patients listed in the German Pelvic Trauma Registry between April 30, 2004 and July 29, 2011; 3034 of 5340 (57%) patients were female. Demographic data and parameters indicating the type and severity of injury were recorded for patients who died in hospital (nonsurvivors) and compared with data of patients who survived (survivors). The median followup was 13 days (range, 0-1117 days). RESULTS: A total of 238 (4%) patients died a median of 2 days after trauma. The main cause of death was massive bleeding (34%), predominantly from the pelvic region (62% of all patients who died because of massive bleeding). Fifty-six percent of nonsurvivors and 43% of survivors were male. Nonsurvivors were characterized by a higher incidence of complex pelvic injuries (32% versus 8%), less isolated pelvic ring fractures (13% versus 49%), lower initial blood hemoglobin concentration (6.7 ± 2.9 versus 9.8 ± 3.0 g/dL) and systolic arterial blood pressure (77 ± 27 versus 106 ± 24 mmHg), and higher injury severity score (ISS) (35 ± 16 versus 15 ± 12). CONCLUSION: Patients with pelvic fractures who did not survive were characterized by male gender, severe multiple trauma, and major hemorrhage. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Initial experience using a pelvic emergency simulator to train reduction in blood loss.

BACKGROUND: Because the average exposure of surgeons to pelvic injuries with life-threatening hemorrhage is decreasing, training opportunities are necessary to prepare surgeons for the rare but highly demanding emergency situations. We have developed a novel pelvic emergency simulator to train surgeons in controlling blood loss. QUESTIONS/PURPOSES: We (1) described the design and use of the simulator; and (2) determined whether the simulator correctly identified proper and improper mechanical stabilization and bleeding control. METHODS: The device contained two tube systems. The tubes of the first system were passed through the disrupted sacroiliac joint and the symphysis. By reduction (manual traction on the leg) and compression (application of the C-clamp) of the disrupted pelvis, the tubes were pinched by the synthetic bones leading to a stop of simulated blood flow through the tubes of the first system. The tubes of the second system ended in a foam representing the presacral and paravesical venous plexus. By correct preperitoneal packing, the flow into the foam was stopped. Simulated bleeding was monitored by quantifying flow out of a fluid reservoir and flow into fluid samplers. RESULTS: The pelvic emergency simulator has been used for eight training sessions since 2002. Bleeding control by packing was achieved after 6 ± 3 minutes. Total simulated blood loss during the training session was 1296 ± 892 mL. CONCLUSIONS: Our data suggest the simulator can be used as a tool to train surgeons to reduce blood loss in severe pelvic ring injuries.

Increased osteoblast and osteoclast activity in female senescence-accelerated, osteoporotic SAMP6 mice during fracture healing.

BACKGROUND: Previous studies have shown that fracture healing depends on gender and that in females, ovariectomy-induced osteoporosis impairs the healing process. There is no information, however, whether the alteration of fracture healing in osteoporosis also depends on gender. MATERIALS AND METHODS: Therefore, we herein studied fracture healing in female and male senescence-accelerated osteoporotic mice, strain P6 (SAMP6), including biomechanical, histomorphometric, and protein biochemical analysis. RESULTS: Bending stiffness was reduced in male and female SAMP6 mice compared with senescence-resistant strain 1 (SAMR1) controls. This was associated with elevated serum concentrations of tartrate-resistent acid phosphatase form 5b (TRAP) in both female and male SAMP6 mice. Callus size, however, was significantly larger in female SAMP6 mice compared with male SAMP6 mice and female SAMR1 controls. This indicates a delayed remodeling process in female SAMP6 mice. The delay of callus remodeling in female SAMP6 mice was associated with a significantly higher osteoprotegerin (OPG) callus tissue expression and increased serum concentrations of osteocalcin (OC) and deoxypyridinoline (DPD), indicating elevated osteoblast and osteoclast activities. CONCLUSION: The present study shows that remodeling during fracture healing in female, but not in male, SAMP6 mice is delayed, most probably due to an increased osteoblast and osteoclast activity.

Melatonin impairs fracture healing by suppressing RANKL-mediated bone remodeling.

BACKGROUND: Melatonin, the major pineal hormone, is known to regulate distinct physiologic processes. Previous studies have suggested that it supports skeletal growth and bone formation, most probably by inhibiting bone resorption. There is no information, however, whether melatonin affects fracture healing. We therefore studied in a mouse femur fracture model the influence of melatonin on callus formation and biomechanics during fracture healing. METHODS AND MATERIALS: Thirty CD-1 mice received 50 mg/kg body weight melatonin i.p. daily during the entire 2-wk or 5-wk observation period. Controls (n = 30) received equivalent amounts of vehicle. Bone healing was studied by radiological, biomechanical, histomorphometrical, and protein biochemical analyses at 2 and 5 wk after fracture. RESULTS: Biomechanical analysis at 2 wk after fracture healing showed a significantly lower bending stiffness in melatonin-treated animals compared with controls. A slightly higher amount of cartilage tissue and a significantly larger callus size indicated a delayed remodeling process after melatonin treatment. Western blot analysis showed a significantly reduced expression of receptor activator of nuclear factor-κB ligand (RANKL) and collagen I after melatonin treatment. The reduced expression of RANKL was associated with a diminished number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts within the callus of the newly formed bone. CONCLUSIONS: Because bone resorption is an essential requirement for adequate remodeling during fracture healing, we conclude that melatonin impairs fracture healing by suppressing bone resorption through down-regulation of RANKL-mediated osteoclast activation.

High bone concentrations of homocysteine are associated with altered bone morphology in humans.

Accumulation of homocysteine and S-adenosylhomocysteine in bone has been shown to be associated with reduced bone quality in rats. The aim of the present study was to investigate whether high bone concentrations of homocysteine and S-adenosylhomocysteine as well as a low methylation capacity are related to an impaired bone morphology in humans. Concentrations of homocysteine and its precursors S-adenosylhomocysteine and S-adenosylmethionine were measured in femoral bone samples of eighty-two males and females (age 71 (SD 8) years) who underwent elective hip arthroplasty. Cancellous bone structure was analysed by histomorphometry. In addition, blood was sampled to measure serum concentrations of homocysteine. Results of bone and serum analyses were grouped for individuals with high or low bone concentrations of homocysteine, S-adenosylhomocysteine and S-adenosylmethionine, as well as for individuals with a high or a low methylation capacity, which is indicated by a low or a high S-adenosylhomocysteine:S-adenosylmethionine ratio (n 41, each). Histomorphometry showed a higher trabecular separation and a lower trabecular thickness, trabecular number and trabecular area in individuals with high bone concentrations of homocysteine and S-adenosylhomocysteine compared with individuals with low bone concentrations of homocysteine and S-adenosylhomocysteine. There was no association between the S-adenosylhomocysteine:S-adenosylmethionine ratio and bone morphology. It was found that 48 % of bone homocysteine was bound to the collagen of the extracellular bone matrix. Blood analyses demonstrated a significant correlation between serum and bone homocysteine. The results of the present study indicate an association between altered bone morphology and elevated bone concentrations of homocysteine and S-adenosylhomocysteine, but not between altered bone morphology and methylation capacity.

Exercise enhances angiogenesis during bone defect healing in mice.

The aim of the present study was to investigate the effect of exercise on angiogenesis during bone defect healing in mice. We evaluated angiogenesis during cranial bone defect healing by intravital fluorescence microscopy (IVM) at days 0-21. To characterize the type of bone repair, we performed additional histomorphometric analyses at days 3-15. IVM was conducted in mice, which were housed in cages supplied with running wheels (exercise group; n=7) and compared to IVM results of mice, which were housed in cages without running wheels (controls; n=7). In the exercise group, we additionally performed correlation analyses between results of the IVM and the running distance. IVM showed an accelerated decrease of bone defect area in the exercise group compared to the control group. This was associated with a significantly higher blood vessel diameter in animals undergoing exercise at days 9 and 12 and a significant correlation between running distance and blood vessel density at day 9 (r = 0.74). Histomorphometry showed osseous bridging of the defect at day 9. The newly woven bone was covered by a neo-periosteum containing those blood vessels, which were visible by IVM. We conclude that exercise accelerates bone defect healing and stimulates angiogenesis during bore repair.