Treatment Of Osteoporosis In Japan Research Articles

Efficacy and safety of vitamin K2 for postmenopausal women with osteoporosis at a long-term follow-up: meta-analysis and systematic review.

Vitamin K2 supplementation has been revealed to be effective in the prevention and treatment of osteoporosis in Japan, but further proof for the effectiveness of this practice is still needed. To investigate whether vitamin K2 supplementation plays a role in maintaining bone mineral density (BMD) and reducing the incidence of fractures for postmenopausal women with osteoporosis at a long-term follow-up. We searched systematically throughout the databases of PubMed, Cochrane library, and EMBASE from the dates of their inception to November 16 2021 in this meta-analysis and systematic review, using keywords vitamin K2 and osteoporosis. Nine RCTs with 6853 participants met the inclusion criteria. Vitamin K2 was associated with a significantly increased percentage change of lumbar BMD and forearm BMD (WMD 2.17, 95% CI [1.59-2.76] and WMD 1.57, 95% CI [1.15-1.99]). There were significant differences in undercarboxylated osteocalcin (uc-OC) reduction (WMD -0.96, 95% CI [-0.70 to 0.21]) and osteocalcin (OC) increment (WMD 26.52, 95% CI [17.06-35.98]). Adverse reaction analysis showed that there seemed to be higher adverse reaction rates in the vitamin K2 group (RR = 1.33, 95% CI [1.11-1.59]), but no serious adverse events related to vitamin K2 supplementation. This meta-analysis and systematic review seemed to support the hypothesis that vitamin K2 plays an important role in the maintenance and improvement of BMD, and it decreases uc-OC and increases OC significantly at a long-term follow-up. Vitamin K2 supplementation is beneficial and safe in the treatment of osteoporosis for postmenopausal women.

Long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis: 3-year post-marketing surveillance study

Denosumab is a humanized IgG2 monoclonal antibody that was approved for the treatment of osteoporosis in Japan in 2013. This study aimed to investigate the long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis in daily clinical practice. This 3-year, prospective, observational, post-marketing study included patients who initiated treatment with denosumab (60mg/6months) for osteoporosis. Data were assessed at baseline, 3, 6, 12, 24 and 36months. Key endpoints were adverse events (AEs), adverse drug reactions (ADRs), occurrence of osteoporotic fractures, bone mineral density (BMD), and bone turnover markers. Multivariate analyses were conducted to identify predictors of hypocalcaemia and percent change in BMD. Overall, 3534 patients were assessed (mean 75.7years; 89.8% women). In total, 298 patients (8.4%) developed ADRs; the most common was hypocalcaemia (3.9%). Hypocalcaemia risk was significantly increased in patients with creatinine clearance < 30mL/min, no prior use of bisphosphonates, prior use of calcium and vitamin D preparations, baseline serum calcium < 8.5mg/dL, and no concomitant use of calcium or vitamin D preparations. Six patients had adjudicated osteonecrosis of the jaw. Lumbar spine BMD increased significantly from baseline (mean percent change: 11.4% at 36months). All bone turnover markers decreased significantly from baseline. Over 3years, 3.3% of patients developed a new osteoporotic fracture. This study confirmed the long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis in daily clinical practice. No new safety signals were identified.

Status quo of osteoporosis treatment in Japan disclosed by the National Database of Health Insurance Claims and Specific Health Checkups: too late in treatment initiation and too few in treated patients?

To analyze the current status and trend of osteoporosis treatment in Japan by analyzing the data on main drugs for osteoporosis disclosed in the National Database open data. We used the National Database open data released by the Ministry of Health, Labour and Welfare in September 2018. Data on bisphosphonates, denosumab, and teriparatide were extracted to calculate the number of patients treated with these drugs based on the number of prescriptions filed. Using these prescription numbers, the proportion of patients treated with bisphosphonates, denosumab, or teriparatide among osteoporosis patients was calculated. Further, the data on the incidence of hip fractures were employed to validate the appropriateness of the timing of treatment initiation to osteoporosis patients in Japan. The number of patients in men administered bisphosphonates, denosumab, or teriparatide was about one tenth of that in women. The proportion of osteoporosis patients in men treated with bisphosphonates, denosumab, or teriparatide was highest in age group over 80years at 19.4%. The proportion of osteoporosis patients in women treated with bisphosphonates, denosumab, or teriparatide was highest in age group 70-79years at 23.7%. The incidence of hip fractures increases sharply over 80years of age in both genders. Our findings suggested that osteoporosis treatment should be initiated in younger age, especially in men, in order to avoid osteoporotic fractures in Japan.

Eldecalcitol effects on osteoblastic differentiation and function in the presence or absence of osteoclastic bone resorption.

Eldecalcitol (ELD) is an active vitamin D3 analog, possesses anti-resorption properties and is an approved therapeutic drug for the treatment of osteoporosis in Japan. However, the effect of ELD on osteoblasts in a distinct cell microenvironment, including in the presence or absence of osteoclastic bone resorption, is undetermined. In the current study, the effect of bone resorption supernatant on the ELD-mediated regulation of viability, differentiation and receptor activator of ΝF-κB ligand/osteoprotegerin (RANKL/OPG) expression was assessed in MC3T3-E1 pre-osteoblast cells. The murine macrophage-like cell line RAW 264.7 was induced to differentiate into functional osteoblasts. Bone resorption supernatant was prepared by culturing osteoclast with a bovine cortical bone specimen. Mouse MC3T3-E1 cells were subsequently treated with ELD combined with differentiated osteoclast cell culture (OCS) or osteoclast bone resorption model supernatants. Cell counting kit-8, alkaline phosphatase (ALP) activity, reverse transcription-quantitative (RT-q) PCR and western blot analysis were used to assess cell viability, osteogenic activity and RANKL and OPG expression in MC3T3-E1 cells. The OCS and OCS + ELD treatment exhibited significantly increased MC3T3-E1 cell viability when compared with the control group. However, ELD, bone resorption culture supernatant (BRS) and ELD + BRS treatments significantly decreased MC3T3-E1 cell viability. The results of ALP activity analysis, RT-qPCR and western blot analysis demonstrated that ELD treatment and OCS decreased the osteogenic markers (ALP and RUNX2), however, BRS increased them. All treatments enhanced the expression of RANKL and RANKL/OPG ratio. The results of the current study revealed that ELD inhibits osteoblastic differentiation in vitro. However, in the presence of BRS, which mimics the local bone microenvironment in vivo, the net effect on osteogenesis was positive. Furthermore, osteoclasts and bone matrix-derived factors increased the RANKL/OPG ratio, thereby potentiating osteoclastic activity.

Sequential treatment of osteoporosis with anti-sclerostin.

Romosozumab is a humanized anti-sclerostin monoclonal antibody that has just been approved for the treatment of osteoporosis in Japan. Romosozumab causes both transient stimulation of bone formation and continuous suppression of resorption, thereby increasing bone mineral density and decreasing fracture incidence. Because the effect of romosozumab is reversible, sequential therapy with anti-resorptives after romosozumab will be necessary. This overview summarizes the results of ARCH study demonstrating superior efficacy of romosozumab compared to alendronate and effect of sequential therapy with alendronate. Possible adverse effect of romosozumab on cardiovascular diseases will also be discussed.

Once-weekly teriparatide reduces serum sclerostin levels in postmenopausal women with osteoprosis

Once-weekly teriparatide treatment is widely used in the treatment of osteoporosis in Japan but the mechanisms causing the increase in bone mineral density (BMD) of the lumbar spine remain unknown. Methods: This prospective study examined the effects of once-weekly teriparatide treatment on the serum levels of sclerostin, osteocalcin, and bone formation markers as well as BMD of the lumbar spine and femoral neck in 32 postmenopausal women with osteoporosis. Results: The mean age of subjects was 76.3 ± 7.0 years old. Teriparatide significantly reduced serum sclerostin levels at 12 and 18 months in postmenopausal women with osteoporosis, and significantly increased serum osteocalcin levels at 3,12 and 18 months and PINP levels at 1 and 3 months, respectively. Teriparatide treatment significantly increased BMD of the lumbar spine at 6, 12, and 18 months, but did not affect BMD of the femoral neck. Examination of the relationships between percent changes in bone metabolic indices and BMD of the lumbar spine during the teriparatide treatment showed serum sclerostin changes at 3 months were negatively correlated with BMD changes of the lumbar spine at 6, 12, and 18 months. Serum osteocalcin changes were not correlated with BMD changes in the lumbar spine at 12 months. Conclusions: The present study showed that once-weekly teriparatide treatment reduced serum sclerostin levels in postmenopausal women with osteoporosis. The effects of teriparatide on sclerostin may be associated with the response of the BMD of the lumbar spine.

Recent topics in the treatment of osteoporosis in Japan

Recent topics in the treatment of osteoporosis in Japan

Erratum to: Cost-effectiveness analysis of once-yearly injection of zoledronic acid for the treatment of osteoporosis in Japan

Model-based economic evaluation was performed to assess the cost-effectiveness of zoledronic acid. Although zoledronic acid was dominated by alendronate, the incremental quality-adjusted life year (QALY) was quite small in extent. Considering the advantage of once-yearly injection of zoledronic acid in persistence, zoledronic acid might be a cost-effective treatment option compared to once-weekly oral alendronate. The purpose of this study was to estimate the cost-effectiveness of once-yearly injection of zoledronic acid for the treatment of osteoporosis in Japan. A patient-level state-transition model was developed to predict the outcome of patients with osteoporosis who have experienced a previous vertebral fracture. The efficacy of zoledronic acid was derived from a published network meta-analysis. Lifetime cost and QALYs were estimated for patients who had received zoledronic acid, alendronate, or basic treatment alone. The incremental cost-effectiveness ratio (ICER) of zoledronic acid was estimated. For patients 70 years of age, zoledronic acid was dominated by alendronate with incremental QALY of −0.004 to −0.000 and incremental cost of 430 USD to 493 USD. Deterministic sensitivity analysis indicated that the relative risk of hip fracture and drug cost strongly affected the cost-effectiveness of zoledronic acid compared to alendronate. Scenario analysis considering treatment persistence showed that the ICER of zoledronic acid compared to alendronate was estimated to be 47,435 USD, 27,018 USD, and 10,749 USD per QALY gained for patients with a T-score of −2.0, −2.5, or −3.0, respectively. Although zoledronic acid is dominated by alendronate, the incremental QALY is quite small in extent. Considering the advantage of annual zoledronic acid treatment in compliance and persistence, zoledronic acid may be a cost-effective treatment option compared to alendronate.

Cost-effectiveness analysis of once-yearly injection of zoledronic acid for the treatment of osteoporosis in Japan

SummaryModel-based economic evaluation was performed to assess the cost-effectiveness of zoledronic acid. Although zoledronic acid was dominated by alendronate, the incremental quality-adjusted life year (QALY) was quite small in extent. Considering the advantage of once-yearly injection of zoledronic acid in persistence, zoledronic acid might be a cost-effective treatment option compared to once-weekly oral alendronate.IntroductionThe purpose of this study was to estimate the cost-effectiveness of once-yearly injection of zoledronic acid for the treatment of osteoporosis in Japan.MethodsA patient-level state-transition model was developed to predict the outcome of patients with osteoporosis who have experienced a previous vertebral fracture. The efficacy of zoledronic acid was derived from a published network meta-analysis. Lifetime cost and QALYs were estimated for patients who had received zoledronic acid, alendronate, or basic treatment alone. The incremental cost-effectiveness ratio (ICER) of zoledronic acid was estimated.ResultsFor patients 70 years of age, zoledronic acid was dominated by alendronate with incremental QALY of −0.004 to −0.000 and incremental cost of 430 USD to 493 USD. Deterministic sensitivity analysis indicated that the relative risk of hip fracture and drug cost strongly affected the cost-effectiveness of zoledronic acid compared to alendronate. Scenario analysis considering treatment persistence showed that the ICER of zoledronic acid compared to alendronate was estimated to be 47,435 USD, 27,018 USD, and 10,749 USD per QALY gained for patients with a T-score of −2.0, −2.5, or −3.0, respectively.ConclusionAlthough zoledronic acid is dominated by alendronate, the incremental QALY is quite small in extent. Considering the advantage of annual zoledronic acid treatment in compliance and persistence, zoledronic acid may be a cost-effective treatment option compared to alendronate.

Efficacy of zoledronic acid for osteoporosis:evidence from studies abroad.

Zoledronic acid is a nitrogen-containing bisphosphonate that has the strongest and the most persistent anti-resorptive activity. Once-yearly zoledronic acid has recently been approved for the treatment of osteoporosis in Japan. This overview summarizes abundant evidence of zoledronic acid, obtained from studies abroad, for its efficacy for postmenopausal, male and glucocorticoid-induced osteoporosis.

PMS54 - Cost-Effectiveness Analysis of Once-Yearly Injection of Zoledronic Acid For The Treatment of Osteoporosis In Japan

Model-based economic evaluation was performed to assess the cost-effectiveness of zoledronic acid. Although zoledronic acid was dominated by alendronate, the incremental quality-adjusted life year (QALY) was quite small in extent. Considering the advantage of once-yearly injection of zoledronic acid in persistence, zoledronic acid might be a cost-effective treatment option compared to once-weekly oral alendronate. The purpose of this study was to estimate the cost-effectiveness of once-yearly injection of zoledronic acid for the treatment of osteoporosis in Japan. A patient-level state-transition model was developed to predict the outcome of patients with osteoporosis who have experienced a previous vertebral fracture. The efficacy of zoledronic acid was derived from a published network meta-analysis. Lifetime cost and QALYs were estimated for patients who had received zoledronic acid, alendronate, or basic treatment alone. The incremental cost-effectiveness ratio (ICER) of zoledronic acid was estimated. For patients 70 years of age, zoledronic acid was dominated by alendronate with incremental QALY of −0.004 to −0.000 and incremental cost of 430 USD to 493 USD. Deterministic sensitivity analysis indicated that the relative risk of hip fracture and drug cost strongly affected the cost-effectiveness of zoledronic acid compared to alendronate. Scenario analysis considering treatment persistence showed that the ICER of zoledronic acid compared to alendronate was estimated to be 47,435 USD, 27,018 USD, and 10,749 USD per QALY gained for patients with a T-score of −2.0, −2.5, or −3.0, respectively. Although zoledronic acid is dominated by alendronate, the incremental QALY is quite small in extent. Considering the advantage of annual zoledronic acid treatment in compliance and persistence, zoledronic acid may be a cost-effective treatment option compared to alendronate.

Treatment of osteoporosis with eldecalcitol, a new vitamin D analog: a comprehensive review and meta-analysis of randomized clinical trials.

ObjectiveEldecalcitol (ELD) is an active form of vitamin D analog that has been approved for the treatment of osteoporosis in Japan. Over recent years, a number of multicenter, randomized controlled clinical trials have been conducted. Our goal is to comprehensively summarize the results from these studies.MethodsWe searched the databases MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials up to February 28, 2015. Each database was searched using search terms “Eldecalcitol” and “ED-71” and the results were combined. The retrieved data from three independent clinical trials included a total of 1,332 patients with osteoporosis. After the data were pooled from three trials, RevMan software was used to conduct meta-analyses to determine the effects of ELD on bone mineral density (BMD) and bone turnover marker (BTM) type I collagen amino-terminal telopeptide (NTX). Effects of ELD on some of the bone formation and bone resorption parameters, incidence of vertebral fractures at the lower spine, and health-related quality of life (HRQOL) in patients with osteoporosis were also summarized.ResultsWith a test for overall effectZ=6.35, ELD could increase lumbar BMD (P<0.00001). In comparison with alphacalcidol, ELD suppressed the NTX level to a greater degree (test for overall effectZ=3.82,P<0.0001). ELD was also found to suppress bone alkaline phosphatase (BALP) by 19% (P<0.01) and osteocalcin by 19% (P<0.01) at the dose of 0.75 μg/day. Compared to alfacalcidol, ELD showed higher potency in suppressing serum BALP (26±9 vs 32±11 U/L,P<0.05) and amino-terminal propeptide of procollagen I (PINP) (42±15 vs 59±23 ng/mL,P<0.05). In addition, ELD was found to be more effective in reducing the incidence of vertebral fractures at the lower spine (P=0.029).ConclusionOur meta-analysis showed that ELD was more potent than alphacalcidol in reducing BTM (NTX). Clinical data together suggest that ELD is efficient in treating osteoporosis by increasing lumbar BMD; suppressing BTMs, including NTX, BALP, osteocalcin, and PINP; resulting in the reduction in the incidence of vertebral fractures at the lower spine; and increasing the HRQOL in patients with osteoporosis.

On "2015 Guidelines for Prevention and Treatment of Osteoporosis". Drug-induced osteoporosis: glucocorticoid-induced osteoporosis

Osteoporosis is the most common and important adverse effect of glucocorticoid (GC) therapy. Since GC-induced bone loss is most rapid during the initial 3 - 6 months and primary prevention of bone loss is especially important, guidelines for management of GC-induced osteoporosis have been published overseas and in Japan. The Japanese Society for Bone and Mineral Research (JSBMR) has updated the Guidelines on the Management and Treatment of Glucocorticoid-induced Osteoporosis (GIO) and has incorporated a new scoring method. By analyzing five Japanese GIO cohorts from primary and secondary prevention studies, age, GC dose, lumbar BMD, and prior fragility fractures were identified as factors predicting future fracture and the fracture risk for an individual can be calculated as the sum of the scores for each risk factor. The guidelines were updated on the basis of a score of 3 as the optimal cut-off score for pharmacological intervention. Among the agents approved for the treatment of osteoporosis in Japan, the committee comprehensively reviewed validity for both primary and secondary prevention and assessed the benefit for both BMD and fracture prevention based on the results of clinical studies. Both alendronate and risedronate are recommended as first-line treatment. Ibandronate, teriparatide, and active vitamin D3 derivatives are recommended as alternative option.

Analysis of bone metabolism during early stage and clinical benefits of early intervention with alendronate in patients with systemic rheumatic diseases treated with high-dose glucocorticoid: Early DIagnosis and Treatment of OsteopoRosis in Japan (EDITOR-J) study.

We conducted a prospective multicenter study to assess early changes in the dynamics of bone metabolism in patients with systemic connective tissue diseases following commencement of high-dose glucocorticoid therapy and the benefits of early treatment with bisphosphonate and vitamin D analogue. The subjects of this randomized controlled trial were 106 female patients with systemic connective tissue diseases treated for the first time with glucocorticoids at doses equivalent to prednisolone ≥20mg/day (age≥18years). One week after initiation of glucocorticoid therapy, patients were randomly assigned to treatment with alfacalcidol at 1μg/day (n=33), alendronate 35mg/week (n=37), and alfacalcidol plus alendronate (n=36). The primary endpoints were changes in lumbar spine bone density at 6months of treatment and the frequency of bone fracture at 12months. Commencement of glucocorticoid therapy was associated with a rapid and marked bone resorption within 1week. The combination of alfacalcidol and alendronate administered after the first week of glucocorticoid therapy halted the pathological processes affecting bone metabolism, increased bone density, and reduced the incidence of bone fracture over a period of 12months. Taken together, the use of the combination of alfacalcidol and alendronate improved bone metabolism, increased bone density, and significantly reduced the incidence of bone fracture during 1-year high-dose glucocorticoid therapy.

Abstract 2806: Effect of ED-71, an analogue of Vitamin D3, on intestinal neoplasia in the Apc+/Min-FCCC mouse model

Abstract Numerous studies have demonstrated an inverse relationship between circulating Vitamin D levels and risk of colorectal cancer. Although calcitriol, the most active form of Vitamin D3, exhibits promising antitumorigenic activity, its use as a chemopreventive agent has been restricted by its hypercalcemic effect at therapeutic doses. Eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropyloxy) Vitamin D3 or ED-71), a novel analog of calcitriol, is more potent than calcitriol in stimulating bone modeling and is approved for the treatment of osteoporosis in Japan. The goal of the present study was to assess the activity of ED-71 against colorectal adenomas in a unique mouse model of spontaneous multiple intestinal neoplasia (Apc+/Min-FCCC mice). In a preliminary dose-finding study, male Apc+/Min-FCCC mice (6 weeks old, 6-7/group) were treated with vehicle (medium chain triglyceride (MCT)), calcitriol (0.25 μg/kg body weight (bw)), or ED-71 (0.2, 0.1, 0.05, 0.025, 0.0125 μg/kg bw) every other day by gavage for 6 weeks. Body weight was recorded weekly and mice were euthanized at the end of the study. ED-71 was well tolerated at all doses tested, with no significant difference in body weight observed in treated animals as compared to controls. Drug toxicity was assessed by measuring serum calcium levels by colorimetric assay (BioVision Inc.) and hepatic alkaline phosphatase (ALP) by ELISA (Antibodies-online.com). No significant effect of ED-71 on serum calcium levels and hepatic ALP activity was observed. However, because some concern exists regarding the ability of mice treated with high-dose ED-71 (0.2 μg/kg bw) to maintain their body weight long-term, ED-71 doses of 0.05 and 0.1 μg/kg bw were selected for the long-term efficacy study. Prior to entry on this study, male Apc+/Min-FCCC mice (6 weeks old) were prescreened endoscopically to determine tumor-bearing status. Mice were randomized based on tumor status (tumor-free or tumor-bearing) and body weight to one of four treatment groups: vehicle (MCT), calcitriol (0.25 μg/kg bw), ED-71 (0.05 μg/kg bw) or ED-71 (0.1 μg/kg bw). Drugs were administered by gavage every other day for 14 weeks. At the end of the study, intestinal tissue was examined grossly and tumor multiplicity was recorded. No significant effect of ED-71 on tumor multiplicity was observed in tumor-bearing mice. However, in tumor-free mice (11-13/group), treatment with ED-71 (0.1 μg/kg bw) reduced the incidence of gross tumors by 36% (P = 0.017) and colon tumor multiplicity by 30% as compared to that of controls (63.6% vs. 100%, 1.4 ± 0.4 vs. 2.0 ± 0.4, respectively). These findings suggest that ED-71 is effective in inhibiting colon tumorigenesis when given to mice prior to tumor formation. These promising data provide support for future studies to determine the potential utility of ED-71 for the prevention of colorectal cancer in high-risk subjects. (Supported by NCI HHSN261201200015I) Citation Format: Wen-Chi L. Chang, Esther Kaunga, Harry S. Cooper, Lisa Vanderveer, Jing Peng, Yongchao Zhang, Chen S. Suen, Margie L. Clapper. Effect of ED-71, an analogue of Vitamin D3, on intestinal neoplasia in the Apc+/Min-FCCC mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2806. doi:10.1158/1538-7445.AM2015-2806

Impact of Osteonecrosis of the Jaw on Osteoporosis Treatment in Japan: Results of a Questionnaire-Based Survey by the Adequate Treatment of Osteoporosis (A-TOP) Research Group.

Dentists request a discontinuation of antiresorptive agents, such as bisphosphonate, before and after tooth extractions to prevent osteonecrosis of the jaw (ONJ). However, little is known about how this affects ONJ and osteoporosis treatment and how medical professionals and dentists cooperate to treat ONJ in patients with osteoporosis. This study aimed to clarify the impact of ONJ on osteoporosis treatment in Japan. A structured questionnaire including 14 key clinical queries was sent to 488 medical professionals as part of the Japanese Osteoporosis Intervention Trial (JOINT)-04, and 206 responses were received. A total of 173 respondents had received discontinuation requests from dentists. Of these, 28 respondents experienced 30 adverse events including ten fractures and one incidence of ONJ. The respondents who refused discontinuation requests observed no cases of ONJ. Approximately 16 % of respondents had patients who discontinued osteoporosis treatment, following a requested drug discontinuation, after tooth extraction. Dentists requested discontinuations for many medications that were not associated with the incidence of ONJ. Approximately 76 % of respondents had never requested oral health care from dentists before osteoporosis treatment and 72 % reported no cooperation between dentists and medical professionals in their region. Our results suggest that drug discontinuation may increase adverse events and disturb osteoporosis treatment without completely preventing ONJ. Currently, both medical professionals and dentists in Japan still continue to recommend their own treatment position. A forum to share information about ONJ among medical professionals, dentists, and patients is required.

Effects of eldecalcitol on cortical bone response to mechanical loading in rats.

BackgroundMechanical loading of bones activates modeling and suppresses remodeling by promoting bone formation. Eldecalcitol is approved for the treatment of osteoporosis in Japan and is often used in patients undergoing exercise therapy. However, the effects of eldecalcitol on bone formation during mechanical loading are unknown. The aim of this study was to clarify the influence of eldecalcitol administration on bone response to mechanical loading using a four-point bending device.MethodsForty six-month-old female Wistar rats were randomized into four groups based on eldecalcitol dose (vehicle administration (VEH), low dose (ED-L), medium dose (ED-M), and high dose (ED-H)). Loads of 38 N were applied in vivo to the right tibia for 36 cycles at 2 Hz, by four-point bending, 3 days per week for 3 weeks. After calcein double-labeling, rats were sacrificed and tibial cross sections were prepared from the region with maximal bending at the central diaphysis. Histomorphometry was performed on the entire periosteal and endocortical surface of the tibiae, dividing the periosteum into lateral and medial surfaces.ResultsThe effects of external loading on bone formation parameters were significant at all three surfaces. Bone formation parameters were highest in the ED-H group, and the effects of eldecalcitol on bone formation rate were significant at the endocortical surface. In addition, the interaction between loading and eldecalcitol dose significantly affected bone formation rate at the endocortical surface.ConclusionsEldecalcitol enhanced the cortical bone response to mechanical loading and a synergistic effect was observed in a rat model.

Vitamin D3 analogs for the treatment of osteoporosis.

Vitamin D supplementation is recommended whenever patients are given therapeutic drugs for osteoporosis, to make their calcium (Ca) balance positive. Vitamin D is converted to 25-hydroxyvitamin D in the liver, and then activated to become 1α,25-dihydroxyvitamin D in the kidneys. The active vitamin D acts in the intestine to stimulate Ca absorption and maintain the Ca balance. 2β-(3-Hydroxypropyloxy)-1α,25-dihydroxyvitamin D3 (eldecalcitol) and 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) are newly developed vitamin D analogs, with a substitution at the 2 position of 1α,25-dihydroxyvitamin D3 (calcitriol). Eldecalcitol and 2MD share common structural and biological characteristics. Both compounds increase serum Ca levels more markedly than calcitriol, increase bone mineral density (BMD), and improve bone strength in ovariectomized (OVX) rats. In a randomized, placebo-controlled, double-blind, 1 year clinical trial, eldecalcitol dose-dependently increased lumbar and hip BMD and suppressed bone turnover markers in patients with osteoporosis. Whereas, 2MD markedly increased the bone turnover markers, but it did not change the BMD of postmenopausal women with osteopenia in a 1 year clinical trial. After a randomized, double-blind, 3 year fracture-prevention trial comparing it with alfacalcidol, eldecalcitol was approved for the treatment of osteoporosis in Japan. On the other hand, the manufacturer discontinued the clinical development of 2MD. In this review, we discuss the similarities and differences between these 2 compounds, and the reasons why different outcomes resulted from their clinical trials.

Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials.

To identify the role of vitamin K2 for the prevention and treatment of osteoporosis in postmenopausal women, we conducted this meta-analysis of 19 randomized controlled trials. Our results showed that vitamin K2 might play a role in maintaining the bone mineral density and in reducing the incidence of fractures for postmenopausal women with osteoporosis. Vitamin K2 has been revealed to be effective in the prevention and treatment of osteoporosis in Japan, which was not confirmed in western countries. Thus, we conduct this meta-analysis to verify the hypothesis that vitamin K2 plays a role in the prevention and treatment of osteoporosis for postmenopausal women. We searched the Cochrane Library, Pub Med, EMBASE, and ISI web of knowledge (until December 1, 2013) and reference lists of eligible articles. A meta-analysis of all-including randomized controlled trials was then performed. Nineteen randomized controlled trials encompassing 6759 participants have met the inclusion criteria. Subgroup analysis of postmenopausal women with osteoporosis revealed a significant improvement of vertebral BMD for both medium-term and long-term results favoring vitamin K2 group (p < 0.00001 and p = 0.0005). However, no significant difference in BMD changes was revealed for the non-osteoporosis subgroup analysis. As for the incidence of fractures, pooled analysis of the seven related studies demonstrated no significant difference in the incidence of fractures favoring vitamin K2 (RR = 0.63, p = 0.08). However, sensitivity analysis by rejecting the study inducing heterogeneity demonstrated a significant difference in the incidence of fractures favoring vitamin K2 (RR = 0.50, p = 0.0005). Significant differences were found in undercarboxylated osteocalcin reduction and osteocalcin increment. The result of adverse reaction analysis showed that vitamin K2 group seemed to have a higher adverse reaction rate (RR = 1.22, p = 0.06). This meta-analysis seemed to support the hypothesis that vitamin K2 plays kind of a role in the maintenance and improvement of vertebral BMD and the prevention of fractures in postmenopausal women with osteoporosis. The reduction of undercarboxylated osteocalcin and increment of osteocalcin may have some relation to the process of bone mineralization. However, the effect of vitamin K2 for postmenopausal women without osteoporosis had not been identified. Further high-quality RCTs with large sample size are needed to confirm the role of vitamin K2 in osteoporosis for postmenopausal women.

Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone

Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6months improved the mechanical properties of the lumbar spine in ovariectomized (OVX) cynomolgus monkeys. ELD treatment increased lumbar BMD, suppressed bone turnover markers, and reduced histomorphometric parameters of both bone formation and resorption in vertebral trabecular bone. In this study, we elucidated the effects of ELD on bone quality (namely, mineralization, microarchitecture, microdamage, and bone collagen crosslinks) in OVX cynomolgus monkeys in comparison with OVX-vehicle control monkeys. Density fractionation of bone powder prepared from lumbar vertebrae revealed that ELD treatment shifted the distribution profile of bone mineralization to a higher density, and backscattered electron microscopic imaging showed improved trabecular bone connectivity in the ELD-treated groups. Higher doses of ELD more significantly reduced the amount of microdamage compared to OVX-vehicle controls. The fractionated bone powder samples were divided according to their density, and analyzed for collagen crosslinks. Enzymatic crosslinks were higher in both the high-density (≥2.0mg/mL) and low-density (<2.0mg/mL) fractions from the ELD-treated groups than in the corresponding fractions in the OVX-vehicle control groups. On the other hand, non-enzymatic crosslinks were lower in both the high- and low-density fractions. These observations indicated that ELD treatment stimulated the enzymatic reaction of collagen crosslinks and bone mineralization, but prevented non-enzymatic reaction of collagen crosslinks and accumulation of bone microdamage. Bone anti-resorptive agents such as bisphosphonates slow down bone remodeling so that bone mineralization, bone microdamage, and non-enzymatic collagen crosslinks all increase. Bone anabolic agents such as parathyroid hormone decrease bone mineralization and bone microdamage by stimulating bone remodeling. ELD did not fit into either category. Histological analysis indicated that the ELD treatment strongly suppressed bone resorption by reducing the number of osteoclasts, while also stimulating focal bone formation without prior bone resorption (bone minimodeling). These bidirectional activities of ELD may account for its unique effects on bone quality.