Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K<Subscript>2</Subscript> in postmenopausal women

Alendronate decreases the risk of femoral neck fracture by suppressing bone turnover, and also decreases the serum total osteocalcin level. A low serum carboxylated osteocalcin level or high undercarboxylated osteocalcin level could be risk factors for femoral neck fracture. Vitamin K mediates the carboxylation of osteocalcin, but the effect of alendronate therapy with or without vitamin K₂ supplementation remains unknown. Forty-eight postmenopausal women were enrolled in a 1-year prospective randomized trial and assigned to alendronate monotherapy (5 mg/day) (group A, n = 26) or vitamin K₂ (45 mg/day) plus alendronate (5 mg/day) (group AK, n = 22). Bone mineral density was measured by dual-energy X-ray absorptiometry at 0 and 12 months; bone turnover parameters were measured at 0, 3, and 12 months. Four patients discontinued alendronate therapy, and we analyzed the remaining 44 patients (23 in group A and 21 in group AK) who completed 1 year of treatment. Alendronate decreased undercarboxylated osteocalcin; carboxylated osteocalcin was not affected. Addition of vitamin K₂ enhanced the decrease of undercarboxylated osteocalcin levels and led to a greater increase of femoral neck bone mineral density. Alendronate monotherapy does not decrease carboxylation of osteocalcin, and combination of vitamin K₂ and alendronate brings further benefits on both osteocalcin carboxylation and BMD of femoral neck in postmenopausal women with osteoporosis.     

Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women.

Osteocalcin, also called bone gla protein, is a unique noncollagenous protein of the extracellular matrix of bone that circulates in blood. Oseteocalcin contains three residues of the vitamin K-dependent gamma-carboxyglutamic acid (gla) responsible for the affinity of osteocalcin for bone mineral. In animals treated with the vitamin K antagonist warfarin, the osteocalcin content of bone is markedly reduced and the fraction of osteocalcin released into the circulation is increased. Most studies have shown that osteocalcin increases with aging in women, reflecting an increase in bone turnover, especially after the menopause. To determine if this increase in osteocalcin could be associated with impaired carboxylation, we measured total and noncarboxylated osteocalcin in the serum of 72 women of various ages: 22 premenopausal (31 +/- 7 years old), 20 early postmenopausal (54 +/- 3 years), and 30 elderly women (85 +/- 8 years). As previously reported, total serum osteocalcin was significantly increased in early postmenopausal and elderly women. Noncarboxylated serum osteocalcin was slightly increased in early postmenopausal women (0.95 +/- 0.4 versus 0.65 +/- 0.5 ng/ml in premenopausal women), markedly elevated in elderly women (1.59 +/- 1.1 ng/ml, p less than 0.001), and correlated with age (r = 0.47, p less than 0.001). Elderly women had values of the same magnitude as in 10 patients on chronic warfarin therapy (1.94 +/- 1.1 ng/ml). As a consequence, the increase in carboxylated serum osteocalcin was significant in early postmenopausal women but not in elderly women. Serum levels of vitamin K1 and of menaquinones 6, 7, and 8 were measured in some of the young and elderly women.(ABSTRACT TRUNCATED AT 250 WORDS)     

Short-Term Effect of Vitamin K Administration on Prednisolone-Induced Loss of Bone Mineral Density in Patients with Chronic Glomerulonephritis

Glucocorticoid-induced osteoporosis has been reported to be caused by enhanced bone resorption and suppressed bone formation. To clarify whether administration of vitamin K, which enhances bone formation, prevents prednisolone-induced loss of bone mineral density (BMD), a randomized, prospective, controlled study was conducted on 20 patients with chronic glomerulonephritis scheduled for treatment with prednisolone. All patients were initially treated with 0.8 mg/kg body weight/day of prednisolone (maximum of 40 mg) for 4 weeks, tapering to 20 mg/day over approximately 6 weeks. Ten patients received prednisolone alone (Group 1), and the other 10 patients received prednisolone plus 15 mg of menatetrenone, vitamin K, three times per day (Group 2). BMD of the lumbar spine measured by dual-energy X-ray absorptiometry (DXA) and biochemical markers of bone metabolism in blood and urine were evaluated before and 10 weeks after administration of prednisolone alone or with menatetrenone. In Group 1, treatment with prednisolone significantly reduced BMD of the lumbar spine from 1.14 ± 0.12 to 1.10 ± 0.11 g/cm² (P= 0.0029). Serum intact osteocalcin and procollagen type I C-peptide (PICP) concentrations, biochemical markers of bone formation, were markedly reduced. A biochemical marker of bone resorption, urinary excretion of deoxypyridinoline, was significantly reduced. In Group 2, prednisolone-induced reduction of BMD was prevented by menatetrenone administration (1.09 ± 0.09 to 1.07 ± 0.07 g/cm², P= 0.153). Menatetrenone prevented reduction of PICP concentration by prednisolone but not in serum intact osteocalcin concentration and urinary excretion of deoxypyridinoline. Thus, treatment with prednisolone resulted in loss of BMD of the lumbar spine associated with suppression of both bone formation and bone resorption. Menatetrenone is a useful agent in preventing prednisolone-induced loss of BMD. Received: 7 July 1998 / Accepted: 13 August 1999     

Evaluation of bone turnover in type I osteoporosis using biochemical markers specific for both bone formation and bone resorption

The aims of the study were to evaluate the use of bone-specific biochemical markers of turnover in type I osteoporosis, to test for evidence of heterogeneity of bone turnover in this condition, and to attempt to devise an uncoupling index by using the relationship between bone-specific biochemical markers of bone formation and bone resorption. In women with type I osteoporosis (mean age 64 years, SD 5;n=63) the mean level of serum osteocalcin, a specific biochemical marker of bone formation, was 9.9 ng/ml (SD 2.0), which was higher than the level in normal postmenopausal women (mean age 65 years, SD 6;n=8.9 ng/ml (SD 2.0;p<0.01). The variance of serum osteocalcin levels in the two groups was similar. Compared with this 11% increase in the biochemical marker for bone formation, the markers of bone resorption, total urinary deoxypyridinoline (bone-specific), pyridinoline and hydroxyproline were increased by 40% (p<0.0001), 61% (p<0.0001) and 25% (p<0.01), respectively. Furthermore, these biochemical markers of bone resorption had greater variance in women in type I osteoporosis than in the normal postmenopausal women (p<0.001). The urinary excretion of the free crosslinks deoxypyridinoline, pyridinoline and glycosylated pyridinoline were increased by 26% (p<0.001), 17% (p<0.01) and 13% (NS) respectively. An uncoupling index was calculated for the difference between urinary deoxypyridinoline and serum osteocalcin using the results from the normal women and expressed asz-scores. We conclude that the pyridinium crosslinks of collagen enable better discrimination between normal and osteoporotic women than does hydroxyproline. In osteoporosis there appears to be heterogeneity of bone resorption. Finally, an uncoupling index indicated that in osteoporosis bone resorption was increased to a greater extent than bone formation as compared with normal postmenopausal women.     

The Effect of Fluvastatin on Parameters of Bone Remodeling

Statins decrease the hepatic biosynthesis of cholesterol, and reduce the incidence of myocardial infarction in women who have already experienced a myocardial infarction. Statins also reduce the risk of atherosclerosis in diabetic patients, but it is unknown whether they influence the glucose tolerance. It has further been suggested that they may influence bone metabolism. Vitamin C is an antioxidant and it decreases serum cholesterol moderately. Antioxidants may also have other metabolic effects, but these are insufficiently studied. The aim of the present study was to investigate the metabolic effects of the cholesterol-lowering agent fluvastatin and the antioxidant vitamin C. Sixty-eight elderly, postmenopausal women with osteoporosis and mild hypercholesterolemia were randomly assigned to 12 weeks open treatment with either fluvastatin (40 mg daily) + 500 mg vitamin C (n = 45) or vitamin C only (n = 23). We measured biochemical markers of bone formation (serum osteocalcin and total alkaline phosphatase) and bone resorption (serum and urinary CTX), parameters related to diabetes and serum lipids and lipoproteins. Fluvastatin in combination with vitamin C had no effect on bone formation markers. We found a weak decrease in parameters of bone resorption, which was significant from baseline, but not different between the two groups. There were no significant effects on any of the other markers of either fluvastatin or vitamin C. The lipid-lowering effect of fluvastatin was confirmed with a decrease of 20% and 30% in serum total cholesterol and LDL-cholesterol, respectively. We conclude that fluvastatin given in clinically relevant doses has no influence on parameters of bone remodeling. Other statins remain to be investigated. Received: 6 June 2000 / Accepted: 4 December 2000     

The effect of vitamin K2 on bone metabolism in aged female rats

Reactive oxygen species (ROS) may contribute to aging and osteoporosis resulting from marked decreases in plasma antioxidants in aged osteoporotic women. On the other hand, high-dose vitamin K₂ (menaquinone-4: menatrenone, MK-4) supplementation has been reported to reduce ovariectomy-induced bone loss in rats and to decrease osteoporotic fracture in postmenopausal women. However, the mechanism by which vitamin K₂ prevents osteoporosis is unclear. Recently, vitamin K₂ has been suggested to preserve antioxidant activity as a novel function. Therefore, we investigated the effect of vitamin K₂ on the osteoporosis of aged rats by evaluating the relationships between serum antioxidant levels and bone metabolism. Aged female rats exhibited significantly lower serum alkaline phosphatase activity and osteocalcin level, together with lower serum levels of antioxidants such as 17-estradiol, macrophage migration inhibitory factor (MIF) and glutathione peroxidase (GPx) activity, as compared with young female rats. On the other hand, vitamin K₂ supplementation (500 mg/kg, food intake) for 98 days led to a significantly increased serum vitamin K₂ level (3,045±915 ng/ml in the vitamin K₂ supplemented group vs. 4.6±3.4 ng/ml in the control diet group; P <0.0001) with increased serum alkaline phosphatase activity and MIF level ( P <0.05). Unexpectedly, however, it failed to increase the serum level of antioxidants such as GPx. Nor did it affect bone metabolism markers such as oteocalcin and osteopontin, which were significantly lower than in the young female rats ( P <0.05). Finally, the histomorphometric properties of the proximal tibia in the femur were not altered by vitamin K₂. These results suggest that high-dose vitamin K₂ supplementation neither improves lowered antioxidant levels nor stimulates bone formation in aged rats.     

Carboxylated and intact osteocalcin predict adiponectin concentration in hemodialyzed patients

Purpose Disrupted bone metabolism in patients with chronic kidney disease (CKD) is associated with elevated concentrations of biochemical bone markers. Recently, animal studies show the role of osteocalcin in energy metabolism, which is partially confirmed in humans. The aim of our study was to evaluate the relationships between serum concentrations of bone markers and indices of energy metabolism in CKD patients on maintenance hemodialysis; in particular, the relationship between various forms of osteocalcin and adiponectin. Patients and methods The cross-sectional study included 155 hemodialyzed stage 5 CKD patients. Serum concentrations of glucose, insulin, adiponectin, bone alkaline phosphatase (bALP), tartrate resistant acid phosphatase (TRAP), carboxylated (cOC), undercarboxylated (ucOC), and intact osteocalcin (OC) were determined. Results In total cohort, bALP, TRAP, cOC, and ucOC negatively correlated with BMI. All analyzed bone markers positively correlated with adiponectin in total cohort and in men. In multiple linear regression analysis including all patients, log(cOC) and log(intact OC) were the only bone markers that predicted log(adiponectin) (beta?=?0.22; p?=?0.016 and beta?=?0.26; p?=?0.010) independently of sex, dialysis vintage, CRP, insulin, iPTH concentrations, BMI, and age. Conclusions Our data confirm the positive association between cOC, intact OC, and adiponectin concentrations in CKD patients on maintenance hemodialysis.     

Comparative study of quantitative ultrasonography and dual-energy X-ray absorptiometry for evaluating renal osteodystrophy in children with chronic kidney disease

Our aim was to assess bone parameters in children with chronic kidney disease (CKD) with both dual-energy X-ray absorptiometry (DXA) and quantitative ultrasonography (QUS) and additionally with biochemical markers of bone turnover. Twenty children (12 boys and 8 girls) with CKD and a mean decimal age of 9.47 ± 4.44 years were included in the study where anthropometric parameters (height and weight), pubertal status, bone mineral density (BMD) at lumbar spine, speed of sound (SOS) measured by QUS at radius and at tibia, and biochemical markers of bone metabolism were measured. Six patients (30%) had tibial SOS Z score <−1, and 52.7% had radial SOS Z score <−1, whereas only 16.67% had BMD Z score <−1. Patients had significantly increased levels of serum intact parathormone (p < 0.001), serum bone alkaline phosphatase (BAP) (p < 0.001) and serum N-terminal-mid fragment (aminoacids 1-43) of osteocalcin (p < 0.001) compared to controls, whereas serum osteoprotegerin was significantly decreased in patients compared to controls (p = 0.001). SOS was significantly correlated to BAP (r = −0.586, p = 0.013 and r = −0.709, p = 0.001, respectively, for radius and tibia). In conclusion no association between DXA and QUS measurements was documented in our study, whereas QUS was better correlated to biochemical indices of ROD.     

Undercarboxylated osteocalcin and bone mass in 8–12 year old children with cystic fibrosis

Young adults with cystic fibrosis (CF) frequently develop bone disease. One suggested aetiological factor is suboptimal vitamin K status with impaired carboxylation of osteocalcin and abnormal bone formation. METHODS: We measured bone mineralization and turnover in thirty-two 8-12 year old CF patients (14 boys) using Dual Energy X-ray absorptiometry (whole body (WB) and lumbar spine (LS)), 25-OH Vitamin D, PTH and markers of bone formation (plasma osteocalcin, N-terminal pro-peptide of type 1 collagen (P1NP)), plus an indirect measure of vitamin K status, undercarboxylated osteocalcin (uc-OC). RESULTS: LS bone mineral density (BMD) standard deviation (SD) scores were < -1.0 in 20% of subjects. Size-adjusted LS and WB bone mass was normal. Compared to reference data, % uc-OC was high and P1NP low. LS bone mass was predicted by % uc-OC but not other markers (0.4% decrease in size-adjusted LSBMC (p=0.05); 0.04 SD decrease in LSBMAD (p=0.04) per 1% increase in uc-OC). CONCLUSION: Markers suggestive of sub-optimal vitamin K status and low bone formation were present despite normal size-adjusted bone mass. The association between LSBMC and % uc-OC is consistent with the hypothesis that sub-optimal vitamin K status is a risk factor for CF bone disease. This should ideally be investigated in an intervention trial.     

Effect of Soy Protein on Bone Metabolism in Postmenopausal Japanese Women

We conducted a cross-sectional study of the effects of soybean protein intake on bone mineral density and biochemical markers in 85 postmenopausal Japanese women. Nutrients in the diet of postmenopausal Japanese women visiting the osteoporosis unit, including subjects with normal lumbar spine bone mineral density (L2–4 BMD), were investigated by questionnaire, and the calculated daily energy, protein, soy protein and calcium intake were obtained. L2–4 BMD was measured with dual-energy X-ray absorptiometry, and assays done of serum alkaline phosphatase (ALP) and serum intact osteocalcin (IOC) as bone formation markers and urinary pyridinoline (UPYR) and urinary deoxypyridinoline (UDPYR) as bone resorption markers. Soy protein intake was significantly associated with the Z-score for L2–4 BMD (r= 0.23, p = 0.038) and UDPYR (r =−0.23, p = 0.034). Stepwise multiple regression analyses showed that soy protein intake is significantly associated with the Z-score for L2–4 BMD (β= 0.225, p = 0.04) and UDPYR (β=−0.08, p = 0.03) among four nutritional factors. These results suggest that high soy protein intake is associated with a higher bone mineral density and a lower level of bone resorption, but further studies are needed to confirm the causal dynamic mechanisms. Received: 17 September 1999 / Accepted: 29 February 2000     

Short-term menatetrenone therapy increases gamma-carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis: a randomized prospective study

The effect of vitamin K₂ (menatetrenone) on bone turnover was investigated in postmenopausal patients with osteoporosis. A 6-month open-label, randomized prospective study was conducted in 109 patients. The control group (n = 53) received calcium aspartate (133.8 mg of elemental calcium daily), while the menatetrenone group (n = 56) received 45 mg of menatetrenone daily for 6 months. Serum and urinary levels of bone turnover markers were monitored. The serum level of undercarboxylated osteocalcin (uc-OC) was significantly lower (P < 0.001) in the menatetrenone group than in the control group (at 1 month), while there was a higher level of osteocalcin containing gamma-carboxylated glutamic acid (Gla-OC) in the menatetrenone group than the control group (P = 0.018). Significant differences of uc-OC and Gla-OC between the two groups were observed from 1 month onward. In addition, a higher level of intact osteocalcin was found in the menatetrenone group compared with the control group after 6 months (P = 0.006). Assessment of bone resorption markers showed that menatetrenone therapy was associated with significantly higher urinary N-telopeptide of type I collagen (NTX) excretion compared with the control group after 6 months, while there was no significant difference of urinary deoxypyridinoline excretion between the two groups. In conclusion, one month of menatetrenone therapy enhanced the secretion and gamma-carboxylation of osteocalcin, while urinary NTX excretion was increased after 6 months of treatment. Further investigations are required to determine whether the effects of menatetrenone on bone turnover are associated with fracture prevention.     

Physical Fitness,Adiposity, and Diets as Surrogate Measures of Bone Health in Schoolchildren: A Biochemical and Cross-Sectional Survey Analysis

This study aimed to investigate the associations between adiposity, muscular fitness (MF), diet, sun exposure, and physical activity profiles as surrogate measures with bone health status in a sample of schoolchildren aged 8–18?yr old. A total of 250 Egyptian schoolchildren aged 8–18?yr were randomly invited to participate in these cross-sectional survey analyses. Calcaneal broadband ultrasound attenuation (c-BUA), bone mineral density (BMD), and bone formation markers (total calcium, serum bone alkaline phosphatase, and osteocalcin) were measured as markers of bone health. Adiposity profile, MF, physical activity (PA), sun exposure, Ca, and vitamin D dietary intake as related cofactors of bone health were measured by using prevalidated questionnaires and standard analytical techniques. A total of 85% (n?=?213) of the study population showed normal bone health and 14.8% (n?=?37) had abnormal bone health; most of them are girls (67.6%) classified according to BMD and c-BUA Z-scores into osteopenia (9.6%) and osteoporosis (5.2%). Compared with boys, higher correlations between c-BUA, bone mineral content, and BMD measures in the femoral neck, lumbar spine, whole body, and bone markers were reported in girls with lower bone mass. There was a positive significant correlation between body mass index, adiposity, sun exposure, MF, PA status, Ca and vitamin D intake, and c-BUA and BMD score analyses. These parameters were shown to be associated with about ~57.3%–88.4% of bone health characteristics of children and adolescents with osteopenia and osteoporosis. In children and adolescents, sun exposure, Ca and vitamin D diets, adiposity, PA, and changes in the levels of Ca, osteocalcin, and serum bone alkaline phosphatase were shown to be associated with bone health. Also, a significant correlation was reported between c-BUA score, dual-energy X-ray absorptiometry-BMD measures, and bone markers at clinically important bone sites of girls and boys. However, further clinical trials should be studied to consider c-BUA and bone markers as the benchmark estimates of bone mass for diagnostic purposes in young ages.     

Low serum levels of intact osteocalcin in patients with congestive heart failure

 Impaired bone metabolism is a frequent complication following heart transplantation. Little is known, however, about possible alterations in bone turnover of pretransplant patients with congestive heart failure (CHF). We therefore studied biomarkers of bone turnover in 21 male patients with CHF (New York Heart Association [NYHA] classification > II) compared with 21 controls (NYHA classification < II). Biomarkers of bone formation (intact osteocalcin and carboxy-terminal propeptide of type I collagen), markers of bone resorption (N-telopeptide and C-telopeptide of type I collagen), undercarboxylated osteocalcin (an indicator of fracture risk), and concentrations of calcium, parathyroid hormone, and vitamin D metabolites (25-hydroxyvitamin D and calcitriol) were measured in fasting blood samples. Serum levels of intact osteocalcin were 44.5% lower (P < 0.01), and the ratio of undercarboxylated-to-intact osteocalcin was 113% higher (P < 0.01) in the patients in comparison with the controls. Moreover, patients had 34% lower 25-hydroxyvitamin D levels (P < 0.01) and 22% lower calcitriol levels (P < 0.05) than the controls. The bone resorption markers, N-telopeptide and C-telopeptide; the bone formation marker, carboxy-terminal propeptide of type I collagen; parathyroid hormone levels; and albumin-adjusted serum calcium concentrations did not differ between patients and controls (all P values > 0.05). In summary, there were no biochemical signs of enhanced bone collagen resorption in pretransplant CHF patients. However, the low serum levels of intact osteocalcin and the high ratio of undercarboxylated-to-intact osteocalcin deserve further consideration. Received: September 13, 2002 / Accepted: January 27, 2003 RID="*" ID="*" Offprint requests to: A. Zittermann Acknowledgments. This study was supported by the Pinguin Foundation, Düsseldorf, Germany.     

Effects of vitamin K2 in hemodialysis patients with low serum parathyroid hormone levels

In patients with adynamic bone disease, the bone contains few osteoblasts or osteoclasts and bone turnover is slow, so the risk of fracture is increased. The decrease of bone remodeling may also decrease the capacity of bone to buffer calcium, leading to an increase of the calcium x phosphate product and an increased risk of arterial calcification. Such findings emphasize that an effective treatment for adynamic bone disease is required. The present study investigated the influence of vitamin K2 (menatetrenone) on hemodialysis patients with low serum parathyroid hormone levels by using bone metabolism markers. The subjects were 32 hemodialysis patients (19 men and 13 women) aged from 27 to 76 years with an intact parathyroid hormone (PTH) level of less than 65 pg/ml and an intact osteocalcin level below 20 ng/ml. All patients received oral menatetrenone therapy (45 mg/day) for 12 months. To obtain control data on bone metabolism markers in hemodialysis patients with normal bone turnover, we selected 50 patients who had intact PTH levels within the range that maintains relatively normal bone turnover, that is, from 120 to 250 pg/ml. The baseline levels of all bone metabolism markers were significantly lower in our patients than in the normal PTH control group. There was a significant increase of gamma-carboxyglutamate (Gla) osteocalcin, bone alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase (TRACP), and cross-linked N-terminal telopeptide of type 1 collagen (NTx) levels after vitamin K2 administration. Type 1 procollagen carboxyterminal propeptide (P1CP) and intact osteocalcin both showed a significant increase after 12 months of treatment. Although there was no significant change of the alkaline phosphatase (ALP) level during the 12 months before the start of vitamin K2 therapy, there was a significant increase of alkaline phosphatase after vitamin K2 administration. Adjusted calcium, serum phosphate, and intact PTH showed no significant changes throughout the study. These changes of bone metabolism markers suggested that vitamin K2 therapy can improve bone remodeling in hemodialysis patients with low serum PTH levels.     

Dietary vitamin K intake is associated with bone quantitative ultrasound measurements but not with bone peripheral biochemical markers in elderly men and women

BackgroundVitamin K may have a protective role against bone loss and osteoporotic fractures associated to aging, although data in humans are inconsistent and the mechanisms involved are still unknown. The main objective of the study was to assess the associations between vitamin K intake, bone density, bone structure quality and biochemical bone metabolism markers in elderly subjects. We also analyzed the relationship between changes in vitamin K intake and the evolution of bone quality markers after two years of follow-up.MethodsCross-sectional analysis was carried out on 365 elderly subjects, 200 of whom were also included in a 2-year longitudinal follow-up study. Usual dietary intakes were assessed using a semi-quantitative 137-item food frequency questionnaire (FFQ). Vitamin K intake was estimated using the USDA database. Bone biochemical markers were measured in a subset of 125 subjects. Quantitative ultrasound assessment (QUS) was performed at the calcaneus to estimate bone mineral density (BMD), speed of sound (SOS), broadband ultrasound attenuation (BUA) and the quantitative ultrasound index (QUI).ResultsDietary intake of vitamin K was significantly associated with higher BMD and better QUS. No significant associations were found between vitamin K intake and bone biochemical markers. Those subjects who increased their vitamin K intake showed a lower loss of BMD, a lower decrease in SOS and a nonsignificant increase in BUA.ConclusionsHigh dietary vitamin K intake was associated with superior bone properties. Moreover, an increase in dietary vitamin K was significantly related to lower losses of bone mineral density and smaller increases in the porosity and elasticity attributed to aging, which helps to explain the previously described protective effect of vitamin K intake against osteoporotic fractures.     

Vitamin K Status and Bone Mass in Women With and Without Aortic Atherosclerosis: A Population-Based Study

Gammacarboxyglutamate (Gla) is an uncommon amino acid formed by vitamin K action. Increasing evidence indicates that Gla-proteins are involved in the regulation of calcification processes in both bone tissue and atherosclerotic vessel wall. In a population-based study we have previously shown that in a group of 113 postmenopausal women the presence of abdominal aortic calcifications is associated with a reduced vitamin K status. In the present study we investigated whether this reduced vitamin K status was also associated with differences in bone mass or circulating calciotropic hormone levels. Serum immunoreactive osteocalcin with low affinity for hydroxyapatite (irOC_free) was used as a marker for vitamin K status. After correction for age it was found that women with atherosclerotic calcifications had a 7% lower bone mass as measured by metacarpal radiogrammetry (mean difference: 3.2 mm², 95% CI: −0.2–6.5, P= 0.06). No differences between both groups of women were observed for serum intact parathyroid hormone (PTH) and serum 25-hydroxyvitamin D levels. In the atherosclerotic women (n = 34), markers for vitamin K status were inversely associated with bone mass (r =−0.47, P= 0.013), whereas no such association was found in the nonatherosclerotic women (n = 79). It is concluded that the atherosclerotic women in this study may be at higher risk for osteoporotic fractures as evidenced by their lower bone mass and higher serum irOC_free levels. The finding that in atherosclerotic women vitamin K status is associated with bone mass supports our hypothesis that vitamin K status affects the mineralization processes in both bone and in atherosclerotic plaques. Received: 15 January 1996 / Accepted: 3 May 1996     

Dietary phylloquinone depletion and repletion in postmenopausal women: effects on bone and mineral metabolism

Introduction Vitamin K has been implicated in increased bone fracture risk. Despite a potential role of vitamin K in bone, little is known about the effects of altered dietary phylloquinone intake on the underlying components of bone and mineral metabolism. Methods A 84-day in-house dietary phylloquinone (vitamin K) depletion–repletion study was undertaken in 21 postmenopausal women (mean age: 70 years) to assess the effects of altered vitamin K status on intestinal calcium (Ca) absorption, urinary and serum Ca and phosphorus (P), serum calcemic hormones, and serum biomarkers of bone turnover [osteocalcin and N-telopeptide type 1 collagen cross-links (NTx)] and the response to 1,25-dihydroxyvitamin D treatment (1 μg/day×7 d). Results The group receiving calcitriol treatment (n=11) had higher Ca absorption, urinary Ca, urinary and serum P and serum osteocalcin and lower serum parathyroid hormone (PTH).There were no significant effects of acute (4-week) phylloquinone depletion on response to 1,25-dihydroxyvitamin D treatment or on measures of bone formation or mineral metabolism. However, phylloquinone treatment had a significant effect (p<0.04) on serum NTx. Phylloquinone repletion, up to five times (450 μg phylloquinone per day) the currently recommended adequate intake level of dietary phylloquinone for women, significantly reduced serum NTx (16.8±0.9 nmol bone collagen equivalents (BCE) per liter following repletion vs 18.4±1.1 nmol BCE per liter following depletion; p< 0.01). Conclusions These findings suggest that altering vitamin K status in postmenopausal women by manipulating phylloquinone intake does not have an acute affect on intestinal Ca absorption, renal mineral excretion, or bone formation, but high phylloquinone intake may modestly reduce bone resorption. The impact of high phylloquinone intake on bone mineral density and fracture risk needs to be ascertained in randomized clinical trials.     

Mineral density and bone remodelling markers in patients with calcium lithiasis

Study Type – Aetiology (case control) Level of Evidence 3b What’s known on the subject? and What does the study add? Hypercalciuria is related with bone mineral density loss. This study demonstrates the relationship between recurrent calcium nephrolithiasis and bone mineral density loss and their correlation with bone markers.

OBJECTIVES

? To show that a relationship exists between the loss of bone mineral density (BMD) and calcium renal lithiasis and that bone remodelling markers correlate with changes in BMD. ? It is possible that many cases hypercalciuria are related to the increase of bone turnover and the predominance of bone resorption phenomena.

PATIENTS AND METHODS

? The present study comprised a transversal investigation in three groups: group O, without lithiasis; group A, with a single episode of lithiasis; and group B, with relapsed calcium renal lithiasis. ? An analysis was made of body mass index; abdominal X‐ray and/or urography and renal ultrasonography; osteocalcin and β‐crosslaps bone markers; calcium and citrate concentrations in the urine; and femur and spinal column bone densitometry. ? The results were analyzed by analysis of variance and Pearson’s correlation coefficient.

RESULTS

? Patients with relapsed calcium renal lithiasis present a greater BMD loss than those in the O or A groups. ? Densitometry: T‐score femur ?0.2 group O, ?0.5 group A, ?1.2 group B (P= 0.001); T‐score column ?0.6 group O, ?0.6 group A, ?1.3 group B (P= 0.05). ? A statistically significant negative correlation exists between values of β‐crosslaps and T‐score femur (R=?0.251; P= 0.009) and T‐score column (R=?0.324; P= 0.001); thus, a higher concentration of β‐crosslaps was accompanied by a lower value of the T‐score and a greater loss of BMD. ? A positive relationship is observed between β‐crosslaps and osteocalcin (R= 0.611; P < 0.001) and between calciuria and cocient β‐crosslaps/osteocalcin (R= 0.303; P= 0.001).

CONCLUSIONS

? A statistically significant relationship is shown between the loss of BMD and relapsed calcium renal lithiasis. ? Determination of bone remodelling markers (i.e. osteocalcin and β‐crosslaps) facilitates the diagnosis of osteopaenia/osteoporosis in these patients.     

Serum bone gla protein (BGP) and other markers of bone mineral metabolism in postmenopausal osteoporosis

Summary Bone gla protein, the vitamin K-dependent protein synthesized by osteoblasts and measured in blood by radioimmunoassay, has been used as an index of the rate of bone turnover. The relationship of bone gla protein with other markers of bone mineral metabolism was determined in 31 untreated postmenopausal women with the osteoporotic syndrome. In addition to serum osteocalcin (BGP) we measured parathyroid hormone (PTH) (carboxyl and mid-molecule fragments), 25(OH)D, alkaline phosphatase, estradiol (E₂), estrone (E₁), dietary calcium intake, 24 hour urinary calcium excretion, and bone mineral density by CT scan of the lumbar vertebrae. Significant osteopenia was present on CT in untreated postmenopausal osteoporotic women (bone density in 18 out of 31 was below the critical value of 60 mg/cm³). Serum BGP correlated positively with CT scan (r+0.647,P<0.001). CT and age were negatively correlated (r−0.661,P<0.001) while CT and E₂ showed a positive correlation (r+0.554,P<0.01). Unexpectedly, BGP and age revealed a significant negative correlation (r−0.421,P<0.05). These findings suggest a state of low bone turnover in this group with untreated postmenopausal osteoporosis.     

Vitamin K2 inhibits glucocorticoid-induced bone loss partly by preventing the reduction of osteoprotegerin (OPG)

We have recently demonstrated that glucocorticoid (GC) suppresses bone formation and enhances bone resorption, with resultant bone loss. This altered bone turnover is not due to the action of parathyroid hormone (PTH), but appears to be related to the suppression of osteoprotegerin (OPG). As vitamin K2 (menatetrenone) has been used for the treatment of osteoporosis, the present study was carried out to evaluate the effect of vitamin K2 on GC-induced bone loss. Twenty patients with chronic glomerulonephritis treated with GC for the first time were chosen for this study. Ten patients received GC alone (group A) and the other 10 patients each received 15 mg of vitamin K2 per day in addition to GC (group B). Markers of bone metabolism, including serum OPG, osteocalcin (OC), bone-specific alkaline phosphatase activity (BAP), PTH, tartrate-resistant acid phosphatase (TRAP), and bone mineral density (BMD), were measured before and during the treatment. OPG was significantly decreased in group A (P < 0.001), while no significant change was seen in group B. TRAP was markedly increased in both groups, more particularly in group A (P < 0.01). PTH was decreased in group A, but was increased in group B. OC was decreased at month 1 but subsequently increased until month 12 in both groups. BAP had decreased at month 3 in group A (P < 0.05), but not in group B. BMD of the lumbar spine was significantly reduced after 6 months (P < 0.01), and 12 months (P < 0.001) of treatment in group A, whereas there was no remarkable change in group B. The present study demonstrated that the inhibition exerted by vitamin K2 of the reduction in OPG induced by GC may, at least in part, play a role in the prevention and treatment of GC-induced bone loss.