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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2691
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 6 2281-2286
Copyright © 2008 by The Endocrine Society

Reciprocal Relation between Marrow Adiposity and the Amount of Bone in the Axial and Appendicular Skeleton of Young Adults

Natascia Di Iorgi, Michael Rosol, Steven D. Mittelman and Vicente Gilsanz

Giannina Gaslini Institute (N.D.I.), University of Genova, 16126 Genova, Italy; and Departments of Radiology (N.D.I., M.R., V.G.) and Pediatrics (S.D.M., V.G.), Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California 90027

Address all correspondence and requests for reprints to: Vicente Gilsanz, M.D., Childrens Hospital Los Angeles, Department of Radiology, MS #81, 4650 Sunset Boulevard, Los Angeles, California 90027. E-mail: vgilsanz{at}chla.usc.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Studies in the elderly suggest a reciprocal relation between increased marrow adiposity and bone loss, supporting basic research data indicating that osteoblasts and adipocytes share a common progenitor cell. However, whether this relation represents a preferential differentiation of stromal cells from osteoblasts to adipocytes or whether a passive accumulation of fat as bone is lost and marrow space increases with aging is unknown. To address this question and avoid the confounding effect of bone loss, we examined teenagers and young adults.

Methods: Using computed tomography, we obtained measurements of bone density and cross-sectional area of the lumbar vertebral bodies and cortical bone area, cross-sectional area, marrow canal area, and fat density in the marrow of the femurs in 255 sexually mature subjects (126 females, 129 males; 15–24.9 yr of age). Additionally, values for total body fat were obtained with dual-energy x-ray absorptiometry.

Results: Regardless of gender, reciprocal relations were found between fat density and measures of vertebral bone density and femoral cortical bone area (r = 0.19–0.39; all P values ≤ .03). In contrast, there was no relation between marrow canal area and cortical bone area in the femurs, neither between fat density and the cross-sectional dimensions of the bones. We also found no relation between anthropometric or dual-energy x-ray absorptiometry fat values and measures for marrow fat density.

Conclusions: Our results indicate an inverse relation between bone marrow adiposity and the amount of bone in the axial and appendicular skeleton and support the notion of a common progenitor cell capable of mutually exclusive differentiation into the cell lineages responsible for bone and fat formation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A consistent body of literature indicates that mesenchymal stem cells differentiate into bone or fat through alternative activation of mutually exclusive transcriptional programs (1, 2, 3, 4, 5). Depending on the interplay of molecular, biochemical, and physical stimuli, these progenitor cells in the bone marrow are capable of self-regeneration and differentiation into the cell lineages responsible for bone and fat formation. In vitro studies have extensively examined the role of multiple hormones and their receptors (6, 7, 8, 9, 10, 11, 12), cytokines (13, 14, 15) and other serum factors (16, 17), glucocorticoids (18), and mechanical stimuli (19) in the commitment of mesenchymal cells isolated from bone marrow stroma toward adipocytic or osteoblastic lineages. Among various osteopenic animal models, an inverse relation between bone marrow fat and bone density has also been demonstrated in ovariectomy and immobilization studies (20, 21, 22).

In humans, it has been suggested that bone loss with aging is likely the consequence of a preferential differentiation by mesenchymal cells into the adipocyte cell lineage and that osteoporosis may result from an increased number of adipocytes at the expense of bone-forming osteoblasts (23, 24, 25), a view with significant therapeutic potential. Systemic and/or local interventions with osteogenic mesenchymal cells or factors that enhance the osteogenic differentiation of these progenitor cells could be of great advantage in the prevention and treatment of bone loss. Indeed, pathological, epidemiological, and imaging studies dating back as far as 1932 have consistently reported a reciprocal relation between trabecular bone loss and increased marrow adiposity in age-related and postmenopausal osteoporosis (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36). Previous imaging investigations to analyze this relation used a combination of dual-energy x-ray absorptiometry to measure bone and magnetic resonance (MR) techniques to evaluate marrow fat in the axial skeleton (32, 33, 34, 35, 36). These studies provide evidence that increased marrow fat, like low bone density, is a predictor of vertebral osteoporotic fractures and suggest that increases in marrow fat and decreases in bone formation are immutably coupled (36). However, whether the relation between adipose and bone tissues in elderly humans is the unintended consequence of a passive accumulation of fat as bone is lost and marrow space increases or is the clinical translation of preferential differentiation by mesenchymal cells into the adipose cell lineage remains a matter of debate.

To avoid the confounding effect of bone thinning with aging, we examined the possible relations between the amount of bone in the axial and appendicular skeletons and measures of marrow fat density in a large cohort of healthy young sexually mature men and women during the time of life when peak bone mass occurs.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The participants were 255 healthy teenagers and young adults, 126 females, 129 males, 15–24.9 yr of age, who were recruited from schools and colleges in the Los Angeles area. The investigational protocol was approved by the hospital institutional review board and informed consent was obtained. Candidates for this study were excluded if they had a diagnosis of any underlying disease or chronic illness, they had been ill for more than 2 wk during the previous 6 months, they had been admitted to the hospital at any time during the previous 3 yr, or they were taking any medications regularly. Females who were pregnant were also excluded. All potential candidates underwent a physical examination by a pediatric endocrinologist, and only those who had achieved sexual maturity (Tanner stage V of sexual development) were included (37). Thereafter, height, weight, and body mass index (BMI) were determined.

Computed tomography (CT) and dual-energy x-ray absorptiometry measurements

Subjects underwent CT measurements of bone and marrow using a General Electric Hilite Advantage scanner (General Electric Healthcare, Milwaukee, WI) and a standardized mineral reference phantom for simultaneous calibration (CT bone densitometry package; General Electric). All scans were obtained by the same CT technologist using the following technical factors: 80 kVp (vertebra) or 120 kVp (femur), 70 mA, 2 sec, and 10-mm slice thickness. We acquired measurements of cancellous bone density and cross-sectional area (cortical bone area; square centimeters) in the first three lumbar vertebral bodies and cortical bone area (cm2), femoral cross-sectional area (square centimeters), marrow canal area (square centimeters), and fat density in the marrow at the midshafts of the femurs. After accounting for the size of the bones, values for the tissue density of cancellous bone best represent the amount of bone in the axial skeleton, whereas measures of cortical bone area best reflect the amount of bone in the appendicular skeleton (38). The coefficients of variation for bone measurements in young adults are between 0.6 and 1.5% (39) and was calculated to be less than 1% for marrow fat density.

CT numbers express the measure of the linear attenuation of the x-ray beam through the medium in that space and are defined as Hounsfield units (HU), using the linear attenuation coefficient of water (HU = 0) and air (HU = –1000). Using these parameters, Hounsfield units for fat fall between a range of negative values (40). For the purpose of this study, CT values for fat density and bone density in Hounsfield units were converted into density values (grams per cubic centimeters) based on previously published studies that calculated CT attenuation values for several human tissues (41, 42, 43). It should be stressed that because marrow is comprised of hematopoietic tissue with a density of 1.06 g/cm3 and fatty tissue with a density of 0.92 g/cm3, the higher the density of marrow tissue, the lower the fraction of marrow fat (43). This fraction changes during growth and throughout life in a predictable and orderly age-, bone-, and site-specific fashion (44, 45, 46). In the vertebral body and metaphyses of the long bones, the conversion from hematopoietic to fatty marrow progresses at a relatively slow pace with great variability and may continue throughout life, whereas in the diaphyses of the long bones, the marrow reaches its adult pattern by 15 yr of age when it is mostly comprised of fat. Hence, at this site, CT values for the density of the marrow, even in young adulthood, mainly reflect the tissue density of fat because the influence of blood is minimized.

Measurements of total body fat mass were obtained using a fan beam dual-energy x-ray absorptiometry densitometer (Delphi W; Hologic, Inc., Waltham, MA) in array mode and were analyzed with the manufacturer’s software; the coefficients of variation for these measurements have been reported to range from 1.2 to 5% (47, 48, 49).

Statistical analyses

Student’s t test for unpaired data were used to compare mean values between genders and simple correlations to investigate the association between age, anthropometric parameters, fat density, and dual-energy x-ray absorptiometry body fat body and bone measures. Linear regressions analyses were done for both males and females using cancellous bone density and femoral cortical bone area as dependent variable and height, weight, dual-energy x-ray absorptiometry body fat, vertebral or femoral cross-sectional area, and fat density as independent variables. The StatView statistical software (SAS Institute Inc. Cary, NC) was used for these analyses. Quantitative variables are expressed as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows age, anthropometric measurements, and values for bone and body composition in all study subjects. As expected, values for height, weight, and CT bone measures were significantly greater in males, whereas those for total fat mass by dual-energy x-ray absorptiometry were greater in females; there were no gender differences in age or BMI. Values for marrow adiposity in the femur were significantly higher in males than females, but the effect of gender did not persist once the greater cortical bone area of males was taken into account using linear regression analyses. Regardless of gender, age was not associated with marrow fat.


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  		TABLE 1. Age, anthropometric parameters, and bone, marrow, and fat mass measurements in 129 males and 126 females

 
Substantial reciprocal relations were observed between the density of marrow fat and measures of vertebral bone density and femoral cortical bone area, regardless of gender. The strength of these inverse associations was similar for males and females but was more pronounced in the axial (r = 0.36 and 0.39 for females and males, respectively; both P values < 0.0001) than in the appendicular skeleton (r = 0.22 and 0.19 for females and males, respectively; both P values < 0.05) (Fig. 1Go). Multivariate regression analyses showed fat density to independently predict femoral cortical bone area and cancellous bone density, even after controlling for weight, height, dual-energy x-ray absorptiometry fat mass, and bone size. On average, marrow fat accounted for 8.5 and 10.9% of the variance in vertebral cancellous bone density and 0.8 and 3.5% of the variance of femoral cortical bone area in females and males, respectively (Table 2Go).


Figure 1
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  		FIG. 1. Correlations between CT values for the tissue density of the marrow and measures of cancellous bone density at the vertebral body (A) and cortical bone area of the femur (B) in both males and females. Higher CT values for marrow density indicate a lesser amount of fat, hence, the reciprocal relation between marrow adiposity and the amount of bone.

 

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  		TABLE 2. Multivariate regression analyses for the prediction of CT BD parameters in the axial and appendicular skeleton of 129 males and 126 females

 
In contrast to the significant relation found between fat density and measures of the amount of bone in the axial and appendicular skeleton, there was no significant association between fat density and values for vertebral cross-sectional area (r = 0.05, P = 0.57 for females; r = –0.10, P = 0.25 for males) or femoral cross-sectional area (r = 0.10, P = 0.26 for females; r = –0.02, P = 0.85 for males). There was also no relation between values for marrow canal area and cortical bone area in the femurs, regardless of gender (r = 0.17, P = 0.06 for females; r = 0.01, P = 0.90 for males).

We found no association between marrow adiposity and anthropometric or dual-energy x-ray absorptiometry fat values; this was true for both females and males (r between 0.07 and 0.17; all P values < 0.05). Measures of dual-energy x-ray absorptiometry total fat were negatively related to values of bone density after accounting for weight, height, marrow adiposity, and bone size (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We found that in healthy teenagers and young adults, the amount of bone in the axial and appendicular skeleton is inversely related to marrow adiposity, as measured by CT. This reciprocal relation between vertebral cancellous bone and femoral cortical bone with marrow fat persisted, even after controlling for anthropometric parameters, bone dimensions, and measures of total body fat and was present in both men and women. In contrast, there was no relation between marrow adiposity and the size of the vertebrae or the femurs. These findings indicate that an inverse association between bone marrow adiposity and bone accumulation exists in young adults at the time of peak bone mass and support the notion of a common progenitor cell capable of a mutually exclusive differentiation into the cell lineages responsible for bone and fat formation.

Our results complement histomorphometric data of the iliac crest and vertebral bodies showing greater marrow fat content in subjects with reduced bone density and osteoporosis when compared with age-matched controls (28, 30, 50). They are also in agreement with previous imaging studies showing an inverse association between dual-energy x-ray absorptiometry values of bone mineral density and MR measures of marrow fat in older men and women, some even suggesting that marrow adiposity could be an independent predictor of osteoporosis and fractures (32, 33, 35, 36). The results of this study also indicate that the dimensions of the medullary space and the amount of cortical bone in the femurs of young men and women are independent skeletal phenotypes, arguing against the idea that variations in marrow fat are merely the passive consequence of changes in size of the marrow cavity but supporting the notion that marrow adipocytes and osteoblasts share a common progenitor.

When comparing gender differences in CT measures of marrow fat density in the femurs, we found that males had greater adiposity than females, a finding in accordance with prior investigations measuring vertebral fat in adult men and women using MR (31, 51). However, in our study the effect of gender did not persist once the greater cortical bone area of males was taken into account, consistent with analytical models, suggesting that the appendicular skeleton optimizes its morphology equally in men and women, depending on mechanical demands. The concomitant presence of a greater amount of bone and fat in the femurs of men is a provocative finding, supporting the hypothesis that sexual dimorphism in bone mass results from an increased proliferation of mesenchymal cell (due to greater mechanical stresses in the male skeleton), rather than solely from a gender effect in mesenchymal cell differentiation. Future studies are needed to determine the degree to which variations in the proliferation and modulation of mesenchymal cell contribute to gender difference in bone mass.

Unexpectedly, we found that, regardless of gender, CT values for femoral marrow adiposity were not related to weight or BMI and were not associated with dual-energy x-ray absorptiometry values for total body fat mass, suggesting distinct metabolic functions of body and marrow fat. Indeed, the greater marrow adiposity and lesser total body fat in men, when compared with women, underscores the independence of these two fat depots. Previously, two studies had analyzed the relation between marrow adiposity and body fat in humans; one observed that the ratio between the amount of marrow fat and bone mineralization was not related to weight or BMI in either gender, whereas the second found a positive relation between visceral and marrow adiposity, which was lost after accounting for age and menopausal status (35, 52). These findings are consistent with animal investigations indicating that marrow fat is not affected by insulin or long periods of starvation (53, 54). It should be noted that, regardless of difference in metabolic functions, both body fat and marrow fat had a negative association with bone structure, in accord with recent reports providing evidence that fat mass, despite increased mechanical loading, is not beneficial to bone (55, 56).

Two technical characteristics regarding CT must be considered for the appropriate interpretation of the current results. First, beam hardening and the preferential loss of lower-energy photons from a polychromatic x-ray beam causes CT to underestimate the amount of fat in the marrow cavity of long bones, and it is likely that these errors minimize the strength of the relation we found between bone and fat in the femurs. Second, the limited geometric resolution of CT when compared with the size of the trabeculae does not allow for accurate measurements of cancellous bone density, which are influenced by marrow fat and give rise to volume averaging errors. However, because measurements of marrow fat were obtained at a different site, the influence of vertebral adiposity was minimized.

The relatively large number of subjects, the inclusion of both genders, the evaluations of both trabecular and cortical bone, and the examination of teenagers and young adults to avoid the confounding effects of aging and bone loss are strengths of this study. The cross-sectional design is a major limitation, and further investigations, including longitudinal studies of adolescents and young adults, will be needed to establish a causal association. Additionally, our results are limited to the young mature skeleton and cannot be extrapolated to other age groups or populations.

In conclusion, bone acquisition in the axial and appendicular skeleton of healthy teenagers and young adults is inversely related to marrow adiposity. Our results in the mature skeleton around the time when bone mass reaches its peak complement evidence in the elderly, showing an association between bone loss and increased fat in the marrow cavities. These findings support the notion of a common progenitor cell capable of a mutually exclusive differentiation into the cell lineages responsible for bone and fat formation. Deciphering the mechanisms that influence the inseparable reciprocal transformation of mesenchymal cells into osteoblasts or adipocytes could lead to the development of strategies to maximize bone mass and prevent osteoporosis.


   Footnotes
 
This work was supported by grants from the Department of the Army (DAMD17-01-1-0817) and the National Institutes of Health (ROI-AR052744-02).

First Published Online April 1, 2008

Abbreviations: BMI, Body mass index; CT, computed tomography; HU, Hounsfield unit; MR, magnetic resonance.

Received December 6, 2007.

Accepted March 24, 2008.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
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