Glucocorticoid replacement therapy and fibrinolysis in patients with hypopituitarism

Background Hypopituitarism is associated with increased cardiovascular mortality, and it has been suggested that unphysiological glucocorticoid replacement regimens might contribute to this risk. Traditional glucocorticoid replacement regimens have often led to excessive serum cortisol levels. The hypercortisolaemia of Cushing’s syndrome is associated with an increased risk of thromboembolism. Objective To examine whether short‐term higher‐dose hydrocortisone replacement regimens adversely affect the fibrinolytic system. Design Crossover study comparing tailored low‐dose (LD) glucocorticoid regimen (mean, 17·5 mg hydrocortisone daily), with a traditional high‐dose (HD, 30‐mg hydrocortisone daily) regimen for 2 weeks. Patients Ten patients with hypopituitarism and ACTH deficiency – median (range) age, 59 (41–75) years – and 10 age‐ and sex‐matched controls. Nine patients had growth hormone deficiency (five replaced), nine patients had TSH deficiency (nine replaced), eight had gonadotrophin deficiency (five replaced). During the study, other pituitary hormone replacement therapy remained unchanged. Patients with acromegaly and Cushing’s syndrome were excluded. Measurements Hourly serum cortisol for 11 h, plasminogen activator inhibitor‐1 (PAI‐1), tissue plasminogen activator (tPA) and fibrinogen levels after 2 weeks of treatment with both LD and HD regimens. Results No overall significant differences were found between the three groups using the Kruskal–Wallis test: PAI‐1: [median (range)] HD, 25 (5–53) ng/ml; LD, 21 (4–56) ng/ml; controls, 27 (8–51); P = 0·3; tPA: HD, 10 (5–15) ng/ml; LD, 10 (4–13) ng/ml; controls 10 (3–13); P = 0·46; and fibrinogen: HD, 2·5 (1·8–3·5) g/l; LD, 3·0 (2·3–4·4) g/l; controls, 2·6 (1·6–3·2): P = 0·97 In addition, no significant differences between HD and LD using Wilcoxon’s paired test; PAI‐1 (P = 0·91), tPAag (P = 0·47) and fibrinogen (P = 0·09). Conclusions An increased dose of hydrocortisone for 2 weeks creates excessive glucocorticoid exposure, but does not significantly affect fibrinolytic‐coagulation parameters.     

Moderate physical activity is associated with higher bone mineral density in postmenopausal women

OBJECTIVES: To determine the associations between different levels of habitual physical activity, hormone replacement therapy (HRT), and bone mineral density (BMD) in postmenopausal women. DESIGN: Cross-sectional. SETTING: Academic medical center. PARTICIPANTS: Twenty sedentary women, 20 active nonathletic women, and 23 endurance-trained athletes, all of whom were postmenopausal, with half of each group on and half not on HRT. MEASUREMENTS: BMD and body composition determined by dual energy x-ray absorptiometry, maximal oxygen consumption (VO2max), dietary history by questionnaire, and vitamin D receptor (VDR) genotyping on deoxyribonucleic acid. RESULTS: Body weight was higher in the active nonathletic than in the sedentary and athletic women. Body fat was lower and VO2max higher in the athletic women than in the sedentary and the active nonathletic women. Physical activity level was significantly associated with BMD in three of the five measurements taken (L1-L4 lumbar spine, trochanter, total body; all P < .05). These differences were also generally significant after adjusting for body weight. The association between physical activity status and BMD at the neck of the femur and Ward's triangle bordered on significance (P = .07-.09). At most sites, the active nonathletic women had higher BMD than did the sedentary and athletic women. HRT was significantly associated only with total body BMD (P < .05). The groups were similar in terms of dietary habits (protein, calcium, sodium, phosphorus intake); VDR genotypes; and family, smoking, and nutritional histories. CONCLUSION: Given the similarity of the groups with respect to other factors that affect BMD, it appears that prolonged low-to-moderate-intensity physical activity, but not the same number of years of higher-intensity training for competitive events, was independently associated with higher BMD.     

Androgens and bone density in women with hypopituitarism

Hypopituitarism is associated with osteopenia and a reduction in lean body mass. We have recently demonstrated markedly reduced serum androgen levels in women with hypopituitarism. We hypothesized that serum androgen levels and lean body mass are important determinants of bone mineral density (BMD) in women with hypopituitarism. In addition, because IGF-I may stimulate androgen secretion in women, we investigated whether GH administration results in an increase in serum androgen levels. Sixteen women with a history of pituitary disease of adult-onset and serum GH levels less than 5 ng/ml on stimulation testing underwent BMD and body composition testing by dual-energy x-ray absorptiometry. Univariate regression analysis revealed strong correlations between androgen levels and BMD [lateral spine BMD and dehydroepiandrosterone sulfate (DHEAS) (r = 0.68, P = 0.03), total hip BMD and free T (r = 0.60, P = 0.01), Ward's triangle BMD and DHEAS (r = 0.68, P = 0.004), Ward's triangle BMD and free T (r = 0.54, P = 0.03), femoral neck BMD and free T (r = 0.52, P = 0.04), and femoral neck BMD and DHEAS (r = 0.51, P = 0.04)]. When adjusted for age using Z scores, correlations at the femoral neck no longer reach significance. Correlations between androgens and BMD at other sites, including anterior-posterior spine and total body, were not significant, and neither total T nor androstenedione correlated with BMD at any site. Lean body mass strongly correlated with BMD [total hip (r = 0.80, P = 0.0002), total body (r = 0.78, P = 0.0003), trochanter (r = 0.74, P = 0.001), Ward's triangle (r = 0.56, P = 0.02), femoral neck (r = 0.53, P = 0.04), and anterior-posterior spine (r = 0.52, P = 0.04)]. In stepwise regression models, DHEAS determined 47% of the variation in Ward's triangle BMD (R(2) = 0.47, P = 0.004) and 46% of lateral spine BMD (R(2) = 0.46, P = 0.03). Lean body mass determined 64% of the variation in total hip BMD (R(2) = 0.64, P = 0.0002), 62% of total body (R(2) = 0.62, P = 0.0003), and 55% of trochanter BMD (R(2) = 0.55, P = 0.001). Subjects were then randomized to receive GH at a dose of 12.5 microg/kg per day or placebo for 12 months in a double-blind protocol. Serum androgen levels were obtained at baseline, 1, 3, 6, 9, and 12 months after initiation of GH. Androgen levels did not increase in the women receiving GH for 12 months, compared with those receiving placebo. Stimulation of androgen secretion is therefore unlikely to be a mechanism underlying the improvement in BMD, body composition, or quality of life observed with GH administration. In conclusion, androgen levels and lean body mass may be important determinants of BMD in women with hypopituitarism. It remains to be determined whether androgen replacement therapy itself or an increase in lean body mass achieved as a result of androgen administration will result in an improvement in BMD in this population.     

Smoking is associated with lower bone mineral density and reduced cortical thickness in young men

CONTEXT: Smoking has previously been associated with reduced areal bone mineral density (aBMD) in elderly subjects, but the association remains controversial in adolescents. OBJECTIVE: The aim of this study was to determine whether smoking was associated with aBMD or volumetric BMD (vBMD) and bone size in young men. DESIGN AND SETTING: aBMD was measured using dual x-ray absorptiometry. vBMD and bone size were measured using peripheral quantitative computerized tomography (pQCT). Smoking habits were assessed using questionnaires. Levels of sex steroids, PTH, and 25-OH-vitamin D were measured in serum. PARTICIPANTS: The population-based Gothenburg Osteoporosis and Obesity Determinants (GOOD) study includes 1068 young men, age 18.9 +/- 0.6 yr (mean +/- SD). MAIN OUTCOME MEASURE: The main outcome measure was smoking as predictor of bone parameters and serum sex hormone levels. RESULTS: Of the study subjects, 8.7% smoked daily. Bone parameters were compared between smokers and nonsmokers. Smokers had significantly lower aBMD (dual x-ray absorptiometry) of the total body (crude: -2.1%; adjusted for age, height, weight, calcium intake, and physical activity: -1.8%), lumbar spine (crude: -4.3%; adjusted: -3.3%), and trochanter (crude: -6.6%; adjusted: -5.0%) than nonsmokers. Using peripheral quantitative computerized tomography, we found that smokers had lower cortical thickness of both the radius (crude: -2.8%; adjusted: -2.9%) and tibia (crude: -4.5%; adjusted: -4.0%) than the nonsmokers, whereas no difference was seen for cortical vBMD. Smokers had higher serum levels of total and free testosterone and lower 25-OH-vitamin D than nonsmokers. Adjustment for testosterone and/or 25-OH-vitamin D levels did not alter the associations between smoking and bone parameters. CONCLUSIONS: We demonstrate that smoking was associated with lower aBMD and reduced cortical thickness in young men.     

Low grip strength is associated with bone mineral density and vertebral fracture in women

OBJECTIVES: Grip strength has been reported to be associated with bone mass locally at the forearm and also at distant skeletal sites, including the spine and hip. Less is known about the association between low grip strength and risk of vertebral fracture. The aim of this study was to examine the association between low grip strength, bone mineral density at the hip and spine, and vertebral fracture in middle-aged and elderly European men and women. METHODS: Men and women aged 50 yr and over were recruited for participation in a screening survey of vertebral osteoporosis across Europe. Subjects who agreed to take part had an interviewer-administered questionnaire and lateral spinal radiographs performed. Subjects were assessed also for grip strength using a handgrip dynamometer (range 0-300 mmHg). A subsample of those recruited had bone mineral density measurements performed at the spine and femoral neck. Subjects had repeat lateral spine radiographs performed a mean of 3.8 yr following the baseline survey. Linear regression analysis was used to determine the association between low grip strength and bone mineral density at the hip and spine. Logistic regression was used to determine the association between grip strength and both prevalent and incident vertebral fracture. RESULTS: One thousand two hundred and sixty-five men and 1380 women with data concerning grip strength and bone mineral density were included in the analysis. In women, after age adjustment, compared with those with 'normal' grip, those with 'impaired' (231-299 mmHg) and low grip (<231 mmHg) had significantly lower bone mass at the spine and femoral neck. In men, those with low grip strength had a lower BMD at the spine and hip than those in the normal group. However, because of the small numbers with submaximal grip strength, the confidence intervals around all estimates included zero. Adjustment for body size and levels of physical activity had little effect on the results. In addition, among women, after adjustment for age, body mass index and physical activity levels, compared with those with normal grip, those with low grip strength had an increased risk of developing incident vertebral fracture (odds ratio = 2.67; 95% confidence interval 1.13, 6.30). Further adjustment for spine bone density had little influence on the association (odds ratio = 2.60). CONCLUSIONS: In women, low grip strength is associated with low bone mineral density at both the spine and hip and an increased risk of incident vertebral fracture. These associations cannot be explained by differences in body size or lifestyle.     

Vitamin D depletion in hip fracture women is associated with the occurrence of simultaneous upper limb fractures independently of bone mineral density

IntroductionSevere vitamin D deficiency is associated with the occurrence of simultaneous fractures at both hip and upper limb due to a single fall. We hypothesized that reduced bone mineral density (BMD) could explain the association.MethodsWe investigated 549 white women consecutively admitted to a rehabilitation hospital because of their first fall-related hip fracture. Thirty-three (6%) of the 549 women sustained a concomitant upper limb fracture of either distal radius (24 women) or proximal humerus (nine women). We assessed serum levels of 25-hydroxyvitamin D, hip BMD by dual-energy X-ray absorptiometry, and spine deformity index scores by lateral spine radiographs, 19.5 ± 7.1 (mean ± SD) days after fracture occurrence.ResultsSerum levels of 25-hydroxyvitamin D were significantly lower in the 33 women with concomitant fractures of both hip and upper limbs than in the remaining 516 (mean difference between groups 5.6 ng/ml, 95% CI from 3.5 to 7.6, P < 0.001). Conversely, no significant differences were found in hip BMD or spine deformity index scores between the two groups. After adjustment for eight potential confounders, the occurrence of simultaneous fractures due to a single fall was significantly associated with low levels of 25-hydroxyvitaimn D (P = 0.001), but not with femoral BMD or spine deformity index scores.ConclusionThe association between severe vitamin D deficit and the occurrence of concomitant fractures at both hip and upper limbs due to a single fall is independent of femur BMD. Further investigations should focus on altered fall pattern or reaction to fall.     

Calcium-sensing receptor gene polymorphism is not associated with bone mineral density in Italian postmenopausal women

OBJECTIVE: Calcium-sensing receptor (CaR) is a candidate gene for osteoporosis susceptibility. Several CaR polymorphisms have been identified and an association between the A986S genotype and serum calcium levels has been found in Canadian postmenopausal women. We investigated whether the presence of 986S allele was associated with bone mineral density (BMD) and osteoporotic fractures. DESIGN: The study group consisted of 164 Italian postmenopausal women without fragility fracture (Fx(-)) and 55 women with fracture (Fx(+)). METHODS: A fragment of exon 7 of CaR gene containing three polymorphisms (A986S, R990G and Q1011E) was amplified by PCR and sequenced. Anthropometric characteristics and BMD were evaluated. RESULTS: The A986S polymorphism was the most commonly observed (27.9%), whereas the other two CaR polymorphisms, R990G and Q1011E, occurred in a minority of cases (8.8 and 5.5% respectively). There was no significant difference in the frequency distribution of any CaR allele between Fx(-) and Fx(+) patients. Body mass index was found to predict BMD at the lumbar spine and femoral neck. The A986S polymorphism and Years since menopause were not independent predictors of BMD at any site. As far as fracture occurrence, there was no statistically significant difference in the prevalence of fractures between women carrying or not carrying the 986S allele. CONCLUSIONS: Our data do not support a role of A986S CaR polymorphism in BMD and in the prevalence of fragility fractures in Italian postmenopausal women.     

The effect of low dose nylestriol-levonorgestrel replacement therapy on bone mineral density in women with postmenopausal osteoporosis

OBJECTIVE: Recently our studies have shown that nylestriol in combination with levonorgestrel prevented bone loss, decreased bone turnover rate and increased the maximal loading of bone without obvious side effects in retinoic acid (RA) induced osteoporotic rats. In addition to the animal experiments, we evaluate the effect of Compound Nylestriol Tablet (CNT) on bone mineral density (BMD) in women with postmenopausal osteoporosis. Compound Nylestriol Tablet, which contains 0.5 mg of nylestriol (cyclopentylethinyl estriol) and 0.15 mg of levonorgestrel per tablet, was authorized as a new anti-osteoporotic agent for clinical trial in postmenopausal osteoporosis. METHODS: One year's clinical observation was performed in 191 eligible patients who were randomly divided into two groups (A and B). In group A, 119 patients were treated for one year with CNT (one tablet per week) and in group B, 72 patients with placebo. Bone mineral density of lumbar antero-posterior spine (L1-L4), lateral spine, total hip and total forearm positions including radius+ulna at the ultra distal areas, mid areas, and one-third areas, were measured before and after treatment. Biochemical parameters and effects of CNT on uterus, and breast were observed. RESULTS: We found that patients treated with CNT had a significant decrease of bone loss in total forearm, including radius+ulna at the ultra distal, mid, and 1/3 areas compared with control subjects (all P < 0.05). An improved BMD tendency could be seen at the lumbar spine. There were no differences in the observed biochemical variables. No side-effects on uterus, or mammary glands observed. None of the patients had uterine bleeding or vertebral fractures during one year's CNT treatment. CONCLUSION: These data suggested that CNT is effective, safe and convenient in treating postmenopausal osteoporosis.     

Genetic variant in the aquaporin 9 gene is associated with bone mineral density in postmenopausal women

This study investigated whether single nucleotide polymorphisms (SNP) in the aquaporin 9 (AQP9) gene is associated with bone mineral density (BMD) in Thai postmenopausal women, after an initial genome-wide screening using high-throughput SNP genotyping in pooled DNA samples. Subjects consisted of 516 postmenopausal women aged 50 or more. High-throughput SNP screening was performed by comparing the estimated allele frequency derived from hybridization signal intensities of pooled DNA samples on the Affymetrix 500 K SNP genotyping chip set. The SNP was then genotyped for each subject individually. Data were expressed as mean ± SEM. Pooled DNA SNP screening revealed the allele frequency of an intronic A/T SNP rs2414539 in the AQP9 gene as being different between subjects with femoral neck BMD in tertiles 1 and 3. Individual genotyping in all subjects revealed that femoral neck BMD in subjects with TT, TA, and AA genotypes were 0.79 ± 0.06 (n = 3), 0.75 ± 0.01 (n = 98), and 0.71 ± 0.01 g/cm(2) (n = 415), respectively. The presence of the T allele in rs2414539 was associated with femoral neck BMD (r = 0.11, P < 0.05) but not with lumbar spine BMD. The relationship was still significant after controlling for body weight and age (P < 0.05). Genetic variation in the AQP9 gene is associated with femoral neck BMD in postmenopausal women, and may represent one of the susceptibility genes for phenotypes related to bone mass.     

Reduced bone mineral density is associated with breast arterial calcification

BACKGROUND: Arterial calcification, a marker of atherosclerosis, results from a complex process of biomineralization resembling bone formation. Breast arterial calcification (BAC) has been associated with angiographic and clinical cardiovascular disease. The purpose of this study was to determine the association between reduced bone mineral density (BMD) and BAC, which may share a common pathophysiology. METHODS: We conducted a retrospective study of 228 women (55% Hispanic, mean age 64 +/-10 yr) who had both mammography and BMD evaluation at Columbia University Medical Center from 2001-2003. Each mammogram was reviewed for the presence of BAC using standardized methods. BMD was measured using dual-energy x-ray absorptiometry and categorized as normal, low bone density (osteopenia), or osteoporosis as defined by the World Health Organization. Univariate and multivariate logistic regression analyses were performed to evaluate the association between reduced BMD and BAC. RESULTS: The prevalence of BAC, low bone density (osteopenia), and osteoporosis was 39, 42, and 29%, respectively. Women with BAC were significantly more likely to be older, Hispanic, and postmenopausal and have osteoporosis as compared with women without BAC. In age-adjusted analyses, women with BAC were more likely to have reduced BMD (odds ratio 3.0, P < 0.01) as compared with women without BAC. Furthermore, osteoporosis was strongly associated with the presence of BAC (odds ratio 3.5, P < 0.01). CONCLUSION: These data suggest that osteoporosis and arterial calcification are strongly and independently correlated. Reduced BMD may identify women at risk of vascular disease.     

High plasma leptin is not associated with higher bone mineral density in insulin-resistant premenopausal obese women

Obesity's protective effect on bone density may be mediated through increased muscle mass, fat mass, increased estrogen, and possibly insulin and leptin levels. To determine the impact of leptin and insulin on bone metabolism, we studied 48 obese normally cycling premenopausal women (age, 31 +/- 10 yr; body mass index, 35.7 +/- 5 kg/m2): 28 insulin resistant (IR) and 20 insulin sensitive (IS) by McAuley index. Anthropometric, body composition, and bone mineral density (BMD) measurements were made, and serum leptin, insulin, free testosterone, IGF-I, bone remodeling markers, and calciotropic hormones were measured. Anthropometric, lifestyle, and biochemical markers were similar in the two groups. Despite higher circulating insulin and leptin levels, IR subjects had similar mean values of serum osteocalcin but higher C-telopeptide (P = 0.052). They had similar BMD at all skeletal sites compared with IS subjects. In the IR group, fat mass but not lean mass, serum leptin, insulin, testosterone, and IGF-I levels correlated positively with hip and/or total-body bone density with R varying between 0.38 and 0.65; no correlations were observed at the spine. Conversely, in the IS group, lean mass, but not fat mass, and only IGF-I correlated with hip BMD/total-body bone mineral content. In conclusion, there is a dichotomy in the impact of body composition parameters and insulin and leptin levels on bone parameters in obese individuals. The interaction between the fat-related endocrine system and bone seems to be complex and may be modulated by local resistance to the putative protective effect of insulin and leptin on bone.     

Thyroxine suppressive therapy decreases bone mineral density in post-menopausal women

OBJECTIVE Hyperthyroidism is associated with increased bone turnover and decreased bone mass. This study aimed to evaluate the bone mineral density (BMD) of post-menopausal women on long-term thyroxine suppressive therapy. DESIGN An age and sex-matched cross-sectional study. PATIENTS Thirty-four post-menopausal women with carcinoma of thyroid, post total thyroidectomy nd M ablation, on L-T4 for 12 2 ± 6–6 years (mean±SD). Controls were 34 age-matched healthy Southern Chinese women. MEASUREMENTS Total body and regional BMDs were determined by dual-energy X-ray absorptiometry. Bone turnover was assessed by biochemical markers. RESULTS In the thyroxine treated group, total body mineral content was significantly lower than the controls (1652±356 vs 1994±270 g meaniSD, P<0 005). They also had lower BMDs in the lumbar spine, femoral neck, trochanter and Ward's triangle (0 75 ± 0 15 vs 0 92 ± 0 16 g/ cm2, P<0005; 0–62±0–12 vs 0–70±0–12 g/cm2, P<0–01; 0–55±0–14 vs 063±015 g/cm2, P<0.001; 055±014 vs 0–63 ±0–14 g/cm², P < 0.005 respectively.) The thyroxine treated group also had higher serum alkaline phosphatase and osteocalcin levels as well as urinary hydroxypro-line excretion, suggesting that they had high turnover bone loss. However, the Z-scores of the various regional BMDs were correlated only with the serum osteocalcin level and showed no correlation with the serum thyroxine level or with the dosage or duration of thyroxine treatment. CONCLUSION Long-term thyroxine suppressive therapy was associated with bone loss and preventive therapy may be indicated in these post-menopausal women at risk of osteoporosis.     

Vitamin D receptor gene polymorphisms are associated with the risk of fractures in postmenopausal women, independently of bone mineral density

CONTEXT: Osteoporosis is a systemic disease with a strong genetic component. Vitamin D receptor (VDR) gene polymorphisms explain only a small part of the genetic influence on the level of bone mineral density (BMD), whereas their effect on fracture remains uncertain. OBJECTIVE: The objective of this study was to investigate the relationships between VDR genotypes and fracture risk. DESIGN: A prospective population-based cohort was studied. SUBJECTS: A total of 589 postmenopausal women (mean age, 62 yr) were followed prospectively during a median (interquartile) of 11 (1.1) yr. MAIN OUTCOME MEASURE: The study measured incidents of vertebral and nonvertebral fractures. RESULTS: VDR allele B was significantly and dose dependently overrepresented in women who fractured, including 34 and 86 women with first incident vertebral and nonvertebral fragility fractures, respectively. This corresponded to an odds ratio of 1.5 (95% confidence interval, 0.95-2.40) for heterozygous carriers (bB, n = 286) and 2.10 (95% confidence interval, 1.16-3.79) for homozygous carriers (BB, n = 90) of the B allele, compared with women with the bb genotype (n = 213). VDR genotype groups did not differ for demographics, physical activity, grip strength, personal and maternal history of fracture, and calcium intake. The association was independent of BMD of the spine, hip, and radius, and of the BMD loss at the radius. The relationship between VDR polymorphisms and fracture risk was not altered after adjustment for baseline circulating levels of bone turnover markers, estradiol, dehydroepiandrosterone sulfate, SHBG, IGF-I, intact PTH, and 25 hydroxyvitamin D. CONCLUSION: VDR genotypes are associated with the risk of fracture in postmenopausal women independently of BMD, rate of postmenopausal forearm BMD loss, bone turnover, and endogenous hormones. The mechanisms by which VDR genotypes influence bone strength remain to be determined.     

Bone mineral density and metabolism in premenopausal women taking l-thyroxine replacement therapy

BACKGROUND AND OBJECTIVE Excess endogenous thyroxine causes bone loss, but the effects of exogenous thyroxine are disputed. We report on bone mass and metabolism in women taking l -thyroxine therapy. DESIGN Cross-sectional and longitudinal studies. PATIENTS Cross-sectional study: 40 healthy premenopausal women with autoimmune thyroiditis taking either physiological (serum TSH usually normal, 0·35–3·3 mU/l) or suppressive (serum TSH usually < 0·35 mu/l) doses of l -thyroxine; patients were also compared with previously acquired age and weight matched premenopausal volunteers with no history of thyroid dysfunction. Longitudinal study: 28 patients were followed-up ≥ 1 year later. MEASUREMENTS In all subjects bone mineral density (BMD) was measured at the anteroposterior lumbar spine and left hip (femoral neck, greater trochanter and Ward's area) using dual-energy X-ray absorptiometry, and physical activity assessed using the Framingham physical activity index. Serum osteocalcin (OC), PTH and vitamin D, and urinary pyridinoline and deoxypyridinoline excretion were measured in patients. RESULTS Cross-sectional study: The patient groups were well matched for disease duration and physical activity although the suppressed group were slightly younger (mean 3·1 (SD 7·5) vs 43·3 (3·9) years, P < 0·05). BMD, serum OC, PTH and vitamin D, and urinary cross-link excretion did not differ significantly between the two groups. Multivariate analysis of the whole group suggested that BMD at the femoral neck and greater trochanter was related positively to weight and physical activity and negatively to thyroxine dose (μg/kg/day) and patient age. At the lumbar spine BMD was reduced non-specifically in the presence of thyroid disease and treatment, but this effect appeared to decline with increasing duration of therapy. A similar analysis of the patient group suggested that urinary cross-link excretion correlated positively with thyroxine dose, and negatively with duration of treatment. Longitudinal study: Annualized changes in BMD were inversely related to thyroxine dose (μg/kg/day) at all sites but achieved statistical significance only at the femoral neck and Ward's area. CONCLUSION We did not find any effect of persistent historical TSH suppression on current bone mass, and this might relate to the relative insensitivity of older TSH assays. However, the cross-sectional and longitudinal data suggest that high daily doses of thyroxine In relation to patient body weight might adversely affect bone mass, particularly at the hip. These findings support the contention that excess exogenous thyroxine might predominantly deplete skeletal sites, such as the femoral neck, rich in cortical bone.