Association between adeno-associated virus 2 and severe acute hepatitis of unknown etiology in Japanese children.

INTRODUCTION: Outbreaks of acute hepatitis of unknown etiology (AHUE) in children were reported in Western countries in 2022. Previous studies found that adeno-associated virus 2 (AAV2) and its helper viruses, such as human adenovirus (HAdV) and human herpesvirus-6 (HHV-6), are frequently detected in patients with AHUE. However, the existence of hepatitis associated with AAV2 prior to AHUE outbreaks in 2022 had not yet been investigated. We aimed to investigate the association between AAV2 and pediatric acute hepatitis in Japanese children, as well as the incidence of AAV2-related hepatitis prior to 2022. METHODS: Preserved blood samples obtained from 49 pediatric patients with acute hepatitis between 2017 and 2023 were retrospectively analyzed. Blood samples from 50 children with acute illnesses and 50 children with chronic conditions were used as controls. Viral DNA loads were quantitated using real-time PCR. RESULTS: AAV2 DNA was detected in 12 % (6/49) of acute hepatitis cases but in only one acute illness and none of the chronic-condition control cases. The concentration of AAV2 DNA in the six acute hepatitis cases was higher than that in the acute-illness control case. Co-infection with one or more helper viruses, including HAdV, HHV-6, cytomegalovirus, and Epstein-Barr virus, was observed in five AAV2-positive cases. CONCLUSIONS: Our results indicated the sporadic occurrence of pediatric severe hepatitis associated with AAV2 infection in Japan prior to the AHUE outbreaks in 2022. Our findings suggest that co-infection with AAV2 and helper viruses plays a role in developing severe hepatitis.

Comparison of Whole Blood and Plasma for Monitoring Cytomegalovirus and Epstein-Barr Virus.

Monitoring Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection after transplantation is recommended to enable preemptive therapy. However, the most suitable sample type remains unclear. Patients who underwent hematopoietic stem cell or liver transplantation were included in this study. Viral loads in sequential whole-blood and plasma samples were retrospectively analyzed. EBV DNA was detected more frequently in whole blood (55%) than in plasma (18%). The detection rate of CMV DNA was similar between the two sample types. The correlation of viral loads between the two sample types were 0.515 and 0.688 for EBV and CMV, respectively. Among paired samples in which EBV DNA was detected in whole blood, the plasma EBV detection rate was significantly higher in patients who underwent hematopoietic stem cell transplantation than in those who underwent liver transplantation. The viral DNA load in whole blood and plasma showed similar trends. The EBV detection rate was higher in whole blood, and a high correlation was observed between CMV DNA loads and whole blood and plasma. These results indicate that whole blood is more sensitive for monitoring both EBV and CMV, whereas plasma is a potential alternative sample for monitoring CMV.

Serum Proteomic Profiles of Patients with Chronic Recurrent Multifocal Osteomyelitis.

OBJECTIVES: Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disease characterized by sterile bone inflammation; however, its pathophysiology is poorly understood. Thus, this study aimed to characterize the serum proteomic profiles of patients with CRMO to better understand the molecular mechanisms underpinning CRMO pathogenesis. METHODS: Proteomic profiling of the sera collected from 11 patients with CRMO (five patients were in active phase, six were in inactive phase) was conducted using liquid chromatography-mass spectrometry. Sera from four children without inflammatory diseases were used as controls. Pathway analysis was performed to identify the upregulated and downregulated proteins in patients with active CRMO. RESULTS: Compared with the control group, 19 and 41 proteins were upregulated and downregulated, respectively, in patients with active CRMO. Pathway and process enrichment analyses revealed that axon guidance was the most enriched category of upregulated proteins in patients with active CRMO, followed by neutrophil degranulation and mitogen-activated protein kinase cascade regulation. In comparison to patients with inactive CRMO, 36 proteins, including 11 keratin proteins, were upregulated and highly enriched in the intermediate filament organization category. Rho GTPase pathway-related proteins were downregulated in ibuprofen-treated patients. CONCLUSION: Proteomic analysis identified upregulated proteins in the sera of patients with acute CRMO. These proteins can be used as biomarkers for disease diagnosis and activity. Furthermore, we anticipate that this study will contribute to a deeper understanding of the pathophysiology of CRMO, which, in turn, will contribute to the discovery of potential novel therapeutic targets.

Nanopore sequencing in distinguishing between wild-type and vaccine strains of Varicella-Zoster virus.

BACKGROUND: The introduction of varicella vaccines into routine pediatric immunization programs has led to a considerable reduction in varicella incidence. However, there have been reports of varicella, herpes zoster, and meningitis caused by the vaccine strain of varicella-zoster virus (VZV), raising concerns. Establishing the relationship between the wild-type and vaccine strains in VZV infections among previously vaccinated individuals is crucial. Differences in the single nucleotide polymorphisms (SNPs) among vaccine strains can be utilized to identify the strain. In this study, we employed nanopore sequencing to identify VZV strains and analyzed clinical samples. METHODS: We retrospectively examined vesicle and cerebrospinal fluid samples from patients with VZV infections. One sample each of the wild-type and vaccine strains, previously identified using allelic discrimination real-time PCR and direct sequencing, served as controls. Ten samples with undetermined VZV strains were included. After DNA extraction, a long PCR targeting the VZV ORF62 region was executed. Nanopore sequencing identified SNPs, allowing discrimination between the vaccine and wild-type strains. RESULTS: Nanopore sequencing confirmed SNPs at previously reported sites (105,705, 106,262, 107,136, and 107,252), aiding in distinguishing between wild-type and vaccine strains. Among the ten unknown samples, nine were characterized as wild strains and one as a vaccine strain. Even in samples with low VZV DNA levels, nanopore sequencing was effective in strain identification. CONCLUSION: This study validates that nanopore sequencing is a reliable method for differentiating between the wild-type and vaccine strains of VZV. Its ability to produce long-read sequences is remarkable, allowing simultaneous confirmation of known SNPs and the detection of new mutations. Nanopore sequencing can serve as a valuable tool for the swift and precise identification of wild-type and vaccine strains and has potential applications in future VZV surveillance.

Oxidative stress is an essential factor for the induction of anhydrobiosis in the desiccation-tolerant midge, Polypedilum vanderplanki (Diptera, Chironomidae).

The sleeping chironomid (Polypedilum vanderplanki) is the only insect capable of surviving complete desiccation in an ametabolic state called anhydrobiosis. Here, we focused on the role of oxidative stress and we observed the production of reactive oxygen species (ROS) in desiccating larvae and in those exposed to salinity stress. Oxidative stress occurs to some extent in desiccating larvae, inducing carbonylation of proteins. Oxidative stress overcomes the antioxidant defenses of the larvae during the first hour following rehydration of anhydrobiotic larvae. It facilitates the oxidation of DNA and cell membrane lipids; however, these damages are quickly repaired after a few hours. In addition to its deleterious effects, we demonstrated that artificial exposure to oxidative stress could induce a response similar to desiccation stress, at the transcriptome and protein levels. Furthermore, the response of anhydrobiosis-related genes to desiccation and salinity stress was inhibited by antioxidant treatment. Thus, we conclude that oxidative stress is an essential trigger for inducing the expression of protective genes during the onset of anhydrobiosis in desiccating of P. vanderplanki larvae.

Proteomic Analysis Reveals Novel Plasma Biomarkers for Neurological Complications in Patients With Congenital Cytomegalovirus Infection.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection is a leading cause of nonhereditary neurological complications. When considering antiviral treatment, it is important to differentiate between symptomatic and asymptomatic patients. This study aimed to identify candidate plasma biomarkers for neurological complications of cCMV infection using proteomic analysis. METHODS: This study retrospectively enrolled five patients with symptomatic cCMV infection, four with asymptomatic cCMV infection with isolated sensorineural hearing loss (SNHL), and five with asymptomatic cCMV infection. The plasma samples were collected during neonatal period. The peptides were analyzed using liquid chromatography-mass spectrometry. The concentrations of differentially expressed proteins were validated using an enzyme-linked immunosorbent assay. RESULTS: A total of 456 proteins were identified and quantified. The levels of 80 proteins were significantly different between patients with and without cCMV-related symptoms including isolated SNHL. The levels of 31 proteins were significantly different between patients with and without neuroimaging abnormalities. The plasma concentrations of Fms-related receptor tyrosine kinase 4 in patients with cCMV-related symptoms were significantly higher than those in patients with asymptomatic cCMV infection. Moreover, plasma peptidylprolyl isomerase A levels were significantly higher in patients with neuroimaging abnormalities than in those without. CONCLUSIONS: Proteomic analysis of patients with cCMV infection showed that Fms-related receptor tyrosine kinase 4 and peptidylprolyl isomerase A could be novel diagnostic biomarkers for neurological complications of cCMV infection.

Lung-Cancer Risk in Mice after Exposure to Gamma Rays, Carbon Ions or Neutrons: Egfr Pathway Activation and Frequent Nuclear Abnormality.

Lung is one of the high-risk organs for radiation-induced carcinogenesis, but the risk of secondary lung-cancer development after particle-beam therapy and the underlying mechanism(s) remain to be elucidated. To investigate the effects of particle-beam radiation on adjacent normal tissues during cancer therapy, 7-week-old male and female B6C3F1 mice were irradiated with 0.2-4 Gy of gamma rays (for comparison), carbon ions (290 MeV/u, linear energy transfer 13 keV/µm), or fast neutrons (0.05-1 Gy, mean energy, ∼2 MeV), and lung-tumor development was assessed by histopathology. Mice irradiated with ≥2 Gy of carbon ions or ≥0.2 Gy of neutrons developed lung adenocarcinoma (AC) significantly sooner than did non-irradiated mice. The relative biological effectiveness values for carbon ions for lung AC development were 1.07 for male mice and 2.59 for females, and the corresponding values for neutrons were 4.63 and 4.57. Genomic analysis of lung ACs revealed alterations in genes involved in Egfr signaling. Hyperphosphorylation of Erk and a frequent nuclear abnormality (i.e., nuclear groove) were observed in lung ACs of mice irradiated with carbon ions or neutrons compared with ACs from non-irradiated or gamma-ray-irradiated groups. Our data indicate that the induction of lung AC by carbon ions occurred at a rate similar to that for gamma rays in males and approximately 2-to 3-fold greater than that for gamma rays in females. In contrast, the effect of neutrons on lung AC development was approximately 4- to 5-fold greater than that of gamma rays. Our results provide valuable information concerning risk assessment of radiation-induced lung tumors after particle-beam therapy and increase our understanding of the molecular basis of tumor development.

Total hip arthroplasty after rotational acetabular osteotomy for developmental dysplasia of the hip: a retrospective observational study.

BACKGROUND: Total hip arthroplasty after osteotomy is more technically challenging than primary total hip arthroplasty, especially concerning cup placement. This is attributed to bone morphological abnormalities caused by acetabular bone loss and osteophyte formation. This study aimed to investigate the clinical and radiological outcomes of total hip arthroplasty after rotational acetabular osteotomy compared with those of primary total hip arthroplasty, focusing mainly on acetabular deformity and cup position. METHODS: The study included 22 hips that had undergone rotational acetabular osteotomy and 22 hips in an age- and sex-matched control group of patients who underwent total hip arthroplasties between 2005 and 2020. We analyzed cup abduction and anteversion; lateral, anterior, and posterior cup center-edge angle; hip joint center position; femoral anteversion angle; and presence of acetabular defect using postoperative radiography and computed tomography. Operative results and clinical evaluations were also analyzed. RESULTS: The clinical evaluation showed that the postoperative flexion range of motion was lower in total hip arthroplasty after rotational acetabular osteotomy than in primary total hip arthroplasty, although no significant difference was noted in the postoperative total Japanese Orthopedic Association hip score. The operative time was significantly longer in the rotational acetabular osteotomy group than in the control group, but there was no significant difference in blood loss. The lateral cup center-edge angle was significantly higher and the posterior cup center-edge angle was significantly lower in the total hip arthroplasty after rotational acetabular osteotomy, suggesting a posterior bone defect existed in the acetabulum. In total hip arthroplasty after rotational acetabular osteotomy, the hip joint center was located significantly superior and lateral to the primary total hip arthroplasty. CONCLUSIONS: In total hip arthroplasty after rotational acetabular osteotomy, the cup tended to be placed in the superior and lateral positions, where there was more bone volume. The deformity of the acetabulum and the high hip center should be considered for treatment success because they may cause cup instability, limited range of motion, and impingement.

Eccentric Rotational Acetabular Osteotomy Using Computed Navigation Guidance for Developmental Dysplasia of the Hip, Sacroiliac Fusion, and Femoroacetabular Impingement Owing to Acetabular Retroversion: A Case Report.

BACKGROUND: Developmental dysplasia of the hip (DDH) is the main factor that causes secondary osteoarthritis of the hip (hip OA). Acetabular retroversion results in pincer-type femoroacetabular impingement (FAI), and this is also known to cause secondary hip OA. However, few cases of DDH with acetabular retroversion have been reported, and there is no definite opinion on the optimal treatment. We report a rare case of DDH and FAI owing to acetabular retroversion and dysostosis of the sacroiliac joint that was treated with eccentric acetabular rotational osteotomy (ERAO) using navigation guidance. CASE PRESENTATION: A 27-year-old woman presented with DDH and acetabular retroversion with FAI and dysostosis of the sacroiliac joint on the contralateral side. We performed ERAO using computed navigation guidance and improved the coverage and retroversion of the acetabulum. The acetabular anteversion angle improved from 1° retroversion to 9° anteversion after surgery, the center edge angle improved from 18° to 43°, and the acetabular head index improved from 69% to 93%. The cam lesion of the femur was resected. The Harris Hip Score improved from 55.7 to 100 points at the final examination 2 years after surgery. CONCLUSIONS: In this rare case of DDH and FAI, ERAO using computed navigation guidance accurately improved the coverage and retroversion of the acetabulum.

RGB-color forward-viewing spectrally encoded endoscope using three orders of diffraction.

Spectrally encoded endoscopy (SEE) is an ultra-miniature endoscopy technology that encodes each spatial location on the sample with a different wavelength. One challenge in SEE is achieving color imaging with a small probe. We present a novel SEE probe that is capable of conducting real-time RGB imaging using three diffraction orders (6th order diffraction of the blue spectrum, 5th of green, and 4th of red). The probe was comprised of rotating 0.5 mm-diameter illumination optics inside a static, 1.2 mm-diameter flexible sheath with a rigid distal length of 5 mm containing detection fibers. A color chart, resolution target, and swine tissue were imaged. The device achieved 44k/59k/23k effective pixels per R/G/B channels over a 58° angular field and differentiated a wide gamut of colors.

Enhancement of morphine-induced antinociception after electroconvulsive shock in mice.

Electroconvulsive therapy (ECT) has been applied for chronic pain for decades. The amounts of opioids to treat pain are sometimes reduced after a series of ECT. The effect of ECT on morphine-induced analgesia and its mechanism underlying the reduction of morphine requirement has yet to be clarified. Therefore, we administered electroconvulsive shocks (ECS) to mice and investigated the antinociceptive effect of morphine in a hot plate test. We examined the expression level of µ-opioid receptor in the thalami of mice 25 h after administration of ECS compared to the thalami of mice without ECS administration using western blotting. ECS disturbed the development of a decrease in the percentage of maximal possible effect (%MPE), which was observed 24 h after a morphine injection, when ECS was applied 25, 23, 21, and 12 h before the second administration of morphine. We also examined the effect of ECS on the dose-response curve of %MPE to morphine-antinociception. Twenty-five hours after ECS, the dose-response curve was shifted to the left, and the EC50 of morphine given to ECS-pretreated mice decreased by 30.1% compared to the mice that were not pretreated with ECS. We also found that the expression level of µ-opioid receptors was significantly increased after ECS administration. These results confirm previous clinical reports showing that ECT decreased the required dose of opioids in neuropathic pain patients and suggest the hypothesis that this effect of ECT works through the thalamus.

Prosthetic joint infection after total hip arthroplasty caused by Sneathia sanguinegens: A case report (CARE-complaint).

INTRODUCTION: Sneathia sanguinegens(S sanguinegens) is a gram-negative rod-shaped bacterium mostly reported to cause a perinatal infection, and there are no reports of S sanguinegens in prosthetic joint infection (PJI). The purpose of this report is to describe a very rare case of PJI after total hip arthroplasty (THA) caused by S sanguinegens. PATIENT CONCERNS: A 79-year-old woman presented with right coxalgia, inability to walk, and a fever of 39°C. She had undergone THA 28 years earlier for osteoarthritis of the hip. DIAGNOSES: The diagnosis was acute late-onset PJI, because blood tests revealed marked inflammatory reaction and computed tomography showed an abscess at the right hip joint; synovial fluid analysis resulted in detection of a gram-negative bacillus. INTERVENTION: Surgical debridement with retention of the implant and antibiotic therapy was performed. OUTCOMES: One month after surgery, polymerase chain reaction (PCR) assay showed that the pathogen was 99.9% likely to be S sanguinegens. There has been no recurrence of infection or loosening of the implant in the 2 years since her surgery. LESSONS: PCR should facilitate detection of previously unknown pathogens and potentially novel bacterial species.

Accumulation of microdamage and low bone mass in the femoral head as a cause of subchondral insufficiency fracture in a patient with osteogenesis imperfecta.

Subchondral insufficiency fractures of the femoral head are generally considered to be osteoporosis-related fragility fractures. There have been reports of microfractures being found in subchondral bone on pathological examination. However, the mechanism of these microfractures is not known. In this report, we describe a patient with osteogenesis imperfecta who developed a subchondral insufficiency fracture of the femoral head after a fall that had resulted in a subcapital femoral neck fracture. Bipolar hemiarthroplasty was performed, and bone at the femoral head and neck was sampled for pathophysiological examination. Hematoxylin and eosin staining revealed microfractures and microcallus in the subchondral bone in the femoral head, indicating healing of a subchondral insufficiency fracture before the subcapital femoral neck fracture. Moreover, decreased bone volume and accumulated microdamage were observed in the subchondral bone but not in the cancellous bone in the femoral neck. These findings suggest that subchondral insufficiency fracture of the femoral head is a stress fracture caused by accumulation of microdamage in fragile subchondral bone.

Accumulation of microdamage in subchondral bone at the femoral head in patients with end-stage osteoarthritis of the hip.

In end-stage osteoarthritis (OA) of the hip, the effect of bone metabolism with and without cartilage is unclear. In this study, we aimed to investigate histomorphology and microdamage in the subchondral bone of the femoral head in areas with and without articular cartilage in patients with end-stage OA. Nineteen femoral heads were evaluated in 10 women who underwent total hip arthroplasty for OA and in nine cadaveric controls (CNT). Chondral thickness and subchondral bone plate thickness (SBP.Th) were measured in 5-mm-wide areas where cartilage was lost (area A) or preserved (area B) in OA and in corresponding areas in the load-bearing portion of the femoral head in the CNT. Histomorphometry and microdamage in 5 × 5-mm areas of cancellous bone were assessed. SBP.Th and bone volume were significantly greater in area A than in area B or in the CNT. Osteoid volume was significantly greater in area A than in area B or in the CNT. There was no significant difference in eroded surface between area A and CNT. Microcrack density was significantly greater in area A than in area B or in the CNT. Although accumulation of microdamage was caused by concentration of stress on the subchondral bone in the cartilage loss area in end-stage OA, remodeling for microdamage repairing mechanism was not enhanced. It was considered that the subchondral cancellous bone volume was increased because of modeling, not remodeling, by stress concentration due to articular cartilage loss.

Weekly teriparatide treatment increases vertebral body strength by improving cortical shell architecture in ovariectomized cynomolgus monkeys.

Weekly teriparatide treatment is reported to reduce the incidence of osteoporotic vertebral fractures. However, the effect of weekly teriparatide on cortical bone has not been clarified. This study aimed to examine the effects of weekly teriparatide treatment on bone mass, intracortical structure, and remodeling of the lumbar vertebral cortical shell and its relation to mechanical properties in ovariectomized cynomolgus monkeys. Female monkeys, aged 9 to 15 years, were divided into four groups: (1) SHAM group, (2) ovariectomized group (OVX group), (3) OVX with 1.2 µg/kg once-weekly teriparatide group (LOW group), (4) OVX with 6.0 µg/kg once-weekly teriparatide group (HIGH group). After 18 months, all animals were double-labeled with calcein, and lumbar vertebrae were analyzed with histomorphometry and compressive mechanical tests. Following ovariectomy, we found reductions in the anterior cortical shell area of the vertebrae and reductions in nearly all of the tested vertebral mechanical properties. Weekly teriparatide significantly preserved the anterior cortical shell area and the energy absorption capacity of the lumbar vertebrae in a dose-dependent manner. Multiple regression analyses indicated that improved mechanical properties were more associated with the increased anterior cortical shell area rather than the cancellous bone volume. The intracortical structure of the Haversian canals was also preserved following teriparatide treatment after ovariectomy. These findings suggest the importance of the cortical shell as a therapeutic target in the treatment of osteoporosis. Weekly teriparatide treatment increases the compressive mechanical strength of the lumbar vertebrae by thickening the anterior cortical shell.

Once-Weekly Teriparatide Treatment Prevents Microdamage Accumulation in the Lumbar Vertebral Trabecular Bone of Ovariectomized Cynomolgus Monkeys.

The effect of teriparatide treatment on microdamage accumulation has yet to be examined in animal studies. The purpose of this study was to investigate the effect of once-weekly teriparatide treatment on bone microdamage accumulation and the relationship between microdamage parameters and bone mass, architecture, turnover, and collagen cross-linking in the lumbar vertebral trabecular bone of ovariectomized (OVX) cynomolgus monkeys. Female monkeys were divided into four groups (n = 18-20 per group): (1) SHAM group, (2) OVX group, (3) OVX with 1.2 µg/kg once-weekly teriparatide group (LOW group), (4) OVX with 6.0 µg/kg once-weekly teriparatide group (HIGH group). After 18 months, all animals were double-labeled with calcein for histomorphometry. L3 and L7 lumbar vertebrae were harvested and analyzed for differences in histomorphometry, microdamage, and collagen cross-linking. The iliac crest was also analyzed for differences in bone turnover. In the OVX group, cancellous bone mass was reduced and microdamage accumulation was increased as compared with the SHAM control. Once-weekly teriparatide at both doses prevented the decrease in bone mass and increase in microdamage accumulation, and improved the distribution of collagen cross-linkage types. Regression analyses indicated that decreased microdamage accumulation was associated with reduced non-enzymatic cross-link pentosidine rather than increased cancellous bone mass or enzymatic cross-links. These findings suggest that once-weekly teriparatide treatment decreases microdamage accumulation by recovering the balance in collagen cross-links.

Effect of Age at Exposure on the Incidence of Lung and Mammary Cancer after Thoracic X-Ray Irradiation in Wistar Rats.

Epidemiology studies have shown that children are at greater overall risk of radiation-induced cancer, but the modifying effect of age at exposure in different tissues is heterogeneous. Early epidemiology findings of increased lung cancer risk with increasing age at the time of exposure have been dismissed, with suggestions that the trend is an artefact from a failure to adequately correct for the effects of tobacco smoking. Yet, differing models used in subsequent analyses have shown that the increased susceptibility with age, counter to the overall solid tumor trend, can either be confirmed or discounted depending on the model parameters used. In this study, we analyzed the induction of tumors in female Wistar rats exposed to increasing thoracic doses of X-ray as neonates, juveniles or young adults, to allow the effect of age at exposure in this early period to be observed in the absence of any interactions with smoking. Histology was used to compare tumor subtypes among groups, and genomic DNA copy number alterations in a number of tumors arising after irradiation at different ages were examined. Induction of lung cancers increased with radiation dose, with the frequency of early occurring lung adenomas greater in rats irradiated at older ages. At the highest dose, the rats irradiated at 5 or 15 weeks of age showed increased age-specific rates of lung adenocarcinomas in later life compared to those irradiated at 1 week of age. However, thoracic mammary gland tumors induced by the highest dose at the later ages significantly decreased the lifespan in these groups, reducing the number of rats at risk of radiation-induced lung adenocarcinoma. There was no induction of mammary tumors outside of the irradiated field. Lung adenocarcinomas showed widespread DNA copy number aberrations at the chromosome level, but the only recurrent lesions were intragenic Fhit deletions and losses on chromosome 4. The results presented here suggest that the risk of radiation-induced lung cancer after irradiation may not monotonically decrease with age, and demonstrate that increasing lung cancer risk with exposure age can be observed independent of corrections for smoking, and that mammary tumors may show a similar relationship with age.

Effects of suppressed bone remodeling by minodronic acid and alendronate on bone mass, microdamage accumulation, collagen crosslinks and bone mechanical properties in the lumbar vertebra of ovariectomized cynomolgus monkeys.

Collagen crosslinking is an important determinant of the quality of bone material. We have previously shown that suppressed bone turnover by high doses of minodronic acid and alendronate increases compressive strength of vertebra, but also increases microdamage accumulation, in monkey bone. The aim of this study is to examine the effects of these bisphosphonates on collagen crosslinks and intrinsic material properties, in addition to microdamage accumulation, in vertebral cancellous bone in ovariectomized cynomolgus monkeys. Sixty female monkeys aged 9-17years were divided into five groups: sham and ovariectomized groups were treated daily for 17months with lactose vehicle, and the other three groups were given minodronic acid daily at 0.015 or 0.15mg/kg or alendronate daily at 0.5mg/kg orally. After sacrifice, lumbar vertebrae were subjected to histomorphometry, microdamage measurement, analysis of collagen crosslinking and compressive mechanical tests. Minodronic acid caused dose-dependent suppression of increased bone remodeling due to ovariectomy, and low-dose minodronic acid suppressed remodeling same level as alendronate. However, low-dose minodronic acid did not change microdamage accumulation, collagen maturity and the pentosidine level, whereas high-dose minodronic acid and alendronate increased these parameters. Compressive ultimate load was increased following high-dose minodronic acid and alendronate, but no treatment altered the reduction in intrinsic material properties caused by ovariectomy. These findings suggest that deterioration of bone material and formation of pentosidine and microdamage induced by minodronic acid is less than that expected based on the extent of remodeling suppression, in comparison with alendronate, but this was not reflected in any significant change of mechanical properties.