menatetrenone and Osteoporosis

The effect of the anti-osteoporosis medicine, menatetrenone (vitamin K(2); menaquinone-4) on the skeleton remains a matter of controversy. The objective of the present review study was to evaluate the effect of menatetrenone on the skeleton of postmenopausal women, men and glucocorticoid-treated patients.. PubMed was used to search the literature for randomized controlled trials (RCTs), meta-analyses and systematic reviews. Thirteen RCTs, one meta-analysis and one systematic review were available for analysis.. Except for one large Japanese RCT (Phase IV trial: Osteoporotic Fracture (OF) study, n = 4378), RCTs with small sample size showed non-significant or modest effect on bone mineral density (BMD) in postmenopausal women and patients treated with glucocorticoid, positive effect on hip geometry in postmenopausal women and efficacy against fractures (mainly vertebral fractures) in postmenopausal women with osteoporosis. A post hoc analysis of the OF study showed that the incidence of vertebral fractures decreased in postmenopausal women with at least five vertebral fractures. A meta-analysis study, but not a systematic review study, showed efficacy against vertebral and non-vertebral fractures mainly in postmenopausal women with osteoporosis. There was no available evidence for men with osteoporosis.. The present review of the literature revealed some evidence of a positive effect of menatetrenone on the skeleton of postmenopausal women and in patients treated with glucocorticoid.. Menatetrenone is considered to be a second-line medicine for postmenopausal osteoporotic women with an increased risk for vertebral fractures.

Topics: Bone Density; Clinical Trials as Topic; Humans; Osteocalcin; Osteoporosis; Spinal Fractures; Treatment Outcome; Vitamin K 2

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an iatrogenic disease and a significant concern to patients and dentists. Bisphosphonates are used for millions of men and women with osteoporosis, with the rationale being that these medications increase bone mineral density and decrease fracture risk. Clinicians will undoubtedly encounter some patients who are taking bisphosphonate medications. Recognizing the risk factors for BRONJ, understanding the pathophysiology of BRONJ, and enacting a reasonable approach to prevent BRONJ in patients is crucial to providing safe and effective treatments. This article proposes a rational approach for moving BRONJ away from a risk management and quality assurance model that is currently being used by dentists, to a preventive model. The role of collagen as postulated in this article cannot be ignored in the pathophysiology and potential prevention and treatment of osteoporosis and BRONJ. Studies from the medical literature support the safety and efficacy of MK4 as a potential therapeutic agent in preventing and treating osteoporosis and BRONJ. While the approach outlined herein requires additional study, the conceptual framework based on a broad review of the osteonecrosis of the jaw (ONJ) literature provides a means to begin to address this situation in a proactive, rather than reactive, way.

Topics: Bisphosphonate-Associated Osteonecrosis of the Jaw; Collagen; Diphosphonates; Humans; Osteoporosis; Vitamin K 2

A high incidence of fractures, particularly of the hip, represents an important problem in patients with AD, who are prone to falls and may have osteoporosis. The odds ratio reported for fracture prevalence between elderly persons with and without AD is 6.9. We previously demonstrated that deficiency of 25-hydroxyvitamin D due to sunlight deprivation and vitamin K deficiency due to malnutrition contributed to reduced bone mineral density in patients with AD and were associated with a high risk of hip fracture. Treatment with menatetrenone, risedronate or regular sunlight exposure are safe and effective in increasing bone mass and reducing the risk of hip fracture in patients with AD.

Topics: Accidental Falls; Bone Density; Dementia; Etidronic Acid; Hip Fractures; Humans; Hyperparathyroidism, Secondary; Osteoporosis; Risedronic Acid; Risk; Risk Factors; Sunlight; Vitamin D Deficiency; Vitamin K 2; Vitamin K Deficiency

Bone loss and impaired bone quality have been proposed as major causes of increased bone fragility in osteoporosis. The proposed determinants of the material properties of bone are the degree of secondary mineralization, microdamage accumulation, and collagen cross-link formation that is affected by bone turnover rate. Recently, we demonstrated that (1) three years bisphosphonate increases the degree of mineralization, collagen maturity, and non-enzymatic cross-link, pentosidine without changing the amount of enzymatic cross-link and (2) the changes in collagen cross-link formation after treatment of bisphosphonate were associated with microdamage accumulation, which were independent of the mineral content (Saito M, Osteoporos Int, in press) and (3) urinary excretion of pentosidine predicts vertebral fracture (Shiraki M, Saito M, et al, J Bone Miner Metab, 2008) . In this review, I described effects of drugs for osteoporosis on bone material properties.

Topics: Animals; Bone and Bones; Bone Density Conservation Agents; Bone Remodeling; Calcification, Physiologic; Collagen; Diphosphonates; Glycation End Products, Advanced; Humans; Hydroxycholecalciferols; Osteoporosis; Raloxifene Hydrochloride; Vitamin K 2

Menatetrenone (MK-4) is a form of vitamin K(2) (VK(2)) which is utilized for the treatment of osteoporosis. MK4 has a grade B as a total recommendation rate in the Japanese guideline for the prevention and treatment of osteoporosis in 2006 based on the current clinical evidences. The effects of fracture prevention by MK-4 are assumed to be based on the increase of bone mineral density as well as the improvement of bone quality. Recent researches suggest that VK affects bone metabolism via nuclear receptor in addition to the carboxylation of VK dependent proteins.

Topics: Bone and Bones; Bone Density; Evidence-Based Medicine; Fractures, Bone; Humans; Meta-Analysis as Topic; Osteoporosis; Practice Guidelines as Topic; Vitamin K 2

Topics: Bone and Bones; Bone Density; Bone Density Conservation Agents; Calcitonin; Diphosphonates; Femoral Neck Fractures; Humans; Hypercalcemia; Osteoporosis; Stroke; Vitamin D; Vitamin D Deficiency; Vitamin K 2

Vitamin K2 (menatetrenone) treatment was reported to significantly prevent new clinical fracture (chi2 = 10.935;p = 0.0273) in a 2-year group comparison study of patients with osteoporosis, although it only maintained the baseline bone mineral density. This result strongly suggested that another factor was involved in promoting bone strength apart from an increase in bone mineral density. With respect to the therapeutic effect of menatetrenone treatment on corticosteroid-induced osteoporosis over 2 years, the incidence of a new vertebral fracture was 13.3% in the menatetrenone treatment group versus 41% in the control group, indicating that this treatment could prevent fractures. Multivariate logistic regression analysis was performed to investigate independent risk factors for new vertebral fractures, and treatment with menatetrenone showed a preventive effect on fracture with an odds ratio of 0.03 and a risk rate of 0.003.

Topics: Animals; Bone and Bones; Bone Density; Fractures, Bone; Humans; Osteoporosis; Vitamin K 2

Osteoporosis with increased risk of bone fracture is a disabling syndrome that naturally occurs as long as one ages and moves on two legs. Recent progress in bone cell biology has shed light on the mechanisms underlying the anti-osteoporotic properties of drugs that have been in use for a long time, providing a fresh stage for novel pharmacotherapies. In addition, large scale clinical trials developed in the past decade appear not only to rationalize the clinical utilities of these drugs but also to provide new concepts for the development of new therapeutic modalities. Progress in the fields of basic and clinical research field is briefly reviewed herein.

Topics: Alendronate; Androgens; Animals; Binding Sites; Bone Remodeling; Clinical Trials as Topic; Estrogen Replacement Therapy; Estrogens; Estrogens, Non-Steroidal; Evidence-Based Medicine; Humans; Isoflavones; Osteoblasts; Osteoclasts; Osteoporosis; Phytoestrogens; Plant Preparations; Selective Estrogen Receptor Modulators; Vitamin D; Vitamin K 2

Topics: Alendronate; Calcitonin; Clinical Trials as Topic; Drug Approval; Estriol; Etidronic Acid; Europe; Humans; Isoflavones; Japan; Osteoporosis; Practice Guidelines as Topic; Raloxifene Hydrochloride; United States; Vitamin K 2

Objective Vitamin K2 (menatetrenone) is an effective treatment for patients with postmenopausal osteoporosis. We herein performed a subanalysis of patients with systemic autoimmune diseases undergoing glucocorticoid therapy in our previous prospective study. Methods Sixty patients were categorized into a group with vitamin K2 treatment (n=20, Group A) and a group without vitamin K2 treatment (n=40, Group B). All patients were treated with bisphosphonates. Results Serum levels of osteocalcin and undercarboxylated osteocalcin decreased significantly after the start of glucocorticoid therapy in both groups, while the serum osteocalcin level was significantly higher in Group A than Group B during the third (p=0.0250) and fourth weeks (p=0.0155). The serum level of the N-terminal peptide of type I procollagen, a bone formation marker, decreased during glucocorticoid therapy, but was significantly higher in Group A than Group B during the fourth week (p=0.0400). The bone mineral density and fracture rate showed no significant differences between the two groups. Conclusion Although vitamin K2 improves bone turnover markers in patients with osteoporosis on glucocorticoid therapy, it has no significant effect on the bone mineral density and fracture rate after 1.5 years of treatment.

Topics: Autoimmune Diseases; Biomarkers; Bone Density; Collagen Type I; Diphosphonates; Female; Glucocorticoids; Humans; Male; Middle Aged; Osteoporosis; Prospective Studies; Vitamin K 2

Osteoporosis is one of the major complications of glucocorticoid therapy. Osteoporosis is usually defined by the levels of bone mineral density (BMD) assessed by dual energy X-ray absorptiometry (DEXA); however, glucocorticoids often induce fractures in patients with normal BMD. Thus, novel diagnostic approaches are required. In this study, we examined whether multidetector-row computed tomography (MDCT) is useful to assess the bone status in glucocorticoid-induced osteoporosis (GIO). Because bisphosphonates have been proven to prevent bone fracture in GIO, we tried to detect the therapeutic effects of bisphosphonates in GIO by MDCT. Fifteen Japanese patients with immunoglobulin A nephropathy who had normal renal function were enrolled in this open-label randomized trial. Patients were randomly divided into three groups-calcitriol (VD), menatetrenone (VK), or bisphosphonate (Bis). Bone conditions were analyzed twice by three different methods-bone turnover markers, DEXA, and MDCT-at the start and 6 months after the start of therapy. Both bone markers and DEXA could not detect significant differences among the therapeutic groups; however, MDCT-based analyses detected the preventive effects of bisphosphonates in GIO. Compared to VD, Bis improved structural indices, such as bone volume fraction, trabecular separation, marrow star volume, and structure model index whereas the difference between VD and VK was not significant. Finite element analysis revealed that simulated fracture load in the Bis group was significantly improved. These findings suggested that MDCT-based assessment is superior to bone markers and/or DEXA in assessing the therapeutic effect of bisphosphonates on GIO.

Topics: Adolescent; Adult; Biomarkers; Bone and Bones; Bone Density; Bone Density Conservation Agents; Calcitriol; Diphosphonates; Female; Glucocorticoids; Humans; Male; Middle Aged; Multidetector Computed Tomography; Osteoporosis; Prospective Studies; Vitamin K 2; Young Adult

A high incidence of fractures, particularly of the hip, represents an important problem in patients with Alzheimer disease (AD), who are prone to falls and have osteoporosis. We previously found that vitamin K deficiency and low 25-hydroxyvitamin D (25-OHD) with compensatory hyperparathyroidism cause reduced bone mineral density (BMD) in female patients with AD. This may modifiable by intervention with menatetrenone (vitamin K2) and risedronate sodium; we address the possibility that treatment with menatetrenone, risedronate and calcium may reduce the incidence of nonvertebral fractures in elderly patients with AD. A total of 231 elderly patients with AD were randomly assigned to daily treatment with 45 mg of menatetrenone or a placebo combined with once weekly risedronate sodium, and followed up for 12 months. At baseline, patients of both groups showed high undercarboxylated osteocalcin (ucOC) and low 25-OHD insufficiency with compensatory hyperparathyroidism. During the study period, BMD in the treatment group increased by 5.7% and increased by 2.1% in the control group. Nonvertebral fractures occurred in 15 patients (10 hip fractures) in the control group and 5 patients (2 hip fractures) in the treatment group. The relative risk in the treatment group compared with the control group was 0.31 (95% confidence interval, 0.12-0.81). Elderly AD patients with hypovitaminosis K and D are at increased risk for hip fracture. The study medications were well tolerated with relatively few adverse events and effective in reducing the risk of a fracture in elderly patients with AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Bone Density; Bone Density Conservation Agents; Etidronic Acid; Female; Hemostatics; Hip Fractures; Humans; Hyperparathyroidism; Male; Osteoporosis; Risedronic Acid; Vitamin D; Vitamin K; Vitamin K 2

The recommended dose of Menatretenone is 45 mg three times a day; however the compliant in daily practice is not convenient. This study shows the twice dose per day is inferior to the recommended dose. This study used the level of Gla protein in osteocalcin as a parameter for the comparison. The mean of three-time dose a day is 11.27 nanogram per milliliter while the mean of the other group is 6.07 nanogram per milliliter after the three-month treatment.

Topics: Aged; Calcium; Female; Humans; Middle Aged; Osteoporosis; Treatment Outcome; Vitamin D; Vitamin K 2

Osteoporosis is a common complication of anorexia nervosa (AN). Although weight recovery and resumption of menses are important goals in AN treatment, they are often achieved only after a prolonged period of recovery. Therefore, it becomes important to find therapies with the potential to prevent further decreases in bone mineral density (BMD). We conducted a non-randomized study of the effects of menatetrenone (vitamin K2) on bone loss in patients with AN. Lumbar BMD was longitudinally measured by Dual Energy X-ray Absorptiometry (DXA) in 10 patients with AN who chose to receive menatetrenone treatment (MED+ group) and 11 patients who did not (MED- group). During the mean 0.9-year follow-up period, the BMD of the lumbar vertebrae of the MED+ group decreased significantly less than that of the MED- group (-2.8% and -6.9%, respectively). Among bone metabolism markers, gamma-carboxyglutamic acid osteocalcin significantly increased (128.6% and 28.3%, respectively) and urine deoxypyridinoline significantly decreased (-44.5% and -13.7%, respectively) more in the MED+ group than in the MED- group. These differences in BMD and bone metabolism markers may be attributable to menatetrenone treatment. The results suggest that menatetrenone may be beneficial in the prevention of bone loss in patients with AN. Randomized placebo-controlled studies are needed to confirm these findings.

Topics: Adult; Anorexia Nervosa; Blood Chemical Analysis; Bone Density; Female; Follow-Up Studies; Hemostatics; Humans; Male; Osteoporosis; Urinalysis; Vitamin K 2; Weight Gain

Significant reduction in bone mineral density (BMD) occurs in patients with Parkinson's disease (PD), correlating with immobilization and with vitamin D deficiency, and increasing the risk of hip fracture, especially in elderly women. As a biological indicator of compromised vitamin K status, an increased serum concentration of undercarboxylated osteocalcin (Oc) has been associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women. We evaluated treatment with vitamin K(2) (menatetrenone; MK-4) in maintaining BMD and reducing the incidence of nonvertebral fractures in elderly female patients with PD. In a random and prospective study of PD patients, 60 received 45 mg of MK-4 daily for 12 months, and the remaining 60 (untreated group) did not. At baseline, patients of both groups showed vitamin D and K(1) deficiencies, high serum levels of ionized calcium, and glutaminic residue (Glu) Oc, and low levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1,25-(OH)(2)D and compensatory PTH secretion. BMD in the second metacarpals increased by 0.9% in the treated group and decreased by 4.3% in the untreated group (p < 0.0001). Vitamin K(2) level increased by 259.8% in the treated group. Correspondingly, significant decreases in Glu Oc and calcium were observed in the treated group, in association with an increase in both PTH and 1,25-(OH)(2)D. Ten patients sustained fractures (eight at the hip and two at other sites) in the untreated group, and one hip fracture occurred among treated patients (p = 0.0082; odds ratio = 11.5). The treatment with MK-4 can increase the BMD of vitamin D- and K-deficient bone by increasing vitamin K concentration, and it can also decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1,25-(OH)(2)D concentration.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Bone Density; Chi-Square Distribution; Female; Humans; Osteoporosis; Parkinson Disease; Patients; Prospective Studies; Statistics, Nonparametric; Vitamin D Deficiency; Vitamin K 2

Bone loss frequently appears in the natural history of liver disease. The effects of therapy for osteoporosis associated with cirrhosis of the liver are still controversial. We evaluated the effects of vitamin K2 on osteopenia in women with cirrhosis.. The subjects were 50 women with cirrhosis who had underlying hepatitis viral infections. Half of the patients were randomly assigned to receive vitamin K2 (menatetrenone). The bone mineral density (BMD) of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry at entry and at 1-yr intervals for 2 yr.. The percentages of change from the initial BMD at 1 and 2 yr after initiation of the study were, respectively, +0.1 +/- 2.6% and -0.5 +/- 3.5% for the vitamin K2-treated group and -2.2 +/- 2.4% and -4.6 +/- 3.9% for the control group. The changes in BMD at each timepoint differed significantly between the control and treated groups (p = 0.008 for 1 yr and p = 0.002 for 2 yr). In the vitamin K2-treated group, the ratio of osteocalcin to undercarboxylated osteocalcin in those patients with increases in BMD after 1 yr of treatment was significantly lower than that in patients showing decreases in BMD (p = 0.017). No adverse effects of vitamin K2 were noted.. Vitamin K2 can prevent bone loss and may therefore be useful in the management of bone disease in women with cirrhosis of the liver.

Topics: Absorptiometry, Photon; Adult; Aged; Bone Density; Female; Hemostatics; Hepatitis B; Hepatitis C; Humans; Liver Cirrhosis; Lumbar Vertebrae; Middle Aged; Osteoporosis; Time Factors; Vitamin K 2

We have reported that alfacalcidol plus menatetrenone, a vitamin K2 with four isoprene units (menaquinone-4), treatment is useful for improving bone problems in children with skeletal unloading. The aim of this study was to evaluate the effect of menatetrenone on bone metabolism in long-term glucocorticoid-treated children with alfacalcidol treatment. Twenty children who had been treated with fixed dosages of prednisolone and alfacalcidol (0.03 microg/kg/day) for 24 weeks were enrolled in a prospective pilot study, and assigned to receive alfacalcidol (0.03 microg/kg/day) or alfacalcidol (0.03 microg/kg/day) plus menatetrenone (approximately 2 mg/kg/day). Bone biochemical markers and bone mineral density (BMD) were measured at baseline and after the 12-week treatment. In the group receiving alfacalcidol plus menatetrenone, serum carboxylated osteocalcin (OC) (p =0.0022) and lumbar BMD (p=0.0029) increased and serum undercarboxylated OC (p=0.0004) decreased significantly in comparison to the group receiving alfacalcidol; further, the change of lumbar BMD showed an inverse correlation to the change of serum undercarboxylated OC (r=-0.744, p=0.0134) and positive correlations to the baseline values of bone turnover markers such as serum levels of intact OC, bone-specific alkaline phosphatase and type I procollagen carboxyl extension peptide and urinary levels of deoxypyridinoline and N-telopeptide of type I collagen. No adverse effect was observed. This is a small short-term study, but its results suggest that menatetrenone effectively and safely increases lumbar BMD probably through carboxylation of OC in long-term prednisolone-treated children with alfacalcidol treatment who have a high bone turnover. Randomized double-blind controlled trials are needed to confirm our findings.

Topics: Adolescent; Bone Density; Child; Child, Preschool; Female; Glucocorticoids; Humans; Hydroxycholecalciferols; Lumbar Vertebrae; Male; Osteocalcin; Osteoporosis; Prednisolone; Prospective Studies; Vitamin K; Vitamin K 2

The administration of menaquinone-4 (MK-4), one of subclasses of vitamin K2, significantly reduces bone loss in postmenopausal osteoporotic women. However, concerns have been raised about whether vitamin K administration alters the hemostatic balance by inducing a thrombotic tendency. We investigated were whether the administration of vitamin K in the form of MK-4 induced a thrombotic tendency in 29 elderly patients with osteoporosis (5 men, 24 women; age range 78.7+/-5.1 years). Patients were administered 45 mg/day (three times a day, 30 min after each meal) of MK-4 for 12 weeks. Blood samples were obtained from the patients at 0, 4 and 12 weeks after the start of MK-4 administration. A number of hemostatic parameters remained stable under the markedly increased plasma levels of MK-4. However, in patients with suspected vitamin K deficiency, whose plasma levels of vitamin K or factor VII were low, vitamin-K-dependent clotting factors such as factor VII and prothrombin were gradually increased after administration of MK-4. No changes in the sensitive molecular markers such as TAT and F1+2, which reflect the amount of thrombin generated in the blood stream, were observed, even in those patients with suspected vitamin K deficiency. These results indicate that MK-4 can be administered safely, with regard to maintaining the hemostatic balance, to osteoporotic patients receiving no anticoagulant therapy.

Topics: Aged; Aged, 80 and over; Blood Coagulation Factors; Cyanoacrylates; Female; Hemostasis; Hemostatics; Humans; Male; Osteoporosis; Osteoporosis, Postmenopausal; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Glucocorticoid-induced osteoporosis has been reported to be caused by enhanced bone resorption and suppressed bone formation. To clarify whether administration of vitamin K, which enhances bone formation, prevents prednisolone-induced loss of bone mineral density (BMD), a randomized, prospective, controlled study was conducted on 20 patients with chronic glomerulonephritis scheduled for treatment with prednisolone. All patients were initially treated with 0.8 mg/kg body weight/day of prednisolone (maximum of 40 mg) for 4 weeks, tapering to 20 mg/day over approximately 6 weeks. Ten patients received prednisolone alone (Group 1), and the other 10 patients received prednisolone plus 15 mg of menatetrenone, vitamin K, three times per day (Group 2). BMD of the lumbar spine measured by dual-energy X-ray absorptiometry (DXA) and biochemical markers of bone metabolism in blood and urine were evaluated before and 10 weeks after administration of prednisolone alone or with menatetrenone. In Group 1, treatment with prednisolone significantly reduced BMD of the lumbar spine from 1.14 +/- 0.12 to 1.10 +/- 0.11 g/cm2 (P = 0.0029). Serum intact osteocalcin and procollagen type I C-peptide (PICP) concentrations, biochemical markers of bone formation, were markedly reduced. A biochemical marker of bone resorption, urinary excretion of deoxypyridinoline, was significantly reduced. In Group 2, prednisolone-induced reduction of BMD was prevented by menatetrenone administration (1.09 +/- 0.09 to 1.07 +/- 0.07 g/cm2, P = 0.153). Menatetrenone prevented reduction of PICP concentration by prednisolone but not in serum intact osteocalcin concentration and urinary excretion of deoxypyridinoline. Thus, treatment with prednisolone resulted in loss of BMD of the lumbar spine associated with suppression of both bone formation and bone resorption. Menatetrenone is a useful agent in preventing prednisolone-induced loss of BMD.

Topics: Absorptiometry, Photon; Adolescent; Adult; Anti-Inflammatory Agents; Bone Density; Calcium; Chronic Disease; Drug Therapy, Combination; Female; Glomerulonephritis; Hemostatics; Humans; Male; Middle Aged; Osteoporosis; Phosphates; Prednisolone; Vitamin K; Vitamin K 2

We attempted to investigate whether vitamin K2 (menatetrenone) treatment effectively prevents the incidence of new fractures in osteoporosis. A total of 241 osteoporotic patients were enrolled in a 24-month randomized open label study. The control group (without treatment; n = 121) and the vitamin K2-treated group (n = 120), which received 45 mg/day orally vitamin K2, were followed for lumbar bone mineral density (LBMD; measured by dual-energy X-ray absorptiometry [DXA]) and occurrence of new clinical fractures. Serum level of Glu-osteocalcin (Glu-OC) and menaquinone-4 levels were measured at the end of the follow-up period. Serum level of OC and urinary excretion of deoxypyridinoline (DPD) were measured before and after the treatment. The background data of these two groups were identical. The incidence of clinical fractures during the 2 years of treatment in the control was higher than the vitamin K2-treated group (chi2 = 10.935; p = 0.0273). The percentages of change from the initial value of LBMD at 6, 12, and 24 months after the initiation of the study were -1.8 +/- 0.6%, -2.4 +/- 0.7%, and -3.3 +/- 0.8% for the control group, and 1.4 +/- 0.7%, -0.1 +/- 0.6%, and -0.5 +/- 1.0% for the vitamin K2-treated group, respectively. The changes in LBMD at each time point were significantly different between the control and the treated group (p = 0.0010 for 6 months, p = 0.0153 for 12 months, and p = 0.0339 for 24 months). The serum levels of Glu-OC at the end of the observation period in the control and the treated group were 3.0 +/- 0.3 ng/ml and 1.6 +/- 0.1 ng/ml, respectively (p < 0.0001), while the serum level of OC measured by the conventional radioimmunoassay (RIA) showed a significant rise (42.4 +/-6.9% from the basal value) in the treated group at 24 months (18.2 +/- 6.1% for the controls;p = 0.0081). There was no significant change in urinary DPD excretion in the treated group. These findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures, although the vitamin K2-treated group failed to increase in LBMD. Furthermore, vitamin K2 treatment enhances gamma-carboxylation of the OC molecule.

Topics: Absorptiometry, Photon; Amino Acids; Biomarkers; Bone Density; Bone Remodeling; Female; Fractures, Spontaneous; Humans; Incidence; Lumbar Vertebrae; Osteocalcin; Osteoporosis; Radionuclide Imaging; Treatment Outcome; Vitamin K; Vitamin K 2

The efficacy and side effects of oral vitamin K2 therapy were examined in 20 children and adults with probable secondary osteoporosis who had been hospitalized for a long period, due to severe mental and/or physical handicaps. Vitamin K2 was given for 12 months. Bone mineral density significantly increased 4 months after starting oral vitamin K2 therapy (p = 0.0038) and it retained the elevated level after 12 months of treatment. This therapy was particularly effective in patients with severe locomotor dysfunction. Serum total protein levels significantly decreased following the start of this therapy (p = 0.0012). The reasons of this decrease and its causal relationship to the administration of vitamin K2 are unknown, and should be investigated further.

Topics: Adolescent; Adult; Bone Density; Disabled Persons; Female; Humans; Male; Motor Activity; Osteoporosis; Vitamin K; Vitamin K 2

Osteoporosis is a progressive metabolic disease characterized by decreased bone mineral density and increased fracture risk. Previous studies have shown that higher intake of vitamin K (VK) correlates with a reduced risk of osteoporosis. However, the effect of menaquinone-4 (MK-4), a specific form of VK, still remains obscure. Therefore, in this study, we investigated the effects of MK-4 on osteoclast differentiation by differentiating RAW 264.7 cells into osteoclasts with the help of receptor activator of nuclear factor-kappa B ligand (RANKL), assessed the mRNA expression of osteoclast-specific genes, and studied the effects of MK-4

Topics: Animals; Bone Resorption; Cell Differentiation; Female; Humans; Mice; NF-kappa B; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Ovariectomy; RANK Ligand; RNA, Messenger

Topics: Female; Fractures, Compression; Humans; Osteocalcin; Osteoporosis; Prospective Studies; Spinal Fractures; Vitamin K 2; Vitamins

The purpose of the present study was to examine the effects of vitamin K2 on cortical and cancellous bone mass, cortical osteocyte and lacunar system, and porosity in sciatic neurectomized rats. Thirty-four female Sprague-Dawley retired breeder rats were randomized into three groups: age-matched control, sciatic neurectomy (NX), and NX + vitamin K2 administration (menatetrenone, 30 mg/kg/day p.o., three times a week). At the end of the 8-week experiment, bone histomorphometric analysis was performed on cortical and cancellous bone of the tibial diaphysis and proximal metaphysis, respectively, and osteocyte lacunar system and porosity were evaluated on cortical bone of the tibial diaphysis. NX decreased cortical and cancellous bone mass compared with age-matched controls as a result of increased endocortical and trabecular bone erosion and decreased trabecular mineral apposition rate (MAR). Vitamin K2 ameliorated the NX-induced increase in bone erosion, prevented the NX-induced decrease in MAR, and increased bone formation rate (BFR/bone surface) in cancellous bone, resulting in an attenuation of NX-induced cancellous bone loss. However, vitamin K2 did not significantly influence cortical bone mass. NX also decreased osteocyte density and lacunar occupancy and increased porosity in cortical bone compared with age-matched controls. Vitamin K2 ameliorated the NX-induced decrease in lacunar occupancy by viable osteocytes and the NX-induced increase in porosity. The present study showed the efficacy of vitamin K2 for cancellous bone mass and cortical lacunar occupancy by viable osteocytes and porosity in sciatic NX rats.

Topics: Animals; Bone and Bones; Bone Density; Cell Count; Denervation; Female; Femur; Osteocytes; Osteoporosis; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Tibia; Vitamin K 2

Prior 8-week treatment with menatetrenone, MK-4, followed by 8-week risedronate prevented the shortcomings of individual drugs and significantly increased the strength of ovariectomized ICR mouse femur compared to the ovariectomized (OVX) controls. Neither MK-4 following risedronate nor the concomitant administration may be recommended because they brought the least beneficial effect.. The objective of this study was to determine the best combinatory administration of risedronate at 0.25 mg/kg/day (R) with vitamin K(2) at approximately 100 microg MK-4/kg/day (K) to improve strength of osteoporotic mouse bone.. Thirteen-week-old ICR mice, ovariectomized at 9-week, were treated for 8 weeks with R, K, or R plus K (R/K), and then, either the treatment was withdrawn (WO) or switched to K or R in the case of R and K. After another 8 weeks, the mice were killed, and mechanical tests and analyses of femur properties by peripheral quantitative computed tomography, microfocus X-ray tube computed tomography, and confocal laser Raman microspectroscopy were carried out.. The K to R femur turned out superior in parameters tested such as material properties, bone mineral density, BMC, trabecular structure, and geometry of the cortex. The increased cross-sectional moment of inertia, which occurred after K withdrawal, was prevented by risedronate in K to R. In addition to K to R, some properties of R to WO diaphysis and K to WO epiphysis were significantly better than OVX controls.. Prior treatment with MK-4 followed by risedronate significantly increased femur strength in comparison to the OVX controls.

Topics: Animals; Body Weight; Bone Density Conservation Agents; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Etidronic Acid; Female; Femur; Mice; Mice, Inbred ICR; Osteoporosis; Ovariectomy; Risedronic Acid; Vitamin K 2

A HPLC fluorescence determination method for Vitamin K derivatives (Vitamin K(1), phylloquinone, PK and K(2), menaquinones, MK-4 and MK-7) using post-column reduction and internal standards was developed. Selectivity and reproducibility were increased by optimized chromatography conditions and satisfactory precision and accuracy were attained by using synthetic internal standards. After addition of internal standards to plasma samples, lipids were extracted with ethanol and hexane. Chromatography was performed by isocratic reverse phase separation on a C18 column. Vitamin K derivatives were detected at 430 nm with excitation at 320 nm for MK-4 and 240 nm for PK and MK-7. The detection limits for MK-4, PK and MK-7 were 4, 2 and 4 pg, respectively. The recoveries of MK-4, PK and MK-7 were greater than 92% and the inter- and intra-assay R.S.D. values were 5.7-9.2% for MK-4, 4.9-9.6% for PK and 6.3-19.3% for MK-7. The data showed good correlation between proposed method and LC-APCI/MS method for MK-4 (R(2)=0.988), PK (R(2)=0.979) and MK-7 (R(2)=0.986). The method allows the determination of Vitamin K for evaluating their clinical and nutritional status.

Topics: Chromatography, High Pressure Liquid; Fluorescence; Humans; Osteoporosis; Reference Standards; Spectrometry, Mass, Electrospray Ionization; Vitamin K; Vitamin K 2

We report here the development of a precise and sensitive method for the determination of vitamin K homologues including phylloquinone (PK), menaquinone-4 (MK-4), and menaquinone-7 (MK-7) in human plasma using HPLC-tandem mass-mass spectrometry with atmospheric pressure chemical ionization (LC-APCI-MS/MS). The method involves the use of stable isotope (18)O-labeled internal standard compounds, which were synthesized in our laboratory, and the selection of a precursor and product ion with a MS/MS multiple reaction monitoring method. The average intraassay and interassay variation values for PK, MK-4, and MK-7 were <10%. Average spiked recoveries from authentic compounds added to normal human plasma samples for PK, MK-4, and MK-7 were 98-102%. Mean plasma concentrations of PK, MK-4, and MK-7 from healthy subjects (n = 20) were 1.22 +/-0.57, 0.39 +/- 0.46, and 6.37 +/- 7.45 ng/mL, respectively. We conclude that this novel LC-APCI-MS/MS method should be useful for the evaluation of vitamin K status in postmenopausal women and elderly subjects and provides useful information for the treatment and prevention of osteoporosis with vitamin K.

Topics: Calibration; Chromatography, High Pressure Liquid; Humans; Mass Spectrometry; Osteoporosis; Oxygen Isotopes; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Fluorescence; Vitamin K; Vitamin K 1; Vitamin K 2

Menatetrenone (MK-4) is a vitamin K2 homologue that has been used as a therapeutic agent for osteoporosis in Japan. However, there is no far any reported evidence that MK-4 ameliorates a pre-existing condition of reduced bone mineral density (BMD) in vivo. In this study, we evaluated the effect of MK-4 in a rat model of established bone loss through immobilization caused by sciatic neurectomy. Unilateral sciatic neurectomy (SNx) was performed in rats, and 10 or 30 mg/kg of MK-4 or vehicle was administered to the rats three weeks after operation. Seven weeks after operation, the rats were sacrificed and BMD and bone histomorphometric parameters were measured to assess the effects of MK-4. While BMD of the distal femoral metaphysis was significantly decreased after SNx, MK-4 administration increased BMD in the neurectomized rats. Bone formation was decreased continuously and bone resorption was initially increased in SNx rats. Four weeks treatment of MK-4 increased bone formation and suppressed bone resorption. In addition, increased carboxylated osteocalcin and decreased undercarboxylated osteocalcin in serum were observed in MK-4-administered rats. These results indicated that MK-4 rescued bone volume by improving osteoblast dysfunction and accelerating gamma carboxylation of osteocalcin. MK-4 may be useful for treating disuse osteopenia.

Topics: Animals; Bone Density; Bone Resorption; Disease Models, Animal; Male; Osteoblasts; Osteocalcin; Osteogenesis; Osteoporosis; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Vitamin K 2

Vitamin K2 (menaquinone) acts on the bone metabolism. Menatetrenon (MK-4) is a vitamin K2 homologue that has been used as a therapeutic agent for osteoporosis in Japan. Rat models of immobilization induced by sciatic neurectomy are characterized by transiently increased bone resorption and sustained reduction in bone formation. Using such a rat model, we investigated the efficacy of MK-4 on bone loss. Male Sprague-Dawley rats were subjected to unilateral sciatic neurectomy and administered MK-4 for 28 d beginning day 21 after operation. The effect of MK-4 on the immobilized bone was assessed by measuring the bone mineral density of the femur, breaking force of the femoral diaphysis, and bone histomorphometry in tibial diaphysis. The BMD on both the femoral distal metaphysis and diaphysis was reduced by sciatic neurectomy. The administration of MK-4 ameliorated this reduction in a dose-dependent manner. The administration of 30 mg/kg MK-4 ameliorated the reduction in bone strength. An improvement in bone formation was observed following the administration of MK-4. These results suggest that MK-4 has a therapeutic potential for immobilization-induced osteopenia.

Topics: Absorptiometry, Photon; Animals; Bone Density; Bone Resorption; Disease Models, Animal; Dose-Response Relationship, Drug; Immobilization; Male; Osteoporosis; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Tensile Strength; Vitamin K 2

Vitamin K2 (menatetrenone) has been used for the treatment of osteoporosis in Japan. We investigated the effects of ovariectomy (OVX) and vitamin K2 on the calcium (Ca) balance in 20-week-old female Fischer rats. Vitamin K2 (31 mg/kg per day) was given to animals as a dietary supplement. At weeks 4 and 8 after OVX, a Ca balance study was performed for 5 days. The intestinal Ca transport was determined using the everted gut-sac technique at week 9. The Ca balance was poorer in the OVX-control group than in the sham-control group at weeks 4 and 8 after OVX. The Ca balance improved significantly in the vitamin K2 groups as compared with the sham- and OVX-control groups. The intestinal Ca transport decreased due to OVX and was higher in the vitamin K2 administration groups than in the sham- and OVX-control groups, but not to a significant extent. The bone mineral density in the femoral metaphysis as well as the cortical area and cortical thickness in the femoral diaphysis in the OVX-control group were lower than in the sham-control group. The administration of vitamin K2 significantly inhibited an OVX-induced decrease in cortical area and cortical thickness in the femur. These findings suggest that the poor Ca balance observed in ovariectomized rats may be improved by vitamin K2; vitamin K2 may be involved in preventing bone loss in vivo.

Topics: Animals; Biological Transport; Body Weight; Bone Density; Calcium; Feces; Female; Femur; Homeostasis; Intestinal Mucosa; Intestines; Organ Size; Osteoporosis; Ovariectomy; Rats; Rats, Inbred F344; Uterus; Vitamin K 2

We conducted this study to evaluate the characteristic effects of alfacalcidol (ALF) and menatetrenone (VK) in preventing bone loss using an ovariectomized rat model of osteoporosis. Bilateral ovariectomy (OVX) or sham operation was performed on 10-month-old female Wistar rats. OVX caused a significant decrease in the bone mass and the mechanical strength of the lumbar vertebra as well as the femur 6 months after surgery. VK treatment (30 mg/kg, food intake) required a 6-month period to prevent the bone loss induced by estrogen deficiency, whereas ALF (0.1 or 0.2 mg/kg, p.o.) increased the bone mass and the mechanical strength of the lumbar vertebra as well as the femur in a 3-month treatment period, far above the level in the sham-operated rats. Neither ALF or VK caused hypercalcemia, despite administration for as long as 6 months. By doing a micro-CT analysis of the vertebral trabecular microstructure, it was revealed that ALF treatment increased the interconnections and the plate-like structures and that VK significantly increased the trabecular number. It was also indicated that the increase in spinal strength by ALF treatment was closely associated with improvement of the microstructure, but not VK. The results of histomorphometric analysis showed that ALF caused a significant suppression of bone resorption yet maintained formation in the endocortical perimeter, and also stimulated bone formation in the periosteal perimeter, thereby causing an increase in cortical area. No marked effect of VK on histomorphometric parameters was observed, whereas VK as well as ALF maintained the material strength at femoral midshaft of the normal level, suggesting that VK affected bone quality and thereby prevented the decrease in mechanical strength of femur caused by OVX. In conclusion, it was demonstrated that the two drugs, ALF and VK, differed markedly in their potency and mechanisms for improving bone strength. These results have important implications in understanding the characteristic actions of vitamin K and active vitamin D on bone metabolism.

Topics: Animals; Anticarcinogenic Agents; Biomechanical Phenomena; Bone Density; Bone Resorption; Disease Models, Animal; Female; Femur; Hydroxycholecalciferols; Lumbar Vertebrae; Osteoporosis; Ovariectomy; Rats; Rats, Wistar; Reference Values; Vitamin K 2

The effect of dietary vitamin K2 (menaquinone-7) on bone loss in ovariectomized (OVX) rats was investigated. OVX rats were freely given experimental diets containing menaquinone-4 (MK-4; 12mg/100g diet) or menaquinone-7 (MK-7; 18.1mg/100g diet) for 24 days; MK-4 and MK-7 were equal in molar concentrations. This feeding caused a remarkable increase of MK-4 and MK-7 concentrations in the serum and femur of OVX rats. OVX-induced decrease in the femoral dry weight and femoral calcium content was prevented by the feeding of dietary MK-4 or NK-7. In separate experiments, OVX rats were freely given experimental diets containing the fermented soybean (natto; including 9.4 microg MK-7/100g diet) without or with added MK-7 (37.6 microg/100g diet) for 77 days. Feeding produced a significant elevation of MK-4 and MK-7 concentrations in the serum of OVX rats. In this case, a significant increase in the femoral MK-4 content was observed but MK-7 was not detected in the femoral tissues. OVX-induced decreases in the femoral dry weight and femoral calcium content were significantly prevented by the feeding of diets containing natto with MK-7 added (37.6 microg/100g diets). This study demonstrates that the intake of dietary MK-7 has a preventive effect on bone loss caused by OVX. This effect may be partly caused by MK-4, which is formed by degradation of MK-7.

Topics: Animals; Bone and Bones; Bone Density; Calcium; Disease Models, Animal; Female; Fermentation; Glycine max; Osteocalcin; Osteoporosis; Ovariectomy; Rats; Rats, Wistar; Vitamin K; Vitamin K 2

This paper presents a design for randomized clinical trials in which incomplete data are collected on the occurrence of potentially recurrent events through periodic monitoring. In particular, events are assumed to arise according to a point process, but information is available at the times of monitoring only if one or more events has occurred since the preceding monitoring point. The event process is modelled via a piecewise Poisson process, and a proportional rates model is introduced to represent the difference in event rates between treatment groups. The design was developed on the basis of a Wald-type test derived from the generalized estimating equations of Liang and Zeger (Biometrika 73, 13-22 (1986)). Robustification of the variance of the estimator of the treatment effect was considered under a random effects model with a semi-parametric mixture distribution. The design was adopted to address issues which arose in an osteoporosis trial conducted in Japan.

Topics: Calcium; Computer Simulation; Hemostatics; Humans; Osteoporosis; Poisson Distribution; Proportional Hazards Models; Radiography; Randomized Controlled Trials as Topic; Research Design; Spinal Injuries; Spine; Vitamin K; Vitamin K 2

[14C]Menaquinone-4 was administered orally once daily at a dose of 4 mg/kg for ten days to female rats of different ages to determine its blood and tissue distribution with particular attention to its distribution in bone. Animals aged 10 and 30 months were either ovariectomized or sham-operated as a control, and young rats aged 7 weeks were used as untreated controls. Blood concentrations of radioactivity at 24h after each dose during repeated administration increased daily and approached a steady rate by the seventh dose. Higher concentrations of radioactivity in blood (plasma) were observed in older animals than in the younger ones, but there was little difference between ovariectomized rats (OVX rats) and sham-operated rats (Sham rats). In tissue samples collected at 1.5 h after administration, the liver, adipose tissue, spleen and adrenals showed higher concentrations of radioactivity than the other organs and the plasma. IN bone tissues, the bone marrow (BM) and cancellous tissue (CT) of the femur showed radioactivity concentrations which were higher than that in the plasma, and these increased during repeated administration. Finally, at 24 h after the last dose, the concentrations of radioactivity in bone tissues of older animals (BM, 5,807.2 ng eq/g; CT, 5,264.8 ng eq/g in OVX rats aged 10 months and BM, 11,479.3 ng eq/g; CT, 4,023.0 ng eq/g in OVX rats aged 30 months) were several times higher than those in younger animals (BM, 2,771.6 ng eq/g; CT, 890.2 ng eq/g in 7-week-old untreated rats). The values in OVX rats were also higher than those in Sham rats. Furthermore, micro autoradiography studies of femur sections from OVX rats indicated that [14C] Menaquinone-4 localized in cancellous tissue where bone is known to be actively remodelled. The concentrations of radioactivity in cancellous tissue and bone marrow of OVX rats aged 10 and 30 months were comparable to the pharmacologically effective concentrations of Menaquinone-4 (10(-6)-10(-5) M) in in vitro studies on bone formation. These findings suggest that orally administered Menaquinone-4 distributes specifically into the bone tissues of ovariectomized rats and this is consistent with its effect as a therapeutic agent for osteoporosis.

Topics: Aging; Animals; Autoradiography; Bone and Bones; Bone Marrow; Carbon Radioisotopes; Drug Stability; Female; Kinetics; Osteoporosis; Ovariectomy; Rats; Rats, Inbred F344; Tissue Distribution; Vitamin K; Vitamin K 2

The effects of menatetrenone, a vitamin K2 homologue, on bone loss induced by ovariectomy in rats were studied in 3 experiments. Menatetrenone was given as a dietary supplement. In experiment 1, at 2 weeks postovariectomy, menatetrenone (10 mg/kg/day given for 2 weeks) inhibited the decrease in bone density of the femoral metaphysis induced by the ovariectomy. In experiment 2, menatetrenone (3 or 30 mg/kg/day given for 6 months) inhibited the decrease in bone strength of the femur and the decrease in calcium and hydroxyproline content of the femoral diaphysis at 6 months postovariectomy. In experiment 3, menatetrenone treatment, at 30 or 100 mg/kg/day for 6 months, protected against the decrease in bone strength and calcium and hydroxyproline content in the bone loss model induced by ovariectomy and calcium-deficient diet. These findings suggest that menatetrenone protects against the bone loss induced by ovariectomy.

Topics: Animals; Bone Density; Calcium, Dietary; Female; Femur; Osteoporosis; Ovariectomy; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Vitamin K; Vitamin K 2