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Purpose: This study evaluated the efficacy, safety, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of SB16 versus reference denosumab (DEN) up to 18 months in postmenopausal osteoporosis (PMO) patients, and assessed outcomes after switching from DEN to SB16 compared to those who continued with DEN or SB16., Methods: 457 PMO patients were initially randomized, with 407 re-randomized at Month 12 to either continue DEN (DEN+DEN), switch to SB16 (DEN+SB16), or continue SB16 (SB16 + SB16) through Month 18. Efficacy was assessed by the percent change from baseline in bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck. Safety, PD, PK, and immunogenicity were evaluated throughout the study period., Results: Mean percent changes from baseline in lumbar spine, total hip, and femoral neck BMD at Month 18 were comparable across treatment groups, indicating comparable efficacy between SB16 and DEN. The mean percent change in lumbar spine BMD was 6.8 % (SB16 + SB16), 6.2 % (DEN+SB16), and 6.8 % (DEN+DEN). Total hip BMD increased by 4.4 %, 3.5 %, and 4.0 %, and femoral neck BMD by 3.4 %, 3.1 %, and 2.7 % for SB16 + SB16, DEN+SB16, and DEN+DEN, respectively. Safety profiles were similar among groups, with no new safety concerns identified after switching. Only one patient in the DEN+SB16 group developed non-neutralizing anti-drug antibodies by Month 18, indicating a low immunogenicity risk for SB16., Conclusion: Switching from DEN to SB16 demonstrated comparable efficacy, safety, PD, PK, and immunogenicity in PMO patients relative to those who continued DEN. SB16 was well tolerated over 18 months, demonstrating comparable outcomes to DEN., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yoon-sok Chung reports a relationship with Amgen that includes: speaking and lecture fees. Yoon-sok Chung reports a relationship with Samsung Bioepis that includes: consulting or advisory and funding grants. Bente Langdahl reports a relationship with Amgen that includes: consulting or advisory and speaking and lecture fees. Bente Langdahl reports a relationship with UCB that includes: consulting or advisory and speaking and lecture fees. Bente Langdahl reports a relationship with Gedeon-Richter that includes: speaking and lecture fees. Bente Langdahl reports a relationship with Astellas that includes: speaking and lecture fees. Bente Langdahl reports a relationship with AstraZeneca that includes: speaking and lecture fees. Bente Langdahl reports a relationship with Samsung Bioepis that includes: funding grants. Rafal Plebanski reports a relationship with Samsung Bioepis that includes: funding grants. Edward Czerwinski reports a relationship with Amgen that includes: consulting or advisory and speaking and lecture fees. Edward Czerwinski reports a relationship with Samsung Bioepis that includes: funding grants. Eva Dokoupilova reports a relationship with AbbVie that includes: funding grants. Eva Dokoupilova reports a relationship with Eli Lilly that includes: funding grants. Eva Dokoupilova reports a relationship with GSK that includes: funding grants. Eva Dokoupilova reports a relationship with Novartis that includes: funding grants. Eva Dokoupilova reports a relationship with Biopharma SPRL that includes: funding grants. Eva Dokoupilova reports a relationship with Pfizer that includes: funding grants. Eva Dokoupilova reports a relationship with Sanofi that includes: funding grants. Eva Dokoupilova reports a relationship with Hexal AG that includes: funding grants. Eva Dokoupilova reports a relationship with Gilead that includes: funding grants. Eva Dokoupilova reports a relationship with Janssen that includes: funding grants. Eva Dokoupilova reports a relationship with Galapagos that includes: funding grants. Eva Dokoupilova reports a relationship with Samsung Bioepis that includes: funding grants. Jerzy Supronik reports a relationship with Samsung Bioepis that includes: funding grants. Jan Rosa reports a relationship with Samsung Bioepis that includes: funding grants. Andrzej Mydlak reports a relationship with Samsung Bioepis that includes: funding grants. Rafal Sapula reports a relationship with Zamosc Rehabilitation Clinic that includes: employment. Rafal Sapula reports a relationship with Polish Rehabilitation Society that includes: board membership. Rafal Sapula reports a relationship with Medical Rehabilitation for Lublin Region that includes: consulting or advisory. Rafal Sapula reports a relationship with Samsung Bioepis that includes: funding grants. Anna Rowinska-Osuch reports a relationship with Samsung Bioepis that includes: funding grants. Ki-Hyun Baek reports a relationship with Samsung Bioepis that includes: funding grants. Audrone Urboniene reports a relationship with Samsung Bioepis that includes: funding grants. Robert Mordaka reports a relationship with Samsung Bioepis that includes: funding grants. Sohui Ahn reports a relationship with Samsung Bioepis that includes: employment. Sohui Ahn reports a relationship with Samsung Biologics that includes: equity or stocks. Young Hee Rho reports a relationship with Samsung Bioepis that includes: employment. Young Hee Rho reports a relationship with Samsung Biologics that includes: equity or stocks. Jisuk Ban reports a relationship with Samsung Bioepis that includes: employment. Jisuk Ban reports a relationship with Samsung Biologics that includes: equity or stocks. Richard Eastell reports a relationship with AstraZeneca that includes: consulting or advisory. Richard Eastell reports a relationship with Immunodiagnostic Systems that includes: consulting or advisory. Richard Eastell reports a relationship with Sandoz that includes: consulting or advisory. Richard Eastell reports a relationship with Samsung Bioepis that includes: consulting or advisory. Richard Eastell reports a relationship with CL Bio that includes: consulting or advisory. Richard Eastell reports a relationship with CureTeQ that includes: consulting or advisory. Richard Eastell reports a relationship with Biocon that includes: consulting or advisory. Richard Eastell reports a relationship with Grunenthal that includes: consulting or advisory. Richard Eastell reports a relationship with Takeda that includes: consulting or advisory. Richard Eastell reports a relationship with Theramex that includes: consulting or advisory. Richard Eastell reports a relationship with UCB that includes: consulting or advisory. Richard Eastell reports a relationship with Pharmacosmos that includes: speaking and lecture fees. Richard Eastell reports a relationship with Alexion that includes: speaking and lecture fees. Richard Eastell reports a relationship with Radius that includes: speaking and lecture fees. Richard Eastell reports a relationship with UCB that includes: speaking and lecture fees. Richard Eastell reports a relationship with Amgen that includes: speaking and lecture fees. Richard Eastell reports a relationship with Samsung Bioepis that includes: travel reimbursement. Richard Eastell reports a relationship with CL Bio that includes: travel reimbursement. Richard Eastell reports a relationship with Alexion that includes: funding grants. Richard Eastell reports a relationship with CL Bio that includes: funding grants. Richard Eastell reports a relationship with Osteolabs that includes: funding grants. Richard Eastell reports a relationship with DSMB for Biocon that includes: Chairman. Richard Eastell reports a relationship with DSMB for CureTeQ that includes: Chairman. Richard Eastell reports a relationship with DSMB for STOPFOP that includes: Chairman. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Bone mineral density (BMD) assessments alone might not be sufficient for assessing fracture risk in the whole population, and decreased balance is an important risk factor for fracture. The aim of this study was to evaluate the association between baseline physical performance and fracture risk., Methods: This community-based cohort study was conducted in rural areas. The follow-up examination was performed in 4015 subjects for approximately 4 years. We used the one-leg standing time (OLST) to assess static balance and the timed up-and-go test (TUGT) to assess dynamic balance. Fractures were assessed during the medical interview., Results: The participants were divided into quartile groups according to their performance level, and the lowest baseline OLST performance was associated with a 2.1-fold increased risk of major osteoporotic fracture (MOF) independent of age, gender, hip BMD, fall incidence, and lifestyle factors. The participants in the low performance quartile of baseline OLST or TUGT performance had an increased incidence of osteoporosis and falling compared to that in the participants in the highest baseline performance quartile after adjusting for covariates. Among the participants with a femoral neck T-score above -2.5, the participants with an OLST below 14 s had a 1.7-fold higher risk of MOF than the participants with an OLST of 14 s or more., Conclusions: The measurement of static balance by the OLST predicted the risk of fracture in Korean adults independent of BMD and fall history. Our results suggest that the OLST may have clinical utility in identifying individuals at risk of fracture, especially those who might not be adequately identified by BMD measurements alone., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Bone loss is highly prevalent after gastrectomy in gastric cancer patients. Therefore, the efficacy of medical treatment should be evaluated in patients undergoing gastrectomy., Methods: We conducted an unblinded, randomized controlled trial of patients who underwent gastrectomy to treat gastric cancer. The intention-to-treat participants (n = 107) were randomly assigned to receive either alendronate at a weekly dose of 70 mg and daily elemental calcium (500 mg) with cholecalciferol (1000 IU) or daily elemental calcium (500 mg) with cholecalciferol (1000 IU) only. The primary endpoint was defined by the changes in bone mineral density of four measurement sites: the lumbar spine, femur neck, total hip, and trochanter. Changes in bone turnover markers, osteocalcin and collagen I carboxyterminal telopeptide were also observed., Results: At baseline, there were no differences between the two groups in bone mineral density. In the lumbar spine and trochanter, there were no significant percentage changes compared with the baseline in the alendronate group, but a significant decrease was noted in the control group (p < 0.001 for both lumbar spine and trochanter). In the femur neck and total hip, a larger decrease was observed compared with the baseline in the control group (p < 0.001 for both femur neck and total hip). Significant percentage increases in serum osteocalcin compared with baseline were noted in the control group (p for trend <0.001), but there was no change in the alendronate group (p for trend = 0.713). Collagen I carboxyterminal telopeptide significantly declined in the alendronate group over 12 months (p for trend <0.001)., Conclusions: Prevention and treatment with bisphosphonate effectively reduces bone loss by suppressing bone resorption in gastric cancer patients undergoing gastrectomy., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: It has been demonstrated that bone mineral density (BMD) loss is substantial within the first 12 months after allogeneic hematopoietic stem cell transplantation (alloHSCT). Declines in BMD showed a disproportionate cortical bone loss even though trabecular bone is metabolically more active than cortical bone. This finding suggests a unique mechanism. However, the structural bone deficits after alloHSCT have not been well characterized. The trabecular bone score (TBS) has emerged as a method to assess bone microarchitecture. The aim of this study was to evaluate the changes in BMD and TBS in patients who received alloHSCT with follow-up of two years., Methods: All patients 18 years and older who received alloHSCT between 2009 and 2015 at Seoul St. Mary's Hospital, Korea were included. They were segregated into a first group (A, n = 24) that was evaluated for BMD at the time of alloHSCT and 12 months posttransplant and a second group (B, n = 44) that was evaluated for BMD at 12 and 24 months following alloHSCT., Results: Subjects in group A experienced a decrease in BMD at the femoral neck and total hip between the time of transplantation and 12 months posttransplantation: 0.056 ± 0.057 (5.48%) and 0.072 ± 0.063 (6.84%), respectively. Subjects in group B experienced an increase in BMD at the lumbar spine and total hip between 12 and 24 months post-alloHSCT: 0.047 ± 0.064 (4.90%) and 0.017 ± 0.045 (2.16%), respectively. In group A, TBS at 12 months post-alloHSCT decreased 0.028 ± 0.067 (1.92%) from the baseline (p = 0.086). In group B, TBS at 24 months post-alloHSCT increased 0.010 ± 0.049 (0.78%) from the 12 months post-alloHSCT evaluation (p = 0.149). TBS change was positively associated with BMD changes at all measured sites. The cumulative dose of glucocorticoid therapy was associated with loss of BMD at all measured sites and TBS. In addition, the dose of total body irradiation (TBI) was negatively associated with TBS., Conclusions: In summary, this study delineated longitudinal microarchitectural changes in bone structure occurring in the context of alloHSCT. TBS change per 12 months was insignificant during the two years following alloHSCT. Therefore, our data represented disproportionate cortical bone loss in the context of the microarchitecture., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Periostin is preferentially expressed by the periosteum, which mainly covers the long bones. Therefore, the role of periostin in osteoporotic fracture (OF) may differ depending on bone type. We performed a case-control study to investigate whether periostin can serve as a predictor of OF risk, particularly after dividing OFs into non-vertebral and vertebral fractures., Methods: Among 532 consecutive postmenopausal women not taking any drug or without any disease that could affect bone metabolism, 133 cases with OF (i.e., non-vertebral and/or vertebral fractures) and 133 age- and body mass index-matched controls were enrolled. Non-vertebral (i.e., forearm, humerus, hip, and pelvis; n=81) and morphological vertebral (n=62) fractures were identified by an interviewer-assisted questionnaire and lateral thoracolumbar radiographs, respectively. Bone mineral density (BMD) and plasma periostin levels were also measured., Results: Plasma periostin was markedly higher in subjects with non-vertebral fracture than their controls even after adjustment for BMD and potential confounders (P=0.006). Each standard deviation increment of plasma periostin was associated with a multivariable-adjusted odds ratio of 1.59 for non-vertebral fracture. The odds for non-vertebral fracture were 2.48-fold higher in subjects in the highest periostin tertile compared with those in the lowest periostin tertile (95% confidence interval=1.10-5.61). However, associations between plasma periostin and vertebral fracture were not observed, regardless of the adjustment model used. Consistently, plasma periostin levels were inversely associated with proximal femur BMD (P=0.007 to 0.030) but not lumbar spine BMD. In subgroup analyses, plasma periostin had no correlation with the levels of classical bone turnover markers., Conclusions: Plasma periostin may be a potential biomarker of the risk of OF, especially in non-spinal skeletal sites, such as the limbs, rather than spine., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Studies on the effects of levothyroxine (LT4) therapy on bone and bone metabolism have yielded conflicting results. This 1-year prospective study examined whether LT4 in patients with well-differentiated thyroid carcinoma (DTC) is a risk factor for bone mass loss and the subsequent development of osteoporosis. We examined 93 patients with DTC over 12months after initiating LT4 therapy (early postoperative period). We examined another 33 patients on long-term LT4 therapy for DTC (late postoperative period). Dual energy X-ray absorptiometry was performed at baseline and after 1year. The mean bone losses during the early postoperative period in the lumbar spine, femoral neck, and total hip, calculated as the percentage change between levels at baseline and 12months, were -0.88, -1.3 and -0.81%, respectively. Bone loss was more evident in postmenopausal women (lumbar spine -2.1%, femoral neck -2.2%, and hip -2.1%; all P<0.05). We compared the changes in annual bone mineral density (BMD) in postmenopausal women according to calcium/vitamin D supplementation. Bone loss tended to be higher in the postmenopausal women receiving no supplementation. There was no decrease in BMD among patients during the late postoperative period. The mean bone loss was generally greater in the early than in the late postoperative group, and this was significant at the lumbar spine (P=0.041) and femoral neck (P=0.010). TSH-suppressive levothyroxine therapy accelerates bone loss, predominantly in postmenopausal women and exclusively during the early post-thyroidectomy period., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Nuclear factor of activated T cell (NFAT) is a key transcription factor for receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. However, it is unclear whether NFAT plays a role in the expression of RANKL in osteoblasts. High extracellular calcium ([Ca(2+)](o)) increases intracellular calcium, enhances RANKL expression in osteoblasts/stromal cells, and induces osteoclastogenesis in a coculture of osteoblasts and hematopoietic bone marrow cells. Because intracellular calcium signaling activates the calcineurin/NFAT pathway, we examined the role of NFAT activation on high [Ca(2+)](o)-induced RANKL expression in MC3T3-E1 subclone 4 (MC4) cells. Among the family of NFAT transcription factors, expression of NFATc1 and NFATc3, but not NFATc2, NFATc4 or NFAT5, was observed in MC4 cells. High [Ca(2+)](o) increased the expression levels of NFATc1, NFATc3 and RANKL. Cyclosporin A and FK506, inhibitors of calcineurin phosphatase, blocked high [Ca(2+)](o)-induced expression of NFAT and RANKL. Knockdown of NFATc1 and NFATc3 by siRNA prevented high [Ca(2+)](o)-induced RANKL expression, whereas overexpression of NFATc1 and NFATc3 induced RANKL expression. Furthermore, overexpressed NFATc1 upregulated NFATc3 expression, but NFATc1 knockdown decreased NFATc3 expression. Chromatin immunoprecipitation and reporter assay results showed that NFATc3, but not NFATc1, directly binds to the RANKL promoter and stimulates RANKL expression. In summary, these results demonstrate that high [Ca(2+)](o) increases expression of RANKL via activation of the calcineurin/NFAT pathway in osteoblasts. In addition, high [Ca(2+)](o) induces the activation and expression of NFATc1; NFATc3 expression and activity are subsequently increased; and NFATc3 directly binds to the RANKL promoter to increase its expression., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Changes in bone and mineral metabolism that occur after gastrectomy have long been recognized. Gastrectomy has been identified as a risk factor for decreased bone mass and the increased fracture incidence. Previous investigations concerning postgastrectomy bone disease have been observational studies. No prospective studies have been reported that quantify the amount of bone loss after gastrectomy within the same patients. This study investigated 46 patients undergoing gastrectomy for gastric adenocarcinoma and analyzed 36 patients (58.1+/-10.8 years, 24 men and 12 women) who had dual energy X-ray absorptiometry (DXA) performed before and 1 year after gastrectomy. Systemic adjuvant chemotherapy was administered to 14 patients. Blood was sampled from all patients to determine serum calcium, phosphorous, and bone turnover marker levels before gastrectomy and at 1, 3, 6 and 12 months after surgery and for serum parathyroid hormone (PTH) and 25-hydroxyvitamin D levels before and 12 months after surgery. The mean bone loss in the lumbar spine, total hip, femoral neck, and trochanter, which was calculated as the percentage change from the baseline to the level measured at 12 months, was 5.7% (P<0.01), 5.4% (P<0.01), 6.6% (P<0.01) and 8.7% (P<0.01), respectively. Bone loss was generally greater in the group receiving chemotherapy. The serum calcium and phosphorous levels were not changed significantly and remained within the normal range throughout the observation period. After gastrectomy, the level of ICTP increased and reached a peak at 1 and 3 months, and progressively declined to baseline by 12 months. The osteocalcin levels were not coupled to an increase before 6 months. The level of 25-hydroxyvitamin D at 12 months postgastrectomy was not significantly changed compared to the baseline, however, the PTH levels increased by a mean of 63.6% at 12 months compared to the baseline (P<0.01). Significant correlations were found between the percent change in the BMD at the lumbar spine and total hip and the percentage change for the PTH level from their baselines to 12 months. The changes in the BMD at total hip, femoral neck, and trochanter also correlated to the change in body weight at 12 months. The data obtained by this study provides evidence that profound bone loss occurs in the setting of a bone remodeling imbalance during the early postgastrectomy period and allows the speculation that the gastrectomy related bone loss may be partially due to an overproduction of PTH.

This study prospectively investigated the changes of the serum levels of the sex steroids, IL-7, soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and osteoprotegerin (OPG) in bone marrow transplantation (BMT) recipients. This study also examined whether the changes of these cytokine levels and sex steroids actually influence bone turnover and post-BMT bone loss by correlation analysis. Data were analyzed from 39 patients (33.6+/-6.4 years, 19 men and 20 women) who had DXA performed before BMT and at 1 year after BMT. The bone turnover markers, sex steroids and the cytokine levels were measured before BMT and serially after BMT. The mean bone loss in the lumbar spine and the total proximal femur was 5.9% (P < 0.01) and 11.3% (P < 0.01), respectively. During the immediate post-BMT period, bone formation decreased, whereas the bone resorption increased. For the female recipients, the estradiol levels declined at 1 week after BMT, and they did not recover to the basal levels. For the male recipients, the testosterone levels decreased at 1 week and then it increased to its baseline level. The IL-7 levels reached their maximum at 1 week and then declined to baseline level by 3 months. The serum sRANKL, OPG levels and the sRANKL/OPG ratio showed their peak at post-BMT 3 weeks. The mean daily dose of steroid was associated with suppressed bone formation, enhanced bone resorption and increased sRANKL levels. The IL-7 levels were also noted to be either positively correlated with the levels of ICTP or they were negatively correlated with the levels of osteocalcin at 1 and 3 weeks after BMT. Bone loss at the lumbar spine and the proximal femur was influenced by the decreased sex steroids and increased IL-7 levels. During the observation period, the IL-7 levels showed positive correlations with the sRANKL levels and the sRANKL/OPG ratio. For the female patients, the serum IL-7 levels were negatively associated with the estradiol levels at 1 and 3 weeks after BMT. All these findings suggest that IL-7 plays an important role for post-BMT bone loss, and this possibly happens via the RANKL pathway. These data also suggest that the up-regulation of IL-7 during the early post-BMT period may result from a deficiency of estrogen.