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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2700-2704
Copyright © 1999 by The Endocrine Society

Original Studies

Use of Vitamin K2 (Menatetrenone) and 1,25-dihydroxyvitamin D3 in the Prevention of Bone Loss Induced by Leuprolide1

Yoshiaki Somekawa, Miki Chigughi, Misako Harada and Tomoko Ishibashi

Department of Obstetrics and Gynecology, Toride Kyodo General Hospital, Toride, Ibaraki, 302-0022 Japan

Address all correspondence and requests for reprints to: Yoshiaki Somekawa, M.D.. Toride Kyodo General Hospital, Hongo 2–1-1 Toride, Ibaraki, 302-0022 Japan. E-mail: pv2t-sigi{at}asahi-net.or.jp


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The purpose of this study is to evaluate the efficacy of vitamin K2 and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in preventing bone loss induced by estrogen deficiency during therapy with the GnRH agonist (GnRH-a) leuprolide.

One hundred ten women (mean age, 46.2 ± 0.5 yr), receiving leuprolide therapy for estrogen-dependent diseases (such as endometriosis and uterine leiomyomas), were randomly allocated into four groups (group A, leuprolide only; group B, leuprolide with vitamin K2; group C, leuprolide with 1,25-(OH)2D3; and group D, leuprolide with vitamin K2 and 1,25-(OH)2D3). Bone mineral density of the lumbar spine was measured by dual-energy x-ray absorptiometry before and after 6 months of treatment. Bone formation and resorption markers were also measured before and after 6 months of treatment.

There were no significant differences in the background parameters among the four groups. Bone mineral density was reduced in all four groups, but the percent changes varied slightly, at -5.25% (group A), -3.72% (P < 0.05 vs. group A) (group B), -4.13% (group C), and -3.59% (P < 0.01 vs. group A) (group D), respectively. Bone formation markers were significantly increased in all four groups, and the percent changes of bone formation markers were highest in group B.

Bone resorption markers also increased significantly in all four groups after treatment of 6 months. Group B tended to have the highest percent changes of bone resorption markers among the four groups, but these increases were not significantly different between any of the groups.

Vitamin K2, especially when combined with 1,25-(OH)2D3, can partially prevent bone loss caused by estrogen deficiency. However, because this effect is attributable mainly to the activation of bone formation, it is not sufficient to eliminate bone loss induced by GnRH-a therapy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THOUGH THE GnRH agonist leuprolide is a frequently used medicine (as a pseudomenopausal therapy), it has several side effects, including a moderate reduction of bone mineral densities (BMD), caused by the accelerated activation of osteoclasts through the suppressed estradiol (E2) levels. A number of studies demonstrated that add-back therapies [such as estrogen replacement (1), PTH (2), and ipriflavone (3)] are useful in preventing these bone losses.

Recent studies have also demonstrated that vitamin K2 was effective in preventing bone resorption, by inducing apoptosis of osteoclasts (4), through the inhibition of osteoclast formation (5), or through the inhibition of PG E2 synthesis in organ culture (6). These inhibitory effects were not found with vitamin K1 (5). Two types of vitamin K exist in nature: vitamins K1 and K2. Vitamin K1 is a single compound (phylloquinone, 2-metyl-3-phytyl-1, 4-naphthoquinone), usually contained in plants, whereas the term vitamin K2 (menaquinones) covers a series of vitamers with varying numbers of isoprene units (from 1–4) at the 3 position of the quinone structure. Menatetrenone (menaquinone-4), the form of vitamin K2 with 4 isoprene units at the 3 position of the quinone structure, has been reported to be the most potent vitamin K (7). As a result, menatetrenone has been developed for the treatment of osteoporotic patients. It has two effects: enhancement of osteoblast function, and inhibition of osteoclast function. Vitamin D3 supplementation has been proven to prevent bone loss in elderly women, mainly by increasing calcium (Ca) availability (8). Vitamin K2 improved bone mass in patients with high 1,25(OH)2D3 serum levels more than in patients with low 1,25(OH)2D3 serum levels (9). Koshihara et al. (10) reported that vitamin K2 enhanced human osteoblast-induced mineralization, and these effects differ in the presence or absence of 1,25(OH)2D3. These studies suggest a cooperative effect of 1,25-(OH)2D3 and vitamin K2 on the prevention of bone loss caused by GnRH agonists.

Although the effects of vitamin K2 on bone metabolism have been fairly well investigated in vitro, the effects in vivo, especially in humans, have been poorly defined. The present study sought to assess the effects of a daily supplement of 1,25-(OH)2D3 and vitamin K2 in preventing bone loss during leuprolide treatment in Japanese women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

One hundred ten Japanese women, 24–52 yr old, with endometriosis and/or uterine leiomyomas, agreed to participate in this study. Each patient’s body weight and height were measured, and the body mass index (BMI) was calculated as weight/height2 (kg/m2). The body weight of these women was within 30% of their ideal body weight (11); those who were performing excessive exercise, as well as heavy smokers and alcoholics, were excluded. Women with liver disease, ischemic heart disease, diabetes, renal disease, metabolic or other endocrine diseases which could influence bone turnover, or a history of carcinoma were also excluded from the study. All women had no previous history of metabolic bone disease and were receiving no medications that could affect Ca absorption and bone turnover. The study was approved by the local ethics committees and performed in accordance with the Declaration of Helsinki. Each subject gave her informed consent before participation in the study.

Study protocol

sc leuprolide acetate (Leuprin, provided by Takeda Chemical Industries Co., Ltd., Tokyo, Japan) was administered to the 110 women at a dose of 1.88 mg/month. The first vial of leuprolide acetate was administered early in the follicular phase (second to fifth day of the cycle). These 110 women were randomized into 4 groups; the first group was given only leuprolide acetate (group A, n = 28), the second group was given leuprolide acetate together with oral menatetrenone (Glakay, Eisai Co. Ltd., Tokyo, Japan) at 45 mg/day (group B, n = 28), the third group was given leuprolide acetate together with oral 1,25-(OH)2D3 (Rocaltrol, Roche, Basel, Switzerland) at 0.5 µg/day (group C, n = 26), and the fourth group was given leuprolide acetate together with oral menatetrenone at 45 mg and 1,25-(OH)2D3 at 0.5 µg/day (group D, n = 28). These regimens were continued for 6 months, and bone markers and BMD at the lumbar spine were measured before and at the end of treatment. Variables in the backgrounds of the patients in each group (such as age, weight, BMI, age of menarche, gravidity, parity, FSH, and serum E2) were compared. Six women receiving leuprolide acetate withdrew from the study (3 for side effects and 3 for personal reasons), and 104 women completed the study (27 in group A, 26 in group B, 25 in group C, and 26 in group D).

Blood and 2-h urine specimens were collected during the follicular phase (between days 4–8 of the cycle) as baseline parameters in all subjects, between 0800–1000 h, after an overnight fast, for determination of FSH, E2, Ca, serum intact osteocalcin (iOC), serum total alkaline phosphatase (ALP), urine pyridinoline (Pyr) corrected by creatinine excretion, and urine deoxypyridinoline (D-Pyr) corrected by creatinine excretion. All samples were stored at -70 C until analysis. Serum Ca was measured before treatment, 3 months into the treatment, and at the end of treatment, using an autoanalyzer (Toshiba-200FR, Tokyo, Japan). The intraassay coefficients of variation (CVs) for serum Ca were below 1%.

Serum levels of E2 were measured before treatment, after 3 months of treatment, and at the end of treatment. Serum levels of FSH were measured by immunoradiometric assay (Daiichi Pharmaceutical Company Ltd. Radioisotope Laboratories, Tokyo, Japan). The serum level of E2 was measured by RIA (Diagnostic Products Corporation, Los Angeles, CA). The intraassay CVs for FSH and E2 were 4.1% and 3.2%, respectively.

Measurements of bone markers

Serum iOC and serum ALP were measured as bone formation markers before and after 6 months of treatment. ALP was analyzed using standard laboratory methods, and the intraassay CVs for ALP were less than 1%. Serum iOC was measured by a new sandwich enzyme immunoassay, using antibodies to the N- and C-terminal regions of human osteocalcin (12). These values of serum iOC reflect bone formation more precisely because unrelated fragments are excluded from the measurements. The intraassay CVs for iOC were less than 5.4%.

At the same time, the urine total Pyr cross-links, Pyr and D-Pyr, were measured as bone resorption markers. Urinary concentrations were assessed with urine collected over 2 h (0800–1000 h) and corrected for creatinine excretion. Urinary Pyr and D-Pyr were measured according to a previously described procedure (13). Urine samples were hydrolyzed, and the cross-links were extracted by chromatography on cellulose. Extracted cross-links were separated isocratically by reverse-phase high-performance chromatography and identified by their fluorescence on a spectrometer. CVs were less than 10% for both Pyr and D-Pyr.

All measurements of markers were carried out in duplicate, and the means of the results were used.

Bone densitometry

BMD at the lumbar spine (L2–L4) was measured by dual-energy x-ray absorptiometry using a Hologic, Inc. QDR-4500 A densitometer (Hologic, Inc., Waltham, MA). BMD was measured before and after the treatment of leuprolide for 6 months. To minimize measurement variations, differences of total spine areas in two points are set within 5%. Total BMD CVs for the spine were within 1%.

Statistical analysis

Results are given as the mean ± SD. Data analysis was performed using a Stat View 4.02 software package. Baseline parameters were compared between the groups by one-way factorial ANOVA and multiple comparison tests for continuous variables; the Kruskal-Wallis test was used for noncontinuous variables. ANOVA for repeated measures was used to evaluate the significance of any changes in the bone markers and BMD. Differences in the percent of changes among the four groups were also tested by one-way factorial ANOVA. The plan of analysis was to compare first the B and C groups to the A group and then compare the D group to the A group. The B, C, and D groups were also compared with each other. Correlation between bone markers was analyzed by the Pearson’s correlation matrix method. A level of P < 0.05 was defined as statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
There were no significant differences among any of the groups in the background parameters, baseline BMD, or any of the bone markers (Table 1Go). Mean E2 levels were under 10 pg/mL after 3 and 6 months of treatment in all four groups. To assess the relative effects of leuprolide acetate, menatetrenone, and vitamin D3 on these bone markers and BMD, results are expressed as percent changes from baseline values.


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  		Table 1. Baseline clinical and laboratory characteristics in four groups

 
Lumbar BMD decreased by different amounts in the four groups after 6 months of treatment (Fig. 1Go): -5.25 ± 0.52% (A), -3.72 ± 0.61% (B), -4.13 ± 0.70% (C), and -3.59 ± 0.35% (D). The differences between (A) and (B) and between (A) and (D) are significant at P < 0.05 and P < 0.01, respectively. We noted small, but significant, increases (2.3% in group A, 2.4% in group B, 3.8% in group C, and 3.6% in group D) in serum Ca after 6 months of treatment, but these percent changes were not significantly different, compared among the groups.



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  		Figure 1. Percent changes in lumbar BMD, after 6 months of treatment, in groups A, B, C, and D, in comparison with respective baseline values. *, P < 0.05, compared with group A; **, P < 0.01, compared with group A (by one-way factorial ANOVA).

 
Both bone formation markers significantly increased in all four groups after 6 months of treatment. The values for iOC were 47.3 ± 8.5% (A), 102.5 ± 17.3% (B), 62.9 ± 13.3% (C), and 95.6 ± 21.5% (D). The differences between A and B and A and C were significant at P < 0.05. Serum ALP increased by 12.2 ± 3.0% (A), 30.1 ± 3.8% (B), 19.3 ± 4.0% (C), and 28.6 ± 4.8% (D). The differences between A and B were significant at P < 0.01, and those between A and D were significant at P < 0.05 (Fig. 2Go) The percent changes of bone formation markers were the highest in group B.



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  		Figure 2. Percent changes in bone formation markers, after 6 months of treatment, in groups A, B, C, and D, in comparison with respective baseline values. The top panel shows the percent changes in serum total ALP, and the bottom panel shows changes in serum intact osteocalcin (iOC). *, P < 0.05, compared with group A or group B; **, P < 0.01, compared with group A (by one-way factorial ANOVA).

 
Bone resorption markers also increased significantly in all four groups after 6 months of treatment. For urine Pyr, the values were as follows: 31.9 ± 9.0% (A), 39.8 ± 8.4% (B), 38.9 ± 6.9% (C), and 32.3 ± 7.1% (D). The increases of urine D-Pyr were 58.9 ± 9.2% (A), 75.7 ± 8.1% (B), 59.7 ± 8.7% (C), and 68.7 ± 11.4% (D). The percent changes of bone resorption markers tended to be the highest in group B, but these increases were not significantly different among the groups (Fig. 3Go).



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  		Figure 3. Percent changes in bone absorption markers, after 6 months of treatment, in groups A, B, C, and D, in comparison with respective baseline values. The top panel shows the percent changes in urine Pyr corrected by creatinine excretion, and the bottom panel shows urine D-Pyr corrected by creatinine excretion.

 
Correlation analysis revealed that only in group D was urine D-Pyr significantly and positively correlated (r = 0.485; P < 0.05) with serum iOC after 6 months of treatment (Fig. 4Go). Additionally, only in group D were significant positive correlations noted between the percent change (from the baseline) in serum iOC and urine Pyr (r = 0.462; P < 0.05), as well as in serum iOC and urine D-Pyr (r = 0.555; P < 0.01). In these bone markers, percent changes (from the baseline) in BMD are significantly negatively correlated with urine D-Pyr in group A (r = 0.552, P < 0.05) and in group D (r = 0.441, P < 0.05). Significant positive correlation between percent changes (from the baseline) in BMD and serum iOC (r = 0.493, P < 0.05) is noted only in group D.



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  		Figure 4. Correlation between serum iOC and urinary D-Pyr corrected by creatinine excretion in group D.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Reductions in BMD, caused by estrogen deficiency during therapy with GnRH-a (such as leuprolide) are thought to be mainly caused by augmented resorption of bone accompanying activation of osteoclasts (14, 15, 16). Add-back therapies, such as estrogen replacement (1), ipriflavone (3), bisphosphonate (17), and tibolone (18) are effective in preventing these bone losses through inhibition of bone resorption, with a secondary decrease in bone formation. Bisphosphonate is slightly different from others; it decreases bone turnover by interfering with osteoclast function. Combinations of GnRH-a with estrogen-containing regimens may mitigate the benefits of GnRH-a therapy in patients with estrogen-sensitive disorders. In contrast, PTH increases bone formation, with associated increases in bone resorption. The mechanism whereby PTH increases bone mass is unclear, but PTH-mediated increases in bone turnover and the therapeutic effects of PTH decline during extended periods of treatment (2).

Recent studies have demonstrated that vitamin K2 has two effects: enhancement of osteoblast function, and inhibition of osteoclast function. Several in vitro studies have proved that vitamin K2 was effective in preventing bone resorption, partly through induction of apoptosis of osteoclasts (4), and partly through the inhibition of osteoclast formation (5). Vitamin K2 has also been shown to affect bone formation. Vitamin K2 is a cofactor for {gamma}-carboxylase that catalyzes the posttranslational conversion of specific glutamic acid residues on osteocalcin to {gamma}-carboxyglutamic acid (19). Osteocalcin (bone {gamma}-carboxyglutamic acid protein) synthesized by osteoblasts (20) plays an important role in Ca deposition in bone because of its affinity to Ca ions (21). These data suggest that vitamin K2 activates osteoblasts and promotes calcification of bone; it also suppresses bone resorption.

Our study has shown three intriguing findings. First, bone loss induced by estrogen deficiency is partially prevented by vitamin K2, but it is not fully prevented, even with additional 1,25-(OH)2D3. The differences between percent reduction and percent compensation among four groups represent the net differences of preventive effects on osteoporosis of estrogen, vitamin K2, 1,25-(OH)2D3, and vitamin K2 added with 1,25-(OH)2D3. Our study groups consisted of relatively elderly women; therefore, the percent change of BMD may have been larger than in younger women.

Second, our study shows that bone formation markers such as iOC and ALP increased significantly higher in groups B and D. The data do not support an inhibitory effect of vitamin K2 on bone resorption. Bone resorption markers such as urine Pyr and D-Pyr were not significantly different in the four groups of patients. These data are not consistent with in vitro data (4, 5). Under normal conditions, an increase or decease in bone resorption is coupled to a compensatory increase or decrease in bone formation, to ensure that homeostasis of osteocalcin and osteoblast balances the protection against net bone loss. Vitamin K2 may be effective in preventing bone resorption in vitro; but in vivo, its main role is the activation of bone formation, setting in motion the so-called bone coupling process. The resulting increased osteoclast activity may counteract the prevention of bone resorption and may not actually lead to a reduction of bone resorption.

In our study, 1,25-(OH)2D3 did not prevent the leuprolide-induced bone loss in group C; changes of bone formation and bone resorption did not significant. There are some potential limitations of our study. Because all of patients in this study consumed a regular diet that contained 550 mg Ca/day (average for this age group) and did not receive any restriction or supplementation, there exists the possibility that inadequate Ca intake might cause our failure to see satisfactory effects of 1,25-(OH)2D3.

Third, in group D (1,25-(OH)2D3 added to vitamin K2 and leuprolide administration), bone loss induced by leuprolide is prevented most effectively, although bone formation and resorption markers were not different from those in group B (vitamin K2 added to leuprolide). A significant correlation of osteoclasts (reflected in urine D-Pyr levels) and osteoblasts (reflected in serum iOC levels), after 6 months of treatment, is observed only in group D. Our study suggests a preventive effect of 1,25-(OH)2D3 on bone resorption, at least when added to vitamin K2. Contrary to our expectation, bone formation markers are not increased by adding 1,25-(OH)2D3 to vitamin K2, yet positive correlations have been observed in this group between osteoclasts reflected in urine D-Pyr levels and osteoblasts reflected in serum iOC levels, after 6 months treatment. We hypothesize that of 1,25-(OH)2D3, added to vitamin K2, promotes the coupling of bone and restores homeostasis of osteocalcin and osteoblast balance faster than in nontreated or vitamin K2-only or 1,25-(OH)2D3-only patients. It is possible that the combination therapy of 1,25-(OH)2D3 and vitamin K2 is more effective in longer periods of treatment. Additional work will be required to confirm or refute this concept.


   Acknowledgments
 
The authors gratefully thank the patients who agreed to participate in this study, and also Hiroshi Hirasawa and Kazuyoshi Hosoya for their assistance with the laboratory procedures.


   Footnotes
 
1 Presented, in part, at the 4th European Congress on Osteoporosis, Berlin, Germany, September 12–14, 1998. Back

Received January 14, 1999.

Revised May 4, 1999.

Accepted May 11, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  16. Johansen JS, Riis JB, Hassager C, Moen M, Jacobson J, Christiansen C. 1988 The effect of a gonadotropin-releasing hormone agonist analog (Nafarelin) on bone metabolism. J Clin Endocrinol Metab. 67:701–705.[Abstract]
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