Biomedical subjects

J H Tobias

Publications and source records attributed to J H Tobias.

At least 19 recordsLinked to original sources

PubMed2006

Gender differences in the ratio between humerus width and length are established prior to puberty.

SUMMARY: On a sample of 1,317 children aged 9.9 years we developed a novel method of measuring humeral dimensions from total body dual-energy X-ray absorptiometry (DXA) scans and showed that gender differences in the ratio between humeral width and length are established prior to puberty. INTRODUCTION: It is recognised that long bone cross-sectional area is greater in males compared to females, which is thought to reflect more rapid periosteal bone growth in boys. However, it is currently unclear whether these findings reflect gender differences in bone size or shape. In the present study, we investigated whether gender differences exist in the balance between longitudinal and periosteal long bone growth in children, leading to gender differences in bone shape, based on a novel method for evaluating shape of the humerus. We also examined whether these differences are established prior to puberty. METHODS: Length, area and width of the humerus were estimated from total body DXA scans in 1,317 children aged 9.9 +/- 0.33 years, who had participated in a nested case-control study of fractures within the Avon Longitudinal Study of Parents and Children (ALSPAC) (a geographically based birth cohort based in South West England). No differences were observed with respect to parameters of humeral geometry according to fracture history, and so both groups were pooled for further analysis. Aspect ratio (AR) of the humerus was calculated as humeral width divided by length. Total body height and weight were measured at the same time as the DXA scan. Puberty was assessed using self-completion questionnaires. RESULTS: Humeral width and length were positively associated with age and height in boys and girls combined (P<0.001), and with Tanner stage in girls (P<0.002). In contrast, age, height and Tanner stage were not related to humeral AR. We then examined gender differences in humeral shape according to pubertal stage. In prepubertal children (i.e. Tanner stage 1), humeral length was similar in boys and girls, but width (1.92 vs 1.88 cm, P<0.001) and area (47.7 vs 46.9 cm(2), P<0.001) were greater in boys, resulting in a greater AR (7.78 vs 7.53, P<0.001). Similar gender differences were observed in early pubertal children (i.e. Tanner stage 2). CONCLUSION: We conclude that the greater periosteal diameter of boys compared to girls reflects differences in the balance between longitudinal and periosteal bone growth. Interestingly, resulting gender differences in humeral AR are established in prepubertal children.

Absorptiometry, Photon↗

PubMed2006

Estrogen receptor alpha regulates area-adjusted bone mineral content in late pubertal girls.

CONTEXT: Whether the action of estrogen in skeletal development depends on estrogen receptor alpha as encoded by the ESR1 gene is unknown. OBJECTIVES: The aim of this study was to establish whether the gain in area-adjusted bone mineral content (ABMC) in girls occurs in late puberty and to examine whether the magnitude of this gain is related to ESR1 polymorphisms. DESIGN: We conducted a cross-sectional analysis. SETTING: The study involved the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based prospective study. PARTICIPANTS: Participants included 3097 11-yr-olds with DNA samples, dual x-ray absorptiometry measurements, and pubertal stage information. OUTCOMES: Outcome measures included separate prespecified analyses in boys and girls of the relationship between ABMC derived from total body dual x-ray absorptiometry scans and Tanner stage and of the interaction between ABMC, Tanner stage, and ESR1 polymorphisms. RESULTS: Total body less head and spinal ABMC were higher in girls in Tanner stages 4 and 5, compared with those in Tanner stages 1, 2, and 3. In contrast, height increased throughout puberty. No differences were observed in ABMC according to Tanner stage in boys. For rs2234693 (PvuII) and rs9340799 (XbaI) polymorphisms, differences in spinal ABMC in late puberty were 2-fold greater in girls who were homozygous for the C and G alleles, respectively (P = 0.001). For rs7757956, the difference in total body less head ABMC in late puberty was 50% less in individuals homozygous or heterozygous for the A allele (P = 0.006). CONCLUSIONS: Gains in ABMC in late pubertal girls are strongly associated with ESR1 polymorphisms, suggesting that estrogen contributes to this process via an estrogen receptor alpha-dependent pathway.

Bone Density↗

PubMed2006

Use of clinical risk factors to identify postmenopausal women with vertebral fractures.

INTRODUCTION AND HYPOTHESIS: Previous studies have been unable to identify risk factors for prevalent vertebral fractures (VF), which are suitable for use in selection strategies intended to target high-risk sub-groups for diagnostic assessment. However, these studies generally consisted of large epidemiology surveys based on questionnaires and were only able to evaluate a limited number of risk factors. Here, we investigated whether a stronger relationship exists with prevalent VF when conventional risk factors are combined with additional information obtained from detailed one-to-one assessment. METHODS: Women aged 65-75 registered at four geographically distinct GP practices were invited to participate (n=1,518), of whom 540 attended for assessment as follows: a questionnaire asking about risk factors for osteoporosis such as height loss compared to age 25 and history of non-vertebral fracture (NVF), the get-up-and-go test, Margolis back pain score, measurement of wall-tragus and rib-pelvis distances, and BMD as measured by the distal forearm BMD. A lateral thoraco-lumbar spine X-ray was obtained, which was subsequently scored for the presence of significant vertebral deformities. RESULTS: Of the 509 subjects who underwent spinal radiographs, 37 (7.3%) were found to have one or more VF. Following logistic regression analysis, the four most predictive clinical risk factors for prevalent VF were: height loss (P=0.006), past NVF (P=0.004), history of back pain (P=0.075) and age (P=0.05). BMD was also significantly associated with prevalent VF (P=0.002), but its inclusion did not affect associations with other variables. Factors elicited from detailed one-to-one assessment were not related to the risk of one or more prevalent VFs. The area under ROC curves derived from these regressions, which suggested that models for prevalent VF had modest predictive accuracy, were as follows: 0.68 (BMD), 0.74 (four clinical risk factors above) and 0.78 (clinical risk factors + BMD). Analyses were repeated in relation to the subgroup of 13 patients with two or more VFs, which revealed that in this instance, the Margolis back pain score and rib-pelvis distance were associated with the presence of multiple VFs (P=0.022 and 0.026, respectively). Moreover, the predictive value as reflected by the ROC curve area was improved: 0.80 (BMD), 0.88 (the four most predictive clinical risk factors consisting of the height loss, past NVF, Margolis back pain score and rib-pelvis distance) and 0.91 (clinical risk factors + BMD). CONCLUSIONS: Evaluation of additional risk factors from detailed one-to-one assessment does not improve the predictive value of risk factors for one or more prevalent vertebral deformities in postmenopausal women. However, the use of factors such as the Margolis back pain score and rib-pelvis distance may be helpful in identifying postmenopausal women at high risk of multiple prevalent VFs.

Aged↗

PubMed2006

Adipose tissue stimulates bone growth in prepubertal children.

CONTEXT: Fat mass represents a positive influence on bone mass in adults, independently of other factors such as lean mass, but whether a similar action occurs in children is unclear. OBJECTIVE: Our objective was to examine the relationship between fat mass and bone mass in children. DESIGN AND SETTING: We conducted combined cross-sectional and prospective analyses at university research clinics. PARTICIPANTS: Participants included children aged 9.9 yr from a large population-based birth cohort in southwest England. OUTCOMES: Relationships between total body fat mass were measured by dual-energy x-ray absorptiometry at age 9.9 yr, and 1) total-body-less-head bone mass and area at age 9.9 and 2) increase in bone mass and area over the following 2 yr. RESULTS: There was a strong positive relationship between total body fat mass and total-body-less-head bone mass and area, even after adjustment for height and/or lean mass (P < 0.001). There was a similar positive association between total body fat mass and increase in bone mass and area over the following 2 yr in boys and Tanner stage 1 girls. In contrast, no association was present between fat mass and gain in bone mass and size in Tanner stage 2 girls, whereas a negative association was seen in Tanner stage 3 girls (puberty-fat mass interaction, P < 0.001). CONCLUSIONS: In prepubertal children, fat mass is a positive independent determinant of bone mass and size and of increases in these parameters over the following 2 yr, suggesting that adipose tissue acts to stimulate bone growth. However, this relationship is attenuated by puberty.

Absorptiometry, Photon↗

PubMed2006

Association between bone density and fractures in children: a systematic review and meta-analysis.

OBJECTIVE: The objective of this article was to systematically review all published studies that investigated the association between bone density and fractures in children. DESIGN: Potentially relevant articles were identified by searching electronic databases. Duplicates were removed, abstracts were inspected, and relevant articles were obtained. Studies were included in the systematic review if participants were <16.0 years old, were healthy, had extractable data on bone mass, and had fractures as the outcome. RESULTS: Ten case-control studies were identified. No prospective studies were found. There was no evidence of heterogeneity between studies or of funnel-plot asymmetry. Eight of the studies were included in the meta-analysis, because they presented results as means and standard deviations of bone density in cases and controls. The pooled standardized mean difference for bone mass in children with and without fractures, from a fixed-effects model, was -0.32 (95% confidence interval: -0.43 to -0.21). CONCLUSIONS: Evidence for an association between bone density and fractures in children is limited. The results from this meta-analysis suggest that there is an association between low bone density and fractures in children. Although there was no evidence of heterogeneity or publication bias, this meta-analysis is based on case-control studies that are prone to bias. Large, well-conducted prospective cohort studies are required to confirm the association between bone density and fractures in children.

Bone Density↗

PubMed2005

Bone mass in childhood is related to maternal diet in pregnancy.

Evidence that birth weight is related to bone mass in later life suggests that the intrauterine environment programs the trajectory of subsequent bone development. To explore this hypothesis, we examined whether maternal diet in pregnancy, as assessed by the maternal food frequency questionnaire (FFQ) completed at 32 weeks gestation, is related to bone mass of the child, as measured by total body DXA carried out at age 9 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Diet records were linked to DXA scan results for the total body and spine sub-region and pooled between pre- and early pubertal boys and girls (n=4,451). Regression analysis was carried out between DXA values and dietary factors following adjustment for social and other confounding factors. Maternal magnesium intake was related to total body BMC (beta=4.9, 7.4-23.1; g) and BMD (beta=4.9, 2.5-7.3; g/cm2 x10(3)) (standardized regression coefficient with 95% confidence limits; P<0.001). An equivalent relationship was no longer observed after adjusting for the height of the child, to which magnesium intake was also related (beta=0.48, 0.20-0.77; cm; P=0.001). Maternal intake of potassium was related to spinal BMC (beta=1.8, 0.8-2.9; g) and BMD (beta=10.5, 4.9-16.0; g/cm2 x10(3)) (P=0.001), which was no longer observed after adjusting for the weight of the child, to which potassium intake was also related (beta=0.52, 0.16-0.88, P=0.005; kg). A significant association was also observed between maternal dietary folate intake and spinal BMC adjusted for bone area using a linear regression model (beta=0.55, 0.16-0.94; g; P=0.006), which persisted after adjusting for height and weight. Our observation that constituents of maternal diet are related to DXA measures at age 9 is consistent with the hypothesis that the trajectory of bone development in childhood is programmed by early life factors.

Absorptiometry, Photon↗

PubMed2004

Tamoxifen stimulates cancellous bone formation in long bones of female mice.

Selective estrogen receptor modulators (SERMs) have been developed as a means of targeting estrogen's protective effect on the skeleton in the treatment of postmenopausal osteoporosis. Although it is well established that SERMs such as tamoxifen inhibit bone resorption in a similar manner to estrogen, whether this agent shares estrogen's stimulatory action on bone formation is currently unclear. To address this question, we compared the effect of treatment for 28 d with 17beta-estradiol (E2; 0.1, 1.0 mg/kg x d) and tamoxifen (0.1, 1.0, or 10 mg/kg x d) on cancellous bone formation at the proximal tibial metaphysis of intact female mice. E2 stimulated the formation of new cancellous bone throughout the metaphysis. A similar response was observed after administration of tamoxifen, the magnitude of which was approximately 50% of that seen after E2. As expected, E2 was found to suppress longitudinal bone growth, but in contrast, this parameter was stimulated by tamoxifen. We conclude that tamoxifen acts as an agonist with respect to estrogen's stimulatory action on bone formation but as an antagonist in terms of estrogen's inhibition of longitudinal growth, suggesting that the protective effect of SERMs on the skeleton is partly mediated by stimulation of osteoblast activity.

Animals↗

PubMed2004

Rapid hip bone loss in active Crohn's disease patients receiving short-term corticosteroid therapy.

BACKGROUND: Uncertainty over whether corticosteroids cause bone loss in patients with Crohn's disease may reflect their short, intermittent use. AIM: We investigated whether a 2-month course of prednisolone is associated with detectable bone loss. METHODS: Fifteen patients with active Crohn's disease and 19 controls with inactive Crohn's disease were recruited. Bone mineral density of the lumbar spine and hip was measured at baseline and 2 and 8 months. RESULTS: At 2 months, significant bone loss was found in patients with active disease (femoral neck -2.7%, P < 0.002; Ward's triangle -3.9%, P < 0.01). Although bone mineral density was still lower at 8 months, these differences were no longer significant (-1.3% and -3.4%, femoral neck and Ward's triangle, respectively). No significant change in hip bone mineral density was observed in controls. Previous corticosteroid use was not significantly associated with baseline bone mineral density, although significant independent associations were observed between weight, site of disease and lumbar spine bone mineral density, and between dietary calcium deficiency and femoral neck and Ward's triangle bone mineral density. CONCLUSION: Significant bone loss at the hip can be detected in patients receiving corticosteroid treatment for 2 months for active Crohn's disease ; however, it remains unclear whether this is because of disease activity or its treatment. This rapid bone loss may represent a risk factor for fracture and justify bone protective therapy.

Adult↗

PubMed2004

Effect of a case-finding strategy for osteoporosis on bisphosphonate prescribing in primary care.

Case-selection strategies have been advocated for identifying patients who would benefit from primary care to prevent osteoporosis. However, the effectiveness of this approach is unclear. To address this question, we performed a randomized control trial to determine whether a case-selection strategy to identify patients with clinical risk factors for osteoporosis, combined with open access to dual X-ray absorptometry (DXA) scans, influences bisphosphonate prescribing in ten GP practices in Avon. Practices were randomized to two groups: the first identified women aged 45-75 years at high risk of osteoporosis and provided open access to DXA scans for 12 months; the second had no case-finding strategy and no DXA scan access. Bisphosphonate prescribing was ascertained by searching computerized patient records every 3 months during the intervention and a subsequent 6-month follow-up period. Overall, the number of subjects in each practice who were prescribed bisphosphonates increased by 50% (p<0.001), and the proportion of bisphosphonates prescribed as aminobisphosphonates increased 3-fold (p<0.001). The magnitude of these changes was similar in both groups. However, of the patients prescribed bisphosphonates, approximately twice as many in group 1, as compared with group 2, had a previously documented low-trauma fracture, as assessed at the end of the 12-month intervention period (p=0.01). Furthermore, at study's end, of the 30 patients in group 1 receiving bisphosphonates who had received DXA scans, 80% had osteoporosis as defined by t-score<-2.5. We conclude that use of a case-selection strategy for osteoporosis in primary care, combined with open access to DXA scans, appears to target bisphosphonate therapy to those at high risk of osteoporotic fractures. In contrast, the overall rate of bisphosphonate prescribing is unaffected by this intervention.

Absorptiometry, Photon↗

PubMed2003

Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice.

The P2X7 receptor is a member of the family of P2X purinergic receptors, which upon sustained activation forms large pores in the plasma membrane. In cells of hematopoietic origin, P2X7 receptor activation has been shown to lead to multiple downstream events, including cytokine release, cell permeabilization, and apoptosis. This receptor has also been implicated in the generation of multinucleated giant cells, polykaryons, and osteoclasts. We have recently demonstrated that a blockade of this receptor inhibits osteoclast formation in vitro; therefore, we examined mice deficient in the P2X7 receptor in the context of bone. These mice were healthy and displayed no overt skeletal problems. Furthermore, we were able to demonstrate their ability to form multinucleated cells, in particular osteoclasts, both in vivo and in vitro. We also demonstrate the ability of P2X7R-/- multinucleated osteoclasts, upon stimulation with maitotoxin (MTX), to form pores in the plasma membrane in vitro. These findings are consistent with the existence of an endogenous pore structure present in osteoclast precursor cells that can be activated either by the P2X7 receptor, or in its absence, by alternative signals to mediate fusion and pore formation. These data provide further insight into the mode of action of the P2X7 receptor.

Animals↗

PubMed2002

Estrogen-induced osteogenesis in intact female mice lacking ERbeta.

We recently found that estrogen receptor (ER) antagonists prevent high-dose estrogen from inducing the formation of new cancellous bone within the medullary cavity of mouse long bones. In the present investigation, we studied the role of specific ER subtypes in this response by examining whether this is impaired in female ERbeta(-/-) mice previously generated by targeted gene deletion. Vehicle or 17beta-estradiol (E(2)) (range 4-4,000 microg. kg(-1). day(-1)) was administered to intact female ERbeta(-/-) mice and wild-type littermates by subcutaneous injection for 28 days. The osteogenic response was subsequently assessed by histomorphometry performed on longitudinal and cross sections of the tibia. E(2) was found to cause an equivalent increase in cancellous bone formation in ERbeta(-/-) mice and littermate controls, as assessed at the proximal and distal regions of the proximal tibial metaphysis. E(2) also resulted in a similar increase in endosteal mineral apposition rate in these two genotypes, as assessed at the tibial diaphysis. In contrast, cortical area in ERbeta(-/-) mice was found to be greater than that in wild types irrespective of E(2) treatment, as was tibial bone mineral density as measured by dual-energy X-ray absorptiometry, consistent with previous reports of increased cortical bone mass in these animals. We conclude that, although ERbeta acts as a negative modulator of cortical modeling, this isoform does not appear to contribute to high-dose estrogen's ability to induce new cancellous bone formation in mouse long bones.

Animals↗

PubMed2002

Novel therapeutic targets in osteoporosis.

Osteoporosis is a common condition in which significant bone loss occurs resulting in an increased risk of sustaining fractures. Several licensed therapies are available to treat this condition, which suffer from several disadvantages including limited efficacy, high cost and poor long-term patient adherence as a consequence of significant side effects and inconvenient methods of administration. A wide range of therapeutic targets have been developed to provide a basis for developing newer therapies which overcome these limitations. These can be subdivided into those that are primarily directed towards inhibiting osteoclast-dependent bone resorption and those that stimulate osteoblastic bone formation. Targets can be grouped as follows: systemic factors such as steroid and peptide hormones; local factors produced in bone involved in osteoblast and osteoclastic regulation; and cellular targets such as cell membrane receptors and attachment proteins, cellular enzymes and nuclear transcription factors. To date, only a small proportion of these targets have yielded novel compounds to have entered clinical trials. However, it is anticipated that these will provide the basis for significant numbers of new therapies for osteoporosis in the foreseeable future.

Animals↗

PubMed2001

Characterisation of the temporal sequence of osteoblast gene expression during estrogen-induced osteogenesis in female mice.

Osteoblast differentiation under in vitro conditions is associated with increased expression of non-collagenous bone proteins including osteocalcin, osteopontin, and osteonectin, the exact function of which remain poorly understood. To determine whether these proteins play an important role in the formation of mineralised bone matrix by osteoblasts in vivo, we analysed the time-course of their expression during estrogen-induced osteogenesis in female mice, and compared this with the formation of new cancellous bone. Female mice were sacrificed prior to or following treatment with 17beta-estradiol for up to 32 days (500 microg/animal/week). Total RNA was extracted from femurs, and changes in expression of genes for a range of osteoblast-derived proteins assessed by Northern blot analysis. In parallel experiments, the time course of cancellous bone formation was determined by measuring bone mineral density (BMD) of the distal femur. Estrogen led to a rapid increase in BMD, which reached significance by Day 16. This was preceded by three-fold increases in expression of alkaline phosphatase (ALP) and type I collagen (COL I) at Days 8 and 12 respectively. In contrast, osteocalcin, osteopontin, and osteonectin expression showed no change during this initial period, although modest increases were observed at later times (i.e., Days 20 and 24). Our results suggest that osteocalcin, osteopontin, and osteonectin are not involved in the initial phase of the osteogenic response to estrogen, suggesting that these non-collagenous bone proteins do not play a direct role in the formation of mineralised bone matrix by osteoblasts in vivo.

Alkaline Phosphatase↗

PubMed2001

Effects of combination therapy with PTH and 17beta-estradiol on long bones of female mice.

Parathyroid hormone (PTH) is thought to increase trabecular bone mass in postmenopausal women by stimulating osteoblast function. A similar action may contribute to estrogen's protective effect on the skeleton, which we have explored in female mice, in which estrogen induces an exaggerated osteogenic response. In the present investigation, we used this model to determine whether an interaction exists between stimulatory effects of PTH and estrogen on osteoblast function in cancellous bone. An initial dose response study was performed where PTH (hPTH, 1-38) was administered to ten-week-old intact female mice by daily sc injection for 28 days, at doses of 1, 10, 100 microg/kg. In a subsequent study, intact female mice were given PTH and/or 17beta-estradiol (E2) 10 and 40 microg/kg/day respectively. Femoral BMD was assessed by peripheral DXA (PIXImus), and histomorphometry was performed to analyse changes in cancellous and cortical bone. PTH caused a small gain in femoral BMD, and increased the extent of periosteal bone formation surfaces, but had relatively little effect on other skeletal parameters when given alone. As previously found, E2 produced a large increase in femoral BMD, stimulated cancellous and endocortical bone formation, but inhibited periosteal bone formation. In mice treated with combination therapy, a greater increase in femoral BMD was observed compared to that following treatment with either agent alone. No differences in indices of cancellous bone were found between animals treated with E2 compared to the combination group. However, cortical area and periosteal bone formation rate were significantly greater in the latter group. We conclude that PTH and E2 exert an additive effect on bone mass in long bones of female mice, possibly reflecting an ability of PTH to oppose E2-induced suppression of periosteal bone formation.

Absorptiometry, Photon↗

PubMed2001

Role of endothelial nitric oxide synthase in estrogen-induced osteogenesis.

It is well recognized that high-dose estrogen induces a marked osteogenic response in long bones of female mice. In light of evidence which suggests that nitric oxide synthase (NOS) plays a role in regulation of osteoblast activity, we analyzed whether NOS is involved in mediating this response. Intact female mice were administered 17beta-estradiol (E(2)) either alone or in combination with N(G)-nitro-L-arginine methylester (L-NAME) or aminoguanidine (AG), over 24 days. The former inhibits both constitutive and inducible isoforms of NOS, whereas the latter is a selective inhibitor of inducible NOS. Bone mineral density (BMD) of the femur was subsequently measured by dual-energy X-ray absorptiometry (DXA), and histomorphometry performed at the proximal metaphysis on longitudinal tibial sections. As expected, E(2) given alone led to a marked accumulation of cancellous bone at the proximal tibial metaphysis, associated with a significant gain in femoral BMD, and an increase in cancellous mineralizing surfaces as assessed by histomorphometry. Neither L-NAME nor AG affected cancellous histomorphometric indices when given alone. However, when administered in combination with L-NAME, the magnitude of the skeletal response to E(2) was significantly reduced. The tendency for L-NAME to reduce estrogen-induced bone formation within the proximal tibial metaphysis was more marked distally compared with proximally. In contrast, AG showed no tendency to suppress the osteogenic response to E(2). Subsequently, we examined the effect of E(2) administration on expression within mouse femoral bone marrow of endothelial NOS (eNOS), which is the predominant constitutive isoform of NOS within bone. No change in eNOS mRNA levels was observed following E(2) administration, as assessed by reverse transcription-polymerase chain reaction (RT-PCR). Taken together, our results suggest that eNOS plays a role in mediating estrogen-induced bone formation in intact female mice, possibly as a consequence of posttranscriptional regulation of eNOS activity by estrogen.

Animals↗

PubMed2001

Analysis of the contribution of dydrogesterone to bone turnover changes in postmenopausal women commencing hormone replacement therapy.

Although gestagens have been reported to influence bone metabolism, whether these contribute to the beneficial effects of hormone replacement therapy (HRT) on the skeleton of postmenopausal women is currently unclear. To address this question, we compared changes in bone turnover markers after commencing HRT in 26 postmenopausal women randomized to receive 8 weeks of treatment with 2 mg estradiol daily or 2 mg estradiol plus 10 mg dydrogesterone daily. Serum and second morning void urine samples were obtained at baseline (twice) and after 1, 2, 4, and 8 weeks. Serum estradiol was measured by RIA, urinary total deoxypyridinoline (DPD) excretion by high pressure liquid chromatography, and serum osteocalcin and C-terminal procollagen peptide by enzyme-linked immunosorbent assay. The increase in serum estradiol after treatment with estradiol alone was slightly, but significantly, greater than that in the combination group (P = 0.04). Although estradiol suppressed urinary DPD excretion to a greater extent when given alone (P = 0.02), osteocalcin levels were significantly higher in this group than in women receiving combination therapy (P = 0.04). To assess the effect of dydrogesterone on the balance between formation and resorption in more detail, we subsequently compared the ratio between formation and resorption markers in the two treatment groups. We found that osteocalcin/DPD and C-terminal procollagen peptide/DPD ratios were significantly higher in women treated with estradiol alone (P < 0.0001 and P = 0.002, respectively), suggesting that dydrogesterone may reduce formation relative to resorption. These results suggest that gestagens may reduce estrogen's beneficial effects on the skeleton of postmenopausal women, as assessed over the first 8 weeks of replacement therapy.

Amino Acids↗

PubMed2000

Is high-dose estrogen-induced osteogenesis in the mouse mediated by an estrogen receptor?

Although estrogen is known to induce new bone formation in the long bones of female mice, this response is only thought to occur following administration of high doses, suggesting that it may not be mediated by a conventional estrogen receptor. To address this question further, we first examined the stereospecificity of this response by comparing the potency of 17beta-estradiol (E(2)) in stimulating cancellous bone formation at the proximal tibial metaphysis of intact female mice with that of the relatively inactive stereoisomer, 17alpha-estradiol (alphaE(2)). We found that E(2) was significantly more potent than alphaE(2), as assessed by histomorphometry. To provide further evidence for an estrogen-receptor-mediated process, we examined whether E(2)-induced osteogenesis in intact female mice could be inhibited by the estrogen receptor antagonist, ICI 182,780 (ICI). Although ICI itself had no effect on histomorphometric indices of the proximal tibial metaphysis when given alone, it significantly inhibited the osteogenic response to E(2). Finally, we examined the dose dependency of E(2)-induced osteogenesis at the proximal tibial metaphysis in intact mice. We found that E(2) stimulated cancellous bone formation in a dose-dependent manner over a wide dose range (i. e., 1-4000 microg/kg per day), with significant increases observed at doses of 4 microg/kg per day and beyond. Our results raise the possibility that estrogen-induced osteogenesis in the mouse represents an estrogen-receptor-mediated response that is not confined solely to supraphysiological estrogen levels.

Animals↗

PubMed2000

Effects of high-dose estrogen on murine hematopoietic bone marrow precede those on osteogenesis.

High-dose estrogen both stimulates new medullary bone formation and suppresses hematopoiesis in mouse long bones. To determine whether the latter response is a direct consequence of the former, we compared the time course of estrogen's effects on osteogenesis and hematopoietic bone marrow. Flow cytometry was employed to measure hematopoietic subpopulations in bone marrow from femurs of female mice killed at different times after commencing 0.5 mg estradiol/wk to each animal. Estrogen markedly reduced the number of leucocytes (CD11a positive), which had already diminished by 75% after 4 days and had virtually disappeared by 18 days. Specific populations showed a similar pattern of decline after estrogen, including B lymphocytes, monocytes, and endothelial cells. In contrast, the osteogenic precursor population showed a marked increase after estrogen treatment, as assessed by assaying alkaline phosphatase-positive colony-forming units (fibroblastic) ex vivo. However, this rise did not reach significance until 8 days after estrogen administration, suggesting that it follows rather than precedes estrogen's effects on hematopoiesis. We conclude that estrogen does not suppress hematopoiesis in mouse long bones as a direct consequence of its effects on osteogenesis.

Animals↗