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Vitamin K Nutrition and Osteoporosis
Abstract
Although the abundance of vitamin K-dependent proteins in bone suggests an important function, the precise role of vitamin K in skeletal health remains to be determined. Serum concentrations of vitamin K are reportedly reduced in older individuals and persons with osteoporotic fracture. Whether this is causally related to vitamin K insufficiency or simply reflects inadequate nutritional status is unclear. Circulating levels of undercarboxylated osteocalcin may be a sensitive marker of vitamin K inadequacy and have been reported to be increased in both postmenopausal women and individuals who sustain hip fracture. It is also possible that vitamin K indirectly affects the skeleton via control of renal calcium excretion. The effect of vitamin K antagonists (oral anticoagulants) on both renal calcium excretion and bone density is controversial. Thus, many of the reports implicating a role for vitamin K insufficiency in the development of osteoporosis are conflicting. This review summarizes current knowledge regarding a possible role of vitamin K insufficiency in the pathogenesis of osteoporosis.
... Taze tatlı yoncanın aşırı tüketimi, hayvanlarda şiddetli hemorajilere sebep olduğundan ani ölümlere neden olmaktadır. 46,47 Gebe hayvanlarda dikumarol plasenta aracılığıyla yavruya geçtiğinden, yeni doğan yavrular da bundan etkilenebilmektedirler. Dikumarol zehirlenmelerinde gebe hayvanlarda embriyonik ölümler ve abortlar gözlendiği belirtilmektedir. ...
... Dikumarol zehirlenmelerinde gebe hayvanlarda embriyonik ölümler ve abortlar gözlendiği belirtilmektedir. 1,46 Küflü tatlı yoncanın tüketimi sonucu hayvanlarda ortaya çıkan klinik bulgular, hayvanın yaşına ve alınan dikumarol miktarına bağlı olarak değişmektedir. Eğer rasyonla alınan dikumarol miktarı azsa klinik belirtiler geç ortaya çıkmaktadır. ...
... Warfarin zehirlenmesinde hematom, epistaksis, gastrointestinal kanamalar, eklemlerdeki kanamalara bağlı olarak topallık ve yürüyüş tutukluğu, bazen de ani ölümler görülmektedir. 46 K vitamini yetmezliği oluşturan durumlar şu şekilde sınıflandırılmaktadır. ...
In normal care and feeding conditions, healthy ruminants are able to meet their requirements
for vitamin C and K by synthesis. As most of ingested ascorbic acid is broken down in
rumen, ruminants are more sensitive to vitamin C deficiency than monogastric animals. In ruminants,
vitamin K deficiency occurs due to anorexia, digestive system disorders, failure in intake and
impairment in synthesis of the vitamin. Several disorders and conditions increase vitamin C and K
requirements. In this review, information has been presented related with vitamin C and K deficiencies
in ruminants.
... This compound has a high affinity to the calcium in the hydroxy apatite molecule. Additionally, vitamin K may influence calcium absorption in the gut, calcium excretion in the kidney (82) and bone formation in conjunction with vitamin D (5). The classic role of vitamin K is maintain the normal haemostasis by mediation of the synthesis of several blood coagulation factors in the liver. ...
... To be representative of people aged 65 and over in Great Britain, free-living subjects were recruited by sex and age groups. Men and women in age groups of 65-74 years, [75][76][77][78][79][80][81][82][83][84] years and over 85 years were recruited by equal number of 230 in each group, except that of men over 85years, which was calculated to be 100 persons. ...
p>This study tests the hypothesis that a diet, which complies with current healthy dietary guidelines, is associated with lower plasma alkaline phosphatase (ALP) and stronger handgrip strength as markers of bone health and muscle performance in older people. The study also examines whether men, and those with optimal early nutrition will benefit more from a healthy diet than women and those from a less than optimal early environment. This is the first study to examine the effect of a healthy dietary pattern and to explore its interactions with sex and body size measurements on bone health and muscle performance in the elderly.
The secondary analyses undertaken in this study are based on the data of the National Diet and Nutrition Survey (NDNS) conducted on a UK nationally-representative sample of 1687 men and women aged 65 years and over. Principal component analysis (PCA) was used to summarise dietary patterns, by which seven statistically independent eating patterns were generated.
The healthy dietary pattern identified by PCA characterised by a high intake of vegetables, fruits, cereals, fish and other seafood, showed that strongest negative (beneficial) association with ALP (r = -0.17, p<0.001) and the strongest positive association with hand-grip strength (r = 0.20, p<0.001). Multiple regression analysis controlling for energy intake, a number of confounders and various nutrients, identified the healthy diet as the strongest predictor for serum ALP and handgrip strength in elderly men and women, separately. Subjects in the highest fourth of the healthy diet in comparison to the lowest, were less likely to have high levels of plasma ALP (OR = 0.4, 95% CI, 0.3 - 0.6) after adjustment for known confounders. Healthy diet was of the most benefit for heaviest and tallest men but not heavier and taller women. For those within the shortest and thinnest group, the association between healthy diet and ALP did not reach statistical significance.</p
... The current RDA was set on the basis of limited data, utilizing the maintenance of normal clotting function as the primary criterion for adequacy; this intake of the vitamin may not result in maximum ␥-carboxylation of osteocalcin (Knapen et al. 1989). Because of this, there has been increased interest in the possible involvement of higher intakes of vitamin K in the maintenance of bone health (Binkley and Suttie 1995, Shearer et al 1996. ...
... The current RDA for vitamin K (1 g/kg body weight) is in the same range as the average intake from food sources in the North American population (Booth and Suttie 1998). There are indications , Sokoll et al. 1997) that normal intakes of vitamin K do not support all measures of vitamin K sufficiency, and there are some indications that skeletal health may be improved by vitamin K intakes higher than those normally consumed (Binkley and Suttie 1995, Shearer et al. 1996. If future studies support increased intakes of vitamin K, it is likely that the amounts desired will be difficult to obtain from diets and that supplementation will be needed. ...
Phylloquinone (K) absorption was assessed in 22- to 30-y-old human subjects consuming a standard test meal [402 kcal (1682 kJ), 27% energy from fat]. The absorption of phylloquinone, measured over a 9-h period as the area under the curve (AUC), was higher (P < 0.01) after the consumption of a 500-μg phylloquinone tablet [27.55 ± 10.08 nmol/(L · h), n = 8] than after the ingestion of 495 μg phylloquinone as 150 g of raw spinach [4.79 ± 1.11 nmol/(L · h), n = 3]. Less phylloquinone (P < 0.05) was absorbed from 50 g of spinach (AUC = 2.49 ± 1.11 nmol/(L · h) than from 150 g of spinach. Absorption of phylloquinone from fresh spinach (165 μg K), fresh broccoli (184 μg K) and fresh romaine lettuce (179 μg K) did not differ. There was no difference in phylloquinone absorption from fresh or cooked broccoli or from fresh romaine lettuce consumed with a meal containing 30 or 45% energy as fat.
... Ponadto zwiększa poziom osteokalcyny (głównego białka macierzy kostnej), co może mieć korzystny wpływ na proces tworzenia tkanki kostnej [14]. Wyróżnia się witaminę K 1 (fitochinon) oraz K 2 (menachinon) [12,17]. Witamina K 1 jest słabo wchłaniana z przewodu pokarmowego, a jej główną rolą w ustroju jest aktywacja w wątrobie czynników krzep-nięcia zależnych od witaminy K. Wartościowym źródłem tej witamin są zielone warzywa, takie jak kapusta włoska, szpinak, brokuł, brukselka, natka pietruszki. ...
... Jest produkowana głównie endogennie przez bakterie flory jelitowej. Znajduje się również w produktach fermentowanych, a bardzo duże jej ilości znajdują się w japońskiej potrawie nattō otrzymywanej z przefermentowanych nasion soi [17,19,20]. ...
Ważną częścią postępowania profilaktycznego jak i terapeutycznego w osteoporozie jest prawidłowe żywienie. Przy pomocy odpowiedniej diety, regularnej aktywności fizycznej i higienicznym trybie życia można wyraźnie zmniejszyć objawy choroby (Gennari 2001, Eastell, Lambert 2002).
... Vitamin K is a fat-soluble vitamin with a naphthoquinone skeleton and various lipophilic side chains (1,2). There are two main vitamin K compounds, which differ with respect to their side chain. ...
... Menaquinones (MKs) have isoprenoid side chains with 4-14 repeats and are found in animal products; they are also produced in various bacterial fermentation processes and are, therefore, found in fermented products such as cheese and pickles (3). Vitamin K acts as a cofactor for post-translational carboxylation, in which g-glutamyl carboxylase converts certain protein-bound glutamate residues into g-carboxy glutamate (Gla) (2,4). At least 14 types of proteins with glutamate residues, designated vitamin K-dependent Gla-proteins, have been discovered. ...
Vitamin K is essential for bone health, but the effects of low-dose vitamin K intake in Japanese subjects remain unclear. We investigated the effective minimum daily menaquinone-7 dose for improving osteocalcin gamma-carboxylation. Study 1 was a double-blind, randomized controlled dose-finding trial; 60 postmenopausal women aged 50-69 y were allocated to one of four dosage group and consumed 0, 50, 100, or 200 mu g menaquinone-7 daily for 4 wk, respectively, with a controlled diet in accordance with recommended daily intakes for 2010 in Japan. Study 2 was a double-blind, randomized placebo-controlled trial based on the results of Study 1; 120 subjects aged 20-69 y were allocated to the placebo or MK-7 group and consumed 0 or 100 mu g menaquinone-7 daily for 12 wk, respectively. In both studies, circulating carboxylated osteocalcin and undercarboxylated osteocalcin were measured. The carboxylated osteocalcin/undercarboxylated osteocalcin ratio decreased significantly from baseline in the 0 mu g menaquinone-7 group, in which subjects consumed the recommended daily intake of vitamin K with vitamin K-1 and menaquinone-4 (Study 1). Menaquinone-7 increased the carboxylated osteocalcin/undercarboxylated osteocalcin ratio dose dependently, and significant effects were observed in both the 100 and 200 mu g groups compared with the 0 mu g group. Undercarboxylated osteocalcin concentrations decreased significantly, and the carboxylated osteocalcin/undercarboxylated osteocalcin ratio increased significantly in the 100 mu g menaquinone-7 group compared with the placebo group (Study 2). Daily menaquinone-7 intake >= 100 mu g was suggested to improve osteocalcin y-carboxylation.
... On the other hand, warfarin prevents the activation of MGP and Gas-6; therefore, long-term use of warfarin is reported to be associated with osteoporotic fractures [2]. In addition, it is known that low vitamin K is associated with reduced bone mineral density (BMD) [3]. BMD tests can identify osteoporosis and determine the risk for fractures [4]. ...
... Since warfarin is a vitamin K antagonist, patients who are on warfarin therapy must be prohibited from taking vitamin K-rich foods. Vitamin K-dependent bone proteins and extracellular matrix such as OC, MGP, and Gas-6 play an important role in controlling bone remodeling [3] [9]. These proteins and their matrix are activated with γcarboxylation of glutamic acid residues. ...
... On the other hand, warfarin prevents the activation of MGP and Gas-6; therefore, long-term use of warfarin is reported to be associated with osteoporotic fractures [2]. In addition, it is known that low vitamin K is associated with reduced bone mineral density (BMD) [3]. BMD tests can identify osteoporosis and determine the risk for fractures [4]. ...
... Since warfarin is a vitamin K antagonist, patients who are on warfarin therapy must be prohibited from taking vitamin K-rich foods. Vitamin K-dependent bone proteins and extracellular matrix such as OC, MGP, and Gas-6 play an important role in controlling bone remodeling [3,9]. These proteins and their matrix are activated with γcarboxylation of glutamic acid residues. ...
Background: Stroke prevention by warfarin, a vitamin K antagonist, has been an integral part in the management of atrial fibrillation. Vitamin K-dependent matrix Gla protein (MGP) has been known as a potent inhibitor of arterial calcification and osteoporosis. Therefore, we hypothesized that warfarin therapy affects bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction.
Methods: We studied 42 atrial fibrillation patients high-risk for atherosclerosis having one or more coronary risk factors. Twenty-four patients had been treated with warfarin for at least 12 months (WF group), and 18 patients without warfarin (non-WF group). Bone alkaline phosphatase (BAP) and under carboxylated osteocalcin (ucOC) and receptor activator of nuclear factor-kappa B ligand (RANKL) were measured as bone metabolism markers. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) index measured by Endo-PAT2000 was used as an indicator of vascular endothelial function.
Results: There were no significant differences in patient background characteristics and other clinical indicators between the two groups. In WF group, the ucOC levels were significantly higher than those in non-WF group (10.3 ± 0.8 vs. 3.4 ± 0.9 ng/mL; P < 0.01), similarly, the RANKL levels in WF group were higher than those in non-WF group (0.60 ± 0.06 vs. 0.37 ± 0.05 ng/mL; P = 0.007). Moreover, RH-PAT index was significantly lower in WF group compared to those in non-WF group (1.48 ± 0.11 vs. 1.88 ± 0.12; P = 0.017).
Conclusions: Long-term warfarin therapy may be associated with bone mineral loss and vascular calcification in 60–80 year old hypertensive patients.
http://www.sciencedirect.com/science/article/pii/S2214647415000896
... Além disso, existem alguns relatos na literatura que descreveram uma relação entre a vitamina K e algumas proteínas dependentes de vitamina K (proteínas C, S, Z e M), sugerindo outras funções além de sua ação coagulante. As proteínas C e S desempenham um papel anticoagulante em vez de pró-coagulante na hemostasia normal (Stenflo, 1999), e também estão envolvidas na regulação da renovação óssea (Binkley e Suttie, 1995). As funções das proteínas M e Z ainda são desconhecidas. ...
... In addition, there are some cases in the literature that describe a relationship between vitamin K and some vitamin K-dependent proteins (proteins C, S, Z, and M), suggesting other functions in addition to its clotting action. Proteins C and S play an anticoagulant rather than a procoagulant role in normal hemostasis (Stenflo, 1999), and are also involved in the regulation of bone turnover (Binkley e Suttie, 1995). The functions of proteins M and Z are still unknown. ...
... Além disso, existem alguns relatos na literatura que descreveram uma relação entre a vitamina K e algumas proteínas dependentes de vitamina K (proteínas C, S, Z e M), sugerindo outras funções além de sua ação coagulante. As proteínas C e S desempenham um papel anticoagulante em vez de pró-coagulante na hemostasia normal (Stenflo, 1999), e também estão envolvidas na regulação da renovação óssea (Binkley e Suttie, 1995). As funções das proteínas M e Z ainda são desconhecidas. ...
... In addition, there are some cases in the literature that describe a relationship between vitamin K and some vitamin K-dependent proteins (proteins C, S, Z, and M), suggesting other functions in addition to its clotting action. Proteins C and S play an anticoagulant rather than a procoagulant role in normal hemostasis (Stenflo, 1999), and are also involved in the regulation of bone turnover (Binkley e Suttie, 1995). The functions of proteins M and Z are still unknown. ...
... Biffin et al. (2008a) found that Thoroughbred yearlings with radiological lesions had a significantly lower BMD than did those with clean X-rays. Binkley and Suttie (1995) found that in adults, a maximum VK supplemental intake of 1000 μg was effective in reducing percentage ucOC to its lowest level. Biffin et al. (2010) suggested that to attain 90% carboxylation of OC, 7 mg of vitamin K/day was required by a 500 kg horse using a bioavailable soluble form (Quinaquanone ® ; KQ); however, it is important to note that this pertains only to horses without access to fresh green pasture (Biffin et al. 2008a). ...
Vitamin K (VK) has long been known for its essential role in blood coagulation. However, over the past decade, evidence has mounted for its intrinsic and essential roles in other functions within the body, including bone metabolism, calcification, brain development and glucose metabolism. Thus, VK should no longer be considered a single-function ‘haemostasis vitamin’, but rather as a ‘multi-function vitamin’. While current research has focused on its emerging role in human nutrition, the role that VK plays in other species such as the horse has not been well described, with most of our current understanding having been extrapolated from other species, especially rodents. This review assesses the current state of knowledge of VK as it pertains to human and animal nutrition, and, where data exist, its metabolism and nutrition in the horse is explored. Future research on the roles of VK as they pertain to horses, particularly extra-hepatic functions, is necessary. Such insight will allow a greater understanding of how VK is metabolised, facilitating the development of recommendations to assist in the health, growth, and longevity of horses.
... However, at present, a clear role for vitamin K in this respect remains in question [3], despite years of fairly compelling related findings in multiple realms including various human studies, both comparative and prospective [14]. ...
This mini review examines whether: 1) Vitamin K, an important dietary compound that can also be partially synthesized intrinsically is a potentially important bone building or modeling determinant whose presence might influence the onset and progression of osteoporosis a key determinant of fragility fractures and 2) whether any evidence points to its application as being desirable among vulnerable aging adults with low vitamin K status or at risk for fragility fractures for other reasons.
... The distal colon contains the majority of menaquinones, but the terminal ileum, which contains menaquinone-producing bacteria and bile salts required for menaquinone solubilization, is the most promising site of absorption [6]. As a result, despite the fact that intestinal microflora produce significant amounts of menaquinones, bacterial menaquinone has limited bioavailability, and diet is the primary source of functionally accessible vitamin K2 [6,7]. Intestinal menaquinones do not compensate for a short-term drop in dietary vitamin K consumption, according to recent research [4]. ...
Vitamin K1 (phylloquinone), K2 (menaquinone), and K3 (phylloquinone) are the three types of vitamin K. (menadione). Vitamin K2 is found in both tissue and bacterial products (animal products or fermented foods). Vitamin k2 has nine chemical variations, with the number of isoprenyl units in their side chains determining the majority of them. The most frequent form of vitamin k2 in the human diet is the short chain, water soluble menatetrenone, which is generated by bacterial conversion of vitamin k1, as well as a tissue derivative (MK-4).MK-7, MK-8, and MK-9 are long-chain menaquinones (longer than MK-4) that are more prevalent in fermented foods like natto, a traditional Japanese meal prepared from soya beans fermented with bacillus subtilis var. Anaerobic bacteria in the colon create longer-chain menaquinones (MK-10 to MK-13), but they are poorly absorbed and have minimal physiological impact at this level. The effects of vitamin K2 on overall dentistry are the topic of this review.
... Osteocalcin, a vitamin K-dependent protein, is rich within the dentin and mineralized tissue of animal bones. The special calcium bond structure in osteocalcin combines with calcium ions and is deposited in bone (Binkley & Suttie, 1995), so the content of calcium in vertebrae was a valued indicator of vertebrae quality. Previous studies indicated that both vitamin K deficiency and the toxicity of the excessive MSB could impair bone mineralization and increase the occurrence of bone deformities (Rebhun et al., 1984;Smith et al., 1943;Roy & Lall, 2007). ...
An 8-week feeding trial investigated the optimum dietary vitamin K3 requirements of largemouth bass. A total of 600 healthy fish (12.96 ± 0.07 g) were fed diets containing varying levels of vitamin K3 at 0.78 (K0), 5.80 (K5), 10.82 (K10), 15.84 (K15), and 20.85 (K20) mg/kg with four replicates per level. Results showed that dietary vitamin K3 enhanced growth, with weight gain rate and specific growth rate in K15 trials significantly higher than K0 trials (P < 0.05). No significant difference was observed in the content of crude protein, crude lipid, moisture, ash, and phosphorus in muscle tissue (P > 0.05). However, the supplementation of vitamin K3 significantly contributed to calcium accumulation in muscle tissues and vertebrae (P < 0.05) and increased red blood cell counts (P < 0.05). The blood coagulation time decreased significantly with increasing dietary vitamin K3 from 0.78 to 10.82 mg/kg (P < 0.05) before stabilizing (P > 0.05). The antioxidant capacity was improved with the addition of vitamin K3, which was inconsistent with the changes in malondialdehyde and MK-4 (a form of menaquinone) within liver and serum, suggesting that the toxicity of excessive artificial vitamin K3 may account for this difference. Using regression analysis, the appropriate dietary vitamin K3 levels within a largemouth bass diet was determined to be in the range of 9.93–15.22 mg/kg, which will provide a reference for the preparation of vitamin premix and artificial diet for largemouth bass.
... The contribution of gut-produced MKn to vitamin K nutriture in humans is not fully understood. 43 However, broad-spectrum antibiotics reduce total hepatic MKn levels in patients, implying a connection between the microbiome and bioavailable vitamin K in the liver. 44 Additionally, cephalosporins can induce hypoprothrombinemia either through the elimination of MKn producers or inhibition of vitamin K-epoxide reductase and vitamin K-dependent carboxylase. ...
Infection with Helicobacter pylori causes chronic inflammation and is a risk factor for gastric cancer. Antibiotic treatment or increased dietary folate prevents gastric carcinogenesis in male INS-GAS mice. To determine potential synergistic effects, H. pylori-infected male INS-GAS mice were fed an amino acid defined (AAD) diet with increased folate and were treated with antibiotics after 18 weeks of H. pylori infection. Antibiotic therapy decreased gastric pathology, but dietary folate had no effect. However, the combination of antibiotics and the AAD diet induced anemia, gastric hemorrhage, and mortality. Clinical presentation suggested hypovitaminosis K potentially caused by dietary deficiency and dysbiosis. Based on current dietary guidelines, the AAD diet was deficient in vitamin K. Phylloquinone administered subcutaneously and via a reformulated diet led to clinical improvement with no subsequent mortalities and increased hepatic vitamin K levels. We characterized the microbiome and menaquinone profiles of antibiotic-treated and antibiotic-free mice. Antibiotic treatment decreased the abundance of menaquinone producers within orders Bacteroidales and Verrucomicrobiales. PICRUSt predicted decreases in canonical menaquinone biosynthesis genes, menA and menD. Reduction of menA from Akkermansia muciniphila, Bacteroides uniformis, and Muribaculum intestinale were confirmed in antibiotic-treated mice. The fecal menaquinone profile of antibiotic-treated mice had reduced MK5 and MK6 and increased MK7 and MK11 compared to antibiotic-free mice. Loss of menaquinone-producing microbes due to antibiotics altered the enteric production of vitamin K. This study highlights the role of diet and the microbiome in maintaining vitamin K homeostasis.
... Osteocalcin status as an indicator of vitamin K 2 deficiency in inflammatory bowel disease children -a pilot study łącznie w procesach związanych z krzepnięciem krwi, jednak badania przeprowadzone w ostatnich trzech dekadach sugerują istotną rolę tej witaminy, jako kofaktora γ-karboksylazy -enzymu zaangażowanego m.in. w metabolizm kostny, prewencję osteoporozy czy proces uwapnienia naczyń krwionośnych [2,3]. ...
Wprowadzenie. Witamina K jako kofaktor γ-karboksylazy bierze
udział w metabolizmie kości. Wśród dzieci zapotrzebowanie na nią jest
największe. Pacjenci pediatryczni z nieswoistymi zapaleniami jelit (NZJ)
wydają się być szczególnie narażeni na niedobory tej witaminy z uwagi
na toczący się proces zapalny.
Cel. Ocena poziomu wit. K i D w kontekście podaży z dietą oraz stężenia
w surowicy krwi osteokalcyny niekarboksylowanej (nieaktywnej)
(ucOC), osteokalcyny karboksylowanej (cOC) i stosunku ucOC do
cOC (UCR) – jako wskaźnika statusu wit. K2 wśród dzieci zdrowych
z grupy kontrolnej oraz dzieci z NZJ w okresie remisji.
Materiały i metody. Do badania prospektywnego pilotażowego
włączono 24 dzieci (15 zdrowych oraz 9 z NZJ w remisji klinicznej),
średni wiek dzieci 12 lat. Od każdego uczestnika pobrano próbkę
krwi, celem oznaczenia stężeń cOC oraz ucOC przy pomocy testów
ELISA oraz wit. D3 przy użyciu metod standardowych. Dodatkowo
przeprowadzono ilościową ocenę spożycia witamin przy pomocy
wywiadu 24-h.
Wyniki. W obu grupach zaobserwowano niską realizację normy na wit.
K – średnio na poziomie 39,21% (dzieci z NZJ) i 32,23% (dzieci zdrowe)
oraz wit. D średnio 45,00% (dzieci z NZJ) i 32,60% (dzieci zdrowe).
Mediana UCR w surowicy krwi wynosiła 1,85 w grupie dzieci zdrowych
oraz 1,11 ng/ml w grupie dzieci z NZJ. Poziom wit. D3 był zaskakująco
niski w obu grupach; w grupie zdrowej wnosił 15,40 ug/ml, a w grupie
z NZJ – 27,20 ug/ml (p=0,0027). Jedynie 7/24 dzieci (w tym 6 z NZJ)
otrzymywało suplementację witaminową.
Wnioski. Dzieci nie realizują z dietą norm żywienia na składniki biorące
udział w obrocie kostnym. Niedobór witamin był większy u dzieci
zdrowych niż u dzieci z NZJ w okresie remisji klinicznej. Wskazane są
dalsze badania na większych grupach dzieci.
... Osteocalcin status as an indicator of vitamin K 2 deficiency in inflammatory bowel disease children -a pilot study łącznie w procesach związanych z krzepnięciem krwi, jednak badania przeprowadzone w ostatnich trzech dekadach sugerują istotną rolę tej witaminy, jako kofaktora γ-karboksylazy -enzymu zaangażowanego m.in. w metabolizm kostny, prewencję osteoporozy czy proces uwapnienia naczyń krwionośnych [2,3]. ...
Wprowadzenie. Witamina K jako kofaktor γ-karboksylazy bierze
udział w metabolizmie kości. Wśród dzieci zapotrzebowanie na nią jest
największe. Pacjenci pediatryczni z nieswoistymi zapaleniami jelit (NZJ)
wydają się być szczególnie narażeni na niedobory tej witaminy z uwagi
na toczący się proces zapalny.
Cel. Ocena poziomu wit. K i D w kontekście podaży z dietą oraz stężenia
w surowicy krwi osteokalcyny niekarboksylowanej (nieaktywnej)
(ucOC), osteokalcyny karboksylowanej (cOC) i stosunku ucOC do
cOC (UCR) – jako wskaźnika statusu wit. K2 wśród dzieci zdrowych
z grupy kontrolnej oraz dzieci z NZJ w okresie remisji.
Materiały i metody. Do badania prospektywnego pilotażowego
włączono 24 dzieci (15 zdrowych oraz 9 z NZJ w remisji klinicznej),
średni wiek dzieci 12 lat. Od każdego uczestnika pobrano próbkę
krwi, celem oznaczenia stężeń cOC oraz ucOC przy pomocy testów
ELISA oraz wit. D3 przy użyciu metod standardowych. Dodatkowo
przeprowadzono ilościową ocenę spożycia witamin przy pomocy
wywiadu 24-h.
Wyniki. W obu grupach zaobserwowano niską realizację normy na wit.
K – średnio na poziomie 39,21% (dzieci z NZJ) i 32,23% (dzieci zdrowe)
oraz wit. D średnio 45,00% (dzieci z NZJ) i 32,60% (dzieci zdrowe).
Mediana UCR w surowicy krwi wynosiła 1,85 w grupie dzieci zdrowych
oraz 1,11 ng/ml w grupie dzieci z NZJ. Poziom wit. D3 był zaskakująco
niski w obu grupach; w grupie zdrowej wnosił 15,40 ug/ml, a w grupie
z NZJ – 27,20 ug/ml (p=0,0027). Jedynie 7/24 dzieci (w tym 6 z NZJ)
otrzymywało suplementację witaminową.
Wnioski. Dzieci nie realizują z dietą norm żywienia na składniki biorące
udział w obrocie kostnym. Niedobór witamin był większy u dzieci
zdrowych niż u dzieci z NZJ w okresie remisji klinicznej. Wskazane są
dalsze badania na większych grupach dzieci.
... Although the data are controversial, accumulating evidence suggests that a low vitamin K level is associated with osteoporosis and increased risk of fracture, CVD, and mortality [65][66][67]. A high dietary vitamin K intake may benefit bone and vascular health. ...
Vascular calcification (VC) and malnutrition associated with cardiovascular disease are common in patients with chronic kidney disease (CKD) treated with dialysis. VC, which reflects vascular aging, and malnutrition are also encountered in the non-CKD elderly population. This similarity of clinical findings suggests that the progression of CKD is related to aging and the existence of a causal relationship between VC and malnutrition. To retard renal progression, a low- or very-low-protein diet is usually recommended for CKD patients. Dietary education may induce malnutrition and deficiency of important nutrients, such as vitamins K and D. Menaquinone-7, a type of vitamin K2, is under investigation for inhibiting VC in elderly patients without CKD, as well as for prevention of VC in patients with CKD. Nutritional vitamin D, such as cholecalciferol, may be considered to decrease the required dose of active vitamin D, which increases the risk of VC due to increased calcium and phosphate loads. Omega-3 fatty acids are important nutrients and their ability to inhibit VC needs to be evaluated in clinical trials. This review focuses on the ability of supplementary nutrients to prevent VC in patients with CKD, in whom dietary restriction is essential.
... Vitamin K is a fat-soluble vitamin that plays a key role in normal bone metabolism. Vitamin K deficiency has, indeed, been reported to be a frequent finding in subjects with osteoporosis and pathological fractures 39 . Vitamin K deficiency has also been associated with osteopathy in patients with Crohn's disease and, more interestingly, in subjects with cystic fibrosis who often suffer from PEI 40 . ...
Background
Osteopathy is common in patients with chronic pancreatitis (CP), but previous studies carry several limitations. Vitamin K is essential for bone metabolism, but its role in this setting has never been investigated. Our aim is to assess the prevalence of osteoporosis and osteopenia in CP patients, and to investigate the association between osteopathy and CP features and nutritional parameters, especially vitamin D and K levels.
Methods
Multicentre cross-sectional study on CP patients diagnosed according to M-ANNHEIM criteria. Bone density was evaluated by dual-energy X-ray absorptiometry and pancreatic function by faecal elastase. Nutritional evaluation included vitamin D and vitamin K. Differences between patients with or without osteopathy were evaluated. The association between investigated variables and bone density were analysed with logistic regression analysis.
Results
In total, 211 CP patients were enrolled at eight Centres (67% men; mean age 60). In total, 18% had advanced-marked CP, 56% suffered from pancreatic exocrine insufficiency and disease aetiology was alcoholic in 43%. Vitamin D and K were deficient in 56% and 32%, respectively. Osteopenia was diagnosed in 42% and osteoporosis in 22%. In the multivariate analysis, female sex (OR 2.78), age (OR 1.07 per year) and higher BMI (OR 0.84) were associated with the presence of osteoporosis. In male patients, the only factor associated with osteoporosis was vitamin K deficiency (OR 4.23).
Conclusion
The present data confirm a high rate of osteopathy in CP patients and highlight the relevance of vitamin K deficiency as only factor associated with osteoporosis in male patients for the first time.
... A number of findings have shown that menaquinone-4 (MK-4, vitamin K 2 ) may play a role in suppressing the growth and recurrence of HCC both in vitro and in vivo [5][6][7][8][9][10]. MK-4 has been used for osteoporosis, in particular, for postmenopausal women, and therefore, its long-term safety has been established [11][12][13][14][15]. MK-4 was speculated to be an ideal adjuvant agent if it could reduce the cumulative recurrence of HCC by preventing de novo carcinogenesis or suppressing tumor growth in a clinical trial. ...
Hepatocellular carcinoma (HCC) shows poor prognosis owing to its very frequent recurrence even after curative treatment. Thus, an effective and safe long-term chemopreventive agent is strongly in demand. Menahydroquinone-4 (MKH) is an active form of menaquinone-4 (MK-4, vitamin K2) that is involved in the synthesis of vitamin K-dependent proteins in the liver. We hypothesized that efficient delivery of MKH might be critical to regulate HCC proliferation. The discovery of a suitable prodrug targeting HCC in terms of delivery and activation could reduce the clinical dose of MK-4 and maximize efficacy and safety. We previously showed that MKH dimethylglycinate (MKH-DMG) enables effective delivery of MKH into HCC cells and exhibits strong antitumor effects compared with MK-4. In this study, we prepared anionic MKH hemi-succinate (MKH-SUC) and non-ionic MKH acetate (MKH-ACT), in addition to cationic MKH-DMG, and evaluated MKH delivery profiles and antitumor effects in vitro. MKH-SUC showed the highest uptake and the most efficient release of MKH among the examined compounds and exhibited rapid and strong antitumor effects. These results indicate that MKH-SUC might have a good potential as an MKH delivery system for HCC that overcomes the limitations of MK-4 as a clinical chemopreventive agent.
... It is difficult to define "normal" or "abnormal" values for serum OC and/or UcOC, as the types of assays used in different laboratories vary 35,36 and results need to be standardized 36 . However, many studies have shown that UcOC concentrations increase with age, from about 20% of total OC in the third to fifth decade of life to 40-50% of total OC in the later years [30][31][32][33]37 . ...
ECKO Extension Protocol 2005—Protocol for the Trial Extension
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... Few who do not eat adequate vegetables, or are taking lots of antibiotics may need vitamin K supplement. Vitamin K has an important role in bone metabolism [24,34,58]. Vitamin K is a cofactor in the (gamma)-carboxylation of many proteins, in particular osteocalcin. ...
Skeletal fragility leading to fractures, particularly in the spine and hip, are a major concern. Adequate calcium and vitamin D intake from childhood and throughout one's life span is critical for the maintenance of a healthy skeleton. Genetics, hormonal milieu, and lifestyle factors, diet and weight bearing exercise are important in achieving the peak bone mass. In addition to calcium and vitamin D, many dietary factors, such as protein, vitamin K and E, magnesium, phytoestrogens, and micro-nutrients, also contribute to the skeletal health; and insufficiencies of any of these may enhance bone loss and fractures. In addition, the Western diet generates an acidic environment leading to an excess acid load on the kidneys, promoting calcium and protein losses and a negative impact on the skeleton. These effects can be negated by the extra consumption of fruits and vegetables that are rich in potassium, magnesium, and calcium, which generate alkalinity and neutralizes free radicals that help to conserve skeletal calcium. Fruits and vegetables are an important component of our food that provides essential nutrients achieving metabolic balance and skeletal health.
... The vitamin K content in HCC cells has the ability to restrict DCP production [1,[28][29][30]. MKH, a fully reduced form of MK-4, is a cofactor of γ-glutamyl carboxylase (GGCX) that converts glutamate residue into the γ-carboxyglutamate residue of vitamin K-dependent proteins such as prothrombin [31][32][33]. ...
Recently, new therapeutics have been developed for hepatocellular carcinoma (HCC). However, the overall survival rate of HCC patients is still unsatisfactory; one of the reasons for this is the high frequency of recurrence after radical treatment. Consequently, to improve prognosis, it will be important to develop a novel anti-tumor agent that is especially effective against HCC recurrence. For clinical application, long-term safety, together with high anti-tumor efficacy, is desirable. Recent studies have proposed menahydroquinone-4 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of menahydroquinone-4 (MKH), as a promising candidate for HCC treatment including the inhibition of recurrence; MKH-DMG has been shown to achieve good selective accumulation of MKH in tumor cells, resulting in satisfactory inhibition of cell proliferation in des-γ-carboxyl prothrombin (DCP)-positive and DCP-negative HCC cell lines. In a spleen-liver metastasis mouse model, MKH-DMG has been demonstrated to have anti-proliferation and anti-metastatic effects in vivo. The characteristics of MKH-DMG as a novel anti-HCC agent are presented in this review article.
... VITAMIN K. Vitamin K is a cofactor for an enzyme necessary for the posttranslational carboxylation of specific glutamic acid residues to form ~,-carboxyglutamate on prothrombin and factors VII, IX, and X of 13 factors required for normal coagulation of blood (Suttie, 2001). Four other vitamin K-dependent plasma proteins that inhibit coagulation have been found (Brinkley and Suttie, 1995). In addition, vitamin K-dependent proteins are found in calcified tissue, including bone, dentine, atherosclerotic tissue, and renal stones (Olson, 1984). ...
Nutrition involves various chemical and physiological activities that transform food elements into body elements. The type and composition of diets used in production and experimental rat colonies are major considerations for maintaining animals in good health or obtaining consistent experimental results. The best diet for a particular rat colony depends on production or experimental objectives. Diets for laboratory rats are classified according to the degree of ingredient refinement such as natural ingredient, purified, and chemically defined diets. Diets formulated with appropriately processed whole grains, such as wheat, corn, or oats, and commodities that have been subjected to limited refinement, such as fishmeal, soybean meal, or wheat bran, are referred to as natural ingredient diets. Diets formulated with only refined ingredients are referred to as purified diets. In these diets, casein or isolated soy protein are examples of protein sources; sugar or starch is a source of carbohydrates; and vegetable oil or animal fat is added as a source of energy and essential fatty acids. Diets formulated entirely with chemically pure compounds are designated as chemically defined diets. Amino acids, sugars, triglycerides, inorganic salts, and vitamins are used to provide the required nutrients.
... 30% de l'ostéocalcine synthétisée n'est pas incorporée dans la matrice osseuse. Le taux circulant d'une fraction de cette protéine non incorporée est utilisé comme indice de formation osseuse (Binkley and Suttie 1995). ...
Over the course of a day, weight bearing bones experience numerous stimulations : mechanical loadings varying in magnitude and frequency, but also electric fields. However, the biological effects of mechanical strain or electrical field on bone cells are poorly understood. In the present in vitro study, osteoblasts were submitted to only one kind of physical stimulus or a combination of stimuli, and the responses were compared. In the perspective of improving the qualities of bone substitute, we analysed parameters essential for a successfull osteointegration : the extracellular matrice (ECM) as host-biomaterial interface, and angiogenic factors which induce implant vascularization. We investigated the effects of complex mechanical strains based on signals of "low magnitude / high frequency" (LMHF) applied to 3D cultures (macroporous hydroxyapatite). Our study shows that an appropriate combined strain regimen (3 Hz+25Hz) has the potential to functionalise cellularized bone-like constructs. ECM synthesis was promoted by LMHF and the osteogenic properties of this ECM were enhanced while VEGF was not affected. Another system was developed to apply an electric field to cell cultures. Some parameters indicated that cells are sensitive to electric fields ; however VEGF expression was not affected. In contrast, when the physical stimulations were combined (LMHF strain + electric field) gene expression of factors implicated in angiogenesis (VEGF, TGFß1, FGF2...) was increased. The complex stimuli whose effects were analysed in this work could be used as a tool for the functionalization of a cellularized bone substitutes
Introduction:
Chronic pancreatitis is a heterogeneous and complex syndrome that, in most cases, causes pain as a cardinal symptom and affects both the morphology and function of the pancreas, leading to several serious complications.
Areas covered:
The present review, based on a non-systematic PubMed search updated to June 2023, aims to present the current available evidence on the role of gastroenterologists in the diagnosis and treatment of both local and systemic complications by either endoscopic or medical treatments.
Expert opinion:
At diagnosis and during chronic pancreatitis follow-up, particular care is needed to consider not only the clinically manifest signs and symptoms of the disease, such as pain, jaundice, gastrointestinal obstruction, and pseudocysts, which require multidisciplinary discussion to establish the best treatment option (endoscopic or surgical), but also less evident systemic complications. Pancreatic exocrine and endocrine insufficiency, together with chronic inflammation, addiction, and dysbiosis, contribute to malnutrition, sarcopenia, and osteopathy. These complications, in turn, increase the risk of infection, thromboembolic events, and death. Patients with chronic pancreatitis also have an increased risk of psychiatric disorders and pancreatic cancer onset. Overall, patients with chronic pancreatitis should receive a holistic evaluation, considering all these aspects, possibly through multidisciplinary care in dedicated expert centers.
Background & Objective
Ulcerative colitis (UC) is an inflammatory bowel disease, usually begins in the rectum and can involve the entire colon. Damage done by this condition can lead to several intestinal and extraintestinal manifestations (EIMs). Due to malnutrition, malabsorption and medications used in UC patients, bone mineral loss seems to happen at a higher pace, compared to healthy population. In this study, we aim to investigate bone mineral density (BMD) and its related biomarkers like Vitamin K, Vitamin D and Calcium in patients with UC.
Method
One hundred and one documented UC patients with at least one year of treatment entered our study. BMD was measured with dual X-ray absorptiometry. Lab tests were done to examine Vitamin K, Vitamin D, Calcium and Magnesium levels in patients’ serum.
Results
Among 101 patients, 32 (31.7%) were men and 69 (68.3%) were women. The mean age of participants was 32.15 ± 9.46 years. The mean duration of the disease was 6.24 ± 3.30 years. Based on the femoral T-score index, 75 (74.3%) patients had normal femoral density, 24 (23.8%) were osteopenic and (2%) 2 patients had osteoporosis. Bone loss significantly correlated with age and disease. Patients with lower BMI tend to have lower BMD values. The data analysis revealed lower levels of Vitamin K, Vitamin D and Calcium in UC patients significantly decreased bone density indexes, except for lumbar T-score which did not showed a clear relationship with serum Vitamin K. Also, the cumulative dose of prednisolone significantly reduced all BMD indicators, especially in patients with longer disease durations.
Conclusion
BMD in UC patients seems to decrease at a higher pace and it's associated with lower levels of Vitamin K, Vitamin D and Calcium in serum as well as corticosteroid consumption. Close follow-ups, dietary supplements and corticosteroid usage limitations could be beneficial for UC patients and decrease the risk of developing osteoporosis.
Vitamin K is required for the ɣ-carboxylation of specific glutamic acid residues within the Gla domain of the 17 vitamin K-dependent proteins (VKDPs). The timely detection and correction of vitamin K deficiency can protect against bleeding. Vitamin K also plays a role in bone metabolism and vascular calcification. Patients at increased risk of vitamin K deficiency include those with a restricted diet or malnutrition, lipid malabsorption, cancer, renal disease, neonates and the elderly. Coagulation assays such as the prothrombin time have been used erroneously as indicators of vitamin K status, lacking sufficient sensitivity and specificity for this application. The measurement of phylloquinone (K 1 ) in serum is the most commonly used marker of vitamin K status and reflects abundance of the vitamin. Concentrations <0.15 µg/L are indicative of deficiency. Disadvantages of this approach include exclusion of the other vitamin K homologues and interference from recent dietary intake. The cellular utilisation of vitamin K is determined through measurement of the prevalence of undercarboxylated VKDPs. Most commonly, undercarboxylated prothrombin (Protein Induced by Vitamin K Absence/antagonism, PIVKA-II) is used (reference range 17.4–50.9 mAU/mL (Abbott Architect), providing a retrospective indicator of hepatic vitamin K status. Current clinical applications of PIVKA-II include supporting the diagnosis of vitamin K deficiency bleeding of the newborn, monitoring exposure to vitamin K antagonists, and when used in combination with α-fetoprotein, as a diagnostic marker of hepatocellular carcinoma. Using K 1 and PIVKA-II in tandem is an approach that can be used successfully for many patient cohorts, providing insight into both abundance and utilisation of the vitamin.
For the past two decades there has been increasing recognition of the health benefits of consuming diets rich in fruits and vegetables. Early studies by Wattenberg focused awareness on the potential role of dietary constituents in prevention of cancer. In animal studies, he investigated the inhibition of several chemically induced cancers by a wide range of natural compounds in human food.
The prevalence of obesity in combination with sarcopenia (the age-related loss of muscle mass and strength or physical function) is increasing in adults aged 65 years and older. A major subset of adults over the age of 65 is now classified as having sarcopenic obesity, a high-risk geriatric syndrome predominantly observed in an ageing population that is at risk of synergistic complications from both sarcopenia and obesity. This Review discusses pathways and mechanisms leading to muscle impairment in older adults with obesity. We explore sex-specific hormonal changes, inflammatory pathways and myocellular mechanisms leading to the development of sarcopenic obesity. We discuss the evolution, controversies and challenges in defining sarcopenic obesity and present current body composition modalities used to assess this condition. Epidemiological surveys form the basis of defining its prevalence and consequences beyond comorbidity and mortality. Current treatment strategies, and the evidence supporting them, are outlined, with a focus on calorie restriction, protein supplementation and aerobic and resistance exercises. We also describe weight loss-induced complications in patients with sarcopenic obesity that are relevant to clinical management. Finally, we review novel and potential future therapies including testosterone, selective androgen receptor modulators, myostatin inhibitors, ghrelin analogues, vitamin K and mesenchymal stem cell therapy.
Introduction History Chemical Structure, Properties, and Antagonists Analytical Procedures Metabolism Functions Requirements Natural Sources Deficiency Supplementation Toxicity References
Injuries to the musculoskeletal system are common and place a significant burden on modern-day health care systems. Within the United States alone, there are more than 6 million fractures a year (1), with hip fractures making up a significant proportion (2). These tend to be concentrated among the elderly osteoporotic population and are a major cause of morbidity and mortality (3).
Schädigungen, die im Rahmen angeborener Stoffwechselerkrankungen auftreten, sind entweder Folge der toxischen Wirkung eines pathologisch erhöhten Metaboliten des Intermediärstoffwechsels oder die Folge eines durch den Defekt entstandenen Mangels. Die Behandlungsprinzipien sind dabei immer:
Verhinderung der Anhäufung toxischer Substrate und Metaboliten.
Zufuhr eines limitierenden Metaboliten nach einem metabolischen Block.
Zufuhr eines Metaboliten, dessen Fehlen eine eigene Problematik verursacht.
Kalzium gehört zu den wichtigsten Elementen des menschlichen Organismus. Es besitzt für viele Funktionen (Blutgerinnung, Muskelkontraktion u.v.a.m.) eine entscheidende Bedeutung und ist für die Statik des Knochens unverzichtbar. Aus diesen Gründen unterliegt die Regulation das Kalziumspiegels im Blut vielfältigen und feinen Regulationsmechanismen.
In the next 30 to 40 years, the population of adults over the age of 65 years of age is estimated to double [1]. As the population of the United States ages, there is a concurrent need to address the morbidity associated with ageing. Rudman et al. [2], examined a population of nursing home residents and found that nearly 70% of the residents had a reduced body mass index (BMI), a 50% incidence of anemia, and a majority had a serum albumin 003C3.5 g/dl. They also found that all of the study group had a dietary intake 003C50% of the recommended dietary allowance (RDA) of several essential nutrients including: zinc, magnesium, manganese, copper, vitamin E retinol, nicotinic acid, pyridoxine, and folic acid. With this in mind, it is important to consider that institutionalized elderly may be deficient in their dietary intake of several essential vitamins. This dietary deficiency may lead to further health complications.
ECKO Protocol 2001—Initial Protocol for the Trial
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Vitamin K is a fat-soluble vitamin that may have a protective role against agerelated bone loss. Vitamin K refers to a family of compounds with a common chemical structure, 2-methyl-1,4-napthoquinone (Fig. 1). Phylloquinone, or vitamin K1, is present in foods of plant origin. Green, leafy vegetables contain the highest content of phylloquinone, and contribute up to 60% of total phylloquinone intake (1,2). Certain plant oils, margarine, spreads, and salad dressings, derived from plant oils, are also important dietary sources of phylloquinone, whereas animal fat sources, such as butter, are not (3,4). Recently, phylloquinone has been added in varying amounts to some dietary supplements. During the process of hydrogenation of certain phylloquinone-rich vegetable oils, phylloquinone is converted to 2′,3′-dihydrophylloquinone, which differs from the parent form by saturation of the 2′,3′ double bond of the phytyl side chain (5) (Fig. 1). Dihydrophylloquinone is found exclusively in hydrogenated phylloquinone-rich vegetable oils, which are widely used by industry in food preparation because of their physical characteristics and oxidative stability.
The concept that specific food components play important roles in tissue growth and repair has been evident since the writings of early Egyptian, Greek, and Asian philosophers. For example, nutrition is a topic in the Hippocratic collection; the Papyrusebers (written about 1580–1570 B.c.) prescribes beef liver for eye diseases. The concept that vitamins are essential dietary compounds, however, did not evolve with any clarity until the early 1900s. Up to the early 1900s, it was widely held that only the major constituents in the diet (i.e., carbohydrates, protein, fat, and some minerals) were needed for nourishment (1). Nevertheless, the view that small amounts of certain factors seemed necessary for optimal growth and development eventually became apparent. It is now appreciated that vitamin status influences a number of relationships important to metabolic regulation. Consequently, a goal in this chapter is to provide a summary of the functions for each of the compounds now conventionally classified as vitamins or vitamin-like. A perceptive on vitamin requirements will also be developed. To the extent that vitamin status influences the ability to deal with foreign antigens and infections, another goal is to amplify those aspects of vitamin function important to the discussion of acquired, adaptive, and innate immunity that are developed elsewhere throughout this volume.
When compared with other menadione derivatives such as menadione sodium bisulphite (MSB), menadione nicotinamide bisulphite (MNB), an organic salt combining menadione and nicotinamide, shows better stability towards physical and chemical factors once it is added to pre-mixes or foods. The present work evaluates the bioavailability of the two vitamins present in this compound and toxicity in the pig. To assess vitamin bioavailability, pigs were given small amounts of food containing MNB or equivalent amounts of MSB and nicotinamide in the free form. Menadione and nicotinamide concentrations in blood samples drawn-at set times after the diets were given did not reveal any significant differences between the two modes of administration. Haematic levels of both vitamins in animals receiving MNB, or MSB and nicotinamide, were after 2, 4, 8 and 12 h higher (P < 0.001) than those of untreated animals. The tolerance level to MNB was evaluated in pigs given diets containing graded amounts of MNB (100, 500, 2500 mg/kg) for 28 days. No significant (P > 0.05,) differences were recorded in live weight, food intake and gain/food ratio in pigs given these diets when compared with those given an unsupplemented diet. Haemoglobin and bilirubin levels did not differ between animals given various amounts of MNB and control animals. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in pigs given 100 mg/kg of MNB did not show significant differences when compared with those observed in pigs given an unsupplemented control diet. In pigs on the diets supplemented with 500 and 2500 mg/kg of MNB there was a significant increase in the two enzymatic activities as compared with controls (P < 0.001 and P < 0.01). In the case of ALT this had disappeared by 28 weeks. MNB is a good source of vitamin K for the pig and does not appear to have any adverse effects, even when administered at levels higher than those normally used in pig food supplementation.
In 1990 osteoporosis was redefined, for the first time in nearly a century, as a condition of skeletal fragility due to decreased bone mass and to microarchitectural deterioration of bone tissue, with consequent increased risk of fracture. This definition was conceptually important because it both acknowledged and encouraged a shift in thinking about osteoporosis from an anatomic to a dynamic condition. Low bone mass became a risk factor for fracture, rather than, as formerly, the defining feature of the disease. This redefinition accompanied a growing recognition that osteoporosis is not a single disorder but a group of more or less discrete fracture syndromes, multifactorial both in etiology and in pathogenesis.
Osteoporosis is a condition of skeletal fragility due to decreased bone mass and to micro architectural deterioration of bone tissue, with consequent increased risk of fracture. Many nutrients and lifestyle interact to determine bone density and risk for osteoporosis. Knowledge of bone acquisition during childhood and adolescents has assumed a key role in predicting age-related bone loss in later years. There are also unique issues of bone metabolism that occur with pregnancy and lactation that help determine nutrient intake recommendations for women during those years. Although dietary adequacy of calcium is primarily associated with bone density, many other vitamins and minerals play important roles in the development and maintenance of normal bone. Vitamin D adequacy and its metabolites play a key role, especially with advancing age.
Dietary supplementation with dried plums has been shown to be effective in preventing bone loss and restoring bone tissue in animal models of postmenopausal and age-related osteoporosis. The mechanisms of this dried fruit's effects on bone are due in part to its ability to downregulate proinflammatory cytokines that stimulate bone resorption by osteoclasts and enhance the bone-forming capacity of osteoblasts. These promising results have generated a great deal of interest in dried plum as a functional food as well as spawned efforts to identify the bioactive components.
Keywords: Antioxidant; Bone; Estrogen; Inflammation; Menopause; Osteoblasts; Osteoclasts; Osteopenia; Osteoporosis; Oxidation; Oxidative stress; Plum; Prune
The complete amino acid sequence of bovine bone matrix Gla protein (MGP) was determined by automatic sequence analysis of the intact protein and of peptides isolated from tryptic and BNPS-skatole digests. This 79-residue, vitamin K-dependent protein contains a single disulfide bond and 4.8 gamma-carboxyglutamate (Gla) residues, one each at positions 37, 41, 48, and 52, and 0.8 Gla and 0.2 Glu at position 2. There is sufficient sequence homology between MGP and bone Gla protein (BGP) to indicate that these two bovine bone proteins arose by gene duplication and subsequent divergent evolution. Although MGP has a very low solubility in water compared to BGP, there is no hydrophobic domain in MGP which could account for its insolubility, and the overall fraction of hydrophobic residues is 32% for MGP compared to 43% for BGP. MGP is the first vitamin K-dependent protein to be discovered which has several non-gamma-carboxylated residues to the NH2-terminal side of its Gla residues. The presence of NH2-terminal Glu residues between the putative targeting domain for the gamma-carboxylase in the MGP leader sequence and the mid-molecule Gla residues suggests that the gamma-carboxylase may have additional, as yet unrecognized, specificity requirements which determine the susceptibility of Glu residues for gamma-carboxylation.
In comparison to normal prothrombin, the abnormal prothrombin produced in response to vitamin K antagonists has been found to bind much less tightly, if at all, to phospholipid surfaces. As a consequence, the activation of abnormal prothrombin by Factor Xa and Ca2+ is not accelerated by the addition of phospholipid to the mixture while the activation of normal prothrombin under these conditions is greatly accelerated by phospholipid addition. In the absence of phospholipid, however, the rate of activation of abnormal prothrombin by Factor Xa and Ca2+ in both the presence and absence of Factor Va is indistinguishable from that of normal prothrombin. The distribution of the partial proteolysis products during activation by Factors Xa, Va, and Ca2+ also appears to be the same for both prothrombins. These observations provide an explanation for the function in prothrombin activation of the gamma-carboxyglutamate residues formed in the vitamin K-dependent carboxylation of prothrombin.
The bovine plasma zymogen prothrombin contains a number of gamma-carboxyglutamic acid residues which are not found in an abnormal prothrombin produced when cattle are given the vitamin K antagonist dicoumarol. These modified glutamic acid residues appear to be formed post-translationally by a reaction which requires vitamin K. It has been shown that postmitochondrial supernates from vitamin K-deficient rats incorporate added H-14-CO3- minus into microsomal proteins upon the addition of vitamin K. This incorporation is dependent upon the presence of the prothrombin precursor in the microsomal preparations, and upon factors which are present in the postmicrosomal supernatant. Most of the radioactive protein which can be obtained from the microsomal pellet by extraction with 0.25% Triton X-100 has been identified as prothrombin and it can be shown that all of the radioactivity is in the amino-terminal activation fragment of prothrombin. This portion of the protein has previously been shown to contain the gamma-carboxyglutamic acid residues. Hydrolysis of the purified radioactive prothrombin resulted in a loss of 50% of the radioactivity and subsequent chromatography of the amino acid hydrolyzate demonstrated that the remaining radioactivity was entirely in glutamic acid. These results are consistent with the hypothesis that all of the H-14-CO3- minus was incorporated into the carboxyl groups of gamma-carboxyglutamic acid residues.
An osteoblast-like human osteosarcoma cell line (U2-OS) has been shown to possess a vitamin K-dependent carboxylation system which is similar to the system in human HepG2 cells and in liver and lung from the rat. In an 'in vitro' system prepared from these cells, vitamin K1 was shown to overcome warfarin inhibition of gamma-carboxylation carried out by the vitamin K-dependent carboxylase. The data suggest that osteoblasts, the cells involved in synthesis of vitamin K-dependent proteins in bone, can use vitamin K1 as an antidote to warfarin poisoning if enough vitamin K1 can accumulate in the tissue. Five precursors of vitamin K-dependent proteins were identified in osteosarcoma and HepG2 cells respectively. In microsomes (microsomal fractions) from the osteosarcoma cells these precursors revealed apparent molecular masses of 85, 78, 56, 35 and 31 kDa. When osteosarcoma cells were cultured in the presence of warfarin, vitamin K-dependent 14C-labelling of the 78 kDa precursor was enhanced. Selective 14C-labelling of one precursor was also demonstrated in microsomes from HepG2 cells and from rat lung after warfarin treatment. In HepG2 cells this precursor was identified as the precursor of (clotting) Factor X. This unique 14C-labelling pattern of precursors of vitamin K-dependent proteins in microsomes from different cells and tissues reflects a new mechanism underlying the action of warfarin.
The recycling of vitamin K in the liver occurs via one or two dithiol-dependent reductases, which are strongly inhibited by coumarin derivatives such as warfarin. This inhibition may be partly overcome by the action of a NADH-dependent reductase, which is relatively insensitive for warfarin. In this paper we demonstrate that the osteoblast-like osteosarcoma UMR 106 does not contain the NADH-dependent reductase. Assuming that a similar enzyme distribution occurs in normal osteoblasts this explains the observation of Price and Kaneda, that the administration of vitamin K to rats efficiently counteracted the effect of warfarin on blood coagulation, but that the vitamin had no effect on the Gla-content of serum osteocalcin.
In this paper we present the following observations:
1) In sheep vitamin K-antagonists like phenprocoumon induce a decrease of the serum levels of osteocalcin (bone Gla-protein) and of the affinity of the circulating osteocalcin for hydroxyapatite.
2) In sheep vitamin K counteracts the effect of phen-procoumon on the blood coagulation system, but not that on the osteocalcin production.
3) In human subjects vitamin K-antagonists also lead to decreased levels of serum osteocalcin and a low affinity of the protein for hydroxyapatite.
4) These two variables reached steady-state levels within 24 h after the start of oral anticoagulant treatment and - at continu-ation of the therapy - they remained low for at least several years.
Warfarin and other 4‐hydroxycoumarins are effective antithrombotic agents. They affect four blood coagulation proteins that act sequentially to produce thrombin. Coumarin therapy decreases the biological activity of these proteins, and therefore decreases the rate at which blood clots. As the mechanism by which these drugs act has become clear, it has also been found that vitamin K will overcome the effects of coumarin anticoagulation and can be used to control bleeding side effects of coumarin therapy. Vitamin K is necessary for activity of a liver enzyme, the vitamin K‐dependent carboxylase. A second enzyme that recycles an inactive to an active form of the vitamin is inhibited by coumarins. The ability of other liver enzymes to bypass the coumarin‐sensitive step greatly enhances the safety of 4‐hydroxycoumarins.
The osteoclast, the multinucleated giant cell of bone, is derived from circulating blood cells, most likely monocytes. Evidence has accrued that is consistent with the hypothesis that the recruitment of monocytes for osteoclast development occurs by chemotaxis. In the present study, we have examined the chemotactic response of human peripheral blood monocytes and related polymorphonuclear leucocytes to three constituents of bone matrix: peptides from Type I collagen, alpha 2-HS glycoprotein, and osteocalcin (bone gla protein). The latter two substances are among the major noncollagenous proteins of bone and are uniquely associated with calcified connective tissue. In chemotaxis assays using modified Boyden chambers, Type I collagen peptides, alpha 2HS glycoprotein, and osteocalcin evoke a dose-dependent chemotactic response in human monocytes. No chemotaxis is observed on PMNs despite their ontogenetic relationship to monocytes and their documented sensitivity to a broad range of other chemical substances. Our observations are consistent with the view that osteoclast precursors (monocytes) are mobilized by chemotaxis, and suggest that the chemoattractants responsible for this activity are derived from the bone matrix or, in the case of collagen and osteocalcin; directly from the osteoblasts which produce them.
Summary We have found that theγ-carboxyglutamic acid (GLA)-containing protein from bone (BGP, osteocalcin) has chemotactic activityin vitro for a number of cells which are found adjacent to endosteal bone surfacesin vivo. Using the Boyden chamber technique for measuring cell chemotaxisin vitro, we have shown that BGP is chemotactic for cultured human breast cancer cells, human and mouse monocytes, and for cultured
rat osteosarcoma cells which have the characteristics of osteoblasts. The migration of these cells in response to BGP is unidirectional
and not due to spontaneous or random migration. A synthetic peptide (Phe-Tyr-Gly-Pro-Val), which is identical to the carboxyterminal
peptide cleaved from BGP when digested by trypsin, is also chemotactic for the same cells. BGP retains its chemotactic activity
after conversion of theγ-carboxyglutamic acid residues to glutamic acid, indicating that this biological effect requires neitherγ-carboxyglutamate nor the ability of BGP to bind calcium. Since BGP is released from bone during states of increased bone
turnover, it is possible that this chemotactic effect of the protein may be a mechanism for recruitment of these cells to
sites of active bone remodeling.
In anin vivo model of osteoclastic bone resorption, we previously showed that osteocalcin-deficient bone particles (BPs), derived from
warfarin-treated rats, were resorbed 50% as well as normal BPs and that they recruited fewer osteoclastic cells with decreased
tartrate-resistant acid phosphatase (TRAP) activity. In order to determine the specificity of the resorption response, we
evaluated the fate of implanted mixtures of normal and osteocalcin-deficient BPs. Normal and warfarin-treated donor rats were
prelabeledin vivo with oxytetracycline to permit identification of BPs from either source. Normal, osteocalcin-deficient, and 50∶50 mixtures
of BPs (either labeled or unlabeled) were implanted into normal rats and recovered 12 days later for enzymatic (TRAP) and
nondecalcified histomorphometric analyses. The incorporated oxytetracycline had no signficant effect on resorption of bone
particles. The recovered osteocalcin-deficient BPs were surrounded by fewer osteoclastic cells, were resorbed less, and contained
less extractable TRAP activity than normal BPs. In mixed BP implants with normal and osteocalcin-deficient BPs, each type
of bone particle elicited the same tissue response as when implanted separately. Remarkably, the different particles evoked
dissimilar osteoclastic responses and were resorbed to different extents, even when adjacent within the same implant. These
data suggest that osteocalcin may act as a substrate signal for resorption and that osteocalcin in the normal BPs does not
influence the cellular response to adjacent osteocalcin-deficient BPs.
A human osteosarcoma cell line, HOS TE85 cells, and a mouse osteoblastic cell line, MC3T3-E1 cells, were cultured for 3 days in a medium containing various concentrations of menaquinoe-4 (vitamin K2). As a result, the proliferation of HOS cells was suppressed by vitamin K2 in a dose dependent manner up to 56 % of control by 10−7M of vitamin K2 and that of MC3T3-E1 cells was suppressed to 84 % of control by 10−6M of vitamin K2. Vitamin K2 increased alkaline phosphatase activity in both kinds of cells. Warfarin counteracted the effect of vitamin K2 on osteoblastic cell proliferation. Our results show that vitamin K2 modulates proliferation and function of osteoblastic cells by some mechanisms including γ-carboxylation system.
A highly sensitive, simple and reliable one-step sandwich enzyme immunoassay (EIA) for the γ-carboxylated form of osteocalcin (Gla-OC) has been developed using a monoclonal antibody. The minimum amount of Gla-OC detected by this EIA was approximately 0.2 ng/ml when a 10 μl aliquot of the sample was used. The serum Gla-OC level in 30 healthy subjects was 3.6 ± 2.19 ng/ml (mean) ± SD. A significant increase was seen in patients with chronic renal failure (20.3 ± 4.60 ng/ml), atherosclerosis (8.3 ± 4.94 ng/ml) and osteoporosis (10.1 ± 4.60 ng/ml). The correlation between the values obtained by the sandwich EIA and competitive RIA methods was given by the linear regression equation, y = 2.896 + 0.759x, for which the correlation coefficient (r) was 0.815 (n = 58). This newly developed Gla-OC specific EIA may be useful for the diagnosis of metabolic bone disease and ectopic calcification.
Plasma bone Gla protein (BGP) was determined by radio-immunoassay in 266 healthy adults, men (n = 132) and women (n = 134), aged 20-79 years. In the women aged 30-69 years, plasma BGP increased significantly with age (r = 0.44, p less than 0.001), and a particularly steep increase was seen from 1.1 +/- 0.5 (mean +/- 1 SD) in the fifth decade to 2.0 +/- 1.4 nmol/l in the seventh decade. In men, aged 30-69 years, no correlation was found between plasma BGP and age (r = -0.07, NS). Plasma bone Gla protein is removed from the circulation mainly by the kidneys and the increased plasma BGP in the women could be caused by decreased renal clearance. The interrelationship was analysed by means of partial correlation. When creatinine clearance was held constant in women, BGP still correlated positively with age (r = 0.40, p less than 0.001), but not with creatinine clearance (r = 0.003, NS) when age was fixed. Plasma BGP was significantly increased above normal in 35 patients with chronic renal failure (10.2 +/- 14.6 nmol/l). Non-linear regression analysis showed that plasma BGP was within the normal range when 24-h creatinine clearance was greater than 30 ml/min, and large increases in plasma BGP did not occur until the 24-h creatinine clearance was below 20 ml/min. We conclude that, in normal subjects and patients with mild to moderate renal failure, plasma elevations of BGP reflect increased bone turnover rather than decreased renal clearance.
Treatment with high dosages of Vitamin K completely inhibited the effect of Warfarin on blood coagulation but had essentially no ability to counteract the effect of Warfarin on the gamma-carboxylation of bone G1a protein (BGP; osteocalcin). Provided that rats received the appropriate dosage of Vitamin K prior to and concurrent with the administration of Warfarin, daily dosages as high as 7.7 mg Warfarin per 100 g body weight had no effect on blood coagulation times. This Warfarin dosage is approximately 150 times higher than the 50 micrograms per 100 g body weight which caused coagulation times to double in rats which did not receive Vitamin K. In dramatic contrast, the dosage of Warfarin required to reduce the gamma-carboxylation status of BGP to one-half normal, 30 micrograms per 100 g body weight, was essentially unaffected by Vitamin K treatment. These results indicate the existence of a major difference between the metabolism of Vitamin K by the hepatocytes which synthesize coagulation factors and the osteoblasts which synthesize BGP. The practical consequence of this difference is that it is now possible to antagonize the action of Vitamin K in osteoblasts, as well as in other cells which have the same Vitamin K metabolism, without affecting blood coagulation times.
Protein S is a vitamin K dependent protein of unknown function, which is present in mammalian plasma. It was isolated from bovine plasma by barium citrate adsorption and elution, ammonium sulfate fractionation, and column chromatography on DEAE-Sephadex, heparin-agarose, and polyhomoarginine-Sepharose. Bovine Protein S (Mr 64,200) is a single-chain glycoprotein with an amino-terminal sequence of Ala-Asn-Thr-Leu-Leu-. It contains 7.0% carbohydrate and 10 residues of gamma-carboxyglutamic acid per mol of protein. Human Protein S (Mr 69,000) is also a single-chain glycoprotein with an amino-terminal sequence of Ala-Asn-Ser-Leu-Leu-. It contains 7.8% carbohydrate and 10 residues of gamma-carboxyglutamic acid per mol of protein. These results indicate that Protein S from bovine or human plasma shows many similarities to the other vitamin K dependent proteins present in plasma.
Bone contains a small protein, rich in the vitamin K-dependent calcium-binding amino acid γ-carboxyglutamate (Gla). This protein, named osteocalcin, is extractable by neutral EDTA demineralization and contains over 80% of the total peptide Gla found in bone. Osteocalcin binds Ca2+ ions with moderate affinity (2 moles of Ca2+/6500 g of protein; Kd = 0.83 mM). Osteocalcin appears in embryonic chick bones (mandible, calvaria, tibiotarsus, and femur) coincident with the first histologically observable deposition of bone mineral at 8 to 12 days after fertilization. The quantity of this protein increases dramatically during development with characteristic onset and kinetics for each type of bone. In the long bone diaphysis (midshaft), the fraction of noncollagen protein represented by osteocalcin increases 100- to 200-fold between the 8th and 20th day. Relative to total bone protein, the increase is about 35-fold. Osteocalcin may play a role in the development of mineralized tissues and may be a characteristic product of cells differentiated with respect to bone and/or cartilage formation.
Osteocalcin (bone Gla-protein) is a vitamin K-dependent protein synthesized by osteoblasts. Its hydroxylapatite binding capacity (HBC) is generally used to estimate the Gla-content of circulating osteocalcin. Here we have used the HBC of serum osteocalcin as a marker for the vitamin K-status in pregnant women and their offspring. For all cases investigated the HBC values in the cord samples were substantially lower than in the corresponding maternal ones. Babies from mothers who had been treated with vitamin K during the last 6 weeks prior to delivery, had significantly higher HBC values than those from a placebo group. The results presented in this paper are indicative for a generally occurring vitamin K deficiency in newborns. At delivery the HBC in untreated women was low as well. In both the placebo- and the vitamin K-group a good correlation was found between the HBC values in paired samples from mother and child. Whether the maternal HBC value may be used as a prenatal marker for estimating the fetal vitamin K-status remains to be seen.
Protein-S is a vitamin K (Vit K)-dependent protein synthesized by hepatocytes, megakaryocytes, and endothelial cells and plays an important role in the regulation of hemostasis. Two cases of free protein-S congenital deficiency were recently reported to be associated with osteopenia. We hypothesized that this osteopenia could be the result of a bone deficit of protein-S synthesized by bone cells. Using enzyme-linked immunoassay, immunocytochemistry, immunoblotting, and immunoprecipitation after labeling with [35S]methionine, we have shown that this protein is secreted by three human osteosarcoma cell lines and by human adult osteoblast-like cells. In addition, protein-S was present in protein extracts of human bone matrix. Protein-S secreted by MG 63 cells increased linearly from 1-7 days of culture, was biologically active, and was regulated by warfarin, as previously described for the other cell types secreting protein-S. Vit K had no direct effect on protein-S secretion or activity, but could overcome the effects of warfarin. In conclusion, in addition to osteocalcin and matrix gamma-carboxyglutamic acid (Gla) protein, osteoblasts secrete another Vit K-dependent protein, which is a constituent of the bone matrix. Our data suggest that osteopenia occurring in patients with congenital protein-S deficiency might be related to a deficiency of protein-S secretion by the osteoblasts. This finding raises the intriguing possibility that protein-S might play a role in bone turnover and bone mass.
Patients with spinal cord injuries among others, commonly develop neurogenic heterotopic ossification. Current treatment with Didronel (disodium etidronate) inhibits bone matrix mineralization but not matrix production. To eliminate much morbidity and cost, a more efficatious prophylactic treatment is desirable. Because one of the proteins in bone, osteocalcin, is produced by a vitamin K-dependent carboxylation, this raises the possibility that treatment with warfarin may prevent the formation of ectopic bone. In the present study, 227 cases of spinal cord injury were reviewed. Among these patients, 15% were treated with warfarin and another 15% developed heterotopic ossification. None of the patients who were treated with warfarin developed heterotopic ossification, thus suggesting that warfarin may inhibit heterotopic ossification. Further prospective studies are planned.
Vitamin K is a substrate for a liver microsomal enzyme that catalyzes the conversion of specific glutamyl residues to gamma-carboxyglutamyl residues in a limited number of proteins. These include the vitamin K-dependent clotting factors: prothrombin (factor II), factor VII, factor IX, and factor X. In the absence of vitamin K, nonfunctional clotting factors are synthesized and hemorrhage can result. A Recommended Dietary Allowance of 1 micrograms/kg body weight has been established for vitamin K. Advances in analytic techniques and more sensitive clotting factor assays will make it possible to define the human requirement for this vitamin more accurately. A limited amount of data on the vitamin K content of foods is now available and reasonable estimates of intake can be calculated. Green leafy vegetables constitute the major source of vitamin K in the diet.
Osteoporosis is a very important age-related health problem. The body's composition changes with age, and these changes are a true reflection of aging and of the individuals's nutritional status. Mineral content changes have been reported in vertebral osteoporosis. Interestingly, enough, there have not been reports on concomitant water, fat, and fat-free mass changes associated with this condition. In this report, changes in the latter parameters are compared between patients with osteoporosis and controls. The four components (water, mineral, fat, and fat-free mass) were found significantly reduced (p less than 0.001) in osteoporosis. Serum albumin and protein mass were also reduced (p less than 0.001).
Vitamin K1 functions in the conversion of glutamate residues, present in certain bone peptides, into the putatively active gamma-carboxyglutamate form. We have shown previously that the circulating levels of vitamin K1 are depressed in osteoporotic patients. However, it is known that menaquinones (vitamin K2:MK) may be more effective than vitamin K1 in this conversion of the inactive to active form of glutamate residues. A procedure for measuring such menaquinones has now demonstrated a marked deficiency of MK-7 and MK-8 in patients with osteoporotic fractures. It is suggested that estimates of circulating levels of K1, MK-7, and MK-8 might provide a biochemical risk marker of osteoporotic fractures.
59 elderly patients (mean age 82) with femoral neck fractures were randomised into two groups. 27 patients received daily an oral nutrition supplement (250 ml, 20 g protein, 254 kcal) for a mean of 32 days; 32 patients acted as controls. On admission most patients had nutritional deficiencies. Despite being offered adequate quantities, nutritional requirements were not met during the hospital stay. Clinical outcome was significantly better in the supplemented group (56% favourable course vs 13% in controls) during the stay in the convalescent hospital. The rates of complications and deaths were also significantly lower in supplemented patients (44% vs 87%). 6 months after the fracture the rates of complications and mortality were significantly lower in supplemented patients (40% vs 74%). The median duration of hospital stay was significantly shorter in the supplemented group (24 vs 40 days). Thus the clinical outcome of elderly patients with femoral neck fracture can be improved by once daily dietary oral supplementation.
In experimental and clinical studies, conflicting results regarding the effect of oral anticoagulant therapy on bone metabolism have been reported. To measure a possible influence of long-term anticoagulant therapy with phenprocoumon on peripheral bone mass, measurements of peripheral bone mineral content (BMC) and serum osteocalcin levels were performed with single photon absorptiometry in a total of 78 patients on anticoagulant treatment. We studied 43 women (mean age 66 years ± 2 SEM) and 35 men (mean age 65 years ± 2 SEM) with a median duration of phenprocoumon therapy of I year (1–9 years). In all patients, the medical history gave no symptoms of metabolic bone disease, or diseases or medications causing osteoporosis.
Both in the male and female groups, mean peripheral BMC was significantly decreased (male: P<0.01, female: P<0.003) when compared with corresponding controls. Serum OC-levels measured in 16 patients were also significantly lower than those of the controls (P<0.02).
Our data of decreased BMC and low serum OC-levels indicate reduced bone mass in patients on long-term anticoagulant therapy with phenprocoumon. This may imply an influence of anticoagulants on bone metabolism resulting in decreased bone format ion.
Specific cellular interactions with components of the extracellular matrix can influence cellular differentiation and development of many tissues. The extracellular matrix of bone is composed of organic constituents and a solid phase of calcium and inorganic phosphate (apatite). When implanted subcutaneously in rats, particles of bone matrix (BPs) recruit progenitors that differentiate into multinucleated cells with osteoclastic features. Because BPs deficient in osteocalcin, a bone matrix protein, were less efficient at promoting osteoclast formation than were normal BPs, we directly examined the influence of osteocalcin on osteoclast differentiation. We evaluated tissue responses to particles of synthetic crystalline apatite alone (Ap), having many of the features of native apatite of mature bone, or to apatite prepared with osteocalcin (Ap/OC), bovine serum albumin (Ap/BSA) or rat bone collagen (Ap/Col). Twelve days after subcutaneous implantation in normal rats, Ap, Ap/BSA, and Ap/Col particles generated a mild foreign body reaction with multinucleated cells in direct contact with the particles; these cells were negative for tartrate-resistant acid phosphatase (TRAP) activity and lacked ruffled borders. In contrast, Ap particles containing approximately 0.1% osteocalcin were partially resorbed and they generated more multinucleated cells that were TRAP-positive, were immunoreactive with an antibody against tartrate-resistant purple acid phosphatase, and displayed ultrastructural features of active osteoclasts including ruffled borders and clear zones. These data support the hypothesis that osteocalcin may function as a matrix signal in the recruitment and differentiation of bone-resorbing cells.
We measured bone osteocalcin concentrations in EDTA extracts from iliac crest cortical bone specimens obtained postmortem from 63 men and 71 women (age range 19-90 years), and serum osteocalcin levels in healthy blood donors, 49 men and 49 women (age range 21-65 years). Bone and serum osteocalcin concentrations were higher in men than in women, and an age-related decline was observed in both sexes. In women, however, a temporary increase in serum (P less than 0.05) osteocalcin was seen in the sixth decade. This study shows sex- and age-related changes in bone osteocalcin consistent with changes in serum osteocalcin, confirming that serum measurement of osteocalcin reflects bone levels. As osteocalcin reflects osteoblastic activity and thus bone formation, the overall decline in bone and serum osteocalcin in men and women, and the increase in serum osteocalcin in the sixth decade in women, indicate that aging is associated with a decrease in bone formation and turnover and that osteoblastic activity and bone turnover are stimulated at the menopause.
Two unrelated children with thrombotic disease associated with inherited protein S deficiency and osteopenia have been identified. Measurement of protein S yielded markedly reduced levels of free protein S (less than 12.5%) in both propositi, a normal level of total protein S (79%) in propositus #1, and markedly reduced level of total protein S (34%) in propositus #2. Bone densitometry measurements of the two children revealed trabecular vertebral bone mineral content below two standard deviations. This defect is associated with vertebral body compression fractures in propositus #2. Therefore, it is hypothesized that protein S deficiency is associated with abnormalities of bone mineral density.
1. Through the vitamin K1 cycle, phylloquinone is now known to play an active role, not only in relation to prothrombin, but also in the synthesis of bone peptides.
2. The recent development of a sensitive method allowed the demonstration of a deficit of vitamin K1 in the circulation of osteoporotic subjects.
3. Vitamin K2, namely the menaquinones of various chain-lengths, has been shown by others to be more effective than vitamin K1 in the curative rat bioassay.
4. Earlier reports had shown that the concentration of menaquinones in human liver may exceed that of vitamin K1. But previous methods were too insensitive for testing the normal circulating levels of menaquinones in the human.
5. The new sensitive method has now been applied to measuring the circulating levels of vitamin K1 and of two of the menaquinones, namely menaquinone-7 and menaquinone-8.
6. In normal individuals, the circulating levels of vitamin K1 were the same, irrespective of age.
7. In young normal subjects, the combined levels of menaquinone-7 and menaquinone-8 were at least the same as the level of vitamin K1. In elderly normal subjects, there was a marked deficit of menaquinone-8.
Warfarin and other 4-hydroxycoumarins are effective antithrombotic agents. They affect four blood coagulation proteins that act sequentially to produce thrombin. Coumarin therapy decreases the biological activity of these proteins, and therefore decreases the rate at which blood clots. As the mechanism by which these drugs act has become clear, it has also been found that vitamin K will overcome the effects of coumarin anticoagulation and can be used to control bleeding side effects of coumarin therapy. Vitamin K is necessary for activity of a liver enzyme, the vitamin K-dependent carboxylase. A second enzyme that recycles an inactive to an active form of the vitamin is inhibited by coumarins. The ability of other liver enzymes to bypass the coumarin-sensitive step greatly enhances the safety of 4-hydroxycoumarins.
Serum levels of bone gla protein (BGP) have been reported to increase with aging and hence to reflect an age-related increase in bone remodeling activity. To evaluate the relationship between aging and serum BGP levels in a study of longitudinal design, we measured BGP concentrations in 77 normal men at 6 month intervals over a 3 year period. Mean BGP levels at the onset (4.95 +/- 1.5 ng/ml) increased significantly during the study (p = 0.004), and the mean of individual BGP slopes was positive (0.38 +/- 0.6 ng/ml per year, p = 0.0001). The rate of change in BGP was not related to serum creatinine levels or dietary calcium intake.
Recent literature indicates that the vitamin K cycle plays a role in the calcification process, presumably via its intervention on gamma-carboxylation of the noncollagenous proteins of bone osteocalcin and matrix gamma-carboxyglutamic acid protein. The major clinical evidence of this interference is fetal bone defect caused by oral anticoagulants given to the mother during the first trimester of pregnancy. No bone abnormalities have been reported so far in adults receiving oral anticoagulants. We studied 56 women who had had cardiac valve replacement and who were given acenocoumarol as anticoagulant, and 61 age-matched women who were in the same New York Heart Association functional class but who were not taking anticoagulants. Osteocalcin serum levels were comparable between the two groups; bone density values measured at appendicular bone were significantly lower in patients taking acenocoumarol. No significant correlation was found between duration of treatment and bone density. Significant osteopenia was present in the women being treated with oral anticoagulants.
To determine whether vitamin K administration affects urinary calcium excretion in postmenopausal women.
Before- and after-trials with a 2-week treatment period.
Healthy postmenopausal women (55 to 75 years old) were recruited from the convents in and around Maastricht. Controls (25 to 40 years old) were healthy premenopausal volunteers.
Daily administration of 1 mg of vitamin K for 2 weeks.
Serum immunoreactive osteocalcin: hydroxylapatite binding (HAB) capacity of serum immunoreactive osteocalcin; excretion of calcium, hydroxyproline, and creatinine in the urine during the last 2 h of a 16-h fasting period.
In premenopausal women, no effect of vitamin K administration was seen. In the postmenopausal group, vitamin K induced increased serum immunoreactive osteocalcin concentration; normalization of the HAB capacity of serum immunoreactive osteocalcin (this marker was less than 50% that of the controls in the pretreatment samples); a decrease in urinary calcium excretion, notably in the "fast losers" of calcium; and a parallel decrease in urinary hydroxyproline excretion in the fast losers of calcium.
The serum immunoreactive osteocalcin level may vary with vitamin K status. This variance should be taken into consideration if osteocalcin is used as a marker for osteoblast activity. Vitamin K is one factor that may play a role in the loss of bone mass in postmenopausal osteoporosis.
Bone has high levels of two proteins which contain the vitamin K-dependent Ca2+ binding amino acid, gamma-carboxyglutamic acid (Gla). Bone Gla protein (BGP, osteocalcin) is a 49 residue water soluble protein and matrix Gla protein (MGP) is a 79 residue water insoluble protein. BGP is synthesized only by calcified tissues while MGP is synthesized by calcified tissues, cartilage, and all soft tissues tested. The synthesis of both proteins in osteoblastic cells is stimulated by 1,25(OH)2D3. Treatment of rats with the vitamin K antagonist Warfarin causes secretion of a non-gamma-carboxylated BGP which cannot bind to hydroxyapatite. Warfarin treatment reduces bone levels of BGP to 2% of normal, but does not appear to affect the structure of bone. The only abnormality seen in rats treated with Warfarin is the mineralization of several cartilages. The pattern of cartilage calcification is similar to that seen in the fetal Warfarin syndrome in humans, and may be due to abnormal synthesis of MGP.
The relationship between dietary phylloquinone, serum and liver concentrations of phylloquinone, and various indices of vitamin K adequacy have been studied in male rats fed a purified diet containing various levels of phylloquinone. In excess of 500 micrograms phylloquinone/kg diet was needed to prevent the most sensitive signs of vitamin K deficiency. Liver phylloquinone concentrations were shown to be correlated with dietary phylloquinone intake. Serum phylloquinone was not correlated with either diet or liver concentration of phylloquinone and did not increase with increased dietary intake until the liver contained sufficient vitamin to maintain optimal synthesis of vitamin K-dependent proteins. Because of the rapid loss of vitamin from the liver, prior ingestion of a high level of vitamin K had little influence on liver vitamin K concentrations beyond the first 2 d of a deficient period. When rats consumed a diet containing 500 micrograms phylloquinone/kg diet in 3 h, liver and serum phylloquinone concentrations fluctuated drastically following this feeding period. During the subsequent 24-h period, liver phylloquinone concentrations decreased to a level that would not support maximal activity of the hepatic vitamin K-dependent carboxylase.
We have used cDNA probes for two small vitamin K-dependent bone matrix proteins, bone Gla protein (BGP) and matrix Gla protein (MGP), to evaluate the possibility that either of these proteins might be synthesized by the various soft tissues previously shown to have gamma-carboxylase activity. BGP mRNA was found in bone but not in any of the soft tissues tested, a result which reinforces the view that plasma BGP is a specific marker for bone metabolism. In contrast, MGP mRNA was found in all rat tissues examined. Lung and heart have 10-fold higher levels of MGP mRNA than bone, and kidney has a 5-fold higher level. Despite the high levels of MGP mRNA in heart and kidney, these tissues contain 40-500-fold lower concentrations of MGP protein than bone. Immunofluorescence was used to identify cells that contain MGP in kidney, lung, heart, and spleen. In each tissue, MGP was found in discrete tissue-specific cell types. In most of the soft tissues tested, MGP is the first well characterized substrate for the vitamin K-dependent carboxylase found to be synthesized. The exceptionally broad tissue distribution for MGP synthesis demonstrates that the function of MGP is not specific to connective tissues, and the low levels of MGP antigen in soft tissues with high MGP mRNA levels indicate that MGP is unlikely to act solely by virtue of its accumulation in an extracellular matrix.
Vitamin D-deficient, second generation, rachitic rats showed significant decrease in bone Gla protein (BGP) levels in circulation and in the skeleton. 1,25 dehydroxyvitamin D3 (1,25(OH)2D3) exhibited the most potent influence on serum BGP levels in a dose-dependent manner. At a dose 25 ng/100 g body weight 1,25(OH)2D3 showed a cumulative effect, i.e., the longer the treatment, the more circulating BGP was detected. 24,25 dehydroxyvitamin D3 (24,25(OH)2D3) at the same doses did not show similar effect on the serum BGP levels, regardless of the serum calcium levels. Bone BGP levels assayed at various sites representing endochondral and intramembranous ossification demonstrated an opposite pattern. 1,25(OH)2D3 administration was not sufficient to restore bone BGP levels to normalcy, whereas in animals treated with 24,25(OH)2D3, bone BGP and calcium levels were significantly higher than control (Vitamin D3-repleted) levels. The present results can be explained by the dual action of 1,25(OH)2D3 on both synthesis and release of BGP by bone turnover, whereas 24,25(OH)2D3 stimulates synthesis and accumulation of BGP in bone. These observations imply that caution is required in the interpretation of clinical data based solely on serum BGP determination.
Osteocalcin (a vitamin K-dependent, bone-specific protein) is widely accepted as a marker of osteoblastic activity. The present study was conducted to determine if a vitamin K deficiency would affect fracture healing by virtue of an alteration in osteocalcin metabolism. Thirty male Sprague-Dawley rats were divided into two groups. The control group was fed a diet that was lacking in, but offered water replete with vitamin K. The experimental group was fed a vitamin K-deficient diet and was offered water that was lacking in vitamin K. After two weeks, vitamin K deficiency was established in the experimental group as shown by decreased urinary excretion of ycarboxyglutamic acid and an elevation of serum prothrombin times to between two to two and one-half times the control values. At this time, a standard, closed femoral fracture was produced. Six weeks later, the animals were killed. The bones were biomechanically tested in torsion. Subsequent to mechanical testing, the calluses were retrieved, and the osteocalcin content and the degree of gamma carboxylation of the osteocalcin in the calluses were measured. The results show that despite significant alterations in the gamma carboxylation of osteocalcin and elevation of prothrombin times to two to two and one-half times the control values, there were no differences in the mechanical properties of the calluses. Furthermore, there were no differences in the content or gamma carboxylation of osteocalcin in these calluses. Apparently, in vitamin K deficiency, fracture callus achieves normal mechanical properties and may have a mechanism for the gamma carboxylation of glutamic acids in osteocalcin despite a substantial depression of this activity in the rest of the body.
(C) Lippincott-Raven Publishers.
This is a report of an experimental system to study differentiation of bone-resorbing osteoclasts and demonstrates that osteocalcin, an extracellular bone-specific component, is necessary for the recruitment of osteoclast progenitor cells. The subcutaneous implantation of devitalized bone particles (BPs) elicits the recruitment and differentiation of osteoclasts that resorb the BPs. In a previous study, we showed by histomorphometric analysis that BPs that were deficient in osteocalcin were resorbed only 60% as well as normal BPs. In this study, the mechanism of this difference was investigated by measurements of recruitment, differentiation and activity of bone resorbing cells by normal and osteocalcin-deficient BP. Mononuclear cells were attracted to control BPs soon after implantation. In dramatic contrast, cellularity was depressed around osteocalcin-deficient BPs with very few mononuclear cells within the implant on day 5 (35% of control cellularity). In implants of normal BPs, tartrate-resistant acid phosphatase-positive multinucleated cells were evident by day 5; very few appeared in implants of osteocalcin-deplete BPs even by day 12. The amount of tartrate-resistant acid phosphatase activity in homogenates of the osteocalcin-deficient bone particle specimens not only lagged behind controls but never reached the maximum activity of control BP specimens. These data support the hypothesis that osteocalcin may function as a matrix signal in the recruitment and/or activation of cells for bone resorption.