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