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.

Relationships between intestinal calcium absorption, serum vitamin D metabolites and smoking in postmenopausal women.

Smoking has been associated with low bone density, fractures and poor intestinal calcium absorption. Calcium absorption is a critical factor in calcium balance in postmenopausal women but the mechanisms causing decreased absorption efficiency in postmenopausal smokers are controversial and poorly defined. We performed a cross-sectional study of 405 postmenopausal women attending a clinic for the management of osteoporosis to compare intestinal calcium absorption efficiency, serum vitamin D metabolites and parathyroid hormone levels in postmenopausal women who had never smoked, who were smokers previously or who were current smokers, to examine the relationships between these variables in smokers. Two hundred and fifty-two of the women had never smoked, 79 had smoked previously and 74 were current smokers. The hourly fractional rate of calcium absorption was similar in non-smokers and those who had previously smoked. Radiocalcium absorption was less in the 74 smokers compared with the 331 non-smokers [0.60 (0.29 SD) vs 0.71 (0.27); p = 0.004], as were serum calcitriol (p<0.001) and parathyroid hormone (PTH) (p<0.01). There was no difference in the relationship between calcium absorption and serum calcitriol between smokers (r = 0.38) and non-smokers (r = 0.28); hence the impaired calcium absorption in the smokers was almost entirely attributable to suppression of the PTH-calcitriol endocrine axis. In postmenopausal women smoking is associated with a reduction in calcium absorption efficiency due to suppression of the PTH-calcitriol axis. This impairment of calcium absorption could lead to accelerated bone loss and limit the usefulness of dietary calcium supplementation.

The relation between bone density, free androgen index, and estradiol in men 60 to 70 years old.

The cause of age-related bone loss in men is poorly understood. Previous studies of the relationship between bone density and serum androgens have yielded inconsistent results, perhaps partly because age is a determinant of both. Recent studies suggest that serum estrogen levels influence bone density in adult men. In order to determine whether bone mineral density (BMD) and bone turnover are associated with serum sex steroids, we investigated 37 normal men within a narrow age range (60-70 years). Bone mineral density at the forearm, hip, and spine, testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI:T/SHBG), estradiol (E), free estradiol index (FEI:E/SHBG), and markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type I C-terminal extension peptide) and bone resorption (hydroxyproline/creatinine [OHPr/Cr], deoxypyridinoline/creatinine [Dpd/Cr], pyridinoline/creatinine, collagen type I cross-linked telopeptide) were measured. Bone mineral density was positively related (r > 0.35, p < 0.05 at all sites) to log FAI, whereas there was no significant relationship between BMD and either serum total testosterone, serum E, or FEI. Bone density at the spine and hip were inversely related to both OHPr/Cr (r > -0.41, p < 0.05 for all sites) and Dpd/Cr (r > -0.36, p < 0.05 for all sites). OHPr/Cr (r = -0.41, p < 0.05) and Dpd/Cr (r = -0.41, p < 0.05) were both inversely related to log FAI. We conclude that BMD and bone turnover in adult men are related to plasma free androgens.

Effect of perimenopause on calcium absorption: a longitudinal study.

OBJECTIVE: Cross-sectional studies suggest that the rise in calcium requirement at the menopause may be attributable, at least in part, to a fall in intestinal calcium absorption. The aim of the present study was to determine the effect of the menopause on intestinal calcium absorption and the relationship between any change in calcium absorption and serum calcitriol. METHODS: Radiocalcium absorption and serum calcitriol were measured in 72 women aged 47.3 (standard error, SE 0.19) years who were initially premenopausal (as judged by menstrual history and serum follicle stimulating hormone (FSH)) and again 18 months later. RESULTS: Calcium absorption fell at the second visit from 0.72 (0.029)/h to 0.64 (0.029)/h (p = 0.003). Serum calcitriol had also fallen at the second visit from 124 (4.2) pmol/l to 111 (4.0) pmol/l (p = 0.007). At that visit, serum FSH exceeded the premenopausal reference range in 11 subjects and the menstrual cycle had become irregular in 24 of them. In the 11 women with raised FSH at the second visit, radiocalcium absorption fell from 0.85/h (0.097) at baseline to 0.57/h (0.049) (p = 0.008), but only from 0.70/h (0.028) to 0.65/h (0.033) (not significant) in the remaining 61. Similarly, radiocalcium absorption fell significantly (p = 0.003) in the 24 women with irregular menses, but not in the remaining 48 who continued to menstruate regularly. These changes in calcium absorption were still significant after correction for changes in calcitriol levels. CONCLUSION: The perimenopause is associated with a fall in calcium absorption, which is only in part attributable to a fall in calcitriol levels.

Biochemical variables in pre- and postmenopausal women: reconciling the calcium and estrogen hypotheses.

There is controversy as to whether the rise in urinary calcium at the menopause is the cause or the result of the rise in bone resorption at that time. In an attempt to resolve this issue, we have compared the relevant biochemical variables in 102 premenopausal volunteers (mean age 37 years; range 21-52) and 86 apparently normal postmenopausal women (mean age 55 years; range 40-60). We measured the fasting serum calcium, creatinine, proteins, electrolytes and intact parathyroid hormone (PTH), and the urinary calcium and creatinine both after an overnight fast and in a 24-h collection. We calculated serum calcium fractions, creatinine clearance and the notional tubular maximum reabsorptive capacity for calcium. Creatinine excretion and clearance were lower in the post- than in the premenopausal women after correction for surface area and age. Total serum calcium was higher in the post- than in the premenopausal women but this was accounted for by the higher ligand concentrations in the former. Fasting and 24-h urinary calcium were also higher in the post- than in the premenopausal women due in part to the former's higher filtered load of calcium (due to their higher serum complexed calcium) but mainly to their reduced tubular reabsorption of calcium despite their slightly raised serum PTH. Our analysis resolves the rise in urinary calcium at the menopause into its two components: increased filtered load and reduced tubular reabsorption. The changes in these two variables, neither of which can be attributed to increased bone resorption, produce an increase in calcium requirement that is sufficient to account for postmenopausal bone loss. However, the translation of this menopausal increase in calcium requirement into an increase in bone resorption at near-normal serum PTH levels requires some menopause-dependent change in the responsiveness of the bone to calcium demand. We suggest that this change may occur at the level of the osteoclasts and that estrogen may modify the calcium feedback setpoint in these cells in a manner analogous to calcitonin. This model resolves the apparent conflict between the estrogen and calcium hypotheses and explains the synergism between these two treatment modalities.

Prepubertal oophorectomy limits the accumulation of cancellous bone in the femur of growing rats with long-term effects on metaphyseal bone architecture.

Bone loss after oophorectomy of adult rats is more rapid and complete in the metaphysis than in the epiphysis of the femur, particularly in the proximal region of the metaphysis distant from the growth plate. This study was undertaken to determine the effects of prepubertal oophorectomy, on femoral cancellous bone acquisition during growth. Rats were oophorectomized (OVX) or sham operated at 3 weeks of age and killed at intervals up to 78 weeks for scanning electron microscopy and histomorphometry of the distal femur. Differences in cancellous bone architecture between the two groups was evident after 6 weeks of age. Relatively minor differences were found in the part of the metaphysis near the growth plate and in the epiphysis, with less trabeculae in the primary spongiosa and 1 to 2 less trabeculae/mm in the secondary spongiosa. However, as metaphyseal growth proceeded, trabeculae were present for a greater distance up the femoral shaft in controls than in OVX rats, with mean BV/TV in the proximal part of the metaphysis increasing from 1.4% at 6 weeks to 13.4% at 20 weeks in controls, with no increase in the OVX rats. We find that the lack of ovarian hormones increases the rate of destruction of trabeculae near the metaphyseal-diaphyseal junction.

Trabecular spacing in post-menopausal Australian women with and without vertebral fractures.

Histomorphometric measurements were made from iliac crest biopsies of 32 women with vertebral fractures and 37 women without fracture. All were post-menopausal Australian women who had presented with back pain to a hospital out-patient endocrinology clinic. Bone from the fracture cases was characterised by loss of individual trabecular elements, with the remaining trabeculae being spaced further apart than those in the non-fracture women (p less than 0.0001). This resulted in a significant decrease in trabecular bone volume (p less than 0.01). In addition osteoid surface was reduced (p less than 0.01). Dynamic parameters of bone turnover were not significantly different between the two groups. These data should be useful for the assessment of iliac bone histomorphometry in Australian post-menopausal women suspected of having osteoporosis.

Treatment of malignancy-associated hypercalcemia with norethisterone: a case report.

Hypercalcemia is a common cause of morbidity in cancer patients. The mechanism of malignancy-associated hypercalcemia includes increased bone resorption and decreased renal calcium clearance which also occur in primary hyperparathyroidism. Norethisterone can inhibit bone resorption and has recently been shown to be effective treatment for mild hyperparathyroidism in post menopausal women. We report the successful use for the first time of norethisterone (5 mg daily) in a case of malignancy-associated hypercalcemia after other standard agents failed.

New approaches to the problems of osteoporosis.

Professor Urist's contributions to the understanding of osteoporosis are worthy of reevaluation at this time, when interest in the field has reached unprecedented heights. Recent advances in technology have greatly increased our understanding of osteoporosis by showing that there is no loss of bone in normal premenopausal women, and that the loss which starts at the menopause can be attributed to an increase in bone resorption. It is suggested that the primary event is a rise in plasma calcium that leads to a rise in obligatory urinary calcium loss, which in turn increases the calcium requirement. The subset of the postmenopausal population who develop fractures (particularly in the spine) show additional risk factors, which include malabsorption of calcium (which further increases bone resorption) and reduced adrenal androgen production (which may produce a fall in bone formation). The treatment of established cases requires control of bone resorption by calcium supplementation and/or hormone therapy, with the addition of calcitriol if malabsorption of calcium is present. Stimulation of bone formation is more difficult, but there is a suggestion that this may be possible with the use of anabolic steroids.