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Original Studies |
Epidemiology, Demography, and Biometry Program (J.A.L., M.V., T.H.), National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892; St. Joseph Hospital (C.J.R.), Bangor, Maine 04401; Hebrew Rehabilitation Center for Aged (M.T.H., D.P.K.), Research and Training Institute, and Harvard Medical School Division on Aging, Boston, Massachusetts 02131; National Heart, Lung and Blood Institute’s Framingham Heart Study (P.W.F.W.), National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Jean A. Langlois, Division of Acute Care, Rehabilitation Research, and Disability Prevention, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, 4770 Buford Highway, NE (MS F-41), Atlanta, Georgia 30341-3724. E-mail: JAL7{at}CDC.GOV
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Abstract |
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 Top Abstract IntroductionParticipants and MethodsResultsDiscussionReferences |
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0.01) and protein intake in a subset of
participants (0.006 < P < 0.07). A threshold
effect of higher BMD was evident at each of the 3 femoral sites and the
spine (P < 0.03) but not at the radius for women
in the highest quintile of IGF-I (
179 g/liter) vs. those in the
lowest four quintiles. IGF-I was not significantly associated with BMD
in men. These results indicate that higher IGF-I levels are associated
with greater BMD in very old women, and suggest that future clinical
trials employing GH may have a role in the development of treatments
for older women with osteoporosis. |
Introduction |
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TopAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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The hypothesis that a deficiency in GH and insulin-like growth factor I (IGF-I) is a major cause of aging (7), and that restoration of the GH-IGF-I axis may prevent age-related decline, including bone loss (8, 9), has received considerable scientific and public attention (10). One of the most abundant growth factors present in bone (11), IGF-I has been shown to stimulate bone formation (12, 13). Declines in skeletal (14, 15) and serum (16, 17, 18) IGF-I levels with age parallel decreases in bone mass with age (14, 15, 19, 20), suggesting a relationship between decreased IGF-I levels and age-related bone loss.
Few studies of the GH axis and bone have focused specifically on elderly people (21, 22, 23). Some have found no relationship between IGF-I and bone mineral density (BMD) (22, 24, 25), and the few reports of an association between serum IGF-I levels and BMD (21, 23, 26, 27, 28, 29, 30, 31) may have overestimated the association by not accounting for factors such as weight loss (17, 32) and protein intake (33, 34, 35, 36) that can influence both IGF-I level (17, 33, 36) and BMD (32, 34, 35, 36).
The objective of this study was to determine the cross-sectional association between IGF-I and BMD in very old women and men from the Framingham Heart Study.
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Participants and Methods |
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TopAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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Details of the Framingham Heart Study design and methods have been described elsewhere (37). Briefly, the original population-based cohort of 5209 women and men aged 30–62 yr, initially recruited for an examination of risk factors for cardiovascular disease, has been examined biennially since 1948. In 1992–1993, 1161 of the participants were still alive and 932 took part in the 22nd examination (exam 22). Of the 229 people who did not participate in exam 22, 213 (93%) were residing in nursing homes or physically unable to come to the Framingham Clinic. A total of 792 of the exam 22 participants (500 women and 292 men) had both IGF-I and BMD measurements of the hip and radius. After further exclusion of 1 woman and 3 men with an IGF-I measurement below the level of assay sensitivity (<20 g/liter), and 74 women and 32 men with missing data for one or more potentially associated variables, data for a total of 425 women and 257 men aged 72–94 were used in these analyses.
Both women and men excluded from the study (n = 250) were older
(P < 0.001) and were more likely to report needing
help from another person to walk a mile or to walk up and down stairs
(P < 0.003) than those who were included. There were
no significant differences (P 0.05) between people
excluded and those included for any other variables for either women or
men.
Of the 425 women, 362 (85%) returned for a separate clinic visit for
measurement of BMD at the spine, and of the 257 men, 217 (84%)
returned for BMD spine measurement. Women who did not have spine BMD
measurements had significantly lower protein intake (P
= 0.02) than those who had spine measurements, but they did not differ
with regard to age or any other characteristics (P
0.4). Men with missing spine BMD measurements were older
(P = 0.03); had a significantly lower mean body mass
index (BMI) (P = 0.02) and IGF-I level
(P = 0.005); had a lower BMD at Ward’s area
(P < 0.001), the trochanter (P <
0.001), and the femoral neck (P < 0.001); and were
more likely to be physically disabled (P = 0.02) than
those who had spine BMD measurements. They did not differ significantly
with regard to protein intake (P = 0.77) and BMD at the
radius (P = 0.09).
This study was approved by the Institutional Review Boards for Human Subjects of the Boston Medical Center and the Hebrew Rehabilitation Center for Aged, Boston, Mass., and all participants gave written informed consent.
IGF-I
The methods for ascertaining IGF-I level have been described previously (17). The measurements were obtained from blood drawn in the early afternoon from participants in a nonfasting state and delivered within 2 h of venipuncture by local courier to the United States Department of Agriculture Human Nutrition Research Center on Aging (Tufts University, Boston, MA), separated, and stored at -80 C. Serum on dry ice was then shipped to Endocrine Sciences, Inc. (Calabasas Hills, CA). IGF-I was measured by RIA after acid ethanol extraction (38) in three batches. Results by RIA after ethanol extraction have been shown to be highly correlated (r = 0.98) with those obtained after acid-gel chromatography (39). The distribution of IGF-I values was normal in both women and men. Separate sex-specific quintiles were determined for the total study population and for the subset of participants with spine BMD measurements.
BMD
BMD of the proximal femur and lumbar spine were measured using a Lunar DPX-L dual x-ray absorptiometer (Lunar Radiation Corp., Madison, WI), and BMD of the proximal radius was measured at the one-third site using a Lunar SP2 single-photon absorptiometer. Precision for the single-photon absorptiometer was 3%. Femoral densities were measured at three sites: Ward’s area, femoral neck, and trochanter. Lumbar spine BMD was determined as the average of measurements obtained at L2–L4. Standard positioning was used, including medial rotation of the femur to obtain a clear scan of the femoral neck. For both the femur and the radius, the right side was scanned, except in people with previous fracture or joint replacement in which the left side was scanned.
Potential confounders
Weight and height measurements were performed in a standardized
fashion using a stadiometer and a balance scale. BMI was calculated as
weight(kg)/height2 (m). Percent weight change in the past 4
yr was calculated as [weight (measured in 1988–1989) - weight
(measured in 1992–1993)/weight (measured in 1988–1989)] x 100, and
categorized as loss >5%, gain or loss 5%, or gain >5%. Mobility
limitation was based on responses to 2 questions: "Are you able to
walk up and down stairs to the second floor without any help?"; and
"Are you able to walk a mile (about 8 blocks) without help?".
Participants who reported that they needed help from another person to
perform either of these tasks were categorized as having mobility
limitation. A more detailed assessment of level of physical activity
was not available at this examination. Current cigarette smokers were
defined as people who reported regularly smoking cigarettes in the past
year. Among women, current estrogen use was defined as reported use of
estrogen (oral, patch, or cream).
Information on protein intake, available for a subset of the study population (n = 564), was obtained at exam 20 (1988–1989) using the Willett 126-item semiquantitative food frequency questionnaire (40). The Willett food frequency questionnaire measures usual protein intake and ranks individuals very well in relation to their actual intake (40). Calorie-adjusted protein intake (40) was computed and included in selected regression models.
Statistical analysis
Data were analyzed using SAS (SAS Institute, Inc.,
Cary, NC). Baseline characteristics of women and men were compared
using Student’s t tests and 
-square tests. The remaining
analyses were performed separately for women and men. Age-adjusted
means and percentages for the potential confounders (age, BMI, weight
change, mobility limitation, smoking, estrogen use, protein intake) by
quintile of IGF-I were determined using analysis of covariance.
The association of IGF-I with BMD also was determined using analysis of covariance. In separate models, IGF-I was included as: 1) a continuous variable; 2) quintiles; and 3) quintiles I-IV vs. quintile V (highest IGF-I). The analysis by quintile, which was used to check for nonlinear associations, was planned a priori and is consistent with previous analyses of the IGF-I data (17). The analysis comparing the lowest four quintiles with the highest quintile was then used to check for a threshold effect of high IGF-I on BMD (women only). All models were adjusted for the potential confounders excluding protein intake; selected models were further adjusted for protein intake using the subset of participants for whom these data were obtained (n = 564 for the three femoral sites and the radius; n = 493 for the lumbar spine). Except for the analyses of spine BMD and those including protein intake, the results reported are for the 425 women and 257 men who had data for all other variables. No adjustments were made for multiple comparisons; instead, either exact P values are reported or a level of significance of P < 0.01 is used.
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Results |
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TopAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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compares the characteristics
of women and men in the study. The mean age was similar (78.7 yr for
women and 78.1 yr for men). Women had a significantly lower BMI, a
higher percentage of mobility limitation, a lower mean IGF-I level, and
a lower mean BMD at all sites compared with men. There were no
significant differences in weight change or cigarette smoking.
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and 3 show the age-adjusted means and
percentages for potential confounders by quintile of IGF-I in women and
men, respectively. In both sexes there was a significant trend toward
increased age with lower levels of IGF-I. There was no significant
association between quintile of IGF-I and any other variable for either
sex.
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and 5 show the associations between IGF-I and
BMD in women and men, respectively. After adjustment for potential
confounding in multivariate models with IGF-I as a continuous variable,
at all five BMD sites (Ward’s area, femoral neck, trochanter, radius,
and lumbar spine) higher IGF-I was associated with greater BMD in
women; no statistically significant association was observed in men.
The findings were similar in models adjusting for age only and in
multiple covariate-adjusted models.
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To determine whether the associations were influenced by possible
confounding by protein intake, further adjustment for protein intake
was performed in a subset of participants (n = 564 for the three
femoral sites and the radius; n = 493 for the lumbar spine). For
both sexes, the results for IGF-I as a continuous variable after
adjustment for protein intake were largely unchanged (women: Ward’s
area, P = 0.02; femoral neck, P = 0.02;
trochanter, P = 0.06; radius, P = 0.04;
lumbar spine, P = 0.007; men: all four sites
P 0.45). These results were similar in models
adjusting for age only (data not shown).
In adjusted models checking for a threshold effect of high IGF-I in women only, those in the highest quintile of IGF-I had significantly greater mean BMD, compared with women in the other four quintiles of IGF-I combined, at four of the five BMD sites (Ward’s area, P = 0.001; femoral neck, P = 0.0008; trochanter, P = 0.005; lumbar spine, P = 0.02); there was no difference at the radius (P = 0.14). These results also were similar in models adjusting for age only and in covariate-adjusted models, with and without adjustment for protein intake (data not shown).
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Discussion |
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TopAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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The results of previous cross-sectional studies of IGF-I and BMD in women (21, 24, 26, 27, 41) and in men (22, 23, 30, 31, 41, 42) have been inconsistent. Our findings agree with several studies that reported higher IGF-I concentrations associated with greater BMD in women (21, 27), and lower serum IGF-I concentrations in women with established osteoporosis (28, 29) or spinal fracture (26) than in healthy women. Only one previous study focused exclusively on elderly women (21) and the exclusion from that study of women with a wide range of health impairments limits the generalizability of the findings. A recent study of women and men aged 55 yr and older also reported a positive association between IGF-I and BMD at the hip and spine in women but not in men (41). Our results are similar to another study of elderly men that reported no relationship between IGF-I and BMD measured at several sites (22). They differ, however, from a recent study of elderly men reporting significant associations between IGF-I and both femoral neck and lumbar spine BMD (23), and from studies reporting significantly lower IGF-I concentrations in younger men with idiopathic osteoporosis (30, 31, 42). Differences in the age and overall health status of the participants in previous studies likely explain the different findings compared with our study.
This study goes beyond previous studies to show that higher IGF-I is associated with greater BMD in very old women even after adjustment for a range of factors that might be related to both IGF-I concentrations and BMD. Nutrition and health status, especially as indicated by protein intake and recent weight loss, are important determinants of both IGF-I level (17, 33, 36) and BMD (32, 34, 35, 36) that have not been considered in previous studies.
The mechanism by which IGF-I may influence BMD in women is complex and has not been well studied. IGF-I has been reported to decline during (43) and after menopause (27, 43), suggesting an interrelationship between IGF-I concentrations, estrogen levels, and bone loss in postmenopausal women. Although IGF-I levels decline with loss of estrogen (43), maintenance of relatively high levels of IGF-I postmenopause in some women may explain in part their higher BMD. This hypothesis is supported by our finding of an apparent threshold effect of higher IGF-I on BMD in the very old women in our study, but confirmation in other studies is needed.
Reasons for the differences in the association of IGF-I and BMD between older women and men in our study are unclear. Our findings in women are in keeping with recent evidence that reported a strong functional association between IGF-I and BMD among in-bred strains of female mice (44). Corresponding evidence from male animal studies was not available, however, and far less is known about the regulation of IGF-I and its relationship to age and BMD in older men. Men maintain higher levels of IGF-I (15, 16, 17), sex hormones (45, 46), and BMD (45, 46) into old age than women. Thus, differences between men and women in the relationship between IGF-I and both sex hormone concentrations (47) and IGF-specific binding proteins, which influence the bioactivity of IGF-I (29, 42), may be important, but this requires further investigation.
The results of previous studies of GH therapy to decrease age-related bone loss have been mixed. One early study reported increased spine BMD with GH therapy in GH-deficient elderly men (8); however, subsequent clinical trials with recombinant human GH (rhGH) in elderly men and women revealed minimal or no increase (48, 49, 50, 51, 52, 53) or a decline (54) in BMD at various sites. However, the finding of increased bone formation over resorption in older women after a short course of low-dose rhIGF-I (55), suggests that longer term administration could conceivably enhance bone mass. Our findings in women support the recommendation that longer term clinical trials be conducted to determine the efficacy and safety of low-dose rhIGF-I to achieve anabolic effects on bone (9).
There are several limitations to this study. First, because the results are cross-sectional, a cause-and-effect relationship between IGF-I and BMD can only be inferred. Because IGF-I levels in old age remain relatively stable during shorter time periods (56) however, a single measurement of IGF-I likely represents an individual’s status for several years previously. Results from longitudinal studies of the relationship between changes in IGF-I and bone loss with age have not yet been published but are needed to confirm our findings. Second, because the study population was predominantly white, our findings may not be generalizable to older people of other races or ethnic groups. Furthermore, some participants who were not physically able to come to the Framingham clinic for BMD testing and a blood sample to determine IGF-I levels, including participants residing in nursing homes, were excluded from the study. If we had been able to include these participants, who tended to be very old and thus were likely to have had lower IGF-I levels (16, 17) and lower BMD (19, 20), it is possible that we would have found a stronger association between IGF-I level and BMD. Third, men who did not have spine BMD measurements were significantly older, more physically disabled, and had lower IGF-I levels and BMD at other sites than the men with spine measurements who were included in the study. If we had been able to include these men in our study, we might have found an association between low IGF-I level and spine BMD; however, the nonsignificant associations for this site were similar to those observed at the femur and the radius. Fourth, people with pathological conditions that could affect IGF-I levels were not excluded from the study; however we adjusted for other health-related factors that may be associated with both IGF-I and BMD including BMI, weight loss, impaired physical function, and protein intake. Fifth, protein intake was ascertained 4 yr previously because more recent protein intake data were not yet available. Inclusion of protein intake assessed at the same time as IGF-I measurement would allow for more complete adjustment for this factor. Finally, IGF-I bioactivity is also affected by IGF-specific binding proteins that were not measured in this study. Further delineation of the IGF regulatory system, including its relationship to changes in sex hormone concentrations with age, will be necessary to understand the mechanism by which IGF-I influences BMD in older people.
In conclusion, this study substantiates the relationship between higher IGF-I levels and the maintenance of BMD in very old women but not in men. Longitudinal studies are needed, however, to verify that declines in IGF-I are associated with age-related bone loss and to clarify the mechanisms underlying the association. These results suggest that future clinical trials employing GH may have a role in the development of treatments for older women with osteoporosis.
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Footnotes |
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2 Supported by National Heart, Lung and Blood Institute, NIH Contract
N01-HC-38038.
Received May 21, 1998.
Revised August 12, 1998.
Accepted August 17, 1998.
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