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RETRACTED: Abnormal calcium homeostasis in disabled stroke patients with low 25-hydroxyvitamin D
Bone 34 (2004) 710 – 715 www.elsevier.com/locate/bone
Abnormal calcium homeostasis in disabled stroke patients with low 25-hydroxyvitamin D Yoshihiro Sato, a,b,* Masahide Kaji, a Yoshiaki Honda, b Norimasa Hayashida, c Jun Iwamoto, d Tomohiro Kanoko, e and Kei Satoh f a
Department of Neurology, Kurume University Medical Center, 155-1 Kokubu-machi, Kurume, Japan b Department of Neurology, Mitate Hospital, Tagawa 826-0041, Japan c Department of Neuropsychiatry, Mitate Hospital, Tagawa, Japan d Department of Sport Medicine, Keio University School of Medicine, Tokyo, Japan e Department of Rehabilitation Medicine, Institute of Brain Science, Hirosaki University School of Medicine, Zaifu-cho, Hirosaki, Japan f Department of Vascular Biology, Institute of Brain Science, Hirosaki University School of Medicine, Zaifu-cho, Hirosaki, Japan Received 12 June 2003; revised 16 December 2003; accepted 22 December 2003
Abstract Disabled elderly stroke patients occasionally have very low serum 25-hydroxyvitamin D (25-OHD), which may be due to sunlight deprivation and malnutrition. Many of such patients have very low level of serum 1, 25-dihydroxyvitamin D (1, 25-[OH]2D; calcitriol), and immobilization-induced hypercalcemia may be responsible for inhibition of renal synthesis of calcitriol. To elucidate determinants of serum 1, 25-[OH]2D levels in elderly poststroke patients, we measured serum indices of bone and calcium metabolism and metacarpal bone mineral density (BMD). Patients whose serum 1, 25-[OH]2D concentration was below the mean-3 SD of normal control subjects were defined as the low 1, 25-[OH]2D group and the rest of the patients were designated as the normal group. Mean illness duration was 59 months in the normal group and 20 months in the low group. The Barthel index (BI), which predicts the degree of immobilization, was significantly lower in the low group than in the normal group. Mean serum 1, 25-[OH]2D and 25-OHD concentrations in the normal group were 36.7 pg/ml and 4.4 ng/ ml, respectively; and those in the low group were 14.2 pg/ml and 1.8 ng/ml, respectively. Multiple regression analysis identified illness duration and calcium level as independent determinants of 1, 25-[OH]2D in both groups, and PTH in the normal group and 25-OHD in the low group were additional independent determinants. BMD in stroke patients was significantly lower than that in controls, and BMD in the normal group was lower as compared to the low group. BMD correlated negatively with 1, 25-[OH]2D and PTH in the normal group, and hyperparathyroidism may contribute to reduced BMD. These results suggest that treatment of decreased bone mass in stroke patients has to be individualized according to vitamin D status and calcium homeostasis. D 2004 Elsevier Inc. All rights reserved. Keywords: Calcitriol; Hypercalcemia; Immobilization; Stroke; Vitamin D
Introduction Recent advances in diagnosis and treatment have increased the number of elderly stroke survivors with severe disability. As few nursing home beds are available for the elderly population in Japan, many of disabled stroke patients undergo long-term hospitalization. Poststroke physical state has become an increasingly important issue in stroke management. The risk of hip fracture after stroke is
* Corresponding author. Department of Neurology, Mitate Hospital, 3237 Yugeta, Tagawa 826-0041, Japan. Fax: +81-947-46-3090. E-mail address: [email protected] (Y. Sato). 8756-3282/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2003.12.020
reported to be two to four times greater than that in a reference population [1]. Fractures occur relatively late after stroke onset, and most of fractures are on the hemiplegic side [2 –4]. We previously found low serum 25-hydroxyvitamin D (25-OHD) in patients during long-term hospitalization following stroke (5.9 F 4.1 ng/ml) and almost half of them had 25-OHD concentration less than 5 ng/ml [5]. The deficiency may have resulted from malnutrition and sunlight deprivation [5]. Very low level of serum 25-OHD is most often due to reduced cutaneous production of vitamin D in housebound or hospitalized elderly patients [6 – 13] or in women who adopt strict dress codes prohibiting exposure of uncovered skin [14]. The deficiency also may result from malabsorp-
Y. Sato et al. / Bone 34 (2004) 710–715
tion [15], liver disease [16], or anticonvulsant therapy. In patients with very low serum concentrations of 25-OHD, calcium absorption is low, leading to mild hypocalcemia and secondary hyperparathyroidism [10,17]. In these conditions, serum 1, 25-dihydroxyvitamin D (1, 25-[OH]2D; calcitriol) concentration is maintained within normal range by the increase in parathyroid hormone (PTH)-stimulated 1a-hydroxylase activity [10,17]. However, serum 1, 25-[OH]2D concentration sometimes declines despite mild hyperparathyroidism because of impaired renal function with advancing age [18]. In a previous study of elderly poststroke patients, we demonstrated that immobilization-related hypercalcemia inhibits production of 1, 25-[OH]2D in the kidney [19]. In such patients, serum 1, 25-[OH]2D level is normal or low although serum 25-OHD may be less than 5 ng/ml. To elucidate the determinants of the serum concentration of 1, 25-[OH]2D in stroke patients with very low serum 25-OHD, we studied disabled elderly poststroke patients who had been hospitalized for more than 1 year and had 25-OHD levels less than 5 ng/ml. We monitored serum indices of bone metabolism, bone mineral density (BMD), and degree of immobilization, and analyzed the correlations of these measurements with serum concentration of 1, 25-[OH]2D.
Materials and methods First, we screened patients with poststroke hemiplegia for decreased serum 25-OHD. Subjects were consecutive patients, from November 1997 to January 1998, with hemiplegia who had been hospitalized for at least 1 year in the Department of Geriatric Neurology of the Futase Social Insurance Hospital. All the patients were older than 65 years. Patients who had diseases or were taking medication that may interfere with vitamin D metabolism were excluded from study. Also, patients with illness duration less than 1 year, multiple strokes, or total disability were excluded. Diagnosis of stroke was made from clinical findings and computed tomography taken in both acute and chronic phases. Patients in the present study are not the same group of patients in our previous reports [5,19]. Type of stroke was classified according to the Classification of Cerebrovascular Diseases (version III) of the US National Institute of Neurological Disorders and Stroke [20]. Serum 25-OHD concentration was measured in 171 elderly patients and 83 cases with serum 25-OHD concentrations <5 ng/ml were enrolled in the study. Volunteers older than 65 years were recruited from the local community as controls. Persons who were non-ambulatory, had conditions such as osteoporosis, had taken any drugs known to alter bone metabolism, or had vertebral or nonvertebral fractures were excluded. Eighty healthy agematched controls were studied (40 men and 40 women). Body weight (BW) and Barthel index (BI) [21], a functional dependence scale, were assessed in each patient.
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Clinical severity of hemiplegia was evaluated by the longterm score of the Scandinavian Stroke Scale (SSS) [22]. An improved microdensitometric method employing computed X-ray densitometry (CXD; Teijin Diagnostics, Tokyo) [23,24] was used to determine BMD in the bilateral second metacarpals as described previously [5,25 –27]. On the day of bone evaluation, a fasting blood sample was obtained and analyzed for ionized calcium, parathyroid hormone (intact PTH, 1 – 84), intact bone Gla protein (BGP; a bone formation marker [28]), pyridinoline crosslinked carboxy-terminal telopeptide of type I collagen (ICTP; a bone resorption marker [29]), 25-OHD, 1, 25-[OH]2D, and creatinine, as described previously [25 – 27,30]. When 25OHD was undetectable, attempts were made to measure it with concentrated serum. Stroke patients were divided according to serum 1, 25-[OH]2D concentration and assigned either to a group with serum 1, 25-[OH]2D concentrations no lower than the mean-3 SD of controls (the normal group) and a group with concentrations below this value (the low group). Patients and control subjects completed a questionnaire concerning diet and sunlight exposure. Patients who consumed less vitamin D than the Japanese recommended daily allowance (100 IU) were defined as low dietary consumers of the vitamin. Sunlight exposure in the preceding year was graded by subjects as almost none, less than 15 min per week, or longer [31]. This study was approved by the institutional ethics committee. Written informed consent was obtained from controls and patients or their family members if the patients had paralysis precluding the completion of document. Data are presented as the mean F SD. Group differences of categorical data were tested by x2 analyses. One-way ANOVA and Fisher’s protected least significant difference were used to assess differences between the two stroke groups and the controls. Differences in BMD were calculated by paired t tests. Spearman’s rank correlation coefficients (SRCC) were calculated to analyze the relationships between 1, 25-[OH]2D or BMD and each variable. Multiple regression analysis was performed to estimate the independent effects of putative predictors on 1, 25-[OH]2D concentration in each stroke group. P values less than 0.05 were considered statistically significant.
Results Characteristics of study subjects Characteristics of the patient groups are shown in Table 1. No differences were observed between the two patient groups in terms of age, gender, or types of stroke. Duration of illness was significantly longer in the normal group than that in the low group. BI and hemiplegia score (low score means severe hemiplegic) were significantly lower in the low group than in the normal group. Also, BW, dietary intake of vitamin D, and sunlight exposure in
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Table 1 Clinical profiles of stroke patients Variables
Table 2 Serum biochemical parameters and bone mineral density
1, 25-dihydroxyvitamin D (1, 25-[OH]2D) concentration Normal group (z23 pg/ml) (n = 40)
Age (years) 73 F 11 Gender (M/F) 20/20 Brain infarction/brain 28/12 hemorrhage Duration of illness, months 59 F 26 Barthel index 64 F 26 Degree of hemiplegiab 14 F 4 Body weight 53 F 7 Sunlight exposure/week >15 min 31 (78%) <15 min 9 (22%) Dietary intake of vitamin D 143 F 11
P*
Low group (<23 pg/ml) (n = 43) 75 F 7 24/22 30/13 20 45 9 50
F F F F
14 35 4 4
18 (42%) 25 (58%) 66 F 31
0.34 0.84a 0.98a <0.0001 0.0071 <0.0001 0.0401
0.001a <0.0001
Values are mean F SD. a 2 x analyses. b Degree of hemiplegia was evaluated by the Scandinavian Stroke Scale [22]. * Unpaired t test.
the low group were in the low group than those in the normal group.
Variables
Control (n = 80)
Low group (n = 43)
P#
F 0.6y F 11.4y
1.8 F 0.9z 14.2 F 3.6z
<0.0001 <0.0001
F 0.20
2.60 F 0.12z
<0.0001
F 33
32 F 15§
0.0216
F 3.7
3.8 F 3.4§,*
0.0009
Normal group (n = 40)
25-OHD (ng/ml) 21.5 F 3.2 4.2 1, 25-[OH]2D 50.3 F 9.2 36.7 (pg/ml) Ionized calcium 2.44 F 0.08 2.42 (mEq/l) Intact PTH 40 F 16 46 (pg/ml) Intact BGP 6.8 F 4.5 6.3 (ng/ml) ICTP (ng/ml) 7.1 F 1.2 7.6 Creatinine 0.89 F 0.14 0.94 (mg/ml) Bone mineral density (mm Al) Hemiplegic 2.57 F 0.34 1.60 side Intact side 2.58 F 0.35 1.88
F 2.9 F 0.15
10.6 F 4.1z 0.91 F 0.35
<0.0001 0.61
F 0.55y,§
1.83 F 0.46y
<0.0001
F 0.56y,** 2.01 F 0.48y,** <0.0001
Values are mean F SD. 1,25-[OH]2D, 1, 25-dihydroxyvitamin D; Ca, calcium; PTH, parathyroid hormone; BGP, bone Gla protein; ICTP, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen. * P < 0.02 vs. control. ** P < 0.0001 vs. hemiplegic side. # Difference among the three groups (ANOVA). y P < 0.0001 vs. control. z P < 0.0001 vs. control and normal group. § P < 0.0001 vs. normal group.
Serum biochemical indices and bone changes Serum concentrations of 25-OHD and 1, 25-[OH]2D were lower in the two patient groups as compared to the controls (Table 2). The mean serum 1, 25-[OH]2D levels were 39.1 pg/ml in the normal group and 15.2 pg/ml in the low group. Serum concentrations of 25-OHD were significantly lower in the low group than in the normal group. The mean serum calcium concentration was significantly higher in the low group than in the normal group or in controls. While calcium concentration was lower in the normal group than in controls, this difference did not attain statistical significance. PTH concentrations were significantly higher in the normal group than in the low group. Serum BGP was significantly lower and ICTP higher in the low group as compared to the normal group. No significant difference in serum creatinine concentration was evident among the three groups. BMD on both sides in the two stroke groups were significantly lower than that in controls. Notably, BMD were higher in the low group than in the normal group, although this difference was not statistically significant. Also, as previously reported [32], BMD on the hemiplegic side was significantly lower than on the contralateral nonhemiplegic side. Relationship between 1,25-dihydroxyvitamin D or bone mineral density and clinical variables (Table 3) SRCCs between serum 1, 25-[OH]2D concentration and each variable were analyzed separately in the normal and
low groups (Table 3). In the normal group, significant correlations were observed between 1, 25-[OH]2D and patient age, illness duration, serum calcium concentration, or serum PTH concentration, while 1, 25-[OH]2D correlated with illness duration, BI, serum calcium concentration, or serum 25-OHD concentration in the low group. Only in the normal group, BMD on both sides correlated negatively with serum 1, 25-[OH]2D concentration (hemiplegic side, r = 0.428, P = 0.0075; non-hemiplegic side, r = 0.570, P = 0.0004) and with serum PTH concentration (hemiplegic side, r = 0.614, P = 0.0001; non-hemiplegic side, r = 0.510, P = 0.0014). A negative correlation was also seen Table 3 Relationships between 1, 25-dihydroxyvitamin D and clinical variables Variables
Age Illness duration Barthel index Ionized calcium Intact parathyroid hormone 25-hydroxyvitamin
1, 25-Dihydroxyvitamin D Normal group
Low group
0.547*** 0.576*** 0.164y 0.441*** 0.341* 0.105y
0.102y 0.333* 0.511*** 0.585*** 0.201y 0.371**
Values represent Spearman’s rank correlation coefficients (SRCC) with the P value as symbols. * P < 0.05. ** P < 0.01. *** P < 0.001. y Not significant.
Y. Sato et al. / Bone 34 (2004) 710–715 Table 4 Multiple regression analysis of 1, 25-dihydroxyvitamin D with selected independent variables 1, 25-Dihydroxyvitamin D
Age Illness duration Barthel index Ionized calcium Intact parathyroid hormone 25-hydroxyvitamin D Multiple R Adjusted R2 F
Normal group
Low group
SC
P
SC
P
0214 0.650 – 0.281 0.239 – 0.786 0.618 14.177
0.11 <0.0001 – 0.0179 0.0351 –
– 0.258 0.04 0.422 – 0.404 0.823 0.677 40.388
– 0.0033 0.95 <0.0001 – 0.0001
SC = standardized coefficient.
between BMD on the non-hemiplegic side and illness duration in the normal group (r = 0.324, P = 0.0430). On the other hand, the low group had a positive correlation between BMD on the hemiplegic side and degree of paralysis in the hand (r = 0.354, P = 0.0248). In both groups, BMD did not correlate significantly with other variables including BI or serum 25-OHD concentration (data not shown). Serum ionized calcium concentrations correlated negatively with serum PTH concentration only in the low group (r = 0.442, P = 0.0042), while a negative correlation between PTH and 25-OHD was observed only in the normal group (r = 0.369, P = 0.0211). In both groups, serum calcium concentration correlated negatively with illness duration (normal group, r = 0.321, P = 0.0448; low group, r = 0.598, P = 0.0001). In the low group, BI correlated negatively with serum levels of ionized calcium (r = 0.396, P = 0.0112) and ICTP (r = 0.378, P = 0.0156). Multiple regression analysis (Table 4) Age, illness duration, serum calcium, and PTH were selected as independent variables for multiple regression analysis, and 1, 25-[OH]2D as the dependent variable in the normal group (Table 4). Illness duration, serum calcium concentration, and serum PTH concentration were independent predictors of serum 1, 25-[OH]2D level. In the low group, multiple regression analysis was performed with illness duration, BI, 25-OHD, and calcium as independent variables (Table 4). A significant correlation was observed between serum 1, 25-[OH]2D concentration and illness duration, serum 25-OHD concentration, and serum calcium concentration (Table 4).
Discussion We assessed determinants of serum 1, 25-[OH]2D concentration in disabled elderly stroke patients with long-term hospitalization and abnormally low level of serum 25-OHD.
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Illness duration, serum calcium, and serum PTH were independent determinants of serum 1, 25-[OH]2D in the normal group, while illness duration, calcium, and 25-OHD, but not PTH, were determinants of serum 1, 25-[OH]2D in the low group. In our previous study of elderly poststroke patients with vitamin D insufficiency (mean serum 25-OHD concentration, 11.6 ng/ml), determinants of 1, 25-[OH]2D were BI, calcium, and PTH [19]. Thus, determinants of serum 1, 25-[OH]2D concentration in disabled elderly stroke patients are different between the patient group with almost undetectable levels of 25-OHD and those with mild deficiency. As previously reported [19,26], serum ionized calcium concentrations were increased in disabled poststroke patients and correlated with BI in the low 1, 25[OH]2D group, implying the presence of immobilizationrelated hypercalcemia in this group. Additionally, serum ICTP concentrations increased with increasing degree of immobility in the low group. From these data, hypercalcemia clearly reflected increased bone resorption [27]. Negative correlations were also seen between calcium concentration and PTH in the low group. Thus, the low group had more severe immobility, causing hypercalcemia which in turn suppressed PTH secretion; and compensatory hyperparathyroidism did not occur despite severe 25-OHD deficiency. Relatively low PTH may be one of the factors that suppressed renal synthesis of 1, 25-[OH]2D in the low group. Since 25OHD was a determinant of 1, 25-[OH]2D, substrate (i.e., 25OHD) deficiency may also have contributed to low serum 1, 25-[OH]2D. Previous studies reported that serum 25-OHD deficiency leads to a decrease in serum 1, 25-[OH]2D concentration in neurological patients with immobilizationrelated hypercalcemia [25,27,30,33]. In contrast to the low group, serum calcium concentration was low in the normal group, and this indicates that hypocalcemia due to 25-OHD deficiency may overshadow hypercalcemia due to milder immobilization. In fact, the average serum ICTP level in this group was lower than that in the low group. The longer duration of illness may have contributed to improved mobilization in these patients. Hypocalcemia leads to the development of compensatory hyperparathyroidism resulting in increased renal synthesis of 1, 25-[OH]2D; and negative correlation was observed between PTH and 25-OHD levels. Thus, serum PTH, calcium levels, and illness duration were determinants of serum 1, 25-[OH]2D concentration in the normal group. In both groups, 1, 25-[OH]2D correlated positively with illness duration and negatively with calcium. Negative correlations were also seen between illness duration and calcium in both groups. Serum concentrations of 1, 25[OH]2D may have been low in the early stage following stroke and subsequently increased during the chronic stage in both patient groups. Renal impairment is common after stroke and may have affected the activation of vitamin D and thereby BMD. Although there was no significant difference in serum creatinine levels among the patient groups,
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this does not exclude the role of renal impairment, and precise assessment of renal function by creatinine clearance or glomerular filtration rate [34] may be required to clarify the role. Thus, compensatory hyperparathyroidism in the normal group and insufficient correction of hypercalcemia in the low group may account for the prominence of calcium and illness duration as the determinants of 1, 25-[OH]2D; and PTH in the normal group and 25-OHD in the low group were also found to be determinants of 1, 25-[OH]2D. In our previous investigation of chronically disabled elderly patients following stroke, the most significant determinants of metacarpal BMD was serum levels of 25-OHD (mean, 11.5 ng/ml) [25]. In the present study, metacarpal BMD was lower in the normal group than in the low group, and BMD correlated negatively with 1, 25-[OH]2D and PTH only in the normal group. BMD differences between the two stroke groups may have resulted from hyperparathyroidism in the normal group, since hyperparathyroidism enhances renal synthesis of 1, 25-[OH]2D and decreases BMD, resulting in negative correlations of BMD with 1, 25[OH]2D and PTH in this group. Although the reason for lack of correlation between BMD and such variables in the low group is unknown, distribution of the subjects in a limited range may have resulted in a random dispersion. The results of the present study are important in that they have some therapeutic implications. In most patients with very low serum 25-OHD, treatment with relatively large dose of vitamin D is necessary [10,17]. We previously found only one fourth of acute stroke patients had sufficient serum levels of 25-OHD [35], and the preventive measures for fractures should be initiated in an acute stroke unit. Vitamin D metabolites, 1, 25-[OH]2D (calcitriol) [36] or 1a(OH)D3, are generally used to treat patients with abnormally low 25-OHD levels [17]; however, in the treatment of elderly patients with low 25-OHD, an alternative to vitamin D should be considered [37] since immobilizationrelated hypercalcemia may disturb calcium homeostasis[19,25,26]. In the low group, treatment with ergocalciferol, cholecalciferol, or dihydrotachysterols may be useful for correcting abnormally decreased serum 25-OHD, since one of the major causes of 1, 25-[OH]2D deficiency is 25OHD deficiency. Calcitonin [38] may be effective in correcting immobilization-induced hypercalcemia and improving renal production of 1, 25-[OH]2D in such patients. Bisphosphonates [39,40] may be also beneficial in preventing osteoclastic bone resorption due to immobilization, and we previously found, in patients with hemiplegia, that bisphosphonate etidronate markedly increase serum 1, 25[OH]2D by inhibiting immobilization-related hypercalcemia [41]. Thus, vitamin D formulations such as ergocalciferol combined with calcitonin or a bisphosphonate may be considered in stroke patients with low 1, 25-[OH]2D. The presence of compensatory hyperparathyroidism was obvious in the normal group, and exogenous 1, 25-[OH]2D should be avoided in such patients since it may further
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Abnormal calcium homeostasis in disabled stroke patients with low 25-hydroxyvitamin D Yoshihiro Sato, a,b,* Masahide Kaji, a Yoshiaki Honda, b Norimasa Hayashida, c Jun Iwamoto, d Tomohiro Kanoko, e and Kei Satoh f a
Department of Neurology, Kurume University Medical Center, 155-1 Kokubu-machi, Kurume, Japan b Department of Neurology, Mitate Hospital, Tagawa 826-0041, Japan c Department of Neuropsychiatry, Mitate Hospital, Tagawa, Japan d Department of Sport Medicine, Keio University School of Medicine, Tokyo, Japan e Department of Rehabilitation Medicine, Institute of Brain Science, Hirosaki University School of Medicine, Zaifu-cho, Hirosaki, Japan f Department of Vascular Biology, Institute of Brain Science, Hirosaki University School of Medicine, Zaifu-cho, Hirosaki, Japan Received 12 June 2003; revised 16 December 2003; accepted 22 December 2003
Abstract Disabled elderly stroke patients occasionally have very low serum 25-hydroxyvitamin D (25-OHD), which may be due to sunlight deprivation and malnutrition. Many of such patients have very low level of serum 1, 25-dihydroxyvitamin D (1, 25-[OH]2D; calcitriol), and immobilization-induced hypercalcemia may be responsible for inhibition of renal synthesis of calcitriol. To elucidate determinants of serum 1, 25-[OH]2D levels in elderly poststroke patients, we measured serum indices of bone and calcium metabolism and metacarpal bone mineral density (BMD). Patients whose serum 1, 25-[OH]2D concentration was below the mean-3 SD of normal control subjects were defined as the low 1, 25-[OH]2D group and the rest of the patients were designated as the normal group. Mean illness duration was 59 months in the normal group and 20 months in the low group. The Barthel index (BI), which predicts the degree of immobilization, was significantly lower in the low group than in the normal group. Mean serum 1, 25-[OH]2D and 25-OHD concentrations in the normal group were 36.7 pg/ml and 4.4 ng/ ml, respectively; and those in the low group were 14.2 pg/ml and 1.8 ng/ml, respectively. Multiple regression analysis identified illness duration and calcium level as independent determinants of 1, 25-[OH]2D in both groups, and PTH in the normal group and 25-OHD in the low group were additional independent determinants. BMD in stroke patients was significantly lower than that in controls, and BMD in the normal group was lower as compared to the low group. BMD correlated negatively with 1, 25-[OH]2D and PTH in the normal group, and hyperparathyroidism may contribute to reduced BMD. These results suggest that treatment of decreased bone mass in stroke patients has to be individualized according to vitamin D status and calcium homeostasis. D 2004 Elsevier Inc. All rights reserved. Keywords: Calcitriol; Hypercalcemia; Immobilization; Stroke; Vitamin D
Introduction Recent advances in diagnosis and treatment have increased the number of elderly stroke survivors with severe disability. As few nursing home beds are available for the elderly population in Japan, many of disabled stroke patients undergo long-term hospitalization. Poststroke physical state has become an increasingly important issue in stroke management. The risk of hip fracture after stroke is
* Corresponding author. Department of Neurology, Mitate Hospital, 3237 Yugeta, Tagawa 826-0041, Japan. Fax: +81-947-46-3090. E-mail address: [email protected] (Y. Sato). 8756-3282/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2003.12.020
reported to be two to four times greater than that in a reference population [1]. Fractures occur relatively late after stroke onset, and most of fractures are on the hemiplegic side [2 –4]. We previously found low serum 25-hydroxyvitamin D (25-OHD) in patients during long-term hospitalization following stroke (5.9 F 4.1 ng/ml) and almost half of them had 25-OHD concentration less than 5 ng/ml [5]. The deficiency may have resulted from malnutrition and sunlight deprivation [5]. Very low level of serum 25-OHD is most often due to reduced cutaneous production of vitamin D in housebound or hospitalized elderly patients [6 – 13] or in women who adopt strict dress codes prohibiting exposure of uncovered skin [14]. The deficiency also may result from malabsorp-
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tion [15], liver disease [16], or anticonvulsant therapy. In patients with very low serum concentrations of 25-OHD, calcium absorption is low, leading to mild hypocalcemia and secondary hyperparathyroidism [10,17]. In these conditions, serum 1, 25-dihydroxyvitamin D (1, 25-[OH]2D; calcitriol) concentration is maintained within normal range by the increase in parathyroid hormone (PTH)-stimulated 1a-hydroxylase activity [10,17]. However, serum 1, 25-[OH]2D concentration sometimes declines despite mild hyperparathyroidism because of impaired renal function with advancing age [18]. In a previous study of elderly poststroke patients, we demonstrated that immobilization-related hypercalcemia inhibits production of 1, 25-[OH]2D in the kidney [19]. In such patients, serum 1, 25-[OH]2D level is normal or low although serum 25-OHD may be less than 5 ng/ml. To elucidate the determinants of the serum concentration of 1, 25-[OH]2D in stroke patients with very low serum 25-OHD, we studied disabled elderly poststroke patients who had been hospitalized for more than 1 year and had 25-OHD levels less than 5 ng/ml. We monitored serum indices of bone metabolism, bone mineral density (BMD), and degree of immobilization, and analyzed the correlations of these measurements with serum concentration of 1, 25-[OH]2D.
Materials and methods First, we screened patients with poststroke hemiplegia for decreased serum 25-OHD. Subjects were consecutive patients, from November 1997 to January 1998, with hemiplegia who had been hospitalized for at least 1 year in the Department of Geriatric Neurology of the Futase Social Insurance Hospital. All the patients were older than 65 years. Patients who had diseases or were taking medication that may interfere with vitamin D metabolism were excluded from study. Also, patients with illness duration less than 1 year, multiple strokes, or total disability were excluded. Diagnosis of stroke was made from clinical findings and computed tomography taken in both acute and chronic phases. Patients in the present study are not the same group of patients in our previous reports [5,19]. Type of stroke was classified according to the Classification of Cerebrovascular Diseases (version III) of the US National Institute of Neurological Disorders and Stroke [20]. Serum 25-OHD concentration was measured in 171 elderly patients and 83 cases with serum 25-OHD concentrations <5 ng/ml were enrolled in the study. Volunteers older than 65 years were recruited from the local community as controls. Persons who were non-ambulatory, had conditions such as osteoporosis, had taken any drugs known to alter bone metabolism, or had vertebral or nonvertebral fractures were excluded. Eighty healthy agematched controls were studied (40 men and 40 women). Body weight (BW) and Barthel index (BI) [21], a functional dependence scale, were assessed in each patient.
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Clinical severity of hemiplegia was evaluated by the longterm score of the Scandinavian Stroke Scale (SSS) [22]. An improved microdensitometric method employing computed X-ray densitometry (CXD; Teijin Diagnostics, Tokyo) [23,24] was used to determine BMD in the bilateral second metacarpals as described previously [5,25 –27]. On the day of bone evaluation, a fasting blood sample was obtained and analyzed for ionized calcium, parathyroid hormone (intact PTH, 1 – 84), intact bone Gla protein (BGP; a bone formation marker [28]), pyridinoline crosslinked carboxy-terminal telopeptide of type I collagen (ICTP; a bone resorption marker [29]), 25-OHD, 1, 25-[OH]2D, and creatinine, as described previously [25 – 27,30]. When 25OHD was undetectable, attempts were made to measure it with concentrated serum. Stroke patients were divided according to serum 1, 25-[OH]2D concentration and assigned either to a group with serum 1, 25-[OH]2D concentrations no lower than the mean-3 SD of controls (the normal group) and a group with concentrations below this value (the low group). Patients and control subjects completed a questionnaire concerning diet and sunlight exposure. Patients who consumed less vitamin D than the Japanese recommended daily allowance (100 IU) were defined as low dietary consumers of the vitamin. Sunlight exposure in the preceding year was graded by subjects as almost none, less than 15 min per week, or longer [31]. This study was approved by the institutional ethics committee. Written informed consent was obtained from controls and patients or their family members if the patients had paralysis precluding the completion of document. Data are presented as the mean F SD. Group differences of categorical data were tested by x2 analyses. One-way ANOVA and Fisher’s protected least significant difference were used to assess differences between the two stroke groups and the controls. Differences in BMD were calculated by paired t tests. Spearman’s rank correlation coefficients (SRCC) were calculated to analyze the relationships between 1, 25-[OH]2D or BMD and each variable. Multiple regression analysis was performed to estimate the independent effects of putative predictors on 1, 25-[OH]2D concentration in each stroke group. P values less than 0.05 were considered statistically significant.
Results Characteristics of study subjects Characteristics of the patient groups are shown in Table 1. No differences were observed between the two patient groups in terms of age, gender, or types of stroke. Duration of illness was significantly longer in the normal group than that in the low group. BI and hemiplegia score (low score means severe hemiplegic) were significantly lower in the low group than in the normal group. Also, BW, dietary intake of vitamin D, and sunlight exposure in
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Table 1 Clinical profiles of stroke patients Variables
Table 2 Serum biochemical parameters and bone mineral density
1, 25-dihydroxyvitamin D (1, 25-[OH]2D) concentration Normal group (z23 pg/ml) (n = 40)
Age (years) 73 F 11 Gender (M/F) 20/20 Brain infarction/brain 28/12 hemorrhage Duration of illness, months 59 F 26 Barthel index 64 F 26 Degree of hemiplegiab 14 F 4 Body weight 53 F 7 Sunlight exposure/week >15 min 31 (78%) <15 min 9 (22%) Dietary intake of vitamin D 143 F 11
P*
Low group (<23 pg/ml) (n = 43) 75 F 7 24/22 30/13 20 45 9 50
F F F F
14 35 4 4
18 (42%) 25 (58%) 66 F 31
0.34 0.84a 0.98a <0.0001 0.0071 <0.0001 0.0401
0.001a <0.0001
Values are mean F SD. a 2 x analyses. b Degree of hemiplegia was evaluated by the Scandinavian Stroke Scale [22]. * Unpaired t test.
the low group were in the low group than those in the normal group.
Variables
Control (n = 80)
Low group (n = 43)
P#
F 0.6y F 11.4y
1.8 F 0.9z 14.2 F 3.6z
<0.0001 <0.0001
F 0.20
2.60 F 0.12z
<0.0001
F 33
32 F 15§
0.0216
F 3.7
3.8 F 3.4§,*
0.0009
Normal group (n = 40)
25-OHD (ng/ml) 21.5 F 3.2 4.2 1, 25-[OH]2D 50.3 F 9.2 36.7 (pg/ml) Ionized calcium 2.44 F 0.08 2.42 (mEq/l) Intact PTH 40 F 16 46 (pg/ml) Intact BGP 6.8 F 4.5 6.3 (ng/ml) ICTP (ng/ml) 7.1 F 1.2 7.6 Creatinine 0.89 F 0.14 0.94 (mg/ml) Bone mineral density (mm Al) Hemiplegic 2.57 F 0.34 1.60 side Intact side 2.58 F 0.35 1.88
F 2.9 F 0.15
10.6 F 4.1z 0.91 F 0.35
<0.0001 0.61
F 0.55y,§
1.83 F 0.46y
<0.0001
F 0.56y,** 2.01 F 0.48y,** <0.0001
Values are mean F SD. 1,25-[OH]2D, 1, 25-dihydroxyvitamin D; Ca, calcium; PTH, parathyroid hormone; BGP, bone Gla protein; ICTP, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen. * P < 0.02 vs. control. ** P < 0.0001 vs. hemiplegic side. # Difference among the three groups (ANOVA). y P < 0.0001 vs. control. z P < 0.0001 vs. control and normal group. § P < 0.0001 vs. normal group.
Serum biochemical indices and bone changes Serum concentrations of 25-OHD and 1, 25-[OH]2D were lower in the two patient groups as compared to the controls (Table 2). The mean serum 1, 25-[OH]2D levels were 39.1 pg/ml in the normal group and 15.2 pg/ml in the low group. Serum concentrations of 25-OHD were significantly lower in the low group than in the normal group. The mean serum calcium concentration was significantly higher in the low group than in the normal group or in controls. While calcium concentration was lower in the normal group than in controls, this difference did not attain statistical significance. PTH concentrations were significantly higher in the normal group than in the low group. Serum BGP was significantly lower and ICTP higher in the low group as compared to the normal group. No significant difference in serum creatinine concentration was evident among the three groups. BMD on both sides in the two stroke groups were significantly lower than that in controls. Notably, BMD were higher in the low group than in the normal group, although this difference was not statistically significant. Also, as previously reported [32], BMD on the hemiplegic side was significantly lower than on the contralateral nonhemiplegic side. Relationship between 1,25-dihydroxyvitamin D or bone mineral density and clinical variables (Table 3) SRCCs between serum 1, 25-[OH]2D concentration and each variable were analyzed separately in the normal and
low groups (Table 3). In the normal group, significant correlations were observed between 1, 25-[OH]2D and patient age, illness duration, serum calcium concentration, or serum PTH concentration, while 1, 25-[OH]2D correlated with illness duration, BI, serum calcium concentration, or serum 25-OHD concentration in the low group. Only in the normal group, BMD on both sides correlated negatively with serum 1, 25-[OH]2D concentration (hemiplegic side, r = 0.428, P = 0.0075; non-hemiplegic side, r = 0.570, P = 0.0004) and with serum PTH concentration (hemiplegic side, r = 0.614, P = 0.0001; non-hemiplegic side, r = 0.510, P = 0.0014). A negative correlation was also seen Table 3 Relationships between 1, 25-dihydroxyvitamin D and clinical variables Variables
Age Illness duration Barthel index Ionized calcium Intact parathyroid hormone 25-hydroxyvitamin
1, 25-Dihydroxyvitamin D Normal group
Low group
0.547*** 0.576*** 0.164y 0.441*** 0.341* 0.105y
0.102y 0.333* 0.511*** 0.585*** 0.201y 0.371**
Values represent Spearman’s rank correlation coefficients (SRCC) with the P value as symbols. * P < 0.05. ** P < 0.01. *** P < 0.001. y Not significant.
Y. Sato et al. / Bone 34 (2004) 710–715 Table 4 Multiple regression analysis of 1, 25-dihydroxyvitamin D with selected independent variables 1, 25-Dihydroxyvitamin D
Age Illness duration Barthel index Ionized calcium Intact parathyroid hormone 25-hydroxyvitamin D Multiple R Adjusted R2 F
Normal group
Low group
SC
P
SC
P
0214 0.650 – 0.281 0.239 – 0.786 0.618 14.177
0.11 <0.0001 – 0.0179 0.0351 –
– 0.258 0.04 0.422 – 0.404 0.823 0.677 40.388
– 0.0033 0.95 <0.0001 – 0.0001
SC = standardized coefficient.
between BMD on the non-hemiplegic side and illness duration in the normal group (r = 0.324, P = 0.0430). On the other hand, the low group had a positive correlation between BMD on the hemiplegic side and degree of paralysis in the hand (r = 0.354, P = 0.0248). In both groups, BMD did not correlate significantly with other variables including BI or serum 25-OHD concentration (data not shown). Serum ionized calcium concentrations correlated negatively with serum PTH concentration only in the low group (r = 0.442, P = 0.0042), while a negative correlation between PTH and 25-OHD was observed only in the normal group (r = 0.369, P = 0.0211). In both groups, serum calcium concentration correlated negatively with illness duration (normal group, r = 0.321, P = 0.0448; low group, r = 0.598, P = 0.0001). In the low group, BI correlated negatively with serum levels of ionized calcium (r = 0.396, P = 0.0112) and ICTP (r = 0.378, P = 0.0156). Multiple regression analysis (Table 4) Age, illness duration, serum calcium, and PTH were selected as independent variables for multiple regression analysis, and 1, 25-[OH]2D as the dependent variable in the normal group (Table 4). Illness duration, serum calcium concentration, and serum PTH concentration were independent predictors of serum 1, 25-[OH]2D level. In the low group, multiple regression analysis was performed with illness duration, BI, 25-OHD, and calcium as independent variables (Table 4). A significant correlation was observed between serum 1, 25-[OH]2D concentration and illness duration, serum 25-OHD concentration, and serum calcium concentration (Table 4).
Discussion We assessed determinants of serum 1, 25-[OH]2D concentration in disabled elderly stroke patients with long-term hospitalization and abnormally low level of serum 25-OHD.
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Illness duration, serum calcium, and serum PTH were independent determinants of serum 1, 25-[OH]2D in the normal group, while illness duration, calcium, and 25-OHD, but not PTH, were determinants of serum 1, 25-[OH]2D in the low group. In our previous study of elderly poststroke patients with vitamin D insufficiency (mean serum 25-OHD concentration, 11.6 ng/ml), determinants of 1, 25-[OH]2D were BI, calcium, and PTH [19]. Thus, determinants of serum 1, 25-[OH]2D concentration in disabled elderly stroke patients are different between the patient group with almost undetectable levels of 25-OHD and those with mild deficiency. As previously reported [19,26], serum ionized calcium concentrations were increased in disabled poststroke patients and correlated with BI in the low 1, 25[OH]2D group, implying the presence of immobilizationrelated hypercalcemia in this group. Additionally, serum ICTP concentrations increased with increasing degree of immobility in the low group. From these data, hypercalcemia clearly reflected increased bone resorption [27]. Negative correlations were also seen between calcium concentration and PTH in the low group. Thus, the low group had more severe immobility, causing hypercalcemia which in turn suppressed PTH secretion; and compensatory hyperparathyroidism did not occur despite severe 25-OHD deficiency. Relatively low PTH may be one of the factors that suppressed renal synthesis of 1, 25-[OH]2D in the low group. Since 25OHD was a determinant of 1, 25-[OH]2D, substrate (i.e., 25OHD) deficiency may also have contributed to low serum 1, 25-[OH]2D. Previous studies reported that serum 25-OHD deficiency leads to a decrease in serum 1, 25-[OH]2D concentration in neurological patients with immobilizationrelated hypercalcemia [25,27,30,33]. In contrast to the low group, serum calcium concentration was low in the normal group, and this indicates that hypocalcemia due to 25-OHD deficiency may overshadow hypercalcemia due to milder immobilization. In fact, the average serum ICTP level in this group was lower than that in the low group. The longer duration of illness may have contributed to improved mobilization in these patients. Hypocalcemia leads to the development of compensatory hyperparathyroidism resulting in increased renal synthesis of 1, 25-[OH]2D; and negative correlation was observed between PTH and 25-OHD levels. Thus, serum PTH, calcium levels, and illness duration were determinants of serum 1, 25-[OH]2D concentration in the normal group. In both groups, 1, 25-[OH]2D correlated positively with illness duration and negatively with calcium. Negative correlations were also seen between illness duration and calcium in both groups. Serum concentrations of 1, 25[OH]2D may have been low in the early stage following stroke and subsequently increased during the chronic stage in both patient groups. Renal impairment is common after stroke and may have affected the activation of vitamin D and thereby BMD. Although there was no significant difference in serum creatinine levels among the patient groups,
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this does not exclude the role of renal impairment, and precise assessment of renal function by creatinine clearance or glomerular filtration rate [34] may be required to clarify the role. Thus, compensatory hyperparathyroidism in the normal group and insufficient correction of hypercalcemia in the low group may account for the prominence of calcium and illness duration as the determinants of 1, 25-[OH]2D; and PTH in the normal group and 25-OHD in the low group were also found to be determinants of 1, 25-[OH]2D. In our previous investigation of chronically disabled elderly patients following stroke, the most significant determinants of metacarpal BMD was serum levels of 25-OHD (mean, 11.5 ng/ml) [25]. In the present study, metacarpal BMD was lower in the normal group than in the low group, and BMD correlated negatively with 1, 25-[OH]2D and PTH only in the normal group. BMD differences between the two stroke groups may have resulted from hyperparathyroidism in the normal group, since hyperparathyroidism enhances renal synthesis of 1, 25-[OH]2D and decreases BMD, resulting in negative correlations of BMD with 1, 25[OH]2D and PTH in this group. Although the reason for lack of correlation between BMD and such variables in the low group is unknown, distribution of the subjects in a limited range may have resulted in a random dispersion. The results of the present study are important in that they have some therapeutic implications. In most patients with very low serum 25-OHD, treatment with relatively large dose of vitamin D is necessary [10,17]. We previously found only one fourth of acute stroke patients had sufficient serum levels of 25-OHD [35], and the preventive measures for fractures should be initiated in an acute stroke unit. Vitamin D metabolites, 1, 25-[OH]2D (calcitriol) [36] or 1a(OH)D3, are generally used to treat patients with abnormally low 25-OHD levels [17]; however, in the treatment of elderly patients with low 25-OHD, an alternative to vitamin D should be considered [37] since immobilizationrelated hypercalcemia may disturb calcium homeostasis[19,25,26]. In the low group, treatment with ergocalciferol, cholecalciferol, or dihydrotachysterols may be useful for correcting abnormally decreased serum 25-OHD, since one of the major causes of 1, 25-[OH]2D deficiency is 25OHD deficiency. Calcitonin [38] may be effective in correcting immobilization-induced hypercalcemia and improving renal production of 1, 25-[OH]2D in such patients. Bisphosphonates [39,40] may be also beneficial in preventing osteoclastic bone resorption due to immobilization, and we previously found, in patients with hemiplegia, that bisphosphonate etidronate markedly increase serum 1, 25[OH]2D by inhibiting immobilization-related hypercalcemia [41]. Thus, vitamin D formulations such as ergocalciferol combined with calcitonin or a bisphosphonate may be considered in stroke patients with low 1, 25-[OH]2D. The presence of compensatory hyperparathyroidism was obvious in the normal group, and exogenous 1, 25-[OH]2D should be avoided in such patients since it may further
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