Bone density and bone-related biochemical variables in normal men: a longitudinal study

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.     

Lack of influence of the androgen receptor gene CAG-repeat polymorphism on sex steroid status and bone metabolism in elderly men

OBJECTIVE: Population means for serum testosterone (T) levels in healthy men decrease with ageing but there is considerable interindividual variability of serum T in elderly men. Ultimate androgen action is mediated through the androgen receptor. Subtle differences in androgen sensitivity might contribute to serum T variability through the T negative feedback regulation. The androgen receptor gene (AR) contains in exon 1 a polymorphic trinucleotide CAG-repeat, whose length modulates androgen receptor action. The aims of the study were to assess the potential contribution of the AR CAG-repeat polymorphism in the interindividual variability of serum T and in the determination of bone metabolism in ambulatory elderly men. DESIGN AND PATIENTS: We used cross-sectional baseline data of a longitudinal study investigating the process of ageing, in particular the changes in hormonal status and bone metabolism, in a cohort of 273 community-dwelling healthy men, between age 71 and 86 years. MEASUREMENTS: AR CAG-repeat length was determined by automated DNA sequencing of exon 1 of the AR gene. Serum T, sex hormone binding globulin, LH and oestradiol were measured by specific immunoassays. Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry. Bone turnover was assessed by measurement of serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-terminal type I procollagen peptide, serum and urinary C-terminal telopeptides of type I collagen and urinary deoxypyridinoline levels, with use of immunoassays. RESULTS: No significant association was found between the AR CAG-repeat length and either total or free T, LH or the androgen sensitivity index (LHxT). BMD measurements at the hip and the forearm were not associated with AR CAG-repeat length and there was no association of this AR polymorphism with any of the biochemical markers of bone turnover. Results were not different after adjustments for age and body mass index. CONCLUSIONS: The findings of the present study do not support the view that in community-dwelling, healthy elderly men the androgen receptor gene CAG-repeat polymorphism has a substantial impact on interindividual variability of serum testosterone levels or on the determination of bone turnover and bone mineral density.     

Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men

Male osteoporosis is an increasingly important health problem. It is known that sex steroid hormones play an important role in regulating bone turnover and bone mass in males as well as in females. However, the exact mechanism of bone loss in men remains unknown. In the present study, 200 elderly men (age range, 55-85 yr) were followed for 4 yr to evaluate the relationships between hormone levels, bone turnover markers, bone mineral density, and rates of bone loss. Femoral and lumbar bone mineral density, bone ultrasound parameters at the os calcis, serum testosterone (T), serum estradiol (E(2)), SHBG levels, and bone turnover markers (urinary crosslaps and bone alkaline phosphatase) were evaluated for each man at enrollment and 4 yr afterward. The free androgen index (FAI) and free estrogen index (FEI) as well as measures of the bioavailable sex hormones [calculated bioavailable E(2) (c-bioE(2)) and T (c-bioT)] were calculated from total hormone levels and SHBG. In the total population, T, c-bioT, c-bioE(2), FAI, and FEI, but not E(2), decreased significantly with age, whereas SHBG increased significantly. Subjects with FEI, c-bioE(2), and E(2) levels below the median showed higher rates of bone loss at the lumbar spine and the femoral neck as well as higher speed-of-sounds decrease at the calcaneus with respect to men with FEI, c-bioE(2), and E(2) levels above the median. Serum bone alkaline phosphatase and urinary crosslaps were significantly higher in men with FEI, c-bioE(2), and E(2) in the lower quartile than in men with FEI, c-bioE(2), and E(2) levels in the higher quartile. No statistically significant differences were observed in relation to T, c-bioT, or FAI levels. Finally, the ratio between E(2) and T, an indirect measure for aromatase activity, increased significantly with age and was higher in normal than in osteoporotic subjects. In conclusion, results from the present study indicate an important role of estrogens, and particularly of the ability to aromatize T to E(2), in the regulation of bone loss and bone metabolism in elderly men.     

IGF-I and testosterone levels as predictors of bone mineral density in healthy, community-dwelling men

OBJECTIVE: Age-related decline in IGF-I and gonadal hormones have been postulated to play an important role in the pathogenesis of age-related bone loss in men. In this cross-sectional study, the relation between serum IGF-I and gonadal hormones with bone mineral density (BMD) was examined in community-dwelling men. DESIGN AND SUBJECTS: Serum IGF-I, testosterone and BMD were examined in 61 community-dwelling men over the age of 27, who were randomly selected from the Calgary cohort of 1000 subjects in the Canadian Multicentre Osteoporosis Study. In the present study, IGF-I, serum testosterone, SHBG, free androgen index (FAI), parathyroid hormone (PTH), 25-hydroxy-vitamin D [25(OH)D] and other markers of bone turnover were measured. BMD was measured at the spine and hip (HOLOGIC 4500). Simple linear regression was used to assess the linear relation between IGF-I, testosterone, BMD and other biochemical markers of bone metabolism and potential confounding variables and subsequent multivariate regression models were constructed separately for each BMD measurement to assess the importance of IGF-I and testosterone in the presence of potential confounding variables. RESULTS: Serum IGF-I, FAI and SHBG significantly decreased as a function of age, whereas serum levels of PTH increased. Only 25(OH)D, total testosterone and FAI were positively associated with serum IGF-I after adjusting for age and BMI. Multiple linear regression models revealed that IGF-I was a significant predictor of BMD at the total hip, femoral neck and femoral trochanter neck (P < or = 0.001). In contrast, the FAI was a significant predictor of BMD at the lumbar spine and wards area (P < or = 0.011), and SHBG was a significant predictor at the total hip and femoral trochanter (P < or = 0.045). CONCLUSION: These data support the hypothesis that the age-related decline in bone mass in men is associated with declining levels of IGF-I and testosterone.     

The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males

OBJECTIVE: Bone metabolism and bone density (BD) are influenced by sex hormones. Testosterone (T) action is exerted through the androgen receptor (AR). We investigated the potential impact of the CAG repeat (CAGR) polymorphism within the AR gene on BD and bone metabolism in healthy younger males. PATIENTS AND MEASUREMENTS: The number of CAGRs in 110 healthy men aged 20-50 years was determined by sequence analysis. We assessed BD by the radiation-free method of quantitative ultrasound (QUS) of the phalanges. Serum levels of bone-specific alkaline phosphatase (BAP) and urine secretion of free deoxypyridinoline (DPD, corrected for creatinine), serum levels of sex hormones, body fat content and lifestyle factors were determined. RESULTS: In stepwise multiple regression models controlling for age, body fat content and lifestyle factors, the number of CAGRs was an independent negative predictor of BD (partial r = - 0.286, P = 0.001), whereas it was positively associated with markers of bone turnover (for BAP: partial r = 0.32, P= 0.001; for DPD: partial r = 0-241, P = 0.013). Levels of free T and oestradiol showed an independent and positive association with BD; age contributed significantly to lower BD. Age and free T were negatively associated with markers of bone turnover, whereas oestradiol showed a positive correlation with BAP and DPD. ANOVA in groups according to age and the CAGR length suggested an increased age-dependent bone loss in subjects with a CAGR length of 22-31 compared with 14-21 CAGRs (overall P < 0.01). CONCLUSIONS :A high number of CAG repeats within the androgen receptor gene attenuates testosterone effects on bone density and bone metabolism. This seems to be associated with accelerated age-dependent bone loss.     

SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density

CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.     

Body composition, sex steroids, IGF-1, and bone mineral status in aging men

BACKGROUND: Bone loss in elderly men is associated with changes in body composition and reduced secretion of endogenous anabolizing hormones. The independent influences of body composition and endocrine factors on male bone metabolism, however, are unclear. METHODS: Bone mass density (BMD) (bone mass content [BMC, g]/projected bone area [BA, cm2]) at different skeletal sites, skeletal muscle, and body fat mass were measured by dual-energy X-ray absorptiometry in 129 men aged 20 to 95 years. Free testosterone, 17-beta-estradiol, dehydroepiandrosterone-sulfate, and insulin-like growth factor 1 (IGF-1) serum concentrations were measured. Because BMD may fail to control for differences in skeletal size, the associations of bone mass with body composition and hormones were studied by comparing BMD regression models incorporating age and knee height only with BMC regression models also incorporating BA. RESULTS: Skeletal muscle had close associations (p at least < .01) with BMD and BMC at almost all skeletal sites, but the strength of these associations was generally reduced in BMC with respect to BMD models. Weak associations (p < .05) were found in both models for fatness with femoral bone and for 17-beta-estradiol with total body and femoral bone. The association of 17-beta-estradiol with spinal bone was significant (p < .05) in the BMD but not in the BMC model. No association of BMC or BMD with androgens and IGF-1 reached significancy. CONCLUSIONS: Skeletal muscle may be more important than fatness and anabolizing hormones in preserving bone mass in elderly men. In contrast to traditional belief, estrogens may be more important than androgens and IGF-1 in male bone metabolism.     

Endogenous sex steroid, GH and IGF-I levels in normal elderly men: relationships with bone mineral density and markers of bone turnover.

There are studies concerning the association among endogenous sex steroids, growth hormone (GH), insulin-like growth factor-I (IGF-I) and bone mineral density (BMD) in both men and women. However, little is known concerning the association of these parameters with markers of bone turnover in healthy elderly men. We studied the association of BMD (dual energy X-ray absorptiometry of spine, hip and forearm) and markers of bone turnover (bone-specific alkaline phosphatase, serum C-terminal propeptide of type I collagen, and serum osteocalcin reflecting formation, urine deoxypyridinoline and calcium excretion in relation to creatinine excretion reflecting resorption) with endogenous sex steroids, GH and IGF-I in 14 elderly normal men (age range 60-79 years). There was a negative correlation between age and dehydroepiandrosterone sulphate (DHEAS) (r=-0.60, p=0.022) and a positive correlation between GH and IGF-I (r=0.53, p=0.048). Serum estradiol concentrations correlated with BMD at distal 1/3 radius (r=0.41, p=0.1) and mid-radius (r=0.47, p=0.08), and negatively correlated with age (r=-0.45, p=0.09). There was no correlation of estradiol with bone turnover markers, testosterone, free testosterone, DHEAS, GH and IGF-I. Serum GH and IGF-I levels showed no correlation with BMD (all sites) and bone turnover markers. Serum total testosterone concentrations positively correlated with BMD at distal 1/3 radius (r=0.47, p=0.09), femoral neck (r=0.56, p=0.037) and Ward's triangle (r=0.49, p=0.07). These data suggest that serum estradiol and testosterone levels are associated with BMD in elderly men, possibly indicating their contribution to skeletal maintenance in old age. However, correlations of IGF-I, GH and DHEAS with BMD and bone turnover markers are lacking in the group studied.     

Evaluation of bone mineral density, hormones, biochemical markers of bone metabolism, and osteoprotegerin serum levels in patients with ankylosing spondylitis

OBJECTIVE: To evaluate bone metabolism in patients with ankylosing spondylitis (AS) and test the hypothesis that osteoprotegerin (OPG) serum concentrations are correlated with the severity of bone loss as assessed by bone mineral density (BMD) and biochemical markers of bone turnover. Osteoporosis occurs frequently in patients with AS and OPG represents a soluble decoy receptor that neutralizes receptor activator of nuclear factor-kB ligand (RANKL), an essential cytokine for osteoclast function. METHODS: Clinical data, radiographs of the spine, BMD of lumbar spine and the femur, biochemical markers of bone turnover, and serum levels of OPG were evaluated in 264 patients with AS (72% men) and 240 age-matched healthy controls (76% men). RESULTS: OPG serum levels were significantly lower in patients with AS compared to controls (1.84 +/- 1.15 vs 3.54 +/- 2.18 pmol/l, p < 0.001), and in contrast to controls, were not positively correlated with age. In addition, BMD of the hip and the femoral neck were significantly lower in patients with AS than in controls. There were positive correlations in patients with AS between BMD of the femoral neck and free testosterone serum levels in men and free estradiol serum levels in women, respectively. Patients with AS and osteoporosis had higher biochemical markers of bone resorption and inflammatory activity. CONCLUSION: Bone loss in patients with AS is associated with low sex steroid hormone serum levels, high biochemical markers of bone resorption and inflammatory activity, low OPG serum levels, and lack of compensatory age-related increase of OPG serum levels.     

Differential effects of androgens and estrogens on bone turnover in normal men

The physiologic role of androgens and estrogens in the maintenance of normal bone turnover in men is a fundamental issue in bone biology. To address this question, we randomized 70 men between the ages of 20 and 44 yr to receive one of three treatment regimens. Group 1 (n = 25) received a GnRH analog (goserelin acetate 3.6 mg by sc injection every 4 wk) alone for 12 wk to suppress endogenous gonadal steroids to prepubertal levels. Group 2 (n = 22) received goserelin plus transdermal testosterone (Androderm 5 mg topically daily) to normalize circulating testosterone and estradiol levels. Group 3 (n = 23) received goserelin plus testosterone plus an aromatase inhibitor (anastrozole 1 mg orally daily) to induce selective estrogen deficiency. The selective effects of androgens and estrogens on skeletal homeostasis were then assessed by measuring changes in biochemical markers of bone turnover and analyzing the between-group differences. Bone resorption markers increased in both the hypogonadal group (group 1) and in the group with selective estrogen deficiency (group 3). Urinary deoxypyridinoline excretion increased more in group 1 than in group 3 (P = 0.023), suggesting a significant effect of androgens on bone resorption, whereas serum N-telopeptide levels increased more in group 3 than in group 2 (P = 0.037), suggesting a significant effect of estrogen on bone resorption. Bone formation markers initially declined in all groups and then increased in groups 1 and 3. The between-group comparisons were consistent for all formation markers. Bone formation markers increased more in group 1 than in group 2 (P = 0.001, 0.037, 0.005 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Bone formation markers also increased more in group 1 than in group 3 but these differences were not statistically significant (P = 0.065 0.073, 0.099 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Taken together, these data suggest that both androgens and estrogens play independent and fundamental roles in regulating bone resorption in men. These data also suggest that androgens may play an important role in the regulation of bone formation in men.     

Recombinant human chorionic gonadotropin but not dihydrotestosterone alone stimulates osteoblastic collagen synthesis in older men with partial age-related androgen deficiency

Several randomized trials of androgen supplementation in older men have been undertaken. However, the relative contributions of testosterone (T) and estrogens on bone metabolism in aging men are controversial. Within the setting of two double-blind, placebo-controlled studies, we evaluated the effect of dihydrotestosterone (DHT) and recombinant human chorionic gonadotropin (rhCG) on bone turnover in healthy, community-dwelling older men with partial androgen deficiency (total T < or = 15 nmol/liter). In the first study, 35 men (age 68.3 +/- 6.8 yr; baseline T, 13.9 +/- 3.3 nmol/liter) were randomized to receive either daily transdermal DHT (n = 17) or placebo for 3 months. In the second study, 40 men (age 67.4 +/- 5.4 yr; baseline T, 11.4 +/- 2.2 nmol/liter) were randomized to receive either rhCG s.c. (n = 20), two injections weekly, or placebo for 3 months. The following parameters were measured before, monthly during, and 1 month after treatment: serum T, estradiol (E2), and LH; markers of bone formation, serum amino-terminal propeptide of type I procollagen (S-PINP) and osteocalcin; markers of bone resorption, serum carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline. Compared with placebo, treatment with DHT significantly increased serum DHT and suppressed LH and T levels, whereas E2 concentrations and markers of bone turnover did not change. In contrast, rhCG therapy significantly increased both T and E2, with the increases in E2 being supraphysiological. At the same time, rhCG significantly increased S-PINP concentrations with peak levels after 1 month (Delta40%; P = 0.02 compared with placebo). In contrast, serum osteocalcin and carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline levels did not change. The change in S-PINP levels correlated with the change in E2 levels (r = 0.59; P = 0.02) but not with a change in T. We conclude that in older men with partial age-related androgen deficiency, rhCG treatment stimulates osteoblastic collagen formation proportionally to increased E2 concentrations but does not alter markers of mature osteoblastic function or bone resorption. In contrast, treatment with a pure, nonaromatizable androgen (DHT) has no effect on bone turnover despite a 20-fold increase in serum levels. Bone resorption was not accelerated during unchanged (DHT) or increased (rhCG) E2 levels, suggesting that minimal E2 levels are needed to maintain stable resorption, although direct androgen receptor-mediated effects cannot be excluded. If androgen supplementation is required for aging men, aromatizable androgens with sufficient endogenous estrogenic activity may have the most beneficial effects on bone.     

Effect of excess endogenous androgens on bone density in young women

To determine whether endogenous androgens influence bone density in young women, we studied 27 normal women and 19 women with androgen excess, as defined by increased serum bioavailable testosterone (bio T) concentrations. The women ranged from 21-48 yr of age. The 2 groups were comparable with respect to age, anthropomorphic measures, nutrition, gynecological history, and serum cortisol and estradiol levels. Trabecular (lumbar) and cortical (radial) bone density were quantitated by computerized tomography and single photon absorptiometry, respectively. Serum obtained during the follicular phase of the cycle was assayed for bio T, total T, dehydroepiandrosterone sulfate, androstenedione (Adione), and 3 alpha-androstanediol glucuronide (3-Adiol-G). Trabecular bone density was significantly higher in the androgen excess group [172 +/- 7 (+/- SE) vs. 153 +/- 5 mg/mL; P = 0.03]; controlling for serum Adione (but not for serum bio T, total T, dehydroepiandrosterone sulfate, or 3 alpha-androstanediol glucuronide, or 3-Adiol-G) abolished this difference. Similarly, serum Adione correlated more strongly than the other androgens with trabecular bone density (r = 0.31; P = 0.03). Average cortical bone density was not higher in the androgen excess group (0.740 +/- 0.014 vs. 0.722 +/- 0.008 g/cm2; P = 0.27). Among the 27 normal women, cortical density was correlated to serum bio T (r = 0.47; P = 0.01) and total T (r = 0.53; P = 0.004), but not to the other androgens. We conclude that supraphysiological levels of endogenous androgens are associated with increased trabecular bone density in young women. Serum Adione appeared to be the best marker for the impact of androgen on trabecular density. Among normal women, cortical bone density was related to serum T.     

Association between serum testosterone concentration and collagen degradation fragments in men with type 2 diabetes mellitus

The aim of the present study was to evaluate relationships between serum endogenous androgens and urinary concentration of cross-linked N-telopeptides of type I collagen (NTx), a bone resorption marker, in men with type 2 diabetes mellitus because low androgen concentrations are associated with both osteoporosis and cardiovascular disease. Relationships between serum free testosterone and urinary NTx concentrations were investigated in 246 consecutive men with type 2 diabetes mellitus. In addition, relationships between urinary NTx concentration and other variables including age, duration of diabetes, blood pressure, serum lipid concentration, hemoglobin A(1c), and body mass index were evaluated. Urinary NTx concentrations were 27.8 (26.4-29.3) nmol of bone collagen equivalent per millimole of creatinine, correlating inversely with serum free testosterone (r = -0.263, P < .0001). Multiple regression analysis identified serum free testosterone (beta = -.292, P < .0001), hemoglobin A(1c) (beta = .144, P = .0404), and smoking status (beta = .143, P = .0402) as independent determinants of urinary NTx. In conclusion, serum free testosterone concentration correlated inversely with urinary NTx concentration, which may partly account for an observed link between osteoporosis and cardiovascular disease in men with type 2 diabetes mellitus.     

Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status.

Previous studies have suggested an important role for androgens and estrogens in bone metabolism in men. However, their local mode of action has not been clearly established. Osteoprotegerin (OPG) is a secreted decoy receptor that inhibits osteoclast formation and activity by neutralizing its cognate ligand. To assess the role of OPG on bone metabolism in men, we conducted a study aimed at evaluating OPG serum levels and their correlation with age, bone mineral density, biochemical markers of bone turnover, and testosterone and estradiol levels in 252 men, aged 19-85 yr. Serum concentrations of OPG increased significantly with age (r = 0.41; P = 0.0001), and were positively correlated with free testosterone index and free estradiol index (r = 0.20; P < 0.002 and r = 0.15; P < 0.03, respectively) after adjustment for age and body weight. Beyond the age of 40 yr, OPG serum concentrations were negatively correlated with urinary excretion of total deoxypyridinoline (r = -0.20; P < 0.01) and PTH serum levels (r = -0.23; P < 0.01). In contrast, there was no correlation with biochemical markers of bone formation, 25-hydroxyvitamin D(3) levels, or bone mineral density at any site. Our data reveal that age as well as androgen and estrogen status are significant positive determinants, whereas PTH is a negative determinant, of OPG serum levels in men. These data suggest that OPG may be an important paracrine mediator of bone metabolism in elderly men and highlight the role of estrogens in the homeostasis of the male skeleton.     

Effects of suppression of estrogen action by the p450 aromatase inhibitor letrozole on bone mineral density and bone turnover in pubertal boys

The essential role of estrogen (E) in regulation of developing peak bone mass in males was confirmed when young adult men were described who cannot respond to or produce E because of defective E receptor alpha or P-450 aromatase enzyme, respectively. These men had significantly reduced bone mineral density (BMD) despite normal or supranormal androgen concentrations, and E administration improved BMD in the men with aromatase deficiency, whereas testosterone (T) was ineffective. Because new P450 aromatase inhibitors may prove to be potential drugs in various growth disorders, the effect of suppression of E action on developing peak bone mass has to be closely evaluated. In this study, we explored the effects of suppression of E synthesis on bone metabolism in pubertal boys. A total of 23 boys with constitutional delay of puberty were randomized to receive T and placebo or T and a specific and potent P450 aromatase inhibitor, letrozole. We determined BMD in the lumbar spine and the femoral neck. Bone resorption was studied by measuring the serum concentration of cross-linked carboxyterminal telopeptide of type I collagen by two different methods (CTx and ICTP), and bone formation by determining the serum concentrations of carboxyterminal propeptide of type I procollagen (PICP), osteocalcin, and alkaline phosphatase. We demonstrated previously that, during treatment with T and placebo, the concentrations of androgens and E increased. During treatment with T and letrozole, the E concentrations remained at the pretreatment level, but the androgen concentrations increased; the increase in the T concentration was more than 5-fold higher than during treatment with T and placebo. We did not observe any significant differences in the changes in bone mineral content, BMD, or bone mineral apparent density, an estimate of true volumetric BMD, between the treated groups. Lumbar spine bone mineral apparent density increased in both treated groups; but in the T- plus letrozole-treated group, the increase was statistically significant only 6 months after discontinuation of letrozole treatment. All bone resorption and formation markers increased during treatment with T and placebo. During treatment with T plus letrozole, CTx, PICP, and osteocalcin remained unchanged, whereas ICTP and alkaline phosphatase increased. Thus, 1-yr treatment with this new P450 aromatase inhibitor in pubertal boys is unlikely to be associated with any major harmful effect on developing peak bone mass. However, to convincingly exclude such effects, particularly rare or minor ones, will require a study with a larger sample size; and thus, close follow-up of bone metabolism during treatment with P450 aromatase inhibitors is still warranted.     

Factors influencing bone loss in rheumatoid arthritis: a longitudinal study

OBJECTIVES: To assess the occurrence of bone loss in rheumatoid arthritis (RA) and to determine the factors influencing bone loss (particularly the usefulness of bone turnover markers) over an 18-month period. METHODS: A total of 51 patients were studied, 6 men and 45 females (of whom 35 were menopausal). Their mean age was 56 +/- 10 years and the mean RA duration was 12 +/- 10 years. Twenty-eight (55%) were receiving corticosteroids (10 mg/day for a mean duration of 6 +/- 5 years). Several clinical and biological parameters reflecting disease activity or severity were recorded both at the 0 and 18-month investigations. Bone turnover was assessed at baseline by measuring the serum levels of 4 biological markers. Three of them reflected bone formation, i.e., procollagen type I C-terminal propepeptide (PICP), procollagen type I N-terminal propeptide (PINP) and osteocalcin (OC). The fourth, procollagen type I-C terminal telopeptide (ICTP), reflected bone resorption. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry both at the lumbar spine (LS) and femoral neck (FN) at baseline and 18 months later. RESULTS: Bone loss occurred both at the LS: 2.1%, [95% CI: 0.8%-3.4%, P < 0.005] and femoral neck: 3.1%, [95% CI: 1.1%-5.1%, P < 0.005]. Bone loss was markedly increased for postmenopausal women at the FN: 5.3% [95% CI: 2.9%-7.6%, P < 0.005]. Bone loss was not statistically significantly different between users and non-users of steroids. Bone loss at the LS was significantly correlated with both osteocalcin (r = 0.51, P < 0.01) and ICTP levels (r = 0.32, P < 0.05). FN bone loss was correlated with the osteocalcin level only (r = 0.34, P < 0.05). Fast losers (bone loss at the LS above the median) had higher OC (P < 0.01) and ESR (P < 0.05) levels at baseline as compared with slow losers (bone loss at the LS below the median). CONCLUSION: Bone loss occurs in RA particularly at the FN and seems to be influenced by increased bone turnover and high levels of inflammation.     

A prospective study of bone loss and turnover after allogeneic bone marrow transplantation: effect of calcium supplementation with or without calcitonin

Transplantation of solid organs including heart, kidney, and liver is associated with rapid bone loss and increased rate of fracture; data on bone marrow transplantation recipients (BMT) are scarce. The purpose of the present study was to examine the magnitude, timing, and mechanism of bone loss following allogeneic BMT, and to study whether bone loss can be prevented by calcium with or without calcitonin. Sixty-nine patients undergoing allogeneic BMT for malignant blood diseases were enrolled into the study. Forty-four (22 women, 22 men) completed 6 months, and 36 patients 1 year follow-up. They were randomized to receive either no additional treatment (n = 22), or oral calcium 1 g twice daily for 12 months (n = 12) or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months (n = 10). Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward's triangle) was measured by dual-energy X-ray absorptiometry (DXA). Bone turnover rate was followed with markers of bone formation and resorption (serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal (PICP) and aminoterminal propeptide (PINP), serum type I collagen carboxyterminal telopeptide (ICTP)). Serum testosterone was assayed in men. Calcium with or without calcitonin had no effect on bone loss or bone markers; consequently the three study groups were combined. During the first 6 post-transplant months BMD decreased by 5.7% in the lumbar spine and by 6.9% to 8.7% in the three femoral sites (P < 0.0001 for all); no significant further decline occured between 6 and 12 months. Four out of 25 assessable patients experienced vertebral compression fractures. Markers of bone formation reduced: B-ALP by 20% at 3 weeks (P = 0.027), PICP by 40% (P < 0.0001) and PINP by 63% at 6 weeks (P < 0.0001), with a return to baseline by 6 months. The marker of bone resorption, serum ICTP was above normal throughout the whole observation period, with a peak at 6 weeks (77% above baseline, P < 0.0001). In male patients serum testosterone decreased reaching a nadir (57% below baseline) at 6 weeks (P = 0.0003). In conclusion, significant bone loss occurs after BMT. It results from imbalance between reduced bone formation and increased bone resorption; hypogonadism may be a contributing factor in men. Bone loss can not be prevented by calcium with or without calcitonin.     

Abstracts

Patients with glycogen storage disease (GSD) types I, III and IX show reduced bone mineral content, but there is scarce data on new serum and urine markers of bone turnover or their relationship to bone densitometry. Six GSD I, four GSD III and four GSD IX patients underwent bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry. Free pyridinoline (fPYD):creatinine and free deoxypyridinoline (fDPD):creatinine ratios were analysed on random urines. Procollagen type I C-terminal propeptide, procollagen type I N-terminal propeptide (PINP), carboxyterminal telopeptide of type I collagen and bone-specific alkaline phosphatase were analysed in serum. Some GSD I and GSD III patients had low or very low BMD. There was no difference in total body BMD z-score between the GSD types after adjusting for height (p=0.110). Bone marker analysis showed no consistent pattern. Urine fPYD:creatinine ratio was raised in four GSD I and two GSD III patients, while serum PINP was inappropriately low in some of these patients. There was no clear correlation between any markers of bone destruction and total body z-score, but the patient with the lowest total body z-score showed the highest concentrations of both urinary fPYD:creatinine and fDPD:creatinine ratios. We conclude that some GSD I and GSD III patients have very low bone mineral density. There is no correlation between mineral density and bone markers in GSD patients. The inappropriately low concentration of PINP in association with the raised urinary fPYD:creatinine and fDPD:creatinine ratios seen in two GSD I patients reflect uncoupling of bone turnover. All these findings taken together suggest that some GSD I and GSD III patients may be at an increased risk of osteoporosis.     

Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment

Long-term glucocorticoid therapy in men is associated with loss of bone and muscle mass as well as a decrease in serum testosterone. We tested the effect of two androgens, testosterone and its minimally aromatizable analog nandrolone, on muscle mass (dual x-ray absorptiometry), muscle strength (knee flexion and extension by isokinetic dynamometry), bone mineral density (BMD), and quality of life (Qualeffo-41 questionnaire) in 51 men on a mean daily prednisone dose of 12.6 +/- 2.2 mg. Men were randomized, double blind, to testosterone (200 mg mixed esters), nandrolone decanoate (200 mg), or placebo given every fortnight by im injection for 12 months. At 12 months, both androgens increased muscle mass (mean change from baseline +3.5%, +5.8%, and -0.9% in testosterone, nandrolone, and placebo groups, respectively, P < 0.0001) and muscle strength (P < 0.05). Lumbar spine BMD increased significantly only in men treated with testosterone (4.7 +/- 1.1%, P < 0.01). There was no significant change in hip or total body BMD. Testosterone, but not nandrolone or placebo, improved overall quality of life (P < 0.001). These results suggest that androgen therapy may have a role in ameliorating adverse effects of glucocorticoid therapy such as muscle and bone loss and aromatization is necessary for androgen action on bone but not on muscle.     

Serum estradiol, testosterone, and sex hormone-binding globulin as regulators of peak bone mass and bone turnover rate in young Finnish men

To study the role of serum testosterone (T), estradiol (E(2)), and SHBG as regulators of peak bone mass and bone turnover rate in males, a cross-sectional study with data on lifestyle factors collected retrospectively was performed in 204 young Finnish men, 18.3-20.6 yr old. One hundred fifty-four men were recruits of the Finnish Army, and 50 were men of similar age who had postponed their military service for reasons not related to health. Bone mineral content, density, and scan area were measured in lumbar spine and upper femur by dual-energy x-ray absorptiometry. Blood was sampled for determination of serum total and free T, total and free E(2), SHBG, type I procollagen aminoterminal propeptide (PINP), total osteocalcin (TOC) and carboxylated osteocalcin (COC), and tartrate-resistant acid phosphatase 5b (TRACP5b); and urine was collected for determination of type I collagen aminoterminal telopeptide (NTX). Serum sex steroid concentrations did not associate with bone mineral content, scan area, or bone mineral density, adjusted for anthropometric and lifestyle factors at any measurement site. Instead, serum total (r = 0.23; P = 0.008) and free (r = 0.15; P = 0.023) T were positive predictors of serum TOC, whereas serum free E(2) correlated inversely with serum PINP (r = -0.20; P = 0.0039), TOC (r = -0.12; P = 0.086), COC (r = -0.14; P = 0.036), and urinary NTX (r = -0.15; P = 0.041). Interestingly, serum SHBG correlated positively with all the bone markers studied, the correlation coefficients being 0.18 for serum PINP (P = 0.012), 0.24 for TOC (P = 0.0006), 0.24 for COC (P = 0.0005), 0.27 for serum TRACP5b (P < 0.0001), and 0.21 for urine NTX (P = 0.0031). Serum SHBG was also a positive predictor of serum 25-hydroxyvitamin-D level (r = 0.20; P = 0.0036). The correlations of SHBG persisted after adjusting for weight, free E(2), and free T. We conclude that single measurements of serum E(2) and T were not determinants of peak bone mass in this population of young men. However, E(2) and T contributed to bone turnover rate, with serum T increasing bone formation, and serum E(2) suppressing both bone formation and resorption. Moreover, serum SHBG appeared to be an independent positive predictor of bone turnover rate, which also positively associated with serum 25-hydroxyvitamin-D levels.