Vitamin K and Bone: Past, Present, and Future

Throughout the past 20 yr, substantial epidemiologic evidence has emerged suggesting that suboptimal vitamin K status can have an adverse effect on BMD and increase the risk of bone fracture. However, only recently have prospective clinical trials been conducted to determine whether vitamin K plays a role in the prevention of bone loss. In the current issue of Journal of Bone and Mineral Research, Binkley et al. report on the results of a doubleblind placebo-controlled trial of vitamin K supplementation in postmenopausal women. Vitamin K was discovered in 1935 by the Danish biochemist Henrik Dam, who was studying dietary deficiency diseases in chickens. When fed a diet free of fat and cholesterol, the chickens developed intramuscular hemorrhages and uncontrollable bleeding. Dam, with Edward Doisy, isolated the dietary substance required for blood clotting and called it the ‘‘Koagulation Vitamin,’’ or vitamin K. Soon thereafter, inactive prothrombin was shown to be the cause of the bleeding abnormality observed in vitamin K deficiency. Almost simultaneously, dicoumarol was identified as the causative agent of a hemorrhagic disease in cattle fed spoiled sweet clover hay, and its derivative, warfarin, was established as a potent anticoagulant. The mechanism of action of vitamin K remained unknown until 1974 when the modified amino acid, gcarboxyglutamic acid (Gla), was identified in normal prothrombin. The formation of Gla occurs through a unique vitamin K–dependent post-translational carboxylation of specific peptide-bound glutamate residues in a process that is inhibited by warfarin. In the mid-1970s, fetal warfarin syndrome was described. Affected infants manifested bony malformations, stippled epiphyses, and nasal hypoplasia. Mothers of infants with these characteristics were found to have received oral anticoagulation therapy during the first trimester of pregnancy. These findings led to the question of whether vitamin K nutrition or warfarin therapy plays a role in skeletal health and to the discovery of osteocalcin and other vitamin K–dependent proteins in bone. Vitamin K occurs as either phylloquinone (K1) or menaquinones (MK-n). All forms share a common structure, 2-methyl-1,4-napthoquinone, which is necessary for participation in carboxylation, but differ in the number and degree of saturation of isoprenyl side chains. The major dietary form of the vitamin is phylloquinone, which is present in dark green vegetables and certain plant oils. Long-chain menaquinones can be found in fermented foods such as cheeses or in natto, a soybean product popular in Japan. The menaquinones are synthesized by gut bacteria but do not contribute appreciably to vitamin K status in humans. Whereas there is no evidence of change in coagulation times in healthy adults with mild vitamin K deficiency, usual dietary intakes of vitamin K do not support complete carboxylation of osteocalcin. Vitamin K restriction results in an increase in serum uncarboxylated osteocalcin, and supplementation for 2 wk with 400 mg/d K1—equivalent to 2 cups of cooked broccoli— results in a 40% decrease in uncarboxylated osteocalcin. In fact, uncarboxylated osteocalcin (ucOC) in serum is the most sensitive indicator of overall vitamin K nutritional status. It should be pointed out that, because the amount of ucOC is highly correlated to total OC and total osteocalcin reflects osteoblastic activity, the ucOC fraction is expressed as %ucOC. So, what are the implications of vitamin K status for bone health? Papers regarding direct effects of warfarin therapy on BMD in humans are conflicting. Increased fracture risk has been associated with anticoagulant therapy but primarily in studies of the elderly in a long-term care setting. Such studies are problematic because of frequent confounding comorbidities. Within the last 20 yr, a preponderance of studies has advanced the notion that low dietary phylloquinone intake, as assessed by food frequency questionnaires, low circulating vitamin K levels, or high %ucOC is associated with low BMD and increased hip fracture risk. Although most of these studies were relatively small, they have been corroborated by several larger ones. In the Nurses Health Study, risk for hip fracture was significantly greater in the lowest quintile of vitamin K intake; however, a relatively narrow range of vitamin K intake was noted in the entire cohort. In the Framingham Offspring Study, dietary phylloquinone intake was associated with total hip and lumbar spine BMD in women but not in men. All of these studies are hampered by the inability to separate the effects of a single