Effect of Vitamin K Supplementation on Bone Loss in Elderly Men and Women

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1 J Clin Endocrinol Metb April; 93(4): Published online 2008 Februry 5. doi: /jc PMCID: PMC Effect of Vitmin K Supplementtion on Bone Loss in Elderly Men nd Women Srh L. Booth, Gerrd Dlll, M. Kyl She, Cren Gundberg, Jmes W. Peterson, nd Bess Dwson-Hughes U.S. Deprtment of Agriculture Humn Nutrition Reserch Center on Aging t Tufts University (S.L.B., G.D., M.K.S., J.W.P., B.D.-H.), Boston, Msschusetts 02111; nd Deprtment of Orthopedics (C.G.), Yle University School of Medicine, New Hven, Connecticut Address ll correspondence nd requests for reprints to: Srh L. Booth, U.S. Deprtment of Agriculture Humn Nutrition Reserch Center on Aging t Tufts University, 711 Wshington Street, Boston, Msschusetts E-mil: srh.booth@tufts.edu. Received November 8, 2007; Accepted Jnury 25, Copyright 2008 by The Endocrine Society Abstrct Context: Vitmin K hs been implicted in bone helth, primrily in observtionl studies. However, little is known bout the role of phylloquinone supplementtion on prevention of bone loss in men nd women. Objective: The objective of this study ws to determine the effect of 3-yr phylloquinone supplementtion on chnge in bone minerl density (BMD) of the femorl neck bone in older men nd women who were clcium nd vitmin D replete. Design, Prticipnts, nd Intervention: In this 3-yr, double-blind, controlled tril, 452 men nd women (60 80 yr) were rndomized eqully to receive multivitmin tht contined either 500 μg/d or no phylloquinone plus dily clcium (600 mg elementl clcium) nd vitmin D (400 IU) supplement. Min Outcome Mesures: Mesurements of the femorl neck, spine (L2 L4), nd totl-body BMD, bone turnover, nd vitmins K nd D sttus were mesured every 6 12 months. Intent-to-tret nlysis ws used to compre chnge in mesures in 401 prticipnts who completed the tril. Results: There were no differences in chnges in BMD mesurements t ny of the ntomicl sites mesured between the two groups. The group tht received the phylloquinone supplement hd significntly higher phylloquinone nd significntly lower percent undercrboxylted osteoclcin concentrtions compred with the group tht did not receive phylloquinone. No other biochemicl mesures differed between the two groups. Conclusions: Phylloquinone supplementtion in dose ttinble in the diet does not confer ny dditionl benefit for bone helth t the spine or hip when tken with recommended mounts of clcium nd vitmin D. Epidemiologicl evidence hs shown ssocitions between poor vitmin K nutrition nd ge-relted bone loss in elderly men nd women (1,2). Vitmin K is cofctor for the posttrnsltionl γ- crboxyltion of glutmic cid in certin proteins, including osteoclcin, which hs been thought to ct s regultor of bone minerliztion. The minerl-binding cpcity of osteoclcin is dependent on the γ-crboxyltion of its three glutmte residues, such tht prtilly crboxylted osteoclcin my hve reduced binding to the minerl in bone. The proportion of osteoclcin tht is not crboxylted [percent 1/12

2 undercrboxylted osteoclcin (%ucoc)] is used s sensitive mrker of vitmin K sttus (3). Usul dietry intkes of vitmin K do not support complete crboxyltion of osteoclcin (4), nd short-term dietry vitmin K deficiency my increse bone turnover in older dults (5). In recent metnlysis of 13 rndomized controlled trils with dt on bone loss, the uthors concluded tht supplementtion with either of two forms of vitmin K, menquinone-4 (MK-4) nd phylloquinone, reduces bone loss becuse ll but one study reported benefit in bone minerl density (BMD) in response to vitmin K supplementtion (6). However, the optiml dose nd form of vitmin K for this puttive protective effect on bone loss is currently unknown, with the mjority of studies using doses of MK-4 tht re pproximtely 400-fold higher thn current dietry recommendtions of μg phylloquinone/d for women nd men, respectively (7). Furthermore, the studies hd been conducted lmost exclusively in Jpnese postmenopusl women, nd there is little informtion bout the role of vitmin K supplementtion in reducing bone loss in older men or women of other ethnicities. The uthors of the metnlysis concluded tht lthough vitmin K-rich diets should be encourged, lrger clinicl trils were required before conclusions could be drwn regrding the use of vitmin K supplements to reduce frcture risk (6). The primry objective of this study ws to determine whether 3 yr of supplementtion with phylloquinone, in n mount tht is expected to be both nutritionlly optiml nd sfe, would reduce bone loss in older men nd women when tken with recommended mounts of clcium nd vitmin D. Phylloquinone, which is present in lefy green vegetbles nd certin plnt oils, is the predominnt dietry form of vitmin K (8). A secondry objective of this study ws to determine the effect of supplementl phylloquinone on mesures of bone turnover, s defined by serum osteoclcin nd collgen type-i-cross-link N-telopeptides (NTx). Subjects nd Methods Study prticipnts Helthy, mbultory men nd postmenopusl women, ged yr, were recruited though direct milings, newspper dvertisements, nd notices in community centers. Exclusion criteri included kidney stone in the pst 5 yr; hyperthyroidism; bilterl hip surgery; therpy with bisphosphonte, clcitonin, estrogen, tmoxifen, testosterone, or wrfrin in the previous 6 months; known coronry disese; prior open hert surgery; tril fibrilltion; pcemker; femorl neck BMD more thn 1.8 SD below the men for subjects of the sme ge nd sex; lbortory evidence of kidney or liver disese; nd inbility to provide informed consent. We ssessed 599 individuls for eligibility through physicl exmintion nd ssessment of the individuls medicl history nd diet, nlysis of blood nd urine, nd mesurement of femorl neck BMD. Of these, 125 were found to be ineligible. Of those eligible, equl numbers were rndomly ssigned to either tretment (n = 238) or nontretment (n = 236). Of those rndomized, 22 (nine in the tretment group nd 13 in the nontretment group) chose not to enroll (Fig. 1). Study design In this 3-yr, double-blind, controlled tril, study prticipnts cme to the reserch site every 6 12 months for mesurements of BMD, biochemicl ssys, nd other mesurements. Prticipnts were rndomized to either the tretment or nontretment group, with strtifiction ccording to sex. Of the 421 whites, 14 Blcks, four Hispnics, 11 Asins, nd two Ntive Americns who enrolled, 51 discontinued tking one or both of the dily supplements, five died, 13 withdrew for medicl resons, 11 were no longer ble to come to the study site, nd 22 either lost interest or were lost to contct (Fig. 1). All prticipnts signed written informed consent, nd this study ws pproved by the Institutionl Review Bord t Tufts University. This study ws lso registered with CliniclTrils.gov (NCT ). 2/12

3 The mjority of the 51 prticipnts who discontinued tking the supplements did so in the first 6 months. These prticipnts were encourged to return for ll subsequent follow-up study visits. At the lst visit, 401 study prticipnts (88.7% of the 452 enrolled) were evluted nd were included in the min intention-to-tret nlyses. The 358 prticipnts who took the supplements throughout the study period were included in the secondry nlysis. Supplements The subjects were dvised to mintin their usul diets nd to void tking dietry supplements, including clcium, vitmin D, or vitmin K, throughout the study. The tretment group received 500 μg phylloquinone s prt of dily effervescent multivitmin formultion (one tblet), wheres the nontretment group received the multivitmin formultion without phylloquinone (one tblet). The bsic effervescent multivitmin tblet contined vitmin B 1 (1.6 mg), vitmin B 2 (1.8 mg), vitmin B6 (2.1 mg), vitmin B 12 (3 μg), vitmin C (75 mg), vitmin E (12 mg), pntothenic cid (6 mg), nicin (20 mg), folte (160 μg), nd biotin (30 μg). Ech study prticipnt ws instructed to tke the multivitmin tblet ech morning dissolved in 5- to 6-ounce glss of wter. All study prticipnts lso received second dily effervescent tblet tht contined 600 mg elementl clcium in the form of clcium crbonte, nd 10 μg (400 IU) vitmin D in the form of choleclciferol. Subjects were instructed to tke the clcium nd vitmin D supplement t the sme time s the multivitmin tblet. The men rte of dherence with tretment, ssessed on the bsis of pill counts over 3 yr, ws 89.1% for the multivitmin supplemented with phylloquinone nd 88.5% for the group who received the multivitmin without phylloquinone. Adherence to the clcium nd vitmin D supplements ws 92.0% in the phylloquinone group nd 91.0% in the nonphylloquinone group. For those who continued tking the supplements throughout the study, men dherence ws 93.7% for the multivitmin supplemented with phylloquinone nd 93.8% for those tking the multivitmin without phylloquinone. The supplement mnufcturer (Hermes Arzeneimittel GMBH, Munich, Germny) produced 12- month supply on n nnul bsis. The multivitmins contining phylloquinone were pckged in unmrked plstic tubes (20 supplements per tube), identicl to those multivitmins not contining phylloquinone, nd stored t room temperture. Only the phrmcy (Birds Hill Phrmcy, Needhm, MA) nd the study sttisticin were unblinded to the rndomiztion scheme. To verify stbility of the phylloquinone, tblet from 10% of the tubes contining phylloquinone were nlyzed upon receipt nd every 4 5 months. Ech tblet contining phylloquinone contined men ± SD of 564 ± 77 μg phylloquinone upon receipt; t 19 months, the finl content ws 428 ± 32 μg phylloquinone. Mesurements BMD of the spine (L2 L4), femorl neck, nd whole body ws determined t bseline nd 6, 12, 24, nd 36 months of follow-up by dul-energy x-ry bsorptiometry (GE Lunr Prodigy, Mdison, WI). Scnner softwre version 5.0 ws used for cquisition nd nlysis. The group root men squre verge coefficients of vritions for the dul-energy x-ry bsorptiometry mesurements were 1.66% (femorl neck), 1.04% (L2 L4), nd 0.67% (totl body) (9). A phntom ws scnned every other week s control; the BMD of the phntom ws stble throughout the study. Three-yer chnge in BMD ws clculted by subtrcting bseline from the yr 3 mesure t ech ntomicl site. All blood smples were drwn between 0700 nd 1000 h fter minimum of 10-h fst, nd dedicted liquots of plsm nd serum were stored t 80 C nd protected from light until the time of nlysis. Urine mesurements were mde in 24-h collections. Anlyses were performed s the smples were collected. Plsm concentrtions of phylloquinone (done s singlet determintions) were determined by reversed-phse HPLC using post-column chemicl reduction of phylloquinone to hydroquinone, followed by fluorometric detection (10). The totl coefficients of vrition (CV) for the two control ser with n verge phylloquinone result of 1.2 nd 4.5 nmol/liter were 7.4 nd 8.0%, respectively. Plsm 25-hydroxyvitmin D ws mesured by RIA (DiSorin, Stillwter, MN). The totl CV for the in-house 3/12

4 control vlue with men vlue of 20.6 ng/ml ws 16.0%. This control ws run from July 2002 to Jnury Plsm 1,25-dihydroxyvitmin D ws mesured by RIA (DiSorin). An in-house control pool ws run on ll ssys. The totl CV for this control ws 15.9%. The men vlue of the control ws 45.8 pg/ml. This control ws run from October 2002 to Mrch Serum totl nd undercrboxylted osteoclcin ws mesured by RIA, using the method of Gundberg et l. (3). The ntibody recognizes both crboxylted nd undercrboxylted osteoclcin. Crboxylted osteoclcin ws seprted from undercrboxylted osteoclcin by dsorption on hydroxyptite. Totl osteoclcin ws determined in the serum before dsorption nd undercrboxylted osteoclcin ws mesured in the dsorbed serum. The totl CV for the three control ser with n verge totl OC result of 6.4, 14.7, nd 23.8 μg/liter were 8.8, 8.9, nd 7.6%, respectively. Urinry NTx ws mesured by ELISA (Osteomrk Interntionl, Settle, WA). The totl CV for control with men NTx concentrtion of 14.4 nm bone collgen equivlents ws 18.8%. Leisure, household, nd occuptionl ctivity ws estimted with use of the Physicl Activity Scle for the Elderly questionnire (11). Tobcco nd lcohol use ws determined by questionnire. Height ws mesured with stdiometer nd weight with digitl scle. Usul dietry intkes over the yer before entry in the study were ssessed using the Willett Food Frequency Questionnire, which hs been vlidted for the ssessment of vitmin K intke (12). Sttisticl nlysis The two study groups were compred t bseline by using Student s t tests for independent smples. The effect of tretment on bone density ws ssessed by fitting nlysis of covrince models with finl BMD (or, equivlently, chnge in BMD) s the response, tretment s study fctor, nd bseline BMD nd sex s covrites. There were no significnt interctions of sex nd study group in the ANOVA models of chnge in BMD. All nlyses were crried out using SAS version 9.1, nd were considered to be sttisticlly significnt t P < Selected secondry nlyses were restricted to the study prticipnts who completed the study nd took the supplements throughout the study period. There were five outliers (one hd double hip replcement, nd four hd invlid finl scns, possibly due to poor positioning) tht were removed from the nlysis becuse there were no sttisticlly significnt effects regrdless of their inclusion or exclusion. Results As summrized in Tble 1, bseline chrcteristics of the prticipnts were similr in the two tretment groups, with the exception of lower body weight nd lower lumbr spine BMD mong the women in the non-vitmin-k-supplemented group. The vitmin K-supplemented group hd significnt 3-yr increse in plsm phylloquinone concentrtions (P < ) nd significnt 3-yr decrese in %ucoc (P < ), wheres there were no chnges over the sme time period in the non-vitmin-k-supplemented group (Tble 2). With the exception of women in the non-vitmin-k-supplemented group (P = 0.27), there ws n overll increse in men plsm 25-hydroxyvitmin D concentrtions (P < 0.001) nd decrese in men 1,25-dihydroxyvitmin D concentrtions (P < 0.001) in response to dily supplement of 400 IU vitmin D (Tble 2). However, the mgnitude of chnge did not differ between the vitmin K- supplemented group nd the non-vitmin-k-supplemented group. There were no other significnt chnges in mesures over the 3-yr period, including mesures of bone turnover (serum NTx nd totl osteoclcin) (Tble 2). There ws no difference in 3-yr chnge in femorl neck BMD between the vitmin K- nd non-vitmin- K-supplemented groups (P = 0.94) (Fig. 2A). Likewise, there were no differences in 3-yr chnge in lumbr spine or whole-body BMD between the two groups (P = 0.98 nd 0.81, respectively) (Fig. 2, B nd C). There were lso no effects of vitmin K on ny of the outcomes when strtified within ech 4/12

5 group by bseline %ucoc (dt not shown). When the sttisticl nlyses were restricted to those study prticipnts who completed the study nd took the supplements throughout the study period, the results were similr to those reported in the intent-to-tret nlysis (dt not shown). Similrly, when sttisticl nlyses were conducted seprtely for men nd women, the results were similr to those reported for men nd women combined (dt not shown). Discussion In this 3-yr, rndomized, double-blind, controlled tril, dily supplementl vitmin K, in mounts tht re chievble by dietry intke, did not hve n effect on bone helth, s mesured by chnge in BMD or bone turnover in older men nd women who were clcium nd vitmin D replete. Poor vitmin K nutrition hs been linked to osteoporosis in observtionl studies. Dietry surveys indicte tht different subgroups of the popultion, including the elderly, re t risk of vitmin K intkes below the dequte intke, which is defined s μg/d for women nd men, respectively (7,13). The ssocitions between phylloquinone intkes nd low BMD or incresed risk of hip frctures my be suggestive of cuslity or simply consistent with n overll helthy diet. By nture of their study design, observtionl studies usully re unble to isolte the effects of single nutrient from those of the dietry ptterns ssocited with high intkes of foods rich in tht nutrient. Phylloquinone intke my be mrker for n overll helthy diet becuse green lefy vegetbles re consistently the primry dietry form of vitmin K (14). In ddition, high intkes of lkline-producing foods, specificlly the fruits nd vegetbles, nd their ssocited minerls, hve lso been ssocited with higher BMD (15). Food sources rich in vitmin K contin other nutrients nd phytochemicls tht re ssocited with bone helth, thus clinicl trils re required to isolte the effects of vitmin K supplementtion on bone. Results of only two long-term clinicl trils investigting phylloquinone supplementtion on bone loss re currently vilble. In the study by Brm et l. (16), 3-yr intke of 1 mg/d phylloquinone plus clcium nd vitmin D in supplement form reduced bone loss t the femorl neck in postmenopusl women, ged yr, compred with plcebo or supplement contining clcium nd vitmin D (16). There ws no beneficil effect of phylloquinone observed in the spine BMD. These results re confounded by the fct tht the clcium- nd vitmin D-supplemented group hd similr bone loss to the plcebo group t the 3-yr mesures. In second, 2-yr study of helthy, nonosteoporotic women t lest 60 yr of ge, 200 μg phylloquinone plus clcium nd vitmin D dily resulted in modest increse in bone minerl content of the rdius but not t the femorl neck or trochnter (17). In contrst, our results indicte no beneficil effect of phylloquinone supplementtion t doses tht fll between these two published trils. Becuse we did not mesure the ultrdistl rdius in our study, it is not known whether we would hve observed similr positive finding t this ntomicl site to those of Bolton- Smith et l. (17). In ddition, our control group, who received supplementl clcium nd vitmin D in mounts tht hve been demonstrted to reduce ge-relted bone loss in elderly men nd women (18), did not lose bone over the 3-yr period of mesurement. Therefore, we conclude tht phylloquinone supplementtion in doses ttinble in the diet does not confer ny dditionl benefit for bone helth t the spine or hip when tken concurrently with recommended mounts of clcium nd vitmin D. Likewise, phylloquinone supplementtion did not confer ny dditionl benefits on mesures of bone turnover bove tht chieved by clcium nd vitmin D supplementtion lone. There hs been much emphsis on the use of %ucoc s mrker of vitmin K in bone. However, it is still not known wht the physiologicl implictions re for high %ucoc (i.e. poor vitmin K sttus). It hs been reported tht supplementtion with bout 1000 μg/d phylloquinone is necessry to chieve mximl crboxyltion of osteoclcin (19). However, this conclusion cn be influenced by the methodology used to determine %ucoc. In the current study, there ws significnt increse in men plsm phylloquinone concentrtions nd significnt decrese in men %ucoc, which confirms n 5/12

6 improvement in vitmin K sttus in the tretment group. However there ws no concomitnt improvement in bone mesures in the tretment group when compred with the control group, regrdless of bseline %ucoc. In the context of our findings, it is still not known wht the physiologicl implictions re for mximlly crboxylted osteoclcin mesure. The uthors of the first metnlysis to ssess whether orl vitmin K supplementtion cn reduce bone loss nd prevent frctures concluded tht lthough vitmin K-rich diets should be encourged, the burden of proof to justify vitmin K supplementtion in the elderly needed to be estblished in lrger clinicl trils (6). All the studies used in the metnlysis for hip frcture risk were limited to Jpn, which my reflect unique dietry, environmentl, nd/or genetic fctors tht fvor the positive effects of MK-4 supplementtion. The mjority of clinicl trils evluted used dily doses of 45 mg MK-4, which re bout 500-fold higher thn current dequte intkes for women (7). A recent editoril identified unpublished dt from tril involving bout 3000 ptients tht were not included in the metnlysis (20). The unpublished dt indicted lck of effect of 36-month MK-4 supplementtion of 45 mg MK-4/d on frcture risk, which my hve chnged the outcome of the metnlysis hd these dt been vilble for inclusion. MK-4 cn lso be the product of tissue-specific conversion directly from dietry phylloquinone (21), conversion tht cn occur in bone, lbeit in much lower concentrtions compred with those ttined through supplementtion t 45 mg/d. The mechnism by which MK-4 confers potentil protective effect on bone is not well understood, nd it is plusible tht the effects of these doses re conferred by different mechnism to ny puttive effects using nutritionl doses of dietry forms of vitmin K. Supplementl clcium nd vitmin D hs been demonstrted to reduce ge-relted bone loss in elderly men nd women (18), so we designed this study to ddress the question of whether vitmin K supplementtion conferred n effect in ddition to clcium nd vitmin D. Although the biologicl mechnisms re unknown, there is some evidence from observtionl (22) nd intervention (23,24) studies to suggest tht there is either n dditive or synergistic effect of vitmin D nd vitmin K on bone helth. However, in our study, vitmin K did not confer ny dditionl benefit on bone loss. Although their men bseline phylloquinone concentrtions were lower tht those reported in community-bsed smple from the sme geogrphicl region (25), the men nd women who prticipted in our study hd self-reported phylloquinone intkes well bove the current dequte intkes (7) nd were, in generl, helthy popultion for this ge group. It is plusible tht given their helthy sttus nd generous intkes of vitmin K in their usul diets, the dditionl vitmin K did not confer ny dditionl benefit. We lso did not ssess frcture risk or the impct of vitmin K on bone geometry. In conclusion, vitmin K supplementtion in mounts tht re chievble in the diet do not confer ny dditionl benefit on bone helth in helthy older men nd women when tken with recommended mounts of clcium nd vitmin D. Acknowledgments We express our pprecition to Nncy Plermo, Anne Chrette, Molly Dmon, the stff of the Metbolic Reserch Unit nd Nutrition Evlution Lbortory, nd ll the study prticipnts for their invluble contribution to this study. Hermes Arzeneimittel GMBH, Munich, Germny generously donted the supplements used for this study. Dr. Ines Golly of Ludwig-Mximilins University of Munich provided vluble input into the study design nd logistics. Footnotes This work ws bsed upon work supported by the U.S. Deprtment of Agriculture, Agriculturl Reserch Service under Coopertive Agreement No , Ntionl Institutes of Helth (AG14759, HL69272, nd T32 HL A1), nd Americn Hert Assocition ( T). Any opinions, findings, conclusions or recommendtions expressed in this publiction re those of the uthors, nd do not necessrily reflect the view of the U.S. Deprtment of Agriculture. 6/12

7 This study is registered with CliniclTrils.gov (NCT ). This mnuscript hs not been submitted to Clinicl Trils.gov. Disclosure Sttement: S.L.B., M.K.S., C.G., J.W.P., nd B.D.-H. hve nothing to declre; G.D. consulted for legl mtter unrelted to this study. First Published Online Februry 5, 2008 Abbrevitions: BMD, Bone minerl density; CV, coefficients of vrition; MK-4, menquinone-4; NTx, collgen type-icross-link N-telopeptides; %ucoc, percent undercrboxylted osteoclcin. References 1. Booth SL, Tucker KL, Chen H, Hnnn MT, Ggnon DR, Cupples LA, Wilson PW, Ordovs J, Schefer EJ, Dwson-Hughes B, Kiel DP2000 Dietry vitmin K intkes re ssocited with hip frcture but not with bone minerl density in elderly men nd women. Am J Clin Nutr 71: Booth SL, Broe KE, Peterson JW, Cheng DM, Dwson-Hughes B, Gundberg CM, Cupples LA, Wilson PW, Kiel DP2004 Associtions between vitmin K biochemicl mesures nd bone minerl density in men nd women. J Clin Endocrinol Metb 89: Gundberg CM, Niemn SD, Abrms S, Rosen H1998 Vitmin K sttus nd bone helth: n nlysis of methods for determintion of undercrboxylted osteoclcin. J Clin Endocrinol Metb 83: Binkley NC, Krueger DC, Kwhr TN, Engelke JA, Chppell RJ, Suttie JW2002 A high phylloquinone intke is required to chieve mximl osteoclcin γ-crboxyltion. Am J Clin Nutr 76: Booth SL, Lichtenstein AH, O Brien-Morse M, McKeown NM, Wood RJ, Sltzmn E, Gundberg CM2001 Effects of hydrogented form of vitmin K on bone formtion nd resorption. Am J Clin Nutr 74: Cockyne S, Admson J, Lnhm-New S, Sherer MJ, Gilbody S, Torgerson DJ2006 Vitmin K nd the prevention of frctures: systemtic review nd met-nlysis of rndomized controlled trils. Arch Intern Med 166: Dietry Reference intkes for vitmin A, vitmin K, rsenic boron, chromium, copper, iodine, iron, mngnese, molybdenum, nickel, silicon, vndium, nd zinc. Institute of Medicine. Wshington, DC: Ntionl Acdemy Press. 8. Booth SL, Suttie JW1998 Dietry intke nd dequcy of vitmin K. J Nutr 128: White J, Hrris SS, Dlll GE, Dwson-Hughes B2003 Precision of single vs bilterl hip bone minerl density scns. J Clin Densitom 6: Booth SL, Tucker KL, McKeown NM, Dvidson KW, Dlll GE, Sdowski JA1997 Reltionships between dietry intkes nd fsting plsm concentrtions of ft-soluble vitmins in humns. J Nutr 127: Wshburn RA, Ficker JL1999 Physicl ctivity scle for the elderly (PASE): the reltionship with ctivity mesured by portble ccelerometer. J Sports Med Phys Fitness 39: McKeown NM, Jcques PF, Gundberg CM, Peterson JW, Tucker KL, Kiel DP, Wilson PW, Booth SL2002 Dietry nd nondietry determinnts of vitmin K biochemicl mesures in men nd women. J Nutr 132: Booth SL2007 Vitmin K sttus in the elderly. Curr Opin Clin Nutr Metb Cre 10: Erkkil AT, Booth SL, Hu FB, Jcques PF, Mnson JE, Rexrode JE, Stmpfer M, Lichtenstein A2005 Phylloquinone intke s mrker for coronry hert disese risk but not stroke in women. Eur J Clin Nutr 59: New SA2003 Intke of fruit nd vegetbles: implictions for bone helth. Proc Nutr Soc 62: Brm LA, Knpen MH, Geusens P, Brouns F, Hmulyk K, Gerichhusen MJ, 7/12

8 Vermeer C2003 Vitmin K1 supplementtion retrds bone loss in postmenopusl women between 50 nd 60 yers of ge. Clcif Tissue Int 73: Bolton-Smith C, McMurdo ME, Pterson CR, Mole PA, Hrvey JM, Fenton ST, Prynne CJ, Mishr GD, Sherer MJ2007 Two-yer rndomized controlled tril of vitmin K1 (phylloquinone) nd vitmin D3 plus clcium on the bone helth of older women. J Bone Miner Res 22: Dwson-Hughes B, Hrris SS, Krll EA, Dlll GE1997 Effect of clcium nd vitmin D supplementtion on bone density in men nd women 65 yers of ge or older. N Engl J Med 337: Binkley NC, Krueger DC, Engelke JA, Foley AL, Suttie JW2000 Vitmin K supplementtion reduces serum concentrtions of under-γ-crboxylted osteoclcin in helthy young nd elderly dults. Am J Clin Nutr 72: Tmur T, Morgn SL, Tkimoto H2007 Vitmin K nd the prevention of frctures. Arch Intern Med 167:94; uthor reply Thijssen HH, Vervoort LM, Schurgers LJ, Sherer MJ2006 Mendione is metbolite of orl vitmin K. Br J Nutr 95: Szulc P, Chpuy MC, Meunier PJ, Delms PD1993 Serum undercrboxylted osteoclcin is mrker of the risk of hip frcture in elderly women. J Clin Invest 91: [PMCID: PMC288157] 23. Iwmoto I, Kosh S, Noguchi S, Murkmi M, Fujino T, Douchi T, Ngt Y1999 A longitudinl study of the effect of vitmin K2 on bone minerl density in postmenopusl women comprtive study with vitmin D3 nd estrogen-progestin therpy. Mturits 31: Sto Y, Knoko T, Stoh K, Iwmoto J2005 Mentetrenone nd vitmin D2 with clcium supplements prevent nonvertebrl frcture in elderly women with Alzheimer s disese. Bone 36: Booth S, Broe K, Ggnon D, Tucker KL, Hnnn MT, McLen RR, Dwson-Hughes B, Wilson PWF, Cupples LA, Kiel DP2003 Vitmin K intke nd bone minerl density in women nd men. Am J Clin Nutr 77: Figures nd Tbles Figure 1 8/12

9 Study profile. Figure 2 9/12

10 Men (SEM) percent 3-y r chnge in BMD reltive to bseline in the vitmin K ( ) nd non-vitmin K ( ) supplementtion groups. A, Femorl neck; B, lumbr spine; C, totl body. Tble 1 Bseline chrcteristics of vitmin K nd non-vitmin K supplementtion groups Prm eters Men Wom en Vitm in K No Vitm in K Vitm in K No Vitm in K 10/12

11 supplem enttion supplem enttion (n supplem enttion supplem enttion (n (n = 95) = 90) (n = 134) = 133) Age (y r) 69 (5) 69 (6) 68 (6) 68 (5) Height (cm) 17 4 (7 ) 17 4 (7 ) 161 (7 ) 160 (6) Weight (kg) 85 (15) 84 (15) 7 4 (15) 7 0 (14) Smoker, n (%) 3 (3.2) 9 (10.0) 10 (7.5) 3 (2.3) Phy sicl 130 (66.0) 140 (62) 123 (54) 127 (62) ctiv ity score Phy lloquinone 180 (121) 166 (118) 17 3 ( (104) intke (μg/d) BMD (g/cm 2 ) Femorl (0.139) (0.126) (0.118) (0.116) neck Lumbr (0.229) (0.232) (0.205) (0.184) spine Totl body (0.109) (0.109) (0.104) (0.092) Results re men (SD) unless otherwise indicted. Significnt difference between tretment groups t bseline (P < 0.05). Tble 2 Men (SD) initil biochemicl nd BMD mesures nd 3-yr chnge for vitmin K nd non-vitmin K supplementtion groups Men (n = 164) Wom en (n = 237 ) Bseline 3-y r chnge Bseline 3-y r chnge Plsm phy lloquinone (nmol/liter) Vitmin K supplemented 1.4 (2.2) +1.5 (2.4) 1.1 (1.4) +2.3 (2.7 ) Non-v itmin K supplemented 1.1 (1.9) 0.3 (1.8) 1.2 (1.1) +0.1 (1.3) %ucoc Vitmin K supplemented 35.9 (15.7 ) 18.5 (22.9) 42.8 (16.9) 18.7 (20.1) Non-v itmin K supplemented 39.1 (14.9) +0.8 (18.1) 41.6 (17.3) +3.1 (21.0) Plsm 25-hy droxy vitmin D (ng/ml) Vitmin K supplemented 22.8 (9.2) +3.7 (10.2) 22.7 (8.5) +2.3 (9.1) Non-v itmin K supplemented 20.8 (8.0) +4.3 (7.9) 24.3 (8.5) +0.9 (8.7 ) Plsm 1,25-dihy droxy vitmin D (pg/ml) Vitmin K supplemented 46.0 (23.3) 7.4 (25.0) 46.8 (20.7 ) 7.3 (21.5) Non-v itmin K supplemented 44.7 (18.1) 7.2 (19.4) 49.1 (20.0) 8.2 (23.0) Serum totl osteoclcin (ng/ml) Vitmin K supplemented 7.7 (2.6) 0.8 (2.0) 8.7 (3.2) 1.0 (3.0) Non-v itmin K supplemented 7.7 (2.4) 0.8 (1.8) 9.0 (3.1) 0.9 (3.1) NTx (nm BCE) Vitmin K supplemented 14.1 (3.3) +1.1 (4.6) 15.3 (4.0) (6.1) 11/12

12 Non-v itmin K supplemented 14.4 (4.3) +1.3 (5.0) 16.5 (4.8) 1.0 (6.1) C:cretinine rtio, 24-h urine (mg/g) Vitmin K supplemented 93 (62) +8 (51) 131 (69) +5 (60) Non-v itmin K supplemented 95 (56) +13 (50) 143 (7 6) +6 (7 3) Femorl neck BMD (g/cm 2 ) Vitmin K supplemented (0.139) (0.038) (0.118) (0.041) Non-v itmin K supplemented (0.126) (0.036) (0.116) (0.035) Lumbr spine BMD (g/cm 2 ) Vitmin K supplemented (0.229) (0.053) (0.205) (0.057 ) Non-v itmin K supplemented (0.232) (0.048) (0.184) (0.054) Totl-body BMD (g/cm 2 ) Vitmin K supplemented (0.109) (0.025) (0.104) (0.025) Non-v itmin K supplemented (0.109) (0.033) (0.092) (0.023) Significnt difference in 3-yr chnge between tretment groups (P < 0.001). Articles from The Journl of Clinicl Endocrinology nd Metbolism re provided here courtesy of The Endocrine Society 12/12