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Am J Physiol Endocrinol Metab 290: E1098-E1103, 2006. First published January 17, 2006; doi:10.1152/ajpendo.00250.2005
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Relationship of fat mass and serum estradiol with lower extremity bone in persons with chronic spinal cord injury

William A. Bauman,1,2,3,4 Ann M. Spungen,1,2,3,4 Jack Wang,5 Richard N. Pierson, Jr.,5 and Ernest Schwartz1,2

1Department of Veterans Affairs Rehabilitation Research and Development Center of Excellence; 2Spinal Cord Damage Research Center and 3Medical, Spinal Cord Injury, and Research Services, Veterans Affairs Medical Center, Bronx; 4Departments of Medicine and Rehabilitation Medicine, Mount Sinai School of Medicine; and 5Body Composition Unit, Columbia University-St. Luke's/Roosevelt Hospital Center, New York, New York

Submitted 3 June 2005 ; accepted in final form 29 December 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
In the spinal cord injury (SCI) population, a relationship between adiposity and leg bone has not been reported, nor one between serum estradiol and leg bone mass. A cross-sectional, comparative study of 10 male pairs of monozygotic twins discordant for SCI was performed. Relationships were determined among bone mineral density (BMD), bone mineral content (BMC), lean mass, fat mass, and serum sex steroids. In the twins with SCI, significant relationships were evident between leg BMD or BMC with total body percent fat (r2 = 0.49, P < 0.05; r2 = 0.45, P = 0.05), leg fat mass (r2 = 0.76, P < 0.0005; r2 = 0.69, P = 0.005), and serum estradiol (r2 = 0.40, P = 0.05; r2 = 0.37, P = 0.05). By stepwise regression analysis, in the twins with SCI, leg fat mass was found to be the single most significant predictor of leg BMD or BMC (F = 12.01, r2 = 0.76, P = 0.008; F = 50.87, r2 = 0.86, P < 0.0001). In the able-bodied twins, leg lean mass correlated with leg BMD and BMC (r2 = 0.58, P = 0.01; r2 = 0.87, P = 0.0001). By use of within-pair differences, significant correlations were found for leg lean mass loss with leg BMD loss (r2 = 0.56, P = 0.01) or leg BMC loss (r2 = 0.64, P = 0.0005). In conclusion, in twins with SCI, significant correlations were observed between fat mass and leg BMD or BMC as well as between serum estradiol values and leg BMD. The magnitude of the leg muscle mass loss was correlated with the magnitude of bone loss.

bone mineral density; bone mineral content; lean mass; estrogen; paraplegia

IN THE ABLE-BODIED POPULATION, increased body weight has been associated with increased bone mass (13, 26, 36, 39). Bone mineral density (BMD) has been hypothesized to be related to the gravitational effect of body weight and/or enhanced estrogen production due to adiposity (12, 13, 17–19, 22, 34, 35, 39). In several cross-sectional observational studies, estradiol has been found to correlate positively with regional BMD (17–19, 31, 35, 36). In a twin study, 60–80% of the individual variances of both femoral neck BMD and lean mass were attributed to genetic factors, with significant associations between BMD and lean mass in the same individual (29). Persons with chronic spinal cord injury (SCI) have a reduction in lean mass and bone below the level of lesion (32, 33) associated with a relative increase in whole body and regional adiposity (32). For those with SCI who are unable to stand or ambulate, reduction of gravitational and mechanical forces would be expected to attenuate the association between leg muscle mass and BMD or bone mineral content (BMC). A relationship between adiposity and bone below the level of lesion has not been reported in the SCI population and, if found, may suggest a possible hormonal mechanism due to fat cell conversion of precursor sex steroids to estrogens. Employing a monozygotic twin model discordant for SCI, we hypothesized that, in the twins with SCI, there would be loss of the relationship between leg muscle and bone, possibly allowing for an association to be evident between leg bone and measurements of body adiposity, as well as circulating estrogenic compounds.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. Ten male pairs of monozygotic twins discordant for SCI were recruited for study. All twins with SCI had complete motor injuries and were unable to bear weight, preventing ambulation and other activities requiring weight bearing. Except for one subject who used an electric wheelchair, all other subjects used their arms daily in wheelchair-related activities. At the time of study, all subjects were in good health without comorbidities. None was prescribed any medications known to effect bone (e.g., glucocorticoids, bisphosphonates, etc.).

Genetic testing for zygosity was performed in all pairs at six independent, highly polymorphic loci (Lifecodes, Stamford, CT). The data of all 10 pairs were found to be strongly consistent with monozygosity, with a probability of being nonidentical of 1 in 4,096. Institutional Review Board approvals from the Veterans Affairs Medical Center, Bronx, NY, and the Mount Sinai School of Medicine, New York, NY, were obtained before the study was initiated. The subjects were provided with verbal and written information about the study, and written consent was obtained.

Body composition. Dual-energy X-ray absorptiometry (DEXA; model DPX; Lunar Radiation, Madison, WI) was performed to determine tissue compartments by using a total body scanner with standard methods (14, 25, 27, 40). The total body scan was performed by using a DEXA scanner with software version 3.6z and medium scan mode with subjects positioned lying supine on the scan table, as described in the Operational Manual provided by Lunar to users. To minimize the risk of bias by the scan operator, all scan analyses for positioning of the cutting lines to generate regional body composition and bone mineral values were generated automatically and then manually adjusted on all subjects by a single certified DEXA technician to capture the entire limb. The reproducibility expressed as intrasubject standard deviation is 0.9% for fat percentage and 0.0113 gm/cm2 for bone density. Subjects, wearing only a hospital gown and without shoes or jewelry, were asked to lie on the scanning table. Whole body scanning was performed with a congruent beam of stable dual-energy radiation at 40 and 70 keV. The ratio of absorption between the two X-rays of different energies is linearly related to the densities of the fat, soft-tissue lean, and bone, providing a quantitative estimate for each compartment. The procedure for scanning was ~30 min in duration. Total (minus the skull) and regional bone mineral content (BMC) and bone mineral density (BMD) were measured by DEXA. The DEXA software calculated the masses of lean and fat tissue. The precision and accuracy of DEXA for soft tissue has been reported to be 99% with <1% error (23).

Hormonal assays. Blood samples were collected once in the morning before the DEXA scan. Blood for hormone determinations was immediately placed on ice prior to separation by centrifugation at 4°C. The serum or plasma samples were stored at –30°C until assayed. Estradiol concentration was determined by an ImmunChem radioimmunoassay (RIA; mean intra-assay CV = 8.2%; ICN Biomedical Institute, Costa Mesa, CA). Estrone and estrone-sulfate (estrone-s) were assayed by standard RIA (mean intra-assay CV = 6.5 and 6.2%, respectively; Diagnostic Systems Laboratories, Webster, TX). Serum growth hormone was performed by an ImmunChem RIA (mean intra-assay CV = 7.0%; ICN Biomedical Institute). Plasma insulin-like growth factor I (IGF-I) analysis was performed by commercial kit assay using a nonextraction immunoradiometric assay method (mean intra-assay CV = 2.6%; Diagnostic Systems Laboratories). Serum total testosterone was assayed by commercial RIA kit (mean intra-assay CV = 10.9%; ICN Biomedical Institute). Sex hormone-binding globulin (SHBG) was determined by RIA kit (mean intra-assay CV = 2.6%; Diagnostic Systems Laboratories). Serum albumin was measured by autoanalyzer methodology (Beckman Ly 20; Synchron, Brea, CA) by a colorometric assay in the chemistry laboratory of the medical center. The serum free testosterone level was calculated using a standard formula (38). For each determination, all assays were batched and run simultaneously.

Statistical analyses. The results are expressed as means ± SD. Within-pair differences were determined by paired t-tests for comparisons on the continuous variables. The intrapair differences (IPD; SCI minus non-SCI twins) were calculated for leg BMC, leg BMD, and leg lean mass and leg fat mass; as such, a larger negative score expresses a greater difference between a twin pair and thus a greater loss for the SCI twin. Linear regression analyses were used to determine the relationship between appendicular BMD and BMC with regional tissue compartments (fat and lean masses), body mass index (BMI), total body percent fat, and hormones. Stepwise regression was performed to determine the significant predictor(s) of leg BMD.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
The average age of the twins was 41 ± 9 yr, with a range of 25–58 yr (Table 1). The duration of injury of the SCI twins was 16 ± 9 yr, with a range from 1 to 26 yr. Comparing the SCI and non-SCI twins, there was no significant difference for height, but body weight was greater in the non-SCI twins and approached significance (P = 0.06; Table 1). BMI was significantly higher in those with SCI compared with the non-SCI twins (P < 0.05).


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  		Table 1. Demographic characteristics of the twin pairs

 
The results for total and regional BMD, BMC, lean mass, fat mass, and percent total body fat mass are reported in Table 2. Total body and leg BMD, BMC, and lean mass in twins with SCI were significantly less than in the non-SCI twins, whereas there was no significant difference found for the arm. A comparison within each pair of the twins for arm and leg BMD and BMC is provided in Fig. 1. In the SCI twins, total body percent fat approached significance (30 ± 12 vs. 24 ± 10%, P = 0.054). For total body and leg, but not arm, the ratio of fat mass to lean mass was significantly higher in the SCI twins (Table 2).


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  		Table 2. Body composition data

 

Figure 1
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  		Fig. 1. Arm and leg bone mineral density (BMD) and bone mineral content (BMC) in each set of twin pairs. A: arm BMD; B: arm BMC; C: leg BMD; D: leg BMC. bullet, Spinal cord injury (SCI); {circ}, non-SCI.

 
A comparison of the hormone data for the twin groups is shown in Table 3. No significant differences were noted between the groups for any of the variables studied, but IGF-I and free testosterone tended to be lower in the twins with SCI, whereas total estradiol and estrone tended to be higher (Table 3). There were no significant differences between SCI and non-SCI twins for serum albumin or for SHBG (Table 3) or the ratio of estradiol to SHBG (E2/SHBG), a surrogate measurement of bioavailable estradiol.


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  		Table 3. Results of hormones and binding proteins

 
In the twins with SCI, leg BMD and leg BMC were highly correlated with the measurements of total body fat (Table 4) and leg fat (Fig. 2, A and B, and Table 4). Leg lean mass was correlated with leg BMD and leg BMC, albeit failing to reach significance (Fig. 2, C and D, and Table 4). Serum total estradiol, but not bioavailable estradiol, was significantly associated with leg BMD (Table 4). Serum total estradiol was correlated with leg fat mass and measurements of total body adiposity (Table 5). As expected, leg fat mass was highly correlated with both total body fat mass and percent body fat (r2 = 0.85, P < 0.0001; r2 = 0.72, P < 0.001). By stepwise regression, leg fat mass was found to be the single most significant predictor of either leg BMD (F = 25.99, r2 = 0.76, P = 0.0009) or leg BMC (F = 17.24, r2 = 0.69, P = 0.0032); total estradiol was not a significant predictor of any parameters of leg bone. Using the intrapair difference score in the SCI twins, leg lean mass loss was directly associated with leg BMD loss (r2 = 0.56, P = 0.01) and leg BMC loss (r2 = 0.64, P = 0.00037; Fig. 3, A and B). Duration of injury, but not age, was significantly related to loss of leg lean mass (r2 = 0.49, P = 0.02), leg BMD (r2 = 0.53, P = 0.01), and leg BMC (r2 = –0.53, P = 0.01).


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  		Table 4. Correlations of measurements of adiposity and lean mass with bone

 

Figure 2
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  		Fig. 2. Correlations in the leg between soft tissues and BMD and BMC. In SCI twins, there was a strong association between leg BMD and BMC with leg fat. In non-SCI twins, there was a strong association between leg BMD and BMC with leg lean mass. A: leg fat mass vs. leg BMD (SCI: slope = 3.699E-5; r2 = 0.76, P < 0.0005; non-SCI: slope = 4.368E-6, r2 = 0.02, NS). B: leg fat mass vs. leg BMC (SCI: slope = 0.042, r2 = 0.69, P < 0.005; non-SCI: slope = 0.024, r2 = 0.13, NS). C: leg lean mass vs. leg BMD (SCI: slope = 2.209E-5, r2 = 0.14, NS; non-SCI: slope = 2.583E-5, r2 = 0.92, P < 0.05). D: leg lean mass vs. leg BMC (SCI: slope = 0.025, r2 = 0.34, NS; non-SCI: slope = 0.059, r2 = 0.86, P < 0.0001). bullet, SCI; {circ}, non-SCI. Significant correlations are represented by solid line, nonsignificant by broken line.

 

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  		Table 5. Correlations of measures of adiposity and estradiol

 

Figure 3
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  		Fig. 3. Relationships between intrapair difference (IPD) scores for leg lean mass and leg BMD and BMC. In SCI twins, there were strong relationships between leg lean loss and loss of BMD or BMC. A: IPD score for leg lean loss vs. BMD (slope = 2.89E-5, r2 = 0.56, P = 0.01). B: IPD score for leg lean loss vs. BMC (slope = 0.043, r2 = 0.64, P = 0.00037).

 
In the non-SCI twins, leg BMD and leg BMC were positively correlated with leg lean mass (Fig. 2, C and D, and Table 4) but not leg fat mass (Fig. 2, A and B). None of the measurements of total or regional adiposity correlated with leg BMD, although leg BMC was correlated with weight and BMI (Table 4), reflecting body size. By stepwise regression analysis, leg lean mass was found to be the single significant predictor of leg BMD (F = 12.01, r2 = 0.58, P = 0.008) or leg BMC (F = 50.87, r2 = 0.86, P < 0.0001). Estradiol in the non-SCI twins was not significantly correlated with leg lean mass (r2 = 0.01), nor were any of the measurements of total body adiposity (Table 5).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Our primary finding was that leg BMD and BMC were strongly correlated with leg fat and total body fat in twins with SCI, whereas no such correlation was found in the able-bodied (non-SCI) twins. A trend toward higher serum total estradiol in the SCI twins was found, which may be related to increased total body adiposity. In twins with SCI, a significant correlation was found between total serum estradiol and leg BMD. Although not addressed in this report, estrogen may have been generated by leg fat mass, and it may be speculated to have a regional effect on leg bone in the twins with SCI. A secondary finding was that lean leg mass correlated in a similar manner with leg bone mass in both twin groups, although just missing significance in SCI twins.

Increased body weight or BMI has been associated with increased bone mass in women, especially postmenopausal women, but less so in men (8, 13, 21, 24, 36, 39). In the male, the testes account for 15% or less of circulating estrogens (30). Adipose tissue has aromatase activity and is a major source of peripheral conversion of circulating androgen precursors to estrogen (20, 30), with aromatase-deficient men being osteopenic (17). In cross-sectional observational studies in elderly men and women, estradiol, and in particular bioavailable estradiol, has been found to correlate positively with BMD at multiple skeletal sites (17–19, 31, 35); even in men, serum testosterone has not correlated as well as estrogen with BMD. The acute pharmacological ablation of estrogen in elderly men has been reported to increase markers of bone resorption and to suppress markers of bone formation (9). A threshold level for a skeletal estrogen effect to suppress bone resorption and bone loss has been suggested in elderly men, with bioavailable estrogen values below 11 pg/ml demonstrating a significant inverse association between serum bioavailable estradiol levels with markers of bone resorption, a relationship that is absent in those with estradiol levels above this cut-off point (17, 18). Subsets of persons with SCI have been shown to have a reduction in endogenous anabolic hormones testosterone and growth hormone (2, 4, 15, 37). Several etiologies of relative or absolute androgen deficiency may occur in the SCI population, including poor health, malnutrition, adverse medication effects, and higher level and longer duration of injury. In our twins, serum estradiol levels were all above 40 pg/ml and were not estrogen deficient (18). At this time, it is not known whether augmentation of normal levels of estrogen into the supraphysiological range, or possibly administration of a selective estrogen receptor agonist, will have a beneficial effect upon bone loss effect in men with SCI (6).

Although not addressed in our report, and contrary to the positive association of peripheral fat mass with bone mass demonstrated herein, animal studies on disuse osteoporosis have shown an increase in bone marrow fat content. In a rodent model of weightlessness by hindlimb suspension, an accumulation of marrow fat was found to be associated with a diminished rate of longitudinal bone growth, reduced mass of mineralized tissue, and a reduced number of osteoblasts (41). Marrow fat was also increased in rats after spaceflight (16). Osteoblasts and adipocytes are derived from a common bone marrow progenitor cell. As with peripheral fat, marrow fat has been shown to convert androgen to estrogens (10). In a mouse progenitor cell line, estradiol stimulated the differentiation of these cells to osteoblasts and inhibited the formation of adipocytes (5). The exact relationship of marrow fat to the rapid bone loss after acute immobilization due to SCI has not been defined, and such studies would be an area of interest to pursue.

In a prior report from our group on monozygotic twins discordant for SCI (32), a loss of leg muscle mass was described that was continuous and directly correlated with duration of injury. In the present study, our previous findings have been confirmed in additional twin pairs. Correlations between altered body composition and the level of SCI have been observed, with successively higher, more complete spinal cord lesions associated with decreased lean mass (26). There is a high genetic contribution to both BMD and lean mass (29). In our twin pair model discordant for SCI, a strong correlation was shown between the intrapair difference scores for leg lean mass with leg bone, showing a strong relationship between muscle loss and bone loss. Although such a relationship may have been postulated from studies in the able-bodied (7), this finding has previously not been demonstrated in persons with SCI. Significant associations were previously described for leg BMC with leg lean tissue mass in those with either complete or incomplete motor SCI (33) and are also shown in this report, albeit not reaching significance. The relationship between leg lean mass and leg BMD appears similar in SCI and non-SCI groups. A relative reduction of anabolic hormones may contribute to increased adiposity and decreased muscle mass (3, 28). In the study herein, loss of lean body tissue in twins discordant for SCI resulted in a relative increase in the ratio of body fat to lean tissue in SCI compared with non-SCI twins. We have previously described a greater increase in adiposity per unit increment in BMI in persons with SCI than in able-bodied controls (1, 33). Garland et al. (11) reported that those with SCI and osteoporosis at the knee tended to have lower values for BMI, but a continuous relationship between BMI and leg BMD was not described.

In conclusion, in monozygotic twins discordant for SCI, correlations were found between leg BMD and BMC with fat mass. A positive relationship was found between serum estradiol and leg BMD in twins with SCI. These relationships were not found in the non-SCI twins. As expected, a positive relationship was found between leg muscle and leg bone mass in the non-SCI twins. From the intrapair difference scores, the magnitude of the loss of leg muscle mass in SCI twins is correlated with the magnitude of bone loss. This study suggests that, in the absence of the overriding forces of gravity, coordinated muscle function, and ambulation, as in our twin model with SCI, it was possible to demonstrate correlations among fat mass, estradiol, and leg bone. Although the predominant effect on bone is related to reduction in mechanical forces in individuals with SCI, the correlation between regional or total fat mass and leg bone mass, as well as the weaker but significant correlation with estradiol, raises the possibility of a hormonally mediated effect.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
We thank the Spinal Cord Research Foundation for funding our grant entitled "The Influence of SCI on Metabolism: An Analysis of Identical Twins" and the United Spinal Association (formerly the Eastern Paralyzed Veterans Association), The James J. Peters VA Medical Center, Bronx, NY, and the Mount Sinai School of Medicine, New York, NY.


   FOOTNOTES
 

Address for reprint requests and other correspondence: W. A. Bauman, Spinal Cord Damage Research Center, Rm. 1E-02, James J. Peters Veterans Affairs Medical Center, 130 West Kingsbridge Rd., Bronx, NY 10468 (e-mail: wabauman{at}earthlink.net)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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