Functional analysis of functional membrane microdomains in the biosynthesis of menaquinone-7 / 生物工程学报

Functional membrane microdomains (FMMs) that are mainly composed of scaffold proteins and polyisoprenoids play important roles in diverse cellular physiological processes in bacteria. The aim of this study was to identify the correlation between MK-7 and FMMs and then regulate the MK-7 biosynthesis through FMMs. Firstly, the relationship between FMMs and MK-7 on the cell membrane was determined by fluorescent labeling. Secondly, we demonstrated that MK-7 is a key polyisoprenoid component of FMMs by analyzing the changes in the content of MK-7 on cell membrane and the changes in the membrane order before and after destroying the integrity of FMMs. Subsequently, the subcellular localization of some key enzymes in MK-7 synthesis was explored by visual analysis, and the intracellular free pathway enzymes Fni, IspA, HepT and YuxO were localized to FMMs through FloA to achieve the compartmentalization of MK-7 synthesis pathway. Finally, a high MK-7 production strain BS3AT was successfully obtained. The production of MK-7 reached 300.3 mg/L in shake flask and 464.2 mg/L in 3 L fermenter.

Clinical application of zoledronic acid combined with vitamin K2 in percutaneous vertebroplasty for multi-segment osteoporotic vertebral compression fractures / 中国骨伤

OBJECTIVE@#To explore the clinical effect of zoledronic acid combined with vitamin K2 regimen in percutaneous vertebroplasty for multi-segment osteoporotic vertebral compression fractures(OVCFs).@*METHODS@#This study was a retrospective control study. A total of 364 patients with OVCFs who were admitted to our spinal surgery department from January 2014 to January 2017 were selected as the study subjects. According to whether zoledronic acid combined with vitamin K2 was used to treat osteoporosis after surgery, the patients were divided into control group and experimental group. Among them, 257 patients in the control group were treated with calcium carbonate and vitamin D regimen, while 107 patients in the experimental group were treated with zoledronic acid combined with vitamin K2 regimen on the basis of the control group. Visual analogue scale (VAS) score and Oswestry Disability Index (ODI) were used to evaluate the clinical effect. Pre- and post-operative bone mineral density of lumbar spine and proximal femur, vertebral height ratio of responsible vertebral body and Cobb angle of vertebral body were observed by image data. Serological indicators related to bone metabolism were detected by laboratory. The complications such as fever, dizziness, osteoarthritis, muscular and soft tissue pain and adjacent vertebral re-fracture were compared between two groups.@*RESULTS@#There was no significant difference in general data between the two groups (0.05);VAS score in the experimental group was significantly lower than that in the control group 1 month, 3 months and 1 year after operation(0.05), and at the 24 hours, 3 months, 1 year after operation, the experimental group was significantly lower than the control group (0.05). The vertebral height ratio of the responsible vertebral body in experimental group was significantly higher than that in control group and Cobb angle in experimental group was significantly lower than that in control group at 3 months and 1 year after operation (0.05), but at 3 months and 1 year after operation, the bone mineral density of lumbar spine and proximal femur in experimental group was significantly lower than that in control group (0.05). At 1 year after operation the total type I collagen amino-terminal elongation peptide and β-collagen degradation products in experimental group was significantly lower than that in the control group (<0.05), but the 25-hydroxyvitamin D operation in experimental group was significantly higher than that in control group(<0.05). The incidence of postoperative complications such as fever, dizziness, osteoarthritis, muscle and soft tissue pain and adjacent vertebral re-fracture in experimental group was significantly lower than that in control group (<0.05).@*CONCLUSION@#Zoledronic acid injection combined with vitamin K2 regimen can be used for anti-osteoporosis treatment of OVCFs vertebroplasty. It has a definite curative effect and a high safety factor. It is worth popularizing.

The Role of Vitamin D in the Pathogenesis of Adolescent Idiopathic Scoliosis

Several theories have been proposed to explain the etiology of adolescent idiopathic scoliosis (AIS) until present. However, limited data are available regarding the impact of vitamin D insufficiency or deficiency on scoliosis. Previous studies have shown that vitamin D deficiency and insufficiency are prevalent in adolescents, including AIS patients. A series of studies conducted in Hong Kong have shown that as many as 30% of these patients have osteopenia. The 25-hydroxyvitamin D3 level has been found to positively correlate with bone mineral density (BMD) in healthy adolescents and negatively with Cobb angle in AIS patients; therefore, vitamin D deficiency is believed to play a role in AIS pathogenesis. This study attempts to review the relevant literature on AIS etiology to examine the association of vitamin D and various current theories. Our review suggested that vitamin D deficiency is associated with several current etiological theories of AIS. We postulate that vitamin D deficiency and/or insufficiency affects AIS development by its effect on the regulation of fibrosis, postural control, and BMD. Subclinical deficiency of vitamin K2, a fat-soluble vitamin, is also prevalent in adolescents; therefore, it is possible that the high prevalence of vitamin D deficiency is related to decreased fat intake. Further studies are required to elucidate the possible role of vitamin D in the pathogenesis and clinical management of AIS.

An interim safety analysis of hepatocellular carcinoma patients administrating oral vitamin K with or without sorafenib

BACKGROUNDS/AIMS: Vitamin K may plays a role in controlling hepatocellular carcinoma (HCC) cell growth. In this study, we intended to present 5-year experience of 72 patients receiving oral vitamin K with or without sorafenib. Its end-point was to evaluate the safety of combination therapy using sorafenib and vitamin K. METHODS: An interim analysis was performed as a single-arm cross-sectional study, including 72 HCC patients who underwent liver resection or transplantation and administered oral vitamin K2 alone (n=47) or with sorafenib (n=25). RESULTS: In all patients, administration of vitamin K2 analog 45 mg/day did not show any noticeable adverse side-effect during vitamin K therapy of 23.3+/-10.6 months, except for one patient who experienced skin rash at the third day of vitamin K therapy. In 25 patients receiving sorafenib and vitamin K for 6 months or longer, any noticeable adverse side-effect suspected of vitamin K origin was not identified yet. A small proportion of patients showed unexpectedly favorable anti-tumor effects after use of vitamin K with or without sorafenib. CONCLUSIONS: Because add-on of oral vitamin K did not increase the adverse side-effects of sorafenib, a combination therapy with these two agents appears to be worthy of further clinical trial with an expectation of synergistic therapeutic effects.

Vitamin K dependent proteins and the role of vitamin K2 in the modulation of vascular calcification: a review

Vascular calcification, a cause of cardiovascular morbidity and mortality, is an actively regulated process involving vitamin K dependent proteins [VKDPs] among others. Vitamin K is an essential micronutrient, present in plants and animal fermented products that plays an important role as a cofactor for the post-translational gamma -carboxylation of glutamic acid residues in a number of proteins. These VKDPs require carboxylation to become biologically active, and they have been identified as having an active role in vascular cell migration, angiogenesis and vascular calcification. This paper will review the process of vascular calcification and delineate the role that vitamin K2 plays in the modulation of that process, through the activation of VKDPs. One such VKDP is Matrix Gla Protein [MGP], which when activated inhibits osteogenic factors, thereby inhibiting vascular and soft tissue calcification

Effect of Dietary Vitamin K2 Supplementation on Bone Mineral Density in Ovariectomized Rats

Vitamin K has been suggested to plays a role in bone metabolism. The objective of this study was to determine whether vitamin K2 supplementation is related to bone mineral density, bone formation markers, and bone resorption in ovariectomized (OVX) rats. Forty Sprague-Dawley female rats (body weight, 200 +/- 10 g) were divided into four groups: a sham group fed a control diet, a sham group fed a vitamin K2 supplemented diet, OVX fed a control diet, and OVX fed a vitamin K2 supplemented diet (3.5 mg vitamin K2/kg diet). All rats were fed the experimental diets for 6 weeks, and deionized water was provided ad libitum. Serum alkaline phosphatase activity (ALP), osteocalcin, and urinary deoxypyridinoline crosslink values were measured as markers of bone formation and resorption. Bone mineral density (BMD) and bone mineral content were measured in the spine and femur using PIXImus (GE Lunar Co., Madison, WI, USA). No significant differences in body weight gain, food intake, or food efficiency ratio were observed between the control and experimental groups. Serum ALP, osteocalcin, and urinary crosslink values were not significantly different between the vitamin K2 supplemented groups. No significant differences were observed for any of the variables in the sham group. Spine BMD values were significantly lower in the OVX than those in the sham groups. Spine and femur BMD per weight of vitamin K2 tended to be higher than the control diet group within the OVX group, but no significant differences were observed. In conclusion, dietary vitamin K2 supplementation may have a beneficial effect on spine and femur BMD in OVX rats. Further research is needed to understand the potential benefits of vitamin K2 on bone loss in OVX rats.

Prescription Patterns of Anti-osteoporosis Medications by Gynecologists / 대한폐경학회지

OBJECTIVES: To describe prescription patterns by gynecologists for osteoporosis therapy and to compare with the prescription patterns by physicians of other medical specialties based on the data from the Health Insurance Review and Assessment Service. METHODS: A total of 28,568 prescription claims by gynecologists of 633,870 prescription claims by physicians with medications for osteoporosis alone or medications for other indications, including osteoporosis, were analyzed. The medications for osteoporosis alone were, selective estrogen receptor modulators (SERMs), calcitonin (injection or nasal spray), vitamin K2, ipriflavone, and fluoride. The medications for other indications including osteoporosis were estrogen, tibolone, testosterone, calcium, calcium-vitamin D complex, vitamin D, and oxymetholone. RESULTS: Anti-osteoporosis medications were prescribed by 4.7% of gynecologists. Calcium and vitamin D were the most commonly prescribed medications by gynecologists (60.7%), followed by hormones, including tibolone (44%). Bisphosphonates, including bisphosphonate complex, were prescribed by 27.5% of gynecologists and SERMs were prescribed by 3.6% of gynecologists. Amongst all prescribers, the percentage of gynecologists was highest for hormones (50.6%), followed by tibolone (31.0%). When both medications were combined, the percentage of gynecologists among prescribers was 81.6%. The combination rate of calcium with other anti-osteoporosis medications was highest in gynecologists among prescribers of medical specialties (34.1%). CONCLUSION: A very small percentage of gynecologists prescribed anti-osteoporosis medications, while calcium, vitamin D, and hormones, including tibolone, were commonly prescribed by gynecologists.

Prescription Patterns of Anti-osteoporosis Medications by Gynecologists / 대한폐경학회지

OBJECTIVES: To describe prescription patterns by gynecologists for osteoporosis therapy and to compare with the prescription patterns by physicians of other medical specialties based on the data from the Health Insurance Review and Assessment Service. METHODS: A total of 28,568 prescription claims by gynecologists of 633,870 prescription claims by physicians with medications for osteoporosis alone or medications for other indications, including osteoporosis, were analyzed. The medications for osteoporosis alone were, selective estrogen receptor modulators (SERMs), calcitonin (injection or nasal spray), vitamin K2, ipriflavone, and fluoride. The medications for other indications including osteoporosis were estrogen, tibolone, testosterone, calcium, calcium-vitamin D complex, vitamin D, and oxymetholone. RESULTS: Anti-osteoporosis medications were prescribed by 4.7% of gynecologists. Calcium and vitamin D were the most commonly prescribed medications by gynecologists (60.7%), followed by hormones, including tibolone (44%). Bisphosphonates, including bisphosphonate complex, were prescribed by 27.5% of gynecologists and SERMs were prescribed by 3.6% of gynecologists. Amongst all prescribers, the percentage of gynecologists was highest for hormones (50.6%), followed by tibolone (31.0%). When both medications were combined, the percentage of gynecologists among prescribers was 81.6%. The combination rate of calcium with other anti-osteoporosis medications was highest in gynecologists among prescribers of medical specialties (34.1%). CONCLUSION: A very small percentage of gynecologists prescribed anti-osteoporosis medications, while calcium, vitamin D, and hormones, including tibolone, were commonly prescribed by gynecologists.

Risk factors of acquired prothrombin complex deficiency syndrome: a case-control study.

BACKGROUND: Idiopathic vitamin K deficiency in infancy or acquired prothrombin complex deficiency (APCD) is a serious bleeding disorders in infants. It leads to a high mortality rate and permanent neurological sequele among the survivors. A low vitamin K intake by infants is suggested to have a major role in the pathogenesis. To reduce the incidence of this syndrome, its risk factors have to be identified. OBJECTIVE: To determine the risk factors of the acquired prothrombin complex deficiency syndrome in the early infantile period. MATERIAL AND METHOD: A case-control study was conducted in 20 cases and 60 age- and sex-matched controls who were admitted to the Queen Sirikit National Institute of Child Health in Bangkok during August 1991 to August 1993. Feeding type, maternal history of herb-liquor extracts (herbal medicine) use and no history of vitamin K1 prophylactics at birth were identified to be risk factors of the syndrome. All subjects were fed by breast milk with or without formula milk. None of the subjects fed by formula milk were in the case group (Chi-square for trend = 14.77, p = 0.001). RUSULTS: The rate of a maternal history of herb-liquor extracts use in the case group was significantly higher than that of the control group (p = 0.03). Vitamin K2MK4 level in breast milk obtained from the mothers of the infants with maternal history of herb-liquor extracts use was lower than that obtained from the mothers of the infants without maternal history of herb-liquor extracts use (p = 0.03). No infant with history of intramuscular K1 prophylactics was in the case group. Three out of eight infants with history of oral vitamin K1 regimen were cases. Although vitamin K1 and K2MK4 level in breast milk obtained from the cases' mothers were significantly lower than that obtained from the controls' mothers (p = 0.015 and p = 0.003 respectively), there was an overlapping of vitamin K levels among these two groups. CONCLUSION: This study demonstrated that vitamin K in breast milk has a main role in the pathogenesis of this disease. Herb-liquor extracts may be a cause of the APCD syndrome. Intramuscular vitamin K1 prophylactics should be routinely given to all newborn babies who will receive breast feeding. Effectiveness of oral vitamin K1 prophylactics regimen must be studied urgently.

Possible mechanism underlying apoptotic induction effect of vitamin K2 on human MDS cell line MUTZ-1 / 中国实验血液学杂志

The study was aimed to investigate the possible mechanism of vitamin K(2) (VK(2)) on myelodysplastic syndrome (MDS) cell line MUTZ-1 in vitro. The flow cytometry was used to analyze apoptosis rate and the change of cell cycle. The expression of apoptosis-related genes bcl-2, survivin and bax were detected by reverse transcription-polymerase chain reaction (RT-PCR). The activity of caspase-3 was detected by chemiluminescence assay. The results indicated that the apoptosis peak on FCM and positive Annexin-V FITC on cell membrane showed that VK(2) induced apoptosis of MUTZ-1 cells in a dose-and-time-dependent manner, S and G(2) cell decrement, G(0)/G(1) cell arrest, VK(2) significantly down-regulated the expression of bcl-2 and survivin, but had no effect on the expression of bax, the activity of caspase-3 was significantly increased. It is concluded that VK(2) induces apoptosis of MUTZ-1 cells through activating caspase-3 pathways and the apoptosis-related genes bcl-2 and survivin may play important roles in the process of apoptosis induction.

The Effect of Vitamin K2 in Addition to Risedronate on the Patients with Postmenopausal Osteoporosis

OBJECTIVE: To assess the effect of vitamin K2 in addition to risedronate on postmenopausal osteoporosis METHOD: We enrolled 21 postmenopausal osteoporosis women (age: 65.2+/-7.8 years). Ten subjects received risedronate (35 mg, weekly) and vitamin K2 (45 mg, daily) and eleven subjects only received risedronate. They all received calcium citrate 2,130 mg and vitamin D 600 IU daily. The duration of treatment was 7.7+/-1.4 months. Bone mineral density (BMD) of lumbar spine and both femurs, serum osteocalcin and urine deoxypyridinoline were examined at baseline and after treatment. RESULTS: After treatment, BMD, serum osteocalcin and urine deoxypyridinoline were improved in each group but there was no statistical difference between the groups. CONCLUSION: There was no evidence of the benefit of vitamin K2 in addition to risedronate in bone metabolism on postmenopausal osteoporosis.

Effects of Vitamin K2 on the Development of Osteopenia in Rats as the Models of Osteoporosis

Vitamin K2 is widely used for the treatment of osteoporosis in Japan. To understand the effects of vitamin K2 on bone mass and bone metabolism, we reviewed its effects on the development of osteopenia in rats, which characterizes models of osteoporosis. Vitamin K2 was found to attenuate the increase in bone resorption and/or maintain bone formation, reduce bone loss, protect against the loss of trabecular bone mass and its connectivity, and prevent the decrease in strength of the long bone in ovariectomized rats. However, combined treatment of bisphosphonates and vitamin K2 had an additive effect in preventing the deterioration of the trabecular bone architecture in ovariectomized rats, while the combined treatment of raloxifene and vitamin K2 improved the bone strength of the femoral neck. The use of vitamin K2 alone suppressed the increase in trabecular bone turnover and endocortical bone resorption, which attenuated the development of cancellous and cortical osteopenia in orchidectomized rats. In addition, vitamin K2 inhibited the decrease in bone formation in prednisolone-treated rats, thereby preventing cancellous and cortical osteopenia. In sciatic neurectomized rats, vitamin K2 suppressed endocortical bone resorption and stimulated bone formation, delaying the reduction of the trabecular thickness and retarding the development of cortical osteopenia. Vitamin K2 also prevented the acceleration of bone resorption and the reduction in bone formation in tail-suspended rats, which counteracted cancellous bone loss. Concomitant use of vitamin K2 with a bisphosphonate ameliorated the suppression of bone formation and more effectively prevented cancellous bone loss in tail-suspended rats. Vitamin K2 stimulated renal calcium reabsorption, retarded the increase in serum parathyroid hormone levels, and attenuated cortical bone loss primarily by suppressing bone resorption in calcium-deficient rats while maintaining the strength of the long bone in rats with magnesium deficiency. These findings suggest that vitamin K2 may not only stimulate bone formation, but may also suppress bone resorption. Thus, vitamin K2 could regulate bone metabolism in rats, which represented the various models of osteoporosis. However, the effects of vitamin K2 on bone mass and bone metabolism seem to be modest.

Inhibition effect of vitamin K2 on human MDS-JSN04 cell line and its possible mechanism / 中国实验血液学杂志

To study the effects and possible mechanism of Vitamin K(2) (VK(2)) in the treatment of MDS-JSN04 cells, the changes of morphologic features of MDS-JSN04 cells were investigated by cytomorphology, the apoptosis of MDS-JSN04 cells was observed by transmission electron microscope; cellular proliferation was determined by the MTT assay; cell apoptosis, cell cycle shift and expression of myeloid-specific differentiation antigen (CD11b, CD13) were analyzed by flow cytometry (FCM). The expression of apoptosis-related genes bcl-2, survivin and bax were detected by retrotranscriptase polymerase chain reaction (RT-PCR); the activity of caspase-3 was determined by chemiluminescence assay. The results showed that the typical apoptotic morphological features appeared in cells treated with VK(2) for 72 hours; VK(2) induced apoptosis of MDS-JSN04 cells and in a dose-and-time-dependent manner, G(0)/G(1) cell arrest and significantly down-regulated the expression of bcl-2 and survivin, but had no effect on the expression of bax; the activity of caspase-3 significantly increased. It is concluded that VK(2) induces apoptosis of MDS-JSN04 cells through activating caspase-3 pathways and the apoptosis-related genes bcl-2, survivin may play an important role in this process.

Prevention and Treatment of Corticosteroid-Induced Osteoporosis

Osteoporosis is one of the most serious complications of corticosteroid treatment. Loss of bone mineral density (BMD) and fractures occur early in the course of corticosteroid treatment, and thus early recognition of fracture risk and effective intervention based on evidence-based-medicine (EBM) are needed. A study of meta-analysis representing the highest level in a hierarchy of evidence showed that when the outcome measure of interest was limited to changes in lumbar spine BMD, bisphosphonates were the most effective of the agents studied in comparison with no therapy or treatment with calcium, and were also more efficacious than either vitamin D or calcitonin; the efficacy of bisphosphonates was enhanced when used in combination with vitamin D. Randomized controlled trials (RCTs) representing the second level in a hierarchy of evidence showed that bisphosphonates stabilized BMD not only in the lumbar spine, but also in the hip, and that parathyroid hormone (PTH) markedly increased lumbar spine BMD. According to the EBM, bisphosphonates and possibly PTH are suggested to be the most efficacious for preserving BMD. The efficacy of these agents in reducing the incidence of vertebral fractures in patients exposed to corticosteroids remains to be established in meta-analysis studies, although some RCTs have demonstrated the anti-fracture effects of etidronate, alendronate, and risedronate in the spine. Further RCTs of fracture prevention conducted on a large number of patients and their meta-analysis are needed to confirm the efficacy of bisphosphonates, PTH, or other agents in preventing vertebral and nonvertebral fractures.

The Therapeutic Effect of Menatetrenone (Vitamin K2) on Posttransplant Osteoporosis in Renal Transplant Recipient / 대한신장학회잡지

BACKGROUND: Posttransplant osteoporosis in renal transplant recipient is frequently observed complications, but therapeutic modalities are not clearly elucidated. Recent studies indicate that vitamin K2 also play a role in bone metabolism. Therefore, we performed prospective study to evaluate the effect of vitamin K2 (Menatetrenone(R)) on posttransplant osteroporosis. METHODS: Our study included total 83 patients (40 male, 43 female; age 36.9+/-5.5 years) who received a renal transplant more than 6 months ago. They underwent dual-energy X-ray absorptiometry (DEXA) at lumbar spine and femoral neck. The patients with osteoporosis were treated with vitamin K2 (glakay 15 mg) (group 1) or vitamin D3 with calcium carbonate (group 2). The patients without osteoporosis was observed without any treatment (group 3). After one year, follow-up BMD was performed in all patients. RESULTS: Of 83 patients, 44 patients (53.0%) had osteoporosis and 39 patients (47.0%) had not. In group 1 (N=28), vitamin K2 treatment significantly increased BMD at femoral neck (-3.2+/-0.4 vs 2.6+/-0.6, p0.05). In group 2 (N=16), there was significant increase in BMD at femoral neck (-3.0+/-0.6 vs -2.5+/-0.8, p0.05). Between group 1 and 2, there was no significant difference in BMD change. In group 3, BMD decreased at femoral neck (-1.3+/-0.2 vs -1.5+/-0.2) and lumbar spine (-0.8+/-0.2 vs -1.0+/-0.2) during follow-up period. CONCLUSION: Vitamin K2 (Menatetrenone(R)) is effective in treating osteoporosis at femoral neck and its effectiveness is s imilar with that of using vitamin D3 with calcium carbonate.

Combined Treatment with Vitamin K2 and Bisphosphonate in Postmenopausal Women with Osteoporosis

Vitamin K2, as well as bisphosphonates, such as etidronate, alendronate, and risedronate, is widely used in the treatment with osteoporosis in Japan. Etidronate increases the lumbar bone mineral density (BMD), and prevents new vertebral fractures, in patients with osteoporosis, while alendronate and risedronate increase the lumbar and femoral neck BMDs, and prevent new vertebral and femoral neck fractures. Vitamin K2 enhances gamma-carboxylation of bone glutamic acid residues and the secretion of osteocalcin, sustains the lumbar BMD, and prevents osteoporotic fractures in patients with osteoporosis. Bisphosphonates, such as alendronate and risedronate, rather than vitamin K2, should be initially chosen for the treatment of osteoporosis, because they are more efficacious than vitamin K2. Available evidence suggest that risedronate prevents deterioration of the connectivity of the trabeculae in ovariectomized rats, whereas vitamin K2 increase the trabecular thickness, and that a combination of risedronate and vitamin K2 has a synergistic effect on preventing the deterioration of trabecular bone architecture induced by estrogen deficiency. Some studies have shown that combined treatment with etidronate and vitamin K2 appears to be more effective than etidronate alone in the prevention of new osteoporotic vertebral fractures. Based on these findings, combined treatment with vitamin K2 and bisphosphonates may be more efficacious in the prevention new vertebral fractures than a single treatment with bisphosphonate in postmenopausal women with osteoporosis. Thus, this combined treatment should be recommended for the treatment of postmenopausal osteoporosis. It is proposed that the role of vitamin K2 should be emphasized, when used in combination with bisphosphonates, especially in patients with vitamin K deficiency.

Efficacy and safety of Menatetrenone-4 postmenopausal Thai women.

Clinical and comparative study of the efficacy and adverse events of Menatetrenone-4. The control group (n=40) received elemental calcium carbonate 800 mg/day and the Menatetrenone-4 treated group received elemental calcium carbonate 800 mg/day plus vitamin K2 45 mg/day (n=43). The vitamin K2 treated group showed a marked decrease of undercarboxylated osteocalcin at 2 weeks, six months (51.52% p=0.0001) and twelve months (87.26% p=0.0001) compared to the calcium treated group. At the end of the sixth and twelve months both groups did not increase bone mass of the hip but the vitamin K2 treated group increased 0.6 per cent of bone mass of the lumbar spine and decreased bone resorption 65.42 per cent (p=0.0001) compared to the calcium treated group. The calcium treated group was switched to the vitamin K2 treated group at the end of six months and showed a decrease of the level of undercarboxylated osteocalcin the same as the former vitamin K2 treated group. The adverse events were 2 cases of mild skin rash which subsided after cessation of medication.