To test or to not test: A retrospective cross-sectional study on potentially inappropriate use of pathology testing in South Australian hospitals.

OBJECTIVES: To measure rates of potentially inappropriate pathology testing in the hospital setting. METHODS: Retrospective cross-sectional study in hospital setting from July 2021 to December 2021. We examined 3 potentially inappropriate uses: overordering, selection errors, and unnecessary repeat testing. Overordering included vitamin D and lipids (rarely required in acute hospital care). Selection error was the ratio of iron studies to standalone ferritin requests. Unnecessary repeats included any repeat vitamin D, lipids, iron, or ferritin in an episode of care or C-reactive protein (CRP) repeated within 3 days and N-terminal pro-brain natriuretic peptide (NT-proBNP) within 7 days and repeated previously abnormal CRP and NT-proBNP tests. Costs of inappropriate tests were estimated using the Australian Medicare Benefits Schedules. RESULTS: Among 55,904 test requests, 15% (n = 8120) were potentially inappropriate. Vitamin D was frequently ordered (n = 4498), as were lipids (n = 2872). Ratio of iron studies to standalone ferritin was 36. Of 19,233 repeat CRPs, 36% (n = 6947) were within 3 days and 62% (n = 179) of repeat NT-proBNPs were within 7 days of the first test. For initially abnormal tests, 89% of CRPs and 97% of NT-proBNPs remained abnormal. Inappropriate test costs accounted for 12% to 30% of costs. CONCLUSIONS: Frequent potential inappropriate use and selection of pathology tests was observed in South Australian hospitals.

The role of sex hormone-binding globulin (SHBG), testosterone, and other sex steroids, on the development of type 2 diabetes in a cohort of community-dwelling middle-aged to elderly men.

AIMS: Contrasting findings exist regarding the association between circulating sex hormone-binding globulin (SHBG) and testosterone levels and type 2 diabetes (T2D) in men. We examined prospective associations of SHBG and sex steroids with incident T2D in a cohort of community-dwelling men. METHODS: Participants were from a cohort study of community-dwelling (n = 2563), middle-aged to elderly men (35-80 years) from Adelaide, Australia (the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study). The current study included men who were followed for 5 years and with complete SHBG and sex steroid levels (total testosterone (TT), dihydrotestosterone (DHT) and oestradiol (E2)), but without T2D at baseline (n = 1597). T2D was identified by either self-report, fasting glucose (≥ 7.0 mmol/L), HbA1c (≥ 6.5%/48.0 mmol/mol), and/or prescriptions for diabetes medications. Logistic binomial regression was used to assess associations between SHBG, sex steroids and incident T2D, adjusting for confounders including age, smoking status, physical activity, adiposity, glucose, triglycerides, symptomatic depression, SHBG and sex steroid levels. RESULTS: During an average follow-up of 4.95 years, 14.5% (n = 232) of men developed new T2D. Multi-adjusted models revealed an inverse association between baseline SHBG, TT, and DHT levels, and incident T2D (odds ratio (OR) = 0.77, 95% CI [0.62, 0.95], p = 0.02; OR 0.70 [0.57, 0.85], p < 0.001 and OR 0.78 [0.63, 0.96], p = 0.02), respectively. However, SHBG was no longer associated with incident T2D after additional adjustment for TT (OR 0.92 [0.71, 1.17], p = 0.48; TT in incident T2D: OR 0.73 [0.57, 0.92], p = 0.01) and after separate adjustment for DHT (OR 0.83 [0.64, 1.08], p = 0.16; DHT in incident T2D: OR 0.83 [0.65, 1.05], p = 0.13). There was no observed effect of E2 in all models of incident T2D. CONCLUSIONS: In men, low TT, but not SHBG and other sex steroids, best predicts the development of T2D after adjustment for confounders.

Lower Urinary Tract Symptoms, Depression, Anxiety and Systemic Inflammatory Factors in Men: A Population-Based Cohort Study.

BACKGROUND: The relationship between lower urinary tract symptoms (LUTS) and common mental health disorders such as depression and anxiety in men remains unclear. Inflammation has recently been identified as an independent risk factor for LUTS and depression. This study aimed to assess the association between depression, anxiety and LUTS, and the moderating influence of systemic inflammation, in the presence of other biopsychosocial confounders. METHODS: Participants were randomly-selected from urban, community-dwelling males aged 35-80 years at recruitment (n = 1195; sample response rate:67.8%). Of these, 730 men who attended baseline (2002-5) and follow-up clinic visits (2007-10), with complete outcome measures, and without prostate or bladder cancer and/or surgery, neurodegenerative conditions, or antipsychotic medications use, were selected for the present study. Unadjusted and multi-adjusted regression models of incident storage and voiding LUTS and incident depression and anxiety were combined with serum inflammatory markers (high-sensitive C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), myeloperoxidase (MPO), soluble e-selectin (e-Sel)) and socio-demographic, lifestyle, and health-related factors. Hierarchical multiple regression was used to assessed the moderating effect of inflammatory markers. RESULTS: The incidence of storage, voiding LUTS, depression and anxiety was 16.3% (n = 108), 12.1% (n = 88), 14.5% (n = 108), and 12.2% (n = 107). Regression models demonstrated that men with depression and anxiety at baseline were more likely to have incident storage, but not voiding LUTS (OR: 1.26, 99%CI: 1.01-4.02; and OR:1.74; 99%CI:1.05-2.21, respectively). Men with anxiety and storage LUTS at baseline were more likely to have incident depression (OR: 2.77, 99%CI: 1.65-7.89; and OR:1.45; 99%CI:1.05-2.36, respectively), while men with depression and voiding LUTS were more likely to have anxiety at follow-up (OR: 5.06, 99%CI: 2.81-9.11; and OR:2.40; 99%CI:1.16-4.98, respectively). CRP, TNF-α, and e-Sel were found to have significant moderating effects on the development of storage LUTS (1.06, 0.91-1.96, R2 change: 12.7%), depression (1.17, 1.01-1.54, R2 change: 9.8%), and anxiety (1.35, 1.03-1.76, R2 change: 10.6%), respectively. CONCLUSIONS: There is a bidirectional relationship between storage, but not voiding, LUTS and both depression and anxiety. We observed variable moderation effects for selected inflammatory markers on the development of depression, anxiety and storage LUTS.

Longitudinal changes in testosterone over five years in community-dwelling men.

CONTEXT: There are few population-based studies reporting longitudinal changes in total T, LH, FSH, and SHBG levels, and there is limited information on risk factors for their change. OBJECTIVE: The objective of the study was to examine 5-year changes in serum T, LH, FSH, and SHBG levels among Australian men. DESIGN: The study initially included a randomly selected, community-based cohort of 1588 men age 35 years or older at recruitment (mean age, 54 ± 11 y) with available data at 2 visits. Men on medications known to affect, or with established pathology of, the hypothalamo-pituitary gonadal axis were excluded, leaving 1382 for analysis. RESULTS: Mean baseline and follow-up T levels were 16.2 ± 1.4 and 15.6 ± 1.4 nmol/L, a change of -0.13 nmol/L/y. Annualized T changes were associated with obesity, being unmarried, and smoking at baseline, but not with diabetes, hypertension, or cardiovascular disease. T declined in men who had persistent depression or developed chronic disease, and it increased in men who were married, as compared to unmarried, at both time points. In the multivariate analysis, smoking cessation, development of central obesity (waist ≥ 100 cm), or generalized obesity (body mass index ≥ 30 kg/m(2)) resulted in T decreases of 0.36, 0.25, and 0.20 nmol/L/y, respectively. Quitting smoking, developing obesity, and having persisting depression were inversely related to SHBG change. CONCLUSIONS: An age-related decline in T levels is not inevitable but is largely explained by smoking behavior and intercurrent changes in health status, particularly obesity and depression.

Testosterone and modifiable risk factors associated with diabetes in men.

OBJECTIVE: The role of endogenous testosterone in the pathogenesis of type 2 diabetes mellitus remains vague. We investigated whether associations between endogenous testosterone and diabetes prevalence in men could be partially explained by modifiable risk factors. STUDY DESIGN: A random population-based cross-sectional study of 1195 men aged 35-80 years living in the north-west regions of Adelaide, Australia. Data collections occurred between 2002 and 2005, and response rate was 45.1%. MATERIALS AND METHODS: Diabetes (non-specific) was classified by either: (1) self-report for doctor diagnosis of diabetes; (2) prescription medication for diabetes; (3) fasting plasma glucose ≥ 7 mmol/L; or (4) glycosylated haemoglobin ≥ 6.2%. Logistic regressions were used to estimate odds ratios (OR [with 95% confidence intervals]) for diabetes, with stepwise adjustments for demographic, lifestyle, and clinical factors. RESULTS: Diabetes prevalence was positively associated with age groups 45-54 years (2.8 [1.4, 5.8]), 55-64 years (3.9 [1.9, 8.3]) and ≥ 65 years (4.0 [1.8, 8.9]), lowest income group (1.8 [1.0, 3.4]), ex-smoker (1.8 [1.2, 2.9]), lowest (3.2 [1.9, 5.5]) and middle (1.9 [1.1, 3.4]) alcohol tertiles, cardiovascular disease (1.9 [1.2, 2.8]), metabolic syndrome (4.0 [2.6, 6.1]), and lowest plasma total testosterone tertile (1.8 [1.1, 3.0]), but negatively associated with middle (0.5 [0.3, 0.8]) and highest (0.4 [0.3, 0.7]) sugar intake tertiles, arthritis (0.6 [0.3, 1.0]), and elevated LDL cholesterol (0.5 [0.3, 0.8]); ORs showed an inverted 'U' shape for middle and highest voiding lower urinary tract symptoms tertiles. Body composition, muscle strength, and cardio-metabolic factors partially explained the association between low plasma total testosterone and diabetes. CONCLUSIONS: Plasma total testosterone was inversely and independently associated with diabetes prevalence, that might have been partially explained by several modifiable risk factors.

Experimental evidence for the effects of calcium and vitamin D on bone: a review.

Animal models fed low calcium diets demonstrate a negative calcium balance and gross bone loss while the combination of calcium deficiency and oophorectomy enhances overall bone loss. Following oophorectomy the dietary calcium intake required to remain in balance increases some 5 fold, estimated to be approximately 1.3% dietary calcium. In the context of vitamin D and dietary calcium depletion, osteomalacia occurs only when low dietary calcium levels are combined with low vitamin D levels and osteoporosis occurs with either a low level of dietary calcium with adequate vitamin D status or when vitamin D status is low in the presence of adequate dietary calcium intake. Maximum bone architecture and strength is only achieved when an adequate vitamin D status is combined with sufficient dietary calcium to achieve a positive calcium balance. This anabolic effect occurs without a change to intestinal calcium absorption, suggesting dietary calcium and vitamin D have activities in addition to promoting a positive calcium balance. Each of the major bone cell types, osteoblasts, osteoclasts and osteocytes are capable of metabolizing 25 hydroxyvitamin D (25D) to 1,25 dihydroxyvitamin D (1,25D) to elicit biological activities including reduction of bone resorption by osteoclasts and to enhance maturation and mineralization by osteoblasts and osteocytes. Each of these activities is consistent with the actions of adequate circulating levels of 25D observed in vivo.

Serum testosterone bioassay evaluation in a large male cohort.

OBJECTIVE: To assess if a cell-based readout of androgen action in serum demonstrates a closer association with recognized classical parameters of androgen action in men than current measures of serum testosterone (T). DESIGN: To develop, validate and utilize a mammalian cell-based assay to measure specifically bioactive T and determine if this measure is a physiologically relevant fraction of serum T. MEASUREMENTS AND PARTICIPANTS: We have developed a specific serum T bioassay using human prostate cancer cells. A rapid 5-min exposure to 100% serum followed by serum withdrawal confers specificity of the assay to serum T and provides sufficient sensitivity to measure T in male serum samples. Matrix effects were experimentally discounted as a confounding issue. A total of 960 male serum samples from the Florey Adelaide Male Ageing Study (FAMAS) with previous comprehensive cohort data and serum measurements were utilized. RESULTS: Bioassay T measurement in the 960 FAMAS serum samples returned a median of 10.7 nmol/l (1.7-45.4), and was most closely related to immunoassayed total T, but not immunoassayed bioavailable T or calculated free T. Immunoassayed total T demonstrated a positive association with isometric grip-strength (R(2) = 0.127, P < 0.001), self-reported sexual desire (R(2) = 0.113, P < 0.001) and erectile function (R(2) = 0.085, P < 0.05) while bioassay T did not. CONCLUSIONS: While cellular bioassays offer a rapid and sensitive means of identifying the androgenic potential of complex environmental compounds, the utility of such assays in defining a clinically relevant fraction of serum T distinct from total T needs further investigation.

Targeted disruption of the CXCL12/CXCR4 axis inhibits osteolysis in a murine model of myeloma-associated bone loss.

The plasma cell (PC) malignancy, multiple myeloma (MM), is unique among hematological malignancies in its capacity to cause osteoclast (OC)-mediated skeletal destruction. We have previously shown that elevated plasma levels of PC-derived CXCL12 are associated with presence of X-ray detectable osteolytic lesions in MM patients. To further investigate this relationship, plasma levels of CXCL12 and betaCrossLaps, a marker of bone loss, were measured. A strong correlation between levels of CXCL12 and OC-mediated bone resorption was identified. To confirm the OC-activating potential of MM PC-derived CXCL12 in vivo, we established a model of MM-mediated focal osteolysis, wherein MM PC lines, such as RPMI-8226, were injected into the tibias of nude mice. Implanting RPMI-8226 gave rise to osteolytic lesions proximal to the tumor, resulting in a 5% decrease in bone volume (BV) compared with vehicle control. Importantly, bone loss was significantly inhibited with systemic administration of the CXCL12/CXCR4 antagonist T140. Furthermore, implanting CXCL12-overexpressing RPMI-8226 cells resulted in a 13% decrease in BV and was associated with increased OC recruitment proximal to the tumor, increased serum matrix metalloproteinase activity, and increased levels of collagen I degradation products. These findings confirm our hypothesis that MM PC-derived CXCL12 stimulates the recruitment and activity of OC, thereby contributing to the formation of MM osteolytic lesions.

Demographic, physical and lifestyle factors associated with androgen status: the Florey Adelaide Male Ageing Study (FAMAS).

OBJECTIVE: Plasma androgen levels are inversely associated with health in men, the age-related decline of which may result from factors other than ageing per se. This study aimed to determine the effects of demographic, physical and lifestyle factors on age-related androgen status in men. DESIGN: An observational survey of a regionally representative male population residing in the North West regions of Adelaide, Australia. PARTICIPANTS: Study sample includes 1195 men aged 35-81 years with a response rate of 45.1%. MEASUREMENTS: Plasma levels of total testosterone (TT), bioavailable testosterone (BT), SHBG, insulin-like peptide 3 (INSL3), and gonadotrophins were measured along with an extensive list of demographic, physical and lifestyle factors including body composition, muscle strength and biomarkers of chronic diseases, physical activity, nutrition and smoking behaviour. RESULTS: Low TT was mostly associated with high abdominal fat and triglycerides and low muscle strength rather than ageing per se. Low BT was associated with increased age followed by high whole body fat percentage. BT and TT levels were higher in unmarried men and smokers. SHBG levels increased with age, but were also inversely associated with insulin and triglycerides. The Leydig cell specific factor INSL3 was the strongest biomarker associated with both TT and BT. CONCLUSIONS: Factors associated with low androgen status variably include high body fat percentage, low muscle strength and biomarkers of the metabolic syndrome. Reducing exposure to factors that adversely affect androgen status may improve the general health of ageing men by mechanisms yet to be defined.

Vitamin D depletion induces RANKL-mediated osteoclastogenesis and bone loss in a rodent model.

The association between increased risk of hip fracture and low vitamin D status has long been recognized. However, the level of vitamin D required to maintain bone strength is controversial. We used a rodent model of vitamin D depletion to quantify the 25-hydroxyvitamin D (25D) levels required for normal mineralization. Six groups of 10-wk-old male Sprague-Dawley rats (n = 42) were fed a diet containing 0.4% calcium and various levels of dietary vitamin D(3) for 4 mo to achieve stable mean serum 25D levels ranging between 10 and 115 nM. At 7 mo of age, animals were killed, and the histomorphometry of distal and proximal femora and L(2) vertebra was analyzed. Total RNA was extracted from whole femora for real-time RT-PCR analyses. In the distal femoral metaphysis, trabecular bone mineral volume (BV/TV) showed a significant positive association with circulating 25D levels (r(2) = 0.42, p < 0.01) in the animals with serum 25D levels between 20 and 115 nM. Osteoclast surface (Oc.S) levels were positively associated with RANKL:OPG mRNA ratio, higher in groups with lower serum 25D levels, and were independent of serum 1,25D levels. Serum 25D levels <80 nM gave rise to osteopenia as a result of increased osteoclastogenesis, suggesting that levels of 25D >80 nM are needed for optimal bone volume. These data indicate that serum 25D levels are a major determinant of osteoclastogenesis and bone mineral volume and are consistent with the levels of 25D recommended to reduce the risk of fracture in humans.

Vitamin D metabolites and calcium absorption in severe vitamin D deficiency.

Contrary to frequent claims, vitamin D insufficiency does not generally cause malabsorption of calcium because serum 1,25(OH)(2)D, which is the major determinant of calcium absorption, is maintained by secondary hyperparathyroidism. Nevertheless, because malabsorption of calcium has been described in osteomalacia, there must be a 25(OH)D level below which the serum 1,25(OH)(2)D can no longer be sustained, although it has never been defined. This paper seeks to define it. We examined the records of 3661 patients and found 319 with a serum 25(OH)D < or = 40 nM, in whom calcium absorption, serum calcium, PTH, bone markers, and vitamin D metabolites had been measured. They were grouped according to their serum 25(OH)D into four categories, 0-10, 11-20, 21-30, and 31-40 nM, and differences between the groups were tested by ANOVA. Correlations between the variables were also examined. Serum calcium, 1,25(OH)(2)D, and calcium absorption were significantly decreased and serum PTH and alkaline phosphatase (ALP) and urine hydroxyproline were increased in those with 25(OH)D < or = 10 nM. Serum ALP and urine hydroxyproline were more strongly related, inversely, to calcium absorption than to the vitamin D metabolites. We conclude that vitamin D deficiency does not reduce serum 1,25(OH)(2)D, and therefore calcium absorption, until the serum 25(OH)D falls to approximately 10 nM. At this level, the substrate concentration seems to be insufficient to maintain the level of the dihydroxy metabolite despite secondary hyperparathyroidism. Further studies are needed to see how these changes correlate with the histological changes of osteomalacia.

Suppression of parathyroid hormone and bone resorption by calcium carbonate and calcium citrate in postmenopausal women.

This study was conducted to compare the suppressive effects of calcium carbonate and calcium citrate on bone resorption in early postmenopause. Calcium citrate is thought to be better absorbed. We therefore tested the hypothesis that calcium as citrate is more effective than calcium as carbonate in suppressing parathyroid hormone (PTH) and C-terminal telopeptide. Twenty-five healthy postmenopausal women were recruited in this double blind crossover study. The subjects were randomly allocated to receive either 1,000 mg of elemental calcium as carbonate or 500 mg of calcium as citrate. They were given the alternate calcium dose 1 week later. Serum measurements of total and ionized calcium, phosphate, PTH, and CrossLaps were repeated 12 hours after each dose. Analysis of variance found no significant difference between measures for the two salts. Tests for equivalence indicated that 500 mg of calcium citrate may be superior to 1,000 mg of calcium carbonate in raising serum total and ionized calcium (P = 0.04 and 0.05, respectively). For all parameters measured, 500 mg of calcium citrate was at least as beneficial as 1,000 mg of calcium carbonate. Calcium citrate is at least as effective as calcium carbonate in suppressing PTH and C-terminal telopeptide cross-links, at half the dose. This may be because calcium as citrate is better absorbed than calcium as carbonate. If calcium citrate can be used in lower doses, it may be better tolerated than calcium carbonate.

Circulating RANKL is inversely related to RANKL mRNA levels in bone in osteoarthritic males.

INTRODUCTION: The relationship of circulating levels of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) with the expression of these molecules in bone has not been established. The objective of this study was to measure, in humans, the serum levels of RANKL and OPG, and the corresponding levels in bone of mRNA encoding these proteins. METHODS: Fasting blood samples were obtained on the day of surgery from patients presenting for hip replacement surgery for primary osteoarthritis (OA). Intraoperatively, samples of intertrochanteric trabecular bone were collected for analysis of OPG and RANKL mRNA, using real time RT-PCR. Samples were obtained from 40 patients (15 men with age range 50 to 79 years, and 25 women with age range 47 to 87 years). Serum total RANKL and free OPG levels were measured using ELISA. RESULTS: Serum OPG levels increased over the age range of this cohort. In the men RANKL mRNA levels were positively related to age, whereas serum RANKL levels were negatively related to age. Again, in the men serum RANKL levels were inversely related (r = -0.70, P = 0.007) to RANKL mRNA levels. Also in the male group, RANKL mRNA levels were associated with a number of indices of bone structure (bone volume fraction relative to bone tissue volume, specific surface of bone relative to bone tissue volume, and trabecular thickness), bone remodelling (eroded surface and osteoid surface), and biochemical markers of bone turnover (serum alkaline phosphatase and osteocalcin, and urinary deoxypyridinoline). CONCLUSION: This is the first report to show a relationship between serum RANKL and the expression of RANKL mRNA in bone.

Antineoplastic agents target the 25-hydroxyvitamin D3 24-hydroxylase messenger RNA for degradation: implications in anticancer activity.

Calcitriol or 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] has antitumor activity and hence its levels in patients may play an important role in disease outcome. Here, we report that the antineoplastic agents, daunorubicin hydrochloride, etoposide, and vincristine sulfate inhibited the ability of 1,25(OH)(2)D(3) to cause the accumulation of mRNA for kidney 25-hydroxyvitamin D(3) 24-hydroxylase (CYP24), an enzyme which catabolizes this hormone. This was not due to a drug-induced cytotoxic effect, reduction in the expression of the vitamin D receptor or inhibition of the vitamin D receptor-mediated activation of the mitogen-activated protein kinases or CYP24 promoter activity. Interestingly, there was selective degradation of CYP24 mRNA in the presence of the drugs. This was accompanied by an enhancement in the levels of 1,25(OH)(2)D(3) in cells incubated with 25-hydroxy vitamin D(3). These data identify a novel mechanism of action of some commonly used antineoplastic agents which by decreasing the stability of CYP24 mRNA would prolong the bioavailability of 1,25(OH)(2)D(3) for anticancer actions.

Metabolism of vitamin D3 in human osteoblasts: evidence for autocrine and paracrine activities of 1 alpha,25-dihydroxyvitamin D3.

Circulating 1 alpha,25-dihydroxyvitamin D(3) (1,25D) derives from renal conversion of 25-hydroxyvitamin D(3) (25D), by the 25D 1 alpha-hydroxylase (CYP27B1). Blood 25D levels, but not 1,25D levels, are the best indicator of vitamin D status and predict fracture risk in the elderly. We examined the extent to which osteoblasts can metabolize 25D. Well-characterized human primary osteoblasts and osteosarcoma (OS) cell lines were examined for the expression and regulation of genes associated with vitamin D metabolism, using real-time PCR. Primary osteoblasts and OS cell lines were found to express CYP27B1 mRNA and secreted detectable 1,25D in response to 25D. Of the OS cell lines tested, HOS expressed the most CYP27B1 mRNA and secreted the highest levels of 1,25D. All osteoblastic cells examined up-regulated expression of the catabolic regulator of 1,25D, the 25-hydroxyvitamin D-24-hydroxylase (CYP24), when incubated with either 1,25D or 25D. Exposure to physiological levels of 25D resulted in up-regulated transcription of the 1,25D responsive genes, osteocalcin (OCN), osteopontin (OPN) and RANKL. Specific knockdown of CYP27B1 in HOS cells using siRNA resulted in up to 80% reduction in both 1,25D secretion and the transcription of OCN and CYP24, strongly implying that the 25D effect in osteoblasts is preceded by conversion to 1,25D. Incubation with 25D, like 1,25D, inhibited primary osteoblast proliferation and promoted in vitro mineralization. Finally, we detected expression by osteoblasts of receptors for vitamin D binding protein (DBP), cubilin and megalin, suggesting that osteoblasts are able to internalize DBP-25D complexes in vivo. Together, our results suggest that autocrine, and perhaps paracrine, pathways of vitamin D(3) metabolism may regulate key osteoblast functions independently of circulating, kidney derived 1,25D. Our results are therefore consistent with the reported benefits of maintaining a healthy vitamin D status in the elderly to reduce the risk of fractures.

Vitamin D action and regulation of bone remodeling: suppression of osteoclastogenesis by the mature osteoblast.

UNLABELLED: Vitamin D acts through the immature osteoblast to stimulate osteoclastogenesis. Transgenic elevation of VDR in mature osteoblasts was found to inhibit osteoclastogenesis associated with an altered OPG response. This inhibition was confined to cancellous bone. This study indicates that vitamin D-mediated osteoclastogenesis is regulated locally by OPG production in the mature osteoblast. INTRODUCTION: Vitamin D stimulates osteoclastogenesis acting through its nuclear receptor (VDR) in immature osteoblast/stromal cells. This mobilization of calcium stores does not occur in a random manner, with bone preferentially removed from cancellous bone. The process whereby the systemic, humoral regulator is targeted to a particular region of the skeleton is unclear. MATERIALS AND METHODS: Bone resorption was assessed in mice with vitamin D receptor transgenically elevated in mature osteoblasts (OSVDR). Vitamin D-mediated osteoclastogenesis was examined in vitro using OSVDR osteoblasts and osteoblastic RANKL: osteoprotegerin (OPG) examined in vivo and in vitro after vitamin D treatment. RESULTS: Vitamin D-mediated osteoclastogenesis was reduced in OSVDR mice on chow and calcium-restricted diets, with effects confined to cancellous bone. OSVDR osteoblasts had a reduced capacity to support osteoclastogenesis in culture. The vitamin D-mediated reduction in OPG expression was reduced in OSVDR osteoblasts in vivo and in vitro, resulting in a reduced RANKL/OPG ratio in OSVDR compared with wildtype, after exposure to vitamin D. CONCLUSIONS: Mature osteoblasts play an inhibitory role in bone resorption, with active vitamin D metabolites acting through the VDR to increase OPG. This inhibition is less active in cancellous bone, effectively targeting this region for resorption after the systemic release of activated vitamin D metabolites.

Oophorectomy acutely increases calcium excretion in adult rats.

Estrogen deficiency-induced bone loss is associated with complex changes in the calcium fluxes that constitute calcium balance. We studied the effects of oophorectomy on calcium balance and its components within the first 9 wk after the operation. Six-day calcium balance studies were performed on 30-wk-old female Sprague-Dawley rats before either sham operation or oophorectomy (oophx) and at 3-wk intervals for 9 wk postoperation. The rats were fed a diet containing 0.4g Ca/100 g diet and 0.3 g P/100 g diet throughout the study. The postoperative changes in calcium balance (P < 0.05) and net calcium absorption (P < 0.02) were negative in the oophx group compared with the ovary-intact group. The oophx group excreted more calcium via both the kidney (urine Ca, P < 0.05) and the gastrointestinal tract (endogenous fecal Ca, P < 0.05). The postoperation endogenous fecal calcium was higher at 3 wk postoophorectomy than at later times (P < 0.05). Oophorectomy did not affect true calcium absorption up to 9 wk postoophorectomy. Oophorectomy stimulates bone metabolism and our findings indicate that within the first 9 wk after oophorectomy, bone mineral loss is associated with a transient increase in the excretion of calcium by the gastrointestinal tract and the kidney.