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Bone Density and Bone-Related Biochemical Variables in Normal Men

A Longitudinal Study

^a Department of Medicine, University of Adelaide, South Australia, Australia
^b Division of Clinical Biochemistry, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia

F. Scopacasa, Division of Clinical Biochemistry, Institute of Medical and Veterinary Science, Frome Road, Adelaide, South Australia 5000, Australia E-mail: franca.scopacasa{at}adelaide.edu.au.

	Abstract

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Background. The objective of this study was to determine the pattern of forearm bone loss and its relationship to markers of bone turnover and sex steroids in normal men. This was a longitudinal study over a median interval of 41 months. The study was conducted in Adelaide, Australia. Study participants were 123 healthy male subjects, between the ages of 20 and 83 years.

Methods. Fat-corrected forearm bone mineral content (fcBMC), markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type 1 C-terminal extension peptide) and bone resorption (collagen type I cross-linked telopeptide, hydroxyproline/creatinine, pyridinoline/creatinine, and deoxypyridinoline/creatinine), calculated serum bioavailable testosterone, and serum estradiol were measured.

Results. The mean time-weighted rate of change in forearm fcBMC was -0.33% ± 0.72 (SD) per year. Bone loss commenced after 30 years of age and increased with age (p < .001), particularly after age 70 years. There was no relationship between the rate of change in fcBMC and either markers of bone turnover or serum sex steroids.

Conclusions. In normal men, bone loss increases with age; there does not appear to be any relationship between this loss and either markers of bone turnover or levels of free androgen or estrogen.

ALTHOUGH osteoporosis is more common in women, age-related bone loss also occurs in men and is associated with an increase in fracture risk ⁽¹⁾. In Caucasians, 10–15% of vertebral fractures and 20–30% of hip fractures occur in men ⁽²⁾. In women, the patterns and determinants of bone loss have been well studied. At menopause, bone loss occurs as a result of estrogen deficiency, and this is characterized by increased bone turnover, with a relative increase in bone resorption that is sustained throughout life ⁽³⁾. However, in men, the patterns and etiology of bone loss during aging are poorly defined. Cross-sectional studies suggest that aging is associated with bone loss at the radius and hip ^(4)(5)(6)(7), with little or no loss at the spine ^(4)(6)(7)(8). Only eight longitudinal studies have evaluated the effects of aging and bone mineral density in men ^{(1)(5)(9)(10)(11)(12)(13)(14)}. These have provided evidence that bone loss accelerates with age at the radius ^{(1)(5)(9)(10)(11)} and hip ^(1)(13)(14); in contrast, measurements at the spine have yielded discrepant results, with Jones and colleagues ⁽¹⁾ and Dennison and colleagues ⁽¹⁴⁾ (using dual energy x-ray absorptiometry) reporting no loss of bone in older men, while Orwoll and colleagues ⁽⁹⁾ [using computed tomography (CT) scanning] found significant loss at this site.

The effects of aging on biochemical markers of bone turnover in men are also poorly defined and are controversial. A fall in biochemical markers of bone turnover with age has been reported ^{(7)(15)(16)(17)}; while others have suggested that there is no change ^(18)(19) or an increase ^{(20)(21)(22)(23)(24)}. In considering potential factors that may trigger bone loss during aging in normal men, both cross-sectional and longitudinal studies have established that androgen levels (free or bioavailable testosterone) decrease with age ^(25)(26)(27). However, studies that have evaluated the relationship between bone density and plasma androgen concentrations in men have yielded inconsistent results ^{(24)(26)(28)(29)(30)(31)(32)(33)}. Furthermore, most of these studies have been cross-sectional. There is recent evidence that estrogen may also play a role in the maintenance of bone mass in men, as well as in women ^(24)(31)(34). Environmental factors such as calcium intake, smoking, alcohol, and physical activity may also influence the rate of bone loss ^{(4)(10)(35)(36)}.

To further investigate the patterns and determinants of bone loss in normal men, we have performed a longitudinal study of forearm bone density and related this to biochemical markers of bone turnover, serum testosterone, and estradiol, using the cohort reported in our previous cross-sectional study ⁽⁷⁾.

	Methods

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The subjects were derived from the 147 normal Caucasian men who participated in our cross-sectional study performed in 1990–1993 ⁽⁷⁾ and included healthy laboratory staff, hospital workers, their relatives, and healthy husbands of female patients. Of this original cohort, 123 subjects (age range 20–83 years) agreed to participate in the longitudinal study, in which demographic, bone density, and biochemical measurements were repeated after a median interval of 41 months (range 18–67). Of the 24 subjects in the initial cohort who were not included in the follow-up study, 11 could not be located, six were excluded due to incomplete measurements, and seven declined to participate. Subjects who participated in the follow-up study were all healthy and were not taking any medication known to affect mineral metabolism. In all subjects, calculated creatinine clearance was >30 ml/minute [mean 107 ± 26 (SD)]. All subjects gave written, informed consent, and the study protocol was approved by the Research Ethics Committee of the Royal Adelaide Hospital.

In all subjects, dietary intake of calcium, salt, and alcohol; tobacco consumption; and physical activity were evaluated by questionnaire ⁽³⁷⁾ on entry to the study, and these measurements were repeated at the follow-up visit.

Bone Mineral Density
Bone mineral density (BMD) was measured in the distal forearm at baseline and follow-up by single photon absorptiometry with the Molsgaard Bone Mineral Analyser. The forearm was placed in a water bath, and scanning commenced at an interosseous space of 8 mm, with six scans being performed proximal to this point at 4-mm intervals. Forearm fat content, fat-corrected forearm bone mineral content (fcBMC g/cm), and fat-corrected volumetric BMD (vBMD mg/cm³) were calculated ⁽³⁸⁾. The precision error for the fcBMC is approximately 1% ⁽³⁹⁾, which is substantially less than for the currently available techniques to evaluate vertebral and hip density. The high precision of this machine is probably attributable to the constant tissue-like depth throughout the scan region.

Biochemical Measurements
Each subject fasted from 2100 hours, voided on waking, and attended the hospital between 0900 hours and 1100 hours for collection of a venous blood sample and a urine sample. Serum or plasma was analyzed for plasma calcium fractions, alkaline phosphatase (ALP), -glutamyl transferase (GGT), and creatinine by standard methods (DAX 48, Technicon, Tarrytown, NY). Serum testosterone was measured by radioimmunoassay following extraction by in-house procedures [interassay coefficient of variation (CV) 7.2% at 24 nmol/l and limit of detection of 0.2 µg/l]. Sex hormone binding globulin (SHBG) was measured by radioimmunoassay (Farmos, Espoo, Finland, with an interassay CV 5.2% at 11 nmol/l and limit of detection of 6 nmol/l). Bioavailable testosterone (CbT) was calculated from the total testosterone and SHBG concentrations using an equation proposed by Haren and colleagues, and hypogonadism was defined according to the age-specific reference ranges derived from the study ⁽⁴⁰⁾. Dehydroepiandrosterone sulphate was measured by radioimmunoassay (interassay CV 7.6% at 14.1 µmol/l). Serum estradiol was measured at the second visit by the Abbott IM-X microparticle immunoassay (interassay CV 15% at 150 pmol/l). Serum osteocalcin was determined by an in-house radioimmunoassay using a polyclonal antibody that measures both intact osteocalcin and some of its larger fragments (interassay CV 14% at 5 µg/l and limit of detection 0.2 µg/l) ⁽⁷⁾, 25-hydroxyvitamin D (25OHD) by protein binding assay ⁽⁴¹⁾, and 1,25-dihydroxyvitamin D (1,25D) by high performance liquid chromatography (HPLC) and immunoassay ⁽⁴²⁾. Serum parathyroid hormone (PTH) was measured using an immunoradiometric assay for the intact molecule (Incstar, Stillwater, MI, interassay CV 14.5%). Collagen type I cross-linked telopeptide (ICTP) and procollagen type 1 C-terminal extension peptide (PICP) were measured at the first visit only by radioimmunoassay (Farmos, Espoo, Finland, with interassay CV 5.7% at 6.2 µg/l and limit of detection 0.5 µg/l for ICTP; interassay CV 6.6% at 215 µg/l and limit of detection 1.2 µg/l for PICP).

Hydroxyproline (OHPr) (interassay CV 5.5%) and creatinine (Cr) were measured in the urine by standard methods and were expressed as the ratio OHPr/Cr (umol/mmol). Urinary pyridinoline [interassay CV 5.7% and radioimmunoassay (Farmos, Espoo, Finland) with interassay CV 5.7% at 6.2 µg/l and limit of detection 50 nmol/l] and deoxypyridinoline [interassay CV 9.0% and radioimmunoassay (Farmos, Espoo, Finland) with interassay CV 5.7% at 6.2 µg/l and limit of detection 15 nmol/l] cross-linked peptides were measured by HPLC ⁽⁴³⁾ and expressed as nmol/mmol of creatinine (Pyd/Cr and Dpd/Cr, respectively). Urinary sodium, calcium, phosphate, and creatinine were measured and expressed as their molar ratios to urine creatinine.

Statistical Methods
Relationships between rates of change in fcBMC and baseline biochemical variables were examined by simple linear regression and analysis of variance, apart from the relationship with estrogen, as the latter was measured at the follow-up visit only. Age correction was performed by multiple linear regression. Differences between baseline and follow-up measurements were analyzed using Student's paired t test, as the data were distributed normally. Due to the large number of variables, correlations derived from multiple comparisons between rates of change in fcBMC and biochemical variables were considered significant at a p value of < .005 and paired comparisons of biochemical measurements at a p value of < .01. Data are shown as mean ± SD, unless stated otherwise.

The longitudinal data for fcBMC are presented as cumulative sums (cusums). The projection of a segment on the horizontal axis represents the period of time over which the subject was observed; the projection on the vertical axis represents the percent change in measurement over that period of time. The segments are joined end to end, and the total cumulative change during the total number of observed patient-years is represented by the final end point on the graph. The weighted mean slope of the individual segments, using time as the weighting factor, is the slope of the line joining the origin and the end point ⁽⁴⁴⁾. The subjects were also stratified according to age, and a time weighted rate of change in bone density was calculated for each group. Differences between groups were tested with Student's unpaired t test for mean rates of loss.

	Results

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Demographic variables and bone density measurements at baseline and follow-up are summarized in Table 1 . There was no change in dietary calcium, alcohol, or salt intake, or cigarette consumption. Body weight and forearm fat content increased (p < .001 for both), and physical activity decreased (p < .01). The mean vBMD decreased significantly between the two measurements (p < .05). The mean annualized percentage change was inversely related to age in the entire group (r = -.32, p < .0001). The mean annualized time weighted rate of change in fcBMC was -0.33% ± 0.72 (p < .0001). There was no change in fcBMC in the 20 to 30-year-old subjects; in all the subsequent age groups, there was significant bone loss (p < .02 for all groups) (Fig. 1). There was a trend for bone loss to increase across the groups (Fig. 1), with significant differences between the rates of change in the youngest age group (0.01% ± 0.18) and the oldest age groups (-1.5% ± 0.52) (p < .01) and between rates of loss in the subjects 30–70 years of age (-0.34% ± 0.07) and those older than 70 years of age (-1.5% ± 0.52) (p < .001).

View larger version (15K): [in this window] [in a new window]   Figure 1. Cumulative plot of sequential changes in the percentage change in fat-corrected forearm mineral content (fcFMC). Each line segment represents an individual case in which the percentage change in fcFMC is plotted against duration of observation in years. The subjects are stratified into groups according to age. The slopes of the line represent the rates of change in fat-corrected bone mineral content (fcBMC). The weighted mean slopes for each decade are 20–30 years: 0.01 ± 0.18 (NS, n = 12); 31–40 years: -1.18 ± 0.07 (p < .05, n = 34); 41–50 years: -0.38 ± 0.15 (p < .05, n = 20); 51–60 years: -0.43 ± 0.15 (p < .01, n = 25); 61–70 years: -0.53 ± 0.22 (p < .05, n = 24); > 70 years: -1.5 ± 0.52 (p < .05, n = 8).

As there is evidence that bone loss in men begins after age 50 ^(6)(7)(11), subjects were divided at 50 years of age into two subgroups. There was significant bone loss at the forearm in both groups, although loss was greater in the older group (-0.60% ± 1.1 vs -0.22% ± 0.64, p < .05). The change in fcBMC was not related to any of the demographic variables or markers of bone resorption and formation in either of the two subgroups (data not shown). The change in bone density was not related to any of the hormonal variables in either the younger group or the older group.

	Discussion

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We have performed a longitudinal study to determine the effects of aging on forearm fcBMC and bone-related biochemical variables over a 3-year interval in healthy men. The results establish that there is a reduction in forearm fcBMC during this time and suggest that loss in men older than 70 years of age may be accelerated. We were unable to establish a link with bone loss with either biochemical markers of bone turnover or plasma testosterone concentrations.

The mean forearm bone loss of 0.34% in this study is similar to the 0.45% annual loss reported by Slemenda and colleagues ⁽¹⁰⁾ (over 16 years) and less than the 1% annual loss reported by Orwoll and colleagues ⁽⁹⁾ (over 3 years) at this site. Our cross-sectional study in men indicated that bone loss was 0.6% per year in men over 50 years ⁽⁷⁾. In the present study, bone loss in the distal forearm was related to age and appeared to commence after about 40 years (Fig. 1); the rate of loss was greatest in men older than 70 years. Orwoll and colleagues ⁽⁹⁾ found a similar, although weak, relationship at the forearm, while Davis and colleagues ⁽⁵⁾ reported an accelerated rate of bone loss at the calcaneus and radius, particularly in men older than 75 years. Our cross-sectional study suggested that bone loss in the forearm began at about 50 years ⁽⁷⁾. In the current study, when subjects were stratified into two groups up to and above 50 years of age, significant bone loss in the forearm was evident in both groups, with the rate of loss being three times greater in men over 50 (0.60% per annum) when compared with men up to 50 years (0.22% per annum). Hence, bone loss in men appears to commence before age 50 and accelerate after that time. We chose the forearm site for our sequential measurements due to the high precision of the Molsgaard instrument, the established high correlations with other sites, including the hip and spine with this technique ⁽⁴⁵⁾, and the capacity of the forearm measurement to predict fractures in postmenopausal women ⁽⁴⁵⁾. In healthy postmenopausal women, the rate of change in forearm bone density is related to hydroxyproline/creatinine, urine calcium, and serum estrone ⁽⁴⁶⁾. Information relating to the effects of aging on hip and spine would, however, be of interest.

The observed fall in plasma osteocalcin is indicative of a decrease in bone formation. This decline was also evident in our cross-sectional study ⁽⁷⁾. Studies in men relating to the effects of aging on osteocalcin have yielded discrepant results: some studies have found either a fall or no change with age ^(47)(48)(49), and others have found an age-related rise ^(20)(50) in osteocalcin. Histomorphometric studies by Clarke and colleagues ⁽¹⁵⁾ suggest that age-related bone loss in men may partly reflect a decrease in osteoblast function, which would result in decreased bone formation. Although we observed a rise in plasma ALP with age, this increase is likely to be attributable to increased hepatic production that occurs with aging, as GGT (also produced in the liver) also increased with age. Furthermore, in our cross-sectional study, we observed an age-related fall in bone-specific ALP ⁽⁷⁾; the latter is a more specific marker of bone formation.

There was no significant change in urinary deoxypyridinoline or hydroxyproline, suggesting that bone resorption does not increase with age. While hydroxyproline is less than optimal as a marker of bone resorption, this observation is consistent with the study by Francis and colleagues ⁽⁵¹⁾. Furthermore, in our cross-sectional data, there was a slight fall in markers of bone resorption with age ⁽⁷⁾. While there was a rise in pyridinoline excretion in the current study, the magnitude of the change was small, and this marker is less specific than deoxypyridinoline ⁽⁵²⁾. The observed rise in PTH with advancing age is consistent with previous studies ^(7)(53)(54) and is of uncertain etiology in the absence of changes in 1,25D or serum calcium (data not shown).

None of our subjects had 25OHD deficiency. Moreover, there was no significant change in serum 25OHD between the first and second samples, which appears to conflict with other studies showing a fall in 25OHD with age. In this study, the first set of samples were collected over both summer (October–March) (56%) and winter (April–September) months (44%) while the majority of the second set were collected over the winter months (83%). Accordingly, if anything, 25OHD levels may have been expected to be lower in the second set of samples, whereas the mean value was slightly higher. We cannot exclude the possibility that lifestyle may have changed in some of our subjects, who may have retired and consequently had a greater amount of leisure time outdoors.

SHBG fell over the 3-year interval, in contrast to observations in other studies reporting an increase in SHBG with age ^(25)(55)(56), including our cross-sectional study ⁽⁷⁾. Part of the fall in SHBG may potentially be attributable to the rise in body mass index, because SHBG is known to be inversely associated with BMI ⁽⁵⁵⁾.

In comparison to women, who have a rapid rate of bone loss immediately following menopause, the rate of loss in men is slower ^(7)(10). It should, therefore, be recognized that the lack of an association between bone loss and the markers of bone turnover may potentially be due to the relatively slow rate of loss over the 3 years of this study; a longer time interval of observation and a larger cohort would be required to exclude any association.

A number of dietary and demographic variables may potentially affect the rate of bone loss during aging. There is evidence that dietary calcium is an important determinant of BMD at the spine and femoral neck in men ⁽³⁵⁾; high dietary calcium has been associated with suppression of bone resorption in normal men ⁽⁵⁷⁾ and also a decreased risk of hip fracture in both men and women ^(58)(59)(60). Our findings support previous longitudinal studies ^(1)(11) showing no relationship between rate of bone loss at any site and dietary calcium intake, although, as suggested by Heaney ⁽⁶¹⁾, the inherent sources of error in estimates of dietary calcium intake may account for this. In our study, the mean calcium intake was similar to that in other longitudinal studies in men ⁽¹⁾ and was close to the recommended daily allowance of 800 mg ⁽⁶²⁾. The absence of any relationship between the rate of bone loss and physical activity may potentially reflect the wide range of ages and activity in our subjects, as well as the relatively small number of subjects in each age group, limiting the power of the study to address these issues. It may also be more important to consider the physical activity of an individual over a lifetime, particularly activity in the developing years ⁽⁶³⁾. Both smoking and high alcohol consumption have been reported to have an adverse effect on the skeleton ^(10)(64)(65), but we were unable to find evidence of a relationship between rates of bone loss and smoking or alcohol intake. Urinary hydroxyproline was significantly related to salt intake, supporting the concept that a high salt intake increases bone resorption, and is likely to be a risk factor for bone loss ⁽⁶⁶⁾. However, this was not the case with other markers of bone resorption.

Testosterone deficiency has been associated with accelerated bone loss and increased bone turnover ⁽⁶⁷⁾. This may be due to a reduction in serum 1,25D, leading to calcium malabsorption and reduced bone formation. It has been reported that in osteoporotic hypogonadal men treated with testosterone, there is an increase in calcitriol levels, calcium absorption, and bone formation ⁽⁶⁸⁾. Tenover ⁽⁶⁹⁾ reported a decrease in bone resorption and an increase in lean body mass following testosterone treatment in men with testosterone levels in the lower normal range. Kenny and colleagues ⁽⁷⁰⁾ also reported an increased lean body mass as well as an increased bone density at the femoral neck in men older than 65 years with low bioavailable testosterone after treatment with transdermal testosterone, while Snyder and colleagues ⁽⁷¹⁾ found an increase in bone density at the spine in a similar group of men following testosterone treatment. Reid and colleagues ⁽⁷²⁾ have also shown that testosterone therapy in glucocorticoid-treated men decreases bone turnover and increases spinal BMD. Estrogen deficiency may also be an important factor contributing to bone loss in men ⁽³³⁾. Rises in estradiol following testosterone therapy in androgen-deficient men may potentially reduce bone resorption ^(67)(69). We found no significant association between the rate of bone loss and levels of sex steroids or the calculated bioavailable testosterone. Factors such as the increase in weight over time, the wide age range in the study cohort, and the influence of other unmeasured factors, such as calcium absorption, may account for this lack of association. The absence of a fall in plasma testosterone is likely to be attributable to the relatively short duration of follow-up.

In conclusion, forearm bone loss in healthy men is similar to that estimated in our previous cross-sectional study ⁽⁷⁾; while the pattern of loss is different from that in women, its magnitude is probably comparable if the loss due to menopause is subtracted. Bone loss does not appear to be related to plasma testosterone concentrations.

Received August 9, 2001

Accepted November 1, 2001

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