1996 European Foundation for Osteoporosis. Osteoporosis. International. Original Article. Determinants of Bone Mineral Density in Immobilization: A Study on.
Osteoporosis Int (1996) 6:50-54 © 1996European Foundationfor Osteoporosis
Osteoporosis International
Original Article Determinants of Bone Mineral Density in Immobilization: A Study on Hemiplegic Patients A. del Puente 1, N. P a p p o n e 2, M. G. Mandes 1, D. M a n t o v a 1, R. Scarpa ~ and P. Oriente ~ 1RheumatologyUnit, Universityof Naples "FedericoII"; and 2FondazioneClinicadel Lavoro, CampoliM. Tabumo (Benevento),Italy
Abstract. Osteoporosis that develops during immoblization is a severe condition that confers increased risk of fractures with their burden of mortality and disability. The aim of this study was to investigate the determinants of immobilization osteoporosis. As a model of this condition we studied hemiplegic subjects, measuring bone mineral density in the paralyzed lower limb as compared with the non-paralyzed one. In spite of the limits related to the loss of nervous stimulation, this model offers the advantage of a proper control for the complex genetic and environmental cofactors involved. We examined 48 hemiplegic subjects (31 men, 17 women in menopause) admitted consecutively over a 9month period. Mean length of immobilization was 10.9 months for men (range 1-48 months) and 7.8 months for women (range 1-40 months). The average time since menopause was 14.9 years (range 1.7-23.9 years). For each subject the following were performed: questionnaire, medical examination, anthropometric measurements, evaluation of the scores for spasticity and for lower limb motor capacity in order to account for the different degrees of disability among patients. Bone mineral density was measured using dual-energy X-ray absorptiometry (DXA) at both femoral necks. For each patient we defined a percentage difference in bone loss between the paralyzed and non-paralyzed limb. Regression coefficient were calculated by multiple logistic regression. There was significant bone loss in the paralyzed limb in both sexes, accounting for up to 6.3% in women. Multiple regression analysis showed that the degree of bone loss depends significantly and directly on the length of immobilization, even when controlling for Correspondence and offprint requests to: AntonioDel Puente, MD, Cattedra di Rheumatologia, Facolt/t di Medicina, Universitg "FedericoII", Via S. Pansini,5, 1-80131Naples, Italy.Fax: 081-546 3445.
age and sex in the regression model (R = 0.193, p = 0.034). However, when time since menopause was included in the regression model, with length of immobility as a covariate, it was the only significant determinant of bone loss (R -- 0.312, p = 0.039). No additional factors were observed among men. No differences were shown with regard to anthropometric measurements or functional scores. Length of immobilization accounts only for a small fraction of bone toss, which does not exceed 5% of the total variance. Our data show that postmenopausal women should be considered at highest risk for osteoporosis in cases of immobility and that different factors, other than length of immobility, might come into play in determining bone loss in this condition.
Keywords: Hemiplegia; Immobilization; Menopause; Osteoporosis
Introduction Osteoporosis due to immobilization is a rapidly growing field of interest [1]. The increased survival rate following acute events such as stroke or cardiovascular accidents that reduce mobility, and the demographic changes in the general population that entail a growing percentage of more sedentary older age groups, have yielded an exponential increase in the number of individuals potentially affected by this problem [2]. The severe consequences of immobilization osteoporosis mainly fractures, with their burden of mortality and disability [3] - thus justify the growing interest in research on this pathology. Very little is known about the pathogenesis of
Bone Mineral Density in Immobilization
immobilization osteoporosis and, at present, length of immobilization is generally considered the main determinant of the process. This view does not explain several observations such as the significant interindividual variability of the demineralizing effect due to immobilization [4-7]. Length of immobilization itself was not found to be consistently correlated with the degree of demineralization [8]. A major problem in the interpretation of the studies in this field is the presence of several cofactors (genetic and/or environmental) which affect bone mineralization and make the selection of control subjects difficult. Therefore, in the present work, we used a model of immobilization already proposed in the literature [8,9], i.e. hemiplegic patients. In spite of the limitations related to the loss of nervous stimulation, this model offers the advantage of a proper control for the cofactors involved, by measuring bone mineral density in the paralyzed lower limb as compared with the nonparalyzed one. The aims of this study were: (1) to evaluate the difference in mineralization between the paralyzed and non-paralyzed lower limbs in individuals of both sexes, belonging to different age groups and immobilized for various lengths of time; and (2) to investigate the determinants of the degree of bone loss in this condition.
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comprised a subject's capacity for performing active movements and a mobility evaluation. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA; Hologic Q D R 1000) at both femoral necks [13]. For each patient we defined a percentage difference in bone toss between the femoral neck of the paralyzed limb and that of the non-paralyzed limb, which corresponded to the following ratio: [(normal B M D - p a r e t i c BMD)/normal BMD I. The values obtained are not normally distributed; therefore they do not meet the assumptions needed for linear regression analysis [14]. In order to calculate the correlations between degree of bone loss and other variables, the patients were then divided into two groups, using as a cut-off the median value of bone loss (equal to a 3% demineralization). Regression coefficients were computed by multiple logistic regression. The sample size was calculated assuming the conventional value of ¢=0.05 and a value of fl=0.20. The expected difference for the variables of interest between the groups studied was 10%. Given a standard deviation of up to 10% for such variable, the number of individuals needed for each group was calculated to be at least 16. Other statistical analyses included a t-test and computation of 95% confidence intervals (95% CI) for differences.
Subjects and Methods We examined 48 individuals suffering from hemiplegia due to stroke among those who were admitted consecutively to a specialized centre over a 9-month period. Exclusion criteria included an elapsed time of longer than 48 months since the stroke; women of childbearing age; pathologies or intake of drugs known to affect bone metabolism; and inability to maintain the correct position for bone densitometry according to the criteria for quality control our group complies with [10]. The participants were 31 men (mean age 59.0 years; range 27-84 years) and 17 postmenopausal women (mean age 64.6 years; range 52-74 years). Mean length of immobilization was 10.9 months for men (range 1-48 months) and 7.8 months for women (range 1-40 months). The average time since menopause was 14.9 years (range 1.7-23.9 years). Mean body mass index 2 was 26.6 among the men (range 21-35) and 27.5 (kg/m) among the women (range 18--46). After giving informed consent to participation, each individual underwent a medical examination, measurements of body weight and height, and was asked to answer a general questionnaire. Triceps and subscapular skinfold thicknesses were measured by a John Bull (British Indicators, UK) caliper on the left side of the body. To take account of the different degrees of disability among patients, we calculated for each subject their score according to the Ashworth scale for spasticity [11] and their scores of lower limb motor capacity according to Lindmark and Harmin [12]; the latter
Results Table 1 reports the mean value of BMD at the femoral neck of paralyzed and non-paralyzed limbs and mean percentage variations. There was significant bone loss in the paralyzed limb in both sexes, accounting for up to 6.3% in women. Similar significant percentage differences in mean BMD were observed at Ward's triangle (women = 5.1%; men -- 2.7%) and the trochanteric region (women = 4.2%; men = 3.3%). Data were then analyzed to investigate the factors affecting the degree of demineralization. We first examined the unadjusted data. Table 2 shows that the group experiencing the highest bone loss had been subject to a significantly longer immobilization than the group characterized by minimal BMD loss. It is noteworthy that women in the latter Table 1. Mean bone mineral density in gm/cmz (+SE) at the femoral neck of hemiplegic patients
Women (n=17) Men (n=31)
*p 3 % = 1). b Age and sex as covariates (not significant).
out to be a stronger independent determinant of the degree of bone loss than the length of immobility. No significant correlation was found with anthropometric measurements. The results were confirmed when including limb dominance as covariate in the regression models. Note also the lack of significant correlations between degree of bone loss and spasticity score (R = 0.0, p = 0.9), or scores of lower limb motor capacity for performing active movements (R = 0.0, p = 0.7) or for mobility evaluation (R = 0.0, p = 0.6), controlling for age and sex in the logistic regression.
Discussion Several authors have tried to quantify the percentage of mineralized tissue related to the persistence of mechanical stimulation. Experiments carried out with the techniques of limb immobilization (in the case of animal models) or forced bed rest (for human volunteers) found that bone loss ranged from 25% to 45% in 36 weeks in a study performed on 3 healthy volunteers [4], was about 16% in 42 days in rats [5] and ranged 30% to 50% after 40 weeks in dogs [6]. These losses are accompanied by a negative calcium balance. Bedridden patients develop hypercalciuria, a condition that persists throughout the whole period of forced rest. Calcium balance reveals a steady loss of about 200 mg/ day [4]. From a quantitative point of view, comparable results have been reported during space flights, with a loss of about 5.5 g/month of calcium, that is, about 0.4% of total calcium per month. This loss seems to affect mainly the lower limbs. Once again, the range of values is very broad. In flights lasting around 140 days, the range goes from a negligible 3.0% demineralization to a more significant value of 19.8% [7]. Immobilization osteoporosis has also been described in neurological patients [15]. In particular, hemiplegic patients are a useful model for studies of this condition [8,9] because they offer the advantage of a proper control for the complex genetic and environmental cofactors evolved: a comparison of the healthy limb
Bone Mineral Density in Immobilization with the paralyzed limb. The first result of the present study shows, in a sample of such patients, a significant reduction in BMD of the paralyzed lower limb compared with the non-paralyzed one. The result has been confirmed in both sexes. Two other studies have previously been carried out on hemiplegic patients, showing a demineralization of the paralyzed lower limb of about 4% compared with the healthy limb. The first study [9] reported on a relatively small sample of participants who were immobilked for the same length of time. The conclusions do not refer to bone mineral "density" measurement, but to bone mineral "content", which does not account for the size of the measured site. The second study [8] examined a group of men who had been immobilized for an extremely wide range of periods. The authors evaluated lower limb densitometry, deriving it from a total body examination and therefore including in the measurement the whole lower limb and the hemipelvis. In both studies the densitometry was performed with a dual-photon absorptiometry. In the present study, we examined a sample of statistically adequate size. An X-ray densitometric technique (DXA) was used, the precision and accuracy of which are significantly higher and those of the dualphoton techniques [13]. We evaluated BMD at the femoral neck, which is the area of the lower limb with the highest percentage of trabecu!ar bone and the highest fracture risk. In our sample, the factors affecting the degree of bone loss were investigated. Our data indicate the importance of length of immobilization, which is significantly related to the degree of lower limb damage. This result has not previously been reported in hemiplegic patients. In fact, only one of the abovementioned studies [8] has investigated this aspect, but the authors found a positive association only when using a linear regression analysis, which cannot be considered the approach of choice in this case. Hemisparesis can affect mobility to a greater or lesser extent. For example, it is highly likely that these patients, as a group, showed lower general physical activity levels, and there may have been an effect of this even on the unaffected side. Thus, the total amount of bone lost may have been greater than what could be determined by comparing sides. In our sample mobility scores did not associate significantly with degree of bone loss, ruling out the confounding effect on mineralization in both limbs due to the different degrees of disability among patients. With regard to this point, it is important to recall that when the physiological mechanical stimulus on the bone is abolished, as was the case for the paralyzed limbs in our sample, muscle and bone loss occur in spite of intense physical exercise regimens [16], Therefore, in all immobilized patients, the therapeutic approach to osteoporosis should not be limited to rehabilitation techniques. Degree of bone loss did not correlate with anthropometric measurements, although data in postmenopausal women suggest an effect of body fat on bone metablism [17].
53 Length of immobilization itself accounts for only a small fraction of bone loss, which does not exceed 5% of the total variance (Table 3). That is, after an equal immobilization time, there is an extreme interindividual variability in response. This observation suggests that other factors influence the degree of bone loss following immobilization. From this point of view, while no additional factors have been observed among men, our study has emphasized the importance in women of the time elapsed since the beginning of menopause, which is inversely proportional to the degree of bone loss. This parameter has turned out to be significantly more important as an independent determinant of bone loss than the length of immobilization itself. During menopause, dramatic changes occur in the pattern of sex hormones [18]. These changes accelerate bone turnover by removing the inhibitory effect of oestrogens on osteoclast activity [19]. These conditions might therefore make bone metabolism more susceptible to the additional insult represented by the reduction in the physiological mechanical stimulus on bone. A strict analogy can be made vdth the relatively severe deficits that develop with immobilization during adolescence, suggesting the importance of the baseline state of bone turnover. In conclusion, our data suggest that postmenopausal women should be considered at highest risk for osteoporosis in cases of immobility. The identification of other factors that play a role in immobilization osteoporosis might help to define the profile of high-risk subjects who require closer follow-up and more aggressive treatment in cases of immobilization. The impact of this piece knowledge on the approach to the sedentary patient remains to be evaluated.
Acknowledgements. This study was financiallysupported by a grant from the Italian Space Agency(grant no. ASI 92RS95).
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Received for publication 8 March 1995 Accepted in revisedform 22 August 1995
