Pii: s0378-5122(01)00275-4

Maturitas 41 (2002) 211 – 221 Effect of continuous combined therapy with vitamin K and vitamin D on bone mineral density and coagulofibrinolysis function in postmenopausal women Takahisa Ushiroyama *, Atushi Ikeda, Minoru Ueki Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan Received 28 July 2000; received in revised form 7 February 2001; accepted 14 September 2001 Objecti6es: To investigate the therapeutic effect of combined use of vitamin K and D on vertebral bone mineral density in postmenopausal women with osteopenia and osteoporosis. Subjects and methods: We enrolled 172 womenwith vertebral bone mineral density B0.98 g/cm2 (osteopenia and osteoporosis) as measured by dual-energy X-rayabsorptiometry. In this study, we employed the criteria for diagnosis of osteopenia and osteoporosis using dual energyX-ray absorptiometry proposed by the Japan Society of Bone Metabolism in 1996. Subjects were randomized intofour groups (each having 43 subjects in vitamin K therapy group, vitamin D therapy group, vitamin K and D combined therapy group, or a control group receiving dietary therapy alone) and treated with respective agents for2 years, with bone mineral density was measured prior to therapy and after 6, 12, 18, and 24 months of treatment.
The bone metabolism markers analyzed were serum type 1 collagen carboxyterminal propeptide (P1CP), serum intactosteocalcin, and urinary pyridinoline. Tests of blood coagulation function consisted of measurement of activatedpartial thromboplastin time (APTT) and analysis of concentrations of antithrombin III (AT III), fibrinogen, andplasminogen. Results: Combined therapy with vitamin K and D for 24 months markedly increased bone mineral density (4.92 97.89%), while vitamin K alone increased it only 0.13595.44%. The bone markers measured, revealed stimulation of both bone formation and resorption activity. We observed an increase in coagulation and fibrinolyticactivity that was within the normal range, suggesting that balance was maintained in the fibrinolysis – coagulationsystem. Conclusions: Continuous combination therapy with vitamin K and D may be useful for increasing vertebral bone mass in postmenopausal women. Furthermore, the increase in coagulation function observed during this therapywas within the physiological range, and no adverse reactions were observed. 2002 Elsevier Science Ireland Ltd. Allrights reserved.
Keywords: Vitamin K ; Vitamin D ; Bone mineral density; Postmenopause; Coagulofibrinolysis * Corresponding author. Tel.: + 81-726-83-1221; fax: + 81- Postmenopausal women experience accelerated E-mail address: (T. Ushi- bone loss, which leads to osteoporosis and in- 0378-5122/02/$ - see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved.
T. Ushiroyama et al. / Maturitas 41 (2002) 211 – 221 creased risk of development of fractures in the tial to this process. Vitamin K , the human-acti- spine (vertebral crush fractures), forearm (Colles' vated form of vitamin K, is said to promote the fractures) and hip. Osteoporotic fractures of the healing of bone fractures, to have a therapeutic spine and forearm are associated with significant effect on osteoporosis, and to inhibit bone resorp- morbidity, but the most serious consequences of tion [17,18]. It may also play a role in bone bone loss arise in patients with hip fracture, which metabolism other than the g-carboxylation of os- is associated with a significant increase in mortal- teocalcin. The addition of vitamin K and acti- ity (15 – 20%), particularly in the elderly [1]. Sev- to a system of cultured eral approaches are currently available to prevent osteoblasts has been shown to promote calcifica- and treat osteoporosis, including dietary modifica- tion [19]. In Japan, the incidence of fractures in tions and drugs which inhibit bone resorption.
the eastern part of the country is lower than that There are now a variety of treatment approaches in the west, a phenomenon that may be associated available for the management of osteoporosis.
with differences in food culture between the two Inhibitors of bone resorption, including calcium, regions, specifically, in the consumption of natto the vitamin Ds, ipriflavone, bisphosphonates, cal- (fermented soybeans). Natto is rich in the MK-7 citonins and gonadal steroids have been variously (menaquinone-7) form of vitamin K , which has shown to prevent bone loss or to reduce fractures the same effect as the MK-4 form of vitamin K , [2 – 4]. The effect of vitamin supplements on bone one of the medications currently used to treat metabolism indices in patients with osteopenia osteoporosis. Estrogen is an agent of choice for and osteoporosis has received scant attention in both prevention and treatment of postmenopausal the literature. However, some authors have re- osteoporosis; however, once estrogen treatment is ported that vitamin D and K may prevent bone discontinued, bone mass density drop fairly loss and fractures [5 – 11]. There is evidence that quickly, and relatively high incidence of side ef- calcium is important not only for peak bone mass fects have been observed [6]. Long-term adherence development but also in reducing bone loss in to hormone replacement therapy is considered to postmenoapusal women. It has been believed that be low compliance. Effective alternatives for pre- Vitamin D and calcium (and possibly vitamin K) vention of bone loss in recently postmenopausal are vital to prevention of bone loss and fracture.
women include vitamin K and vitamin D. Al- Matsunaga found a synergistic effect of vitamin D though, single therapies with these are effective in and K in reducing bone loss in ovariectomized inhibiting bone loss, prevention of bone loss in rats [10]. Furthermore, it was observed that effi- postmenopausal women is more difficult than cacy of vitamin K was stronger in high bone hormone replacement therapy [7,20,21], and the resorption and high plasma vitamin D level [12].
clinical results of combined therapy have not been Thus, in conditions of high turnover in bone fully examined [9,22,23].
metabolism such as early postmenopausal period, In this communication, we present the results of it is conceivable that the clinical effect of vitamin our study of the clinical effects of combined use of K may increase when the plasma vitamin D level vitamin K and D on postmenopausal osteopenia and osteoporosis, and of its effects on bone metabolism and the coagulofibrinolysis system.
The causes of osteoporosis have not yet been fully elucidated, but recently published reportssuggest a possible involvement of vitamin K defi- 2. Subjects and methods
ciency [13 – 15]. It has been suggested that g-car-boxyglutamic We enrolled 172 women with a bone mineral (osteocalcin, BGP), a bone matrix protein, plays a density of the lumbar spine B0.98 g/cm2, as key role in bone metabolism [16]. The glutamic measured by dual-energy X-ray absorptiometry acid residues of osteocalcin are g-carboxylated by (DEXA, Lunar DPX-L), in the present random- the enzyme carboxylase, and vitamin K is essen- ized study. All subjects were attending the De- T. Ushiroyama et al. / Maturitas 41 (2002) 211 – 221 partment of Obstetrics and Gynecology at Osaka istics of 126 patients at the start of the study. The Medical College for outpatient consultations re- profiles for age, postmenopausal duration, per- lated to climacteric/menopausal conditions. We randomly assigned them to one of the following menopause, serum calcium, serum gonadotropin four groups by month of birth (January – March, and estradiol values, and physique did not differ April – June, July – September, October – Decem- significantly among the four groups. There were ber) after sufficient informed consent: vitamin K no significant differences on one-way factorial analysis of variance (ANOVA) in basal levels of Glakay 45 mg per day), vitamin D therapy group bone mineral density among the four groups.
(43 subjects; 1-a hydroxycholecalciferol: Onealfa 1 The patients were not given specific instructions mg per day), vitamin K and D combined therapy regarding adequate dietary calcium intake and did group (43 subjects), or a control group receiving not take part in a program of exercise. However, dietary therapy alone (43 subjects). This study use of daily products including milk in meals was started with 172 subjects, with 43 patients in each instructed when questions about calcium intake of the four groups, while 12, 26, 38 and 46 were asked. Patients in each group were treated patients dropped out within 6, 12, 18 and 24 for 2 years, during which periodic measurements of bone mineral density and evaluations of bone dropout rate 26.7%). We enrolled 126 patients metabolism markers and coagulofibrinolysis func- who have finished this study of 24 months and tion were performed. Vertebral bone mineral den- analyzed their data. Table 1 shows the character- sity was measured at baseline and after 6, 12, 18 Table 1Initial values for the subjects Number of patients Number of years (S.D.) from Age within 3 years of Mean (S.D.) body mass indexa Mean (S.D.) percent fatb Mean (S.D.) serum calcium level Mean (S.D.) serum phosphate level Mean (S.D.) serum creatinine level Mean (S.D.) plasma hormone le6elsFSH (mIU/ml) Estradiol (pg/ml) a Body mass index expressed as weight (kg)/height (m)2.
b Percent fat was measured by DPH (Lunar Hadiation, Madison, WI, USA).
FSH and LH were greater than 30 and 15 IU/ml, respectively, in all women. Figures in parenthesis indicate 1 standard deviation.
P-value assessed using ANOVA. No significant differences were found in any of the parameters among the groups.
T. Ushiroyama et al. / Maturitas 41 (2002) 211 – 221 and 24 months of therapy by dual energy X-ray 3. Results
absorptiometry (model DPX, Lunar RadiationCorp, Madison, WI, USA) which uses a constant There were no significant differences on one- potential X-ray source at 12.5 fJ and a K-edge way factorial ANOVA in basal levels of bone filter (cecium) to achieve a congruent beam of mineral density among the four groups consisting stable dual energy radiation. The effective energies of the 172 patients who started the study (P = were 6.4 and 11.2 fJ. Bone mineral density was 0.23) and the 126 patients who continued this assessed for the L2-4 region and expressed as the clinical study for 2 years (P = 0.057). However, average areal density (BMD = g/cm2). We defined there were significant differences in this parameter osteopenia as a BMD value below 0.98 g/cm2 and between the combined group and vitamin K2 osteoporosis as a BMD below 0.83 g/cm2. In this (P = 0.0101) and vitamin D (P study, we employed the criteria for diagnosis of for the latter 126 patients on multiple comparison osteopenia and osteoporosis using dual energy by ANOVA. Since 26.7% of the patients dropped X-ray absorptiometry which was proposed by the out over 2 years, although the present study was Japan Society of Bone Metabolism in 1996 [24].
begun with 172 subjects and dropouts include The in vivo and in vitro coefficients of variation patients with relatively high BMD in the com- were 0.73 and 0.41%, respectively. The bone bined therapy group, basal level of BMD was metabolism markers analyzed were serum type 1 significantly lower than those in the vitamin K or D alone therapy group in the evaluation includ- serum intact osteocalcin, and urinary pyridinoline.
ing only those subjects who completed the 2-year Serum type 1 collagen carboxyterminal propeptide study. The following appear to be biased data (P1CP) was measured by radioimmunoassay using given the above considerations. In the vitamin K2 a kit from Orion Diagnostica (Espoo, Finland).
alone group, mean bone mineral density remained Serum intact osteocalcin concentrations were mea- lower than the baseline level (0.876 90.091 g/cm2) sured by radioimmuassay using a kit from Ya- up to 18 months after the start of treatment, but masa Corp (Chiba, Japan). Urinary excretions of was slightly higher (not significant) at 24 months pyridinoline were measured by HPLC (Sumitomo (0.888 90.112 g/cm2). In contrast in the vitamin Metal Bioscience Lab.) according to the methods K and D combined therapy group bone mineral of Eyre et al. [25], and values were corrected using density was 0.052 g/cm2 higher than the baseline the urinary excretion of creatinine. To confirm level (0.820 90.097 g/cm2) at 6 months (PB effects of vitamin K, we monitored the time course 0.001, significant), and higher BMD levels were of changes in urinary concentration of g-carboxyg- sustained up to 24 months (Table 2). The time lutamate (Gla)/Cr. The urinary concentration of course of percentage changes in BMD in the 126 g-carboxyglutamate was measured by HPLC patients who continued this study for 24 months (Sumitomo Metal Bioscience Lab) according to is shown in Fig. 1. There were no significant the methods of Kuwada and Katayama [26]and differences from control for the subjects receiving values were corrected using the urinary excretion vitamin K alone therapy at 6 months (1.31 9 of creatinine. Tests of blood coagulation function 6.94%) or 12 months (0.736 96.09%), whereas the consisted of measurement of activated partial percentage change in BMD was significantly thromboplastin time (APTT) and analysis of con- higher than control at 18 months (0.278 96.55%, centrations of antithrombin III (AT III), fibrino- P B0.05) and 24 months (0.13595.44%, PB gen, and plasminogen. These measurements were 0.05). On the other hand, the percentage increases performed using standard laboratory methods.
in BMD in the vitamin K and D combined Data were statistically analyzed by ANOVA or therapy group were significantly higher (4.10 9 the Wilcoxon signed-rank test, and the level of 5.88% at 6 months; P B0.001, 5.8696.85% at 12 significance was set at P B0.05. Results are pre- months; P B0.001, 5.0198.11% at 18 months; sented as mean and standard deviation (mean 9 P B0.001, and 4.9297.89% at 24 months; PB 0.001) than those in the control group. Compared T. Ushiroyama et al. / Maturitas 41 (2002) 211 – 221 Table 2Vertebral bone mass before and during treatment *PB0.05; **PB0.001, significance was determined using Wilcoxon's signed-rank test, and P-values refer to differences in bone masslevels in the treated groups compared with their levels at the start of the study. Mean (S.D.) values are expressed as g/cm2.
Fig. 1. Percentage changes (mean 9S.D.) from baseline in bone mineral density in all four groups during the 24-month study.
P-value assessed using Wilcoxon signed-rank test.
with the vitamin K or D alone therapy group, P B0.001, vitamin K —combined therapy; PB BMD was significantly increased in the combined 0.01). Furthermore, it was found that there were therapy group from 6 to 24 months after the start more responders to treat in the combined therapy of treatment (vitamin D — combined therapy; group than in the vitamin K and D alone group.
T. Ushiroyama et al. / Maturitas 41 (2002) 211 – 221 In the 24-month treatment, BMD increase of 5% or higher was exhibited by 9.4 and 23.3% of the which was used to confirm the absorption and subjects in the vitamin K and D alone groups, physiological activity of vitamin K , revealed that respectively, but it was exhibited by 45.2% of the the concentration increased significantly with subjects in the combined therapy group (signifi- treatment in both the vitamin K alone therapy cantly higher than in the vitamin D alone group, group (6 M; 53.0 938.2%, 18 M; 82.5956.3%, 24 P = 0.014). In the combined therapy group, more- M; 56.8 938.8%, PB0.01) and the vitamin K2 over, 67.8% of responders had BMD increase of and D combined therapy group (6 M; 43.9 9 2% or higher. Although non-responders with 43.6%, 12 M; 44.9 972.1%, 18 M; 49.9949.5%, BMD decrease up to 22.6% were found, the per- P B0.01). Serum intact osteocalcin and urinary centage of such patients was significantly lower pyridinoline levels tended to increase with dura- than that in the vitamin D alone group (71.9%) tion of treatment (12 and 18 months) in the (P = 0.025) (Table 3).
combined therapy group. Serum intact osteocalcin There were no significant differences among level increased significantly by 36.0 944.8% at 18 any of the groups in any of the background months (P B0.05) in the combined therapy group.
parameters, bone parameters or coagulofibrinoly- Urinary pyridinoline level was significantly in- sis parameters (Table 4). Measurement of urinary creased at 18 months (89.6 9112.3%, PB0.01) Table 3Percentages of responders and non-responders to 24-months treatment Significant differences Increase in BMD5% and more D3-Comb.: P = 0.014, others: n.s.
Decrease in BMD0–2% D3-Comb.: P = 0.025, others: n.s.
Table 4Baseline values of bone metabolism and coagulofibrinolysis parameters Mean (S.D.) intact osteocalcin (ng/ml) Mean (S.D.) P1 CP (ng/ml) Mean (S.D.) urinary Mean (S.D.) g-carboxyglutaminate (Gla)/creatinine (nmol/MCM. Cr.) Mean (S.D.) APTT (s) Mean (S.D.) antithrombin III activity Mean (S.D.) fibrinogen (mg/dl) Mean (S.D.) plasminogen (%) Figures in parenthesis indicate 1 standard deviation. P-value assessed using ANOVA. No significant differences were found in anyof the parameters among the groups. P I CP, type I procollagen C-terminal propeptide; APTT, active partial thromboplastin time.
T. Ushiroyama et al. / Maturitas 41 (2002) 211 – 221 Fig. 2. Percentage changes from baseline in bone metabolism markers in all four groups during the 24-month study. Values areexpressed as mean 9S.E.M. P-value assessed using Wilcoxon signed-rank test. *: PB0.05, **: PB0.01 compared with the baseline.
and 24 months (53.4 955.7%, PB0.05) in the change and changes in serum P1CP levels at 12 vitamin K alone therapy group. In the combined months in the vitamin K treatment group (P = therapy group, urinary pyridinoline level was sig- 0.0012). A significant positive correlations were nificantly increased at 6 (17.5 936.4%, PB0.05), also observed between BMD change and changes 12 (27.5 918.7%, PB0.05), 18 months (29.49 in serum P1CP level (P = 0.034) and intact os- 31.7%, P B0.05) and 24 months (84.5951.9%, teocalcin level (P = 0.035) after 12 months of P B0.01) of treatment.
combined therapy. At 24 months of combined Serum P1CP was approximately 20% higher at therapy, we also observed a positive correlation 6 months (19.8 927.5%, PB0.05) and 12 months between BMD change and intact osteocalcin level (18.7 937.2%, PB0.05) in the vitamin K alone (P = 0.002). On the other hand, we observed a therapy group and returned to baseline levels at significant negative correlation between BMD 24 months. In contrast, in the combined therapy change and change in urine pyridinolin level at 12 group baseline levels were more or less main- (P = 0.001) and 24 months (0.004) of combined tained up to 12 months, but increases of 21.8 ( 922.5)% and 24.2 (923.1)% were then recorded Tests of coagulation function revealed a grad- at 18 months (P B0.05) and 24 months (PB ual decline in APTT in both the vitamin K alone 0.01), respectively (Fig. 2). Table 5 shows the group and combined therapy with vitamin D3 correlation between BMD change and bone group, which fell significantly to 15.0 98.4 and metabolic marker changes during treatment with 14.2 911.5% below baseline at 6 months (PB vitamin K or combined therapy. There was a 0.01) and 18 months (P B0.05), respectively, in significant positive correlation between BMD alone therapy, and fell signifi- T. Ushiroyama et al. / Maturitas 41 (2002) 211 – 221 cantly to 19.1 910.4 and 15.299.5% below base- line at 18 months (P B0.01) and 24 months (PB0.05) in the combined therapy with vitamin D Vitamin K occurs naturally in two forms, K group. Serum AT III activity gradually increased and K . The K congener, menaquinone-4, which over time, and increased significantly to 8.2 96.4 has the most potent g-carboxylation activity, re- and 8.3 97.5% above baseline at 18 months (PB portedly improves bone mass in patients with 0.05) and 24 months (P B0.05), respectively, in involutional osteoporosis [17]. In the present the vitamin K alone therapy, and increased sig- study, we attempted to determine whether combi- nificantly to 11.1 97.4 and 15.297.5% above nation therapy with vitamin K and D yields a baseline at 18 months (P B0.01) and 24 months synergistic effect in maintaining or increasing (P B0.01), in the combined therapy with vitamin bone mineral density due to promotion of calcifi- D group. Serum fibrinogen and plasminogen lev- cation in postmenopausal women with decreased els also tended to increase gradually over time.
bone mass. Treatment with menaquinone-4 alone Significant increases in serum fibrinogen levels for 24 months produced an increase of 0.135 95.44% in BMD, confirming a maintenance effect were observed at 6 months (26.0 941.5%, PB on BMD. For combination therapy consisting of 0.05) from baseline in the vitamin K alone ther- vitamin K and D , however, marked increases in BMD of 5.86 96.85 and 4.9297.89% were ob- (28.1 935.5%, PB0.05) and 24 months (30.29 served at 12 and 24 months, respectively. Com- 33.5%, P B0.05) from baseline in the combined bined therapy appears to have an effect on therapy group. Significant increases in serum plas- vertebral BMD in the first 6 – 12 months, while minogen levels were observed at 18 months thereafter mean rate of increase in BMD decline.
(14.2 912.2%, PB0.05 and 11.998.5%, PB The rate of increase appeared to decrease slightly 0.01) and 24 months (19.6 912.6%, PB0.01 and because the bone metabolic profile was almost 19.2 913.5%, PB0.05) from baseline in both the stabilized by sufficient supplementation of vitamin vitamin K alone therapy group and combined after 12 months, followed by the therapy group (Fig. 3).
effects of physiological aging. However, since the Table 5Correlations between percent changes in vertebral BMD and bone markers Correlation value (R) Regression coefficient Vitamin K alone 12 months therapy Intact osteocalcin Vitamin K alone 24 months therapy Intact osteocalcin Combined therapy with 6itamin K and D 12 months Intact osteocalcin Combined therapy with 6itamin K and D 24 months Intact osteocalcin T. Ushiroyama et al. / Maturitas 41 (2002) 211 – 221 Fig. 3. Percentage changes from baseline in coagulation function in all four groups during the 24-month study. Values are expressedas mean 9S.E.M. P-value assessed using Wilcoxon signed-rank test. *: PB0.05, **: PB0.01 compared with the baseline.
rate of decrease was smaller than the 1.9% per osteoporosis, there is negative imbalance between year exhibited by the control group, it appeared bone resorption and bone formation, resulting in that decrease in BMD could be suppressed by bone loss. We observed significant BMD change combined therapy with vitamin K and D for a at 6 months of combined therapy, while mean period from several years to more than 10 years levels of bone formation markers did not increase after menopause, leading to prevention of bone and bone resorption marker increased signifi- fracture. Koshihara and colleagues described a cantly. Although clear explanation of this contra- synergistic effect in an in vitro system containing diction is difficult, there appeared to be more cultured osteoblasts, in which this process of cal- cases in which osteogenesis became dominant in cification was greatly promoted by the presence of the balance of formation and resorption in bone [27]. Iwamoto et al. reported that metabolism, since there were many responders in vitamin K suppressed decrease in spinal BMD, the combined therapy group. Moreover, the mean compared with vitamin D treatment [28]. In an- values of bone resorption markers did not de- other recent study, vitamin K partially prevented crease compared with the previous value due to bone loss caused by estrogen deficiency, when combined with vitamin D [29].
menopausal period, but the change in such mark- There was a tendency toward higher concentra- ers was sufficient to suppress bone resorption. The tions of intact osteocalcin at times up to 18 significant positive correlation between individual months of treatment in the groups receiving vita- BMD change and serum P1CP level in the 24- min K alone and combined therapy, reflecting month vitamin K alone therapy and the signifi- the fact that bone turnover had increased. In cant positive correlation between individual BMD T. Ushiroyama et al. / Maturitas 41 (2002) 211 – 221 change and serum P1CP level and intact osteocal- raishi for her skillful assistance, and are grateful cin level in the group with combined therapy with to Eizai Pharmaceutical Co Ltd for financial vitamin D suggested that vitamin K can acceler- ate bone formation, and that this formation canbe potentiated by combination with vitamin D .
In recent in vitro studies, menaquinone-4 modu-lated proliferation and function of mouse cultured osteoblastic cells in vitro [30].
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