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- Material and Methods
The objective of this cross-sectional analysis was to examine the correlates of trabecular and cortical volumetric bone mineral density (vBMD) in 3670 community-dwelling men, mean age 73.6 ± 5.9 years. vBMD was measured by quantitative computed tomography (QCT) and areal BMD by dual-energy X-ray absorptiometry (DXA). Demographic, historical, and lifestyle information was obtained by interview, and height, weight, and neuromuscular function were determined by examination. To express the strength of the associations, percent differences (95% confidence interval) were calculated from multivariable linear regression models using the formula 100 (β × unit/mean BMD). Units for continuous variables were chosen to approximate 1 standard deviation (SD). The multivariable linear regression models predicted 15%, 21%, and 20% of the overall variance in trabecular and cortical vBMD of the femoral neck and vBMD of the lumbar spine, respectively. Diabetes was associated with a 16.5% greater trabecular vBMD at the femoral neck and 11% at the lumbar spine but less than 2% for cortical vBMD. For femoral neck trabecular vBMD, the strongest negative correlates were past smoking (−9%), fracture history (−15%), kidney stones (−7%), corticosteroids (−11%), and insulin therapy (−26%). For cortical vBMD, the strongest negative correlate was use of thyroid medication (−2.8%). The strongest negative correlates for lumbar spine trabecular vBMD were fracture history (−5%), antiandrogen use (−19%), height (−8%), and thiazoliainedione use (−22%). Bioavailable estradiol and testosterone levels were positively related and sex hormone–binding globulin was negatively related to trabecular vBMD of the spine. There was no relationship between sex hormones and femoral neck trabecular vBMD. Our conclusion is that correlates of trabecular vBMD and cortical vBMD appear to differ in older men. © 2010 American Society for Bone and Mineral Research
Osteoporotic fractures are considered a major public health problem among older men. The lifetime risk of shoulder, forearm, hip, or spine fractures is estimated at 23.8%; in fact, one-third of all hip fractures occur in men.1–5 The etiology of osteoporotic fractures in men is complex, with low areal bone mineral density (aBMD), reflecting an integration of both cortical and trabecular bone, considered a primary determinant.6–8
Although dual-energy X-ray absorptiometry (DXA) assessments are invaluable in measuring BMD and fracture risk, they provide no insight into the structural characteristics of bone or other elements of bone that might contribute to bone strength. Such factors include the size, shape, geometry, and relative amounts of bone in the cortical and trabecular compartments. Areal measurements are confounded by bone size such that individuals with larger bones have greater aBMD simply because of their larger bones.9 In addition, lumbar spine aBMD might be overestimated in older men because of degenerative, artifactual, and age-related changes.
Computed tomographic scans provide measures of volumetric or 3D BMD and also can separate the cortical and trabecular compartments. At present, there is limited information on the correlates of trabecular or cortical volumetric BMD (vBMD) in older men. These correlates could differ from aBMD and for trabecular and cortical vBMD.
In a previous analysis by Marshall and colleagues, race and ethnic variation in proximal femur structure and vBMD were examined among older men participating in the Osteoporotic Fractures in Men (MrOS) Study. African-American and Asian men had greater cortical thickness and higher trabecular vBMD compared with white men.10
Building on our initial analysis of race and vBMD, the objectives of this analysis were to comprehensively determine the demographic, anthropometric, historical (medical and family), lifestyle, and neuromuscular factors associated with trabecular and cortical vBMD of the proximal femur and lumbar spine in ethnically diverse, community-dwelling older men enrolled in the MrOS Study. A secondary objective was to compare the correlates of vBMD with those of aBMD.
- Top of page
- Material and Methods
In this population of community-dwelling older men, the associations among demographic, anthropometric, lifestyle, historical (medical and family), and neuromuscular factors were stronger for trabecular than cortical vBMD (Tables 5 and 6). Overall, race and diabetes were the strongest consistent positive correlates, whereas history of nontraumatic fractures was the strongest consistent negative correlate. The strong negative association between maternal family history of fracture and trabecular vBMD underscores the importance of identifying the specific genes that contribute to the heritability of trabecular versus cortical vBMD in men. Indeed, a recent paper by Yerges and colleagues22 showed that genetic associations differed for cortical and trabecular vBMD. There was no association between paternal history of fracture, perhaps reflecting a shorter life span in men and less “opportunity” for fracture in this generation. Awareness of lifestyle, behavioral, medical, and historical factors correlated with vBMD may improve our ability to identify men at greatest risk of osteoporosis and related fractures.
Table 5. Multivariate Correlates of Femoral Neck BMD: Areal BMD, Trabecular vBMD, Cortical vBMD
|Variable||aBMD||Trabecular vBMD||Cortical vBMD|
|Demographics|| || || |
| Age||0||− − − −||0|
| Race|| || || |
| White (Ref)|| || || |
| African-American||++ + ++||++ + ++||+++|
| Asian||0||++ + ++||0|
| >High school education||0||0||0|
|Anthropometry|| || || |
| Weight change since age 25||− −||0||0|
| Height||− −||0||0|
| Height change since age 25||−||− − −||0|
|Lifestyle|| || || |
| Past smoking||− −||− − − −||0|
| Physical activity (PASE)||+||0||0|
|Diet|| || || |
| Total calcium||0||+++||0|
|Fracture history|| || || |
| Nontrauma fracture (any)||− − −||− − − − −||− −|
| Mother fracture (any)||− −||− − − −||0|
| Father fracture (any)||0||0||0|
|Medical history|| || || |
| Diabetes||+++||++ + ++||++|
| Kidney stones||− −||− − − −||0|
|Medications|| || || |
| Cox-2 inhibitor||+++||++ + ++||0|
| NSAID||0||− − − −||0|
| Nonthiazide diuretic||++||0||0|
| Thyroid||− − −||0||− −|
| Corticosteroid (any, inhaled or oral)||0||− − − − −||0|
| Insulin||0||− − − − −||0|
|Neuromuscular|| || || |
| Chair stands||0||0||−|
| Grip strength||0||0||0|
|Sex steroid hormones|| || || |
| Bioavailable estradiol||++||0||+|
| Bioavailable testosterone||0||0||0|
| Sex hormone–binding globulin||0||0||0|
Table 6. Multivariate Correlates of Lumbar Spine BMD: Areal BMD, Trabecular vBMD
|Demographics|| || |
| Age||++||− − − −|
| Race|| || |
| White (Ref)|| || |
| African-American||++ + +||++ + ++|
| Hispanic/other||− − −||0|
|Anthropometry|| || |
| Weight change since age 25||− − −||0|
| Height||0||− − − −|
| Height change since age 25||0||0|
|Lifestyle|| || |
| Past smoking||0||− − −|
|Diet|| || |
| Total calcium||0||++|
|Fracture history|| || |
| Nontrauma fracture (any)||− − −||− − − −|
| Mother fracture (any)||− −||0|
|Medical history|| || |
| Diabetes||++ + +||++ + ++|
| COPD||0||− − −|
| Parkinson's||− − − −||0|
| Kidney stones||− −||0|
|Medications|| || |
| Antiandrogen||− − − − −||− − − − −|
| Cox-2 inhibitor||++||0|
| Beta blocker||0||0|
| Corticosteroid (any, inhaled or oral)||− − −||0|
| TZD||− − − −||− − − − −|
|General health|| || |
| Back pain last 12 months||++||0|
|Neuromuscular|| || |
| Gait speed||− −||0|
| Chair stands||−||−|
| Grip strength||0||0|
|Sex steroid hormones|| || |
| Bioavailable estradiol||++||+++|
| Bioavailable testosterone||0||++|
| Sex hormone–binding globulin||− −||− − −|
Diabetes mellitus was associated with higher aBMD and vBMD at both the femoral neck and lumbar spine, with the association strongest for trabecular vBMD. The observation that diabetes was associated with greater BMD is consistent with findings from other studies of aBMD in older men.23–26 Most previous studies were limited to aBMD, but our results are consistent with the results from the Health ABC Study, in which men with diabetes had significantly higher lumbar spine trabecular vBMD.25 Diabetes also was strongly associated with higher trabecular but not cortical vBMD in the peripheral skeleton.27, 28 Since most men in this study had type 2 diabetes, it is possible that hyperinsulinemia may contribute to greater bone density. This finding also may reflect the impact of greater body weight on skeletal loading, although after adjustments for body weight this association still existed, suggesting that additional osteogenic factors may play a role selectively on trabecular but not cortical vBMD. Recent experiments have shown a reciprocal relationship between bone remodeling and energy metabolism.29 In animal experiments, leptin inhibits insulin secretion, and this inhibition appears to be under neuronal control. A component of this neuronal regulation is sympathetic innervation to the osteoblast. Thus the osteoblast itself may be a specific endocrine cell type.
Use of insulin was negatively correlated with trabecular vBMD of the femoral neck. TZDs were negatively associated with trabecular vBMD and aBMD of the lumbar spine but were unrelated to femoral neck trabecular or cortical vBMD. The association with trabecular spine vBMD but not trabecular femoral neck vBMD is somewhat surprising but may reflect the overall lower proportion of trabecular vBMD at the hip. Use of insulin may be a marker of more severe disease and may explain why it is associated with lower vBMD. The negative association between TZDs and lower spine BMD is consistent with the higher fracture rates observed among TZD users.30 Previous reports have shown greater spine and hip aBMD loss in women but not men using TZDs,31 whereas others have shown greater spine and hip aBMD loss in men treated with TZDs.32 It has been suggested that the divergent skeletal responses to TZDs may reflect different genetic backgrounds.33
A number of other medical conditions were correlated with vBMD. Hypertension was associated with greater femoral neck trabecular vBMD but not spine trabecular vBMD in multivariable models. Hypertension also was linked with higher trabecular vBMD at the radius but not tibia using peripheral QCT.27 Hypertension has been associated with abnormalities in calcium metabolism, leading to increased calcium losses and secondary activation of the parathyroid gland.34 The positive association between hypertension and BMD was independent of body weight and may result from confounding by the use of medications that may increase BMD such as thiazide diuretics, a common medication used to treat hypertension.
Previous studies have shown that SSRI use was associated with lower hip aBMD and more rapid bone loss in both sexes.35 We found no association between SSRIs and either aBMD or vBMD, perhaps reflecting lower power in this smaller population of MrOS men.
Several differences between the correlates of aBMD and vBMD are noteworthy. In particular, it is well established that body weight is strongly positively associated with aBMD, but at least for the hip, we found much weaker associations with vBMD. This suggests that body weight facilitates at least some of its positive effects on aBMD through effects on bone size. While past smoking was weakly related to lower aBMD of the femoral neck and unrelated to lumbar spine aBMD, smoking had a strong negative impact on trabecular vBMD at both the spine and hip. A study of Afro-Caribbean men also reported a negative association between smoking and trabecular but not cortical vBMD in the peripheral skeleton.36 The Gothenburg Osteoporosis and Obesity Determinants (GOOD) Study also found no association with cortical vBMD.37 Because trabecular bone is more metabolically active, trabecular bone may be more sensitive to the influences of smoking. Cigarette smoking also has been shown to enhance metabolic clearance of estrogen, which may lead to lower vBMD.38 Another possible mechanism for direct effects of smoking on bone includes a direct effect of nicotine on bone metabolism and BMD by inhibiting the proliferation of osteoprogenitor cells in a concentration-dependent manner.39, 40
Parkinson's disease was strongly associated with lower aBMD of the spine but was not related to spine trabecular vBMD, perhaps reflecting low power owing to the low prevalence of Parkinson' s disease and the increased variability and reduced precision of QCT. We have shown previously that MrOS men with Parkinson's disease experienced faster areal bone loss and had an increased risk of fracture.41
A history of kidney stones was associated with lower femoral neck trabecular vBMD but not cortical vBMD, consistent with observations that individuals who are calcium stone formers have increased bone resorption, lower BMD,42 and higher cytokine activity,43 which would preferentially influence the more metabolically active trabecular bone.
Alcohol consumption was positively related to aBMD at both the spine and hip and cortical vBMD at the femoral neck but was unrelated to trabecular vBMD. The associations, however, were quite modest. Previous studies have shown that moderate alcohol consumption (fewer than 2 drinks per day) has a positive association with aBMD in men but no association with cortical or trabecular vBMD of the peripheral skeleton.36, 44, 45 The mechanism for this association is unclear, but it could reflect a “healthy user” effect because moderate alcohol consumption is associated with a lower total mortality.46 Alcohol also may increase BMD by raising sex steroid hormone levels47 or by direct effects on the aromatase gene.48 More research is needed to further our understanding of why alcohol's beneficial effects may be limited to cortical vBMD.
A 5-year increase in age was associated with a 5% to 10% lower trabecular vBMD at the spine and hip but was not significantly related to cortical vBMD. The lack of association with cortical vBMD is somewhat surprising because most studies have shown age-related losses in both trabecular and cortical vBMD.49 For example, Riggs and colleagues observed a substantial loss in cortical vBMD in men after the average age of 75. However, our results are limited to cross-sectional comparisons across age groups and may mask individual changes in BMD in specific age groups over the long term. The stronger association with trabecular vBMD likely reflects the higher rate of bone turnover in trabecular bone and age-associated increases in bone remodeling.
In multivariate models, higher calcium intake was positively associated with trabecular vBMD at both the hip and spine but was not related to cortical vBMD. This may reflect a beneficial effect of calcium on bone turnover that may be more evident in the more metabolically active trabecular bone.
Corticosteroids were strongly negatively correlated with trabecular vBMD at the hip but not cortical vBMD, likely reflecting the negative effects of glucocorticoids on osteoblasts, osteocytes, and osteoclasts leading to decreased bone formation and excessive bone resorption.50 The major effect on trabecular vBMD is consistent with the observation that fractures in patients receiving chronic glucocorticoid therapy occur more frequently at sites enriched with trabecular bone.51
Men who reported taking thyroid supplements had lower cortical vBMD of the femoral neck but not trabecular vBMD. Biochemical hyperthyroidism has been associated with lower BMD at the trabecular-rich ultradistal (both sexes) and distal (women) forearm.52 This is in contrast to our finding that thyroid hormone supplements have major effects in cortical vBMD. More research is needed on the skeletal effects of thyroid hormones in both men and women.
Use of NSAIDS was associated with lower femoral neck trabecular vBMD but was unrelated to aBMD or cortical vBMD. On the other hand, Cox-2 inhibitors were strong positive correlates of especially femoral neck trabecular vBMD. Examination of the relationships of NSAIDs with BMD by Cox selectivity showed that users of NSAIDs who had higher Cox-2 selectivity had higher BMD values at multiple sites.53 Previous studies that showed positive correlations between NSAIDs and BMD may be spurious because they did not account for Cox-2 selectivity.
In the subset of men with sex steroid hormone data, we found the strongest relationship between sex steroid hormone levels and lumbar spine trabecular vBMD: All three sex hormones were significantly related to trabecular vBMD in the multivariate model, with the strongest association with bioavailable estradiol. This observation is generally consistent with previous studies that demonstrated positive and consistent associations with bioavailable estradiol.54 The stronger association with trabecular vBMD may reflect a direct effect of sex hormones on rates of bone turnover. The magnitude of the association between bioavailable estradiol and lumbar spine vBMD was similar to a 1 SD increase in body weight. Previous studies have not consistently reported an association between testosterone and BMD.55, 56 Most of these studies, however, have been confined to aBMD. We found a positive association between testosterone and trabecular vBMD of the spine, highlighting the need to further explore the influence of sex hormones on trabecular versus cortical bone compartments. Sex hormone–binding globulin was negatively correlated with both aBMD and vBMD of the spine, consistent with the observation that high sex hormone–binding globulin has been linked to an increased risk of fracture.57 In general, the sex steroid hormones were not related to femoral neck vBMD except for a relatively weak association with cortical vBMD. The observation that the sex steroids hormones were more strongly associated with lumbar spine trabecular vBMD than femoral neck vBMD may reflect the relatively small proportion of trabecular vBMD at the femoral neck.
Several associations likely reflected an indication bias, which exists when a drug is prescribed for a condition that itself is associated with the outcome of interest. For example, men reporting use of osteoporosis medications or calcium supplements had lower vBMD values, likely reflecting their diagnosis and treatment of osteoporosis.
This study has several potential limitations. The MrOS cohort is limited to generally healthy community-dwelling men and may not be generalizable to other groups. Some analyses, such as steroid use or smoking, were limited in power because of low numbers; for example, only 3.5% of our cohort were current smokers. Habits and history, which were assessed by questionnaire or through interviews, may be compromised by inaccurate recall. Although we examined a large number of potential correlates, the aggregate effect of all these factors on BMD, however, was modest, which highlights the need to identify new risk factors for variations in vBMD and aBMD. Sex steroid hormones were available on fewer than a third of the sample of men with QCT data. Finally, this study was a cross-sectional design, and therefore, causality cannot be assessed.
On the other hand, this study has several strengths. The MrOS cohort is a large population-based study of ethnically diverse older men. The large number of covariates examined helps to provide greater insight into correlates of vBMD. Given this study design, we were able to directly compare DXA- and QCT-derived measures and to separately examine trabecular and cortical compartments.
In conclusion, in this study of older, ethnically diverse men, a number of important associations that may help to identify men at risk for osteoporosis and related fractures were identified. Correlates of trabecular vBMD and cortical vBMD appear to differ among older men.