Longitudinal Changes in Forearm Bone Mineral Density in Women and Men Aged 2544 Years
The Tromsø Study: A Population-based Study
N. Emaus1,
G. K. R. Berntsen1,
R. M. Joakimsen2 and
V. Fønnebø1
1 Institute of Community Medicine, Faculty of Medicine, University of Tromsø, Tromsø, Norway
2 University Hospital of Tromsø, Tromsø, Norway
Correspondence to Nina Emaus, Institute of Community Medicine, Faculty of Medicine, University of Tromsø, NO-9037 Tromsø, Norway (e-mail: nina.emaus{at}ism.uit.no).
Received for publication January 18, 2005.
Accepted for publication April 28, 2005.
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ABSTRACT
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The aim of this study was to describe and compare bone mineral density (BMD) development in Norwegian women and men aged 2544 years in a population-based, longitudinal study. BMD was measured twice at distal and ultradistal forearm sites by single x-ray absorptiometry in 258 women and 147 men (mean follow-up time, 6.4 (standard deviation, 0.6) years). At the distal site, a small annual gain of approximately 0.1% became a small loss beginning at age 34 years in men and age 36 years in women. At the ultradistal site, BMD change was predicted by age in women only, and bone loss started at age 38 years. A high degree of tracking of BMD measurements was observed for both sexes and both sites, r > 0.93. Depending on total BMD change, participants were grouped into "losers," "nonlosers," and "gainers," and more than 6% lost more than the smallest detectable amount of BMD:
3.46% at the distal site and
5.14% at the ultradistal site. In both sexes, bone mineral content (grams) decreased, whereas area (centimeters squared) increased significantly in "losers" compared with "gainers." This finding might represent physiologic compensation preserving bone strength. No cohort effects were observed when 1994 and 2001 measures from similar age groups were compared.
bone density; bone development; densitometry; follow-up studies; forearm; longitudinal studies; men; women
Abbreviations:
BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density
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INTRODUCTION
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Osteoporotic fractures are a major health problem, with substantial morbidity and costs (1
, 2
). The cause of fracture is complex, but bone fragility is an important contributor to fracture risk (3
). Bone mineral density (BMD) is a good surrogate measure of bone strength, predicting 6070 percent of its variation (4
). A strong relation between BMD level and the probability of fracture has been documented (5
). Although fracture risk is best predicted by BMD measurements from the same anatomic site, no site is superior with respect to predicting all types of fragility fracture (5
). Single x-ray absorptiometry of the distal forearm is thought to be one of the most precise densitometric methods (6
9
), and peripheral BMD measurements can be used to assess fracture risk at both peripheral and central sites (5
, 10
, 11
).
BMD in the elderly is a function of the amount of bone gained during growth and the amount of bone lost during aging (12
, 13
). As such, both peak BMD and subsequent bone loss, as a result of decreasing bone mass and development of microarchitectural abnormalities and microdamage, are important determinants of the risk of osteoporotic fracture later in life (14
17
). Although a period of stability after completion of growth is generally assumed, bone loss probably begins when growth ceases (18
) and might therefore start during the early adult years in both women and men. The ages at which peak bone values are reached, premenopausal bone loss occurs in women, and bone loss occurs in young men have not yet been determined with certainty (19
22
). The associations among change in BMD (in grams per centimeter squared), area (in centimeters squared), and bone mineral content (BMC) (in grams) in young women and men are not clear either (23
).
Longitudinal studies on BMD changes during the third to fifth decades of life in women (24
37
) exist, but only those of Sowers et al. (27
, 29
), Guthrie et al. (30
), Chapurlat et al. (31
), Melton et al. (32
), and Bainbridge et al. (36
) are population based. Some longitudinal studies on BMD changes in young males have been published (28
, 34
, 38
40
); only the study of Khosla et al. (39
) is population based. Longitudinal studies including both sexes are scarce and are based on healthy volunteers (28
, 34
). Because studies based on selected populations may be subject to selection bias (41
), their accuracy might be questioned (20
). Development of bone mass in the age group 2544 years therefore has not been investigated sufficiently. In this age group, tracking and cohort effects have, to our knowledge, not been studied. The aim of the present study was to describe, compare, and explore aspects of BMD development in men and women aged 2544 years in a population-based longitudinal study through the following research questions:
- How does BMD develop in a general population between ages 25 and 44 years?
- Is BMD development similar in the two sexes?
- How well does initial BMD predict BMD at follow-up after 6 years?
- Can any cohort effects be seen before middle age?
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MATERIALS AND METHODS
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Study design and subjects
The Tromsø Osteoporosis Study (TROST) is part of the Tromsø study, a longitudinal, population-based, multipurpose study focusing on lifestyle-related diseases (42
). The Tromsø study was initiated in 1974, with surveys repeated in 19791980, 19861987, 19941995, and 2001. In 1994 (Tromsø IV), the Tromsø Osteoporosis Study measured bone density in 637 subjects (396 women and 241 men) aged 2544 years. These numbers corresponded to 64 percent of the women and 56 percent of the men invited to participate (43
). In 2001 (Tromsø V), 631 of the subjects still living in Tromsø were invited for a reexamination. Bone densitometry was performed on 405 subjects (258 women and 147 men)65 percent of the invited women and 60 percent of the invited men. The follow-up examination included 42 percent of the women and 34 percent of the men originally invited in 1994. After we excluded invalid scans, 253 repeated measurements at both sites in women and 141 and 142 repeated measurements at the distal and ultradistal sites, respectively, in men remained. Mean age at baseline was 36 (standard deviation, 5.3) years for participating women and 36.5 (standard deviation, 5.8) years for participating men. Mean follow-up time was 6.4 (standard deviation, 0.6) years.
Informed consent was obtained prior to both examinations. The regional Committee of Research Ethics and the Norwegian Data Inspectorate approved the study.
Measurements
Bone densitometry was performed at both surveys at the distal and ultradistal forearm sites with two single x-ray absorptiometry devices (DTX-100; Osteometer MediTech, Inc., Hawthorne, California). The distal site includes both the radius and ulna from the 8-mm point (the point at which the ulna and radius are separated by 8 mm) and 24 mm proximally. The ultradistal site includes only the radius and stretches from the 8-mm point up to the radial endplate. The nondominant arm was measured except when it was considered ineligible because of wounds, plaster casts, and so on.
Starting at the second survey, one of the two densitometers underwent a major repair. Later, the x-ray tube had to be replaced in both densitometers. Quality control routines, in which the European Forearm Phantom (QRM GmbH, Meohrendorf, Germany) was used, revealed that one of the machines measured at a higher BMD level before the x-ray tube was replaced, the mean difference being 0.005 g/cm2. The European Forearm Phantom data were used to adjust the differences in densitometer measurement level. The internal variation in each machine studied by using the coefficient of variation (coefficient of variation percent = standard deviation/mean x 100) and by comparing the European Forearm Phantom measurement level during different time periods was satisfactory, with a mean coefficient of variation of 0.9 percent (44
).
The same protocol was used in both studies. Quality control with respect to precision and correction of artifacts in Tromsø IV has been reported previously (9
, 45
). Four trained technicians, one of whom also conducted the Tromsø IV analysis, reanalyzed the scans from Tromsø V. To test for reliability, we obtained three intra-tests (each technician compared with himself or herself) and three inter-tests (each technician compared with the other technicians). Each pair of technicians reviewed a minimum of 27 and a maximum of 127 similar scans. We missed one intra- and inter-test possibility for one technician reviewing 19 of the scans included in this study. At the distal site, there were no significant differences with respect to BMD between the technicians in either intra- or inter-testing. At the ultradistal site, however, there were significant differences in BMD between the technicians in two of the three intra- and two of the three inter-tests. From these tests, we could determine that the measurements of one technician, who reviewed 245 scans, were approximately 0.001 g/cm2 lower than those of the others. This difference would entail an effect of less than 1 percent on the annual bone loss estimates (in grams per centimeter squared) and reduce the percentage change estimates by 0.02 percentage points. We compared annual change estimates (in grams per centimeter squared), and they were not technician influenced, p > 0.29, at any sites (analysis of variance). We therefore decided not to correct the data.
Other measurements
Height and weight were measured, using a Jenix DS-102 stadiometer (Dong Sahn Jenix Co., Ltd., Seoul, Korea), to the nearest centimeter and half kilogram, respectively; study participants wore light clothing without shoes. Conditions that unduly influenced the measurements were recorded. Body mass index was calculated as weight in kilograms divided by the square of height in meters.
Questionnaires
The Tromsø IV participants filled in two self-administered questionnaires on different lifestyle variables, one before entering the study and one during the study. We used data on self-perceived health, level of physical activity, smoking status, and calcium intake to assess possible selection bias in the material. Women's menstrual status at baseline was also derived from answers on the questionnaires or from measured follicle-stimulating hormone levels in 152 of the participants. Women who were not using hormone replacement therapy, who were not pregnant, whose time since last menstruation was less than 180 days, or whose follicle-stimulating hormone level was less than 23 were classified as premenopausal (n = 234). Women who were not using hormone replacement therapy, who were not pregnant, and whose time since last menstruation was 180365 days were classified as perimenopausal (n = 1). Women not using hormone replacement therapy and whose time since last menstruation was more than 365 days were classified as postmenopausal (n = 5). Finally, women using hormone replacement therapy were classified as hormone replacement therapy users (n = 5). When information about menstruation or follicle-stimulating hormone levels was lacking, menopausal status was defined as missing (n = 13). Results of analyses conducted with and without data on nonpremenopausal women were similar, which is why we chose to present the analysis for the entire population only.
Statistical analysis
BMD measurements from intra- and inter-testing were compared by using a one-sample paired t test. To investigate possible selection bias, we compared basic characteristics of those participating in both surveys with those participating in only Tromsø IV by using independent two-sample t-test and chi-square testing for continuous and categorical variables, respectively. BMD change was estimated by determining the difference between Tromsø V and Tromsø IV measurements. Annual BMD change was calculated as the difference between the two measurements divided by the length of each participant's follow-up time. Dividing the difference by the baseline measure and multiplying by 100 enabled us to estimate the annual percentage changes. In this paper, these changes are presented, by 5-year age groups at baseline, as milligrams per centimeter squared with 95 percent confidence intervals. Annual change in area (centimeters squared), BMC (grams), and bone mineral apparent density (BMAD) was calculated in the same way. BMAD at the distal site was estimated according to Katzman et al.: BMAD = BMD/area (46
). Since all areas of the distal site have a constant length of 24 mm, the area is a direct measure of average bone width and is therefore presented as milligrams per centimeter squared. Since both length and width vary for the ultradistal area, BMAD was not calculated for this site.
Regression analysis was used to investigate how age and sex influenced BMD, area, and BMAD changes. Interaction between age and sex was analyzed, and a p value of >0.10 was interpreted as no significant interaction between the variables. To estimate peak bone mass, we plotted annual change against baseline age by using scatter plots with a regression line. The point at which the line of regression crossed zero on the y-axis was interpreted as "end-of-gain and start-of-loss age."
The amount of total BMD change was used to categorize the groups into "losers," "nonlosers," and "gainers." The minimal difference, which represents true biologic change with 95 percent certainty (95 percent detection limit), can theoretically be calculated by using the following formula:
(47
). For an intermediate term between two measurements, median coefficients of variation estimated on our data were 1.25 at the distal site and 1.86 percent at the ultradistal site (9
). Participants gaining or losing more than ±3.46 percent were categorized as true "gainers/losers" at the distal site. At the ultradistal site, the equivalent detection limit was ±5.14 percent. Area and BMC development in the different loss groups was compared by analysis of variance.
Tracking between the first and second measurements was assessed by using Pearson's correlation coefficient. We further divided BMD values measured at baseline and at follow-up into four quartiles, the highest categorized as position 1 and the lowest as position 4 in both studies. The values from both studies were categorized respectively, and each subject's position in both studies was compared. The distribution of quartile BMD positions at baseline according to the different loss groups was assessed with chi-square testing, Fisher's exact test.
To assess the cohort effect, we extracted four comparable cohort groups comprising persons aged 3335 and 4345 years in 1994 and those aged 3335 and 4345 years in 2001. BMD level for the relevant cohort groups was compared by independent two-sample t test. The statistical analysis was performed with SPSS software, version 11 (SPSS, Inc., Chicago, Illinois). A p value of <0.05 was regarded as statistically significant.
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RESULTS
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Comparison of responders and nonresponders
Data for the first study in Tromsø IV were compared for nonresponders, partial responders, and full responders. The analysis gave no indication of any differences between the groups (43
). After Tromsø V, we could use baseline characteristics from Tromsø IV to compare participants lost to follow-up with those who attended both studies. The results from the analysis are displayed in table 1.
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TABLE 1. Comparison of participants lost to follow-up (participating in Tromsø IV only) with those who participated in both the Tromsø IV (19941995) and Tromsø V (2001) longitudinal studies, Norway
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Changes in BMD
The general characteristics at baseline of those who participated in both studies are displayed in table 2 according to 5-year age groups. Changes in BMD in both sexes according to 5-year age groups are shown in table 3 and figure 1.
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TABLE 2. Baseline characteristics of the participants in the Tromsø IV (19941995) and Tromsø V (2001) longitudinal studies, Norway, according to 5-year age groups
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TABLE 3. Annual bone mineral density changes in participants in the Tromsø IV (19941995) and Tromsø V (2001) longitudinal studies, Norway, comparing age groups by sex
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FIGURE 1. Annual percentage changes in bone mineral density (BMD), with 95% confidence intervals, at the distal site (top) and the ultradistal site (bottom), by age in women and men in the longitudinal Tromsø IV (19941995) and Tromsø V (2001) studies, Norway. Trend: p = 0.005 for women and p < 0.001 for men at the distal site, and p = 0.001 for women and p = 0.248 for men at the ultradistal site.
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At the distal site, BMD change was predicted by baseline age (p < 0.001) but not by sex (p = 0.089). There was no significant interaction between baseline age and sex (p = 0.127). For every 5-year increase in age, the BMD-change estimate declined by 0.1 percentage points. Before peak bone density was attained, growth was reduced by 0.1 percentage points for every 5 years. After peak bone density was achieved, bone loss increased by 0.1 percent every 5 years. Peak bone density was attained by age 36 years in women and by age 34 years in men (figure 2).

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FIGURE 2. Annual percentage changes in bone mineral density (BMD), with the line of regression and its 95% confidence interval, at the distal site (top two parts) and the ultradistal site (bottom two parts) in women (left) and men (right) in the longitudinal Tromsø IV (19941995) and Tromsø V (2001) studies, Norway. Peak BMD occurs where the line of regression crosses 0 on the y-axis: age 36 years at the distal site in women, age 34 years at the distal site in men, and age 38 years at the ultradistal site in women; no linear association was found between age and BMD change at the ultradistal site in men.
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At the ultradistal site, BMD change was predicted by sex (p = 0.038), and a linear association was found between baseline age and BMD change in women (p = 0.005). In men, the linear BMD change estimate was not significantly different from zero (p = 0.239). A smaller BMD change in the age group 4044 years compared with the previous age groups indicated a possible nonlinear association at the ultradistal site for men; therefore, test of linear interaction between age and sex was not assessed.
In women, the BMD change estimate at the ultradistal site declined by 0.15 percentage points for every 5-year increase in age. Before peak bone density was attained by age 38 years, growth was reduced by 0.15 percentage points for every 5 years. After peak bone density was achieved, bone loss increased by 0.15 percentage points for every 5 years (figure 2).
One man in the age group 2529 years and one in the age group 4044 years had an annual loss of 0.013 g/cm2 and an annual increase of 0.008 g/cm2, respectively. Excluding these outliers did not alter the lack of association between age and BMD change at the ultradistal site (p = 0.061) for men (figure 2).
Changes in area and BMAD
BMD is size dependent, and BMD changes may reflect changes in size rather than in mineral content. We therefore calculated area and BMC changes, and the results are given in table 4. The area declined slightly and similarly at the distal site, and it increased slightly and similarly in the two sexes at the ultradistal site. Changes in BMAD followed the same pattern as BMD changes in both sexes at the distal forearm site and was negatively predicted by age (p = 0.001) but not by sex (p = 0.16).
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TABLE 4. Annual changes in area, BMC,* and BMAD* in participants in the Tromsø IV (19941995) and Tromsø V (2001) longitudinal studies, Norway, comparing age groups (years) by sex
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"Losers," "nonlosers," and "gainers"
Table 5 displays the distribution of "losers," "nonlosers," and "gainers" for both sexes. The distribution of quartile BMD positions at baseline was not significantly different between loss groups. At both sites and in both sexes, BMC followed the same pattern as BMD, declining in "losers" and increasing in "gainers," whereas the area increased significantly in "losers" and declined in "gainers" (figure 3).
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TABLE 5. Distribution of participants in the Tromsø IV (19941995) and Tromsø V (2001) longitudinal studies, Norway, into different loss groups based on the total percentage of loss compared with baseline bone mineral density
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FIGURE 3. Annual percentage changes in area and bone mineral content (BMC) at the distal site in women (left) and men (right) according to three change groups in the longitudinal Tromsø IV (19941995) and Tromsø V (2001) studies, Norway. Trend: p < 0.001 for area and BMC in women, and p < 0.001 for area and p = 0.004 for BMC in men.
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Tracking and cohort effects
The correlations between the BMD measurements in the two studies were high and were similar for the two sexes: distal and ultradistal sites for women: r = 0.97 and r = 0.93; distal and ultradistal sites for men: r = 0.97 and r = 0.94, respectively (p < 0.001). The correlations in area and BMC were also high at the distal site: r > 0.97 for both sexes. At the ultradistal site, the correlations between area measurements were r = 0.88 for women and r = 0.86 for men, and the correlations between BMC measurements were r = 0.74 for women and r = 0.60 for men.
For both sexes, 7580 percent kept their quartile BMD position from the first to the second survey, whereas 1013 percent either lost or gained one position at the distal site. This loss or gain was evenly distributed from all original quartile positions. A similar pattern was seen at the ultradistal site: 7273 percent kept their quartile position, 1112 percent lost one quartile, and 1214 percent gained one quartile, also from all quartile positions. Two percentfour womenlost two quartiles, all from the highest quartile. From the analysis, we concluded that only those who were close to the quartile "borders" changed positions, and the changes occurred in any direction. As such, the degree of tracking was extremely high for both sexes before middle age.
The BMD levels of the different cohort groups are shown in table 6. No significant differences in BMD levels between the compared cohort groups (p > 0.5) were observed.
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TABLE 6. Cohort-effect analysis of the bone mineral density (g/cm2) of participants in the Tromsø IV (19941995) and Tromsø V (2001) longitudinal studies, Norway
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DISCUSSION
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The main finding from this population-based, longitudinal study was that BMD change at the distal forearm site was similar in the two sexes. An annual increase of approximately 0.1 percent in the age group 2534 years became a small loss at the distal site beginning at age 34 years in men and at age 36 years in women. There was a high degree of tracking, and no cohort effects were observed when measures from similar age groups were compared in 1994 and 2001. A small group of women and men lost a substantial amount of BMD before middle age; however, this loss seemed to be compensated for by an area increase (in centimeters squared).
One of the strengths of this study is its long follow-up period. With the precision of current methods for measuring bone mass, accurate estimates of rates of bone loss require long periods of follow-up (48
), with the small magnitude of the decrease occurring before middle age (49
). More than 6 years of follow-up, including strict quality control of densitometer performance in both studies, provided the opportunity for accurate documentation of changes in bone mass.
Nonresponse may generate selection bias. For both sexes, participants lost to follow-up were younger than those participating in both studies. Since we analyzed the data in 5-year age groups, this bias should not have influenced the estimates, giving smaller numbers for the youngest age groups only. For women, the percentage of present smokers was equal in the two groups, but participating women had smoked 1 year longer than participants lost to follow-up (p = 0.03). However, the total number of cigarettes smoked was not significantly different when the two groups were compared. The percentage of present smokers tended to be higher among the male participants lost to follow-up (p = 0.06), but smoking pack-years and total number of cigarettes smoked were not significantly different in the compared groups. Smoking might influence bone health in a negative direction, with a cumulative effect by age (50
). In our study, smoking pack-years did not predict BMD changes in women (p = 0.163 and p = 0.222 at the distal and ultradistal sites, respectively), and smoking status did not predict BMD changes in men (p = 0.238 and p = 0.051 at the distal and ultradistal sites, respectively). We therefore assume that our results were not influenced by selection bias. To test for its possible effect at the ultradistal site in men, we calculated how BMD changes would be influenced by an increase in the proportion of current smokers in the data, and the effect was negligible.
The findings from our study support the indication that bone loss starts during the third decade of life (18
). Comparable studies with different results have been published. Chapurlat et al. (31
) used dual energy x-ray absorptiometry to follow 196 premenopausal women over 3 years in a population-based study. They found that women aged 3050 years had an annual BMD increase of 0.24, 0.4, and 0.02 percent at the midshaft, distal, and ultradistal radius sites, respectively. The rate of change was not significantly different when women aged 3040 and 4050 years were compared. Khosla et al. (39
) followed a population-based sample of 315 men aged 2290 years over 4 years by using dual energy x-ray absorptiometry. Men aged 2239 and 4059 years had an annual BMD increase of 0.4 and 0.24 percent, respectively, at the mid-distal radius (39
). Age-stratified analysis was not presented. No longitudinal results from the ultradistal radius are reported for young men.
Our findings of bone loss starting at the distal forearm site in the third decade of life are in contrast to Chapurlat et al. (31
) and Khosla et al. (39
) reporting no loss in the comparable age groups. This discrepancy might be influenced by differences in machine performance, length of follow-up, or variations in the population. Our study has its strengths, with the longest follow-up, high response rates, and strict quality control routines. The coefficient of variation reported in the study by Khosla et al. is 2.1 percent compared with our 0.9 percent (43
). However, our study was based on a Scandinavian population that, together with North-American Whites, is known to have the highest incidence of forearm, proximal humerus, and hip fractures (51
55
). The discrepancy in findings might therefore represent true population differences, which should be studied further.
Eighty-five percent of the total bone in the body is cortical, and it is relatively most abundant in the long bone shafts of the appendicular skeleton (56
). With the distal site containing mainly cortical and the ultradistal site mainly trabecular bone (57
), both types can be studied as at the distal forearm. Because of the different environments of the bone cells, decline in trabecular bone mass is thought to begin earlier than cortical bone mass (56
). An earlier and greater bone loss would therefore be expected at the ultradistal site. However, opinions differ regarding this issue (56
), and our findings are in concordance with recent studies from other comparable sites. Bainbridge et al. (36
), who followed a cohort of 614 women aged 2444 years over 6 years, reported an annual bone loss of 0.3 percent beginning by the mid-twenties at the femoral neck (75 percent cortical bone), with no evidence of early bone loss at the lumbar spine (>60 percent cancellous bone) (36
).
BMD changes did not differ significantly at the distal site when the two sexes were compared. At the ultradistal site, the trend regarding change was significant in women but not in men, with women gaining significantly in the age group 2529 years. The main impact of estrogen deficiency is on trabecular bone (58
). Because this study comprised mostly premenopausal women whose sex hormone levels are expected to be high, it was actually not surprising to find that the youngest women, those aged 2529 years, gained a significant amount of BMD at the ultradistal forearm site (table 3, figures 1 and 2).
An annual loss of 0.1 percent over 10 years indicates a loss of approximately 1 percent from peak value, before the more extensive loss starts at middle age in women. As stated by Riis (59
), this loss might not be of any clinical relevance, and the degree of tracking in BMD measurements is high. Tracking of a characteristic is defined as the ability to maintain the same position within a distribution over time (60
, 61
) or the ability to predict future values from earlier measurements (62
, 63
). Despite the high degree of tracking, there was some interindividual variation in both sexes, with 67 percent losing more than 3.46 percent of their BMD in 6 years (more than 0.5 percent annually). This represents a substantial amount of early bone loss, which might lead to an early increased fracture risk (64
). It is interesting to note that the area (in centimeters squared) increased significantly in "losers" compared with "gainers," which might represent a physiologic compensation of periosteal apposition resulting in an increased area that seeks to preserve bone strength (18
, 23
, 65
, 66
).
We observed no cohort effect when measurements from similar age groups in the studies were compared, indicating that BMD changes can be derived from cross-sectional studies in this age group. This observation is in contrast to that of Melton (67
), who argued that cross-sectional data tend to overestimate bone loss rates observed longitudinally at many sites, and to our own cross-sectional data that indicated higher bone loss rates in both sexes at both forearm sites (43
).
In conclusion, changes in BMD in the age group 2544 years are significantly explained by age, but not by sex. The degree of tracking between measurements is high, but a clinically significant group of both women and men experience bone loss before middle age. However, the observed loss might be compensated for by an increase in area, which preserves bone strength. This effect needs to be explored further in other populations.
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ACKNOWLEDGMENTS
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This study was financed by grants from the Norwegian Foundation for Health and Rehabilitation and from the Research Council of Norway.
Conflict of interest: none declared.
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