Effects of risedronate alone or combined with vitamin K2 on serum undercarboxylated osteocalcin and osteocalcin levels in postmenopausal osteoporosis

Kasukawa, Yuji; Miyakoshi, Naohisa; Ebina, Toshihito; Aizawa, Toshiaki; Hongo, Michio; Nozaka, Koji; Ishikawa, Yoshinori; Saito, Hidetomo; Chida, Shoichi; Shimada, Yasuhiro

doi:10.1007/s00774-013-0490-5

Cited by 38 publications

(25 citation statements)

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“…The fraction of imperfect γ-carboxylation is referred to as ucOC, which is produced and released from osteoblasts into the vitamin K insufficiency or deficiency. Serum ucOC is rapidly decreased with Vitamin K 2 treatment [10] . On the other hand, regular intake of vitamin K increases BMD, and reduces the bone fracture risk [11] .…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the high level of serum ucOC induced by long-term warfarin therapy is considered one of the risks of osteoporosis. It has been reported that 4.5 ng/mL of ucOC has a cut-off value to determine vitamin K insufficiency or deficiency for osteoporotic fractures [10] . In addition, it was also reported that serum ucOC is an independent determinant of carotid artery calcification and negatively correlates with renal function [12] .…”

Section: Discussionmentioning

confidence: 99%

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Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis

et al. 2015

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BackgroundStroke prevention by warfarin, a vitamin K antagonist, has been an integral part in the management of atrial fibrillation. Vitamin K-dependent matrix Gla protein (MGP) has been known as a potent inhibitor of arterial calcification and osteoporosis. Therefore, we hypothesized that warfarin therapy affects bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction.MethodsWe studied 42 atrial fibrillation patients at high-risk for atherosclerosis having one or more coronary risk factors. Twenty-four patients had been treated with warfarin for at least 12 months (WF group), and 18 patients without warfarin (non-WF group). Bone alkaline phosphatase (BAP) and under carboxylated osteocalcin (ucOC) and receptor activator of nuclear factor-kappa B ligand (RANKL) were measured as bone metabolism markers. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) index measured by Endo-PAT2000 was used as an indicator of vascular endothelial function.ResultsThere were no significant differences in patient background characteristics and other clinical indicators between the two groups. In WF group, the ucOC levels were significantly higher than those in the non-WF group (10.3 ± 0.8 vs. 3.4 ± 0.9 ng/mL; P < 0.01), similarly, the RANKL levels in the WF group were higher than those in the non-WF group (0.60 ± 0.06 vs. 0.37 ± 0.05 ng/mL; P = 0.007). Moreover, RH-PAT index was significantly lower in the WF group compared to those in the non-WF group (1.48 ± 0.11 vs. 1.88 ± 0.12; P = 0.017).ConclusionsLong-term warfarin therapy may be associated with bone mineral loss and vascular calcification in 60–80 year old hypertensive patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis

et al. 2015

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“…Uncarboxylated osteocalcin (GluOC) constitutes ϳ10% of total circulating osteocalcin in adult mice under normal physiological conditions (2, 10). However, the serum concentration of GluOC is increased in pathological conditions such as vitamin K deficiency and osteoporosis (2,26,31). Animal studies have shown that an increase in the circulating concentration of GluOC prevents obesity and glucose intolerance (10,13,28,30).…”

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confidence: 99%

Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet

Yasutake

Mizokami

Kawakubo‐Yasukochi

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, highsucrose diet. Am J Physiol Endocrinol Metab 310: E662-E675, 2016. First published February 16, 2016 doi:10.1152/ajpendo.00334.2015.-Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion, pancreatic ␤-cell proliferation, and adiponectin expression in adipocytes. Previously, we showed that long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level, improved glucose tolerance, and increased the fasting serum insulin concentration as well as pancreatic ␤-cell area in female mice fed a normal or high-fat, high-sucrose diet. We have now performed similar experiments with male mice and found that such GluOC administration induced glucose intolerance, insulin resistance, and adipocyte hypertrophy in those fed a high-fat, high-sucrose diet. In addition, GluOC increased the circulating concentration of testosterone and reduced that of adiponectin in such mice. These phenotypes were not observed in male mice fed a high-fat, high-sucrose diet after orchidectomy, but they were apparent in orchidectomized male mice or intact female mice that were fed such a diet and subjected to continuous testosterone supplementation. Our results thus reveal a sex difference in the effects of GluOC on glucose homeostasis. Given that oral administration of GluOC has been considered a potentially safe and convenient option for the treatment or prevention of metabolic disorders, this sex difference will need to be taken into account in further investigations. adiponectin; insulin resistance; osteocalcin; sex difference; testosterone OSTEOCALCIN IS A BONE MATRIX PROTEIN synthesized by osteoblasts that also functions as a hormone in the uncarboxylated state to regulate various aspects of physiology, including glucose metabolism, brain function, and male fertility (14,17,30,39,40). Uncarboxylated osteocalcin (GluOC) constitutes ϳ10% of total circulating osteocalcin in adult mice under normal physiological conditions (2, 10). However, the serum concentration of GluOC is increased in pathological conditions such as vitamin K deficiency and osteoporosis (2,26,31). Animal studies have shown that an increase in the circulating concentration of GluOC prevents obesity and glucose intolerance (10,13,28,30). Mice genetically deficient in Esp (a protein tyrosine phosphatase expressed in osteoblasts), a gainof-function model for osteocalcin, were thus protected from obesity, glucose intolerance, and insulin resistance induced by a high-fat diet (14, 30). Continuous administration of GluOC via a subcutaneous osmotic pump lowered blood glucose levels and increased pancreatic ␤-cell mass, insulin secretion, and insulin sensitivity in mice with high-fat diet-or gold thioglucose-induced obesity, with this latter effect being achieved via upregulation of expression of the gene for the insulin-sensitizing adipokine adiponectin in adipocytes (10). Moreove...

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“…A smaller study [40] in 101 women comparing risedronate and K2 bitherapy versus monotherapy with risedronate failed again to demonstrate a reduction in vertebral fracture incidence between the two groups but found that ucOC levels were greater in patients with vertebral fractures treated with risedronate alone, in comparison with bitherapy. Finally, a small study [41] involving 62 postmenopausal women with rheumatoid arthritis and osteopenia or osteoporosis found that combined therapy with alendronate and vitamin K2, decreases ucOC and bone metabolism markers and increases BMD in both lumbar spine and femoral neck.…”

Section: Effect Of Vitamin K Supplements In Association With Othermentioning

confidence: 95%

Vitamin K and Bone Health: A Review on the Effects of Vitamin K Deficiency and Supplementation and the Effect of Non-Vitamin K Antagonist Oral Anticoagulants on Different Bone Parameters

Rodríguez

Curiel

2019

Journal of Osteoporosis

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Although known for its importance in the coagulation cascade, vitamin K has other functions. It is an essential vitamin for bone health, taking part in the carboxylation of many bone-related proteins, regulating genetic transcription of osteoblastic markers, and regulating bone reabsorption. Vitamin K deficiency is not uncommon, as deposits are scarce and dependent upon dietary supplementation and absorption. Vitamin K antagonist oral anticoagulants, which are prescribed to many patients, also induce vitamin K deficiency. Most studies find that low serum K1 concentrations, high levels of undercarboxylated osteocalcin (ucOC), and low dietary intake of both K1 and K2 are associated with a higher risk of fracture and lower BMD. Studies exploring the relationship between vitamin K supplementation and fracture risk also find that the risk of fracture is reduced with supplements, but high quality studies designed to evaluate fracture as its primary endpoint are needed. The reduction in risk of fracture with the use of non-vitamin K antagonist oral anticoagulants instead of warfarin is also of interest although once again, the available evidence offers disparate results. The scarce and limited evidence, including low quality studies reaching disparate conclusions, makes it impossible to extract solid conclusions on this topic, especially concerning the use of vitamin K supplements.

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Effects of risedronate alone or combined with vitamin K2 on serum undercarboxylated osteocalcin and osteocalcin levels in postmenopausal osteoporosis

Cited by 38 publications

References 33 publications

Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis

Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis

Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet

Vitamin K and Bone Health: A Review on the Effects of Vitamin K Deficiency and Supplementation and the Effect of Non-Vitamin K Antagonist Oral Anticoagulants on Different Bone Parameters

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