Predicting the effects of estrogen replacement therapy on lumbar bone mineral density in oophorectomized women: analysis of a 10-year longitudinal study

The purpose of this study was to investigate whether it is possible to predict the long-term effects of estrogen replacement therapy (ERT) on lumbar bone mineral density (BMD) of oophorectomized women based on changes in BMD. In this study, we retrospectively investigated the changes in lumbar BMD of 70 oophorectomized women under ERT for more than 10 years, and examined whether it was possible in the early stage of ERT to predict the amount of lumbar BMD based on various parameters. Seventy oophorectomized Japanese women (56.8±3.9 years old) treated with conjugated equine estrogen (oral) at a dosage of 0.625 mg/day for 10 years were enrolled. Lumbar (L2–L4) BMD was measured annually by dual-energy X-ray absorptiometry (DXA; CV<1.0%). The correlation between changes in BMD after 10 years on ERT (BMD10) and several clinical factors was examined using a stepwise multiple regression model. The change in BMD after 1 year on ERT (%BMD1) was the only independent factor that correlated with changes in BMD after 10 years on ERT; the coefficient of correlation was R ²=0.557 (R=0.750, P<0.001). Based on the %BMD1, the 70 women were divided into two groups: women with a positive change in the 1st year (%BMD10%) in group A (n=40) and those with a negative value in the first year ( %BMD1<0%) in group B (n=30). We investigated the sensitivity and specificity in the coincidence of %BMD1 changes in BMD after 10 years on ERT. The %BMD1 coincided with changes in BMD after 10 years on ERT; the sensitivity was 92.5% and specificity was 70.0%. In conclusion, changes in lumbar BMD on ERT can be predicted from the changes in lumbar BMD at the end of the 1st year.     

Change in Mitochondrial Membrane Potential in Peripheral Blood Lymphocytes,Especially in Natural Killer Cells,Is a Possible Marker for Surgical Stress on the Immune System

There is accumulating evidence that surgical stresses cause impairment of systemic immune responses, which may promote susceptibility to infection as well as growth of remnant cancer cells in cancer patients. Although alterations in numbers, populations, and functions of lymphocytes have been extensively studied to assess modulation of the immune system, the precise mechanisms of immunosuppression caused by surgical stresses have not been identified, nor have methods been developed to estimate the magnitude of surgical stresses on the immune system. In the present study, to evaluate the effects of surgical procedures on the immune system, the mitochondrial membrane potential (_m) of peripheral blood lymphocytes (PBL) from 25 patients who underwent various types of operation was measured by flow cytometry using 3,3-dihexiloxacarbocyanine iodide (DiOC₆(3)) on the day before operation and on postoperative day (POD) 1, POD 3, and POD 7. The _m in PBL, especially in natural killer (NK) cell population, was reduced after major surgery. In particular, the reduction of _m in NK cells appeared to be proportional to the severity of the surgical procedures and reflected the impairment of cellular function. Interestingly, the _m in NK cells was also negatively correlated with the level of plasma noradrenaline after major surgery, suggesting that the reduction of _m in NK cells induced by surgical stresses may bemediated, at least in part, by the accompanying increase in plasma noradrenaline. Monitoring of _m in PBL after operation may be one of the useful markers for estimating the magnitude of surgical stresses on the immune system.     

Effects of unilateral strength training and detraining on bone mineral density and content in young women: A study of mechanical loading and deloading on human bones

This study assessed the effect of unilateral strength training at 80% one repetition maximum and of detraining on bone mineral density (BMD, g/cm^-2) and bone mineral content (BMC, g) in young women. Twelve female physiotherapy students trained their left limb by leg press an average of four times per week for 1 year followed by 3 months of detraining. Twelve students served as controls. Repeated bone measurements were performed by dual energy X-ray absorptiometry of the lumbar spine, femoral neck, distal femur, patella, proximal tibia, and calcaneus. The training increased the muscle strength of the trained limb, and the BMD of the same limb showed a nonsignificant but systematic increase in distal femur, patella, and proximal tibia, and in BMC of the five measured limb sites (considered an index of the total osteogenic effectiveness of the training). Simultaneously, the muscle strength increased in the untrained limb as an evidence of cross-training effect. A corresponding small but systematic increase was also seen in BMD of this limb as well as in BMC. After the cessation of training, leg extension strength was retained but BMD and BMC of the trained and untrained limbs declined towards baseline values in 3 months. The BMD and BMC values in the control group showed an increasing tendency during the follow-up but the changes were less than 1%. The differences of the changes in BMD and BMC between the left and right limb in the control group, as well as between the same limb in the training and control groups were nonsignificant. The findings of this study indicate that unidirectional strength training, intensive enough to induce substantial strength gain, is not an effective stimulus to increase BMD and BMC in young, physically active women. The unilateral training model turned out to be feasible in these subjects, producing a definite cross-training effect in muscle strength and a trend of similar effect in BMD. Further development of the unilateral training model, and studies to test if training produces adaptation in nonloaded bones (i.e., a crosstraining effect), are also warranted.     

Bone mineral density measures in longitudinal studies: The choice of phantom is crucial for quality assessment. The Tromsø study, a population-based study

Determination of change in bone mineral density (BMD) requires high-precision densitometry techniques. The purpose of the study is to investigate to what degree different densitometer phantoms reflect observed changes in human BMD and to investigate to what degree fluctuations in densitometers measurement level influence bone loss estimates. Densitometer influence was assessed using the aluminum forearm phantom (AFP) provided by the manufacturer, the European forearm phantom (EFP) of semi-anthropomorphic calcium-hydroxyapatite, and repeated population measurements on different densitometer combinations. The mean follow-up time was 6.4 years (SD 0.6). Measured population bone loss varied from 4.6%/year to 3.2%/year, depending on densitometer combinations. These variations could not be explained by differences in sex, age, height, weight and baseline BMD. They were predicted by EFP measurements, but not AFP measurements. The EFP measurements indicate that X-ray tube replacement changed the densitometers measurement level in one of three instances, whereas wear and tear did not. We used the EFP data for adjustment of the densitometers measurement levels. After adjustment, the overall crude bone loss was reduced from 4.14% to 3.92%. Mean annual loss was reduced from 0.64% or 0.61%. We conclude that densitometer performance might influence the accuracy of bone loss estimates. Changes in performance are not detected by aluminum phantoms. Quality control of BMD measurements in longitudinal studies should be performed with anthropomorphic calcium-hydroxyapatite phantoms in order to detect possible differences between the participating densitometers measurement levels.     

Effects of Sex Steroid Receptor Specificity in the Regulation of Skeletal Metabolism

The interaction between estrogens and androgens, with their protective effects in bone, and parathyroid hormone (PTH), a calcitropic peptide hormone, is complex but may be better understood with murine models. The purpose of this study was to characterize skeletal phenotypes of mice deficient in estrogen receptor alpha (ER), androgen receptor (AR, mutant tfm), or both, and determine if ER and AR alter osteoblast differentiation and/or PTH response in vitro. Loss of ER resulted in increased long bone length in females, but reduced length in males, suggesting loss of ER reversed sex steroid-dependent skeletal dimorphism. The AR deficient tfm mice (genetically male but phenotypically female) had the longest bones and, similar to males, lengths were reduced with loss of ER. Loss of AR and/or ER resulted in a reduction in femoral bone mineral density (BMD) compared to male wildtype (WT) mice, suggesting tfm mice follow the female sex for BMD. In males or tfm mice, but not females, loss of AR and/or ER caused a reduction in cortical width of the tibia compared to male WT mice. Reduced trabecular bone was found in tibiae of female and tfm mice versus male littermates, suggesting that tfm mice follow the female sex for trabecular bone but loss of ER did not alter trabecular bone levels. Primary calvarial osteoblasts of male WT mice were less responsive to PTH stimulation of cAMP than all other genotypes, suggesting the female chromosomal sex and/or loss of ER or AR results in increased sensitivity to PTH. In conclusion, tfm mice follow the male pattern of long bone development, but imitate females in bone density and trabecular bone. Loss of ER and/or AR results in increased osteoblast sensitivity to PTH and may explain actions of PTH noted in hypogonadal humans.     

Associations of polymorphisms in the vitamin D receptor gene (BsmI and FokI) with bone mineral density in postmenopausal women in Malta

Previous studies have suggested that variations in the vitamin D receptor (VDR) gene are related to bone mineral density (BMD). In this study, the TC transition in the start codon and the GA polymorphism at the 3 end of the VDR gene, identified by endonucleases FokI and BsmI, respectively, were analysed and correlated with BMD in postmenopausal Maltese women (n=104). Genotype frequencies observed for the VDR start codon polymorphism (SCP) were CC: 60.4%; CT: 30.7% and TT: 8.9%, while those observed for the 3 in this study were GG: 16.4%; GA: 51.9%; AA: 31.7%. In postmenopausal women, both lumbar and femoral BMD were observed to be highest in CC homozygotes for the FokI genotype and in GG homozygotes for the BsmI genotype, although in both groups the difference between the genotypes was not statistically significant, even after adjusting BMD for age, BMI and years since menopause. No evidence of linkage disequilibrium between the two alleles was observed.     

Evaluation of single versus multiple cryogen spray cooling spurts on in vitro model human skin

Many commercially available dermatologic lasers utilize cryogen spray cooling for epidermal protection. A previous tissue culture study demonstrated that single cryogen spurts (SCS) of 80 ms or less were unlikely to cause cryo-injury in light-skinned individuals. More recently, multiple cryogen spurts (MCS) have been incorporated into commercial devices, but the effects of MCS have not been evaluated. The aim was to study an in vitro tissue culture model and the epidermal and dermal effects of SCS vs patterns of shorter MCS with the same preset total cryogen delivery time (t_c) and provide an explanation for noted differences. Four different spurt patterns were evaluated: SCS: one 40-ms cryogen spurt; MCS2: two 20-ms cryogen spurts; MCS4: four 10-ms cryogen spurts; MCS8: eight 5-ms cryogen spurts. Actual t_c and total cooling time (t_Total) were measured for each spurt pattern. RAFT tissue culture specimens were exposed to cryogen spurt patterns and biopsies were taken immediately and at days 3 and 7. Actual t_c was increased while t_Total remained relatively constant as the preset t_c of 40 ms was delivered as shorter MCS. Progressively more epidermal damage was noted with exposure to the MCS patterns. No dermal injury was noted with either SCS or MCS. For a constant preset t_c of 40 ms, delivering cryogen in patterns of shorter MCS increased the actual t_c and consequently the observed epidermal cryo-injury as compared to an SCS.     

Mitochondrial membrane potential after low-power laser irradiation

We used the lipophilic cationic fluorescent dye 5,5,6,6-tetrachloro-1,1,3,3-tetraethyl-benzimidazol-carbocyanine iodide (JC-1) to determine mitochondrial membrane potential (m) in Hep-2 cells after irradiation with low-power laser (=635 nm). Through this methodology it was possible to analyze the variation on mitochondrial number and m, in cells irradiated for 100, 150 and 200 s with energy density of 100 mJ/cm². Our results show that JC-1 dye allows the identification of populations with different mitochondria morphology as well as the functionality of this organelle in the cells incubated for 1, 6 and 24 h, after irradiation with low-power laser.     

Dehydroepiandrosterone sulphate and bone mineral density

Several series of data suggest that alterations in adrenal androgen output might be a contributing factor to changes in bone mass. To study the possible relationship between bone density and serum levels of dehydroepiandrosterone sulphate (DHEAS) we investigated 105 women (aged 45–69 years; 76 postmenopausal, 29 perimenopausal). The patients were divided into two groups according to the bone mineral density (BMD) measurement (normal densityn=50, low densityn=55). BMD was measured by dual-energy X-ray absorptiometry of the lumbar spine and femoral neck. Bone mineral content (BMC) of the radius midshaft was measured by single photon absorptiometry. Serum DHEAS level was significantly lower in the low density group than in the normal one (1.91±1.04 v 4.77±2.03 µmol/l,p<0.001). The serum DHEAS level decreased significantly with age in both groups (r=0.43,p<0.001 in the normal group;r=0.35,p<0.01 in the low density group). Unlike the slopes, the positions of the regression lines differed significantly (difference 2.85 µmol/1,p<0.001). Correcting for age by multiple linear regression we established a significant positive relationship between DHEAS and BMD of the lumbar spine and femoral neck, and BMC of radius midshaft as well. Since there was no significant difference between the two groups regarding oestrogens, we suggest that DHEAS may have a non-oestrogenic effect on bone. The odds ratio of a subject with a low (<3.3 µmol/l) serum DHEAS level having low BMD was 40 (confidence interval 13–126). We conclude that serum DHEAS may be a useful indicator of low BMD in peri- and postmenopausal women.     

Bone Mineral Density of the Lumbar Spine is Associated with TNF Gene Polymorphisms in Early Postmenopausal Japanese Women

We investigated the relationships between tumor necrosis factor (TNF) gene polymorphism, circulating TNF-alpha (TNF-) concentrations, and bone mineral density (BMD) in the lumbar spine. TNF gene polymorphisms studied were the Nco I polymorphism within the first intron of TNF-beta (TNF-) and three single nucleotide polymorphisms in the promoter region of the TNF- gene, at positions –857, –863, and –1031. Allelic variants of the TNF gene were identified using restriction fragment length polymorphism (RFLP) analysis in 177 postmenopausal Japanese women within 10 years after menopause, aged 56.4 ± 4.5 years (mean ± SD). A significantly higher prevalence of the alleles TNF--863A (20.3% versus 9.9%) and TNF--1031C (21.3% versus 12.4%) was seen in the low BMD group (Z-score < 0, n = 91) than in the high BMD group (0 Z-score, n = 86). In genotype analysis, although difference did not reach a significant level, women with the rarest allelic variants, i.e., homozygous TNFb1, TNF--863A, and TNF--1031C, showed the lowest BMD Z-scores. Women with another rarest allelic variant, TNF--857T/T had significantly lower BMD Z-scores than did women with TNF--857C/T or –857C/C. The BMD Z-score decreased significantly with an increase in the total number of such rare alleles. Serum concentrations of TNF- did not differ significantly among groups divided by genotypes. Multiple linear regression analysis revealed that the total number of rare alleles, in addition to the body mass index and the number of years since menopause, was an independent predictor of the BMD. These presumptive functional polymorphisms of the TNF gene may be associated with the lumbar spine BMD in early postmenopausal Japanese women.     

Cytotoxic effect of diphtheria toxin used alone or in combination with other agents on human renal cell carcinoma cell lines

Treatment of renal cell carcinoma (RCC) by conventional chemotherapy and immunotherapy has resulted in minimal remissions. Alternative forms of therapy are therefore being sought. The present study investigated the sensitivity of RCC cell lines to several toxins used alone and in combination with other agents. RCC lines were relatively sensitive to the direct cytotoxic effect of diphtheria toxin (DTX), Pseudomonas aeruginosa exotosin A (PEA) and ricin. Furthermore, DTX in combination with tumor necrosis factor- (TNF-) resulted in synergistic cytotoxic activity. The mechanism of synergy was examined. A possible mechanism of resistance to TNF- in tumor cells is the expression of TNF- mRNA or protein. R11 cells did not constitutively express mRNA for TNF-, however, treatment of R11 cells with TNF- induced the expression of TNF- mRNA. When DTX was used in combination with TNF-, the level of TNF- mRNA induced by TNF- was markedly reduced. These studies suggest that DTX in combination with TNF- can overcome the resistance of RCC lines and that the marked downregulation of TNF- mRNA by DTX may play a role in the enhanced cytotoxicity seen with the combination of DTX and TNF-. Furthermore, the combination treatment might also potentiate the antitumor host responses. The implications of these findings in clinical therapy are discussed.     

Comparison of adrenoceptor subtype expression in porcine and human bladder and prostate

We have quantified and characterized ₁-, ₂-and -adrenoceptor subtypes in porcine bladder detrusor and bladder neck, human bladder detrusor, and porcine and human prostate. ₁-, ₂- and -adrenoceptor were identified in radioligand binding studies using [³H]prazosin, [³H]RX 821002 and [¹²⁵I]iodocyanopindolol, respectively, as the radioligands. In porcine male and female detrusor and bladder neck and male prostate, adrenoceptors were detected in the order of abundance > _{2 1} (not detectable), with no major differences between the sexes or between detrusor and bladder neck. In human detrusor and prostate the order of abundance was > _{2 1} (not detectable) and ₁ > ₂. respectively. The ₂-adrenoceptors in all tissues were homogeneously of the _2A-subtype as evidenced by competition binding studies with yohimbine, prazosin, ARC 239 and oxymetazoline. The -adrenoceptors represented a mixed population with a dominance of the ₂-subtype in all tissues as demonstrated by competition binding with ICI 118,551 and CGP 20,712A. We conclude that pigs may be a suitable model for studies of detrusor function with respect to adrenoceptor expression. They may be less suitable for studies of bladder neck or prostate function.     

Analgesic dose-response relation in cervical epidural block

The relationship between the age and the spread of analgesia from different epidural anesthetic doses was examined by studying analgesic dose responses in cervical epidural analgesia. Two different anesthetic doses (5ml or 10ml) of 2% mepivacaine were injected into the cervical epidural space at a constant pressure (80mmHg) using an intravenous apparatus, and the spread of analgesia to pinprick was assessed. The significant correlation was found between the patients age and the number of spinal segments blocked (5ml:r = 0.8498, P < 0.01, 10ml:r = 0.5988, P < 0.01). The inverse linear relationship was found between the patients age and the segmental dose requirement (5ml:r = –0.6754, P < 0.01, 10ml:r = –0.5784, P < 0.01). Patients under 39 years of age showed a direct relationship between the dose injected and the number of spinal segments blocked, enabling prediction of the number of segments blocked with a given dose of local anesthetic. Doubling the epidural dose approximately doubled the number of spinal segments blocked. The analgesic dose-response relation in patients over 60 years of age differed from that in patients under 39 years of age and doubling the epidural dose did not double the number of spinal segments blocked. Progressively more extensive analgesia was obtained from a given dose of local anesthetic with advancing age. It was difficult to limit the extent of analgesia by injecting a smaller dose of local anaesthetic in the elderly.(Hirabayashi Y, Matsuda I, Inoue S et al.: Analgesic dose-response relation in cervical epidural block. J Anesth 2: 22–27, 1988)     

Association of vitamin D and estrogen receptor gene polymorphism with the effects of longterm hormone replacement therapy on bone mineral density

We longitudinally studied whether vitamin D receptor (VDR) and estrogen receptor (ER) gene polymorphisms in Japanese women influenced the effect of longterm hormone replacement therapy (HRT) on bone mineral density (BMD) in the lumbar spine. The 81 subjects were aged 40 to 64 years (mean ± SEM, 49.5 ± 0.6 years), and had received sequential or continuous HRT regimens, including 0.625mg of conjugated equine estrogen and 2.5 to 5mg of medroxy-progesterone acetate, for at least 3 years. Genomic DNA was extracted from blood cells, and analyzed for restriction fragment length polymorphism, using the restriction endonucleases Taq I, Apa I, and Fok I for VDR, and Pvu II and Xba I for ER. At 1 year, subjects with a Taq I genotype of TT (i.e., site absent) showed a significantly greater increase in BMD with treatment (BMD) than subjects with the Tt genotype (2.6 ± 0.5% vs –0.8 ± 1.4%; P = 0.016). A small difference between genotypes remained at 2 years (3.8 ± 0.6% vs 0.8 ± 1.6%; P = 0.069), but no significant difference between genotypes was seen at 3 years. In multiple regression analyses, BMD at 1 year was significantly affected by VDR-Taq I, Apa I, and ER-Pvu II genotypes and by age at treatment initiation, although at 3 years or more, BMD was significantly affected only by age. These results indicate that Taq I VDR gene polymorphism predicted the effect on lumbar BMD for the first year of HRT in Japanese women, and that the differences in BMD versus the polymorphism disappeared if the treatment was continued for over 2 years.     

Skill dependence of radiation exposure for the orthopaedic surgeon during interlocking nailing of long-bone shaft fractures: a clinical study

Introduction The objective of this clinical trial was to determine whether there is a skill dependence for the total amount of radiation exposure to orthopaedic surgeons caused by fluoroscopy during intramedullary fracture fixation.Materials and methods Surgical teams were assigned to either the Senior group or the Junior group according to their professional qualification and clinical appointment. Twenty-two long-bone shaft fractures were stabilized with intramedullary nails. The radiation exposure was measured at different body locations including fingers, trunk and head by means of thermoluminescent LiF:Mg,Cu,P detectors. The total time of fluoroscopy was registered for each operation.Results Mean time of fluoroscopy per operation was 4.43 min for the Senior group and 6.95 min for the Junior group. The surgeons hands were exposed to markedly higher doses (range 0–2.88 mSv Senior group; 0–11.94 mSv Junior group) than their trunk and head (range 0–0.27 mSv Senior group; 0–0.38 mSv Junior group). After analysis of variance, differences between both groups proved to be statistically significant for all fingers measured (p0.02) and for the total time of fluoroscopy (p=0.019).Conclusions Generally, the hands are at higher risk than are the trunk and the head, and this finding is independent of surgical skills. However, an additional hazard is created for the less experienced surgeon by a highly varying and poorly predictable exposure of the hands and time needed for fluoroscopy. Thus, the use of radiation is more consistent and standardized with a skilled surgeon.     

Pied plat réductible traité par la vis d’expansion du sinus du tarse. À propos de 30 cas

Résumé: Dans un pied plat, lobjectif de larthrorise subtalaire est de rétablir des rapports appropriés entre le talus et le calcanéum par limplantation dun espaceur. Le but de cette étude est dévaluer les résultats de la vis dexpansion du sinus du tarse ainsi que le devenir des pieds au recul. Matériel: Trente patients porteurs de pied plat réductible et symptomatique ont participé à cette étude. Il sagissait de 28 hommes et de 2 femmes. Lindication opératoire a été posée sur la coexistence dun handicap fonctionnel liée à la douleur et de léchec du traitement orthopédique. Lâge moyen au moment de lintervention était de 21 ans. Langle de Djian-Annonier était de 134°. Méthodes: Il sagissait dune étude rétrospective. Létat fonctionnel global était évalué au moyen du score de Kitaoka. Résultats: Le recul moyen était de 4 ans. Plus aucun patient ne portait de chaussure orthopédique. Nous navons pas de remaniements articulaires dégénératifs au recul. Le résultat global était: 20 très bien, 4 bien, 2 passable, 4 mauvais. Discussion: Larthrorise par espaceur du sinus du tarse est un geste techniquement simple permettant une correction podoscopique significative du pied plat qui se maintient à la révision. Conclusion: Cette technique simple permet dobtenir des résultats anatomiques et fonctionnels satisfaisants.* Les figures de cet article sont disponibles en couleur sur le site springerlink.com     

Reticulocyte hemoglobin content in hemodialysis patients with acute infection

Background Reticulocyte hemoglobin content (CHr) has recently become available as a direct marker of the iron status in hemodialysis patients undergoing recombinant human erythropoietin (rHuEPO) therapy. This study evaluated the stability of CHr in hemodialysis patients with acute infectious disease.Methods We retrospectively selected 22 hemodialysis patients who had acute respiratory tract infection and who showed transient elevation of C-reactive protein (CRP), and we investigated changes in parameters for erythropoiesis, iron status, and inflammation, i.e., hematocrit (Ht), transferrin saturation (TSAT), CHr, serum ferritin, and CRP, in the preinfection, infection, and postinfection phases. Throughout the observation period, doses of rHuEPO and iron supplements had not been changed. We divided the patients into two groups, those who showed a decrease in Ht in the infection phase (group 1; n = 12) and those who did not show a change in Ht in this phase (group 2; n = 10). We defined the differences between the parameters in the preinfection phase and the infection phase as , and performed correlation analysis between them.Results CRP in group 1 was significantly higher than that in group 2 in the infection phase. In group 1, TSAT significantly decreased, from 32.9 ± 8.8% (preinfection phase) to 16.9 ± 5.0% (infection phase), and CHr also significantly decreased, from 33.1 ± 1.5pg to 30.4 ± 2.0pg. In group 2, however, although TSAT significantly decreased, from 34.8 ± 4.6% to 27.0 ± 9.3%, CHr showed no significant change (from 33.4 ± 0.9pg to 33.0 ± 1.4pg). There was a significantly high correlation between Ht and CHr, but there was a low correlation between Ht and TSAT (r = 0.505; P = 0.0153 versus r = 0.175; P = 0.4420). Furthermore, the correlation between CRP and CHr was quite high (r = –0.722; P = 0.0001).Conclusions TSAT overreacts to inflammation, failing to reveal the correct status of available iron for erythropoiesis in acute inflammatory disease, but the use of CHr is expected to avoid these disadvantages, providing a reliable direct marker of iron status in the acute infection phase.     

Association and Linkage Disequilibrium Analyses Suggest Genetic Effects of Estrogen Receptor α and Collagen IA1 Genes on Bone Mineral Density in Caucasian Women

Estrogen receptor alpha (ER) and collagen IA1 (COLIA1) genes have been suggested as possibly implicated in reduced bone mineral density (BMD). The present study investigated the occurrence of association and linkage disequilibrium between radiographic hand BMD and polymorphic alleles of ER and COLIA1 genes, in human pedigrees of a Chuvasha population in Russia. The study sample included 463 members of 113 pedigrees, mostly nuclear families. We performed association and transmission disequilibrium test (TDT) analyses of the combined PvuII and XbaI RFLPs alleles on the same chromosome (haplotype) of the ER gene with BMD Z scores of cancellous or cortical bone in the hand phalanges. The association analyses were performed separately for both genders in the parental generation, i.e., fathers (n = 114; average age 64.2 y) and mothers (n = 122; average age 62.7 y). The Px haplotype was associated significantly with lower BMD Z scores in mothers only. The difference between subjects who carried one or two copies of the Px haplotype and those lacking it was 0.68 Z scores, P = 0.003 and 0.51 Z scores, P = 0.025 for cancellous and cortical bone, respectively. Multiple linear regression model with age, height, weight, and Px haplotype status as predictors explained 26.7% and 28.3% of the total observed variance in BMD with Px haplotype as independent predictor explaining 5.9%; P = 0.002 and 3%; P = 0.028 (cancellous and cortical bone, respectively). Results of t-TDT for triads of two parents and just one of their female offspring (but not male offspring) suggested the existence of linkage disequilibrium between the two loci of Px haplotype and BMD trait (P = 0.047). No association was found between polymorphic alleles of COLIA1 gene and BMD, but mothers with combined genotypes of Px haplotype of ER gene and s allele of COLIA1 gene had the lowest mean Z scores (–0.944 and –0.788 for cancellous and cortical bone, respectively). We conclude that the Px haplotype of the ER gene is associated with low BMD values in females, as the phenotype is gender dependent (the association was not observed in males), and the s allele of COLIA1 gene in combination with this haplotype contributes to reduced BMD.     

Chronic intramedullary infusion of interleukin-1α increases bone mineral content in rats

Interleukin-1 (IL-1) is known to have a potent bone-resorbing activity in vitro, however, results from in vivo studies are conflicting. We performed experiments with the continuous infusion of recombinant IL-1 directly into the femoral bone marrow of rats for 2 weeks and examined its effects on bone by soft X-ray photographs, bone mineral assessment, and histological examination. Infusion of IL-1 at doses greater than 1 g/ml (0.6 ng/hour) caused sclerosis around the infusion site on soft X-ray photographs, and the bone mineral content of IL-1 infused femora was increased significantly. Histologically, extensive periosteal bone formation was observed around the infusion site and small mononuclear cells replaced the normal fat tissue. Infusion of prostaglandin E₂ alone produced intramedullary bone formation more extensively. Simultaneous infusion of IL-1 and indomethacin (10^-3 M; 179 ng/hour) inhibited the increase of bone mineral content (BMC) induced by IL-1. Thus, the chronic intramedullary administration of IL-1 stimulates bone formation, especially in the periosteum, and increases BMC in intact rats.