Fragility Fracture Network-Japan: The challenge of establishment of a national hip fracture database and successful achievement of nationwide health system change for hip fracture care in Japan.

BACKGROUND: In April 2022, a new reimbursement scheme for hip fracture was implemented by the Japanese health ministry. Japan is one of the world's most aged societies, facing a significant, rapidly growing burden of osteoporosis and fragility fractures. The incidence of hip fractures is projected to increase from 240,000 in 2020 to 320,000 by 2040. In 2015, Fragility Fracture Network-Japan (FFN-Japan) was formally established as a nonprofit organization in order to create the optimal fragility fracture care system in Japan. METHODS: FFN-Japan launched the Japan National Hip Fracture Database (JNHFD) in 2017, initially with only eight participating hospitals across Japan. The number of patients enrolled from May 2017 to the end of 2020 in the JNHFD from the 16 hospitals registered the patients during this period with amounting to 4271 patients in total. FFN-Japan invited officials from the Ministry of Health, Labor and Welfare (MHLW) to participate in round table meetings to discuss the data collected in the JNHFD and to consider opportunities for nationwide improvement in hip fracture care. RESULTS: The proportion of patients who underwent surgery within 36 h of arrival at hospital was 48.1% in 2018, 58.6% in 2019, and 44.9% in 2020 indicating the delay of surgery. Regarding secondary fracture prevention, initiation of osteoporosis treatment during the in-patients was 60.2% in 2018, 54.0% in 2019, and 64.5% in 2020 indicating the inadequate post fracture care. In April 2022, the Central Social Insurance Medical Council of the Japanese MHLW announced a new reimbursement scheme for hip fracture care including two key components: Early surgery (within 48 h from injury) and Secondary fracture prevention immediately after fracture. DISCUSSION: The new reimbursement scheme of hip fracture care in Japan will catalyze and underpin major improvements on acute multidisciplinary care and post-fracture care with secondary fracture prevention. FFN-Japan played a key role on these policy changes to the health system by means the close collaboration and ongoing communication with the government. CONCLUSION: Within five years of establishment of the JNHFD, FFN-Japan in collaboration with visionary leaders from the Japanese government have successfully achieved a major reform of the Japanese health system's reimbursement of hip fracture care. This reform has laid the foundation for transformation of management of this debilitating and life-threatening injury that currently afflicts almost a quarter of a million older Japanese citizens each year.

Histomorphometric analysis of patients with femoral neck fracture and 25-hydroxyvitamin D deficiency: a cross-sectional study.

INTRODUCTION: Vitamin D deficiency causes osteoporosis, bone mineralization disorders, and osteomalacia. Osteomalacia is diagnosed using blood biochemical tests, clinical symptoms, and imaging; however, accurate detection of mineralization disorders requires tissue observation. We investigated the prevalence of bone mineralization disorders and their relationship with serum 25-hydroxyvitamin D (25OHD) levels in patients with untreated osteoporosis with femoral neck fractures. MATERIALS AND METHODS: A non-demineralized specimen was prepared from the femoral head removed during surgery in 65 patients. Bone histomorphometry of cancerous bone in the femoral head center was conducted. Osteoid volume per bone volume (OV/BV) and osteoid thickness (O.Th) were measured as indicators of mineralization disorder. RESULTS: The mean serum 25OHD level (11.9 ± 5.7 ng/mL) was in the deficiency range (< 12 ng/mL). There were no clinically diagnosed cases of osteomalacia (OV/BV > 10% and O.Th > 12.5 µm); however, one case of mineralization disorder, considered histologically pre-osteomalacia (OV/BV > 5% and O.Th < 12.5 µm), was observed (OB/BV, 17.6%; O.Th, 12.3 µm). Excluding this case, those with severe (25OHD < 12 ng/mL, at risk of osteomalacia; n = 39) and non-severe deficiency (25OHD ≥ 12 ng/mL; n = 25) did not significantly differ in OV/BV (%; 0.77 ± 0.54 vs. 0.69 ± 0.38, p = 0.484) or O.Th (µm; 5.32 ± 1.04 vs. 5.13 ± 0.78, p = 0.410). Further, 25OHD and OV/BV were not significantly correlated (R = - 0.124, p = 0.327). CONCLUSION: This is the first study in the twenty-first century to examine serum 25OHD concentrations and bone mineralization disorders in Japanese patients with osteoporosis. The results indicate that vitamin D deficiency does not necessarily cause bone mineralization disorders and rarely leads to osteomalacia.

Varus/valgus stability in imageless robotic-assisted total knee arthroplasty applying three-dimensional assessment of varus/valgus stress X-rays.

BACKGROUND: The postoperative varus/valgus stability assessment in stress X-rays has been established as an evaluation index. However, it is performed by the two-dimensional (2D) method rather than the three-dimensional (3D) method. OBJECTIVE: This study aimed to identify the precision and reproducibility of measuring varus/valgus stress X-rays three-dimensionally and to examine varus/valgus stability under anesthesia in imageless robotic assisted total knee arthroplasty (rTKA). METHODS: This prospective study analyzed 52 consecutive rTKAs (five males, 67 ± 5.3 years; 47 females, 74 ± 5.9 years). Postoperative varus/valgus stress X-rays in knee extension under anesthesia at manual maximum stress were three-dimensionally assessed by 2D-3D image matching technique using the 3D bone and component models. Varus/valgus angle between components (VV angle) in no stress, valgus stress, varus stress, medial joint opening (MJO), and lateral joint opening (LJO) were evaluated, clarifying this method's precision and reproducibility and valgus/varus stability. RESULTS: All parameters' precision and reproducibility had <1° mean differences and high intra- and inter-class correlation coefficients. Bland-Altman plots showed no fixed and proportional bias. Non-stress VV angle, valgus VV angle, varus VV angle, MJO, and LJO were 3.6 ± 1.2°, 1.0 ± 1.4°, 7.1 ± 1.9°, 1.5 ± 1.0 mm, and 2.8 ± 2.7 mm, respectively. CONCLUSION: This prospective study demonstrated that (1) the three-dimensional measurement method provided sufficient precision and reproducibility, and (2) the rTKAs could achieve good postoperative varus/valgus stability with a small standard deviation.

Elevated IL-1ß and Comparable IL-1 Receptor Antagonist Levels Are Characteristic Features of L-PRP in Female College Athletes Compared to Male Professional Soccer Players.

Autologous platelet-rich plasma (PRP) therapy has been becoming popular for the treatment of musculotendinous injuries among athletes. However, for individual and practical variations, clinical success is hardly predictable. To overcome this difficulty, we have been exploring possible criterion candidates for monitoring its clinical effectiveness. In this study, we focused on sex-based differences in young elite athletes and compared the biochemical compositions of their PRP. Leukocyte-rich PRP (L-PRP) was manually prepared from blood samples collected from male professional soccer players (mPSPs) (n = 25) and female college athletes (fCAs) (n = 36). Platelet-derived growth factor-BB (PDGF-BB), transforming-growth factor-ß1 (TGFß1), platelet factor-4 (PF4), interleukin-1ß (IL-1ß), and IL-1 receptor antagonist (IL-1RA) were quantified using an enzyme-linked immunosorbent assay. The levels of PDGF-BB, TGFß1, and PF4 in L-PRP were significantly higher in mPSPs than in fCAs. Conversely, IL-1ß and IL-1RA were detected at significantly and slightly higher levels, respectively, in fCAs than in mPSPs. Our findings suggest that, even though L-PRP from fCAs may have lower potential to induce cell growth and differentiation than that of mPSPs, due to the latter's higher capacity to control inflammation, it does not necessarily imply that PRP treatment in fCAs is less effective. Thus, these cytokine levels should be checked before PRP therapy.

Characterization of Leukocyte- and Platelet-Rich Plasma Derived from Female Collage Athletes: A Cross-Sectional Cohort Study Focusing on Growth Factor, Inflammatory Cytokines, and Anti-Inflammatory Cytokine Levels.

Platelet-rich plasma (PRP) has been increasingly used in sports medicine owing to its various advantages. The purpose of our project was to standardize the parameters before performing large-scale clinical trials in the near future to precisely evaluate individual PRP quality. To examine the effects of regular exercise on PRP quality, this study focused on young female athletes, who have been relatively less studied. Blood samples were obtained from female college athletes (n = 35) and ordinary healthy adults (n = 30), which were considered as controls, and leukocyte-rich PRP (L-PRP) was prepared manually. Body composition indices were determined using a bathroom weight scale equipped with an impedance meter. Growth factors and cytokines were quantified using ELISA kits. Platelet-derived growth factor-BB (PDGF-BB) and Transforming-growth factors ß1 (TGFß1) levels (per platelet) in L-PRP were significantly lower in female athletes than in controls. In contrast, Interleukin-1ß and Interleukin 1 receptor antagonist (IL-1RA) levels (per platelet and L-PRP) in L-PRP were significantly higher in athletes, and this difference was more prominent in IL-1RA. These findings suggest that L-PRP from athletes may facilitate the inflammatory phase of the healing process by regulating the pro-inflammatory and anti-inflammatory balance. These chemical compositions can be adopted as "must-check" parameters to characterize individual PRP preparations prior to clinical trials.

Strategic analysis of body composition indices and resting platelet ATP levels in professional soccer players for better platelet-rich plasma therapy.

Background: Autologous platelet-rich plasma (PRP) therapy is ambiguously thought to be more effective in elite athletes than in sedentary patients, although the possible importance of recipient responsiveness remains poorly understood. To address this issue, along with the well-known PRP quality, in this initial study, we evaluated two candidate biomarkers: body composition indices (BCIs), which reflect systemic physical conditions, and resting platelet ATP levels, which reflect platelet energy expenditure and the mass of energy generation units. Methods: In this cross-sectional cohort study, blood samples were collected from male professional soccer players (PSPs) on a local professional team during the off-season and platelet ATP levels were quantified using an ATP luminescence assay kit. BCIs were measured using the body mass impedance method. Age-matched male sedentary participants were used as the controls. Results: Among the BCIs, the body mass index, basal metabolic rate (BMR), and skeletal muscle weight levels were higher in the PSPs than in the controls. The platelet ATP levels in the PSPs group were significantly lower than those in the control group. The correlation between BMR and platelet ATP levels was moderately negative in the control group, but weakly positive in the PSPs group. Conclusion: Owing to regular physical exercise, PSPs had higher BMR levels and lower platelet ATP levels without a significant mutual correlation compared to sedentary controls. This study did not indicate the influence of these biomarkers on the success of PRP therapy but provided evidence for a better understanding of PRP therapy, particularly for elite athletes.

Buds of new bone formation within the Femoral Head of Hip Fracture Patients Coincide with Zones of Low Osteocyte Sclerostin.

Romosozumab treatment reduces the rate of hip fractures and increases hip bone density, increasing bone formation by inhibiting sclerostin protein. We studied the normal pattern of bone formation and osteocyte expression in the human proximal femur because it is relevant to both antisclerostin treatment effects and fracture. Having visualized and quantified buds of new bone formation in trabeculae, we hypothesized that they would coincide with areas of (a) higher mechanical stress and (b) low sclerostin expression by osteocytes. In patients with hip fracture, we visualized each bud of active modeling-based formation (forming minimodeling structure [FMiS]) in trabecular cores taken from different parts of the femoral head. Trabecular bone structure was also measured with high-resolution imaging. More buds of new bone formation (by volume) were present in the higher stress superomedial zone (FMiS density, N.FMiS/T.Ar) than lower stress superolateral (p < 0.05), and inferomedial (p < 0.001) regions. There were fewer sclerostin expressing osteocytes close to or within FMiS. FMiS density correlated with greater amount, thickness, number, and connectivity of trabeculae (bone volume BV/TV, r = 0.65, p < 0.0001; bone surface BS/TV, r = 0.47, p < 0.01; trabecular thickness Tb.Th, r = 0.55, p < 0.001; trabecular number Tb.N, r = 0.47, p < 0.01; and connectivity density Conn.D, r = 0.40, p < 0.05) and lower trabecular separation (Tb.Sp, r = -0.56, p < 0.001). These results demonstrate modeling-based bone formation in femoral trabeculae from patients with hip fracture as a potential therapeutic target to enhance bone structure. © 2023 American Society for Bone and Mineral Research (ASBMR).

Normal coronal kinematics of dynamic alignment and bony positions relative to the ground in three-dimensional motion analysis during gait: A preliminary study.

BACKGROUND: During gait, healthy knee coronal kinematics of each bony axis and lower extremity alignment are important because they could be useful as reference data for several surgeries and provide clarification of the etiology of diseases around the knee in healthy participants; however, it remains unknown. OBJECTIVE: The objective of this study was to clarify the kinematics of lower extremity alignment and the bony axes relative to the ground during gait, focused on the coronal plane, in healthy individuals by applying our unique three-dimensional (3D) motion analysis. METHODS: The study included 21 healthy individuals, including 9 healthy females and 12 healthy males with an average age of 36 ± 17 years. Knee kinematics were calculated in a gait analysis by combining the data from a motion-capture system and a 3D lower-extremity alignment assessment system on biplanar long-leg radiographs by using a 3D-2D registration technique. The main kinematic parameters were the dynamic position change relative to the ground, applying the femoral anatomical axis (FAA), tibial anatomical axis (TAA), and dynamic alignment in the coronal plane during the stance phase of gait. RESULTS: The average changes in FAA, TAA, and dynamic varus alignment were 3.7° ± 1.2°, 3.5° ± 0.8°, and 3.0° ± 1.2°, respectively. The TAA tilted laterally during the loading response and a plateau area appeared afterwards; the FAA gradually inclined laterally until the terminal stance phase, and the dynamic alignment showed varus angular change during the loading response. CONCLUSIONS: The tibia and femur were found to change approximately 2-5° of the position of the bony axes relative to the ground. In terms of clinical relevance, our findings can be used to clarify the etiology of diseases around the knee joint and as reference data for surgeries.

Physical functions, to be or not to be a risk factor for osteochondritis dissecans of the humeral capitellum?

Background: Physical risk factors for osteochondritis dissecans (OCD) of the humeral capitellum in young baseball players have not been fully elucidated. We aimed to identify the risk factors for capitellar OCD in baseball players aged 8-14 years. Methods: Between December 2018 and December 2019, young baseball players were recruited from 8 regional baseball leagues. Ultrasonography and physical assessments were performed preseason and at the end of the study period. Bilateral passive ranges of motion (ROM) of horizontal adduction of the shoulders, internal rotation (IR) of the hips, and the thoracic kyphosis angle were measured. 1-year follow-ups were scheduled to determine the occurrence of OCD. Players with OCD were categorized into an OCD group; those without OCD and any elbow pain for one year were categorized into a non-injured group. The players' baseline data (age, sex, position in baseball, and Rohrer's Index) were analyzed using univariate analyses. Their physical parameters were analyzed using two-way analysis of variance with repeated measures to investigate OCD-related risk factors. Results: In total, 3651 baseball players attended the 1-year follow-up. Of these, 71 (1.9%) players had OCD of the humeral capitellum. In the OCD group, a significant association was found at baseline and at the end of the study period between a higher Rohrer index at the baseline and a smaller hip IR ROM on the nondominant side. Conclusions: Loss of hip IR ROM on the nondominant side is a newly discovered risk factor related to physical function in the development of OCD.

Fragility Fracture Systems: International Perspectives - Asia & Australia.

Background: The incidence and burden of fragility fractures have reached the level where comprehensive systematic care is warranted to optimize the care of these patients. Hip fractures are the most frequently lethal and independence level changing fragility fractures, responsible for 30-day mortality comparable to high-energy trauma patients with injury severity scores over 12. It is a reasonable expectation that countries have a hip fracture treating system of care in place for this high-risk population. This review explores the systems of care from the Asia-Pacific Perspective. Methods: From the International Orthopaedic Trauma Association's member societies, nations from the Asia-Pacific Region were requested to contribute with an overview of their fragility fracture management systems. The content or the review was standardized by a template of headings, which each country endeavored to cover. Results: Australia, Japan, and South Korea contributed voluntarily from the 5 member countries of the region. Each country has made considerable efforts and achievements with diverse approaches to standardize and improve the care of fragility fractures, particularly hip fractures. Beyond the individual nations' efforts there is also an existing Asia-Pacific Collaborative. The data collection and in some counties the existence of a registry is promising; funding and recognition of the problem among competing health care budget priorities are common. Conclusions: Our review covers some of the countries with strongest economy and highest health care standards. The lack of a universal robust system for hip fracture care is apparent. The data collection from registry initiations is expected to drive system development further in these countries and hopefully fast track the development in other countries within the most populous geographical region of the Earth.

Quality improvement initiatives in the care and prevention of fragility fractures in the Asia Pacific region.

This narrative review summarises ongoing challenges and progress in the care and prevention of fragility fractures across the Asia Pacific region since mid-2019. The approaches taken could inform development of national bone health improvement Road Maps to be implemented at scale during the United Nations 'Decade of Healthy Ageing'. PURPOSE: This narrative review summarises recent studies that characterise the burden of fragility fractures, current care gaps and quality improvement initiatives intended to improve the care and prevention of fragility fractures across the Asia Pacific region. METHODS: The review focuses on published studies, reports and quality improvement initiatives undertaken during the period July 2019 to May 2022. RESULTS: Epidemiological studies conducted in countries and regions throughout Asia Pacific highlight the current and projected increasing burden of fragility fractures. Recent studies and reports document a persistent and pervasive post-fracture care gap among people who have sustained fragility fractures. Global initiatives developed by the Fragility Fracture Network and International Osteoporosis Foundation have gained significant momentum in the Asia Pacific region, despite the disruption caused by the COVID-pandemic. The Asia Pacific Fragility Fracture Alliance has developed educational resources including a Hip Fracture Registry Toolbox and a Primary Care Physician Education Toolkit. The Asia Pacific Osteoporosis and Fragility Fractures Society-a new section of the Asia Pacific Orthopaedic Association-is working to engage orthopaedic surgeons across the region in the care and prevention of fragility fractures. The Asia Pacific Consortium on Osteoporosis developed a framework to support national clinical guidelines development groups. Considerable activity at the national level is evident in many countries across the region. CONCLUSION: Development and implementation of national Road Maps informed by the findings of this review are urgently required to respond to the epidemiological emergency posed by fragility fractures during the United Nations 'Decade of Healthy Ageing'.

Platelet polyphosphate and energy metabolism in professional male athletes (soccer players): A cross-sectional pilot study.

Human platelet polyphosphate (polyP) is a multifunctional molecule; however, its functions are not yet fully understood. A recent study demonstrated that similar to skeletal muscle, polyP is involved in energy metabolism in platelets, which suggests that well-trained athletes may exhibit elevated platelet polyP levels for energy storage. To test this hypothesis, we quantified platelet polyP along with NADH, a component involved in ATP production in non-trained and well-trained male Japanese participants of the same generation. Washed platelets were prepared from the venous blood of young, healthy, non-athletes, and professional soccer players (pro-athletes). NADH and polyP levels were spectrophotometrically determined using tetrazolium reduction and fluorometrically determined using 4',6-diamidino-2-phenylindole at the excitation/emission wavelengths of 425/525 nm. Body weight and impedances were measured simultaneously. Statistical analyses were performed using the Mann-Whitney U test and Spearman correlation coefficient. Although basal metabolic rate levels were significantly higher, platelet polyP levels were significantly lower in pro-athletes than in that in non-athletes. No significant differences were detected in other body compositions or platelet indices between the two groups. The pro-athlete group showed a moderate, nearly significant correlation (R = 0.439; p = 0.0512) between platelet polyP and NADH levels. Taken together with the weak correlation data between polyP and body mass index, it is suggested that platelet polyP levels may be influenced by platelet and body energy metabolic activity. Further biochemical studies are needed to elucidate this mechanism.

Neoadjuvant teriparatide therapy targeting the osteoporotic spine: influence of administration period from the perspective of bone histomorphometry.

OBJECTIVE: Teriparatide (TPTD) is a potent promoter of early-stage osteogenesis and may be a useful adjuvant therapy to reduce complications related to bone fragility in spinal surgery patients with osteoporosis. However, effective neoadjuvant TPTD therapy regimens remain poorly understood. This study aimed to examine the effect of preoperative TPTD administration on cancellous bone with bone histomorphometry and to clarify the timing of preoperative TPTD administration for patients with spinal fusion and osteoporosis. METHODS: In this longitudinal multicenter study, 57 patients with spinal fusion and osteoporosis, who consented to undergo iliac biopsy, were allocated to the following treatment groups: neoadjuvant TPTD therapy group (n = 42) and no neoadjuvant therapy (NTC) group (n = 15). Patients in the TPTD group were categorized into subgroups on the basis of duration of preoperative TPTD administration, as follows: 1 month (n = 9), 2 months (n = 8), 3 months (n = 9), 4 months (n = 7), and 6 months (n = 9). All patient samples were preoperatively double labeled with tetracycline, and iliac biopsies were performed during spinal fusion surgery. Histomorphometric analyses were performed on nondecalcified, thin-sliced specimens. Specimens were classified on the basis of TPTD administration duration and subsequently compared with those of the NTC group. Postoperative complications and Oswestry Disability Index scores were evaluated at 1 and 2 years after surgery. RESULTS: There were no demographic differences between groups. Mineralizing surface/bone surface, a key parameter of dynamic bone formation, started to increase after 1 month of TPTD administration; this increase became significant after 3 months of administration and peaked at 4 months, with a 6-fold increase relative to that of the NTC group. The patients who received preoperative TPTD for 3 months or more had superior clinical results in terms of the osteoporotic complication rate and Oswestry Disability Index scores, except for bisphosphonate-pretreated patients. CONCLUSIONS: When considering neoadjuvant TPTD therapy, the authors recommend at least 3 months of preoperative administration to provide a more substantial anabolic effect from the early postoperative stage.

Disturbance of osteonal bone remodeling and high tensile stresses on the lateral cortex in atypical femoral fracture after long-term treatment with Risedronate and Alfacalcidol for osteoporosis.

An 83 year-old Japanese woman complained of left lateral thigh pain following a low-energy fall 4 months prior to admission. She had been treated for osteoporosis with Risedronate and Alfacalcidol for the previous five years. She was diagnosed with an atypical femoral fracture (AFF) according to the American Society for Bone and Mineral Research (ASBMR) Task Force revised criteria. Radiographs revealed cortical thickening and a transverse radiolucent fracture line in the lateral cortex of the shaft. MRI showed a high intensity signal on the T2WI image 1 cm long in the lateral cortex. The patient had normal levels of bone resorption and formation biomarkers except for low 25(OH) Vitamin D. Double fluorescent labeling was done preoperatively. Due to significant bowing, a corrective osteotomy and intramedullary nailing were performed, and the resected bone wedge was analyzed by bone histomorphometry. Three ground sections of the lateral cortex at the fracture site showed many and large pores, with or without tetracycline labeling. Histomorphometric assessment was done on intracortical pores, classified by a novel criteria, only to assess size of the pores to know prolonged osteoclastic activity and its characteristics of inner surfaces to assess whether bone formation has been occurring or not in labeling period in remodeling cycle, and coalition of multi-pores. Increased size with widespread variation of pores suggested prolonged osteoclastic activity in the reversal/resorptive phase. Bone labeling showed lamellar bone on the endocortical surface. We hypothesize that the case had developed from a regional disturbance of osteonal remodeling in the lateral cortex, in which accumulated microcracks might have initiated a resorption process resulting in resorption cavities, i.e., pores, which became larger due to prolonged activity of secondary osteoclasts. Various sized pores could form lamellar bone, still forming at the time of biopsy, some had formed lamellar bone, but stopped to form before labeling and not to start to form at all, probably due to incomplete coupling. Endocortical lamellar bone might had started to resorbed to smooth off endocortical surface, followed by formation of lamellar bone. The endocortical bone formation was assessed and its formation period is about 2.7 years. A finite element analysis using preoperative CT data revealed high tensile stresses on the lateral aspect of the femur. Histomorphometric results suggest that there might be more pores in the tensile area than the compressive area. These findings may subsequently connect accumulation of microcracks, an increase of size and number of pores and coalition and subsequent fracture in the lateral cortex.

Effects of the linagliptin, dipeptidyl peptidase-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus in obese mice.

Recently, it has been suggested that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), which play important roles in the homeostasis of glucose metabolism, could be involved in the regulation of bone metabolism. Inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades GIP and GLP-1, are widely used clinically as a therapeutic agent for diabetes. However, the effects of DPP-4 inhibitors on bone metabolism remain unclear. In this study, we investigated the effects of linagliptin, a DPP-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus (T2DM). Non-diabetic mice were used as controls, and T2DM mice were administered linagliptin orally on a daily basis for 12 weeks. In T2DM mice, decreased bone mineral density was observed in the lower limb bones along with low serum osteocalcin levels and high serum tartrate-resistant acid phosphatase-5b (TRAP) levels. In contrast, the decreased serum osteocalcin levels and increased serum TRAP levels observed in T2DM mice were significantly suppressed after the administration of linagliptin 30 mg/kg. Bone histomorphometric analysis revealed a reduced osteoid volume and osteoblast surface with an increase in the eroded surface and number of osteoclasts in T2DM mice. This decreased bone formation and increased bone resorption observed in the T2DM mice were suppressed and trabecular bone volume increased following the administration of 30 mg/kg linagliptin. Collectively, these findings suggest that linagliptin may improve the microstructure of trabecular bone by inhibiting both a decrease in bone formation and an increase in bone resorption induced by T2DM.

Effects of the combined administration of risedronate and menatetrenone on bone loss induced by tacrolimus in rats.

Tacrolimus, a calcineurin inhibitor, affects bone metabolism and increases the risk of fracture due to marked bone loss. Bisphosphonates increase the bone mineral density (BMD) in osteoporosis patients. Menatetrenone has less positive effects on BMD but reduces the risk of fracture by improving bone quality. In this study, we investigated the effectiveness of the combined administration of risedronate and menatetrenone against bone loss induced by tacrolimus. Wistar rats were divided into four groups: [1] control, [2] tacrolimus at 1.5 mg/kg, [3] tacrolimus + risedronate at 1.0 mg/kg, and [4] tacrolimus + risedronate + menatetrenone at 20 mg/kg. After the drugs were administered for 4 weeks, bone histomorphometric analysis was performed and bone strength was evaluated using a three point bending method. BMD was measured using quantitative computed tomography. Tacrolimus significantly reduced the BMD and strength properties of the lower limb bones. These tacrolimusinduced decreases were suppressed by risedronate treatment. The combined administration of risedronate and menatetrenone more significantly improved bone strength properties than risedronate alone. Bone histomorphometric analysis revealed a significant increase in bone resorption with tacrolimus. Risedronate alone significantly suppressed the tacrolimus-induced increase in bone resorption but simultaneously reduced bone formation. On the other hand, the combined administration of risedronate and menatetrenone suppressed the tacrolimus-induced increase in bone resorption, in addition to the significant risedronate-induced decrease in bone formation. This study suggests that the combined administration of risedronate and menatetrenone improves bone strength in tacrolimus-treated rats by preventing and ameliorating the risedronate-induced suppression of bone formation.

Rare pancreatic metastasis of undifferentiated pleomorphic sarcoma originating from the pelvis: A case report.

INTRODUCTION: Undifferentiated pleomorphic sarcoma (UPS) is a reclassification of malignant fibrous histiocytoma by the World Health Organization in 2002. UPS, the most common soft tissue sarcoma reported in adults, mostly recurs as lung disease. Pancreatic metastasis of UPS is extremely rare. We present a rare case of pelvic UPS with pancreatic metastasis. PRESENTATION OF CASE: A 69-year-old man was identified as having mediastinal lymphadenopathy on follow-up computed tomography (CT), 2 years after undergoing surgery for gastric adenocarcinoma (pT4aN3M0/IIIC). Subsequent positron emission tomography-CT (PET/CT) indicated pelvic lesions and magnetic resonance imaging (MRI) showed multiple tumors of the left pubis and femur. Histopathology of diagnostic thoracoscopic lymph node dissection and CT-guided needle biopsy of the left pubic lesion showed UPS. Systemic chemotherapy and targeted molecular therapy reduced multiple pelvic and metastatic tumors. Left pubic primary lesion contraction was achieved with intensity-modulated radiation therapy. CT performed 4 years after treatment initiation showed a 40-mm pancreatic head mass. Lesions other than the pancreatic tumor were in remission, and a pancreatoduodenectomy was performed. Histological analysis confirmed pancreatic metastasis of anaplastic pleomorphic sarcoma. DISCUSSION: Reports of pelvic UPS with pancreatic metastasis, as that of the present case, are extremely rare. UPS is malignant potential tumor, and complete excision is the first treatment option, while the usefulness of chemotherapy or radiation therapy remains uncertain. CONCLUSIONS: Complete resection is vital for local control in pancreatic metastasis of UPS. Sites of recurrence are rare; hence, patients must be carefully followed up.

Reference values for the locomotive syndrome risk test quantifying mobility of 8681 adults aged 20-89 years: A cross-sectional nationwide study in Japan.

BACKGROUND: The locomotive syndrome risk test was developed to quantify the decrease in mobility among adults, which could eventually lead to disability. The purpose of this study was to establish reference values for the locomotive syndrome risk test for adults and investigate the influence of age and sex. METHODS: We analyzed 8681 independent community dwellers (3607 men, 5074 women). Data pertaining to locomotive syndrome risk test (the two-step test, the stand-up test, and the 25-question geriatric locomotive function scale [GLFS-25]) scores were collected from seven administrative areas of Japan. RESULTS: The reference values of the three test scores were generated and all three test scores gradually decreased among young-to-middle-aged individuals and rapidly decreased in individuals aged over 60 years. The stand-up test score began decreasing significantly from the age of 30 years. The trajectories of decrease in the two-step test score with age was slightly different between men and women especially among the middle-aged individuals. The two physical test scores were more sensitive to aging than the self-reported test score. CONCLUSION: The reference values generated in this study could be employed to determine whether an individual has mobility comparable to independent community dwellers of the same age and sex.

Low-Frequency Electrical Stimulation of Denervated Skeletal Muscle Retards Muscle and Trabecular Bone Loss in Aged Rats.

Electrical stimulation (ES)-induced muscle contraction has multiple effects; however, mechano-responsiveness of bone tissue declines with age. Here, we investigated whether daily low-frequency ES-induced muscle contraction treatment reduces muscle and bone loss and ameliorates bone fragility in early-stage disuse musculoskeletal atrophy in aged rats. Twenty-seven-month-old male rats were assigned to age-matched groups comprising the control (CON), sciatic nerve denervation (DN), or DN with direct low-frequency ES (DN+ES) groups. The structural and mechanical properties of the trabecular and cortical bone of the tibiae, and the morphological and functional properties of the tibialis anterior (TA) muscles were assessed one week after DN. ES-induced muscle contraction force mitigated denervation-induced muscle and trabecular bone loss and deterioration of the mechanical properties of the tibia mid-diaphysis, such as the stiffness, but not the maximal load, in aged rats. The TA muscle in the DN+ES group showed significant improvement in the myofiber cross-sectional area and muscle force relative to the DN group. These results suggest that low-frequency ES-induced muscle contraction treatment retards trabecular bone and muscle loss in aged rats in early-stage disuse musculoskeletal atrophy, and has beneficial effects on the functional properties of denervated skeletal muscle.

Spinal manifestations in 12 patients with musculocontractural Ehlers-Danlos syndrome caused by CHST14/D4ST1 deficiency (mcEDS-CHST14).

Musculocontractural Ehlers-Danlos syndrome caused by mutations in CHST14 (mcEDS-CHST14) is a recently delineated disorder, characterized by craniofacial, skeletal, visceral, and ocular malformations; and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Spinal lesions, though one of the most serious complications, have not been investigated systematically. In this study, we report detailed and comprehensive information about spinal lesions of 12 patients with a mean age at the first visit of 13.4 years. Eight patients (66.7%) had scoliosis with a Cobb angle ≥10°, including one with severe scoliosis with a Cobb angle ≥45°. Five patients (41.7%) had kyphosis at the thoracolumbar junction with a kyphotic angle ≥20°. Three patients (25%) developed severe thoracolumbar kyphosis with a kyphotic angle ≥50° accompanied by thoracic lordosis with a wedge-like vertebral deformity and anterior vertebral osteophyte at the thoracolumbar junction, and two of them underwent surgical correction: complicated by fistula formation in one and performed safely and effectively through two-staged operation in the other. Six patients (50.0%) had cervical kyphosis, all of whom except one had kyphosis ≥20° at the thoracolumbar level. Two patients (16.7%) had atlantoaxial subluxation, and 10 patients (83.3%) had cervical vertebral malformations. Patients with mcEDS-CHST14 are susceptible to develop scoliosis, thoracolumbar kyphosis, and cervical kyphosis; and are recommended to have regular surveillance including total spine radiology. The present findings also suggest the critical role of dermatan sulfate in the development and maintenance of the spine.