www.npjournal.org The Journal for Nurse Practitioners - JNP 193

Complementary Therapies in Osteoporosis

Darlene Higgs and Cathy Kessenich

ABSTRACTOsteoporosis is a disorder characterized by brittle, fragile bones. It results from unbalanced bone metabolism and often leads to bone fractures and, consequently, a decreased quality of life. It is complex in pathology and requires multifactorialmanagement and treatment. It is imperative that nurse practitioners (NPs) maintaincurrent best-practice knowledge to appropriately manage and treat this increasinglyprevalent and debilitating disease. This article provides a review of informationregarding recent evidence for pharmacological and supplemental therapies in osteoporosis, including strontium ranelate, genistein, and vitamin K.

Keywords: genistein, osteoporosis, strontium, vitamin K© 2010 American College of Nurse Practitioners

Osteoporosis is a disorder of unbalanced boneremodeling. It occurs when bone resorptionexceeds bone formation, resulting in porous

bones and ultimately a decrease in bone density andstrength. Patients with osteoporosis are at great risk forbone fractures, which lead to health care expendituresand a decreased quality of life.

Osteoporotic fractures can occur in any part of theskeleton, but most commonly affect bones of the hip,spine, and wrist. Osteoporosis is influenced by genet-ics, age, sex, race, lifestyle factors, and dietary intake. Itis complex in pathology and therefore requires multi-factorial management and treatment.

Approximately 10 million Americans over 50 yearsof age suffer from osteoporosis and an additional 34million are at risk due to low bone mass. Of those over50 with osteoporosis, approximately half of the womenand a quarter of the men will experience an osteoporo-sis-related fracture within their lifetime. Ensuing frac-tures cost Americans an average of $19 billion each yearand are the cause of 180,000 yearly nursing homeadmissions.1 These numbers are expected to rise in con-junction with the mounting elderly population andincreasing life expectancy.

It is important for nurse practitioners (NPs) to beaware of advances in treatment options for osteoporosis.Every patient is unique and may require treatment alter-natives due to allergic reactions, side effects, or personalpreference. NPs should be aware of current evidence-based knowledge concerning various treatment options tomake them available to patients. Traditional osteoporotictherapy includes pharmacological interventions as well asnutrient supplementation. Current pharmacological treat-ments include oral and intravenous bisphosphonates,selective estrogen receptor modulators (SERMs), calci-tonin, and parathyroid hormone (PTH) injections, whilecalcium and vitamin D are supplemental cornerstones forthe prevention and treatment of osteoporosis. This articleaddresses recent evidence suggesting that strontiumranelate (SR) may be a beneficial pharmacological therapyand also explores the evidence regarding supplementationwith the soy isoflavone genistein and Vitamin K.

STRONTIUM RANELATE Stable strontium, along with calcium and magnesium, is anaturally occurring metal found in the body. It is not tobe confused with the radioactive forms of this element.

Greater than 99% of the body’s strontium content isfound in bone. There are various forms of stable stron-tium, including strontium ranilate, strontium citrate, andstrontium carbonate. In vitro and in vivo studies havefound that stable strontium increases bone formation anddecreases bone resorption.2

Strontium ranelate (SR) is the most extensively stud-ied form of stable strontium and is a relatively newosteoporotic therapy available in Australia and Europe.Unlike other osteoporotic drugs, SR maintains bonestructure by dual mechanism. It both stimulatesosteoblasts and inhibits osteoclasts, thereby simultaneouslyincreasing bone formation and reducing boneresorption.3 Data pooled by the Cochrane Collaborationreview determined that SR decreases vertebral and non-vertebral fracture risk by 37% and 14%, respectively.4 SRappears to effectively reduce vertebral fractures in post-menopausal women but the drug has not yet beenapproved for use in the United States5 and is currentlyunder consideration for approval in Canada.6

SR is composed of 2 stable strontium atoms com-bined with the carrier ranelic acid. While trials haveidentified various aspects of the SR mechanism, the exactpathway remains unclear. In vitro trials suggest that theprimary mechanism of SR may be the activation of cal-cium-sensing receptors (CaR) through its anatomic andionic similarities to calcium. CaR activation is involvedin osteoblast differentiation and osteoclast apoptosis, thusaddressing both bone formation and resorption.3

The most well-known SR studies are the SOTI(Spinal Osteoporosis Therapeutic Intervention) trialand the TROPOS (Treatment of PeripheralOsteoporosis) trial. These large-scale, phase 3, random-ized, double-blind, clinical-controlled trials were con-ducted to determine the effect of 2 grams of oral SRdaily on vertebral and nonvertebral fractures. TheSOTI trial analyzed vertebral fracture risk and theTROPOS study analyzed nonvertebral fracture risk.Both trials were conducted simultaneously in 12 dif-ferent countries and 75 different treatment centers.7

After the 3-year SOTI study, the risk reduction forvertebral fractures was 41%, and the bone mineral density(BMD) increased from baseline by 14.4% at the lumbarspine, 7.2% at the femoral neck, and 8.6% at the totalhip.8 The 3-year TROPOS trial determined that SRreduced the relative risk for nonvertebral fractures by16%.9 For those women considered at high risk for frac-

194 The Journal for Nurse Practitioners - JNP Volume 6, Issue 3, March 2010

www.npjournal.org The Journal for Nurse Practitioners - JNP 195

ture ( 74 years with a BMD of -3 at the femoralneck), the relative risk for incurring a hip fracture wasreduced by 36%. Femoral-neck BMD increased by 8.2%and total-hip-BMD by 9.8%. The TROPOS 5-year fol-low-up reports a nonvertebral fracture risk reduction of15%, and a 43% reduction in the risk for hip fractures.10

While SR appears effective, it is important to recognizethat the SOTI and TROPOS trials were supported byServier, the manufacturer of strontium ranelate.

The main adverse effectsof SR are nausea anddiarrhea,11 with trials showingno increased risk of seriousadverse events in the treat-ment groups.4 After 5-year tri-als, SR appears to have a highsafety profile.10 Practitionersshould be aware that adversecases of DRESS (drug rashwith eosinophilia and systemicsymptoms) have been reportedsince the marketing of SR and, although it is veryrare, it is important to recognize, as the syndrome maybe fatal. In the case of DRESS, SR therapy should bepromptly and permanently discontinued. DRESS usu-ally resolves with termination of therapy.11

SR is marketed as Protelos in countries in which it isapproved. Protelos is in powder form, containing 2 gramsof strontium ranilate and is given orally by suspension ina liquid.12 Strontium is also available to the public insupplemental forms as strontium citrate and strontiumcarbonate. Strontium citrate can be found in dosages of340 mg to 1000 mg and strontium carbonate is presentin various over-the-counter osteoporosis complexes.However, the recommended daily allowance (RDA) forthese strontium forms has not been determined and itsefficacy has not been proven.

GENISTEINThe bone-building effects of soy isoflavones have beenexplored over the past decade. Genistein is a soyisoflavone that has recently gained attention for itsapparent benefit as an osteoporotic therapy for post-menopausal women. Isoflavones are found in soy-richfoods such as soy beans, tofu, and miso. These are staplefoods in Asian populations, where they are consumed at10 to 20 times the rate of Western populations. This

may contribute to the significantly lower rate of osteo-porosis seen in Asian women as compared to Americanwomen.13 Animal trials have shown that genisteinincreases bone mass14 and prevents bone loss.15 Humanclinical trials have shown both a decrease in boneresorption markers and an increase in bone formationmarkers,16-18 along with an increase in BMD.17,18

Genistein appears to facilitate bone changesthrough its phytoestrogenic properties. This plant-

derived estrogen is molecularlysimilar to the endogenousestrogen 17-� estradiol.19

During the peri- and post-menopausal period, estrogendecline causes bone resorptionto accelerate. Estrogen replace-ment therapy (ET) was oncecommonly prescribed therapyfor peri- and post-menopausalwomen. However, this haschanged due to evidence of

the detrimental effects that ET may have on breast anduterine tissue in women, including increased risk ofbreast, endometrial, and ovarian cancer, and cardiovas-cular events, such as heart disease, venous thromboem-bolism, and stroke.17 Genistein may be a safe, naturallyoccurring alternative to ET for the prevention andtreatment of osteoporosis. Trials indicate that genisteinhas a positive effect on bone remodeling withoutaffecting reproductive tissues.16,18

Unlike pharmaceutical estrogen therapy, genistein ishormone-receptor specific. It has a profuse affinity forestrogen receptors in the bone, with less attraction toreceptors in the breast and endometrial tissue. There are2 primary estrogen receptors found in the body, ER-�

and ER-�. ER-� is found primarily in the reproductivetissues, while bone contains large amounts of ER-�.Genistein’s affinity for ER-� is approximately 7 timesgreater than its affinity for ER-�.20 Genistein appearsto replace estrogen and reduce bone resorption withoutaffecting reproductive tissues.16,18 Soy isoflavones mayalso positively affect cardiovasculature, reducing choles-terol and decreasing cardiovascular disease.21 Trialsinvolving various isoflavones (including both food andpill forms of soy isoflavones) have shown increasedBMD at the spine13,22 and Wards triangle.22 Possibly themost noteworthy study on soy isoflavones and bone is

Genistein may be a safe,naturally occurring

alternative to estrogentherapy for the prevention

and treatment ofosteoporosis.

the recently conducted, randomized, double-blind,placebo-controlled trial by Marini et al,17,18 in whichthe isoflavone genistein was used. The trial involvedpostmenopausal women with femoral neck BMD below0.795 g/cm2. Supplementation of 54 of mg pure genis-tein daily for 2 years resulted in a significantly greaterBMD in the lumbar spine andfemoral neck for the interven-tion group. Meanwhile, BMDdecreased in the control group.Genistein also increased mark-ers of bone formation anddecreased markers of boneresorption. Marini et al18 con-tinued to see positive effectson bone mineralization mark-ers and increased BMD duringtheir 3-year follow-up study,conducted to determine the safety of genistein. Theauthors also determined that after 3 years of treatmentwith 54 mg of genistein aglycone, there were no sig-nificant changes in breast density or endometrialthickness.

Genistein may be a safe, effective, and natural alterna-tive to ET for the treatment of osteoporosis in post-menopausal women. It is a bone-receptor-selective phy-toestrogen with the efficacy of ET.16 Clinical trials haveshown that it increases BMD by both enhancing boneformation and reducing bone resorption.16-18 The soyfoods most abundant in isoflavones, including genistein,are: whole soybeans, roasted soy beans, soy flour, tempeh,tofu, miso, and certain protein isolates.21 Genistein canalso be found in supplemental forms. Dosages of 54 to 90mg of genistein daily appear to be effective at enhancingbone remodeling.13,16,17

VITAMIN KVitamin K is a vital element in numerous bone-formingmechanisms of the body. Vitamin K has been shown tomoderately increase BMD but, more importantly, it pre-vents fractures in postmenopausal osteoporotic populations.Unlike other osteoporotic treatments, the antifracture effi-cacy of vitamin K relies primarily on enhanced bonequality rather than increased bone mass.23 Bone qualityencompasses bone turnover, architecture, and matrix.23

There are 2 naturally occurring forms of vitamin K:vitamin K1 (phylloquinone) and vitamin K2

(menaquinone). K1 is the dietary form of vitamin K foundin green leafy vegetables. K2 is found in animal sources,such as fermented dairy and soy products, fish, meat, liver,and eggs, and is also synthesized by intestinal bacteria.24

While both forms of vitamin K have positive effectson bones, K2 is more potent and effective than K1.25 K2

reduces fractures26 and moder-ately increases BMD,26,27 andhas been used in Japan as atreatment for osteoporosis formore than a decade.25 VitaminK may have been overlooked asa treatment option for osteo-porosis in the United Statesbecause of its modest effect onBMD. However, the bone-enhancing effects of vitamin Kbecome more apparent upon

analyzing fractures. The fracture reduction seen in clinicaltrials is likely due to improved bone quality, rather thanincreased bone mass.

Vitamin K improves bone quality by enhancing thearchitectural structure of bone and collagen. While thedetails of the mechanism are uncertain, carboxylation ofosteocalcin appears to be its major means of enhancingbone strength.23 High levels of undercarboxylated osteo-calcin have been linked with low bone density28 and ahigher risk of hip fracture.29 Clinical trials show thatvitamin K increases carboxylation of osteocalcin.25 Theaverage American may not ingest enough vitamin K tosupport carboxylation of osteocalcin.30

Epidemiologic studies have shown that a high intakeof vitamin K correlates with reduced fracture risk.31,32

The Nurses’ Health study determined that women whoate lettuce each day had a 45% lower risk of developing ahip fracture than those women who ate lettuce on aweekly basis or less often.32 The Framingham Heartstudy followed with similar results, finding that partici-pants in the highest vitamin K intake quartile had anadjusted fracture risk reduction of 65% compared tothose in the lowest intake quartile.25,31

Clinical trials also support that vitamin K reducesfractures and elicits positive effects on BMD, particularlywith menaquinone supplementation. A recent meta-analysis concluded with a hip fracture reduction ofapproximately 80% among the reviewed trials of vitaminK supplementation. However, the authors caution that

196 The Journal for Nurse Practitioners - JNP Volume 6, Issue 3, March 2010

Vitamin K has been shownto moderately increase

BMD, but more importantly,it prevents fractures in

postmenopausalosteoporotic populations.

there may be an unidentified reason for such a highreduction in hip fractures, stating that many of the trialsincluded were not high-quality and some had high attri-tion rates. Most occurred in Japan, which may suggestthe findings are not generalizable to other areas.26

Two, randomized, double-blind, placebo-controlledtrials have been conducted to determine the effect ofvitamin K on bone. One trial supplemented withK227and the other K1.33 Until these recent trials, vita-min K research lacked this gold standard of support.

When comparing K2 supplementation to placebo,Purwosunu et al27 reports a significant increase in BMDand a significant decrease in uncarboxylated osteocalcin.The trial was conducted in Indonesia, involving 63postmenopausal women with osteoporosis. The inter-vention group (n = 33) was given 45 mg of K2 with1500 mg of calcium carbonate, and the control groupwas given a placebo with 1500 mg of calcium carbonatedaily for 48 weeks. When compared to baseline, BMDincreased by 1.74 ± 0.43% in the intervention groupand decreased by 0.18 ± 0.24% in the placebo group.Uncarboxylated osteocalcin decreased from baseline by55.9% in the intervention group and 9.3% in the con-trol group, with a significant difference between the 2groups.27 As previously mentioned, uncarboxylatedosteocalcin has been linked with increased fracturerisk.29 Unfortunately, this K2 trial does not report frac-tures that occurred during the study.

Cheung et al33 conducted a trial over a 4-yearperiod using K1 supplementation. No significant dif-ference was found in BMD between the interventionand control groups but there were fewer fractures inthe intervention group. Four hundred forty post-menopausal women with osteopenia were enrolled inthe trial; the intervention group was given 5 mg of K2daily and the control group was given a placebo. BMDdecreased in both the intervention group and the con-trol group (-1.28% and -1.22%, respectively, P = 0.84);however, there were only 9 fractures in the interven-tion group and 20 fractures in the control group.33

Current data suggest that vitamin K increases bonestrength and reduces fractures in postmenopausal patientswith low bone density.26,27,33 While both forms of vita-min K show positive effects, K2 is the more effective ofthe two, and therefore the first choice for supplementa-tion. K2 supplementation has also shown synergisticeffects on bone when combined with vitamin D334,35

and when given in conjunction with bisphosphonates.36

K2 may also be a beneficial adjunct during treatmentwith drugs such as leuprolide and prednisone, as clinicaltrials have shown that it counteracts the bone-depletingeffects of these drugs.36

Daily adequate intake (AI) recommendations for K1are 90 μg for women and 120 μg for men.24 There iscurrently no established recommended daily intake ofK2. With regard to osteoporosis treatment, daily doses of1000 μg of K1 and 45 mg of K2 have been suggestedaccording to research outcomes.25 A safe upper limit ofvitamin K has not been established due to a lack ofadverse effects. The studies reviewed here showed no evi-dence of toxicity at these levels and the only reportedadverse effects were mild gastrointestinal complaints. Thereference range for plasma vitamin K is 1.3 to 1.9ng/mL.37 Serum K2 levels below 1.10 ± 0.07 ng/mLand K1 levels below 0.64 ± 0.06 ng/mL have beenlinked with a lower than normal BMD in post-menopausal women.37

CONCLUSIONSStrontium ranelate can provide osteoporotic patients withboth increased bone formation and decreased boneresorption. While SR is not yet available for prescription inthe United States, it is important for practitioners tounderstand the mechanism and efficacy of the drug, asthey may encounter patients from outside the countrywho are taking this prescriptive therapy. It is also essentialto note that women with osteoporosis may take strontiumcitrate or strontium carbonate as a supplemental therapy.Patients taking these supplements should be advised thattheir safety and efficacy have not been clinically proven.

Genistein is a receptor-selective phytoestrogen withthe efficacy of estrogen therapy16 but without the detri-mental effects on reproductive tissues.18 It increases BMDand reduces bone resorption.16-18 Daily intake of genis-tein may effectively prevent and treat osteoporosis inpostmenopausal populations. Genistein can be ingestedthrough supplements or dietary intake of soy products.Many patients prefer herbal and supplemental therapiesin treating disease. Genistein may be a safe, effective, sup-plemental treatment option for these populations.

K2 appears to safely and effectively increase BMDand reduce fractures.. There is no evidence of vitamin Ktoxicity, and side effects relate only to mild gastrointesti-nal effects.25,26 A daily dose of K2 may be considered as a

www.npjournal.org The Journal for Nurse Practitioners - JNP 197

supplemental therapy for postmenopausal osteopenia andosteoporosis to reduce fractures.

Many Americans prefer supplemental and complemen-tary therapies over prescription agents. It is important to beopen and accepting of patients’ choices and it is equally asimportant to be knowledgeable and honest concerningavailable therapies. A well-rounded treatment regimen forosteoporotic patients includes lifestyle modifications andboth pharmacological and supplemental medication.Treatment of osteoporosis should begin with appropriatelifestyle modifications such as a balanced diet with nutri-tional supplementation if necessary, regular exercise, and fall-prevention strategies. Adjunct pharmacologic and supple-mental therapies should be patient-specific, dependent upondegree of osteoporosis and concomitant clinical conditions.NPs should maintain current knowledge regarding availableevidence-based treatments for osteoporosis, both supple-mental and pharmacologic, to provide the safest and mosteffective options for their patients.

References

1. Alliance for Aging Research. The Silver Book: Osteoporosis, 2009. Available at:http://www.silverbook.org/OsteoporosisSilverbook.pdf. Accessed March 30, 2009.

2. Dahl SG, Allain P, Marie PJ, et al. Incorporation and distribution of strontiumin bone. Bone. 2001;28:446-453.

3. Fonseca JE. Rebalancing bone turnover in favor of formation withstrontium ranelate: implications for bone strength. Rheumatology.2008;47:iv17-iv19.

4. O’Donnell S, Cranney A, Wells, GA, Adachi JD, Reginster JY. Strontiumranelate for preventing and treating postmenopausal osteoporosis (review).Cochrane Database of Systematic Reviews. 2008;3. doi:10.1002/14651858.CD005326.pub3.

5. National Osteoporosis Foundation. Clinicians Guide to Prevention andTreatment of Osteoporosis, 2008. Available at: http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf. Accessed February 30, 2009.

6. Jamal SA. New Treatment Modalities for Osteoporosis. CanadianOrthopaedic Association. Available at: http://www.coa-aco.org/coa_bulletin/issue_73/ jamal_new_treatment_modalities_for_osteoporosis.html. AccessedMarch 31, 2009.

7. Ortolani S, Silvia V. Strontium ranelate: an increased bone quality leading tovertebral antifracture efficacy at all stages. Bone. 2006;38:S19-S22.

8. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate onthe risk of vertebral fracture in women with postmenopausal osteoporosis.N Engl J Med. 2004;350:459.

9. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reducesthe risk of nonvertebral fractures in postmenopausal women withosteoporosis. Treatment of Peripheral Osteoporosis (TROPOS) study. J ClinEndocrinol Metab. 2005;90:2816-2822.

10. Reginster JY, Felsenberg D, Boonen S. Effects of long-term strontiumranelate treatment on the risk of nonvertebral and vertebral fractures inpostmenopausal osteoporosis: results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum. 2008;58:1687-1695.

11. Roux C. Strontium ranelate: short- and long-term benefits for post-menopausal women with osteoporosis. Rheumatology. 2008;47:iv20-iv22.

12. Servier. Protelos. Available at: http://www.servier.co.uk/pdfs/Protelos_SPC.pdf. Accessed March 20, 2009.

13. Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake increases bonemineral density in the spine of menopausal women: meta-analysis ofrandomized controlled trials. Clin Nutr. 2008;27:57-64.

14. Valtuena S, Cashman K, Robins SP, Cassicy A, Kardinaal A, Branca F.Investigating the role of natural phytoestrogens on bone health in post-menopausal women. Br J Nutr. 2003;89:S87-S99.

15. Wang J, Shang F, Liu L, Wang S, Wang J, Mei Q. In vivo and in vitro activityof genistein in osteoporosis. Ind J Pharmacol. 2007;39:103-106.

16. Morabito N, Crisafulli A, Vergara C, et al. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: arandomized double-blind placebo-controlled study. J Bone Miner Res.2002;17:1904-1912.

17. Marini H, Minutoli L, Polito F, et al. Effects of the phytoestrogen genistein onbone metabolism in osteopenic postmenopausal women. Ann Intern Med.2007;146:839-847.

18. Marini H, Bitto A, Altavilla D, et al. Breast safety and efficacy of genisteinaglycone for post-menopausal bone loss: a follow-up study. J ClinEndocrinol Metab. 2008. doi:10.1210/jc.2008-1087.

19. Cotter A, Cashman KD. Genistein appears to prevent early postmenopausalbone loss as effectively as hormone replacement therapy. Nutr Rev.2003;61:346-351.

20. Kuiper GG, Lemmen JC, Carlsson B, et al. Interaction of estrogenicchemicals and phytoestrogens with estrogen receptor β. Endocrinology.1998;139:4252-4263.

21. Tham DM, Gardner CD, Haskell WL. Potential health benefits of dietaryphytoestrogens: a review of the clinical, epidemiological, and mechanisticevidence. J Clin Endocrinol Metab. 1998;83:2223-2235.

22. Ozturk Turhan N, Bolkan F, Iltemir Duvan C, Ardicoglu Y. The effect ofisoflavones on bone mass and bone remodeling markers inpostmenopausal women. Turk J Med Sci. 2008;38:145-152.

23. Iwamoto J, Takeda T, Sato Y. Menatetrenone (Vitamin K2) and bone qualityin treatment of postmenopausal osteoporosis. Nutr Rev. 2006;64:509-517.

24. Nieves JW. Osteoporosis: the role of micronutrients. Am J Clin Nutr.2005;81:1232S-1239S.

25. Adams J, Pepping J. Vitamin K in the treatment and prevention ofosteoporosis and arterial calcification. Am J Health Syst Pharm.2005;62:1574-1581.

26. Cockayne S, Adamson J, Lanham-New S, Shearer MJ, Gilbody S, TogersonDJ. Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166:1256-1261.

27. Purwosunu Y, Muharram, Rachman IA, Reksoprodjo S, Sekizawa A. VitaminK2 treatment for postmenopausal osteoporosis in Indonesia. J ObstetGynaecol Res. 2006;32:230-234.

28. Knapen MH, Nieuwenhuijzen Kruseman AC, Wouters RS, et al. Correlationof serum osteocalcin fractions with bone mineral density in women duringthe first 10 years after menopause. Calcif Tissue Int. 1998;63:375-379.

29. Vergnaud P, Garnero P, Meunier PJ, et al. Undercarboxylated osteocalcinmeasured with a specific immunoassay predicts hip fracture in elderlywomen: the EPIDOS study. J Clin Endocrinol Metab. 1997;82:719-724.

30. Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr.1998;128:785-788.

31. Booth SL, Tucker KL, Chen H, et al. Dietary vitamin K intake and hipfractures in women: a prospective study. Am J Clin Nutr. 2000;71:1201-1208.

32. Feskanish D, Weber P, Willett WC, et al. Vitamin K intake and hip fractures inwomen: a prospective study. Am J Clin Nutr. 1999;69:74-79.

33. Cheung AM, Tile L, Lee Y, et al. Vitamin K supplementation inpostmenopausal women with osteopenia (ECKO Trial): a randomizedcontrolled trial. PLoS Med. 2008;5:1461-1472.

34. Iwamoto J, Takeda T, Ichimura S. Effect of combined administration ofvitamin D3 and vitamin K2 on bone mineral density of the lumbar spine inpostmenopausal women with osteoporosis. J Orthop Sci. 2000;5:546-551.

35. Iwamoto J, Takeda T, Ichimura S. Treatment with vitamin D3 and/or vitaminK2 for postmenopausal osteoporosis. Keio J Med. 2003;52:147-150.

36. Plaza SM, Lamson DW. Vitamin K2 in bone metabolism and osteoporosis.Altern Med Rev. 2005;10:24-35.

37. Fischback F, Dunning MB. A manual of laboratory and diagnostic tests. 8thed. New York: Lippincott Williams & Wilkins; 2008.

38. Kanai T, Takagi T, Masuhiro K, Nakamura M, Iwata M, Saji F. Serum vitaminK level and bone mineral density in post-menopausal women. Int J GynecolObstet.1997;56:25-30.

Darlene Higgs, RN, BSN, is an NP student at theUniversity of Tampa in Tampa, FL. She can be reached atdhiggs@ut.edu. Cathy Kessenich, DSN, ARNP, is aprofessor of nursing at the University of Tampa in Florida.In compliance with national ethical guidelines, the authorsreport no relationships with business or industry that wouldpose a conflict of interest.

1555-4155/10/$ see front matter

© 2010 American College of Nurse Practitioners

doi:10.1016/j.nurpra.2009.10.003

198 The Journal for Nurse Practitioners - JNP Volume 6, Issue 3, March 2010