encyclopedia

Vitamin K

Natural Sources:
Liver, cabbage, broccoli, green leafy vegetables (such as spinach, kale, collard and turnip greens), milk, eggs, citrus fruits. Herbs: Passionflower, juniper and Verbena officinalis.

Forms:
Standardized supplements containing vitamin K including liquid multi-vitamin and mineral products, capsules and tablets and fortified foods; green food supplements.

Therapeutic Uses:
– Bleeding Disorders
– Bone Health
– Carbohydrate Storage
– Cirrhosis
– Diarrhea (prolonged)
– Hemophilia
– Hemorrhage Prevention
– Intestinal Mucosa Damage
– Liver Disease
– Osteoporosis
– Parkinson’s Disease
– Severe Digestive Disorders
– Steroid-induced Osteoporosis
– Ulcerative Colitis
– Vitamin K Deficiency

Overview:

Vitamin K, also known as Phylloquinone (K1) and Menaquinone (K2), is a fat-soluble vitamin that maintains healthy blood clotting and prevents excessive bleeding and hemorrhage. Vitamin K is more specifically necessary for the carboxylation of proteins governing the conversion of the blood clotting agent prothrombin to thrombin. The designation K is derived from the German word, Koagulationsvitamin. Vitamin K is also important for maintaining healthy bone structure and for carbohydrate storage within the body. Vitamin K was first isolated from alfalfa, but is also widespread in higher green plants including green leafy vegetables. Good dietary sources of vitamin K include alfalfa greens, wheat grass, barley grass and kelp. Newborn babies born in hospitals are routinely given an injection of vitamin K3, menadione sodium bisulphite, a synthetically manufactured form of vitamin K, within minutes following birth to prevent the development of life-threatening bleeding caused by low prothrombin levels. Vitamin K occurs in myriad different forms and is rarely given as a supplement aside from its use for newborns because it is naturally produced within the body by beneficial intestinal microflora in the form of vitamin K2. Much of the vitamin K in tissues is from bacterial origin. The microbially synthesized vitamin K is absorbed in the colon. The first time that a hemorrhagic disease in man was recognized as K-avitaminosis was in connection with the cholemic bleeding tendency. This bleeding tendency formerly constituted a great danger in operations on patients suffering from obstructive jaundice from gallstones or a tumor. This was discovered in the early part of 1938. It has since been shown and established that suitable vitamin K treatment can completely eliminate the risk of bleeding in such patients, provided, of course, that the case is not complicated by severe damage of the liver so that vitamin K cannot act.

Chemistry:
Vitamin K, also known as menadione, menaquinone, or phylloquinone, is a derivative of 1,4-naphthoquinone. Pure vitamin K1 was first isolated from green leaves in 1939. The pure vitamin is a yellow oil. It consists of carbon, hydrogen and oxygen, gives a characteristic color reaction with sodium ethylate and shows an absorption spectrum in the ultraviolet. Vitamin K2 was later isolated from putrefied fishmeal and it was shown that this substance was crystalline at room temperature. It melts at 54 degrees centigrade and gives a color reaction and an ultraviolet spectrum similar to that of K1. Both substances are derivatives of 1,4-naphthoquinone. They are easily destroyed by light. Vitamin K1 is 2-methyl-3-phytyl-1,4-naphthoquinone (phytyl is the radical of the high-molecular alcohol phytol which also forms a part of the chlorophyll molecule). Vitamin K2 has a similar structure but the long side chain is different from phytyl; it is longer and has more double bonds. The methyl is essential for activity, but not the phytyl group. In accordance, 2-methyl-1,4-naphthoquinone has a high activity, as first reported in 1939. This substance is now official in the U.S. Pharmacopeia under the name of “Menadione”. The hydroquinones of the natural K-vitamins as well as of menadione are also active and so are their esters. Some of these (artificially prepared) esters are water soluble and useful for parenteral (intravenous) injection.

Suggested Amount:
Vitamin K is not recommended as a supplement because persons having a normal diet are thought to obtain adequate amounts from food and from beneficial intestinal microflora. Consult with a physician prior to taking vitamin K supplements. Recommendations for persons who need supplements are as follows: Men ages 15-24, 70 micrograms/day; Men ages 25+, 80 micrograms/day; Women ages 15-18, 55 micrograms/day; Women ages 19-24, 60 micrograms/day; Women ages 25+, 65 micrograms/day. The dosage administered to patients by doctors through intravenous route to prevent hemorrhage is 10 mg vitamin K3 given the day before an operation, repeated several times during the first two weeks after an operation. Good dietary sources include: raw spinach (1 cup contains 145 mcg); raw broccoli (half cup contains 60 mcg); eggs (1 egg provides 25 mcg).

Drug Interactions:

High levels of vitamin K within the body can interfere with anti-clotting medications such as warfarin (Coumadin).

Contraindications:
Vitamin K supplements are contraindicated for persons taking anti-clotting medications such as warfarin (Coumadin).

Side Effects:
High levels of vitamin K within the body can interfere with anti-clotting medications such as warfarin (Coumadin). Because passionflower hydro-alcoholic extracts, juniper and verbena supply variable quantities of vitamin K, they can also lessen the effect of oral anticoagulant therapy.

References:

Brown JP, Josse RG. 2002. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2002 Nov 12; 167 (10 Suppl): S1-S34.

Hattori M, Morita N, Tsujino Y, Yamamoto M, Tanizawa T. 2001. Vitamins D and K in the treatment of osteoporosis secondary to graft-versus-host disease following bone-marrow transplantation. J Int Med Res 2001 Jul-Aug; 29(4): 381-4.

Kang YA, Bae ON, Lee MY, Chung SM, Lee JY, Chung JH. 2002. Temperature-dependent quinone cytotoxicity in platelets involves arylation. J Toxicol Environ Health A 2002 Sep 27; 65(18): 1367-78.

Klotz LO, Patak P, Ale-Agha N, Buchczyk DP, Abdelmohsen K, Gerber PA, von Montfort C, Sies H. 2002. 2-Methyl-1,4-naphthoquinone, vitamin K(3), decreases gap-junctional intercellular communication via activation of the epidermal growth factor receptor/extracellular signal-regulated kinase cascade. Cancer Res 2002 Sep 1; 62(17): 4922-8.

Zhang W, Negoro T, Satoh K, Jiang Y, Hashimoto K, Kikuchi H, Nishikawa H, Miyata T, Yamamoto Y, Nakano K, Yasumoto E, Nakayachi T, Mineno K, Satoh T, Sakagami H. 2001. Synergistic cytotoxic action of vitamin C and vitamin K3. Anticancer Res 2001 Sep-Oct; 21(5): 3439-44.

AnchorAdditional Information:

Vitamin K Deficiency:
In 1939, a moderate prothrombin deficiency, which could be treated with vitamin K, was reported in some patients living on a very restricted diet (i.e. coffee and doughnuts). An increased bleeding tendency due to reduced absorption of vitamin K from the intestine has also been observed in certain intestinal diseases, where profuse diarrhea occurs and the intestinal mucosa is damaged. This has been found in cases of ulcerative colitis and in a disease called sprue, where the absorption of fat is greatly diminished. Researchers note that when natural fat-soluble vitamin K is given by mouth, it is necessary to give bile acids (i.e. desoxycholic acid) simultaneously with the vitamin in order to assure the absorption of vitamin K. Bile acids are the constituents of bile that aid in the absorption of all fat-soluble substances. The dosage recommended to prevent hemorrhage is 10 mg vitamin K given the day before an operation, repeated several times during the first two weeks after an operation. Researchers also note that overdose with vitamin K does not afford the danger of a too high coagulability of the blood since vitamin K cannot raise the larothrombin content much above the normal value. Vitamin K deficiency can also develop in persons suffering from severe liver damage. The fact that vitamin K cannot act when liver cells are sufficiently damaged, forms the basis of a liver function test.

New Vitamin K Research:
New research has shown that vitamin K2 can prevent bone loss and may be useful in the management of osteoporosis in people with cirrhosis of the liver and Parkinson’s disease and for transplant recipients. However, the latest (2002) clinical practice guidelines for the diagnosis and management of osteoporosis in Canada, do not recommend vitamin K for the average person with osteoporosis. Further studies are being done to establish its usefulness in these cases. It has been shown that vitamin K seems to play a significant role in bone turnover during space flight. Based on studies done during space travel, dietary calcium and vitamin D do not stabilize bone turnover because markers of bone formation are reduced and markers of bone resorption are increased. Researchers concluded that, in contrast to terrestrial conditions, adequate or even high calcium and vitamin D intakes in low-gravity conditions do not efficiently counteract the development of space osteoporosis. Conversely, vitamin K (Konakion) seemed to counteract microgravity-induced reduction of bone formation markers. Perhaps this information may be extrapolated to persons who do not do very much exercise and therefore lose bone density from low activity. Studies also show that vitamin K3 increases intercellular communication and may have potential applications in cancer therapy. Other studies have found anticancer activity from vitamin K3 through cytotoxic activity when placed in an alkaline environment. Researchers have shown that treatment with vitamin C or vitamin K3, or their combination, induced internucleosomal DNA fragmentation in HL-60 cancer cells. Spectroscopy showed that vitamins C and K3 produce free radicals under alkaline conditions and that their combination synergistically enhanced their radical intensities.

Vitamin K Research:

Brown JP, Josse RG. 2002. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2002 Nov 12; 167 (10 Suppl): S1-S34.

OBJECTIVE: To revise and expand the 1996 Osteoporosis Society of Canada clinical practice guidelines for the management of osteoporosis, incorporating recent advances in diagnosis, prevention and management of osteoporosis, and to identify and assess the evidence supporting the recommendations.
OPTIONS: All aspects of osteoporosis care and its fracture complications – including classification, diagnosis, management and methods for screening, as well as prevention and reducing fracture risk – were reviewed, revised as required and expressed as a set of recommendations.
OUTCOMES: Strategies for identifying and evaluating those at high risk; the use of bone mineral density and biochemical markers in diagnosis and assessing response to management; recommendations regarding nutrition and physical activity; and the selection of pharmacologic therapy for the prevention and management of osteoporosis in men and women and for osteoporosis resulting from glucocorticoid treatment.
EVIDENCE: All recommendations were developed using a justifiable and reproducible process involving an explicit method for the evaluation and citation of supporting evidence.
VALUES: All recommendations were reviewed by members of the Scientific Advisory Council of the Osteoporosis Society of Canada, an expert steering committee and others, including family physicians, dietitians, therapists and representatives of various medical specialties involved in osteoporosis care (geriatric medicine, rheumatology, endocrinology, obstetrics and gynecology, nephrology, radiology) as well as methodologists from across Canada. Benefits, harm and costs: Earlier diagnosis and prevention of fractures should decrease the medical, social and economic burdens of this disease.
RECOMMENDATIONS: This document outlines detailed recommendations pertaining to all aspects of osteoporosis. Strategies for identifying those at increased risk (i.e., those with at least one major or 2 minor risk factors) and screening with central dual-energy x-ray absorptiometry at age 65 years are recommended. Bisphosphonates and raloxifene are first-line therapies in the prevention and treatment of postmenopausal osteoporosis. Estrogen and progestin/progesterone is a first-line therapy in the prevention and a second-line therapy in the treatment of postmenopausal osteoporosis. Nasal calcitonin is a second-line therapy in the treatment of postmenopausal osteoporosis. Although not yet approved for use in Canada, hPTH(1-34) is expected to be a first-line treatment for postmenopausal women with severe osteoporosis. Ipriflavone, vitamin K and fluoride are not recommended. Bisphosphonates are the first-line therapy for the prevention and treatment of osteoporosis in patients requiring prolonged glucocorticoid therapy and for men with osteoporosis. Nasal or parenteral calcitonin is a first-line treatment for pain associated with acute vertebral fractures. Impact-type exercise and age-appropriate calcium and vitamin D intake are recommended for the prevention of osteoporosis.
VALIDATION: All recommendations were graded according to the strength of the evidence; where the evidence was insufficient and recommendations were based on consensus opinion alone, this is indicated. These guidelines are viewed as a work in progress and will be updated periodically in response to advances in this field.

Shiomi S, Nishiguchi S, Kubo S, Tamori A, Habu D, Takeda T, Ochi H. 2002. Vitamin K2 (menatetrenone) for bone loss in patients with cirrhosis of the liver. Am J Gastroenterol 2002 Apr; 97(4): 978-81.

OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Vitamin K2 can prevent bone loss and may therefore be useful in the management of bone disease in women with cirrhosis of the liver.

Heer M. 2002. Nutritional interventions related to bone turnover in European space missions and simulation models. Nutrition 2002 Oct; 18(10): 853.

Low energy intake, low calcium intake, low plasma 25-hydroxy-vitamin D or low calcitriol levels, and high salt intake might support the development of space osteoporosis. Therefore, my colleagues and I monitored the daily energy and calcium intakes in eight astronauts during their respective space missions (Spacelab D2, Euromir 94, Euromir 95). In most of these astronauts, energy intake was reduced by more than 20% compared with their calculated energy expenditure. In all three missions, the average daily calcium intake of the eight astronauts was 25% lower than the German recommended daily allowances of 900 mg/d for healthy people without osteoporosis risk. In some astronauts, the calcium intake was extremely low at 53 and 74 mg/d. Sodium intake in these astronauts varied from 39 mEq/d to a very high intake of 462 mEq/d. As a consequence of these results, we examined in the 21-d Mir 97 mission a preventative dietary approach of high calcium intake of at least 1000 mg/d with vitamin D supplementation (650 IU/d of Ergocalciferol) and constant sodium intake (180 mEq/d). Total serum calcium concentration and urinary calcium excretion significantly increased during this mission. Synthesis of 25-OH-cholecalciferol synthesis was markedly reduced because of inadequate ultraviolet light, whereas total 25-OH-Vitamin D levels were unchanged. However, parathyroid hormone and calcitriol levels decreased significantly. Sodium excretion decreased significantly, resulting in positive sodium balances. Based on these results, dietary calcium and vitamin D do not stabilize bone turnover because markers of bone formation were reduced and markers of bone resorption were increased. We concluded that, in contrast to terrestrial conditions, adequate or even high calcium and vitamin D intakes during microgravity do not efficiently counteract the development of space osteoporosis. Conversely, vitamin K (Konakion) seemed to counteract microgravity-induced reduction of bone formation markers. In the 179-d Euromir 95 mission, investigators administered 10 mg of vitamin K from inflight day 86 to day 136 in one astronaut. During and after supplementation, bone formation markers increased significantly during this part of the mission. Therefore, vitamin K seems to play a significant role in bone turnover during space flight.

Hidaka T, Hasegawa T, Fujimura M, Sakai M, Saito S. 2002. Treatment for patients with postmenopausal osteoporosis who have been placed on HRT and show a decrease in bone mineral density: effects of concomitant administration of vitamin K(2). J Bone Miner Metab 2002; 20(4): 235-9.

We have been using hormone replacement therapy (HRT) as the treatment of choice for menopausal symptoms and osteoporosis. Estrogen increases bone mineral density (BMD) for 2 or 3 years, and only maintains BMD thereafter. In the present study, we investigated whether BMD improved with HRT in combination with vitamin K(2). Ninety-four patients with postmenopausal osteoporosis were studied. All patients were placed on HRT for more than 1 year. Ten patients whose BMD had increased up to a plateau and showed a decreasing trend thereafter while they were receiving HRT were placed on HRT in combination with vitamin K(2). The long-term BMD (L(2)-L(4)) profiles of those receiving HRT alone, and the effects of HRT in combination with vitamin K(2) on the BMD profiles were examined. The rate of change in BMD (mean +/- SE) of all patients who underwent HRT alone was 2.9 +/- 1.2% 1 year after the initiation of HRT, 4.6 +/- 1.2% 2 years later, and 5.4 +/- 1.2% 3 years later. The BMD in these patients, which reached a peak increase after 3 years, no longer increased from the following year. When vitamin K(2) was administered concomitantly to 10 patients for 12 months because of the decrease in BMD, their BMD (mean +/- SE) increased significantly, from 0.734 +/- 0.021 g/cm(2) to 0.783 +/- 0.026 g/cm(2) ( P < 0.03; paired- t test). We conclude that HRT in combination with vitamin K(2) significantly improved BMD that was on the decrease after HRT alone. Therefore, as a supplementary drug for postmenopausal osteoporosis, vitamin K(2) is a good therapeutic option for patients who are placed on HRT. Hattori M, Morita N, Tsujino Y, Yamamoto M, Tanizawa T. 2001. Vitamins D and K in the treatment of osteoporosis secondary to graft-versus-host disease following bone-marrow transplantation. J Int Med Res 2001 Jul-Aug; 29(4): 381-4. We report a case of secondary osteoporosis treated with a combination of vitamins D3 and K2, administered orally. A 13-year-old male, diagnosed with highly differentiated acute myelogenous leukaemia, received an allogeneic bone-marrow transplantation. Chronic graft-versus-host disease persisted, thereafter, in the form of severe diarrhoea, rash and allergic conjunctivitis. Since the patient was then at risk from osteoporosis secondary to calcium malabsorption caused by the diarrhoea, dual-energy X-ray absorptiometry and ultrasound analysis were used to measure bone mineral density and bone stiffness, respectively. Both measurements were markedly lower than the average values from patients of matched age, gender and physical characteristics. The osteoporosis did not respond to active vitamin D3 0.1 microg/kg once daily, but when this therapy was combined with vitamin K2 15 mg once daily, an increase in bone mineral density and bone stiffness was observed. In conclusion, vitamin D3 and K2 combination therapy merits further evaluation for the treatment of various types of secondary osteoporosis, including steroid-induced osteoporosis. Kang YA, Bae ON, Lee MY, Chung SM, Lee JY, Chung JH. 2002. Temperature-dependent quinone cytotoxicity in platelets involves arylation. J Toxicol Environ Health A 2002 Sep 27; 65(18): 1367-78. Menadione (MEN), a representative quinone compound, produces cytotoxicity in many cells by arylation with protein thiols and oxidative stress due to redox cycling. Previously it was demonstrated that protein arylation appears to be a primary mechanism for MEN-induced toxicity in platelets. To test the hypothesis that temperature conditions may be important in MEN-induced cytotoxicity in noncancer cells, platelets were incubated with menadione at 25, 37, or 42 degrees C. As temperature was increased, MEN significantly enhanced lactate dehydrogenase (LDH) leakage. MEN-induced depletion of protein thiol levels also increased as temperature was elevated. To investigate the mechanism of temperature-dependent MEN cytotoxicity, MEN-induced platelet toxicity was compared to two other quinone substances. Benzoquinone (BQ), which acts via arylation, produced cytotoxic effects similar to those of MEN. Dimethoxy-1,4-naphthoquinone (DMNQ), which exerts toxicity via oxidative radical generation, failed to produce cytotoxicity at all three temperatures. While MEN and DMNQ enhanced O(2) consumption in a temperature-dependent manner, BQ did not affect this parameter. MEN, which possesses an electrophilic 3-position, was found to react with thiols to form a thioether linkage, a direct indicator of arylation. In the case of MEN uptake kinetics, the amount of cellular uptake was not different at various temperatures, but concentration of MEN in extracellular medium decreased temperature dependently. This might be due to increased arylation capacity binding to cellular proteins as temperature rises. These data suggest that MEN-induced platelet cytotoxicity involves arylation that is temperature related. Zhang W, Negoro T, Satoh K, Jiang Y, Hashimoto K, Kikuchi H, Nishikawa H, Miyata T, Yamamoto Y, Nakano K, Yasumoto E, Nakayachi T, Mineno K, Satoh T, Sakagami H. 2001. Synergistic cytotoxic action of vitamin C and vitamin K3. Anticancer Res 2001 Sep-Oct; 21(5): 3439-44. Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology, Beijing, China. We investigated the combination effect of sodium ascorbate (vitamin C) and menadione (vitamin K3) on the viability of various cultured cells. Human oral squamous cell carcinoma (HSC-2, HSC-3) and human promyelocytic leukemia (HL-60) cells were more sensitive to these vitamins as compared to normal cells (human gingival fibroblast HGF, human periodontal ligament fibroblast HPLF, human pulp cell HPC). The combination of vitamin C and vitamin K3 produced synergistic cytotoxicity against all these 6 cell lines. Treatment with vitamin C or vitamin K3, or their combination, induced internucleosomal DNA fragmentation only in HL-60 cells, but not in the oral tumor cell lines (HSC-2, HSC-3, HSG). ESR spectroscopy showed that vitamins C and K3 produce radicals under alkaline conditions and that the combination of these two vitamins synergistically enhanced their respective radical intensities. Klotz LO, Patak P, Ale-Agha N, Buchczyk DP, Abdelmohsen K, Gerber PA, von Montfort C, Sies H. 2002. 2-Methyl-1,4-naphthoquinone, vitamin K(3), decreases gap-junctional intercellular communication via activation of the epidermal growth factor receptor/extracellular signal-regulated kinase cascade. Cancer Res 2002 Sep 1; 62(17): 4922-8. 2-Methyl-1,4-naphthoquinone, vitamin K(3) (menadione), which is frequently used as a model quinone in cell culture and in vivo studies, was tested for its effects on gap-junctional intercellular communication (GJC). Exposure of WB-F344 rat liver epithelial cells to menadione (50-100 micro M) led to a 50-75% decrease in GJIC. Different from the phorbol ester 12-O-tetradecanoylphorbol 13-acetate, menadione did not induce internalization of gap junctions. Rather, the decreased GJIC was found to be because of phosphorylation of connexin 43, the major connexin in the used cell line, which was mediated by MAPK/ERK kinase (MEK) 1 and MEK 2 as well as by activation of their direct substrates, extracellular signal-regulated kinase (ERK) 1 and ERK 2. Activation of ERK 1/2 was demonstrated to be independent of NAD(P)H:quinone oxidoreductase using the inhibitor dicoumarol, thus excluding redox cycling as the major mechanism causing these menadione effects. A substantial increase in tyrosine phosphorylation was detected in the cell membrane immunocytochemically upon exposure to menadione, consistent with arylation by menadione bearing the responsibility for the signaling events induced and consistent with the fact that protein tyrosine phosphatases are known targets of arylation reactions. ERK activation was attenuated using specific inhibitors of the epidermal growth factor receptor tyrosine kinase. Similarly, these inhibitors as well as inhibitors of MEK 1/2 counteracted the loss in gap-junctional communication elicited by menadione. This is of interest for chemotherapeutic approaches exploiting the bystander-effect, which is based upon intact GJIC. Sato Y, Honda Y, Kaji M, Asoh T, Hosokawa K, Kondo I, Satoh K. 2002. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency. Bone 2002 Jul; 31(1): 114-8. 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. Hirano J, Ishii Y. 2002. Effects of vitamin K2, vitamin D, and calcium on the bone metabolism of rats in the growth phase. J Orthop Sci 2002; 7(3): 364-9. Using 168 female Sprague-Dawley rats, we determined whether the peak bone mass could be increased, and which drugs would be effective in suppressing the rate of decrease in bone mass by continuous administration from childhood. At the age of 3 months, these 168 rats were divided into five groups depending on the type of diet that they were fed (control, regular; group A, vitamin K2; group B, vitamin D; group C, high calcium; group D, vitamins D and K2 and high calcium) and kept to the age of 16 months. Dual-energy X-ray absorptiometry (DXA) was used to measure the bone mineral density of the femoral epiphysis and microcomputed tomography (CT) to analyze its fine structure. The average bone mass increased rapidly with age and reached a peak at the age of 8 months. Peak bone mass for the four drug administration groups was higher than that for the control group. Among these four groups, the peak bone mass was the highest in group C and the rate of decrease the smallest in group D. The results of the present animal study suggest that the peak bone mass of humans can be raised by consuming sufficient amounts of vitamins K2 and D and calcium continuously from childhood, and that this diet will suppress the rate of decrease in bone mass, thus ultimately preventing bone fractures caused by osteoporosis. Uteshev BS, Konollia NA, Prokopenko LG. 2001. [Menadione and roboxin as inducers of immunomodulating activity of erythrocyte stroma]. Eksp Klin Farmakol 2001 Nov-Dec; 64(6): 52-5. [Article in Russian] The erythrocyte stroma of intact rats treated with riboxin can be used, after an additional extracorporal treatment with menadione, as a transaphthogenic softly acting immunostimulant. Introduced into rats with a secondary experimental immunodeficient syndrome caused by indomethacin or gentamycin, this stroma leads to normalization of the humoral immune response to ram erythrocytes.