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(Stroke. 1997;28:2390-2394.)
© 1997 American Heart Association, Inc.

Articles

Long-term Oral Anticoagulation Reduces Bone Mass in Patients with Previous Hemispheric Infarction and Nonrheumatic Atrial Fibrillation

Yoshihiro Sato, MD; Yoshiaki Honda, MD; Haruko Kunoh, MD; Kotaro Oizumi, MD

From the Department of Neurology, Futase Social Insurance Hospital, Iizuka (Y.S., Y.H., H.K.), and First Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan (K.O.).

Correspondence to Dr. Yoshihiro Sato, Department of Neurology, Kurume University Medical Center, 155-1, Kokubumachi, Kurume 839, Japan. E-mail y-sato{at}ktarn.or.jp.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Vitamin K is an essential factor for synthesis of plasma clotting proteins and for site-specific carboxylation of bone Gla protein and other bone matrix proteins. Low vitamin K has been associated with reduced bone mineral density. Warfarin therapy, which inhibits vitamin K–dependent blood-clotting, has been demonstrated to reduce the risk of stroke in nonrheumatic atrial fibrillation. We evaluated vitamin K and bone mineral density in nonrheumatic atrial fibrillation patients who had long-term warfarin therapy after an ischemic stroke.

Methods Sera were collected from 64 patients with nonrheumatic atrial fibrillation and ischemic stroke who had been treated with warfarin, 63 stroke patients without warfarin, and 39 control subjects. All stroke patients in both groups had hemiplegia. Sera were assayed for vitamins K₁ and K₂, bone Gla protein, and 25-hydroxyvitamin D. Bone mineral density was determined in both second metacarpals.

Results Serum vitamin K₁ concentrations (ng/mL) were lower in treated patients (.234±.177 ng/mL) than in untreated patients (.329±.284) or controls (.553±.164). Bone Gla protein was lower in treated patients' sera (1.241±.799 ng/mL) than in untreated patients (4.476±3.226). Concentrations of 25-hydroxyvitamin D were lower in both patient groups. Bone mineral density was lower on both sides in treated patients than in untreated patients (P<.0001). Vitamin K₁ and bone Gla protein were significantly related to bone mineral density bilaterally in treated but not in untreated patients.

Conclusions Bone mineral density was significantly lower in stroke patients with long-term warfarin treatment than in untreated patients. Both warfarin-induced reduction in vitamin K function and lowered vitamin K₁ concentration are probable causes of this osteopenia.

Key Words: atrial fibrillation • bone • osteoporosis • vitamin K • warfarin

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Vitamin K is an essential factor for the synthesis of four plasma clotting proteins including factor II (prothrombin) and factors VII, IX, and X, as well as for site-specific carboxylation of osteocalcin and other bone matrix proteins.^{1 2} Biochemical indicators of reduced vitamin K status have been associated with reduced bone mineral density (BMD) at the hip³ and increased risk of fracture⁴ in otherwise healthy adults. In those who already had sustained a fracture, especially at the hip, serum vitamin K concentrations have been found to be lower than in age-matched controls.^{5 6 7 8} However, warfarin therapy has been demonstrated to reduce the risk of both primary and secondary ischemic strokes from nonrheumatic atrial fibrillation (NRAF).^{9 10 11 12 13 14 15 16} Such oral anticoagulation would seem likely to affect bone metabolism by interference with -carboxylated glutamyl acid protein synthesis in bone. Oral anticoagulants antagonize the effect of vitamin K₁¹⁷ so posttranslational conversion of glutamate to -carboxyglutamate cannot occur, resulting in abnormal bone Gla protein (BGP) that can neither bind to hydroxyapatite nor accumulate in bone. Significant reduction in bone mineral content has been reported in women who underwent long-term warfarin therapy for prosthetic heart valve replacement, for atrial fibrillation, for recurrent venous thromboembolism, or after bypass surgery for peripheral vascular disease.^{18 19}

Our previous measurements in second metacarpal bones on the hemiplegic sides of patients after stroke demonstrated decreased bone mass on the affected side corresponding to degree of palsy²⁰ and vitamin D deficiency,²¹ which might increase the risk of hip fracture. In the present study, we examined the relationship of vitamin K to bone mass in stroke patients and, specifically, whether bone-mass reduction is accelerated by hemiplegic patients given long-term warfarin for NRAF after cerebral infarction.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hemiplegic patients eligible for this study included individuals of either sex 60 years or older, who had received warfarin care through the outpatient clinic of Futase Social Insurance Hospital for more than 1 year after an initial hemispheric infarction caused by chronic NRAF (cardioembolic stroke). Hemispheric infarction was diagnosed in the acute phase by computed tomography, and warfarin treatment was initiated 1 month later, for a mean duration of 5.1 years to prevent recurrent cardioembolic stroke. Patients were excluded if they had rheumatic atrial fibrillation or had received any drug known to alter bone metabolism such as corticosteroids, thyroxine, anticonvulsants, or vitamin D. Other reasons for exclusion included multiple strokes, total disability from stroke, contraindications to warfarin, or severe renal or hepatic insufficiency. Sixty-four patients were enrolled. The daily dose and the duration of anticoagulant treatment with warfarin were determined by the patients' clinic physicians, with the age-adjusted target range for prothrombin time being an international normalized ratio of 2 to 3.

Non–warfarin-treated stroke patients without atrial fibrillation were selected by detailed examination of case notes of patients with supratentorial cerebral infarction to match treated patients with respect to age, sex, illness duration, severity of hemiplegia, and Barthel Index.²² Again, patients who had received any drugs known to alter bone metabolism were excluded. Sixty-three patients with hemiplegia caused by atherothrombotic or lacunar infarction constituted the non-warfarin group. Thirty-nine volunteers (20 men) served as healthy controls.

In addition to Barthel Index,²² clinical severity of the hemiplegia was evaluated using Brunstrom's staging classification,²³ in which a score of 1 is defined as paralysis of the hand, arm, or leg and a score of 6 represents normal strength.

With use of a computed x-ray densitometer (Teijin Limited),^{24 25} BMD of the second metacarpal was measured in both hands. The computed x-ray densitometer method measures bone density at the middle of the second metacarpal using a radiograph of the hand and an aluminum step wedge as a standard (20 steps, 1 mm/step). The computer calculates by comparison with the gradations of the aluminum step wedge as the thickness of an aluminum equivalent (mm Al) with corresponding x-ray absorption.

On the day of bone evaluation, a fasting blood sample was obtained in 64 patients taking warfarin, 63 non-warfarin patients, and 39 healthy controls. Blood samples were analyzed for vitamins K₁ and K₂, intact BGP, 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D, and prothrombin times. Circulating levels of vitamin K including vitamin K₁ (phylloquinone) and vitamin K₂ (menaquinone-4) were measured by high-performance liquid chromatography according to the method of Langenberg and Tjaden.²⁶ Intact BGP was measured with an established enzyme immunoassay using antibodies to N- and C-terminal regions of human BGP (Teijin Diagnostics). Serum 25-OHD was determined using a competitive protein-binding assay, and 1,25-dihydroxyvitamin D was determined by a radioreceptor assay using calf thymus receptor (Nichols Institute Diagnostics). Estimated prothrombin times were expressed in terms of international normalized ratio. In patients receiving warfarin treatment, intake of green leafy vegetables containing abundant vitamin K had been prohibited, whereas this restriction was not imposed on non–warfarin-treated stroke patients or healthy control subjects.

All patients and volunteers were informed of the nature of the study before witnessed consent was obtained from each participant. The protocol of the study was approved by the Human Investigation Committee of the Futase Social Insurance Hospital.

All statistical procedures were performed using the Statview 4.11 software package (Abacus Concepts, Inc.). Data are presented as mean±SD. Unpaired t tests (continuous variables) were used to assess the significance of differences between warfarin-treated patients and untreated patients. For categorical data, group differences were tested by ² analyses. One-way ANOVA and Fisher's protected least significant difference were used to assess differences between the two stroke groups and the controls. To separate the effects of warfarin and paralysis, repeated bilateral measurement of BMD and warfarin treatment was analyzed by repeated-measures ANOVA. Spearman's rank correlation coefficients were calculated to determine the relationship between BMD and each variable. Multivariate linear regression analysis was used to estimate the independent effects of predictor variables on BMD for both sides in each stroke group. A value of P<.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Characteristics of Study Subjects
The clinical characteristics of the two patient groups and control subjects are listed in Table 1. No differences were observed between warfarin-treated and untreated groups in age, sex, duration of illness, degree of hemiplegia, or Barthel Index.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Stroke Patients With or Without Warfarin

BMD and Biochemical Parameters
Table 2 shows BMD and biochemical parameters in the two patient groups and in controls. In warfarin-treated patients, BMD was significantly lower on both hemiplegic and intact sides than in untreated patients. BMD were significantly lower on the hemiplegic side than on the intact side in untreated patients, whereas the BMD was not significantly different in the two hands in the warfarin-treated group. The differences between the intact and hemiplegic sides were significantly higher in untreated patients than in treated patients (F=9.423; P=.0029). Concentrations of vitamin K₁ were significantly lower in both patient groups than the control subjects, whereas no significant difference was noted in the levels of vitamin K₂ between either patient group and controls. Serum concentrations of vitamin K₁ showed a tendency to be lower in treated patients than in untreated patients, although this was not statistically significant. In 37 warfarin-treated patients (58%) and in 34 untreated patients (54%), vitamin K₁ levels were abnormally decreased below a lower limit of .225 ng/mL representing the mean, 2 standard deviations of control subjects. Patients had a lower weekly dietary intake of vitamin K than did controls. Patients with warfarin treatment showed lower concentrations of BGP than did untreated patients. As previously reported,²¹ serum concentrations of 25-OHD and 1,25-dihydroxyvitamin D were lower in both patient groups than in controls.

View this table: [in this window] [in a new window]   Table 2. Bone Mineral Density and Serum Biochemical Parameters

Relationships Between BMD, Vitamins K₁ and K₂, and Each Variable
Spearman's rank correlation coefficients between BMD and each variable are listed separately for warfarin-treated patients (upper line) and untreated patients (lower line) throughout Table 3. In the treated group, positive correlations occurred between BMD on both sides and vitamin K₁, BGP, 25-OHD, and degree of finger paralysis (except for BMD on the intact side and degree of paralysis). In the untreated group, BMD on both sides correlated positively with vitamin K₁, 25-OHD, and degree of finger paralysis (except for BMD on the intact side and degree of paralysis). However, vitamin K₂ levels did not correlate with BMD on either side in either group.

View this table: [in this window] [in a new window]   Table 3. Correlation Between Bone Mineral Density and Each Variable

Multiple Regression Analysis
The results of multiple regression analysis, in which vitamin K₁, BGP, 25-OHD, and degree of finger paralysis were selected as independent variables, with BMD on both sides representing dependent variables, are shown in Table 4. On both sides in the treated group, vitamin K₁, BGP, and 25-OHD were significantly related to BMD. For both intact and hemiplegic sides in the untreated group, 25-OHD was significantly related to BMD, whereas degree of finger paralysis also was related to BMD on the hemiplegic side.

View this table: [in this window] [in a new window]   Table 4. Multiple Regression Analysis of Bone Mineral Density With Vitamin K1, Bone Gla Protein, 25-OHD, and Degree of Finger Paralysis, Selected as Independent Variables

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
BMD on both hemiplegic and intact sides were found to be significantly lower in poststroke hemiplegic patients who had received long-term warfarin treatment to prevent recurrent cardioembolic stroke than in stroke patients without warfarin treatment. Multiple regression analysis showed significant correlations between BMD on both hemiplegic and intact sides and serum concentrations of vitamin K₁, BGP, and serum 25-OHD concentrations in warfarin-treated patients, whereas 25-OHD was significantly related to BMD on both sides in addition to a correlation found between degree of finger paralysis and BMD on the hemiplegic side in untreated patients. Because frank vitamin D deficiency caused by sunlight deprivation and malnutrition was present in both stroke groups as previously reported,²¹ both vitamin K₁ and BGP likely would have remained as key determinants of BMD on both sides in warfarin-treated patients if long-term vitamin D supplementation had been provided in these populations.

Vitamin K has two main sources in humans² : vitamin K₁, provided by foods, especially green, leafy vegetables; vitamin K₂, synthesized by bacteria in the gut. In the present study, a significant decrease was observed in serum concentrations of vitamin K₁ but not of K₂ in post-stroke patients, even in those without warfarin who had not been restricted in vegetable intake. Naturally, vitamin K₁ concentrations were much lower in the warfarin-treated patients who had been strictly limited in consumption of leafy vegetables. Another cause of the vitamin K₁ deficiency in both patient groups was considered to be generally poor nutrition as evidenced by low serum 25-OHD concentrations. In contrast, no significant difference was evident among healthy controls and patient groups in vitamin K₂ concentration, as this form was synthesized by intestinal bacteria.

Although the precise reason for the correlation between low vitamin K concentration and decreased bone mass is unknown, several reports have demonstrated that reduced vitamin K in otherwise healthy adults was associated with reduced BMD in the hip,³ lumbar spine,²⁷ and second metacarpal,²⁸ representing increased risk of bone fracture.⁴ Warfarin antagonizes the activity of vitamin K₁ in the vitamin K cycle, leading to inhibition of posttranslational conversion of glutamate to -carboxylglutamate, binding of abnormal BGP to hydroxyapatite, and accumulation of free BGP in bone.¹⁷ In the present study, serum BGP in warfarin-treated patients was markedly depressed and correlated well with the decrease in BMD. Bone mass reduction has been reported in connection with treatment of humans and animals with warfarin,^{17 18 19 29} and vitamin K has been shown to increase BMD or reduce the loss of bone mass in humans and animals.^{30 31 32 33 34} This low production of fully carboxylated BGP may be a major cause of the reduced BMD in warfarin-treated stroke patients. A recent study showed that vitamin K inhibits osteoclastic bone resorption through a mechanism completely different from that of -carboxylation.^{32 33} These mechanisms may result in a positive correlation between vitamin K₁ and BMD in both warfarin-treated and untreated patients whose serum vitamin K₁ concentration was low. However, vitamin K₁ is not an independent determinant of BMD in this untreated group, as evidenced by multiple regression analysis.

As previously reported,^{20 21} BMD was reduced significantly on the hemiplegic side in stroke patients not receiving warfarin. However, no significant difference in BMD was evident between sides in the warfarin-treated group. The differences between the intact and hemiplegic sides were significantly higher in untreated patients than in treated patients. This implies that warfarin-induced osteopenia influences bone density more than hemiplegic disuse.

As a comparison between metacarpal BMD determined by computed x-ray densitometer and vertebral (L2-4), femoral neck, and overall BMD measurements made by dual-energy x-ray absorptiometry in 251 healthy women showed close correlation,³⁵ reduction in second metacarpal BMD in stroke patients may reflect a generalized decrease throughout the skeleton.

Patients with NRAF and a recent cerebrovascular ischemic episode are at high risk for a subsequent major vascular event.^{36 37} The value of oral anticoagulation has been established in reducing this risk.¹⁵ Hip fracture occurs with increased frequency in patients with post-stroke hemiplegia, even without oral anticoagulation therapy.^{38 39 40 41 42 43} The risk of hip fractures increases further in patients with long-term warfarin treatment for NRAF after hemispheric ischemic stroke with hemiplegia compared with nonanticoagulated hemiplegic patients from noncardioembolic stroke. Patients with NRAF receiving oral anticoagulants for primary prevention of ischemic stroke^{9 11 13 14} also may have reduced bone mass, with resulting increased risk of fracture. Vitamin K supplements in addition to the vitamin D supplements we advocated⁴⁴ may help to decrease the risk of fracture in stroke patients, particularly in the absence of oral anticoagulant therapy. Because accelerated bone resorption occurs after stroke⁴⁵ and bisphosphonate is effective in preventing osteoclastic bone resorption,^{46 47} agents other than vitamin K such as vitamin D and/or bisphosphonates may be preferable in prevention of fractures in post-stroke patients with NRAF to retain full therapeutic benefit from warfarin.

	Acknowledgments

 
The authors thank Masanobu Inoue and Yoriko Sakata for technical assistance in measuring vitamins D and K concentrations.

Received August 4, 1997; revision received October 1, 1997; accepted October 1, 1997.

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