Bone Resorption in Stroke and Institutionalized Subjects

Calcif Tissue Int (2009) 84:118 125 DOI 10.1007/s00223-008-9203-9 Bone Resorption in Stroke and Institutionalized Subjects Michael J. Haddaway Æ Natalie J. Bainbridge Æ Diane E. Powell Æ Michael W. J. Davie Received: 28 April 2008 / Accepted: 11 November 2008 / Published online: 14 January 2009 Ó Springer Science+Business Media, LLC 2009 Abstract Stroke increases the risk of hip fracture on the affected side. Although bone is lost by 1 year, rapidity of onset and relationship with immobility are uncertain. Using the bone resorption marker urinary cross-linked N telopeptide of type I collagen (untx), we examined bone resorption in the first 4 weeks after stroke, relating untx with bone density and mobility in subjects over 60 years. Two separate control groups acted as comparators, healthy (HC) and institutionalized (IC) controls, the latter to control for the effects of institutionalization. untx, urinary calcium (both related to creatinine and log-transformed), heel bone mineral density (BMD), Tinetti scores, and Barthel scores for prestroke function were measured. Log untx/cr was lower in males compared with females, but this difference was not evident in stroke or IC subjects. Log untx/cr was inversely related with BMD in females from both control groups and in male stroke subjects. Tinetti scores were divided into tertiles and were lower in stroke than IC subjects (P \ 0.01). Log untx/cr was similar in stroke and IC subjects in the lowest Tinetti tertile. Log untx/cr was higher in stroke subjects of both sexes in the lowest tertile compared with the higher two tertiles combined (P \ 0.05) and higher in all tertiles compared with HC subjects (P \ 0.05). Subjects with a prestroke Barthel index of B17 had higher log untx/cr compared with HCs. Log uca/cr was higher only in male stroke patients. Bone resorption in stroke starts early, and measures to reduce this are merited. M. J. Haddaway (&) N. J. Bainbridge D. E. Powell M. W. J. Davie Charles Salt Centre for Human Metabolism, Robert Jones & Agnes Hunt Orthopaedic NHS Trust, Oswestry, Shropshire SY10 7AG, UK e-mail: mike.haddaway@rjah.nhs.uk Keywords Stroke Fracture Urinary cross-linked N telopeptide of type I collagen Bone mineral density Mobility The effects of stroke on the skeleton have been the subject of several reviews in recent years [1 3]. Stroke not only leads to accelerated bone loss on the affected side [4 6] but may also be associated with low bone mineral density (BMD) in women at the time of the event [7, 8]. Stroke may be complicated by hip fracture in about 10% of cases [9]. A number of factors, including bone loss, lead to there being a significantly increased risk of fracture in the first 3 years after stroke, with hip fracture occurring at a median time of 24 42 months after the stroke event depending on geographical area [10 12]. The early incidence of fracture after stroke has encouraged studies with antiresorptive agents either orally [13, 14] or intravenously [15, 16]. It is unclear how rapidly bone resorption increases after the onset of stroke. Studies using type I collagen carboxyterminal telopeptide (ICTP) as a marker of bone resorption after stroke have yielded equivocal results. ICTP is commonly elevated in bone disease of neoplasia [17] but is neither elevated in postmenopausal osteoporosis [18] nor responsive to estrogen therapy [19]. An initial report in stroke patients suggested no elevation of ICTP in long-term stroke patients [20], whereas an increase was noted in the acute stroke period [21]. Analysis of the data, however, shows that there is no difference between the levels of ICTP in the two groups of stroke patients. The difference lies clearly in a significant disparity between values in the control groups of similar age (difference in means 1.748 ng/ml, 95% CI 1.04 2.45), and values in the control groups are high compared with other data [22, 23].

M. J. Haddaway et al.: Bone Resorption in Stroke 119 Given the uncertainty engendered by these studies, we have investigated bone resorption using the cross-linked N telopeptide of type I collagen in urine (untx) corrected for creatinine [24], higher values of which are associated with increased bone resorption. We studied both male and female patients within 28 days of the stroke event in order to examine the rapidity of onset of elevated bone breakdown. Whereas loss of bone density can only be detected reliably over periods as long as a year, bone resorption may be studied in the shorter term by measuring breakdown products of collagen. untx is inversely related to change of bone density in men [25] and in women [26]. The strength of the association varies between men and women and with the bone density measurement site, even within the upper femur [25 28], although peripheral bone density measurement sites are not so far represented. We measured bone density at the heel, a useful site in patients with stroke; investigated the relationship of bone turnover with degree of immobility immediately after stroke; and determined whether the expected relationship of untx with bone mineral density (BMD) is maintained. In chronic stroke patients BMD is reduced on the affected side [29, 30] and bone breakdown products correlate with BMD and with mobility. Whether this relationship pertains to the chronic immobility described by Theiler et al. [31] in institutionalized patients or whether there is an additional input due to stroke remains unclear. Bone is made up of both a mineral and an organic component. As well as measuring untx, we examined whether urinary calcium excretion (uca, corrected for creatinine) mirrored untx. Elevation of uca was found after stroke [32] in a study notable for the number of patients under age 60 years (68%) and for the excess of men (66%). We examined whether uca is elevated in men and women separately in a population aged over 60 years. Institutionalization itself may lead to elevated bone turnover markers [31], and we therefore compared results in patients with stroke with both healthy control (HC) subjects and institutionalized control (IC) subjects. Subjects and Methods Acute stroke (AS) patients (n = 197: 92 male, 105 female) were recruited from acute admission wards. Patients were included if the stroke event had taken place within the previous 28 days. Exclusion criteria included unconsciousness, stroke etiologies not associated with cardiovascular disease such as neoplasms (primary or secondary) or vasculitis, presence of cancer, transient ischemic attack, known Paget disease of bone, and age \60 years. A previous stroke did not exclude. Because we were interested in mobility, stroke cases were not categorized other than by their Tinetti score. ICs (n = 286: 218 male, 68 female) were recruited from nursing, residential, and day-care facilities. Apart from not having a stroke, entry criteria were the same as for stroke patients. They were recruited to ensure that the same environmental conditions would apply as for the stroke patients (institutionalized albeit for a longer time) and displayed varying levels of mobility with which to compare the stroke patients. HCs (n = 205: 128 male, 77 female) were subject to more stringent criteria. All had to be [60 years old and to have no known disease. Details of known medical condition, drugs and other medication, fractures (with site and dates), and falls in the previous month were recorded. All assessments except urine collection were performed at one visit. Ethics approval was given by the local research ethics committee. Patients either consented or had consent given by a carer if unable to do so themselves. BMD BMD was measured in all subjects using a PIXI mobile densitometer (GE Lunar, Madison, WI) at the heel. BMD was recorded in the left and right heels for all groups, and stroke side was noted in the stroke group. Dominance was recorded. Data from the HC group were used to derive BMD Z scores for the AS and IC groups. Mobility The AS and IC groups were assessed using the balance component of the Tinetti score [33]. This mobility index consists of five components (sit stand, standing balance, standing eyes closed, 360 o turn, and stand sitting), which in total give a score of 16. The HC group was not assessed as they would by definition achieve the maximum score. For the stroke patients, an additional subjective assessment was made of the prestroke mobility using the Barthel index of self-care and daily living, based on a maximum score of 20. This gave an estimate of the degree of the patient s mobility/ability immediately prior to the stroke. Biochemical Markers Samples from the second morning urine were collected from most subjects (137 AS, 43 female [47%] and 94 male [90%]; 189 HC, 118 female [92%] and 71 male [92%]; and 208 IC, 163 female [75%] and 45 male [66%]). These were mailed by ward staff or the subjects if they had been discharged (or if they were control subjects) to the laboratory on the day of collection. Samples were returned within 7 days of the BMD assessment (mean 4 days) in 84% of

120 M. J. Haddaway et al.: Bone Resorption in Stroke cases. Ward staff and patients were carefully instructed in collection protocol at the time of the assessment. On receipt, the ph was measured to check that conditions for Cr loss (ph 4.5 5.5) had not arisen, and the samples were stored at 20 C until analyzed. untx was measured using ELISA (Osteomark; Ostex International, Seattle, WA). untx was measured in nanomoles per liter bone collagen equivalents, and Cr in millimoles per liter, with the corrected quotient expressed as untx/cr (referred to as untx in the text). The characteristics of this assay have been previously described [24]. uca was measured using a cresolphthalein complexone method [34]. Results were expressed as creatinine corrected, Ca/Cr (referred to as uca in the text). Statistical Methods Grubb s test for outliers was applied to the distributions, and the Kolmogorov Smirnov test was used to detect whether a distribution was significantly different from normal. Both the untx and uca data required logarithmic transformation (log untx, log uca) to achieve a normal distribution. Figures quoted are the mean and SD unless otherwise specified. Comparison between two groups was performed using the t-test and for more than two groups by ANOVA. Correlation between variables was examined by Pearson s coefficient. Tinetti data were divided into tertiles. For some analyses data from the lowest tertiles were compared with data from the higher two tertiles combined. The Mann Whitney U-test was used for nonparametric data. In order to combine data from both sexes for BMD and for log untx, values of these variables were converted into Z scores using the HC values to provide the mean and SD for each 5-year period. The Z score is calculated as ([value in patient mean value for that age]/sd for that age: Note that a positive Z score for untx indicates a bone resorption rate higher than average). Z scores for subjects in the stroke and institutionalized groups were tested for difference from zero using the binomial test. All statistics were performed using SPSS v15 (SPSS Inc., Chicago, IL) apart from Grubbs test, which was performed on GraphPad (www. graphpad.com/quickcalcs). Results The subject group data are summarized in Table 1. Change of Log untx with Age There was no change with age in HCs in any age group or by gender or in males or females aged 60 90 years (ANOVA). Healthy subjects in different age cohorts were therefore pooled to compare different groups. ICs also exhibited no change of untx within the age range studied here. Log untx and Group Log untx was significantly elevated in both male and female AS patients in the acute phase compared with HC Table 1 Baseline data: mean and SD for different groups and outcome measures AS HC IC n Mean SD n Mean SD n Mean SD Female Age (years) 92 77.95 7.86 128 72.29 9.57 218 83.68 7.94 BMD (right heel, gm/cm 2 ) 92 0.39 0.13 128 0.44 0.12 218 0.34 0.14 Z score BMD (right heel) 92-0.18 1.13 128-0.04 0.96 218-0.21 1.23 Log uca a 40-0.36 0.45 119-0.48 0.35 159-0.39 0.38 Log untx a 43 1.99 0.26 118 1.77 0.29 163 1.90 0.34 Tinetti (median, range) 92 1* 0-15 217 9 0 16 Male Age (years) 105 74.21 7.79 77 72.99 8.37 68 82.60 7.37 BMD (right heel, gm/cm 2 ) 105 0.59 0.13 77 0.58 0.12 68 0.51 0.16 Z score BMD (right heel) 105 0.00 1.15 77-0.09 1.05 68-0.71 1.44 Log uca a 95-0.43 0.28 68-0.68 0.32 44-0.64 0.43 Log untx a 94 1.79 0.28 71 1.59 0.28 45 1.85 0.33 Tinetti (median, range) 103 6.5* 0 16 68 9 0 15 Note that Tinetti is shown as median and range since the distribution of mobility data is not normal a uca and untx are both corrected for Cr * P \ 0.01 (Mann Whitney U) compared with ICs

M. J. Haddaway et al.: Bone Resorption in Stroke 121 subjects (P \ 0.01 for both male and female). Log untx was significantly lower in healthy male subjects than in healthy females. In the acute aftermath of stroke, there was still a trend for values to be lower in males, but the difference between male and female was no longer significant. Values of log untx in stroke patients were, however, similar to values in IC subjects. Institutionalization also abolished the difference of log untx between male and females. Healthy subjects demonstrated lower log untx levels than institutionalized subjects (P \ 0.001 for all and for each sex). The legacy of stroke and of institutionalization on log untx appears to be more pronounced in men than in women. untx and Time Since Stroke Use of Z score of log untx, to enable male and female data to be pooled, did not reveal any statistically significant relationship (ANOVA, P = nonsignificant) between log untx and the time after the stroke that the assessment was made (Fig. 1). Correlation of untx with BMD At baseline, log untx correlated inversely with BMD in all groups combined (r =-0.35, P \ 0.01) and both genders (separately, r =-0.22 [male], P \ 0.01; r =-0.35 [female], P \ 0.001). Closer associations of log untx with BMD were seen in female (both healthy and institutionalized, P \ 0.01) subjects than in males (Fig. 2). Log untx was more strongly linked with BMD in male stroke patients (P \ 0.01). There was no significant difference between any of the regression line slopes between groups. Log untx and Mobility (Tinetti score) Tinetti score was lower in stroke than in institutionalized subjects in both males and females (Table 1). For purposes of investigating log untx and mobility, AS and IC subjects were grouped into tertiles of mobility. The lowest tertile had a median Tinetti value of 0.5, with no significant differences (in untx) between AS and IC (when sexes were combined, for the AS and IC groups, respectively). untx values were higher in the lowest tertile compared with healthy normal subjects (see Fig. 3). Values of untx were also higher in the lowest Tinetti tertile compared with the higher two tertiles combined (see Subjects and Methods ). Using Z score of log untx, values of untx in the higher two tertiles combined (median Tinetti = 9) were higher than in healthy normal subjects (P \ 0.01); and this finding still obtained when AS and IC subjects were examined separately (using the binomial test). The analysis remained significant for males and females investigated separately. Urinary Calcium After removing one outlier (female), log uca was normally distributed. Log uca was lower in males than females in the HC (P \ 0.01) and IC (P \ 0.01) groups. There was no difference in log uca between the HC and IC groups. Log uca values were higher only in male patients with stroke compared with HCs (P \ 0.01). Values of log uca in men with stroke were not different from those in women with stroke. Log uca was not different in stroke patients in the lowest tertile of mobility (Tinetti) compared with stroke patients in the higher two tertiles among either males or females. BMD BMD Z scores were not low in AS patients (Table 1). The BMD Z score of IC subjects was significantly below zero in all subjects (P = 0.001). This reduction in IC subjects was found in males (P \ 0.05) and females (P \ 0.05) independently. Prestroke Barthel Fig. 1 Log untx vs. time since stroke (TSI). Pooled data from male and female strokes, stratified into week after stroke that assessment was carried out. Cross-sectional data. No significant difference between groups by ANOVA. Note that more positive Z scores indicate higher rates of bone resorption Mean log untx was significantly higher (P \ 0.05) in patients with pre-barthel assessments of 17 or less compared with those achieving 18 or greater. Although the prestroke Barthel index was higher in some subjects, removal of subjects with prestroke Barthel indices of 17 or

122 M. J. Haddaway et al.: Bone Resorption in Stroke Fig. 2 Changes in log untx with BMD (right heel) for different groups and genders. R 2 values are shown where the correlation (Pearson) is significant (P \ 0.01) lower from subsequent analysis did not affect the significance of the elevation of untx in men and women with stroke. Discussion untx values in our HC men were within the range of mean values (28 46 nmol BCE/mmol Cr) found in other studies [28, 31, 35 38]. Results in HC women were very similar to the median range reported from our center [24] and within the range 34 68 nmol BCE/mmol Cr reported from other centers [28, 31, 35, 38 40]. Although HC subjects were younger than those in the other groups, no difference was found in untx ratios among the different age groups after age 60 years; and the results were therefore pooled. Other studies of subjects over 65 years either amalgamated untx data [36, 38] or showed no change in elderly subjects [35, 37]. Subjects from institutions were used as another control series, following the finding that institutionalized patients exhibited high levels of bone turnover [31], to compare stroke subjects with patients who might be in a similar environment, albeit for a longer time. Immobility is an important cause of increased bone turnover in institutionalized subjects [31], with those most immobile having the highest values of untx. Stroke patients, however, even when the most immobile were excluded, still displayed significantly higher untx compared with HCs. This lowest tertile group of stroke patients, consisting of Tinetti scores 1 and 2 (approximately equivalent to groups 4 and 5 of Theiler et al. [31]), had significantly higher untx than patients in the more mobile Tinetti groups. Acute immobility appears to exert a rapid and significant effect on bone turnover in acute stroke, equivalent to that found long-term in institutionalized subjects with poor mobility. Loss of mobility in stroke subjects does not necessarily bring about the same effects as other causes of limited muscle action on bone. Stroke induces greater loss in the upper limb and

M. J. Haddaway et al.: Bone Resorption in Stroke Fig. 3 Mobility vs. untx. Combining the IC and AS groups, log untx is raised in subjects in the lowest tertile (compared to the upper two tertiles combined) in men (P \ 0.01) and women (P \ 0.05). Dotted horizontal line indicates the mean log untx for HCs (male = 1.59, female = 1.75). Using Z scores of log untx, values for both tertile groups were significantly (P \ 0.01) above zero (from HC reference data). If values for each sex were separated out for males and females (Z scores), these were above zero (P \ 0.05) in the lowest tertile group and in tertile groups two and three combined proximal femur than at the calcaneus, whereas rapid loss of bone at the heel characterizes spinal cord injury and spaceflight [1, 41 43]. During spaceflight, untx (uncorrected for Cr) rises in most studies and remains elevated until the end of flight [43]. During bed rest, results are conflicting, with one study finding that untx (uncorrected for Cr) rises on days 1 and 2 of bed rest and falls thereafter [44], whereas other studies indicated prolonged elevation [43]. Our study, albeit cross-sectional, indicates that stroke is associated with a continued elevation of Cr-corrected untx over 28 days (Fig. 1). uca/cr results in our subjects are at variance both with previous studies on stroke and with spaceflight. The major finding in our subjects was the significant elevation in men with stroke compared to control subjects. Previous studies suggest that uca is elevated after stroke. This might be expected if the majority of patients were male [32], and taking the two sexes into account may explain the difference between our study and others. Similarly, most subjects in the space program have been male [41, 43]. Attention has also been drawn to the role of nutrition in stroke and to the risk of dietary energy restriction [1]. In subjects fed low-energy diets for obesity, elevation of urinary hydroxyproline [45], deoxypyridinoline [46], and serum CTx [47] has been noted, while a decline in BMD has also been reported under conditions of energy restriction [48]. Patients with stroke may have difficulty feeding, and bone turnover may increase as a result of energy restriction. Low vitamin D status in AS patients has also been described [21, 49], and such a state might be influenced by prestroke morbidity. Although we did not measure 25(OH)D, we did find that patients having a reduced Barthel index, estimated from prestroke activity, exhibited higher untx values poststroke. Prestroke morbidity may be important in assessing bone protection poststroke. Low BMD has been associated with acute stroke in women [7, 8] with a deficit of 8% at the femoral neck [8]. We have not, however, been able to extend this finding to the heel. Correlations between BMD and bone turnover markers, including untx, have been described in elderly healthy men and women. The relationship between BMD and untx depends on sex and the skeletal site selected, with untx being associated with about 2 10% of the variance in elderly men and women of BMD at the spine or the femoral neck [36, 50]. Our data in normal subjects tend to show a better relationship in healthy women than in men (Fig. 2), whereas stroke subjects behave in accordance with previously published data for healthy subjects. In both men and women the relationship shows that those with the lowest bone density display the highest rates of bone resorption. The corollary of this finding may mean that these patients not only are most likely to fracture but also resorb bone faster. There are a number of limitations with this study. Although the PIXI device is able to measure both the heel and the forearm and the forearm is potentially a site containing both cortical and cancellous bone, because we have used it in a peripatetic manner, operated single-handedly, the decision was made, partly on manual handling grounds, not to switch between the two functions. The choice of heel over forearm was also made as it was the site of our preliminary work with stroke patients [51]. We are investigating whole-body dualenergy X-ray absorptiometry in stroke, which will address the issue of cortical vs. cancellous bone density changes.

124 M. J. Haddaway et al.: Bone Resorption in Stroke Also, we have chosen to not publish results on the longitudinal changes in resorption markers following stroke as our objective in this study was to report on changes occurring in the early stages after stroke. We hope to report on available data up to 5 years in a subsequent publication. Although other authors have looked at different markers of bone resorption, we settled on the use of untx/cr because of our extensive previous experience in both the short- and long-term variation of this marker [24]. We were also influenced by the recommendation that serum CTx should be taken from a fasting specimen of blood [52], a sample that was much more difficult to achieve compared with a second morning urine since nurses were able to obtain specimens for the latter, though not for the former. Bone resorption in stroke patients increases rapidly after the event. It is greatest in those with the lowest bone density and in the most immobile. 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