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RETRACTED: Vitamin K deficiency and osteopenia in elderly women with Alzheimer’s disease
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Vitamin K Deficiency and Osteopenia in Elderly Women With Alzheimer’s Disease Yoshihiro Sato, MD, Yoshiaki Honda, MD, Norimasa Hayashida, MD, Jun Iwamoto, MD, Tomohiro Kanoko, OT, Kei Satoh, MD ABSTRACT. Sato Y, Honda Y, Hayashida N, Iwamoto J, Kanoko T, Satoh K. Vitamin K deficiency and osteopenia in elderly women with Alzheimer’s disease. Arch Phys Med Rehabil 2005;86:576-81.
© 2005 by American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation
Objective: To analyze the relation between vitamin K status and bone mineral density (BMD) in women with Alzheimer’s disease (AD). Design: Cross-sectional study. Setting: Outpatient departments of neurology and neuropsychiatry at a hospital in Japan. Participants: One hundred women with AD (mean age, 79.8y) and 100 age-matched community dwelling controls (mean age, 80.6y). Interventions: Not applicable. Main Outcome Measures: Patients were divided into 2 groups according to the degree of dementia: the mild AD group was composed of patients with a score in Mini-Mental State Examination (MMSE) of 16 and above (n⫽42); patients in the severe AD group had MMSE scores below 15 (n⫽58). We assessed body mass index (BMI). BMD was measured by computed x-ray densitometry. Serum concentrations of vitamin K1, 25-hydroxyvitamin D (25[OH]D3), intact parathyroid hormone (PTH), and Glu osteocalcin (OC) were measured. Results: BMI was significantly lower in women with more severe AD. Metacarpal BMD (P⬍.02) and serum concentrations of vitamin K1 (P⬍.03) and 25(OH)D3 (P⬍.001) were significantly lower in the severe AD group than in the mild AD group. Serum levels of intact PTH and Glu OC in severely demented patients were higher than those with mild dementia (P⬍.001). Serum PTH concentration correlated negatively with serum 25(OH)D3 level (r⫽⫺.241, P⫽.016). Serum concentration of vitamin K1 correlated positively with that of 25(OH)D3 (r⫽.423, P⬍.001) and MMSE score (r⫽.353, P⬍.001), and negatively with Glu OC (r⫽⫺.580, P⬍.001). Conclusions: In female AD patients, nutritional vitamin K1 deficiency may reduce production of fully carboxylated OC, which in turn may cause reduced BMD. Lower BMIs in more severe AD may imply the presence of general malnutrition in such a patient group. Key Words: Alzheimer disease; Hip fracture; Osteocalcin; Osteoporosis; Rehabilitation; Vitamin K.
LZHEIMER’S DISEASE (AD) is a common neurodegenA erative disorder characterized by progressive loss of memory and cognitive function. Also, advanced AD is associated
From the Departments of Neurology (Sato, Honda) and Neuropsychiatry (Hayashida), Mitate Hospital, Tagawa; Department of Sport Medicine, School of Medicine, Keiko University, Tomohiro (Iwamoto); and Departments of Rehabilitation Medicine (Kanoko) and Vascular Biology (Satoh), and Institute of Brain Science (Kanoko, Satoh), Hirosaki University School of Medicine, Hirosaki, Japan. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Yoshihiro Sato, MD, Dept of Neurology, Mitate Hospital, 3237 Yugeta, Tagawa 826-0041, Japan, e-mail: [email protected]. 0003-9993/05/8603-9152$30.00/0 doi:10.1016/j.apmr.2004.10.005
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with generalized weakness. A high incidence of fractures, particularly of the hip,1-3 is a serious problem for patients with AD, who are prone to falls4 and may have osteoporosis. An odds ratio of 6.9 for fracture prevalence between elderly persons with and without AD has been reported.4 In addition, functional recovery of hip fracture in AD is poor,5-7 and patients with dementia have increased mortality in the 6 months after hip fracture.8 The physical state of AD has increasingly become a critical issue in the management of such patients. Our previous study9 demonstrated that deficiency of 25-hydroxyvitamin D (25[OH]D3) because of sunlight deprivation contributes to reduced bone mineral density (BMD) in AD patients in nursing homes. Kipen et al10 examined demented women living in the community and found that they have normal bone density, hypovitaminosis D, and compensatory hyperparathyroidism. Vitamin K is also responsible for the site-specific carboxylation of osteocalcin (OC) and other bone matrix proteins11; increased serum concentration of Glu OC is an indicator of compromised vitamin K status.12 Increased Glu OC is associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women.13-16 Both AD and osteoporosis occur more frequently in women. However, little is known about bone changes and vitamin K metabolism in elderly women with AD. In this study, we examined bone metabolism, with the focus being on the role of vitamin K in such a patient group. METHODS Participants We recruited 100 ambulatory women from among consecutive patients of our outpatient clinic who were more than 70 years old and met criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, Revised, for dementing disease and probable AD.17 Patients with impairment of renal, cardiac, or thyroid function or those who had known causes of osteoporosis, such as hyperparathyroidism, were excluded. Patients were also excluded if they had been treated with corticosteroids, estrogens, calcitonin, bisphosphonate, calcium, menatetrenone, or vitamin D for 3 months or more in the 12 months preceding the study; women who had been administered these agents for even a brief period in the preceding 2 months were also excluded. None of the patients had had fractures at any site. As controls, 100 cognitively normal, age-matched women without fractures (as determined by radiography) at any sites
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VITAMIN K DEFICIENCY AND OSTEOPENIA IN ALZHEIMER’S, Sato Table 1: Clinical and Demographic Features of Study Subjects Patients (n⫽100) Variable
Controls (n⫽100)
Mild AD (n⫽42)
Severe AD (n⫽58)
P*
Age (y) Duration of illness (y) Rankin Scale† BMI (kg/m2) Sunlight exposure ⬎15min/wk ⬍15min/wk or none Dietary intake of vitamin D (IU)
80.6⫾6.8 — 0⫾0 23.4⫾2.5
79.9⫾5.2 4.4⫾04.6 0.7⫾0.8‡ 23.0⫾2.5
79.7⫾4.5 4.2⫾2.0 2.3⫾1.2储 18.2⫾2.7储
.57 NS ⬍.001 ⬍.001
98 (98%) 2 (2%) 134⫾37
32 (77%) 10 (23%)‡ 137⫾21
17 (29%) 41 (71%) 68⫾31§
— — ⬍.001
NOTE. Values are means ⫾ SD. Mean MMSE scores20 ⫾ SD in mild and severe AD were 20.5⫾3.6 and 11.3⫾2.1, respectively. Abbreviation: NS, not significant. *Differences between the 3 groups (ANOVA). † ADLs were evaluated by the modified Rankin Scale.18 ‡ P⬍.0001 vs controls. 储 P⬍.0001 vs controls and mild AD.
were recruited from the community. The exclusion criteria for the control subjects were the same as for the patients. All patients and controls were informed about the nature of the study. Consent was obtained from each participant or from family members when patients were unable to understand because of dementia. The study protocol was approved by the local ethics committee. Body mass index (BMI) and illness duration were assessed. Activities of daily living (ADLs) were assessed by the Rankin Scale; on this scale, a score of 0 indicates independent daily living and a score of 5 indicates severe disability with total dependence that requires constant nursing care.18 Mean weekly intake of dietary vitamin D was calculated for each subject from a questionnaire completed by patients or family members; patients who consumed less than 100IU of vitamin D (the Japanese recommended daily allowance) were defined as low dietary consumers of the vitamin. Sunlight exposure in the preceding year was assessed by the patients or family members and graded as almost none, less than 15 minutes a week, or longer.19 A Mini-Mental State Examination20 (MMSE) score was assigned to all patients. AD patients were divided into 2 groups: the mild AD group had MMSE scores of 16 points or over, whereas the severe AD group had MMSE scores below 15 points. BMD was measured in the second metacarpal of the right hand using a computer-linked x-ray densitometer.21,a This method measures bone density using a radiograph taken to include both the hand and an aluminum step wedge used as a standard (20 steps, 1mm/step). The computer compares radiograph absorption for the various steps of the wedge with radiograph absorption in the bone region of interest to express the latter as an aluminum equivalent (mmAl). Thus, the estimated BMD is a relative value. Data accumulated from 288 healthy women who were 76 to 85 years22 served as control values for BMD; the normative range of BMD in the healthy subjects was 1.97 to 2.12mmAl. On the day of bone evaluation, fasting venous blood samples were obtained and assayed for the levels of phylloquinone (vitamin K1) and menaquinone (vitamin K2), 25(OH)D3, calcium, intact parathyroid hormone (PTH), and Glu OC. Concentrations of vitamins K1 and K2 were measured by highperformance liquid chromatography following the method of Langenberg and Tjaden.23 When vitamin K2 was undetectable, attempts were made to detect it in concentrated serum. Serum 25(OH)D3 was determined using a competitive protein-binding assay.b Ionized calcium was measured with freshly prepared
serum collected under anaerobic conditions. An ion-selective electrode was used as part of an ionized calcium analysis system.c Intact PTH was measured by immunoradiometric assay.b A commercially available enzyme-immunoassay kitd was used to measure Glu OC.24 On the basis of data reported previously,25 serum 25(OH)D3 concentration was defined as deficient when it was less than 25nmol/L, insufficient when it was 25 to 50nmol/L, and sufficient when it exceeded 50nmol/L. Data are presented as means ⫾ standard deviation (SD); all statistical procedures were performed using a StatView, version J 5.0 software package.e The Student t test was used to compare mean values of continuous variables between the 2 groups. The chi-square test was used to analyze intergroup differences for categorical data. One-way analysis of variance (ANOVA) and the Fisher-protected least significant difference method were used to assess the differences among the 2 AD groups and the controls. Spearman rank correlation coefficients were calculated to determine the relation between BMD and
Fig 1. BMD in the control, mild AD, and severe AD groups. The differences in the BMD among the groups were statistically significant (ANOVA). Error bars represent SDs.
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week. Three (7%) patients in the mild AD group and 31 (53%) in the severe AD group consumed less than the Japanese recommended daily allowance (100IU) of vitamin D. On average, patients in the severe AD group had a lower weekly dietary intake of vitamin D than did those in the mild AD group or control subjects. Serum Biochemical Parameters and BMD The average values of BMD (fig 1) and the serum vitamin K1 level (fig 2A) were the lowest in the patients with severe AD, and there were significant differences among the 2 patient groups and controls. There was no difference in serum K2 concentration among the 3 groups (fig 2B). Conversely, serum concentrations of Glu OC were higher in both groups of patients than in the control subjects, and the mean value was the highest in the severe AD group. The mean values of 25(OH)D3 in both AD groups were in the range of insufficient (mild AD) and deficient (severe AD) levels (fig 3). Serum PTH in both groups of patients was higher than that in the control subjects, with the mean value being highest in the severe AD group. No significant difference was seen in the plasma ionized calcium concentration among the 3 groups (table 2). Interrelationships Among BMD and Other Variables The relations among BMD and other variables were analyzed with the 2 patient groups combined, and the results are summarized in table 3. Metacarpal BMD correlated positively with MMSE scores, BMI, serum concentrations of vitamin K1, and serum 25(OH)D3 levels, and negatively with serum concentrations of PTH and Glu OC and Rankin Scale scores. Serum vitamin K1 concentration correlated positively with serum 25(OH)D3 levels (r⫽.423, P⬍.001) and MMSE scores (r⫽.353, P⬍.001), and negatively with serum Glu OC (r⫽⫺.580, P⬍.001). Both Rankin Scale scores and serum PTH levels correlated negatively with serum concentrations of 25(OH)D3 (r⫽⫺.366, P⬍.001; r⫽⫺.241, P⫽.016, respectively). Multiple Regression Analysis The results of multiple regression analysis, in which MMSE, BMI, vitamin K1, 25(OH)D3, intact PTH, and Glu Fig 2. Serum concentrations of vitamin K in the control, mild AD, and severe AD groups. (A) The differences in the serum concentration of vitamin K1 among the 3 groups were statistically significant (ANOVA). (B) The differences in the serum concentration of vitamin K2 among the 3 groups were not statistically significant (ANOVA, P<.60). Error bars represent SDs.
each variable. Multivariate linear regression analysis was used to estimate independent effects of predictor variables on BMD. P values less than .05 were considered statistically significant. RESULTS Clinical Profiles of Study Subjects Table 1 summarizes clinical information on all participants. There were no significant differences among the study sample for age. Nor were there significant differences between the 2 patient groups in illness duration. BMI was significantly lower in patients with more severe AD. Rankin Scale scores were lower in the patients with severe dementia than in those with mild dementia (P⬍.001). Low scores imply reduced mobility and prevent patients from venturing outdoors. Thus, 41 (71%) patients in the severe AD group and 10 (23%) in the mild AD group had been exposed to sunlight for less than 15 minutes a Arch Phys Med Rehabil Vol 86, March 2005
Fig 3. Serum 25(OH)D3 levels in AD patients and controls. The differences among the 3 groups were statistically significant (ANOVA). Error bars represent SDs.
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VITAMIN K DEFICIENCY AND OSTEOPENIA IN ALZHEIMER’S, Sato Table 2: Serum Biochemical Indices in Controls and 2 Patient Groups Patients (n⫽100) Variable
Controls (n⫽100)
Mild AD (n⫽42)
Severe AD (n⫽58)
P*
Ionized calcium (mmol/L) Intact PTH (ng/L) Glu OC (g/L)
1.23⫾0.01 39.1⫾15.4 3.1⫾4.2
1.23⫾0.01 46.0⫾9.5† 6.3⫾3.7储
1.23⫾0.02 77.8⫾15.2†‡ 13.2⫾7.4†‡
.71 ⬍.001 ⬍.001
NOTE. Values are means ⫾ SD. *Differences among the 3 groups (ANOVA). † P⬍.001 vs controls; ‡P⬍.001 vs group A; 储P⬍.001 vs control.
OC were selected as independent variables, with metacarpal BMD as the dependent variable, are shown in table 4. Rankin Scale, vitamin K1, 25(OH)D3, Glu OC, and PTH were significantly related to BMD (P⬍.037 to P⬍.001), accounting for 33% of the variability of this parameter (adjusted R2⫽.334, F⫽6.605, P⬍.001). DISCUSSION The MMSE is widely used to assess dementia in elderly subjects26,27; its score in community-dwelling elderly subjects has been reported to be from 25.3 to 30.0.28,29 We used the Rankin Scale, which is a simple, short test, to assess the ADLs of the AD patients because they are noncooperative in evaluating their ADLs due to dementia. The scale is viewed as a global functional health index, with an emphasis on physical disability.30 We found that vitamin K1, Glu OC, 25(OH)D3, PTH, and physical immobilization, as characterized by low Rankin Scale scores, were independent determinants of BMD in the metacarpal bone of elderly women with AD. Deficiency of vitamin K1, low serum concentrations of 25(OH)D3, loss of BMD, and high serum concentrations of Glu OC were apparent in the patients with immobility (severe dementia), but less apparent in patients with relatively higher mobility (mild dementia). As previously reported,9 sunlight deprivation and malnutrition were responsible for 25(OH)D3 deficiency in a patient group similar to the milder group in this study. Vitamin K has 2 main sources in humans31: vitamin K1 is supplied through the diet, especially by green leafy vegetables, while vitamin K2 is synthesized by bacteria in the gut. In the present study, a significant decrease in serum vitamin K1, but not K2, was observed in the patients with severe dementia. That deficiency was considered to reflect generally poor nutrition, as
also evidenced by low serum 25(OH)D3. In contrast, no significant difference was found in vitamin K2 levels between healthy controls and AD patients. There are several reports that reduced vitamin K concentrations in otherwise healthy elderly women are associated with reduced BMD in the hip,32 lumbar spine,33 and second metacarpal,34 placing those women at increased risk for fractures.24 Vitamin K has been shown to increase BMD in humans and animals.35,36 Because Glu OC correlated negatively with vitamin K1, low production of fully carboxylated OC due to vitamin K1 deficiency may be a cause of the reduced BMD in AD patients, particularly in those who are functionally dependent. Reduced BMD may have resulted from a combination of disuse due to immobilization, the effect of vitamin D deficiency on bone, and lowered BMD resulting from impaired OC carboxylation (increased Glu OC concentration) caused by nutritional vitamin K1 deficiency. In addition, BMD correlated positively with BMI, and severely demented AD patients had very low BMI. Therefore, general malnutrition may be the primary cause of vitamin K and vitamin D deficiencies and osteopenia. A recent study37 demonstrated that women with an apolipoprotein 4 (APOE4) allele were twice as likely to have hip fractures as were those without APOE4 allele. The APOE4 allele is a well-established risk factor for AD. Although the precise mechanism for the association of APOE4 and bone fracture is not clear, apolipoprotein E phenotype may possibly affect the metabolism of fat-soluble vitamin K as much as triglyceride-rich lipoproteins. In previous studies of patients with Parkinson’s disease or stroke, we found that second metacarpal BMD, as determined by computer-linked x-ray densitometer, correlated with risk of hip fracture,38,39 and reduced second metacarpal BMD was considered to reflect osteopenia throughout the appendicular skeleton.40 Patients at the chronic stage of stroke or Parkin-
Table 3: Correlation Among BMD and Each Variable Variables
BMD
Age MMSE Illness duration Postmenopausal duration Rankin Scale BMI Vitamin K1 Vitamin K2 25(OH)D3 Calcium Intact PTH Glu OC
.181* .454† ⫺.167* ⫺.100* ⫺.413† .308‡ .273‡ .026* .257‡ ⫺.181* ⫺.253‡ ⫺.252‡
NOTE. Values are Spearman rank correlation coefficients, with probability values as per symbols. *Not significant; †P⬍.001; ‡P⬍.01.
Table 4: Multiple Regression Analysis of BMD With Selected Independent Variables BMD Variables
SC
P
MMSE BMI Rankin Scale Vitamin K1 25(OH)D3 Glu OC Intact PTH Multiple R Adjusted R2 F
⫺.139 .187 ⫺.515 .47 .205 ⫺.273 ⫺.289
.29 .06 ⬍.001 .020 .037 .018 .006 .578 .334 6.605
Abbreviation: SC, standardized coefficient.
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son’s disease have a high incidence of hip fracture,38,39 but its incidence in these populations has been reduced with vitamin K therapy.12,41 Similarly, vitamin K is expected to reduce the high incidence of hip fracture in AD. Several studies42-45 have reported a relation between vitamin D deficiency and hip fractures. Hip fracture was the presenting feature in 11 of 37 cases of osteomalacia in elderly subjects,42 while osteomalacia was found in 13% of 130 patients with hip fractures.42 A previous study44 demonstrated that daily supplementation with vitamin D (800IU) reduced hip fracture by 43% in postmenopausal women. Studies are required to determine whether hip fracture incidence can be reduced by the combined use of vitamin K and vitamin D in AD patients. Furthermore, treatment for malnutrition, particularly in patients with severe dementia, may be needed to reduce the high incidence of hip fracture. Based on the results reported here, routine determinations of serum Glu OC and vitamin K1 concentrations are important in management of AD patients. Awareness of deficiencies in vitamin K1 and 25(OH)D3 and of high Glu OC levels enables clinicians to predict risk for hip fractures, which occur frequently in such a patient population.1-3 CONCLUSIONS In women with AD, nutritional vitamin K1 deficiency may reduce production of fully carboxylated OC, which in turn may cause reduced BMD. References 1. Johansson C, Skoog I. A population-based study on the association between dementia and hip fractures in 85-year olds. Aging (Milano) 1996;8:189-96. 2. Melton LJ 3rd, Beard CM, Kokmen E, Atkinson EJ, O’Fallon WM. Fracture risk in patients with Alzheimer’s disease. J Am Geriatr Soc 1994;42:614-9. 3. van Staa TP, Leufkens HG, Cooper C. Utility of medical and drug history in fracture risk prediction among men and women. Bone 2000;31:508-14. 4. Buchner DM, Larson EB. Falls and fractures in patients with Alzheimer-type dementia. JAMA 1987;257:1492-5. 5. Holmes J, House A. Psychiatric illness predicts poor outcome after surgery for hip fracture: a prospective cohort study. Psychol Med 2000;30:921-9. 6. Matsueda M, Ishii Y. The relationship between dementia score and ambulatory level after hip fracture in the elderly. Am J Orthop 2000;29:691-3. 7. Morrison RS, Siu AL. Mortality from pneumonia and hip fractures in patients with advanced dementia. JAMA 2000;284:2447-8. 8. Nightingale S, Holmes J, Mason J, House A. Psychiatric illness and mortality after hip fracture. Lancet 2001;357:1264-5. 9. Sato Y, Asoh T, Oizumi K. High prevalence of vitamin D deficiency and reduced bone mass in elderly women with Alzheimer’s disease. Bone 1998;25:555-7. 10. Kipen E, Helme RD, Wark JD, Flicker L. Bone density, vitamin D nutrition, and parathyroid hormone levels in women with dementia. J Am Geriatr Soc 1995;43:1088-91. 11. Vermeer C, Jie KS, Knapen MH. Role of vitamin K in bone metabolism. Annu Rev Nutr 1995;15:1-22. 12. Sato Y, Honda Y, Kaji M, et al. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson’s disease patients with vitamin D deficiency. Bone 2002;31:114-8. 13. Bitensky L, Hart JP, Catterall A, Hodges SJ, Pilkington MJ, Chayen J. Circulating vitamin K levels in patients with fractures. J Bone Joint Surg Br 1988;70:662-3. Arch Phys Med Rehabil Vol 86, March 2005
14. Hart JP, Shearer MJ, Klenerman L, et al. Electrochemical detection of depressed circulating levels of vitamin K1 in osteoporosis. J Clin Endocrin Metab 1985;60:1268-9. 15. Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD. Circulating levels of vitamin K1 and K2 decreased in elderly women with hip fractures. J Bone Miner Res 1993;8:241-5. 16. Hodges SJ, Pilkington MJ, Stamp TC, et al. Depressed levels of circulation menaquinones in patients with osteoporotic fractures of the spine and femoral neck. Bone 1991;12:387-9. 17. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Standian EM. Clinical diagnosis of Alzheimer’s disease: report on the NINCDS-ADRADA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984;34:939-44. 18. Van Swieten JC, Koudstaal PJ, Visser MC. Interobserver agreement for assessment of handicap in stroke patients. Stroke 1988; 19:604-7. 19. Komar L, Nieves J, Cosman F, Rubin A, Shen V, Lindsay R. Calcium homeostasis of an elderly population upon admission to a nursing home. J Am Geriatr Soc 1993;41:1057-64. 20. Folstein MF, Folstein SF, McHugh PR. “Mini mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98. 21. Matsumoto C, Kushida K, Yamazaki K, Imose K, Inoue T. Metacarpal bone mass in normal and osteoporotic Japanese women using computed X-ray densitometry. Calcif Tissue Int 1994;55: 324-9. 22. Sato Y, Kuno H, Kaji M, Ohshima Y, Asoh T, Oizumi K. Increased bone resorption during the first year after stroke. Stroke 1998;29:1373-7. 23. Langenberg JP, Tjaden UR. Improved method for the determination of vitamin K1 epoxide in human plasma with electrofluorimetric reaction detection. J Chromatgr 1984;289:377-85. 24. Szulc P, Arlot M, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res 1994;9:1591-5. 25. Parfitt AM, Gallagher JC, Heaney RP, Johnston CC, Neer R, Whedon GD. Vitamin D and bone health in the elderly. Am J Clin Nutr 1982;36:1014-31. 26. Yuspeh RL, Vanderploeg RD, Kershaw DA. Validity of a semantically cued recall procedure for the mini-mental state examination. Neuropsychiatry Neuropsychol Behav Neurol 1998;11:20711. 27. Jones RN, Gallo JJ. Dimensions of the Mini-Mental State Examination among community dwelling older adults. Psychol Med 2000;30:605-18. 28. Smith GE, Bohac DL, Waring SC, et al. Apolipoprotein E genotype influences cognitive ‘phenotype’ in patients with Alzheimer’s disease but not in healthy control subjects. Neurology 1998;50: 355-62. 29. Espino DV, Lichtenstein MJ, Palmer RF, Hazuda HP. Evaluation of the Mini-Mental State Examination’s internal consistency in a community-based sample of Mexican-American and EuropeanAmerican elders: results from the San Antonio longitudinal study of aging. J Am Geriatr Soc 2004;52:822-7. 30. de Haan R, Limburg M, Bossuyt P, van der Meulen J, Aaronson N. The clinical meaning of Rankin ‘handicap’ grades after stroke. Stroke 1995;26:2027-30. 31. Shearer MJ. Vitamin K. Lancet 1995;345:229-34. 32. Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest 1993;91:1769-74. 33. Kanai T, Takagi T, Masuhiro K, Nakamura M, Iwata M, Saji F. Serum vitamin K level and bone mineral density in postmenopausal women. Int J Gynecol Obstet 1997;56:25-30.
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34. Jie KS, Bots ML, Vermeer C, Witte JC, Grobbee DE. Vitamin K status and bone mass in women with or without aortic atherosclerosis: a population-based study. Calcif Tissue Int 1996;59:352-6. 35. Akiyama Y, Hara K, Ohkawa I, Tajima T. Effects of menantetrenone on bone loss induced by ovariectomy in rats. Jpn J Pharmacol 1993;62:145-53. 36. Hara K, Akiyama Y, Tajima T, Shiraki M. Menantetrenone inhibits bone resorption partly through inhibition of PGE2 synthesis in vitro. J Bone Miner Res 1993;8:535-42. 37. Johnston JM, Cauley JA, Ganguli M. APOE 4 and hip fracture risk in a community-based study of older adults. J Am Geriatr Soc 1999;47:1342-5. 38. Sato Y, Manabe S, Kuno H, Oizumi K. Amelioration of osteopenia and hypovitaminosis D by 1␣-hydroxyvitamin D3 in elderly Parkinson’s disease patients. J Neurol Neurosurg Psychiatry 1999; 66:64-8. 39. Sato Y, Maruoka H, Oizumi K. Amelioration of hemiplegia-associated osteopenia over 4 years following stroke by 1 ␣-hydroxyvitamin D3 and calcium supplementation. Stroke 1997;28:736-9. 40. Derisquebourg T, Dubois P, Devogelaer JP, et al. Automated computerized radiogrammetry of the second metacarpal and its correlation with absorptiometry of the forearm and spine. Calcif Tissue Int 1994;54:461-5.
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41. Sato Y, Honda Y, Kuno H, Oizumi K. Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients. Bone 1998;23:291-6. 42. Chalmers J, Conacher WD, Gardner DL, Scott PJ. Osteomalacia—a common disease in elderly women. J Bone Joint Surg Br 1967;49:403-23. 43. Chalmers J, Barclay A, Davison AM, MacLeod DA, Williams DA. Quantitative measurements of osteoid in health and disease. Clin Orthop 1969;Mar-Apr(63):196-209. 44. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327:1637-42. 45. Stein MS, Wark JD, Scherer SC, et al. Falls relate to vitamin D and parathyroid hormone in an Australian nursing home. J Am Geriatr Soc 1999;47:1195-201. Suppliers a. Teijin Ltd, 1-1, Uchisaiwaicho 2-chome, Chiyoda-ku, Tokyo 1008585, Japan. b. Nichols Institute Diagnostics, 1311 Calle Batido, San Clemente, CA 92673. c. EMD Biosciences, 10394 Pacific Center Ct, San Diego, CA 92121. d. Takara Shuzo Co, Seta 3-4-1, Otsu, Shiga 520-2193, Japan. e. SAS Institute, 100 SAS Campus Dr, Cary, NC 27513.
Arch Phys Med Rehabil Vol 86, March 2005
Vitamin K Deficiency and Osteopenia in Elderly Women With Alzheimer’s Disease Yoshihiro Sato, MD, Yoshiaki Honda, MD, Norimasa Hayashida, MD, Jun Iwamoto, MD, Tomohiro Kanoko, OT, Kei Satoh, MD ABSTRACT. Sato Y, Honda Y, Hayashida N, Iwamoto J, Kanoko T, Satoh K. Vitamin K deficiency and osteopenia in elderly women with Alzheimer’s disease. Arch Phys Med Rehabil 2005;86:576-81.
© 2005 by American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation
Objective: To analyze the relation between vitamin K status and bone mineral density (BMD) in women with Alzheimer’s disease (AD). Design: Cross-sectional study. Setting: Outpatient departments of neurology and neuropsychiatry at a hospital in Japan. Participants: One hundred women with AD (mean age, 79.8y) and 100 age-matched community dwelling controls (mean age, 80.6y). Interventions: Not applicable. Main Outcome Measures: Patients were divided into 2 groups according to the degree of dementia: the mild AD group was composed of patients with a score in Mini-Mental State Examination (MMSE) of 16 and above (n⫽42); patients in the severe AD group had MMSE scores below 15 (n⫽58). We assessed body mass index (BMI). BMD was measured by computed x-ray densitometry. Serum concentrations of vitamin K1, 25-hydroxyvitamin D (25[OH]D3), intact parathyroid hormone (PTH), and Glu osteocalcin (OC) were measured. Results: BMI was significantly lower in women with more severe AD. Metacarpal BMD (P⬍.02) and serum concentrations of vitamin K1 (P⬍.03) and 25(OH)D3 (P⬍.001) were significantly lower in the severe AD group than in the mild AD group. Serum levels of intact PTH and Glu OC in severely demented patients were higher than those with mild dementia (P⬍.001). Serum PTH concentration correlated negatively with serum 25(OH)D3 level (r⫽⫺.241, P⫽.016). Serum concentration of vitamin K1 correlated positively with that of 25(OH)D3 (r⫽.423, P⬍.001) and MMSE score (r⫽.353, P⬍.001), and negatively with Glu OC (r⫽⫺.580, P⬍.001). Conclusions: In female AD patients, nutritional vitamin K1 deficiency may reduce production of fully carboxylated OC, which in turn may cause reduced BMD. Lower BMIs in more severe AD may imply the presence of general malnutrition in such a patient group. Key Words: Alzheimer disease; Hip fracture; Osteocalcin; Osteoporosis; Rehabilitation; Vitamin K.
LZHEIMER’S DISEASE (AD) is a common neurodegenA erative disorder characterized by progressive loss of memory and cognitive function. Also, advanced AD is associated
From the Departments of Neurology (Sato, Honda) and Neuropsychiatry (Hayashida), Mitate Hospital, Tagawa; Department of Sport Medicine, School of Medicine, Keiko University, Tomohiro (Iwamoto); and Departments of Rehabilitation Medicine (Kanoko) and Vascular Biology (Satoh), and Institute of Brain Science (Kanoko, Satoh), Hirosaki University School of Medicine, Hirosaki, Japan. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Yoshihiro Sato, MD, Dept of Neurology, Mitate Hospital, 3237 Yugeta, Tagawa 826-0041, Japan, e-mail: [email protected]. 0003-9993/05/8603-9152$30.00/0 doi:10.1016/j.apmr.2004.10.005
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with generalized weakness. A high incidence of fractures, particularly of the hip,1-3 is a serious problem for patients with AD, who are prone to falls4 and may have osteoporosis. An odds ratio of 6.9 for fracture prevalence between elderly persons with and without AD has been reported.4 In addition, functional recovery of hip fracture in AD is poor,5-7 and patients with dementia have increased mortality in the 6 months after hip fracture.8 The physical state of AD has increasingly become a critical issue in the management of such patients. Our previous study9 demonstrated that deficiency of 25-hydroxyvitamin D (25[OH]D3) because of sunlight deprivation contributes to reduced bone mineral density (BMD) in AD patients in nursing homes. Kipen et al10 examined demented women living in the community and found that they have normal bone density, hypovitaminosis D, and compensatory hyperparathyroidism. Vitamin K is also responsible for the site-specific carboxylation of osteocalcin (OC) and other bone matrix proteins11; increased serum concentration of Glu OC is an indicator of compromised vitamin K status.12 Increased Glu OC is associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women.13-16 Both AD and osteoporosis occur more frequently in women. However, little is known about bone changes and vitamin K metabolism in elderly women with AD. In this study, we examined bone metabolism, with the focus being on the role of vitamin K in such a patient group. METHODS Participants We recruited 100 ambulatory women from among consecutive patients of our outpatient clinic who were more than 70 years old and met criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, Revised, for dementing disease and probable AD.17 Patients with impairment of renal, cardiac, or thyroid function or those who had known causes of osteoporosis, such as hyperparathyroidism, were excluded. Patients were also excluded if they had been treated with corticosteroids, estrogens, calcitonin, bisphosphonate, calcium, menatetrenone, or vitamin D for 3 months or more in the 12 months preceding the study; women who had been administered these agents for even a brief period in the preceding 2 months were also excluded. None of the patients had had fractures at any site. As controls, 100 cognitively normal, age-matched women without fractures (as determined by radiography) at any sites
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VITAMIN K DEFICIENCY AND OSTEOPENIA IN ALZHEIMER’S, Sato Table 1: Clinical and Demographic Features of Study Subjects Patients (n⫽100) Variable
Controls (n⫽100)
Mild AD (n⫽42)
Severe AD (n⫽58)
P*
Age (y) Duration of illness (y) Rankin Scale† BMI (kg/m2) Sunlight exposure ⬎15min/wk ⬍15min/wk or none Dietary intake of vitamin D (IU)
80.6⫾6.8 — 0⫾0 23.4⫾2.5
79.9⫾5.2 4.4⫾04.6 0.7⫾0.8‡ 23.0⫾2.5
79.7⫾4.5 4.2⫾2.0 2.3⫾1.2储 18.2⫾2.7储
.57 NS ⬍.001 ⬍.001
98 (98%) 2 (2%) 134⫾37
32 (77%) 10 (23%)‡ 137⫾21
17 (29%) 41 (71%) 68⫾31§
— — ⬍.001
NOTE. Values are means ⫾ SD. Mean MMSE scores20 ⫾ SD in mild and severe AD were 20.5⫾3.6 and 11.3⫾2.1, respectively. Abbreviation: NS, not significant. *Differences between the 3 groups (ANOVA). † ADLs were evaluated by the modified Rankin Scale.18 ‡ P⬍.0001 vs controls. 储 P⬍.0001 vs controls and mild AD.
were recruited from the community. The exclusion criteria for the control subjects were the same as for the patients. All patients and controls were informed about the nature of the study. Consent was obtained from each participant or from family members when patients were unable to understand because of dementia. The study protocol was approved by the local ethics committee. Body mass index (BMI) and illness duration were assessed. Activities of daily living (ADLs) were assessed by the Rankin Scale; on this scale, a score of 0 indicates independent daily living and a score of 5 indicates severe disability with total dependence that requires constant nursing care.18 Mean weekly intake of dietary vitamin D was calculated for each subject from a questionnaire completed by patients or family members; patients who consumed less than 100IU of vitamin D (the Japanese recommended daily allowance) were defined as low dietary consumers of the vitamin. Sunlight exposure in the preceding year was assessed by the patients or family members and graded as almost none, less than 15 minutes a week, or longer.19 A Mini-Mental State Examination20 (MMSE) score was assigned to all patients. AD patients were divided into 2 groups: the mild AD group had MMSE scores of 16 points or over, whereas the severe AD group had MMSE scores below 15 points. BMD was measured in the second metacarpal of the right hand using a computer-linked x-ray densitometer.21,a This method measures bone density using a radiograph taken to include both the hand and an aluminum step wedge used as a standard (20 steps, 1mm/step). The computer compares radiograph absorption for the various steps of the wedge with radiograph absorption in the bone region of interest to express the latter as an aluminum equivalent (mmAl). Thus, the estimated BMD is a relative value. Data accumulated from 288 healthy women who were 76 to 85 years22 served as control values for BMD; the normative range of BMD in the healthy subjects was 1.97 to 2.12mmAl. On the day of bone evaluation, fasting venous blood samples were obtained and assayed for the levels of phylloquinone (vitamin K1) and menaquinone (vitamin K2), 25(OH)D3, calcium, intact parathyroid hormone (PTH), and Glu OC. Concentrations of vitamins K1 and K2 were measured by highperformance liquid chromatography following the method of Langenberg and Tjaden.23 When vitamin K2 was undetectable, attempts were made to detect it in concentrated serum. Serum 25(OH)D3 was determined using a competitive protein-binding assay.b Ionized calcium was measured with freshly prepared
serum collected under anaerobic conditions. An ion-selective electrode was used as part of an ionized calcium analysis system.c Intact PTH was measured by immunoradiometric assay.b A commercially available enzyme-immunoassay kitd was used to measure Glu OC.24 On the basis of data reported previously,25 serum 25(OH)D3 concentration was defined as deficient when it was less than 25nmol/L, insufficient when it was 25 to 50nmol/L, and sufficient when it exceeded 50nmol/L. Data are presented as means ⫾ standard deviation (SD); all statistical procedures were performed using a StatView, version J 5.0 software package.e The Student t test was used to compare mean values of continuous variables between the 2 groups. The chi-square test was used to analyze intergroup differences for categorical data. One-way analysis of variance (ANOVA) and the Fisher-protected least significant difference method were used to assess the differences among the 2 AD groups and the controls. Spearman rank correlation coefficients were calculated to determine the relation between BMD and
Fig 1. BMD in the control, mild AD, and severe AD groups. The differences in the BMD among the groups were statistically significant (ANOVA). Error bars represent SDs.
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week. Three (7%) patients in the mild AD group and 31 (53%) in the severe AD group consumed less than the Japanese recommended daily allowance (100IU) of vitamin D. On average, patients in the severe AD group had a lower weekly dietary intake of vitamin D than did those in the mild AD group or control subjects. Serum Biochemical Parameters and BMD The average values of BMD (fig 1) and the serum vitamin K1 level (fig 2A) were the lowest in the patients with severe AD, and there were significant differences among the 2 patient groups and controls. There was no difference in serum K2 concentration among the 3 groups (fig 2B). Conversely, serum concentrations of Glu OC were higher in both groups of patients than in the control subjects, and the mean value was the highest in the severe AD group. The mean values of 25(OH)D3 in both AD groups were in the range of insufficient (mild AD) and deficient (severe AD) levels (fig 3). Serum PTH in both groups of patients was higher than that in the control subjects, with the mean value being highest in the severe AD group. No significant difference was seen in the plasma ionized calcium concentration among the 3 groups (table 2). Interrelationships Among BMD and Other Variables The relations among BMD and other variables were analyzed with the 2 patient groups combined, and the results are summarized in table 3. Metacarpal BMD correlated positively with MMSE scores, BMI, serum concentrations of vitamin K1, and serum 25(OH)D3 levels, and negatively with serum concentrations of PTH and Glu OC and Rankin Scale scores. Serum vitamin K1 concentration correlated positively with serum 25(OH)D3 levels (r⫽.423, P⬍.001) and MMSE scores (r⫽.353, P⬍.001), and negatively with serum Glu OC (r⫽⫺.580, P⬍.001). Both Rankin Scale scores and serum PTH levels correlated negatively with serum concentrations of 25(OH)D3 (r⫽⫺.366, P⬍.001; r⫽⫺.241, P⫽.016, respectively). Multiple Regression Analysis The results of multiple regression analysis, in which MMSE, BMI, vitamin K1, 25(OH)D3, intact PTH, and Glu Fig 2. Serum concentrations of vitamin K in the control, mild AD, and severe AD groups. (A) The differences in the serum concentration of vitamin K1 among the 3 groups were statistically significant (ANOVA). (B) The differences in the serum concentration of vitamin K2 among the 3 groups were not statistically significant (ANOVA, P<.60). Error bars represent SDs.
each variable. Multivariate linear regression analysis was used to estimate independent effects of predictor variables on BMD. P values less than .05 were considered statistically significant. RESULTS Clinical Profiles of Study Subjects Table 1 summarizes clinical information on all participants. There were no significant differences among the study sample for age. Nor were there significant differences between the 2 patient groups in illness duration. BMI was significantly lower in patients with more severe AD. Rankin Scale scores were lower in the patients with severe dementia than in those with mild dementia (P⬍.001). Low scores imply reduced mobility and prevent patients from venturing outdoors. Thus, 41 (71%) patients in the severe AD group and 10 (23%) in the mild AD group had been exposed to sunlight for less than 15 minutes a Arch Phys Med Rehabil Vol 86, March 2005
Fig 3. Serum 25(OH)D3 levels in AD patients and controls. The differences among the 3 groups were statistically significant (ANOVA). Error bars represent SDs.
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VITAMIN K DEFICIENCY AND OSTEOPENIA IN ALZHEIMER’S, Sato Table 2: Serum Biochemical Indices in Controls and 2 Patient Groups Patients (n⫽100) Variable
Controls (n⫽100)
Mild AD (n⫽42)
Severe AD (n⫽58)
P*
Ionized calcium (mmol/L) Intact PTH (ng/L) Glu OC (g/L)
1.23⫾0.01 39.1⫾15.4 3.1⫾4.2
1.23⫾0.01 46.0⫾9.5† 6.3⫾3.7储
1.23⫾0.02 77.8⫾15.2†‡ 13.2⫾7.4†‡
.71 ⬍.001 ⬍.001
NOTE. Values are means ⫾ SD. *Differences among the 3 groups (ANOVA). † P⬍.001 vs controls; ‡P⬍.001 vs group A; 储P⬍.001 vs control.
OC were selected as independent variables, with metacarpal BMD as the dependent variable, are shown in table 4. Rankin Scale, vitamin K1, 25(OH)D3, Glu OC, and PTH were significantly related to BMD (P⬍.037 to P⬍.001), accounting for 33% of the variability of this parameter (adjusted R2⫽.334, F⫽6.605, P⬍.001). DISCUSSION The MMSE is widely used to assess dementia in elderly subjects26,27; its score in community-dwelling elderly subjects has been reported to be from 25.3 to 30.0.28,29 We used the Rankin Scale, which is a simple, short test, to assess the ADLs of the AD patients because they are noncooperative in evaluating their ADLs due to dementia. The scale is viewed as a global functional health index, with an emphasis on physical disability.30 We found that vitamin K1, Glu OC, 25(OH)D3, PTH, and physical immobilization, as characterized by low Rankin Scale scores, were independent determinants of BMD in the metacarpal bone of elderly women with AD. Deficiency of vitamin K1, low serum concentrations of 25(OH)D3, loss of BMD, and high serum concentrations of Glu OC were apparent in the patients with immobility (severe dementia), but less apparent in patients with relatively higher mobility (mild dementia). As previously reported,9 sunlight deprivation and malnutrition were responsible for 25(OH)D3 deficiency in a patient group similar to the milder group in this study. Vitamin K has 2 main sources in humans31: vitamin K1 is supplied through the diet, especially by green leafy vegetables, while vitamin K2 is synthesized by bacteria in the gut. In the present study, a significant decrease in serum vitamin K1, but not K2, was observed in the patients with severe dementia. That deficiency was considered to reflect generally poor nutrition, as
also evidenced by low serum 25(OH)D3. In contrast, no significant difference was found in vitamin K2 levels between healthy controls and AD patients. There are several reports that reduced vitamin K concentrations in otherwise healthy elderly women are associated with reduced BMD in the hip,32 lumbar spine,33 and second metacarpal,34 placing those women at increased risk for fractures.24 Vitamin K has been shown to increase BMD in humans and animals.35,36 Because Glu OC correlated negatively with vitamin K1, low production of fully carboxylated OC due to vitamin K1 deficiency may be a cause of the reduced BMD in AD patients, particularly in those who are functionally dependent. Reduced BMD may have resulted from a combination of disuse due to immobilization, the effect of vitamin D deficiency on bone, and lowered BMD resulting from impaired OC carboxylation (increased Glu OC concentration) caused by nutritional vitamin K1 deficiency. In addition, BMD correlated positively with BMI, and severely demented AD patients had very low BMI. Therefore, general malnutrition may be the primary cause of vitamin K and vitamin D deficiencies and osteopenia. A recent study37 demonstrated that women with an apolipoprotein 4 (APOE4) allele were twice as likely to have hip fractures as were those without APOE4 allele. The APOE4 allele is a well-established risk factor for AD. Although the precise mechanism for the association of APOE4 and bone fracture is not clear, apolipoprotein E phenotype may possibly affect the metabolism of fat-soluble vitamin K as much as triglyceride-rich lipoproteins. In previous studies of patients with Parkinson’s disease or stroke, we found that second metacarpal BMD, as determined by computer-linked x-ray densitometer, correlated with risk of hip fracture,38,39 and reduced second metacarpal BMD was considered to reflect osteopenia throughout the appendicular skeleton.40 Patients at the chronic stage of stroke or Parkin-
Table 3: Correlation Among BMD and Each Variable Variables
BMD
Age MMSE Illness duration Postmenopausal duration Rankin Scale BMI Vitamin K1 Vitamin K2 25(OH)D3 Calcium Intact PTH Glu OC
.181* .454† ⫺.167* ⫺.100* ⫺.413† .308‡ .273‡ .026* .257‡ ⫺.181* ⫺.253‡ ⫺.252‡
NOTE. Values are Spearman rank correlation coefficients, with probability values as per symbols. *Not significant; †P⬍.001; ‡P⬍.01.
Table 4: Multiple Regression Analysis of BMD With Selected Independent Variables BMD Variables
SC
P
MMSE BMI Rankin Scale Vitamin K1 25(OH)D3 Glu OC Intact PTH Multiple R Adjusted R2 F
⫺.139 .187 ⫺.515 .47 .205 ⫺.273 ⫺.289
.29 .06 ⬍.001 .020 .037 .018 .006 .578 .334 6.605
Abbreviation: SC, standardized coefficient.
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son’s disease have a high incidence of hip fracture,38,39 but its incidence in these populations has been reduced with vitamin K therapy.12,41 Similarly, vitamin K is expected to reduce the high incidence of hip fracture in AD. Several studies42-45 have reported a relation between vitamin D deficiency and hip fractures. Hip fracture was the presenting feature in 11 of 37 cases of osteomalacia in elderly subjects,42 while osteomalacia was found in 13% of 130 patients with hip fractures.42 A previous study44 demonstrated that daily supplementation with vitamin D (800IU) reduced hip fracture by 43% in postmenopausal women. Studies are required to determine whether hip fracture incidence can be reduced by the combined use of vitamin K and vitamin D in AD patients. Furthermore, treatment for malnutrition, particularly in patients with severe dementia, may be needed to reduce the high incidence of hip fracture. Based on the results reported here, routine determinations of serum Glu OC and vitamin K1 concentrations are important in management of AD patients. Awareness of deficiencies in vitamin K1 and 25(OH)D3 and of high Glu OC levels enables clinicians to predict risk for hip fractures, which occur frequently in such a patient population.1-3 CONCLUSIONS In women with AD, nutritional vitamin K1 deficiency may reduce production of fully carboxylated OC, which in turn may cause reduced BMD. References 1. Johansson C, Skoog I. A population-based study on the association between dementia and hip fractures in 85-year olds. Aging (Milano) 1996;8:189-96. 2. Melton LJ 3rd, Beard CM, Kokmen E, Atkinson EJ, O’Fallon WM. Fracture risk in patients with Alzheimer’s disease. J Am Geriatr Soc 1994;42:614-9. 3. van Staa TP, Leufkens HG, Cooper C. Utility of medical and drug history in fracture risk prediction among men and women. Bone 2000;31:508-14. 4. Buchner DM, Larson EB. Falls and fractures in patients with Alzheimer-type dementia. JAMA 1987;257:1492-5. 5. Holmes J, House A. Psychiatric illness predicts poor outcome after surgery for hip fracture: a prospective cohort study. Psychol Med 2000;30:921-9. 6. Matsueda M, Ishii Y. The relationship between dementia score and ambulatory level after hip fracture in the elderly. Am J Orthop 2000;29:691-3. 7. Morrison RS, Siu AL. Mortality from pneumonia and hip fractures in patients with advanced dementia. JAMA 2000;284:2447-8. 8. Nightingale S, Holmes J, Mason J, House A. Psychiatric illness and mortality after hip fracture. Lancet 2001;357:1264-5. 9. Sato Y, Asoh T, Oizumi K. High prevalence of vitamin D deficiency and reduced bone mass in elderly women with Alzheimer’s disease. Bone 1998;25:555-7. 10. Kipen E, Helme RD, Wark JD, Flicker L. Bone density, vitamin D nutrition, and parathyroid hormone levels in women with dementia. J Am Geriatr Soc 1995;43:1088-91. 11. Vermeer C, Jie KS, Knapen MH. Role of vitamin K in bone metabolism. Annu Rev Nutr 1995;15:1-22. 12. Sato Y, Honda Y, Kaji M, et al. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson’s disease patients with vitamin D deficiency. Bone 2002;31:114-8. 13. Bitensky L, Hart JP, Catterall A, Hodges SJ, Pilkington MJ, Chayen J. Circulating vitamin K levels in patients with fractures. J Bone Joint Surg Br 1988;70:662-3. Arch Phys Med Rehabil Vol 86, March 2005
14. Hart JP, Shearer MJ, Klenerman L, et al. Electrochemical detection of depressed circulating levels of vitamin K1 in osteoporosis. J Clin Endocrin Metab 1985;60:1268-9. 15. Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD. Circulating levels of vitamin K1 and K2 decreased in elderly women with hip fractures. J Bone Miner Res 1993;8:241-5. 16. Hodges SJ, Pilkington MJ, Stamp TC, et al. Depressed levels of circulation menaquinones in patients with osteoporotic fractures of the spine and femoral neck. Bone 1991;12:387-9. 17. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Standian EM. Clinical diagnosis of Alzheimer’s disease: report on the NINCDS-ADRADA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984;34:939-44. 18. Van Swieten JC, Koudstaal PJ, Visser MC. Interobserver agreement for assessment of handicap in stroke patients. Stroke 1988; 19:604-7. 19. Komar L, Nieves J, Cosman F, Rubin A, Shen V, Lindsay R. Calcium homeostasis of an elderly population upon admission to a nursing home. J Am Geriatr Soc 1993;41:1057-64. 20. Folstein MF, Folstein SF, McHugh PR. “Mini mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98. 21. Matsumoto C, Kushida K, Yamazaki K, Imose K, Inoue T. Metacarpal bone mass in normal and osteoporotic Japanese women using computed X-ray densitometry. Calcif Tissue Int 1994;55: 324-9. 22. Sato Y, Kuno H, Kaji M, Ohshima Y, Asoh T, Oizumi K. Increased bone resorption during the first year after stroke. Stroke 1998;29:1373-7. 23. Langenberg JP, Tjaden UR. Improved method for the determination of vitamin K1 epoxide in human plasma with electrofluorimetric reaction detection. J Chromatgr 1984;289:377-85. 24. Szulc P, Arlot M, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res 1994;9:1591-5. 25. Parfitt AM, Gallagher JC, Heaney RP, Johnston CC, Neer R, Whedon GD. Vitamin D and bone health in the elderly. Am J Clin Nutr 1982;36:1014-31. 26. Yuspeh RL, Vanderploeg RD, Kershaw DA. Validity of a semantically cued recall procedure for the mini-mental state examination. Neuropsychiatry Neuropsychol Behav Neurol 1998;11:20711. 27. Jones RN, Gallo JJ. Dimensions of the Mini-Mental State Examination among community dwelling older adults. Psychol Med 2000;30:605-18. 28. Smith GE, Bohac DL, Waring SC, et al. Apolipoprotein E genotype influences cognitive ‘phenotype’ in patients with Alzheimer’s disease but not in healthy control subjects. Neurology 1998;50: 355-62. 29. Espino DV, Lichtenstein MJ, Palmer RF, Hazuda HP. Evaluation of the Mini-Mental State Examination’s internal consistency in a community-based sample of Mexican-American and EuropeanAmerican elders: results from the San Antonio longitudinal study of aging. J Am Geriatr Soc 2004;52:822-7. 30. de Haan R, Limburg M, Bossuyt P, van der Meulen J, Aaronson N. The clinical meaning of Rankin ‘handicap’ grades after stroke. Stroke 1995;26:2027-30. 31. Shearer MJ. Vitamin K. Lancet 1995;345:229-34. 32. Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest 1993;91:1769-74. 33. Kanai T, Takagi T, Masuhiro K, Nakamura M, Iwata M, Saji F. Serum vitamin K level and bone mineral density in postmenopausal women. Int J Gynecol Obstet 1997;56:25-30.
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34. Jie KS, Bots ML, Vermeer C, Witte JC, Grobbee DE. Vitamin K status and bone mass in women with or without aortic atherosclerosis: a population-based study. Calcif Tissue Int 1996;59:352-6. 35. Akiyama Y, Hara K, Ohkawa I, Tajima T. Effects of menantetrenone on bone loss induced by ovariectomy in rats. Jpn J Pharmacol 1993;62:145-53. 36. Hara K, Akiyama Y, Tajima T, Shiraki M. Menantetrenone inhibits bone resorption partly through inhibition of PGE2 synthesis in vitro. J Bone Miner Res 1993;8:535-42. 37. Johnston JM, Cauley JA, Ganguli M. APOE 4 and hip fracture risk in a community-based study of older adults. J Am Geriatr Soc 1999;47:1342-5. 38. Sato Y, Manabe S, Kuno H, Oizumi K. Amelioration of osteopenia and hypovitaminosis D by 1␣-hydroxyvitamin D3 in elderly Parkinson’s disease patients. J Neurol Neurosurg Psychiatry 1999; 66:64-8. 39. Sato Y, Maruoka H, Oizumi K. Amelioration of hemiplegia-associated osteopenia over 4 years following stroke by 1 ␣-hydroxyvitamin D3 and calcium supplementation. Stroke 1997;28:736-9. 40. Derisquebourg T, Dubois P, Devogelaer JP, et al. Automated computerized radiogrammetry of the second metacarpal and its correlation with absorptiometry of the forearm and spine. Calcif Tissue Int 1994;54:461-5.
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41. Sato Y, Honda Y, Kuno H, Oizumi K. Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients. Bone 1998;23:291-6. 42. Chalmers J, Conacher WD, Gardner DL, Scott PJ. Osteomalacia—a common disease in elderly women. J Bone Joint Surg Br 1967;49:403-23. 43. Chalmers J, Barclay A, Davison AM, MacLeod DA, Williams DA. Quantitative measurements of osteoid in health and disease. Clin Orthop 1969;Mar-Apr(63):196-209. 44. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327:1637-42. 45. Stein MS, Wark JD, Scherer SC, et al. Falls relate to vitamin D and parathyroid hormone in an Australian nursing home. J Am Geriatr Soc 1999;47:1195-201. Suppliers a. Teijin Ltd, 1-1, Uchisaiwaicho 2-chome, Chiyoda-ku, Tokyo 1008585, Japan. b. Nichols Institute Diagnostics, 1311 Calle Batido, San Clemente, CA 92673. c. EMD Biosciences, 10394 Pacific Center Ct, San Diego, CA 92121. d. Takara Shuzo Co, Seta 3-4-1, Otsu, Shiga 520-2193, Japan. e. SAS Institute, 100 SAS Campus Dr, Cary, NC 27513.
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