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Biochemical markers of bone activity in active and sedentary spinal cord injured men.

Introduction

Disruption to the flow of information from the central nervous system and a marked lack of gravitationally influenced mechanical stresses create a unique form of osteoporosis in spinal cord injured (SCI) persons (1-4), characterised by a specific pattern of bone loss below the level of the lesion (5-7). Typically up to 33 per cent of bone mass is lost within the first six moths of injury, stabilizing to approximately 66 per cent of the original bone mass by 12 to 16 months post-injury, which is considered to be close to the fracture threshold of bone (7).

In the able-bodied population, bone mineral density is maintained by physical activity and the combination of force exerted via the long bones and active muscle tensions (8-10). The immobility as a result of spinal cord injury means that any physical activity has to be performed in the seated position thereby removing the gravitational influence on physical activity. Although bone mineral density has been measured in SCI individuals using dual energy X-ray absorptiometry (DXA), this technique does not provide an indicator of bone activity at the cellular level. Previous research using biomarkers of bone activity in SCI have focused on changes in bone mineral density from initial injury to rehabilitation (4, 11,12), but have not investigated the influence of exercise on bone mineral turnover.

In this research we have investigated the use of two bone biomarkers, one for bone reabsorption (urinary deoxypyridinoline, Dpd) and the other for bone formation (bone specific alkaline phosphatase, BAP) in sedentary and physically active SCI men, to establish the rate of bone turnover. This will provide an insight into the effects of active versus sedentary lifestyles in SCI individuals and may have implications in the future treatment of these injuries.

Materials and methods

Participants

Fifteen SCI males participated in this study. Fourteen were chronic, post-traumatic SCI and one classified as sensory and motor incomplete as a result of spinal artery thrombosis (Table 1). They were assigned to one of two groups, active (n=11) or sedentary (n=4) according to their self-reported weekly activity.

The active group reported a mean activity of 12.2 hours/week ([+ or -] 6.0) whereas the sedentary group did not report any significant physical activity. Physical activity levels were assessed using a questionnaire. Ethical approval for this research was obtained from the Otago Southern Regional Health Authority Ethics Committee.

Bone biomarkers

For the bone reabsorption marker, the Dpd concentration was determined using a PyrolinksTM (Metra Biosystems, Mountain View, California) immuno-assay kit from the first void morning urine sample, according to the manufacturers instructions. All urine samples were measured in duplicate and the results expressed as nmol Dpd/mmol creatinine (13).

To determine the rate of bone formation, the bone alkaline phosphatase (BAP) was measured in serum using a competitive immunoabsorbent assay specific for BAP (Metra Biosystems Alkphase-BTM , Mountain View, California). Results were expressed as U/l (14,15).

Statistical analysis

All statistical tests were undertaken using the SPSS statistical package (SPSS Inc, v14.0, Chicago, IL). Shapiro-Wilk testing of normality of data distribution was undertaken. Data for TPI, BAP and Dpd were found to violate the assumption of normality of distribution, therefore non-parametric tests were performed.

Mann-Whitney U tests were used to detect significance between the active and the sedentary groups for TPI, activity levels, bone reabsorption and bone formation. Spearman rank order correlation was used to detect relationships between tome post injury, activity levels, bone reabsorption and bone formation in combined data (n=15) and for the active group (n=11); numbers were to small to perform correlational analysis in the sedentary group (n=4). Significance was accepted at p<0.05.

Results

Demographic details for all participants is presented in Table 1. Data are presented as mean + standard deviation (SD) for clarity, with significance values reported from the Mann-Whitney U test or Spearman correlational analysis. The self reported activity levels between the active and the sedentary groups for time spent exercising per week was significant (12.2 [+ or -] 5.6 vs 0 hours per week, p<0.01), as expected. Sedentary SCI had sustained their injury for a longer duration than the active SCI group (27.0 [+ or -] 14.8 vs 9.6 [+ or -] 9.0 years, p<0.05), and were older (50 + 10 vs 29 + 6 years, p<0.01), respectively

[FIGURE 1 OMITTED]

Bone re-absorption

No significant differences were found for the bone reabsorption marker between the active and the sedentary SCI groups (p>0.05). However, the mean Dpd concentration in the active group (16.8 nmol/mmol creatinine [+ or -] 10.3) was higher than that in the sedentary group (11.8 nmol/mmol creatinine [+ or -] 5.4). In the active group, a moderate positive correlation that approached significance was found between TPI and bone resorption (r=0.57; p=0.065).

Bone formation

BAP activity in the sedentary SCI men was significantly higher than those of the active group (sedentary: 28.0 [+ or -] 6.4 U/l; active: 14.0 [+ or -] 3.6 U/l, p<0.01). When data were combined (n=15), significant correlations were found between bone formation and activity hours (r=-.51, p<0.05; Figure 1) and TPI (r=0.60, p<0.05).

Discussion

Early bone loss associated with spinal cord injury is from the entire skeleton with osteopenia prevalent primarily below the level of the lesion. It would be anticipated therefore that the bone biomarkers, such as Dpd and BAP would give an indication of the net changes of bone cellular activity (16).

Sedentary SCI subjects in this study had higher bone marker formation (BAP) rates than the active SCI subjects, a result which contrasts with studies in able-bodied athletes, in whom exercise has had a positive influence on bone density formation (9,10). While the sedentary SCI group in this study had higher bone formation rates, they had also sustained their injury for a longer time and were older. Previous research has shown that bone formation decreases progressively to a low at 60 days post-injury and reaches a new steady state at approximately 16 to 24 months post-injury (1,11,17), which is maintained to at least 10 years post-injury (7). Bed rest per se is not reported to influence the BAP marker, although these negative findings may have been influenced by the presence of other forms of alkaline phosphatise (18,19).

It is difficult therefore, to ascertain what influence (if any) exercise is having on these subjects. It may well be that duration of the injury plays a greater role in maintaining normal bone formation rates and that the active group may approach these rates later on. This is supported; in part when the sedentary and the active groups are combined, as a significant correlation (r=0.60, p<0.05) was found suggesting bone formation rates increase with time post injury. Conversely, combined group data demonstrated that as activity hours increased, bone formation rates decreased which may be due to the total amount and intensity of exercise being undertaken by the active group.

Previously, it has been reported that bone formation decreased in able-bodied men and women for up to two days following a single session of endurance exercise, but returned to normal activity thereafter (20). In the SCI

subjects in the present study, repetitive bouts of exercise may have had a compounding effect on bone remodelling, preventing a return to baseline formation levels. Sedentary SCI in this study had bone formation rates within the population reference range.

Whilst not statistically significant (p=0.85), the bone reabsorption marker (Dpd) had a higher concentration in active SCI compared with the sedentary group (mean - 16.2 + 10.3 vs 11.8 + 5.4 nmol Dpd/mmol creatinine, respectively). Both groups had values outside the able-bodied males reference range (2.5 to 5.5nmol Dpd/mmol creatinine). Whilst a transient increase in bone reabsorption biomarkers has been identified in able-bodied athletes following intensive exercise (20), both the SCI groups in the present study demonstrate a high level of continuous bone reabsorption.

Although not statistically significant, a trend towards increasing bone resorption with the duration of injury was observed for the active group, but no such association was evident with total activity hours. Previous research has utilised data modelled on mathematical regressions lines deduced from DEXA measurements to predict bone mineral activity. This method, linked to the use of electrically stimulated exercise, has been shown to improve muscle function but does not however, improve the prediction of decreasing bone mineral density in the SCI (21-23), leading to an underestimation in bone reabsorption.

A significant limitation in this study was the low number of sedentary SCI, which did not allow a more rigorous statistical investigation of the data. Despite this, the results presented do provide evidence that remodelling dynamics differ in SCI individuals and vary dependant on physical activity and duration of injury. Further work to validate these results needs to be undertaken, extending these preliminary findings to a larger athletic SCI population to establish how duration and intensity of exercise, and age and duration of injury may affect bone remodelling. We also would caution the use of single measurements of biomarkers of bone remodelling in the SCI population who clearly demonstrate different bone dynamics than seen in the able-bodied population.

Acknowledgement

We are grateful to Dr Gordon Sleivert, Gatrorade Sports Science Institute, Barrington, Illinois, USA for his helpful discussions.

References

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(2.) Hill EL, Martin RB, Gunther E, Morey-Holton E, Holets VR. Changes in bone in a model of spinal cord injury. J Orthop Res 1993; 11: 537-47.

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Lynnette M Jones [1], PhD, Lecturer

Michael Legge [2], PhD, Associate Professor

[1] School of Physical Education

[2] Departments of Biochemistry and Pathology, University of Otago, Dunedin, New Zealand

Author for correspondence: Lynnette Jones, School of Physical Education, University of Otago, PO Box 56, Dunedin 9054, New Zealand. Email: lynette.jones@otago.ac.nz
Table 1. Characteristics of male spinal cord injured subjects

             Age        TPI        Level        Exercise
Subject    (Years)    (Years)     of lesion     (Hrs/wk)

1             26         4        C6/7 (I)          4
2             31         9        C5/6 (I)         11
3             35         19       C5/6 (C)         12
4             32         18       C5/6 (C)        22.5
5             28        12.5      C5/6 (C)         16
6             19         4        C6/7 (C)         10
7             23         4        C5/6 (I)         12
8             40         29        T5 (I)           5
9             31         1        L1-3 (C)         12
10            23        1.3      T12/L1 (I)         8
11            33        1.8        L1 (I)          22
12            58         36        T6 (C)           0
13            35         5         T12 (I)          0
14            51         32       C8/T1 (I)         0
15            54         35      T12/L1 (C)         0

(I) = Incomplete; (C) = Complete; TPI = time post injury
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Author:Jones, Lynnette M.; Legge, Michael
Publication:New Zealand Journal of Medical Laboratory Science
Article Type:Report
Geographic Code:8NEWZ
Date:Aug 1, 2009
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