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Dietary Vitamin K2 Supplement Improves Bone Status After Lung and Heart Transplantation

Forli, Liv1,7; Bollerslev, Jens1,2; Simonsen, Svein3; Isaksen, Gunhild A.1; Kvamsdal, Kari E.1; Godang, Kristin1; Gadeholt, Gaut4; Pripp, Are H.5; Bjortuft, Oystein6

doi: 10.1097/TP.0b013e3181c46b69
Clinical and Translational Research
Free

Background. Osteoporosis is a problem after transplantation. Studies since the last year indicate that vitamin K plays a role in optimal bone health. The aim of this randomized, double blind, prospective longitudinal study was to investigate the effect of a dietary supplement with vitamin K2 (180 μg menakinon-7) on bone mass, the first year after lung and heart transplantation.

Methods. After preoperative baseline investigation of bone mass and bone-related biochemistry, 35 lung and 59 heart recipients were postoperatively randomized to vitamin K2 or placebo and reinvestigated the following year.

Results. In all recipients, 1 year after solid organ transplantation, the difference between vitamin K2 and placebo for the lumbar spine (L2–L4) bone mineral density (BMD) was 0.028 (SE 0.014) g/cm2, P=0.055 and for L2 to L4 bone mineral content was 1.33 (SE 1.91) g/cm2 (P=0.5). In lung recipients separately, the difference for bone mineral content was 3.39 g (SE 1.65), P=0.048 and in heart recipients 0.45 (SE 0.02) g, P=0.9 after controlling for baseline measures. In a forward stepwise linear regression analysis fitted to model differences in the L2 to L4 BMD, controlled for possible confounding variables (including use of bisphosphonate), and the only significant predictors were organ (B=−0.065 g/cm2, P<0.001) and vitamin K2 (B=0.034 g/cm2, P=0.019). Insufficient vitamin D status was common, and the parathyroid hormone was highest in the K2 group indicating a higher need for vitamin D.

Conclusions. One year of vitamin K2 supplement suggest a favorable effect on lumbar spine BMD with different response in lung and heart recipients. Vitamin D status should receive more attention.

1 Medical Department, Rikshospitalet, Oslo University Hospital, Oslo, Norway.

2 Faculty Division, University of Oslo, Rikshospitalet, Oslo University Hospital, Oslo, Norway.

3 Department of Cardiology, Rikshospitalet, Oslo University Hospital, Oslo, Norway.

4 Department of Clinical Pharmacology, Rikshospitalet, Oslo University Hospital, Oslo, Norway.

5 Section of Biostatistics, Research Services Department, Rikshospitalet, Oslo University Hospital, Oslo, Norway.

6 Department of Respiratory Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway.

This work was supported in part by “NattoPharma ASA” (capsules, K vitamin analysis and data plotting) and a grant from “The Norwegian Foundation for Health and Rehabilitation” (L.F.).

The authors declare no conflict of interest.

7 Address correspondence to: Liv Forli, Dr., Rikshospitalet, Oslo University Hospital, N-0027 Oslo, Norway.

E-mail: liv.forli@rikshospitalet.no

Liv Forli participated in research design, in writing of the manuscript, performance of the work, and data analysis; Jens Bollerslev participated in research design and writing of the manuscript; Svein Simonsen participated in research design and writing of the manuscript; Gunhild A. Isaksen contributed new analytic tools; Kari E. Kvamsdal contributed new reagents; Kristin Godang contributed new reagents and participated in the writing of the manuscript; Gaut Gadeholt participated in research design and writing of the manuscript; Are H. Pripp participated in data analysis; and Oystein Bjortuft participated in research design and writing of the manuscript.

Received 30 June 2009. Revision requested 23 July 2009.

Accepted 21 September 2009.

Osteoporosis and bone fractures are common complications after solid organ transplantation, and the immunosuppressive medication is considered to play an important role (1, 2). Although usually not life threatening, it has a negative impact on quality of life, and it is especially important because graft survival is increasing.

Patients with end-stage lung and heart disease have multiple risk factors for osteoporosis (2–5). Low bone mineral density (BMD) is more common in lung transplant candidates, while also in heart recipients fractures are frequent, the first year after transplantation, parallel to the most rapid bone turnover and loss of BMD (6, 7), even after preventive therapy (7).

Increased undercarboxylated osteocalcin (ucOC) is associated with increased bone turnover, risk for low BMD, and hip fracture (8–12). Vitamin K is a cofactor for γ-carboxylation that mediates the conversion of ucOC to carboxylated osteocalcin (a marker of bone formation). Several studies have reported ucOC to be a sensitive biomarker of vitamin K status and to decrease by increased intake (13–19). Diminished detrimental effects of glucocorticoids on bone mass and prevention of new fractures have been reported after vitamin K2 treatment (20, 21). Unlike BMD, bone mineral content (BMC) does not consider the geometry (size, thickness) of the bone, which has an independent contribution to bone strength and fracture risk (22). Vitamin K2 has shown to improve bone strength (23).

Vitamin K is a group name for related components generally subdivided into phylloquinone (K1) and menaquinones (MKs; K2). MKs are further subdivided into short (e.g., MK-4) and long chain MKs (e.g., MK-7). In western countries, vitamin K1 constitutes the major part of vitamin K intake. In other countries, particularly in Japan, the food contains a high amount of MK-7. MK-7 is better absorbed and has longer biological half-life (24) and was, therefore, chosen as K vitamin source in this study.

The aim of this prospective, randomized, placebo controlled, double blind, longitudinal study was to investigate the effect of dietary supplement with vitamin K2 on plasma MK-7 and bone mass, the first year after lung and heart transplantation.

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PATIENTS AND METHODS

Patients

Consecutive stable adult lung and heart transplant candidates evaluated for a first single organ transplant from August 2003 to March 2006 were asked to participate in this study, which was approved by the Regional Ethical Committee. Internationally accepted criteria were applied for listing the patients (25, 26). Baseline investigations were performed after written informed consent was obtained. If the waiting time exceeded 12 months, new baseline investigations were performed. The recipients (35 lungs and 59 hearts) were then actually included in the study 1 to 3 weeks postoperatively, when the clinical condition was stable. The randomization was generated by random permuted blocks. The patients were stratified by patient group (lung/heart), age (≤50/>50 years), and sex. The randomization was performed by Link Medical Research AS, Oslo, Norway. Patient characteristics at baseline are presented in Table 1.

TABLE 1

TABLE 1

All recipients received triple immunosupression with prednisolone, cyclosporine A, and mycophenolatmofetil throughout the study period. The mean cumulative dose (including also intravenous bolus steroid treatment for rejection) during the first postoperative year is presented in Table 2.

TABLE 2

TABLE 2

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Study Design

The recipients were randomized to take either vitamin K2 (180 μg MK-7) or placebo at dinner time. If anticoagulation for some reason was needed, the capsules were withdrawn. Follow-up investigations were performed after 2, 6, and 12 months. The recipients were also advised an intake of vitamin D of 10 to 20 μg and 1000 mg calcium per day, and compliance was controlled at each visit. Routine prescription for bisphosphonate was only for recipients with clinical symptoms of osteoporosis in addition to proven bone fracture shown by x-ray.

A 3% lower loss of BMD among patients treated with vitamin K compared with placebo at 1-year follow-up was considered a clinical significant effect in our study. This effect corresponds to approximately ⅔ of expected standard deviation for changes in BMD for patients after transplantation, based on preliminary studies at Oslo University Hospital. A priori calculations revealed that the required number of participants were 37 in each group, vitamin K2 and placebo. This would give a clinical trial with 80% power and 5% significance level with loss of BMD at 1-year follow-up as outcome, statistically tested with an independent sample t test.

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Biochemical Measurements

Venous blood samples were collected after overnight fasting. Plasma concentrations of calcium, albumin, and creatinine were investigated by our internationally accredited laboratory. Albumin-corrected plasma calcium was calculated as calcium (mmol/L)+ (40-albumin [g/L]×0.02). Glomerular filtration rate was estimated by the modification of diet in renal disease formula (27). Bone formation marker intact osteocalcin (iOC) was measured by IRMA, (Diasorin, Stillwater, MN), and degradation products of the C-terminal telopeptides of type I collagen (CTX)-1 were measured in serum by ELISA (Serum Crosslaps, Nordic Bioscience Diagnostics A/S, Herlev, Denmark). To analyze ucOC (Glu-OC), we used ELISA reagent from TaKaRa (Tokyo, Japan). 25-Hydroxyvitamin D (calcidiol) (radio-immuno assay) and Intact-parathyroid hormone (PTH) (IRMA) were analyzed by reagent from (Diasorin, Stillwater, MN). Calcidiol level at 30 ng/mL was chosen as cutoff point for sufficient vitamin D status (28). Vitamin K was analyzed by high performance liquid chromatography, using a C-18 reversed phase column and fluorometric detection after postcolumn electrochemical reduction, as earlier described (29). Phylloquinone and MKs were measured simultaneously. In all analyses performed, the coefficients of variation were below 10%.

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Bone Mass Measurement

Area BMD at the lumbar spine L2 to L4 region and the femoral neck was measured by dual-energy x-ray absorptiometry, using a Lunar DPX-L software version 4.6 (GE Medical Systems Lunar Corp., Madison WI) until September 2005, and after that a Lunar Prodigy software version 10.10 (from the same manufacturer) was used. Cross calibrations were performed in vivo to avoid systematic error. The results are expressed as a Z scores.

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Statistical Analysis

Data were analyzed using SPSS for Windows, version 16.0 (SPSS Inc., Chicago, IL). Differences between groups were tested by an independent sample t test for means. For the final evaluation of the influence of vitamin K2, the lung and heart patients were pooled and analyzed according to the intention to treat principle. Pearson chi-square test was used to test the differences between vitamin K2 and placebo for adverse events.

BMD at end of treatment in the L2 to L4 region and in the femur neck was analyzed by linear regression. Independent variables were BMD at baseline, capsules (vitamin K2 or placebo), organ (lung or heart), and adjusted for possible confounding variables; body mass index, calcidiol, cumulative glucocorticoid and cyclosporine dose, and the use of anticoagulant and bisphosphonate. Forward stepwise analysis was performed to identify significant predictors.

Two linear mixed models for repeated measurements were fitted to evaluate measurements of ucOC throughout the study. Fixed effects were ucOC at baseline, use of anticoagulant and bisphosphonate at 2, 6, and 12 months, organ, observation time in months and in model A capsules, and in model B plasma MK (pMK)-7 at the same time points. The models had a random intercept and slope for observation time for each patient with a variance component covariance matrix for these random effects and a scaled identity covariance residual matrix. Residual plots to check for outliers and assumptions for the random effects were performed. Missing data were assumed to be completely at random. Data are presented as mean±SD if not otherwise stated, and P values of less than or equal to 0.05 were considered significant.

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RESULTS

Fifty-nine heart recipients completed 2 months and 55 6 months follow-up. Fifty-four heart and all the 35 lung recipients completed the study. Before transplantation, only lung recipients used bisphosphonate (Table 1). Three in each organ group started with bisphosphonate after transplantation. This treatment did not differ between the vitamin K2 and placebo group, neither before nor after transplantation. In addition, two heart recipients received anticoagulant treatment.

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Bone Mass

One year after transplantation, for all patients, after controlling for baseline BMD, the difference between vitamin K2 and placebo for the L2 to L4 region BMD was 0.028 (SE 0.014) g/cm2 (P=0.055) and for the femur neck was 0.005 (SE 0.013) g/cm2 (P=0.7). The percentage change from baseline in BMD (L2–L4) for the treatment groups are shown in Figure 1(c and d). The percentages change from baseline BMD at 2, 6, and 12 months after transplantation for femur neck in vitamin K2 versus placebo in lung patients were −3.5% (4.9) vs. 1.0% (6.2), −2.8% (5.8) vs. −0.3% (2.8), and −0.6% (6.7) vs. 1.2% (7.5) and in the heart patients −2.3% (4.7) vs. −2.4% (3.0), −6.9% (6.0) vs. −6.7% (5.0), −8.5% (6.9) vs. −7.6% (4.9), respectively. Only the effect of vitamin K2 was found to be statistical significant in the multiple linear regression model on differences in L2 to L4 BMD (Table 3). The stepwise analysis and the forward control for this model gave the same result, and the only significant predictors were organ (if heart=1, B=−0.065, P<0.001) and vitamin K2 versus placebo (B=0.034, P=0.019). The other independent variables were excluded from the model. The linear regression model fitted to model differences in femur neck BMD showed no association with the use of vitamin K2. One year after transplantation, after controlling for baseline BMC, the differences between vitamin K and placebo in all patients for L2 to L4 were BMC 1.33 g (SE 1.91) (P=0.5), for lung patients 3.39 g (SE 1.65) (P=0.048), and for heart patients 0.45 g (SE 0.018) (P=0.9).

FIGURE 1.

FIGURE 1.

TABLE 3

TABLE 3

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Vitamin K2

In all recipients, 1 year after transplantation, the differences between vitamin K2 and placebo for pMK-7 were 0.49 (1.07) vs. 2.04 (3.02) ng/mL (P=0.008) and for ucOC −2.2 (11.8) vs. 1.3 (±13.3) ng/mL (P=0.7), respectively. Plasma MK-7 by different organ is shown in Figure 1(a and b). After transplantation, there was a significant increase for iOC in all groups except for vitamin K2 group in the lung patients and no increase for CTX except in vitamin K2 group for heart patients (Table 2). Vitamin D status is presented in Table 4. The β coefficient for vitamin K2 versus placebo in the linear mixed model fitted to model log ucOC after transplantation was negative, but not significant (Table 5, Model A); however, when capsules were substituted by repeated measurement for pMK-7 controlled for baseline pMK-7, the β coefficient was significantly negative (Table 5, Model B).

TABLE 4

TABLE 4

TABLE 5

TABLE 5

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Drop Outs

Ten of the heart patients did not complete 12 months follow-up, and of whom three withdrew the consent to participate. One died early in the K2 group, and autopsy did not reveal any connection to the study, and the rest had adverse effects not related to the medication, and with no difference between the vitamin K2 and placebo groups.

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DISCUSSION

In this study, patients receiving solid organ transplantation for end-stage lung and heart disease vitamin K2 supplement for the first 12 months after transplantation suggested a favorable effect on lumbar spine BMD compared with placebo. Osteoporosis is a significant clinical problem, and clinical trials have focus on preventing bone loss in the early phase after lung and heart transplantation (30–32), and bisphosphonate is the most commonly used medication with proven effect (32–34). Intervention with vitamin K has been performed, mainly either with vitamin K1 or pharmacological doses of MK-4 (13, 35, 36).

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Bone Mass

A suggestive positive effect of vitamin K2 on BMD was indicated in the L2 to L4 region. The greatest effect was seen in the heart recipients, whereas for BMC, it was only seen in the lung recipients. In the case of an increase in BMC, where BMD remains constant, the area increase and may improve bone strength. Vitamin K2 was found to maintain hip bone strength by improving BMC and femur neck width, whereas it had little effect on BMD (23). The lumbar region contains mostly trabecular bone that has a more rapid bone turnover than cortical bone, which is more dominant in the hip. The use of bisphosphonate might have contributed to the differences between the lung and heart recipients, but our results suggest an effect on BMD after controlling for the use. However, studies in postmenopausal osteoporosis and in animal models suggest a benefit of a combination of vitamin K2 and bisphosphonate (37–39).

Children have a much higher bone turnover than adults and if receiving anticoagulant, show vitamin K deficiency resulting in significantly reduced bone mass (40). Transplant recipients have a high bone turnover and may, therefore, be more sensitive to anticoagulant and low vitamin K status. In nontransplanted adults, the use of anticoagulant has shown conflicting results facilitating osteoporosis (41) or not (42).

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Vitamin K2

This study focused on vitamin K2 supplementation and bone mass assessed by osteodensitometry in lung and heart transplanted recipients early after transplantation, and the study is to our knowledge the first using MK-7. The compliance for taking capsules was the same, and bioavailability was assumed similar in both populations. If so, the differences in pMK-7 between the organs could be explained by faster vitamin K2 breakdown in the lung recipients. One pathway of vitamin K2 metabolism is omega-oxidation (43), which has been demonstrated in the lungs (44), but it is unknown if this differs in the transplanted lung.

In this study, we found that iOC increased after transplantation, as reported in earlier studies and indicating a higher bone turnover and bone loss (4, 45, 46). Osteocalcin is excreted in the kidneys (5), and the reduced renal function might have contributed to increased iOC. At baseline, the heart patients had higher iOC and PTH than the lung patients, which fit with the reduced kidney function. Only in the vitamin K2 group in the lung patients, there was no significant increase neither for iOC nor for CTX, indicating less bone turnover than in the other groups. ucOC increased after transplantation, but it was expected to increase less in the vitamin K2 group. Anticoagulants suppress the carboxylation of ucOC (47), and our results confirmed a positive association between ucOC and the use of anticoagulant.

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Vitamin D

The recipients were carefully advised a sufficient intake of vitamin D and calcidiol improved after transplantation. However, many recipients had insufficient vitamin D status. The increase in PTH in the vitamin K2 group also indicates insufficient vitamin D status, and that vitamin D requirement has been higher in this group.

Combined administration of vitamin K and D increase BMD (48, 49). An increase of ucOC may not only be caused by vitamin K deficiency but also caused by vitamin D deficiency (19). Studies in animal and cell models have shown that vitamin D may be necessary prior to the γ-carboxylation of ucOC, because ucOC is induced by the action of activated vitamin D3 (50, 51). An increased requirement for vitamin D could also in part be due to the combined effect of vitamin K2 and bisphosphonate. Sufficient vitamin D is also regarded necessary for the optimal effect of bisphosphonate (52).

Both before and after transplantation, the heart recipients had lower calcidiol status than the lung patients and BMD in the lumbar spine decreased within the range of earlier studies (53). Low serum concentrations of calcidiol have earlier been reported in end-stage congestive heart failure and found to be associated with higher rates of bone loss after transplantation (5), whereas calcitriol has been shown to prevent glucocorticoid-induced osteoporosis (54). The need for vitamin D after transplantation is supported by the observation that supplementation with calcitriol has been found to prevent bone loss in the critical first postoperative year (55).

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Coagulofibrinolysis

The coagulofibrinolysis function after extra vitamin K2 was carefully discussed before start of the study and was considered safe. Ushiroyama et al. (56) examined this after administration of high doses for 24 months and observed an increase in coagulation function, but only within normal physiological range, and no adverse reactions were observed. Vitamin K interferes with the action of anticoagulants (57), and the use of capsules was, therefore, discontinued if anticoagulation was needed.

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Study Limitation

This is the first study to investigate the effect of vitamin K2 on bone loss in lung and heart recipients. Its strength is the prospective, randomized, double blind design. However, in retrospect, we realize that more focus should have been laid on vitamin D intake, which may have limited the effect of vitamin K2, as indicated by an increased PTH, especially in the lung recipients. A higher vitamin D intake might have strengthened the observed effect on the BMD. The renal function was evaluated by estimated glomerular filtration rate by the modification of diet in renal disease formula. This could be a potential limitation, but it should be noted that the formula is extensively validated and has been shown to be accurate in transplantation recipients (58).

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CONCLUSION

Dietary supplementation with vitamin K2, 180 μg per day, the first year after lung and heart transplantation, increased plasma MK-7, however, not significant in the lung recipients. The results suggest that dietary supplement with MK-7 could have a favorable effect on bone mass, for BMD more in the heart than the lung recipients, whereas for BMC only in the lung recipients. PTH was higher in the vitamin K2 supplemented than in the placebo group, indicating an insufficient vitamin D status and a higher need for vitamin D. The results are suggestive, and further studies are needed before vitamin K2 treatment can be generally recommended in clinical practice.

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ACKNOWLEDGMENTS

The authors thank professor Jacob Boe, Department of Respiratory Medicine, Rikshospitalet, for support in the planning process.

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Keywords:

Vitamin K; Bone mineral density; Lung transplantation; Heart transplantation

© 2010 Lippincott Williams & Wilkins, Inc.