Vitamin K<Subscript>2</Subscript> supplementation improves hip bone geometry and bone strength indices in postmenopausal women

Summary Vitamin K mediates the synthesis of proteins regulating bone metabolism. We have tested whether high vitamin K₂ intake promotes bone mineral density and bone strength. Results showed that K₂ improved BMC and femoral neck width, but not DXA-BMD. Hence high vitamin K₂ intake may contribute to preventing postmenopausal bone loss. Introduction Vitamin K is involved in the synthesis of several proteins in bone. The importance of K vitamins for optimal bone health has been suggested by population-based studies, but intervention studies with DXA-BMD as a clinical endpoint have shown contradicting results. Unlike BMC, DXA-BMD does not take into account the geometry (size, thickness) of bone, which has an independent contribution to bone strength and fracture risk. Here we have tested whether BMC and femoral neck width are affected by high vitamin K intake. Methods A randomized clinical intervention study among 325 postmenopausal women receiving either placebo or 45 mg/day of vitamin K₂ (MK-4, menatetrenone) during three years. BMC and hip geometry were assessed by DXA. Bone strength indices were calculated from DXA-BMD, femoral neck width (FNW) and hip axis length (HAL). Results K₂ did not affect the DXA-BMD, but BMC and the FNW had increased relative to placebo. In the K₂-treated group hip bone strength remained unchanged during the 3-year intervention period, whereas in the placebo group bone strength decreased significantly. Conclusions Vitamin K₂ helps maintaining bone strength at the site of the femoral neck in postmenopausal women by improving BMC and FNW, whereas it has little effect on DXA-BMD.     

Vitamin K1 Supplementation Retards Bone Loss in Postmenopausal Women Between 50 and 60 Years of Age

Although several observational studies have demonstrated an association between vitamin K status and bone mineral density (BMD) in postmenopausal women, no placebo-controlled intervention trials of the effect of vitamin K₁ supplementation on bone loss have been reported thus far. In the trial presented here we have investigated the potential complementary effect of vitamin K₁ (1 mg/day) and a mineral + vitamin D supplement (8 µg/day) on postmenopausal bone loss. The design of our study was a randomized, double-blind, placebo-controlled intervention study; 181 healthy postmenopausal women between 50 and 60 years old were recruited, 155 of whom completed the study. During the 3-year treatment period, participants received a daily supplement containing either placebo, or calcium, magnesium, zinc, and vitamin D (MD group), or the same formulation with additional vitamin K₁ (MDK group). The main outcome was the change in BMD of the femoral neck and lumbar spine after 3 years, as measured by DXA. The group receiving the supplement containing additional vitamin K₁ showed reduced bone loss of the femoral neck: after 3 years the difference between the MDK and the placebo group was 1.7% (95% Cl: 0.35–3.44) and that between the MDK and MD group was 1.3% (95% Cl: 0.10–3.41). No significant differences were observed among the three groups with respect to change of BMD at the site of the lumbar spine. If co-administered with minerals and vitamin D, vitamin K₁ may substantially contribute to reducing postmenopausal bone loss at the site of the femoral neck.     

Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K

Vitamin K is essential for the carboxylation of glutamic acid residues, such as osteocalcin. Recent studies have reported that vitamin K reduces vertebral and hip fractures without increasing bone mass in patients with osteoporosis, suggesting that vitamin K could affect bone quality. However, the mechanism is unknown. To investigate the involvement of the carboxylation of osteocalcin in bone quality, the present preliminary study examined serum bone markers and ultrasound velocity, a possible indicator of bone quality, in 14 healthy prepubertal children (eight boys and six girls) aged between 7 and 12 years. Venous blood was collected between 0800 and 0900 h after an overnight fast, and serum levels of intact, carboxylated and undercarboxylated osteocalcin, bone-specific alkaline phosphatase and type I procollagen carboxyl extension peptide were measured. Speed of sound in the right tibia was measured using a SoundScan 2000 Compact (Myriad Ultrasound System, Rehovot, Israel). As a result, there was no significant correlation between the serum bone markers and the Z score for the speed of sound. In contrast, the ratio of serum carboxylated osteocalcin to serum intact osteocalcin was positively correlated with the Z score for the speed of sound (r = 0.621, P = 0.016). These findings suggest, for the first time, that carboxylation of osteocalcin is related to bone quality. Further studies are needed to clarify the role of carboxylation of osteocalcin in bone, and this will provide a new insight into the mechanism of vitamin K treatment in osteoporosis. Received: September 9, 2000 / Accepted: November 30, 2000     

Alendronate treatment results in similar levels of trabecular bone remodeling in the femoral neck and vertebra

Summary  We aimed to determine whether trabecular bone in sites that have different surface-based remodeling rates, the femoral neck and vertebra, are differently affected by alendronate treatment. Alendronate treatment resulted in similar levels of turnover in both sites, suggesting that a lower limit of bone turnover suppression with alendronate may exist. Introduction  Bone turnover suppression in sites that already have a low surface-based remodeling rate may lead to oversuppression that could have negative effects on the biomechanical properties of bone. The goal was to determine how alendronate suppresses bone turnover at sites with different surface-based remodeling rates. Methods  Dynamic histomorphometric parameters were assessed in trabecular bone of the femoral neck and lumbar vertebrae obtained from skeletally mature beagles treated with saline (1 ml/kg/day) or alendronate (ALN 0.2 or 1.0 mg/kg/day). The ALN0.2 and ALN1.0 doses approximate, on a milligram per kilogram basis, the clinical doses used for the treatment of postmenopausal osteoporosis and Paget’s disease, respectively. Results  Alendronate treatment resulted in similar absolute levels of bone turnover in the femoral neck and vertebrae, although the femoral neck had 33% lower pre-treatment surface-based remodeling rate than the vertebra (p < 0.05). Additionally, the high dose of alendronate (ALN 1.0) suppressed bone turnover to similar absolute levels as the low dose of alendronate (ALN 0.2) in both sites. Conclusions  Alendronate treatment may result in a lower limit of trabecular bone turnover suppression, suggesting that sites of low pre-treatment remodeling rate are not more susceptible to oversuppression than those of high pre-treatment remodeling rate.     

No effect of vitamin K1 intake on bone mineral density and fracture risk in perimenopausal women

Introduction Vitamin K functions as a co-factor in the post-translational carboxylation of several bone proteins, including osteocalcin.Aim The aim of this study was to investigate the relationship between vitamin K₁ intake and bone mineral density (BMD) and fracture risk in a perimenopausal Danish population.Design The study was performed within the Danish Osteoporosis Prevention Study (DOPS), including a population-based cohort of 2,016 perimenopausal women. During the study approximately 50% of the women received hormone replacement therapy (HRT). Associations between vitamin K₁ intake and BMD were assessed at baseline and after 5-years of follow-up (cross-sectional design). Moreover, associations between vitamin K₁ intake and 5-year and 10-year changes in BMD were studied (follow-up design). Finally, fracture risk was assessed in relation to vitamin K₁ intake (nested case–control design).Results In our cohort, dietary vitamin K₁ intake (60 μg/day) was close to the daily intake recommended by the Food and Agriculture Organization (FAO). Cross-sectional and longitudinal analyses showed no associations between intake of vitamin K₁ and BMD of the femoral neck or lumbar spine. Neither did BMD differ between those 5% that had the highest vitamin K₁ intake and those 5% that had the lowest. During the 10-years of follow-up, 360 subjects sustained a fracture (cases). In a comparison between the cases and 1,440 controls, logistic regression analyses revealed no difference in vitamin K₁ intake between cases and controls.Conclusion In a group of perimenopausal and early postmenopausal women, vitamin K₁ intake was not associated with effects on BMD or fracture risk.     

Diurnal Variation in Total and Undercarboxylated Osteocalcin: Influence of Increased Dietary Phylloquinone

A diurnal variation exists in blood levels of the vitamin K-dependent bone protein osteocalcin. However, it is not known whether the carboxylated and undercarboxylated constituents of osteocalcin also vary. Therefore, osteocalcin and undercarboxylated osteocalcin were measured in specimens collected every 4 hours over a 24-hour period in nine healthy subjects (five males, four females) ages 20–33 years who were consuming a mixed diet containing 100 μg of phylloquinone. Osteocalcin and undercarboxylated osteocalcin were measured by radioimmunoassay (RIA) before and after treatment with barium sulfate. Although the percent undercarboxylated osteocalcin did not change, a diurnal variation was observed in total osteocalcin, carboxylated osteocalcin, and undercarboxylated osteocalcin, with peak concentrations at 4 a.m. and the lowest concentrations between 12 p.m. and 4 p.m. The difference between the total osteocalcin peak and trough concentrations averaged 28 ± 7 (SEM)%. There were no gender differences in these rhythms. The effect of dietary phylloquinone as a modulator of these rhythms was evaluated in a randomized study by increasing phylloquinone intake to 420 μg/day with fortified corn oil, split between the lunch and dinner meals. Total and carboxylated osteocalcin fluctuations and concentrations were not affected by the dietary treatment. The diurnal variation in undercarboxylated osteocalcin was abolished with supplementation and concentrations at 8 a.m. (14 hours following supplementation) (2.3 ± 0.2 ng/ml) were significantly lower than the unsupplemented levels (2.7 ± 0.2 ng/mL, P= 0.006). The percentage of undercarboxylated osteocalcin was similarly decreased after supplementation (19.7 ± 1.3%) in relation to the mixed diet cycle (24.2 ± 1.6%, P= 0.006) at 8 a.m. on the second day. Dietary supplementation induced a fluctuation in percentage undercarboxylated osteocalcin with a decline in levels starting at approximately 12 a.m. Therefore, additional dietary phylloquinone does not appear to modulate the total osteocalcin diurnal rhythm, but can influence its undercarboxylated component. Received: 14 June 1996 / Accepted: 22 August 1997     

Alendronate preserves femoral head shape and height/length ratios in an experimental rat model: A computer-assisted analysis

Background:

Surgical osteonecrosis of the rat femoral head was induced by detaching the ligamentum teres and stripping the femoral neck periosteum. Bone and marrow necrosis were found from the fifth postoperative day and replaced by creeping substitution. Osteonecrosis of the femoral head results in the flattening to various degrees of roundness and osteoarthritic changes of the hip joint. Alendronate, an osteoclast inhibitor, slows down bone resorption and remodeling. The purpose of this study was to evaluate objectively the influence of alendronate treatment on the rat femoral head shape after six weeks of daily treatment, when compared with controls.

Materials and Methods:

The blood circulation of right femoral head of 20 female Sprague-Dawley rats was interrupted. Twelve were treated by alendronate injections of 200 µg/kg/day and eight controls were treated with saline, both for a total of 42 days. Both femoral head specimens were obtained for computed-assisted morphometry. For each rat, the right operated head was compared with the left, and the alendronate treated group was compared with the control group.

Results:

No differences were found in shape factor and femoral head height/length ratios in the alendronate treated femoral heads. Among the nontreated control group, shape-factor differences were found between the operated and the nonoperated femoral heads.

Conclusion:

Alendronate treatment prevented the distortion and destruction of the femoral head. Osteoclast inhibition might prolong the bone creeping substitution process and could enable secondary bone maturity and mineralization that increases bone strength. Alendronate preserved the femoral head architecture, which might reduce morbidity and disability due to femoral head collapse.     

Infrared analysis of bones in magnesium-deficient rats treated with vitamin K<Subscript>2</Subscript>

In this study, we compared the effects of vitamin K₂ menatetrenone on bone mechanical properties in rats fed a low-magnesium (Mg) diet. In addition, the mechanism of bone quality was examined using Fourier transform infrared imaging (FTIRI). Thirty 4-week-old male Wistar rats were divided into three groups: intact, low-Mg-control, and low-Mg-MK-4 groups. Rats in the low-Mg groups were given a diet containing 6 mg/100 g Mg (intact, 90 mg/100 g). After an 8-week-treatment, the cortical bone mineral content (CtBMC), outer perimeter, and endo perimeter of the femoral diaphysis in the low-Mg-control group were significantly higher, while the maximum load (ML) and elastic modulus (EM) were 81% and 50% of those in the intact group, respectively (respectively, P < 0.05). In the low-Mg-MK-4 group, ML and EM were significantly higher than in the low-Mg-control group (P < 0.05), with no differences in CtBMC. The mineral/matrix ratios for the periosteal and central regions in the low-Mg-control group were 162% and 120% of those in the intact group (both, P < 0.05), respectively. MK-4 significantly inhibited these increases (P < 0.05). We found that the mineral/matrix ratios for the periosteal region of the femoral diaphysis were negatively correlated with EM, suggesting that an increase in the mineral/matrix ratio may be involved in the reduction of EM and that MK-4 may improve EM by improving the mineral/matrix ratio.     

Effect of alendronate and exercise on bone and physical performance of postmenopausal women: a randomized controlled trial

In this randomized, double-blind, placebo-controlled 12-month trial we evaluated effects of weight- bearing jumping exercise and oral alendronate, alone or in combination, on the mass and structure of bone, risk factors for falling (muscle strength and power, postural sway, and dynamic balance), and cardiorespiratory fitness in postmenopausal women. A total of 164 healthy, sedentary, early postmenopausal women were randomly assigned to one of four experimental groups: (1) 5 mg of alendronate daily plus progressive jumping exercise, (2) 5 mg alendronate, (3) placebo plus progressive jumping exercise, or (4) placebo. The primary endpoint was 12-month change in bone mass and geometry (measured with dual-energy X-ray absorptiometry and peripheral computed tomography at several axial and limb sites) and physical performance; the secondary endpoint was change in biochemical markers of bone turnover. The jumping exercise was conducted an average 1.6 +/- 0.9 (mean +/- SD) times a week. Alendronate daily was effective in increasing bone mass at the lumbar spine (alendronate vs placebo 3.5%; 95% CI, 2.2-4.9%) and femoral neck (1.3%; 95% CI, 0.2-2.4%) but did not affect other bone sites. Exercise alone had no effect on bone mass at the lumbar spine or femoral neck; it had neither an additive nor an interactive effect with alendronate at these bone sites. However, at the distal tibia the mean increase of 3.6% (0.3-7.1%) in the section modulus (that is, bone strength) and 3.7% (0.1-7.3%) increase in the ratio of cortical bone to total bone area were statistically significant in the exercise group compared to the nonexercise group, indicating exercise-induced thickening of the bone cortex. Bone turnover was reduced in alendronate groups only. Alendronate had no effect on physical performance while the jumping exercise improved leg extensor power, dynamic balance, and cardiorespiratory fitness. As conclusion Alendronate is effective in increasing bone mass at the lumbar spine and femoral neck, while exercise is effective in increasing the mechanical properties of bone at some of the most loaded bone sites, as well as improving the participants' muscular performance and dynamic balance. Together alendronate and exercise may effectively decrease the risk of osteoporotic fractures.     

Vitamin K<Subscript>2</Subscript> Prevents Hyperglycemia and Cancellous Osteopenia in Rats with Streptozotocin-Induced Type 1 Diabetes

The purpose of the present study was to examine the effect of vitamin K₂ on cancellous and cortical bone mass in rats with streptozotocin (STZ)-induced type 1 diabetes. Twenty-seven male Sprague-Dawley rats aged 12 weeks were randomized by the weight-stratified method into the following three groups: age-matched control group, STZ + vehicle group, and STZ + vitamin K₂ group. STZ (40 + 50 mg/kg) was administered intravenously twice during the initial 1-week period. Vitamin K₂ (menatetrenone, 30 mg/kg) was administered orally 5 days a week. After 12 weeks of treatment, the serum glucose concentration and femoral length and weight were measured and histomorphometric analysis was performed on the cancellous and cortical bone of the distal femoral metaphysis and femoral diaphysis, respectively. STZ administration induced hyperglycemia and a decrease in femoral weight. The STZ + vehicle group also showed cancellous osteopenia due to a decrease in the number of osteoblasts/bone surface (N.Ob/BS) and the osteoblast surface (ObS)/BS without any significant changes in bone-resorption parameters, but it did not have a significant decrease in cortical bone mass. Administration of vitamin K₂ to STZ-treated rats prevented the development of hyperglycemia and a decrease in femoral weight. Vitamin K₂ also prevented cancellous osteopenia by inhibiting the decrease in N.Ob/BS and ObS/BS without significantly affecting bone-resorption parameters, but it did not significantly increase cortical bone mass. These results suggest that vitamin K₂ has beneficial effects on glucose concentration and cancellous bone mass in rats with STZ-induced type 1 diabetes.     

Vitamin K<Subscript>2</Subscript> Improves Renal Function and Increases Femoral Bone Strength in Rats with Renal Insufficiency

Renal insufficiency induces cortical bone loss in rats. The present study examined the influence of vitamin K₂ on renal function, cortical bone mass, and bone strength in rats with renal insufficiency. Thirty male Sprague-Dawley rats (8 weeks old) were randomized by the stratified weight method to the following three groups of 10 animals each: sham operation (control), 5/6 nephrectomy, and 5/6 nephrectomy + oral vitamin K₂ (menaquinone-4, menatetrenone, 30 mg/kg, 5 days/week). Treatment was initiated 10 days after surgery. After 6 weeks of treatment, samples of serum, urine, and bone (femur and tibia) were obtained. Renal function was evaluated, bone histomorphometric analysis was performed on the tibial diaphysis, and the bone mineral density (BMD) and mechanical strength of the femoral diaphysis were determined by peripheral quantitative computed tomography and a three-point bending test, respectively. Nephrectomy induced renal dysfunction, as indicated by increased levels of serum creatinine and urea nitrogen along with a decrease of creatinine clearance; and it also decreased BMD without significantly affecting bone strength at the femoral diaphysis. Vitamin K₂ improved renal function parameters but did not significantly influence BMD at the femoral diaphysis. However, vitamin K₂ decreased the bone marrow area of the tibial diaphysis and increased the stiffness of the femoral diaphysis. These findings suggest that administration of vitamin K₂ improves renal function and increases cortical bone strength without altering BMD in rats with renal insufficiency.     

Treatment of Postmenopausal Women with Osteoporosis or Low Bone Density with Raloxifene

Raloxifene, a selective estrogen receptor modulator (SERM), has been shown to improved bone mineral density (BMD) and serum lipid profiles in healthy postmenopausal women. The objective of this study was to examine the effects of raloxifene on BMD, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This Phase II, multicenter, 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women (mean age ± SD: 60.2 ± 6.7 years) with osteoporosis or low bone density (baseline mean lumbar spine BMD T-score: −2.8). Women were randomly assigned to one of three treatment groups: placebo, 60 mg/day raloxifene-HCl (RLX 60) or 150 mg/day raloxifene-HCl (RLX 150) and concomitantly received 1000 mg/day calcium and 300 U/day vitamin D₃. At 24 months, BMD was significantly increased in the lumbar spine (+3.2%), femoral neck (+2.1%), trochanter (+2.7%) and total hip (+1.6%) in the RLX 60 group compared with the placebo group (p<0.05). The RLX 150 group had increases in BMD similar to those observed with RLX 60. A greater percentage of raloxifene-treated patients, compared with those receiving placebo, had increased BMD (p<0.05). Serum bone-specific alkaline phosphatase activity, serum osteocalcin, and urinary type I collagen:creatinine ratio were significantly decreased in the RLX-treated groups, compared with the placebo group (p<0.01). RLX 60 treatment significantly decreased serum levels of triglycerides, and total- and LDL-cholesterol levels (p<0.01). The rates of patient discontinuation and adverse events were not significantly different among groups. In this study, raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density. Received: 26 December 1998 / Accepted: 31 March 1999     

Raloxifene and Vitamin K2 Combine to Improve the Femoral Neck Strength of Ovariectomized Rats

We evaluated the skeletal effects of two osteoporosis therapies in an ovariectomized rat model, raloxifene and vitamin K₂, as well as the vitamin K₂ plus raloxifene (K + Ral) combination. In two studies, 6-month-old rats were ovariectomized, except for sham-ovariectomy controls (Sham), and dosed orally with vehicle, 30 mg/kg vitamin K₂, 1 mg/kg raloxifene, or the combination of K + Ral for 6 weeks following surgery. Vitamin K₂ had no effect on serum estrogen, low-density lipoprotein cholesterol (LDL-C), or urinary deoxypyridinoline levels, but slightly increased osteocalcin levels compared to Ovx. Raloxifene lowered total cholesterol, LDL-C, osteocalcin, and urinary deoxypyridinoline levels to below Ovx levels, while having no effect on estrogen levels. Raloxifene, but not vitamin K₂, prevented ovariectomy-induced loss of bone in the distal femoral metaphysis and proximal tibial metaphysis, as did the K + Ral combination. Raloxifene, but not vitamin K₂, partially prevented, loss of vertebral bone mineral density (BMD), whereas K + Ral had BMD greater than that of Ovx. Vitamin K₂ increased bone formation rate to above Ovx, whereas raloxifene and K + Ral reduced bone formation rate to Sham levels. Vitamin K₂ had no effect on eroded surface compared to Ovx, while raloxifene and K + Ral reduced eroded surface to Sham levels. Groups were not different in the BMD of femoral midshaft; however vitamin K₂ was observed to increase periosteal mineralizing surface of the tibial shaft to above Ovx, while raloxifene reduced periosteal mineralizing surface toward Sham levels. Femoral neck strength was not different between groups, indicating no significant beneficial effect of either raloxifene or vitamin K₂ at this site. However, K + Ral had reproducibly greater femoral neck strength than Ovx or Sham. Raloxifene, but not vitamin K₂, partially prevented loss of lumbar vertebra strength; but K + Ral was not different from Sham or Ovx. Therefore, raloxifene and vitamin K₂ had complementary effects on bone resorption and formation activities, respectively, resulting in a reproducible, significant improvement of femoral neck strength. These rat data suggest interesting therapeutic possibilities that may require clinical verification. This work was supported by Lilly Research Laboratories.     

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.     

Vitamin K<Subscript>2</Subscript> (menaquinone 4) reduces serum undercarboxylated osteocalcin level as early as 2 weeks in elderly women with established osteoporosis

 Twenty elderly osteoporotic women with vertebral fracture(s) were randomly allocated to two groups; women in the MK₄ group received calcium with menaquinone 4 (MK₄) at a dose of 45 mg/day for 2 weeks, and women in the control group received calcium alone for the same period. Serum intact osteocalcin (OC) and undercarboxylated osteocalcin (uc-OC) levels were measured by immunoradiometric assay and enzyme immunoassay, respectively, at baseline and on the 7th and 14th days following the start of the treatment. There were no differences in the baseline data including age, weight, phylloquinone, menaquinone 4, menaquinone 7, OC, and uc-OC levels between the MK₄ group and the control group. Administration of MK₄ significantly raised the MK₄ level from 0.20 ± 0.10 (mean ± SE) pg/ml to 15.09 ± 5.62 pg/ml (P < 0.04), and reduced serum uc-OC levels from 2.80 ± 0.93 ng/ml to 1.76 ± 0.56 ng/ml (P < 0.05) at the end of the study, respectively. No significant changes in these levels were observed in the control group. Serum OC levels were stable during the period in both groups. In this randomized prospective study, the MK₄ group shows a reduction in the serum uc-OC level within 2 weeks without any significant change in OC, suggesting that the uc-OC is changed to carboxylated OC. This early effect of MK₄ on bone metabolism may be estimated by the measurement of serum uc-OC in elderly osteoporotic women with vertebral fractures. Received: January 21, 2002 / Accepted: November 6, 2002 Offprint requests to: T. Miki     

阿伦膦酸盐对绝经后骨质疏松妇女骨密度的影响

为了解阿伦膦酸盐对骨密度的影响及其安全性和耐受性,对２０名绝经后骨质疏松的妇女中进行阿伦膦酸盐（ａｌｅｎｄｒｏｎａｔｅ）１０ｍｇ／天和安慰剂的随机、双盲、前瞻性研究,为期一年。结果显示,１年后阿伦膦酸盐组与安慰剂组相比,骨密度平均增长率：椎骨分别为４．８７％与－０．２３％;股骨颈分别为６．８９％与－１．８４％,（Ｐ＜０．０５）。副反应仅为轻微胃肠道反应。结论：阿伦膦酸盐能有效增加骨密度,且药物安全,耐受性好     

Vitamin D and HRT: No benefit additional to that of HRT alone in prevention of bone loss in early postmenopausal women. A 2.5-year randomized placebo-controlled study

The study was designed to examine the effect of hormone replacement therapy (HRT) and low-dose vitamin D (Vit D) supplementation on the prevention of bone loss in non-osteoporotic early postmenopausal women and to determine whether Vit D supplementation can give additional benefit to an already optimized estrogen regimen. The effects of HRT and Vit D on bone mineral density (BMD) were studied in postmenopausal women in a 2.5-year randomized placebo-controlled study. The study population was a subgroup of the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) (n=13100). A total of 464 early postmenopausal women were randomized to four groups: (1) HRT (a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate (E₂Val/CPA); (2) vitamin D₃ (cholecalciferol, 300 IU/day); (3) HRT+Vit D; and (4) placebo (calcium lactate; 93 mg Ca²⁺/day). Lumbar (L1–4) and femoral neck BMD were determined by dual-energy X-ray absorptiometry before and after 2.5 years of treatment. After 2.5 years, lumbar BMD had increased by 1.8% in the HRT group (p<0.001) and by 1.4% in the HRT+Vit D group (p=0.002), whereas lumbar BMD had decreased by 3.5% (p<0.001) in the Vit D group and by 3.7% (p<0.001) in the placebo group. The loss of femoral neck BMD was lower in the HRT (–0.3%) and the HRT+Vit D (–0.9%) groups compared with the Vit D (–2.4%) and the placebo groups (–3.7%). This study confirms the beneficial effect of HRT on BMD. It also shows that low-dose vitamin D supplementation has only a minor effect in the prevention of osteoporosis in non-osteoporotic early postmenopausal women and does not give any benefit additional to that of HRT alone.     

Strategy for prevention of hip fractures in patients with Parkinson’s disease

Hypovitaminosis D and K due to malnutrition or sunlight deprivation,increased bone resorption due to immobilization,low bone mineral density(BMD)and an increased risk of falls may contribute to an increased risk of hip fractures in patients with Parkinson’s disease.The purpose of the present study was to clarify the efficacy of interventions intended to prevent hip fractures in elderly patients with Parkinson’s disease.Pub Med was used to search the literature for randomized controlled trials(RCTs)regarding Parkinson’s disease and hip fractures.The inclusion criteria were 50 or more subjects per group and a study period of 1 year or longer.Five RCTs were identified and the relative risk and95%confidence interval were calculated for individual RCTs.Sunlight exposure increased serum hydroxyvitamin D[25(OH)D]concentration,improved motor function,decreased bone resorption and increased BMD.Alendronate or risedronate with vitamin D supplementation increased serum 25(OH)D concentration,strongly decreased bone resorption and increased BMD.Menatetrenone(vitamin K2)decreased serum undercarboxylated osteocalcin concentration,decreased bone resorption and increased BMD.Sunlight exposure(men and women),menatetrenone(women),alendronate and risedronate with vitamin D supplementation(women)significantly reduced the incidence of hip fractures.The respective RRs(95%confidence intervals)according to the intention-to-treat analysis were 0.27(0.08,0.96),0.13(0.02,0.97),0.29(0.10,0.85)and 0.20(0.06,0.68).Interventions,including sunlight exposure,menatetrenone and oral bisphosphonates with vitamin D supplementation,have a protective effect against hip fractures elderly patients with Parkinson’s disease.     

Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women

Summary

We have investigated whether low-dose vitamin K2 supplements (menaquinone-7, MK-7) could beneficially affect bone health. Next to an improved vitamin K status, MK-7 supplementation significantly decreased the age-related decline in bone mineral density and bone strength. Low-dose MK-7 supplements may therefore help postmenopausal women prevent bone loss.

Introduction

Despite contradictory data on vitamin K supplementation and bone health, the European Food Safety Authorities (EFSA) accepted the health claim on vitamin K’s role in maintenance of normal bone. In line with EFSA’s opinion, we showed that 3-year high-dose vitamin K1 (phylloquinone) and K2 (short-chain menaquinone-4) supplementation improved bone health after menopause. Because of the longer half-life and greater potency of the long-chain MK-7, we have extended these investigations by measuring the effect of low-dose MK-7 supplementation on bone health.

Methods

Healthy postmenopausal women (n?=?244) received for 3 years placebo or MK-7 (180 μg MK-7/day) capsules. Bone mineral density of lumbar spine, total hip, and femoral neck was measured by DXA; bone strength indices of the femoral neck were calculated. Vertebral fracture assessment was performed by DXA and used as measure for vertebral fractures. Circulating uncarboxylated osteocalcin (ucOC) and carboxylated OC (cOC) were measured; the ucOC/cOC ratio served as marker of vitamin K status. Measurements occurred at baseline and after 1, 2, and 3 years of treatment.

Results

MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae.

Conclusions

MK-7 supplements may help postmenopausal women to prevent bone loss. Whether these results can be extrapolated to other populations, e.g., children and men, needs further investigation.     

不同给药方案阿仑膦酸钠治疗绝经后妇女骨质疏松症18个月效果研究

目的阿仑膦酸钠是临床治疗绝经后妇女骨质疏松症的首选药物。本实验观察阿仑膦酸钠不同给药方案对绝经后妇女骨质疏松症的治疗效果以及不良反应的发生情况。方法本实验为开放、随机、平行对照临床研究。纳入西安两社区绝经后妇女共80名,年龄49～79岁,绝经年限3～31年。实验分为低剂量组和常规剂量组。低剂量组为每两周口服阿仑膦酸钠一次,每次70mg,疗程18个月。常规剂量组为每周口服阿仑膦酸钠一次,每次70mg,疗程18个月。两组同时每日服用钙尔奇D3600mg。实验主要观察指标为:第二腰椎到第四腰椎(L2-L4)、股骨颈、大转子、股骨干骨密度值变化,血液指标(血钙、血磷、碱性磷酸酶),肝肾功能指标(丙氨酸氨基转移酶、血肌酐),不良反应及新发骨折情况。结果 80例患者全部进入结果分析:①骨密度测定:每组患者治疗18个月后L2-L4、股骨颈、股骨大转子、股骨干的骨密度与治疗前相比均明显升高,差异有显著性意义(P﹤0.05)。低剂量组与常规剂量组相比L2-L4骨密度、股骨颈骨密度、股骨干骨密度值差异无统计学意义(P﹥0.05),表明两种给药方案相比增加骨密度效果相似。②两组患者血液指标及肝肾功能指标治疗前后均在正常范围内,显示两种用药方法均安全可靠。③不良反应主要为上腹部不适,两组不良反应差异有统计学意义(P﹤0.05),低剂量组显著低于常规剂量组。④两组患者均无新发骨折病例。结论阿仑膦酸钠治疗绝经后妇女骨质疏松症安全有效,低剂量用药方案与常规剂量用药方案相比增加骨密度效果和药物安全性相似,用药更加简单方便,不良反应更小,经济效益更高,是临床值得推荐的用药方案。