Influence of estrogen therapy at conventional and high doses on the degree of mineralization of iliac bone tissue: a quantitative microradiographic analysis in postmenopausal women

The beneficial skeletal effects of menopausal estrogen replacement therapy (HRT) are well documented. The role of secondary mineralization of bone as a determinant of bone quality is now well established in postmenopausal women treated with bisphosphonates or SERMs. The aim of present study was to investigate the effect of conventional and high doses of estrogen on the main parameters reflecting the degree of mineralization of bone (DMB). Bone biopsies were obtained from 20 women with osteopenia or osteoporosis before and after 24 months (18 to 38 months) of conventional HRT, and from 19 women who had received high doses of estradiol (implant 100 mg every 3-6 months for 1.5-20 years). DMB parameters (mean DMB, DMB Freq. Max. and Heterogeneity Index of the individual distributions of DMB) were measured using quantitative microradiography in cortical, cancellous, and total bone and expressed as g mineral/cm(3) bone. Values obtained in women before HRT were lower than those reported in pre- and postmenopausal control women. After conventional HRT, there was an increase in mean DMB (total bone) of 4.4 +/- 1.9% (mean +/- SEM) versus pre-treatment values (4.1 +/- 2.1% in cortical bone, 4.5 +/- 2.3% in cancellous bone); these differences did not reach statistical significance (P = 0.055). Results were similar for DMB Freq. Max. but Heterogeneity Index was not significantly changed. After high dose estradiol therapy, mean DMB (total bone) was 6.9 +/- 1.9% higher than in untreated women (8.6 +/- 2.1% in cortical bone, 6.5 +/- 2.1% in cancellous bone); this difference was statistically significant (P 相似文献   

Hormone replacement therapy prevents osteoclastic hyperactivity: A histomorphometric study in early postmenopausal women.

In a randomized, double blind, clinical prospective trial comprising 35 women treated with either hormone replacement therapy (HRT) (cyclic estradiol/norethisterone acetate) or placebo we performed histomorphometric studies on paired bone biopsies obtained before and after 2 years of treatment. Untreated women developed a progressively more negative balance at individual bone multicellular units (BMUs) (i.e., wall thickness-erosion depth) (2.2 +/- 1.7 microm vs. -5.7 +/- 1.4 microm; p < 0.01), while women on HRT displayed preservation of bone balance (2.4 +/- 2.4 microm vs. 2.5 +/- 2.5 microm; NS). No significant differences in wall thickness between the two groups were demonstrable, but the untreated women developed a pronounced increase in erosion depth over 2 years (46.9 +/- 1.8 microm vs. 52.0 +/- 1.9 microm; p < 0.05), while the HRT group revealed no change (47.8 +/- 2.7 microm vs. 44.6 +/- 1.7 microm; NS). Furthermore, the placebo group displayed an increased osteoclastic erosion depth (17.8 +/- 1.6 microm vs. 25.0 +/- 1.7 microm; p < 0.001), compared with unchanged values in the HRT group (20.0 +/- 1.6 microm vs. 16.9 +/- 1.4 microm/day; NS). While the placebo group revealed a slight increase in volume referent resorption rate (35 +/- 8% vs. 38 +/- 8%; NS) the HRT group revealed a pronounced decrease (46 +/- 8% vs. 28 +/- 5%; p < 0.05). No significant changes in marrow star volume (an index of trabecular perforations) were demonstrable in either group. Our results demonstrate that bone remodeling in early postmenopausal women is characterized by progressive osteoclastic hyperactivity, which is reduced by cyclic HRT. This reduction of resorptive activity at the BMU level after HRT seems to precede the reduction in activation frequency demonstrated in previous studies on older postmenopausal women.     

Histomorphometric evidence for increased bone turnover without change in cortical thickness or porosity after 2 years of cyclical hPTH(1-34) therapy in women with severe osteoporosis

Parathyroid hormone (PTH) increases trabecular but may decrease cortical bone mass during treatment of postmenopausal osteoporosis. In a 2-year trial, PTH, with or without sequential calcitonin (CT), was given to 29 osteoporotic women (mean age 67 +/- 7 years), in 3-month cycles [28 days hPTH(1-34), 50 microg/day, +/-42 days CT, 75 units/day, 20 days "free"]. Over 2 years, lumbar spine bone mineral density measurements increased an average of 10%. Paired iliac crest biopsies were obtained 28 days and 2 years after starting the trial. The addition of CT made no difference to changes seen with cyclical PTH alone. Thus, the histomorphometric analyses for all 29 treated patients were compared with a separate group of biopsies from untreated osteoporotic control patients (n = 15). No significant increments in total bone volume or trabecular architecture were seen over 2 years of cyclical PTH treatment, although the light microscopic appearance of bone was normal. At the level of the bone remodeling unit, a twofold increase in total trabecular erosion surface over the control measurements was observed within the first 28 days of PTH treatment (10 +/- 5 vs. 5 +/- 3% trabecular surface, p < 0.01), which was sustained over 2 years. Trabecular bone formation rates (surface referent) were 11 +/- 7 microm(3)/microm(2)/year in control patients and threefold higher in treated patients both acutely (31 +/- 31 microm(3)/microm(2)/year, p < 0.01) and after 2 years (33 +/- 43 microm(3)/microm(2)/year, p < 0. 05). The activation frequency of trabecular remodeling was threefold higher than controls through 2 years of treatment (p < 0.05). The mean wall thickness of completed osteons after 2 years of treatment was significantly larger than controls (28 +/- 7 vs. 22 +/- 5 microm, p < 0.01), suggesting a positive remodeling balance, as well as the histomorphometric evidence of increased bone turnover and the increased resorption surfaces. Over 2 years of cyclical PTH therapy, cortical thickness remained significantly higher than controls (680 +/- 202 vs 552 +/- 218 microm, p < 0.05), without significant changes in cortical porosity. Thus, the histomorphometric changes during cyclical PTH therapy in patients with severe osteoporosis are consistent with increased trabecular bone turnover and a positive remodeling balance, with no evidence for detrimental changes in cortical bone.     

Effect of withdrawal of hormone replacement therapy on bone mass and bone turnover: the OFELY study

The beneficial effects of hormone replacement therapy (HRT) on bone mineral density (BMD) and bone turnover are well documented but whether HRT withdrawal is followed by an accelerated rate of bone loss is still controversial. We analyzed 26 women who have withdrawn HRT during a 6-year follow-up of the OFELY cohort. They were compared with three groups of women from the same cohort: one hundred four healthy postmenopausal women who continued HRT during the 6-year follow-up, 78 untreated postmenopausal women matched for age, and 31 untreated women within 5 years of menopause. Bone markers [serum osteocalcin (Intact OC), bone alkaline phosphatase (Bone ALP), and serum CTX] were performed annually during 4 years and bone mineral density (BMD) was measured at the forearm (DXA) during 6 years. Withdrawal of HRT was followed by a significant bone loss with an annual rate ranged from -0.7 to -1.6% at the radius according to the skeletal site and by a marked increase of bone markers after 6 months: +36 % for osteocalcin, +23% for bone alkaline phosphatase, and +120% for serum CTX (P < 0.05 to P < 0.001). In contrast, in the HRT continuing group, there was no bone loss and no substantial change of bone markers over 4 years. The rate of bone loss after withdrawal of HRT was significantly greater than in postmenopausal women matched for age who never received HRT (2.2 to 2.8 times higher according to the radius area) and not different as compared to the accelerated bone loss observed in untreated women within 5 years of menopause. We conclude that in postmenopausal women who have been on HRT for 6 years, cessation of treatment results in a rapid increase of bone turnover and a rate of bone loss similar to early postmenopausal women during the subsequent 4 years and greater than untreated women of the same age.     

Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels

The cellular mechanisms for bone loss in type I (postmenopausal) osteoporosis are highly controversial. We attempted to resolve this by assessing rates of formation and resorption of iliac cancellous bone by a new histomorphometric method in 89 women with osteoporosis (mean age +/- SD, 66 +/- 6 years) and in 32 carefully selected normal postmenopausal women (64 +/- 6 years). In the osteoporotic women, bone resorption rate was increased by 39% (P less than 0.05) at the cellular level and by 67% (P less than 0.05) at the tissue level, whereas bone formation was unchanged at the tissue level but decreased by 14% (P less than 0.01) at the cellular (osteoblast) level. This pronounced remodeling imbalance (P less than 0.001) was probably exacerbated by a 45% increase (P less than 0.1) in activation frequency of new remodeling foci. These abnormalities were associated with a high rate of cancellous bone loss (median, 5.8%/year versus 0.1% year in controls). Thus, accelerated loss of cancellous bone in type I osteoporosis results from the combination of increased bone resorption and inadequate compensation by bone formation.     

Bone turnover and body weight relationships differ in normal-weight compared with heavier postmenopausal women

Low body weight is associated with increased risk for fractures, whereas higher body weight has been shown to be protective against osteoporosis. This study evaluated whether body weight plays a role regulating bone turnover and mass in normal-weight (body mass index (BMI) <25 kg/m2), overweight (BMI 25-29.9 kg/m2) and obese (BMI> or =30 kg/m2) postmenopausal women who were either receiving hormone replacement therapy [HRT(+)] or not [HRT(-)] (total of six groups). Body weight, BMI, total body bone mineral content (TBBMC), and markers of bone formation (serum osteocalcin) and bone resorption (urinary pyridinoline (PYD) and deoxypyridinoline) were retrospectively analyzed in 210 postmenopausal women. The mean age was 67+/-6 years, with mean body weight of 70.8+/-14.2 kg, ranging from 45.0 to 115.5 kg. Body weight was positively correlated with TBBMC ( r=0.50, p<0.0001). There was a lower TBBMC and higher bone formation rate in normal-weight than obese HRT(-) women, but in women taking HRT there were no differences between BMI categories. In addition, in normal-weight HRT(-) women only, PYD and body weight showed a negative correlation (r=-0.39, p=0.01). Among normal-weight, but not overweight or obese subjects, we observed higher TBBMC and lower bone turnover in the HRT(+) compared with the HRT(-) group. Regression models explained 36% of the variance in TBBMC, mainly through body weight. Additional models could only explain 11-15% of the variance in bone turnover. Taken together, these data suggest that among normal-weight but not obese postmenopausal women, higher bone turnover is associated with lower bone mass, and that only normal-weight women show a different bone turnover profile with HRT treatment. Body weight should be considered an important factor in bone metabolism with relevant clinical implications.     

Hypogonadism and Hormone Replacement Therapy on Bone Mass of Adult Women with Thalassemia Major

We studied bone mass and metabolism in 30 adult women (age 28.5 +/- 1.3) with thalassemia major (TM) and evaluated whether prolonged hormone replacement therapy (HRT) was able to optimize bone accrual. TM patients had reduced bone mass, increased bone turnover and lower serum gonadotropin and estradiol levels compared with 10 normal women of similar age. A significant correlation was found between bone mass and sex hormone levels. Six TM patients with normal ovarian function had normal bone turnover markers and modestly low bone mass (lumbar spine -1.29 +/- 0.31; femoral neck -0.60+/-0.21; Z-score). The other 24 TM women were hypogonadic and had significantly lower bone mass for age (lumbar spine -2.35 +/- 0.2, femoral neck -1.83 +/- 0.2) and increased bone turnover relative to eugonadal women. Of the hypogonadal patients, 13 had taken HRT since age 15 +/- 1 years, but their bone mass and turnover markers were not different than untreated hypogonadal patients. In conclusion, while hypogonadism negatively affects bone mass acquisition in adult TM women, HRT at the standard replacement doses is not sufficient to secure optimal bone accrual.     

Megakaryocyte population in human bone marrow increases with estrogen treatment: a role in bone remodeling?

Skeletal effects of conventional hormone replacement therapy (HRT) are predominately antiresorptive, while high doses of estrogen have anabolic effects. The mechanisms mediating these effects are unclear but may involve cells in the bone marrow. We have investigated the in vivo effects of estrogen on the megakaryocyte (MK) population in bone marrow in 10 postmenopausal women before and after 2 years of conventional HRT, in 11 women after long-term, high-dose estradiol therapy, and in 2 premenopausal and 4 postmenopausal women who had received no previous estrogen treatment. Transiliac crest biopsies were halved and either decalcified and paraffin wax embedded for immunolocalization studies or dehydrated and embedded in LR White resin for histology. MKs were identified morphologically, and the bone marrow cell population and MK number quantified by cell counting in a defined area of view (1 mm(2)) from 5 randomly selected fields of bone marrow. Compared with pretreatment values, significantly higher MK numbers were found after conventional HRT treatment (before treatment, mean +/- SEM; 7.3 +/- 1.1 vs. after treatment, 18.0 +/- 1.6/5 mm(2); p < 0.0001), while the greatest MK number was associated with long-term, high-dose estradiol treatment (32.8 +/- 2.1/5 mm(2); p < 0.0001). Total bone marrow cell number did not differ significantly between groups. Immunolocalization studies revealed more intense estrogen receptor (ER)beta expression in MKs in the high-dose estradiol-treated group but similar levels of weak ERalpha staining in MKs in the control and high-dose estrogen-treated groups. Positive immunoreactivity for transforming growth factor (TGF)beta1, 2, and 3 and TGFbeta receptor I, II, and III was detected in MKs, with more intense staining being demonstrated in the high-dose estradiol-treated group, particularly for TGFbeta2 and TGFbetaRI and II. Our results demonstrate an increase in the MK population in bone marrow from women treated with estrogen. The ability of MKs to express ERs and synthesise TGFbeta, a potent mitogen in osteoblast differentiation, suggests that these cells may play a role in mediating estrogen-induced effects on bone.     

Effects of raloxifene,hormone replacement therapy,and placebo on bone turnover in postmenopausal women

Raloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and prevents incident vertebral fractures in postmenopausal women, while sparing the breast and endometrium from the undesirable stimulation caused by estrogen. How the long-term beneficial effects of raloxifene on bone turnover, as assessed by bone histomorphometry, compare with hormone replacement therapy (HRT) and placebo are not known. We studied 66 healthy postmenopausal women (age 55 to 75 years, mean 63 years) who were randomized to either raloxifene 150 mg/day, HRT (Premarin 0.625 mg/day, and Provera 2.5 mg/day), or placebo for 1 year. All women received 1–1.5 g of calcium/day. Following double tetracycline labeling, transiliac bone biopsies were obtained at baseline and 1 year and analyzed for changes in histologic indexes of bone remodeling on the cancellous surface as well as at the endocortical subdivision of the endosteal envelope, the location of the greatest fraction of postmenopausal bone loss. BMD and biochemical markers of bone turnover were also determined at baseline and 1 year. Four paired biopsies were obtained in the HRT group, six in the raloxifene group, and five in the placebo group. The frequency of remodeling events on cancellous bone and rate of bone formation in both cancellous and endocortical bone increased in the placebo group, while these measurements decreased in both drug treatment groups. Using analysis of mean percentage changes, when compared with the placebo group, these changes were significantly different for both raloxifene and HRT treatment groups (p<0.02). In all subjects, the bone was lamellar with discrete tetracycline labels and there was no evidence of marrow fibrosis or abnormal bone cells. BMD increased from baseline at the lumbar spine (p<0.05 in the HRT group) and in the total body (p<0.05 for both raloxifene and HRT). Compared with that of the raloxifene group, the increase in BMD was greater in the HRT group at the lumbar spine but not in the total body. Serum bone alkaline phosphatase, serum osteocalcin, and urine C-terminal cross-linking telopeptide of type I collagen significantly decreased (p<0.05) in both active treatment groups, changes significantly different from those seen with placebo. Overall, these results support the hypothesis that raloxifene preserves bone mass by reducing the elevated bone turnover found in postmenopausal women receiving placebo, by mechanisms similar to those operative in postmenopausal women receiving HRT.     

Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females

Transilial bone biopsies were obtained from 34 healthy postmenopausal women following in vivo fluorochrome labeling. Stained and unstained undecalcified sections were evaluated using a Merz grid. Standard histomorphometric data from cancellous bone tissue were collected and the results were evaluated and presented as variables commonly used in bone histomorphometry. The normal ranges, medians, means, and standard deviations for the group of 34 are presented in tabular form for structural, surface, basic dynamic, and derived dynamic data. Similar data for individuals grouped by ages 45-54, 55-64, and 65-74 are also presented. Secular trends for the whole group are evaluated. The structural and surface data are not much different from previous reports of sudden-death accident victims, when methodologic differences are considered. The mineral apposition rate (MAR) was 0.53 +/- 0.08 micron/day, similar to previous reports in cancellous bone, but one-third less than in cortical bone. MAR showed a marked decline with age. In contrast, the extent of tetracycline-labeled surfaces varied widely without a secular trend. Double-label surface (dLS/BS) ranged from 0.5 to 8.0% and single-label surface (sLS/BS), from 0.5 to 10.5%. Mineralizing osteoid surface (MS/OS) varied from 2 to 64%. Using only double-label surface to represent mineralizing surface, volume-based bone formation rate (BFR/BV) ranged from 0.7 to 28%/yr, and the remodeling period (Rm.P) varied from 0.28 to 4.5 years. Calculations using other representations of mineralizing surface [double plus one-half single label (MS/BS"); all label (MS/BS')] are also presented. These bone histomorphometric data are important because: (1) they come from a cohort of living subjects that was recruited solely for the purpose of establishing normal bone histomorphometry; (2) they represent the age range of patients with postmenopausal osteoporosis; and (3) they markedly expand the bone histomorphometric database of healthy persons given in vivo fluorochrome labeling prior to transilial biopsy.     

The Effect of Endogenous Parathyroid Hormone in Iliac Bone Structure and Turnover in Healthy Postmenopausal Women

Little is known about the effect of endogenous parathyroid hormone (PTH) on the skeleton in postmenopausal women without hyperparathyroidism. In this study, the effects of PTH on bone were investigated in iliac crest biopsies obtained from 37 healthy white postmenopausal women aged 50–73 years. The results showed that neither cancellous nor cortical bone structure changed with serum PTH levels. In cancellous bone, bone formation (wall thickness, osteoid surface, osteoblast surface, mineralizing surface, and mineral apposition rate) and turnover (bone formation rate at the surface, volume levels, and activation frequency) variables increased with increasing serum PTH levels (all p < 0.05) in univariate analysis. Multiple linear regressions, adjusted for serum 25-OHD, calcium, alkaline phosphatase, age, and BMI, showed that serum PTH level was independently associated with wall thickness, osteoid surface, osteoblast surface, mineralizing surface, and bone formation rate (all p < 0.05). In cortical bone, no histomorphometric variable was correlated with PTH levels. On the endosteal surface, some of the bone formation (osteoid surface, osteoblast surface, mineralizing surface) and turnover (bone formation rate at the bone surface levels and activation frequency) variables were positively correlated with PTH levels (all p < 0.05). None of these variables could be independently predicted by PTH status. We conclude that in healthy postmenopausal women endogenous PTH has a positive effect on bone formation on the cancellous surface. The effects of PTH on the endosteal surface are probably confounded by other factors.     

Human parathyroid peptide treatment of vertebral osteoporosis

Previous studies have shown that treatment with daily injections of human parathyroid peptide (hPTH) 1-34 increase axial cancellous bone mass partially at the expense of peripheral cortical bone. In the present work the same hPTH 1-34 regime given for 12 months has been combined with oestrogen or nandrolone therapy to control peripheral bone resorption. Spinal and iliac cancellous (but not cortical) bone increased by 40%–50% above initial values while no perceptible changes occurred in radial cortical or cancellous bone. The evidence of radiokinetic and histomorphometric studies performed before and in the last months of treatment suggested that bone remodeling had proceeded through a transient anabolic phase with increased activation, but that activation had become normal after 11–12 months in the cancellous bone of the ilium whereas it continued to be raised elsewhere in the skeleton. It is concluded that in combination with oestrogens, hPTH peptides given daily injections hold great promise for the treatment of patients with osteoporosis who have already lost substantial amounts of spinal cancellous bone.     

The benefits of hormone replacement therapy in pre-menopausal women with oestrogen deficiency on haemodialysis.

BACKGROUND: Impaired sexual function is an important cause of depression in uraemic females. Hyperprolactinaemia is frequent, and often associated with decreased serum oestradiol concentration, which can significantly contribute to accelerated bone loss. The aim of the study was to evaluate the effect of hormone replacement therapy (HRT) on sexual function, serum 17beta-oestradiol and prolactin, and bone mineral density (BMD) in pre-menopausal women undergoing haemodialysis. METHODS: Among 63 women on haemodialysis, aged 18-45 years, 23 with secondary amenorrhoea and serum oestradiol < 30 pg/ml were enrolled into the 1 year study. They were divided into: group I (n = 13) treated with transdermal oestradiol with cyclic addition of noretisterone acetate, and control group II (n = 10). BMD was measured with dual energy X-ray absorptiometry (DEXA). RESULTS: No important changes in sexual function and hormonal profile were observed in the control group, whereas in all women from group I the treatment induced regular menses and a marked improvement of libido and sexual activity. Serum 17beta-oestradiol increased after the first month from 20.5 +/- 11.7 to 46.8 +/- 13.6 pg/ml (P < 0.001) and remained at that level until the end of the study, accompanied by a decrease of serum prolactin (from 1457 +/- 1045 to 691 +/- 116 mIU/ml after 12 months; P < 0.001). In group I, the treatment induced an increase in BMD, although significant only in L2-L4 (P < 0.05), whereas in group II a mild insignificant decrease was observed. However, a comparison of BMD values after 12 months in both groups revealed marked (P < 0.01-P < 0.05) differences at all studied sites. CONCLUSIONS: Transdermal HRT allows sustained physiological serum oestradiol concentrations in pre-menopausal women with oestrogen deficiency on haemodialysis, with the restoration of regular menses and a marked improvement in their sexual function. The treatment inhibits bone demineralization and can play an important role in the prevention of early osteoporosis in this group of patients.     

Association of sex hormone status with the bone loss of renal transplant patients.

BACKGROUND: Bone loss is an important problem in renal transplantation recipients. The role of sex hormones in this setting has not been previously addressed. The objective was to investigate whether sex hormone status is associated with bone mass loss in renal transplant recipients. METHODS: Thirty patients (16 men and 14 women, of which eight were post-menopausal) were studied by bone densitometry and bone biopsy. In women, serum oestradiol levels and menopausal status were determined; in men, serum testosterone levels were assessed. RESULTS: Mean age was 48+/-11 years. Time on dialysis was 13+/-17 months, and time since transplantation was 125+/-67 months. Thirteen patients were on cyclosporine A (CsA) monotherapy, 12 on azathioprine plus prednisolone (PRED) dual therapy, and five on CsA, azathioprine and PRED triple therapy. In men, serum testosterone levels were 19.7+/-6.8 nmol/l (mean+/-SD). In pre-menopausal women, oestradiol serum levels were 209(128-289) pmol/l (median (percentiles 25-75%)), and in post-menopausal women 93(54-299) pmol/l (non-significant). Univariate analysis in women demonstrated that serum oestradiol levels were positively correlated with Z scores of osteoblast surface (r=0.70, P=0.005), osteoid surface (r=0.75, P=0.002) and trabecular wall thickness (r=0.68, P=0.008). In men, a weak correlation was seen between serum testosterone levels and the cumulative dose of PRED (r=-0.52, P=0.06). In the multivariate analysis, two models of multiple regression were employed (one for women and one for men), considering the densitometric and histomorphometric variables (Z scores) as dependent variables. Serum testosterone in men did not predict any of the densitometric nor histomorphometric variables analysed, while serum oestradiol in women was an independent predictor for the osteoblast surface (r=0.81, P=0.003), osteoid surface (r=0.82, P=0.009) and trabecular wall thickness (r=0.54, P=0.05). CONCLUSIONS: In female renal transplant recipients, serum oestradiol levels independently predict the bone status, while in men, factors other than testosterone seem to influence bone loss. Our results give rise to the hypothesis that sex hormone replacement therapy may play a role in prevention and/or treatment of the bone loss in women following renal transplantation.     

Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure.

Histomorphometry and microCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume. INTRODUCTION: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1-34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data. METHODS: Fifty-one paired iliac crest bone biopsy specimens (placebo [n = 19], 20 microg teriparatide [n = 18], and 40 microg teriparatide [n = 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (microCT). Data for both teriparatide treatment groups were pooled for analysis. RESULTS AND CONCLUSIONS: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, -24%; p = 0.001) and reduced marrow star volume (teriparatide, -16%; placebo, 112%; p = 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, -12%; placebo, 7%; p = 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, - 14%; p = 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p = 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.     

Number of years since menopause: spontaneous bone loss is dependent but response to hormone replacement therapy is independent

In this study we examine the influence of number of years since menopause on spontaneous bone loss and response to hormone replacement therapy (HRT) in 274 women (56.1 +/- 4.2 years) completing two placebo-controlled HRT studies of 2 or 3 year duration. Both cross sectionally and longitudinally, bone loss in untreated women was greatest closest to menopause and declined thereafter (r = 0.34, p < 0.01 for lumbar spine bone loss and r = 0.25, p < 0.05 for femoral neck bone loss when correlated with number of years since menopause), such that the loss was eliminated in the femoral neck and bone mass increased in the spine in women >10 years after menopause. In contrast, bone turnover was consistently elevated throughout postmenopause, both cross-sectionally and longitudinally. The association with number of years since menopause was counteracted by both 1 and 2 mg estradiol combined with gestodene, piperazine, estrone sulfate in combination with norethisterone, and a combination of 2 mg estradiol and 1 mg norethisterone acetate. In addition, the response to various HRT regimens was independent of baseline bone mass. Whereas bone loss was significantly related to number of years since menopause, all HRT regimens applied arrested bone loss in healthy postmenopausal women, regardless of number of years since menopause.     

Preserved three-dimensional cancellous bone structure in mild primary hyperparathyroidism

By conventional 2-dimensional, histomorphometric analysis, we and others have previously shown that cancellous bone architecture is preserved in mild primary hyperparathyroidism (PHPT). We have now extended these observations to a 3-dimensional analysis using microcomputed tomography (microCT). Iliac crest bone biopsies were analyzed from the following subjects with PHPT: 22 postmenopausal women; 7 premenopausal women; similar numbers of normal pre- and postmenopausal women served as controls. Fifteen men with PHPT were also studied. Postmenopausal women with PHPT demonstrated features of preserved cancellous bone as shown by smaller age-related declines in cancellous bone volume (BV/TV) and connectivity density (Conn.D) and no change in bone surface/total volume (BS/TV) as compared to normal women. In postmenopausal women with PHPT, cancellous bone volume (BV/TV), bone surface/total volume, and connectivity density (Conn.D) were all higher, and trabecular separation (Tb.Sp) was lower than in postmenopausal controls. In sharp contrast to the findings in normal women, no structural variables in PHPT women were correlated with age. Also of note, there was no difference in any 3-dimensional index between women and men with PHPT. We conclude that three-dimensional, cancellous bone microarchitecture is preserved in patients with mild primary hyperparathyroidism.     

Antero-postero differences in cortical thickness and cortical porosity of T12 to L5 vertebral bodies

OBJECTIVE: This study will investigate interrelationships between the cortical shell and cancellous bone trabecular thickness, in vertebral bodies. METHODS: One hundred and sixty vertebral bodies from T12 to L5 were obtained at autopsy. The average age of the cohort was 59.3+/-22.1 years (range = 20-94 years). Cortical thickness, cortical porosity and trabecular thickness from the adjacent cancellous bone were measured. RESULTS: At the mid-vertebral body anterior cortical thickness was significantly greater than posterior cortical thickness (524 +/- 352 vs. 370 +/- 283 microm, respectively, P < 0.0001) and mid-anterior cortical porosity was significantly less than mid-posterior cortical porosity (24 +/- 14% vs. 32 +/- 16%, respectively, P < 0.0001). There were no anterior/posterior differences in trabecular thickness of the cancellous bone adjacent to the cortical walls. CONCLUSION: This study provides a novel perspective of T12 to L5 vertebral body bone, where measurement of cortical thickness and cortical porosity in a cohort of skeletally normal individuals revealed structural differences between load bearing anterior and posterior cortical walls. The data suggest that modulators of change to vertebral body bone may affect the cortical and trabecular bone differently. The relationships between cortical and cancellous bone suggest that the middle sectors of the vertebral body play a critical role in load bearing.     

The carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen in serum as a marker of bone resorption: The effect of nandrolone decanoate and hormone replacement therapy

Carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) in serum has recently been proposed as a new biochemical marker of bone resorption. In the present study we compared serum ICTP with radiopharmaceutical and histomorphometric measurements of bone turnover in postmenopausal women with mild osteoporosis, and assessed the effect of hormone replacement therapy (HRT) (2 mg 17-estradiol plus 1 mg norethisterone daily) and anabolic steroid therapy (50 mg nandrolone decanoate (ND) i.m. every 3 weeks) on serum ICTP in two double-blind placebo-controlled studies with 55 to 75-year-old women. Serum ICTP measured by radioimmunoassay (RIA) correlated significantly with the 24-hour whole body retention of 99m-technetium diphosphonate (Rho=0.47, P<0.001, n=66), but not with histomorphometric measurements of bone turnover in iliac crest biopsies. One year of HRT (n=16) versus placebo (n=15) did not produce significant changes in serum ICTP. Compared with placebo (n=17), 1 year of ND (n=19) produced an increase in serum ICTP of 90±16% (P<0.0001); 6 months after discontinuation of the treatment, serum ICTP had returned to pretreatment values. We conclude that serum ICTP does reflect bone metabolism in postmenopausal osteoporosis, but it is not a sensitive marker of the changes in bone resorption induced by hormone replacement therapy, and it does not correspond with other measures of bone resorption during anabolic steroid therapy.     

Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study.

We sought whether microdamage could rise in postmenopausal osteoporotic women on long-term bisphosphonates, as suggested by recent animal studies. We found few microcracks in iliac bone biopsies, despite a marked reduction in bone turnover. INTRODUCTION: Animal studies suggest that bisphosphonates (BPs) could increase microdamage frequency in a dose-dependent manner, caused by excessively suppressed bone turnover. However, there is limited data in humans receiving BP therapeutic doses for >3 yr. MATERIALS AND METHODS: We measured microcrack frequency and histomorphometry parameters on transiliac bone biopsies in 50 postmenopausal osteoporotic women (mean age = 68 yr) who had received BP therapy (3 on intravenous pamidronate, 37 on oral alendronate, and 10 on oral risedronate) for at least 3 yr (mean treatment duration = 6.5 yr). We compared these results with transiliac bone biopsies obtained from 12 cadavers. We used bulk staining with green calcein as a fluorochrome. The microcracks were quantified in three 100-microm-thick sections using optic microscopy and were confirmed by laser confocal microscopy. Microcrack frequency (number of microcracks/mm2 of bone tissue) was compared between treated women and controls using nonparametric tests. We also explored predictors of microcrack frequency, including age, duration of BP therapy, and activation frequency. RESULTS: Among treated women, cancellous bone microcrack frequency was low (mean, 0.13 microcracks/mm2) and did not differ significantly from that observed in controls (0.05 microcracks/mm2; p = 0.59). Of note, 54% of the treated women and 58% of the controls had no observable microcracks. There was no association between microcrack frequency and the duration of BP therapy (for microcracks/mm2 and duration, Spearman r = 0.04, p = 0.80) and between patients' ages and the number of microcracks (Spearman r = -0.09, p = 0.61). Although bone remodeling parameters were suppressed in treated women, we found no relationship between microcrack density and activation frequency (Spearman r = -0.003, p = 0.99). Also, microcrack frequency was not increased in women with prevalent vertebral fracture compared with those without fractures. CONCLUSIONS: Among postmenopausal osteoporotic women on long-term BPs, microcrack frequency in the iliac bone is low, despite a marked reduction of bone turnover.