Amelioration of Hemiplegia-Associated Osteopenia More Than 4 Years After Stroke by 1α-Hydroxyvitamin D3 and Calcium Supplementation
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 1α-hydroxyvitamin D3 [1α(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 1α(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 1α(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.
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 1α(OH)D3 [a provitamin of 1,25(OH)2D3] or with 1α(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 1α(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
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 1α(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 χ2 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.
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.
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).
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 1α(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.
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.
1α(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 1α(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 1α(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 1α(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, 1α(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 1α(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 1α(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 1α(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 1α(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 1α(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 1α(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 1α(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.
Selected Abbreviations and Acronyms
|BMD||=||bone mineral density|
|CXD||=||computed x-ray densitometer, computed x-ray densitometry|
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.
- Copyright © 1997 by American Heart Association
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