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RETRACTED: An Open-Label Trial Comparing Alendronate and Alphacalcidol in Reducing Falls and Hip Fractures in Disabled Stroke Patients
An Open-Label Trial Comparing Alendronate and Alphacalcidol in Reducing Falls and Hip Fractures in Disabled Stroke Patients Yoshihiro Sato, MD,* Jun Iwamoto, MD,† and Yoshiaki Honda, MD*
Although vitamin D supplementation has been suggested to reduce the risk of falling in ambulatory or institutionalized elderly persons, no study has examined whether it reduces the frequency of falling in immobilized stroke patients who have immobilization-induced hypercalcemia reflecting increased bone resorption leading to inhibited renal synthesis of 1, 25-dihydroxyvitamin D (1, 25-[OH]2D). Bisphosphonate is known to reduce immobilization-induced hypercalcemia by inhibiting bone resorption of calcium. This study compared the efficacy of 2 drugs in reducing the risk of falling in patients with long-standing stroke. Eighty-two elderly patients with poststroke hemiparesis were followed for 1 year. The patients were randomly assigned to one of 2 groups; 41 patients received alendronate 35 mg once weekly, and 41 patients received alphacalcidiol 1 mg daily. The number of falls per person and incidence of hip fracture in the 2 groups were compared. At baseline, all patients had a low serum 1, 25-[OH]2D level. Alphacalcidol therapy enhanced immobilization-induced hypercalcemia by increasing intestinal calcium absorption, leading to a reduction of serum 1, 25-[OH]2D level, while alendronate therapy enhanced 1, 25-[OH]2D production by decreasing hypercalcemia. Alendronate treatment accounted for a 55% reduction in falls (95% confidence interval [CI] 5 25-72%; P 5.0021). During the 1-year study period, hip fracture occurred in 1 of 41 subjects in the alphacalcidol group and in no subjects in the alendronate group. Bone mineral density was increased by 3.2% in the alendronate group and decreased by 0.1% in the alphacalcidol group (P ,.0001). Alendronate therapy increased serum 1, 25-[OH]2D levels by improving immobilization-induced hypercalcemia, which may lead to decreased falling and subsequent hip fractures. Key Words: Bisphosphonate— fall—poststroke patients—hip fracture—vitamin D. Ó 2011 by National Stroke Association
Long-term stroke survivors may be at an increased risk of falling and subsequent fractures, particularly of the hip.1 A fall may result in a hip fracture on the paretic side.2 Elucidation of predisposing factors related to falling is important, especially if these factors are modifiable and falls can be prevented. Approximately 40% of patients fall
From the *Department of Neurology, Mitate Hospital, Tagawa, Japan; and †Institute for Sports Medicine, Keio University School of Medicine, Tokyo, Japan. Received April 28, 2009; revision received August 22, 2009; accepted October 26, 2009. Address correspondence to Yoshihiro Sato, MD, Department of Neurology, Mitate Hospital, 3237 Yugeta, Tagawa 826-0041, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2011 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2009.10.007
within the first year after sustaining a stroke,3 and the incidence of hip fracture is up to 4 times higher in stroke patients compared with controls.4 It has been suggested that vitamin D supplementation reduces the risk of falling in ambulatory or institutionalized elderly persons.5 Previously, the moderate protective effect of vitamin D on fracture risk was attributed primarily to changes in bone mineral density (BMD).6 In an open-label controlled trial, vitamin D supplementation reduced the incidence of fractures within 8-12 weeks of treatment, a finding consistent with vitamin D’s known benefit in muscle strength.7 Skeletal muscle is known to express specific receptors for 1, 25-dihydroxyvitamin D (1, 25-[OH]2D).8 We previously demonstrated that treatment with alphacalcidol can reduce the risk of hip fracture in patients with long-standing stroke.9 In that study, we did not measure serum concentrations of calcium and 1, 25-[OH]2D. An
Journal of Stroke and Cerebrovascular Diseases, Vol. 20, No. 1 (January-February), 2011: pp 41-46
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immobilization-related elevated serum calcium level may inhibit parathyroid hormone (PTH) secretion, and hence renal 1, 25-[OH]2D production, in disabled long-standing stroke patients.10,11 Many of these patients have a very low serum 1, 25-[OH]2D level, and it has been shown that immobilization-induced hypercalcemia may inhibit the renal synthesis of 1, 25-[OH]2D.2 The present study, a 1-year open-label trial, compared the efficacy of alendronate and alphacalcidol therapy in reducing the risk of falling associated with elevated serum 1, 25-[OH]2D level in a cohort of institutionalized elderly stroke survivors.
Materials and Methods Study Population This study compared the occurrence of falls in hospitalized stroke patients with hemiparesis during therapy with either alendronate or alphacalcidol. The subjects were 82 elderly patients with poststroke hemiparesis who were admitted to the Mitate Hospital between October 2007 and December 2008. All of them had sustained a first-ever cerebral infarction or hemorrhage more than 1 year earlier and were in a convalescent stage, with poststroke hemiparesis. Exclusion criteria included dementia, cardioembolic stroke being treated with warfarin, ataxia, total disability, and hospitalization for ,1 year. Individuals who had received any drugs known to alter bone and vitamin D metabolism (eg, anticonvulsants, bisphosphonates, calcium, calcitonin, vitamin D, vitamin K) in the 6 months before the study were excluded. No subject was receiving physical therapy at study entry, and no attempt was made to alter any subject’s diet or activity during the study period. (The mean duration of illness at study entry was .3 years, and physical therapy is not beneficial at such a late convalescent stage of stroke.) Baseline body mass index (BMI) and Barthel index (BI)12 values were recorded for all subjects. Table 1 summarizes the characteristics of the study population. The study design was approved by the local Ethics Committee, and informed consent was obtained from all subjects in the presence of a witness.
Study Protocol The patients were assigned to 1 of the 2 study groups by means of computer-generated random numbering. The trial included an 8-week pretreatment period and a 1-year treatment period. The primary outcome was the number of falls per person occurring during the treatment period. The secondary outcome was the incidence of hip fracture. Each patient’s clinical status was assessed at baseline, and all falls and hip fractures were recorded. Falls occurring during the pretreatment period were recorded as well. For this study, a fall was defined as a fall due to an unexpected loss of balance. Falls were recorded by nurses blinded to the
subjects’ information; date, time, circumstances, and injuries were documented. The subjects received either a weekly 35-mg dose of alendronate (Bonalon; Teijin Pharma, Tokyo, Japan) or a daily 1-mg dose of alphacalcidol (Onealfa, Teijin Pharma). Each study arm comprised 41 subjects. No dose adjustments were made at any time during the study. The subjects were prohibited from taking any other drugs that could affect bone and vitamin D metabolism. No dose adjustments were made at any time during the study. Follow-up assessment was performed by 2 physicians who did not participate in the initial randomization and were blinded to the treatment assignment. Both groups were observed for 1 year. General medical evaluation and serum indices of bone metabolism were assessed at study entry and after 1 year. BMD of the nonaffected second metacarpal bone was measured by computed X-ray densitometry (CXD; Teijin Limited, Tokyo, Japan)13 on the day of study entry and 6 and 12 months later. CXD measures bone density and cortical thickness in the middle of the second metacarpal bone, using a radiogram of the hand and an aluminum step wedge as a standard (20 steps, 1 mm/step). The computer calculates BMD based on the pattern of gradations along the aluminum step wedge. BMD is expressed as the thickness of an aluminum equivalent (mm Al) showing corresponding X-ray absorption. Precision errors (i.e., coefficients of variation) in measuring BMD by CXD range from 0.2% to 1.2%.13 On the morning of the day of bone evaluation, blood and urine samples were obtained from each subject after an overnight fast. Blood samples were analyzed for ionized calcium, intact PTH, 25-hydroxyvitamin D (25-OHD), and 1, 25-[OH]2D as described previously.2 Urinary deoxypyridinoline (D-Pyr), a bone resorption marker, was measured with an enzyme immunoassay kit (Metra Biosystems, Mountain View, CA) and expressed relative to the urinary creatinine concentration (mmol/mol creatinine).14
Statistical Analysis All statistical analyses were performed using Statview J 5.0 software (Abacus Concepts, Berkeley, CA). Values are expressed as mean 6 standard deviation unless stated otherwise. Group differences in the categorical data were evaluated using the c2 test or Fisher’s exact test. The unpaired Student t-test was used to determine the differences between the 2 groups. Spearman’s rank correlation coefficients (SRCCs) were calculated to determine the relationship between BI score and ionized calcium level or urinary D-Pyr, and between ionized calcium and 1, 25[OH]2D. The 2 groups were compared with respect to their laboratory values using Wilcoxon’s rank-sum test. The mean number of excessive falls (i.e., [number of falls during the treatment period] 2 [falls during the pretreatment period]) was compared using the paired t-test. For the adjusted analysis of falls, each patient was categorized
FALLS IN STROKE PATIENTS
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Table 1. Baseline clinical characteristics of the stroke patients
Variable
Stroke patients Alphacalcidol group (n 5 41)
Alendronate group (n 5 41)
P*
Age, years BMI, kg/m2 Duration of illness, years Duration of hospitalization, years Cerebral infarction Lacunar infarction/atherothrombotic infarction Hypertension Diabetes mellitus Hypercholesteromia Current smoker Cerebral hemorrhage BI score Walking aid: no aid/cane/walker Falls in pretreatment period
72.7 6 3.9 22.1 6 4.1 3.2 6 1.6 2.1 6 0.9 30 30/11 27 10 9 8 11 58 6 10 9/14/18 46
73.0 6 4.1 22.5 6 3.5 3.1 6 1.9 2.0 6 0.7 27 28/13 25 12 10 11 14 59 6 11 7/15/19 44
.69 .71 .74 .75 .76y .67y .83y .70y .86y .53y .60y .88 .95y .88y
Values are mean 6 standard deviation. *t-test for scales. yc2 test.
according to a predefined response (0, 1, 2-5, 6-7, or .7 falls), and Poisson regression was used to analyze the statistical differences in the rank-transformed incidence of falls between the 2 groups. Besides treatment, the model included baseline covariates that reached a significant difference of P ,.10 when the 2 arms were compared. The number of subjects was chosen to have sufficient power to detect a difference in the number of falls. A 32% decrease in falls was found in a recent meta-analysis of 5 studies of the effect of vitamin D on falling.5 A standard method for comparing Poisson distributions indicates that a 32% or greater reduction in falls provides 80% power to detect a significant difference between the groups as long as each group contains 44 subjects.15 A P value ,5% was considered statistically significant.
Results Demographic and Baseline Clinical Characteristics of Study Subjects Initial enrollment was 107 elderly patients with poststroke hemiparesis. Exclusion criteria were past history of
fractures (n 5 5); impaired hepatic (serum alanine aminotransferase .50 U/L), renal (serum creatinine .1.5 mg/ dL), cardiac (serum brain natriutetic peptide .20 pg/ mL), or thyroid function (serum thyroxine .11.0 or ,4.5 mg/dL) (n 5 7); known causes of osteoporosis, such as renal osteodystrophy (n 5 1) and familial osteoporosis (n 5 3); or use of any drugs known to alter bone and calcium metabolism for 3 months or longer during the preceding 12 months (n 5 9). Two patients in the alendronate group and 1 patient in the alphacalcidol group dropped out or withdrew from the study because of loss to follow-up or death. Thus, a total of 79 patients (39 in the alendronate group and 40 in the alphacalcidol group) completed the trial; 77 of these patients had good compliance (.90%). Compliance in the remaining 2 subjects ranged from 70% to 90%; and drug compliance distributed almost equally among the 2 groups. Patient characteristics, number of falls (Table 2), and laboratory values (Table 3) did not differ between the 2 groups at baseline. In both groups, mean serum 1, 25-[OH]2D concentration was around 22 pg/mL. Serum ionized calcium levels were high and PTH and 25-OHD
Table 2. Absolute distribution of falls Before therapy (8 weeks)
With therapy (1 year)
Falls
Alphacalcidol
Alendronate
Alphacalcidol
Alendronate
0 1 2-5 6-7 .7 Total Fallers
20 4 5 0 0 29 23
19 5 4 0 0 28 23
8 6 4 3 1 67 14
28 3 2 0 0 10 5
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Table 3. Serum indices of bone metabolism before and after the 1-year period in the 79 subjects who completed the study
Serum 25-OHD, ng/mL Baseline 1 year % change from baseline Serum ionized calcium, mEq/L Baseline 1 year % change from baseline Serum PTH, pg/mL Baseline 1 year % change from baseline Serum 1, 25-[OH]2D, pg/mL Baseline 1 year % change from baseline
Alphacalcidol group
Alendronate group
P*
14.5 6 4.9 11.5 6 6.3y 220.7 6 9.5
14.9 6 5.4 11.8 6 6.0y 221.1 6 10.3
.45z
2.69 6 0.05 2.80 6 0.09y 14.1 6 1.4
2.70 6 0.09 2.51 6 0.05y 27.1 6 0.9
18.5 6 4.0 11.6 6 5.2y 237.2 6 9.7
18.1 6 3.4 42.3 6 8.5y 1233.7 6 20.6
32.8 6 7.6 18.1 6 5.2y 245.2 6 11.5
31.8 6 6.8 62.2 6 8.4y 1195.6 6 34.8
.89 .80z ,.0001 .71z ,.0001 .78z ,.0001
Values are mean 6 standard deviation. Reference ranges for healthy elderly women: 25-OHD, 18.9-24.9 ng/mL; ionized calcium, 2.44-2.60 mEq/L; intact PTH, 23.6-35.0 pg/mL; 1, 25-[OH]2D, 39.4-56.8 pg/mL. *Wilcoxon rank-sum test. yP , .0001 versus baseline value. zUnpaired t-test. P , .01 versus baseline value.
concentrations were low compared with the reference ranges of the normal Japanese population.16 When the 2 patient groups were analyzed together, ionized calcium concentrations correlated negatively with BI (r 5 20.511; P , .0001) and PTH (r 5 20.506; P , .0001) and positively with D-Pyr (r 5 0.603; P ,.0001). There was no correlation between serum 25-OHD and PTH (r 5 0.084; P 5.74).
Follow-Up Falls During the pretreatment period, 79 falls were recorded, including 38 (in 22 patients) in the alendronate group and 41 (in 22 patients) in the alphacalcidol group. Of the 77 falls recorded during the 1-year follow-up period, 10 (in 5 patients) were in the alendronate group and 67 (in 14 patients) were in the alphacalcidol group (Table 2). After adjustment for the covariates, alendronate treatment was associated with a 65% reduction in falls (estimate, 289; 95% confidence interval [CI] 5 35%-89%; P 5.0005). In the analysis of the rank-transformed incidence of falls (Table 2), the following predictors were screened in amultiple regression model: number of falls and fallers during the 8-week pretreatment period, age, height, weight, BMI, use of walking aid (no walking aid, cane, walker), BI score, duration of institutionalized at study entry, duration of observation during the treatment period, and baseline 25-OHD, 1, 25-[OH]2D, and serum PTH values. In the final Poisson regression, alendronate treatment was associated with a 55% reduction in falls (estimate, 20.67; 95% CI 5 24%-73%; P 5.0021). Significant
predictors other than treatment, in order of importance, are as follows: being a faller in the pretreatment period (P 5.0002), number of falls during the pretreatment period (P 5.0039), and age (P 5.0047). In addition to these covariates, low baseline 1, 25-[OH]2D level was a significant predictor of fall risk (P 5.0011). The mean number of excessive falls in fallers during the treatment period was lower in the alendronate group (P 5.0059), suggesting a decrease in recurrent falls with alendronate therapy. The number of fallers also differed between the treatment arms (relative risk [RR] 5 0.7; 95% CI 5 0.5-0.9). Serum Indices of Bone Metabolism During the 1-year observation period, serum 25-[OH]2D level increased to the normal range in the alendronate group, but decreased further in the alphacalcidol group. Serum ionized calcium concentration decreased to the normal range in the alendronate group, but increased further in the alphacalcidol group. Serum PTH concentration increased in the alendronate group and decreased further in the alphacalcidol group. Serum 25-OHD concentration decreased from baseline level in both groups. Bone Changes Figure 1 shows the percent changes from baseline in metacarpal BMD during the 1-year observation period: 13.2 6 0.3 in the alendronate group and 20.1 6 0.4 in the alphacalcidol group. The difference between the 2 groups was statistically significant (P , .0001).
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4
% Change from baseline in BMD
Alendronate group Placebo group
3
2
1
0
-1 0
10
5
15
Month Figure 1. Percent change (mean) from baseline in metacarpal BMD after 6 and 12 months in the 2 treatment groups. Over 12 months, the difference in the percent change in BMD among the 2 groups was significant (P , .001, Wilcoxon rank-sum test).
Hip Fracture Incidence During the 1-year study period, hip fracture due to falling occurred in 1 case in the alphacalcidol group and in 0 cases in the alendronate group.
Discussion Metacarpal CXD measurement has been validated and its accuracy found to be comparable to the better-known but less widely available dual-energy X-ray absorptiometry technique. In previous studies in stroke patients, we found an association between second metacarpal BMD measured by CXD and the risk of hip fractures.16-18 Decreased second metacarpal BMD in stroke patients appears to reflect a decrease in BMD throughout the appendicular skeleton.19 Preventing fractures is one of the important issues in the management of poststroke patients. The high incidence of hip fractures in elderly stroke patients may be attributed to frequent falls and osteoporosis due to disuse.1,2 Our findings show that alendronate therapy reduced the number of falls per patient by 55%, improved immobilization-induced hypercalcemia, increased serum 1, 25-[OH]2D concentration, and prevented hip fractures in elderly stroke patients with increased bone resorption. On the other hand, previous studies using risedronate17 and etidronate20 found no effect of these bisphoshonates on inhibiting falls. This is the first study to document a reduction in falls in frail elderly poststroke patients with a single medication
over a 12-month period. In the present study, immobilization-induced bone resorption may account for the increased serum calcium and urinary D-Pyr levels in both groups, as evidenced by the correlations between BI score and serum calcium or urinary D-Pyr concentration at baseline. Hypercalcemia, in turn, may inhibit the compensatory PTH that otherwise would occur in response to hypovitaminosis D, and in fact we did find a correlation between serum calcium and PTH concentrations. This inhibition would then lead to decreased 1, 25-[OH]2D production. The immobilization-induced hypercalcemia in stroke patients differs significantly from the hypercalcemia of immobilization due to other causes.17 Generally, immobilization-induced hypercalcemia occurs in conditions with high bone turnover, such as in children or adolescents with acute neurologic diseases, including poliomyelitis and spinal cord injury.21 It is associated with a markedly increased serum calcium concentration, and in most cases increased ionized and bound calcium values as well. On the other hand, the hypercalcemia in long-standing stroke patients, most of whom are elderly, is milder and often can be detected only though measurement of the ionized fraction of calcium. Inhibition of the immobilization-induced bone resorption and normalization of hypercalcemia by alendronate may account for the drug’s ability to increase bone mass. Our hypothesis regarding alendronate’s mechanism of action is that the decreased serum calcium concentration due to decreased bone resorption reverses inhibition of the renal synthesis of 1, 25-[OH]2D, and subsequent increases in serum PTH concentration may contribute to increased renal synthesis of 1, 25-[OH]2D. Decreased urinary D-Pyr following alendronate therapy is consistent with alendronate’s effect as an inhibitor of bone resorption. The effectiveness of alendronate therapy in correcting the abnormal calcium metabolism in stroke patients is noteworthy, and implies that alendronate may be useful in improving immobilization-induced hypercalcemia and the resultant inhibition of PTH secretion in patients with immobilization. These mechanisms may explain the efficacy of alendronate in reducing falls and subsequent hip fractures in long-standing stroke patients. Muscle tissues have highly specific nuclear receptors for 1, 25-[OH]2D [8], and vitamin D supplementation has been linked with a decreased risk of falls in ambulatory and institutionalized elderly subjects. Indeed, we previously reported that vitamin D increases muscle strength by resolving the atrophy of type II muscle fibers, which may lead to decreased falls and hip fractures in poststroke hemiparesis.22 On the other hand, alphacalcidol therapy did not increase serum 1, 25-[OH]2D concentration; rather, it increased intestinal calcium absorption, leading to inhibition of PTH secretion and hence of renal synthesis of 1, 25[OH]2D. Thus, alphacalcidol thrapy was not associated with a decrease in falls and hip fractures. This finding
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suggests that active vitamin D supplementation should be avoided in immobilized patients following stroke. In conclusion, elderly stroke patients with hypercalcemia are at increased risk for frequent falls. Treatment with alendronate may increase serum 1, 25-[OH]2D concentration, which may lead to reduced falls and subsequent hip fractures in elderly stroke patients.
References 1. Ramnemark A, Nilsson M, Borsse´n B, et al. Stroke, a major and increasing risk factor for femoral neck fracture. Stroke 2000;31:1572-1577. 2. Sato Y, Kaji M, Oizumi K. Vitamin D deficiency and the risk of hip fractures among disabled elderly stroke patients. Stroke 2001;32:1673-1677. 3. Lamb SE, Ferrucci L, Volapto S, et al. Risk factors for falling in home-dwelling older women with stroke: The Women’s Health and Aging Study. Stroke 2003;34:494-501. 4. Teasell R, McRae M, Foley N, et al. The incidence and consequences of falls in stroke patients during inpatient rehabilitation: Factors associated with high risk. Arch Phys Med Rehabil 2002;83:329-333. 5. Bischoff HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: A meta-analysis. JAMA 2004; 291:1999-2006. 6. Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337:670-676. 7. Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: A randomized controlled trial. J Bone Miner Res 2003;18:343-351. 8. Bischoff HA, Borchers M, Gudat F, et al. In situ detection of 1, 25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue. Histochem J 2001;33:19-24. 9. Sato Y, Maruoka H, Oizumi K. Amelioration of hemiparesis-associated osteopenia over 4 years following stroke by 1,a-hydroxyvitamin D3 and calcium supplementation. Stroke 1997;28:736-739.
10. Sato Y, Fujimatsu Y, Kikuyama M, et al. Influence of immobilization on bone mass and bone metabolism in hemiplegic elderly patients with a long-standing stroke. J Neurol Sci 1998;156:205-210. 11. Sato Y, Oizumi K, Kuno H, et al. Effect of Immobilization upon renal synthesis of 1, 25-dihydroxyvitamin D in disabled elderly stroke patients. Bone 1999;24:271-275. 12. Mahoney FI, Barthel DW. Functional evaluation: The Barthel index. Md St Med J 1965;14:61-65. 13. Matsumoto C, Kushida K, Yamazaki K, et al. Metacarpal bone mass in normal and osteoporotic Japanese women using computed X-ray densitometry. Calcif Tissue Int 1994;55:324-329. 14. Robins SP, Black D, Paterson CR, et al. Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases. Eur J Clin Invest 1991;21:310-315. 15. Cox DR, Hinckley DV. Theoretical Statistics. London: Chapman & Hall, 1974. 16. Sato Y, Kaji M, Tsuru T, et al. Risk factors for hip fracture among elderly patients with Parkinson’s disease. J Neurol Sci 2001;82:89-93. 17. Sato Y, Iwamoto J, Kanoko T, et al. Risedronate therapy for prevention of hip fracture after stroke in elderly women. Neurology 2005;64:811-816. 18. Sato Y, Iwamoto J, Kanoko T, et al. Risedronate sodium therapy for prevention of hip fracture in men 65 years or older after stroke. Arch Intern Med 2005;165:1743-1748. 19. 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;54:461-465. 20. Sato Y, Asoh T, Kaji M, et al. Benefical effect of intermittent cyclical etidronate therapy in hemiplegic patients following an acute stroke. J Bone Miner Res 2000;15:2487-2494. 21. Stewart AF, Adler M, Byers CM, et al. Calcium homeostasis in immobilization: An example of resorptive hypercalciuria. N Engl J Med 1982;306:1136-1140. 22. Sato Y, Iwamoto J, Kanoko T, et al. Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: A randomized controlled trial. Cerebrovasc Dis 2005;20:187-192.
Although vitamin D supplementation has been suggested to reduce the risk of falling in ambulatory or institutionalized elderly persons, no study has examined whether it reduces the frequency of falling in immobilized stroke patients who have immobilization-induced hypercalcemia reflecting increased bone resorption leading to inhibited renal synthesis of 1, 25-dihydroxyvitamin D (1, 25-[OH]2D). Bisphosphonate is known to reduce immobilization-induced hypercalcemia by inhibiting bone resorption of calcium. This study compared the efficacy of 2 drugs in reducing the risk of falling in patients with long-standing stroke. Eighty-two elderly patients with poststroke hemiparesis were followed for 1 year. The patients were randomly assigned to one of 2 groups; 41 patients received alendronate 35 mg once weekly, and 41 patients received alphacalcidiol 1 mg daily. The number of falls per person and incidence of hip fracture in the 2 groups were compared. At baseline, all patients had a low serum 1, 25-[OH]2D level. Alphacalcidol therapy enhanced immobilization-induced hypercalcemia by increasing intestinal calcium absorption, leading to a reduction of serum 1, 25-[OH]2D level, while alendronate therapy enhanced 1, 25-[OH]2D production by decreasing hypercalcemia. Alendronate treatment accounted for a 55% reduction in falls (95% confidence interval [CI] 5 25-72%; P 5.0021). During the 1-year study period, hip fracture occurred in 1 of 41 subjects in the alphacalcidol group and in no subjects in the alendronate group. Bone mineral density was increased by 3.2% in the alendronate group and decreased by 0.1% in the alphacalcidol group (P ,.0001). Alendronate therapy increased serum 1, 25-[OH]2D levels by improving immobilization-induced hypercalcemia, which may lead to decreased falling and subsequent hip fractures. Key Words: Bisphosphonate— fall—poststroke patients—hip fracture—vitamin D. Ó 2011 by National Stroke Association
Long-term stroke survivors may be at an increased risk of falling and subsequent fractures, particularly of the hip.1 A fall may result in a hip fracture on the paretic side.2 Elucidation of predisposing factors related to falling is important, especially if these factors are modifiable and falls can be prevented. Approximately 40% of patients fall
From the *Department of Neurology, Mitate Hospital, Tagawa, Japan; and †Institute for Sports Medicine, Keio University School of Medicine, Tokyo, Japan. Received April 28, 2009; revision received August 22, 2009; accepted October 26, 2009. Address correspondence to Yoshihiro Sato, MD, Department of Neurology, Mitate Hospital, 3237 Yugeta, Tagawa 826-0041, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2011 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2009.10.007
within the first year after sustaining a stroke,3 and the incidence of hip fracture is up to 4 times higher in stroke patients compared with controls.4 It has been suggested that vitamin D supplementation reduces the risk of falling in ambulatory or institutionalized elderly persons.5 Previously, the moderate protective effect of vitamin D on fracture risk was attributed primarily to changes in bone mineral density (BMD).6 In an open-label controlled trial, vitamin D supplementation reduced the incidence of fractures within 8-12 weeks of treatment, a finding consistent with vitamin D’s known benefit in muscle strength.7 Skeletal muscle is known to express specific receptors for 1, 25-dihydroxyvitamin D (1, 25-[OH]2D).8 We previously demonstrated that treatment with alphacalcidol can reduce the risk of hip fracture in patients with long-standing stroke.9 In that study, we did not measure serum concentrations of calcium and 1, 25-[OH]2D. An
Journal of Stroke and Cerebrovascular Diseases, Vol. 20, No. 1 (January-February), 2011: pp 41-46
41
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immobilization-related elevated serum calcium level may inhibit parathyroid hormone (PTH) secretion, and hence renal 1, 25-[OH]2D production, in disabled long-standing stroke patients.10,11 Many of these patients have a very low serum 1, 25-[OH]2D level, and it has been shown that immobilization-induced hypercalcemia may inhibit the renal synthesis of 1, 25-[OH]2D.2 The present study, a 1-year open-label trial, compared the efficacy of alendronate and alphacalcidol therapy in reducing the risk of falling associated with elevated serum 1, 25-[OH]2D level in a cohort of institutionalized elderly stroke survivors.
Materials and Methods Study Population This study compared the occurrence of falls in hospitalized stroke patients with hemiparesis during therapy with either alendronate or alphacalcidol. The subjects were 82 elderly patients with poststroke hemiparesis who were admitted to the Mitate Hospital between October 2007 and December 2008. All of them had sustained a first-ever cerebral infarction or hemorrhage more than 1 year earlier and were in a convalescent stage, with poststroke hemiparesis. Exclusion criteria included dementia, cardioembolic stroke being treated with warfarin, ataxia, total disability, and hospitalization for ,1 year. Individuals who had received any drugs known to alter bone and vitamin D metabolism (eg, anticonvulsants, bisphosphonates, calcium, calcitonin, vitamin D, vitamin K) in the 6 months before the study were excluded. No subject was receiving physical therapy at study entry, and no attempt was made to alter any subject’s diet or activity during the study period. (The mean duration of illness at study entry was .3 years, and physical therapy is not beneficial at such a late convalescent stage of stroke.) Baseline body mass index (BMI) and Barthel index (BI)12 values were recorded for all subjects. Table 1 summarizes the characteristics of the study population. The study design was approved by the local Ethics Committee, and informed consent was obtained from all subjects in the presence of a witness.
Study Protocol The patients were assigned to 1 of the 2 study groups by means of computer-generated random numbering. The trial included an 8-week pretreatment period and a 1-year treatment period. The primary outcome was the number of falls per person occurring during the treatment period. The secondary outcome was the incidence of hip fracture. Each patient’s clinical status was assessed at baseline, and all falls and hip fractures were recorded. Falls occurring during the pretreatment period were recorded as well. For this study, a fall was defined as a fall due to an unexpected loss of balance. Falls were recorded by nurses blinded to the
subjects’ information; date, time, circumstances, and injuries were documented. The subjects received either a weekly 35-mg dose of alendronate (Bonalon; Teijin Pharma, Tokyo, Japan) or a daily 1-mg dose of alphacalcidol (Onealfa, Teijin Pharma). Each study arm comprised 41 subjects. No dose adjustments were made at any time during the study. The subjects were prohibited from taking any other drugs that could affect bone and vitamin D metabolism. No dose adjustments were made at any time during the study. Follow-up assessment was performed by 2 physicians who did not participate in the initial randomization and were blinded to the treatment assignment. Both groups were observed for 1 year. General medical evaluation and serum indices of bone metabolism were assessed at study entry and after 1 year. BMD of the nonaffected second metacarpal bone was measured by computed X-ray densitometry (CXD; Teijin Limited, Tokyo, Japan)13 on the day of study entry and 6 and 12 months later. CXD measures bone density and cortical thickness in the middle of the second metacarpal bone, using a radiogram of the hand and an aluminum step wedge as a standard (20 steps, 1 mm/step). The computer calculates BMD based on the pattern of gradations along the aluminum step wedge. BMD is expressed as the thickness of an aluminum equivalent (mm Al) showing corresponding X-ray absorption. Precision errors (i.e., coefficients of variation) in measuring BMD by CXD range from 0.2% to 1.2%.13 On the morning of the day of bone evaluation, blood and urine samples were obtained from each subject after an overnight fast. Blood samples were analyzed for ionized calcium, intact PTH, 25-hydroxyvitamin D (25-OHD), and 1, 25-[OH]2D as described previously.2 Urinary deoxypyridinoline (D-Pyr), a bone resorption marker, was measured with an enzyme immunoassay kit (Metra Biosystems, Mountain View, CA) and expressed relative to the urinary creatinine concentration (mmol/mol creatinine).14
Statistical Analysis All statistical analyses were performed using Statview J 5.0 software (Abacus Concepts, Berkeley, CA). Values are expressed as mean 6 standard deviation unless stated otherwise. Group differences in the categorical data were evaluated using the c2 test or Fisher’s exact test. The unpaired Student t-test was used to determine the differences between the 2 groups. Spearman’s rank correlation coefficients (SRCCs) were calculated to determine the relationship between BI score and ionized calcium level or urinary D-Pyr, and between ionized calcium and 1, 25[OH]2D. The 2 groups were compared with respect to their laboratory values using Wilcoxon’s rank-sum test. The mean number of excessive falls (i.e., [number of falls during the treatment period] 2 [falls during the pretreatment period]) was compared using the paired t-test. For the adjusted analysis of falls, each patient was categorized
FALLS IN STROKE PATIENTS
43
Table 1. Baseline clinical characteristics of the stroke patients
Variable
Stroke patients Alphacalcidol group (n 5 41)
Alendronate group (n 5 41)
P*
Age, years BMI, kg/m2 Duration of illness, years Duration of hospitalization, years Cerebral infarction Lacunar infarction/atherothrombotic infarction Hypertension Diabetes mellitus Hypercholesteromia Current smoker Cerebral hemorrhage BI score Walking aid: no aid/cane/walker Falls in pretreatment period
72.7 6 3.9 22.1 6 4.1 3.2 6 1.6 2.1 6 0.9 30 30/11 27 10 9 8 11 58 6 10 9/14/18 46
73.0 6 4.1 22.5 6 3.5 3.1 6 1.9 2.0 6 0.7 27 28/13 25 12 10 11 14 59 6 11 7/15/19 44
.69 .71 .74 .75 .76y .67y .83y .70y .86y .53y .60y .88 .95y .88y
Values are mean 6 standard deviation. *t-test for scales. yc2 test.
according to a predefined response (0, 1, 2-5, 6-7, or .7 falls), and Poisson regression was used to analyze the statistical differences in the rank-transformed incidence of falls between the 2 groups. Besides treatment, the model included baseline covariates that reached a significant difference of P ,.10 when the 2 arms were compared. The number of subjects was chosen to have sufficient power to detect a difference in the number of falls. A 32% decrease in falls was found in a recent meta-analysis of 5 studies of the effect of vitamin D on falling.5 A standard method for comparing Poisson distributions indicates that a 32% or greater reduction in falls provides 80% power to detect a significant difference between the groups as long as each group contains 44 subjects.15 A P value ,5% was considered statistically significant.
Results Demographic and Baseline Clinical Characteristics of Study Subjects Initial enrollment was 107 elderly patients with poststroke hemiparesis. Exclusion criteria were past history of
fractures (n 5 5); impaired hepatic (serum alanine aminotransferase .50 U/L), renal (serum creatinine .1.5 mg/ dL), cardiac (serum brain natriutetic peptide .20 pg/ mL), or thyroid function (serum thyroxine .11.0 or ,4.5 mg/dL) (n 5 7); known causes of osteoporosis, such as renal osteodystrophy (n 5 1) and familial osteoporosis (n 5 3); or use of any drugs known to alter bone and calcium metabolism for 3 months or longer during the preceding 12 months (n 5 9). Two patients in the alendronate group and 1 patient in the alphacalcidol group dropped out or withdrew from the study because of loss to follow-up or death. Thus, a total of 79 patients (39 in the alendronate group and 40 in the alphacalcidol group) completed the trial; 77 of these patients had good compliance (.90%). Compliance in the remaining 2 subjects ranged from 70% to 90%; and drug compliance distributed almost equally among the 2 groups. Patient characteristics, number of falls (Table 2), and laboratory values (Table 3) did not differ between the 2 groups at baseline. In both groups, mean serum 1, 25-[OH]2D concentration was around 22 pg/mL. Serum ionized calcium levels were high and PTH and 25-OHD
Table 2. Absolute distribution of falls Before therapy (8 weeks)
With therapy (1 year)
Falls
Alphacalcidol
Alendronate
Alphacalcidol
Alendronate
0 1 2-5 6-7 .7 Total Fallers
20 4 5 0 0 29 23
19 5 4 0 0 28 23
8 6 4 3 1 67 14
28 3 2 0 0 10 5
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Table 3. Serum indices of bone metabolism before and after the 1-year period in the 79 subjects who completed the study
Serum 25-OHD, ng/mL Baseline 1 year % change from baseline Serum ionized calcium, mEq/L Baseline 1 year % change from baseline Serum PTH, pg/mL Baseline 1 year % change from baseline Serum 1, 25-[OH]2D, pg/mL Baseline 1 year % change from baseline
Alphacalcidol group
Alendronate group
P*
14.5 6 4.9 11.5 6 6.3y 220.7 6 9.5
14.9 6 5.4 11.8 6 6.0y 221.1 6 10.3
.45z
2.69 6 0.05 2.80 6 0.09y 14.1 6 1.4
2.70 6 0.09 2.51 6 0.05y 27.1 6 0.9
18.5 6 4.0 11.6 6 5.2y 237.2 6 9.7
18.1 6 3.4 42.3 6 8.5y 1233.7 6 20.6
32.8 6 7.6 18.1 6 5.2y 245.2 6 11.5
31.8 6 6.8 62.2 6 8.4y 1195.6 6 34.8
.89 .80z ,.0001 .71z ,.0001 .78z ,.0001
Values are mean 6 standard deviation. Reference ranges for healthy elderly women: 25-OHD, 18.9-24.9 ng/mL; ionized calcium, 2.44-2.60 mEq/L; intact PTH, 23.6-35.0 pg/mL; 1, 25-[OH]2D, 39.4-56.8 pg/mL. *Wilcoxon rank-sum test. yP , .0001 versus baseline value. zUnpaired t-test. P , .01 versus baseline value.
concentrations were low compared with the reference ranges of the normal Japanese population.16 When the 2 patient groups were analyzed together, ionized calcium concentrations correlated negatively with BI (r 5 20.511; P , .0001) and PTH (r 5 20.506; P , .0001) and positively with D-Pyr (r 5 0.603; P ,.0001). There was no correlation between serum 25-OHD and PTH (r 5 0.084; P 5.74).
Follow-Up Falls During the pretreatment period, 79 falls were recorded, including 38 (in 22 patients) in the alendronate group and 41 (in 22 patients) in the alphacalcidol group. Of the 77 falls recorded during the 1-year follow-up period, 10 (in 5 patients) were in the alendronate group and 67 (in 14 patients) were in the alphacalcidol group (Table 2). After adjustment for the covariates, alendronate treatment was associated with a 65% reduction in falls (estimate, 289; 95% confidence interval [CI] 5 35%-89%; P 5.0005). In the analysis of the rank-transformed incidence of falls (Table 2), the following predictors were screened in amultiple regression model: number of falls and fallers during the 8-week pretreatment period, age, height, weight, BMI, use of walking aid (no walking aid, cane, walker), BI score, duration of institutionalized at study entry, duration of observation during the treatment period, and baseline 25-OHD, 1, 25-[OH]2D, and serum PTH values. In the final Poisson regression, alendronate treatment was associated with a 55% reduction in falls (estimate, 20.67; 95% CI 5 24%-73%; P 5.0021). Significant
predictors other than treatment, in order of importance, are as follows: being a faller in the pretreatment period (P 5.0002), number of falls during the pretreatment period (P 5.0039), and age (P 5.0047). In addition to these covariates, low baseline 1, 25-[OH]2D level was a significant predictor of fall risk (P 5.0011). The mean number of excessive falls in fallers during the treatment period was lower in the alendronate group (P 5.0059), suggesting a decrease in recurrent falls with alendronate therapy. The number of fallers also differed between the treatment arms (relative risk [RR] 5 0.7; 95% CI 5 0.5-0.9). Serum Indices of Bone Metabolism During the 1-year observation period, serum 25-[OH]2D level increased to the normal range in the alendronate group, but decreased further in the alphacalcidol group. Serum ionized calcium concentration decreased to the normal range in the alendronate group, but increased further in the alphacalcidol group. Serum PTH concentration increased in the alendronate group and decreased further in the alphacalcidol group. Serum 25-OHD concentration decreased from baseline level in both groups. Bone Changes Figure 1 shows the percent changes from baseline in metacarpal BMD during the 1-year observation period: 13.2 6 0.3 in the alendronate group and 20.1 6 0.4 in the alphacalcidol group. The difference between the 2 groups was statistically significant (P , .0001).
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4
% Change from baseline in BMD
Alendronate group Placebo group
3
2
1
0
-1 0
10
5
15
Month Figure 1. Percent change (mean) from baseline in metacarpal BMD after 6 and 12 months in the 2 treatment groups. Over 12 months, the difference in the percent change in BMD among the 2 groups was significant (P , .001, Wilcoxon rank-sum test).
Hip Fracture Incidence During the 1-year study period, hip fracture due to falling occurred in 1 case in the alphacalcidol group and in 0 cases in the alendronate group.
Discussion Metacarpal CXD measurement has been validated and its accuracy found to be comparable to the better-known but less widely available dual-energy X-ray absorptiometry technique. In previous studies in stroke patients, we found an association between second metacarpal BMD measured by CXD and the risk of hip fractures.16-18 Decreased second metacarpal BMD in stroke patients appears to reflect a decrease in BMD throughout the appendicular skeleton.19 Preventing fractures is one of the important issues in the management of poststroke patients. The high incidence of hip fractures in elderly stroke patients may be attributed to frequent falls and osteoporosis due to disuse.1,2 Our findings show that alendronate therapy reduced the number of falls per patient by 55%, improved immobilization-induced hypercalcemia, increased serum 1, 25-[OH]2D concentration, and prevented hip fractures in elderly stroke patients with increased bone resorption. On the other hand, previous studies using risedronate17 and etidronate20 found no effect of these bisphoshonates on inhibiting falls. This is the first study to document a reduction in falls in frail elderly poststroke patients with a single medication
over a 12-month period. In the present study, immobilization-induced bone resorption may account for the increased serum calcium and urinary D-Pyr levels in both groups, as evidenced by the correlations between BI score and serum calcium or urinary D-Pyr concentration at baseline. Hypercalcemia, in turn, may inhibit the compensatory PTH that otherwise would occur in response to hypovitaminosis D, and in fact we did find a correlation between serum calcium and PTH concentrations. This inhibition would then lead to decreased 1, 25-[OH]2D production. The immobilization-induced hypercalcemia in stroke patients differs significantly from the hypercalcemia of immobilization due to other causes.17 Generally, immobilization-induced hypercalcemia occurs in conditions with high bone turnover, such as in children or adolescents with acute neurologic diseases, including poliomyelitis and spinal cord injury.21 It is associated with a markedly increased serum calcium concentration, and in most cases increased ionized and bound calcium values as well. On the other hand, the hypercalcemia in long-standing stroke patients, most of whom are elderly, is milder and often can be detected only though measurement of the ionized fraction of calcium. Inhibition of the immobilization-induced bone resorption and normalization of hypercalcemia by alendronate may account for the drug’s ability to increase bone mass. Our hypothesis regarding alendronate’s mechanism of action is that the decreased serum calcium concentration due to decreased bone resorption reverses inhibition of the renal synthesis of 1, 25-[OH]2D, and subsequent increases in serum PTH concentration may contribute to increased renal synthesis of 1, 25-[OH]2D. Decreased urinary D-Pyr following alendronate therapy is consistent with alendronate’s effect as an inhibitor of bone resorption. The effectiveness of alendronate therapy in correcting the abnormal calcium metabolism in stroke patients is noteworthy, and implies that alendronate may be useful in improving immobilization-induced hypercalcemia and the resultant inhibition of PTH secretion in patients with immobilization. These mechanisms may explain the efficacy of alendronate in reducing falls and subsequent hip fractures in long-standing stroke patients. Muscle tissues have highly specific nuclear receptors for 1, 25-[OH]2D [8], and vitamin D supplementation has been linked with a decreased risk of falls in ambulatory and institutionalized elderly subjects. Indeed, we previously reported that vitamin D increases muscle strength by resolving the atrophy of type II muscle fibers, which may lead to decreased falls and hip fractures in poststroke hemiparesis.22 On the other hand, alphacalcidol therapy did not increase serum 1, 25-[OH]2D concentration; rather, it increased intestinal calcium absorption, leading to inhibition of PTH secretion and hence of renal synthesis of 1, 25[OH]2D. Thus, alphacalcidol thrapy was not associated with a decrease in falls and hip fractures. This finding
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suggests that active vitamin D supplementation should be avoided in immobilized patients following stroke. In conclusion, elderly stroke patients with hypercalcemia are at increased risk for frequent falls. Treatment with alendronate may increase serum 1, 25-[OH]2D concentration, which may lead to reduced falls and subsequent hip fractures in elderly stroke patients.
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