Journal of Bone and Mineral Metabolism最新文献

Introduction

To describe the real-world use of romosozumab in Japan, we conducted a chart review of > 1000 Japanese patients with osteoporosis (OP) at high risk of fracture, across multiple medical institutions.

Materials and methods

Treatment-naïve and prior OP-treatment patients who received romosozumab for 12 months followed by ≥ 6 months of sequential OP treatment were included. The primary objective described the baseline demographics and clinical characteristics; secondary objectives evaluated changes in bone mineral density (BMD) and bone turnover markers in all patients and effectiveness of romosozumab in a sub-group of treatment-naïve patients using the fracture risk assessment tool (FRAX^®).

Results

Of the 1027 patients (92.4% female), 45.0% were treatment-naïve. The mean ± SD age of treatment-naïve versus prior OP-treatment patients was 76.8 ± 8.5 and 77.1 ± 8.5 years. The most frequent prior OP treatment was bisphosphonates (45.0%). Romosozumab treatment for 12 months increased BMD at the lumbar spine in all groups; the median percent change from baseline in lumbar spine BMD was higher in the treatment-naïve (13.4%) versus prior OP-treatment group (bisphosphonates [9.2%], teriparatide [11.3%], denosumab [DMAb, 4.5%]). DMAb, bisphosphonates, or teriparatide after romosozumab maintained the BMD gains at all skeletal sites at month 18 in treatment-naïve patients. Most treatment-naïve patients were at high risk of fracture, BMD increased consistently with romosozumab regardless of the baseline fracture risk assessed by FRAX.

Conclusion

This large-scale, multicenter chart review provides clinically relevant insights into the profiles of patients initiating romosozumab, effectiveness of real-world romosozumab use, and sequential therapy in Japanese patients at high risk of fracture.

Clinical studies revealed a relationship between osteoporosis and sarcopenia. Based on this background, crosstalk between muscle and bone has emerged as a novel research field in the past decade. Among the interactions that occur between muscle and bone, humoral factors, such as osteokines and myokines, affect distant muscles and bones, respectively. Recent studies proposed several important myokines that have an impact on bone, such as myostatin and irisin. Signaling by these myokines has potential as a target for drug development and biomarkers for exercise. Mechanical stress, endocrine disorders, and chronic kidney disease partly affect bone through various myokines in crosstalk between muscle and bone. Moreover, the involvement of extracellular vesicles from bone or muscle as communication tools in the interactions between muscle and bone was recently proposed. Further clinical studies are needed to clarify the significance of myokine regulation under physiological and pathophysiological states in humans.

Introduction

The bone tissue is susceptible to hypergravity (+ G) environment. It is necessary to discuss the extent to which specific + G values are beneficial or detrimental to bone tissue. The objective of this study was to characterize the effects of high + G values on mechanical properties, microstructures, and cellular metabolism of bone.

Materials and methods

30 male Wistar rats aged 12 weeks were randomly divided into 5 groups, and bore different + G (namely + 1G, + 4G, + 8G, + 10G and + 12G) environments respectively for 4 weeks, 5 days each week, and 3 minutes each day. The macro-mechanical parameters, microstructure parameters, and mRNA transcription levels of the tibia were determined through the three-point bending method, micro-CT detection, and q-PCR analysis, respectively.

Results

As the + G value increases, hypergravity becomes increasingly detrimental to the macro-mechanical performance of rat tibia. Concerning the microstructure of cancellous bone, there appears to be a favorable trend at + 4G, followed by a progressively detrimental trend at higher G values. In addition, the mRNA transcription levels of OPG and RANKL show an initial tendency of enhanced bone absorption at +4G, followed by an increase in bone remodeling capacity as G value increases.

Conclusion

The higher G values correspond to poorer macro-mechanical properties of the tibia, and a + 4G environment benefits the microstructure of the tibia. At the cellular level, bone resorption is enhanced in the + 4G group, but the bone remodeling capability gradually increases with further increments in G values.

Introduction: The selective androgen receptor modulator ligandrol (LGD-4033 or VK5211) has been shown to improve muscle tissue. In the present study, the effect of ligandrol on bone tissue was investigated in ovariectomized rat model.

Materials and methods: Three-month-old Sprague Dawley rats were either ovariectomized (OVX, n = 60) or left intact (NON-OVX, n = 15). After 9 weeks, OVX rats were divided into four groups: untreated OVX (n = 15) group and three OVX groups (each of 15 rats) treated with ligandrol orally at doses of 0.03, 0.3, or 3 mg/kg body weight. After five weeks, lumbar vertebral bodies (L), tibiae, and femora were examined using micro-computed tomographical, biomechanical, ashing, and gene expression analyses.

Results: In the 3-mg ligandrol group, bone structural properties were improved (trabecular number: 38 ± 8 vs. 35 ± 7 (femur), 26 ± 7 vs. 22 ± 6 (L), 12 ± 5 vs. 6 ± 3 (tibia) and serum phosphorus levels (1.81 ± 0.17 vs.1.41 ± 0.17 mmol/l), uterus (0.43 ± 0.04 vs. 0.11 ± 0.02 g), and heart (1.13 ± 0.11 vs. 1.01 ± 0.08 g) weights were increased compared to the OVX group. Biomechanical parameters were not changed. Low and medium doses did not affect bone tissue and had fewer side effects. Body weight and food intake were not affected by ligandrol; OVX led to an increase in these parameters and worsened all bone parameters.

Conclusion: Ligandrol at high dose showed a subtle anabolic effect on structural properties without any improvement in biomechanical properties of osteoporotic bones. Considering side effects of ligandrol at this dose, its further investigation for the therapy of postmenopausal osteoporosis should be reevaluated.

Introduction: To investigate the differences in the incidence rates of suspected stage 0/1 osteonecrosis of the jaw (ONJ) and incidence risk of relevant clinical findings of suspected stage 0 ONJ between patients treated with sequential therapy comprising weekly teriparatide for 72 weeks followed by alendronate for 48 weeks vs. those who received monotherapy with alendronate for 120 weeks.

Materials and methods: Suspected stage 0/1 ONJ was defined by non-specific symptoms. Tooth mobility and periodontal symptoms (gingival bleeding, swelling, and/or pain) were selected as clinical findings of suspected stage 0 ONJ. Poisson regression models were applied to calculate the incidence rate ratios of suspected stage 0/1 between the teriparatide group (TG) and alendronate group (AG). Generalized linear models were used to calculate the risk ratios of clinical findings between groups.

Results: Two hundred and sixty-one participants in the TG and 344 in the AG answered a structured questionnaire on oral health and were included in this study. There were no significant differences between the groups in the incidence rate of suspected stage 0/1 ONJ at both 72 and 120 weeks. The risk ratio of the TG to AG for tooth mobility was 0.34 (95% confidence interval [CI] 0.13-0.88, p = 0.02) at 72 weeks and 0.90 (95% CI 0.40-2.03, p = 0.83) at 120 weeks. The incidence rate of tooth mobility related to periodontal symptoms decreased in the TG and increased in the AG during the study.

Conclusion: Tooth mobility accompanied by clinical periodontal symptoms may be a useful early sign of stage 0 ONJ.

Introduction: Eldecalcitol (ELD) is an active vitamin D₃ analog (AVD) commonly used to treat osteoporosis in Japan. Although routine monitoring of serum calcium levels during ELD therapy is recommended, little is known about the actual frequency and determinants of monitoring.

Materials and methods: This was a descriptive cohort study using a Japanese electronic medical records database. We identified osteoporosis patients who initiated treatment with ELD or other AVDs (alfacalcidol and calcitriol) between April 1, 2011 and September 10, 2021. The index date for cohort entry was the first prescription date of ELD or other AVDs. The frequency of serum calcium monitoring was evaluated every 6 months. Determinants of serum calcium monitoring were identified using multivariable logistic regression models. We also calculated the incidence of hypercalcemia and the frequency of serum calcium monitoring within 6 months before hypercalcemia.

Results: We identified 12,671 ELD users and 7867 other AVD users. Within 6 months after cohort entry, 45.9% of ELD users and 58.7% of other AVD users underwent serum calcium monitoring. Female sex, no use of systemic corticosteroids, moderate-to-good renal function, treatment in smaller hospitals, and treatment in orthopedic surgery departments were associated with a lower likelihood of receiving serum calcium monitoring during ELD therapy. The incidence of hypercalcemia among ELD users was 6.36 per 100 person-years, with 20.6% of cases not receiving serum calcium monitoring before hypercalcemia.

Conclusion: Our findings suggest that serum calcium monitoring is not given adequate attention during ELD therapy in routine clinical practice.

Introduction: Androgen deprivation therapy (ADT) for prostate cancer causes cancer treatment-induced bone loss (CTIBL), increases the fracture risk 2-3 times, and worsens life prognoses. The Japan Society of Bone and Mineral Research (JSBMR) created a CTIBL treatment manual in 2020; however, no study has validated its use in patients with ADT/CTIBL prostate cancer.

Materials and methods: This study classified 124 patients with prostate cancer without bone metastasis who received ADT into high- and low-risk groups using the JSBMR CTIBL algorithm. Comparisons were made with the period to incident vertebral fracture and the existing International Osteoporosis Foundation (IOF) classification.

Results: The median age was 74 years; the median observation period was 81 months. At 1, 3, 5, 7, and 9 years, the prevalence of incident vertebral fractures was, respectively, 3.3%, 10.7%, 17.9%, 21.4%, and 31.2% in the entire population; 13%, 27%, 36%, 42%, and 58% in the high-risk group (19%); and 1%, 7%, 14%, 17%, and 25% in the low-risk group (81%). The hazard ratio between the two groups was 3.57 (p = 0.0004). Based on multivariate analysis, age, previous vertebral fracture and femoral neck bone density were significant risk factors for incidental vertebral fracture. The JSBMR had a hazard ratio of 3.26 (p = 0.04) relative to 1.13 (p = 0.84) for the IOF, indicating the JSBMR classification performed better.

Conclusion: Taking preventive measures against fractures is necessary, including starting bone-modifying agents early in patients with a high fracture risk. The JSBMR CTIBL manual may be useful for this purpose.

Introduction: Bisphosphonate (BF) therapy is strongly related to the occurrence of medication-related osteonecrosis of the jaw (ONJ). However, no previous study has evaluated if there are sex-related differences on the ONJ establishment together with bone biomechanical alterations, and if they could have a synergy with the ZA treatment.

Materials and methods: This study aimed to analyze the physicochemical properties of mineralized tissues in a zoledronate (ZA)-related osteonecrosis mouse model, by a 2 × 2-factorial design, considering sex (female/male) and treatment (ZA/Saline) factors (n = 8/group). After three ZA (1.0 mg/kg) or saline administrations (days 0, 7, 14), the lower left second molar was extracted (day 42). Further ZA administration (day 49) and euthanasia (day 70) were conducted. After confirmation of ZA-induced jaw necrosis (histologic and microtomographic analysis), spectroscopic and mechanical parameters were assessed.

Results: ZA-treated groups presented lower bone density due to impaired healing of tooth extraction socket. Sex-related alterations were also observed, with lower bone density in females. Regarding biomechanical parameters, sex and treatment exerted independent influences. ZA, although decreasing flexural modulus and yield stress, increases stiffness mainly due to a higher bone volume. Females show less resistance to higher loads compared to males (considering dimension-independent parameters). Additionally, ZA increases crystallinity in bone and dental structure (p < 0.05). In summary, although strongly related to osteonecrosis occurrence, ZA modifies bone and dental mineral matrix, improving bone mechanical properties.

Conclusion: Despite sex-dependent differences in bone biomechanics and density, osteonecrosis was established with no sex influence. No synergistic association between sex and treatment factors was observed in this study.

Introduction: A 2015 survey of the Japan Osteoporosis Society (JOS) on medication-related osteonecrosis of the jaw (MRONJ) revealed that cooperation between physicians and dentists was poor. Discontinuation of antiresorptive agents before tooth extraction was found to increase adverse events without preventing MRONJ. We compared this 2015 survey with a new survey conducted in 2022 to investigate cooperation between physicians and dentists for MRONJ.

Materials and methods: A web-based structured questionnaire including 13 key queries was sent to 3813 physicians who were members of JOS, and 1227 (32.2%) responses were received.

Results: Of the 1227 respondents, 909 (74.1%) had complied with a discontinuation request from a dentist before tooth extraction, although 25.4% of medications were not related to the incidence of MRONJ. Of these, 177 respondents reported 252 adverse events including 10 (1.3%) cases of MRONJ. The prevalence of fractures increased from 4.8% in 2015 to 8.2% in 2022. The rates of respondents who requested oral health care by a dentist before antiresorptive agent therapy and reported cooperation between physicians and dentists were 72.7% and 42.4% in 2022 compared with 32.9% and 24.8% in 2015, respectively. The rates of cooperation among the 47 prefectures in Japan were significantly different, ranging from 10.0 to 83.3% (p = 0.02).

Conclusion: This study confirmed increased cooperation between physicians and dentists for MRONJ in Japan. However, a more equal distribution of cooperation across Japan is necessary to optimally manage MRONJ. Discontinuation of antiresorptive agents is no longer necessary because fractures during discontinuation continue to increase in Japan.

Introduction: The discrepancy between bone mineral density (BMD), the gold standard for bone assessment, and bone strength is a constraint in diagnosing bone function and determining treatment strategies for several bone diseases. Gastric hypochlorhydria induced by clinically used proton pump inhibitor (PPI) therapy indicates a discordance between changes in BMD and bone strength. Here, we used Cckbr-deficient mice with gastric hypochlorhydria to examine the effect of gastric hypochlorhydria on bone mass, BMD, and preferential orientation of the apatite crystallites, which is a strong indicator of bone strength.

Materials and methods: Cckbr-deficient mice were created, and their femurs were analyzed for BMD and preferential orientation of the apatite c-axis along the femoral long axis.

Results: Cckbr-deficient mouse femurs displayed a slight osteoporotic bone loss at 18 weeks of age; however, BMD was comparable to that of wild-type mice. In contrast, apatite orientation in the femur mid-shaft significantly decreased from 9 to 18 weeks. To the best of our knowledge, this is the first report demonstrating the deterioration of apatite orientation in the bones of Cckbr-deficient mice.

Conclusion: Lesions in Cckbr-deficient mice occurred earlier in apatite orientation than in bone mass. Hence, bone apatite orientation may be a promising method for detecting hypochlorhydria-induced osteoporosis caused by PPI treatment and warrants urgent clinical applications.