(Stroke. 1997;28:736-739.)
© 1997 American Heart Association, Inc.
Articles |
Amelioration of Hemiplegia-Associated Osteopenia More Than 4 Years After Stroke by 1
-Hydroxyvitamin D3 and Calcium Supplementation
From the Department of Neurology, Futase Social Insurance Hospital, Iizuka (Y.S., H.M.), and the First Department of Internal Medicine, Kurume University School of Medicine, Kurume (K.O.), Japan.
Correspondence to Yoshihiro Sato, MD, Department of Neurology, Futase Social Insurance Hospital, 1243 Ikawa, Iizuka 820, Japan. E-mail y-sato{at}kurume.ktarn.or.jp
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose It has been demonstrated that bone mass was significantly reduced on the hemiplegic side of stroke patients, which might increase their risk of hip fracture. We evaluated the efficacy of 1
-hydroxyvitamin D3
[1(OH)D3] and supplemental elemental calcium in
maintaining bone mass and decreasing the incidence of hip fractures
after hemiplegic stroke.
Methods In a randomized study, 64 patients with hemiplegia
after stroke with a mean duration of illness of 4.8 years received
either 1 µg 1(OH)D3 daily (treatment group, n=30) or
an inactive placebo (placebo group, n=34) for 6 months and were
observed for this duration. Both groups received 300 mg of elemental
calcium daily. The bone mineral density (BMD) and metacarpal index
(MCI) in the second metacarpals were determined by computed x-ray
densitometry. The incidence of hip fractures in these patients was
recorded.
Results BMD on the hemiplegic side decreased by 2.4% in the treatment group and 8.9% in the placebo group (P=.0021), while BMD on the intact side increased by 3.5% and decreased by 6.3% in the treated and placebo groups, respectively (P=.0177). In the treatment group, the difference in BMD between hemiplegic and nonhemiplegic sides decreased significantly compared with that before randomization. This difference increased in the placebo group. We observed a similar improvement in MCI in the treatment group but not in the placebo group. Four patients in the placebo group suffered a hip fracture compared with none in the treatment group (P=.0362).
Conclusions Treatment with 1(OH)D3 and
supplemental elemental calcium can reduce the risk of hip fractures and
can prevent further decreases in BMD and MCI on the hemiplegic side of
patients with a long-standing stroke. Treatment also may improve these
indices on the intact side.
Key Words: calcium • complications • hemiplegia • osteoporosis • vitamin D
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Four percent to 15% of hip fractures occur as a late complication of stroke, 79% of them occurring on the hemiplegic side.1 2 3 4 5 This has been ascribed to osteopenia on the hemiplegic side.6 Also, it was reported that both motor weakness6 and vitamin D deficiency7 are important in the development of osteopenia. Supplementation with both calcium and 1
(OH)D3 [a provitamin of
1,25(OH)2D3] or with 1(OH)D3
alone increases BMD not only in cortical but also in
trabecular bone such as the lumbar vertebrae and greater
trochanter. Such supplementation is also effective in decreasing the
incidence of vertebral fractures in senile and postmenopausal
osteoporosis.8 9 10 11 12 We conducted a 6-month randomized trial
to evaluate the efficacy of 1(OH)D3 and supplemental
elemental calcium in reducing the severity of osteopenia in the second
metacarpals and decreasing the risk of hip fractures in chronically ill
stroke patients with hemiplegia. |
Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Selection and Exclusion Criteria
For the study we selected 84 outpatients with hemiplegia after stroke who had been examined at Futase Social Insurance Hospital. In addition to the BI,13 the clinical severity of the hemiplegia was evaluated with the staging classification of Brunstrom,14 in which a score of 1 is defined as paralysis of the finger, arm, or leg, while a score of 6 represents normal strength. The diagnosis of stroke was based on the results of clinical evaluation including mode of onset, neurological examination, and CT scans performed in the acute and chronic phases of the disorder. The strokes were classified according to the Classification of Cerebrovascular Diseases III of the National Institute of Neurological Disorders and Stroke.15 The patients completed a questionnaire concerning their sunlight exposure. We considered vitamin D deficiency to have occurred when they had no sunlight exposure during an average week.7 Exclusion criteria were shoulder-hand syndrome, multiple strokes, history of hip fracture, a stroke duration of less than 1 month, or the use of medication known to affect bone metabolism, including estrogen, calcium, vitamin D, corticosteroids, thyroxine, or anticonvulsants.
Medication and Bone Evaluation
After giving informed consent, the stroke patients were randomly
allocated into treatment (n=45) and placebo (n=39) groups. The
clinicians and radiologists were blinded to the data concerning the
patient's drug. The patients in the treatment group received a single
fixed, daily oral dose of 1.0 µg 1(OH)D3 (active
vitamin D3, 1.0 µg tablet) for 6 months. The control
group received a placebo once a day. All patients were given
supplemental calcium as calcium lactate (300 mg elemental calcium). No
dose adjustments were made during the entire course of the study. Both
groups were observed for a period of 6 treatment months. Monthly
follow-up visits included medical and neurological examinations.
Fifteen patients in the treatment group and 5 in the placebo group
dropped out or were withdrawn from the study because of noncompliance,
loss to follow-up, intercurrent illness, or death. Although the dropout
rates were higher in the treatment group by chance, the causes of
dropout did not differ in the two groups. Thus, a total of 64 patients
(30 in the treatment group and 34 in the placebo group) completed the
trial. The starting and final data for only those subjects were
analyzed. Data of the medical and bone evaluations performed
before randomization were used for the determination of baseline
values. The mean duration of illness of these 64 patients was 4.8
years.
Using a CXD (Teijin Limited),16 17 we measured BMD and MCI of the second metacarpal bone on both hands on the day of entry and 6 months later. The CXD method measures bone density and cortical thickness at the middle of the second metacarpal bone, with a radiograph of the hand and an aluminum step wedge (20 steps, 1 mm per step) used as a standard. The computer calculates BMD and MCI on the basis of the pattern expressed as gradations on the aluminum step wedge. The measured BMD can be expressed as the thickness of an aluminum equivalent (mm Al) showing the corresponding x-ray absorption. MCI (d1+d2/D), where d1 is cortical width on the radial side, d2 is cortical width on the ulnar side, and D is bone width, expresses the degree of cortical thickness; d1 and d2 are determined from the two peaks of the densitometric curve, which correspond to the medullary space of the metacarpal bone.
Blood samples were obtained from patients at entry and 6 months later and were analyzed for calcium.
All patients were informed of the nature of the study; 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 with the use of the Statview
4.11 software package (Abacus Concepts, Inc). Data are
presented as mean±SD. The paired t test was used to
assess the significance of the differences of the bone changes between
the hemiplegic and intact sides at entry and the baseline values and
those of 6 months later. Group differences of the categorical data were
tested by 
2 analyses. Spearman's rank
correlation coefficients were calculated to determine the relationship
between the bone changes and degree of paralysis of the finger and leg.
For the BMD and MCI measurements, individual values were computed and
expressed as percent change from baseline. The two groups then were
compared with the Wilcoxon rank sum test in both the hemiplegic
and contralateral intact sides. Values of P<.05 were
considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Characteristics of the Study Subjects
The clinical characteristics of the patients are listed in Table 1
. No statistical differences were observed between the
two groups of stroke patients for age, sex, duration of illness, type
of stroke, BI, degree of hemiplegia, incidence of diabetes mellitus, or
incidence of sun deprivation. The mean BI scores were 87 in
the treatment group and 84 in the placebo group, whereas the mean
values according to Brunstrom's scale of the finger were 3.80 in the
treatment group and 3.58 in the placebo group, which both indicated
that the two patient groups had the same extent of arm weakness and
functional limitations. The mean duration of illness was long-standing
in both groups (treatment group, 5.3 years; placebo group, 4.3 years).
Eighteen patients (60%) in the treatment group and 23 patients (68%)
in the placebo group reported that they had no sunlight exposure during
an average week.
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Bone Changes and Serum Levels of Calcium
As shown in Table 2, the baseline values of BMD and
MCI on both hemiplegic and intact sides were not significantly
different between the two patient groups. Both patient groups also had
lower values of both BMD and MCI on the hemiplegic side than on the
nonhemiplegic side at entry and 6 months later. At entry, correlations
between the degree of paralysis of the finger and leg and side-to-side
differences of BMD and MCI were observed in 64 patients
(r=-.409, P=.0002; r=-.447,
P<.0001; r=-.236, P=.0316;
r=-.427, P<.0001, respectively). Also, the
degree of hemiplegic finger paralysis correlated with BMD and MCI on
the hemiplegic side (r=.295, P=.0192;
r=.376, P=.0028, respectively).
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On the hemiplegic side, the values of both indices decreased during the observation period in the placebo group, and at the end of the study they fell below baseline values. In the treatment group, the values were unchanged and remained at the baseline level. On the intact side the MCI of the placebo group decreased significantly and fell below baseline values, whereas the BMI and MCI of the treatment group remained unchanged before and at the end of therapy. The side-to-side differences in BMD and MCI became significantly smaller in the treatment group, whereas they became significantly larger in the placebo group.
Baseline values in the serum calcium level were not significantly different among the two groups. In the treatment group the serum calcium concentration increased significantly, and it did not change during the observation period in the placebo group. None of the patients developed hypercalcemia during the study period.
Table 3 shows the mean percent changes during the
6-month period in BMD and MCI on the hemiplegic and intact sides of the
treatment and placebo groups. Although all the numeric values of the
changes in both BMD and MCI on the hemiplegic side were negative, the
absolute values were significantly smaller in the treatment group than
in the placebo group, and those on the intact side were positive in the
treatment group and negative in the placebo group. Thus, oral
1(OH)D3 and supplemental elemental calcium can prevent
progressive bone loss on the hemiplegic side and can even increase both
the BMD and MCI on the intact side.
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Hip Fracture Incidence
Hip fractures occurred in four patients in the placebo group on
the hemiplegic side, whereas no fractures were observed in the
treatment group. The incidence of hip fractures was significantly
different between the two groups (P=.034). These fractures
were demonstrated by radiographic examinations.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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1
(OH)D3 is a prodrug that is converted in the liver
to 1,25(OH)2D3, the most potent vitamin D
derivative in bone formation in vivo. Treatment with
1(OH)D3 treatment has been shown to stimulate intestinal
calcium absorption and bone mineralization, as evidenced by the
elevation of BMD values in the lumbar and radial bones and in the
greater trochanter after treatment, and can decrease the rate of
vertebral fracture in the elderly and in postmenopausal
women.8 9 10 11 12
The routine use of both 1(OH)D3 (1 µg/d) and calcium
(300 mg/d)11 in patients with a long-standing hemiplegic
stroke may be beneficial for several reasons, as suggested by this
study. First, supplementation with 1(OH)D3 and calcium
can significantly reduce the risk of hip fractures in patients with
stroke-induced hemiplegia.
Second, the differences in BMD and MCI between the hemiplegic and intact sides were significantly decreased from pretreatment differences in the treatment group but were significantly increased in the placebo group, indicating that treatment can effectively prevent otherwise progressive osteoporosis involving the hemiplegic side.
Third, 1(OH)D3 and supplemental elemental calcium were
shown to not only prevent further bone loss on the hemiplegic side but
also to stimulate bone formation on the intact side in stroke patients,
as evidenced by the elevated BMD and MCI values after treatment.
Furthermore, the oral administration of 0.75 µg/d
1(OH)D3 for 7 months has been shown to increase BMD
significantly in the second metacarpals in patients with senile
osteoporosis by use of the microdensitometric method,18 an
earlier version of the CXD.16 17 This observation was
consistent with the present favorable effect of
1(OH)D3 on the BMD and MCI of the intact side, although
it failed to increase bone mass in the hemiplegic metacarpals.
CXD technology provides highly accurate microdensitometry of
radiographs. The precision errors (coefficients of variation) were
0.2% to 1.2% for BMD and 0.4% to 2.0% for MCI. The precision of the
CXD is almost the same as that of dual-energy x-ray absorptiometry,
which is accepted as the most reliable means of bone mass
measurement.19 A similar effect of 1(OH)D3
in preventing further loss in BMD on the hemiplegic femoral neck is
likely, since the difference in bone density between hemiplegic and
nonhemiplegic sides correlated positively with the degree of hemiplegia
in the lower limb expressed in terms of the classification of
Brunstrom. Indeed, an increase in the BMD of the femoral neck and
trochanter with use of the same regimen as in the present study has
been reported.11 A possible explanation for the reduction
in hip fracture rate is the improvement of bone mineralization of the
femoral neck by a supplement of 1(OH)D3 and elemental
calcium as the result of stimulated osteoblastic and osteoclastic
activities.
A few possible explanations for the discrepancy concerning the effect
of the vitamin between the intact and hemiplegic sides are as follows:
First, certain localized factors, such as paralysis and immobilization,
may diminish the effect of 1(OH)D3 on bone formation on
the hemiplegic side. Indeed, correlations between the degree of finger
paralysis and BMD and MCI on the hemiplegic side were observed. Second,
as already suggested,7 vitamin D deficiency due to
sunlight deprivation and the consequent compensatory
hyperparathyroidism can result in uncoupled and high rates of bone
turnover that cause bone resorption in poststroke hemiplegic patients
(Y. Sato, unpublished data, 1996). A similar situation may be
present in our study patients, since many of them were in a
sunlight-deprived state.
It has been reported that the administration of 1 µg/d
1(OH)D3 and 300 mg/d elemental calcium, which was used
in the present study, depresses bone turnover and increases BMD in
patients with senile osteoporosis.11 Furthermore, it was
shown that this regimen did not inhibit parathyroid hormone secretion,
nor did it increase the serum vitamin D
concentration.11
Supplementation with 20 µg/d cholecalciferol and 1.2 g/d elemental
calcium was shown to inhibit parathyroid hormone secretion and increase
serum vitamin D concentrations, resulting in increased bone density and
the prevention of hip fractures in elderly women.20 On the
other hand, bisphosphonates are the most potent inhibitors
of osteoclastic bone resorption.21 22 23 Therefore, 20 µg
cholecalciferol with 1.2 g calcium or the combination of
1(OH)D3 with bisphosphonates may be a better regimen for
preventing hip fractures on the hemiplegic side of poststroke patients
by increasing bone mass on the affected side.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors would like to thank Munetsugu Kikuyama, PhD, for his assistance in the bone measurements.
Received October 30, 1996; revision received December 23, 1996; accepted January 21, 1997.
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