Untreated Postmenopausal Women Research Articles

Material and nanomechanical properties of bone structural units of cortical and trabecular iliac bone tissues from untreated postmenopausal osteoporotic women

The differences in bone nanomechanical properties between cortical (Ct) and trabecular (Tb) bone remain uncertain, whereas knowing the respective contribution of each compartment is critical to understand the origin of bone strength. Our purpose was to compare bone mechanical and intrinsic properties of Ct and Tb compartments, at the bone structural unit (BSU) level, in iliac bone taken from a homogeneous untreated human population.Among 60 PMMA-embedded transiliac bone biopsies from untreated postmenopausal osteoporotic women (64 ± 7 year-old), >2000 BSUs were analysed by nanoindentation in physiological wet conditions [indentation modulus (elasticity), hardness, dissipated energy], by Fourier transform infrared (FTIRM) and Raman microspectroscopy (mineral and organic characteristics), and by X-ray microradiography (degree of mineralization of bone, DMB). BSUs were categorized based on tissue age, osteonal (Ost) and interstitial (Int) tissues location and bone compartments (Ct and Tb).Indentation modulus was higher in Ct than in Tb BSUs, both in Ost and Int. dissipated energy was higher in Ct than Tb, in Int BSUs. Hardness was not different between Ct and Tb BSUs. In Ost or Int BSUs, mineral maturity (conversion of non-apatitic into apatitic phosphates) was higher in Ct than in Tb, as well as for collagen maturity (Ost). Mineral content assessed as mineral/matrix (FTIRM and Raman) or as DMB, was lower in Ct than in Tb. Crystallinity (FTIRM) was similar in BSUs from Ct and Tb, and slightly lower in Ct than in Tb when measured by Raman, indicating that the crystal size/perfection was quite similar between Ct and Tb BSUs. The differences found between Ost and Int tissues were much higher than the difference found between Ct and Tb for all those bone material properties. Multiple regression analysis showed that Indentation modulus and dissipated energy were mainly explained by mineral maturity in Ct and by collagen maturity in Tb, and hardness by mineral content in both Ct and Tb.In conclusion, in untreated human iliac bone, Ct and Tb BSUs exhibit different characteristics. Ct BSUs have higher indentation modulus, dissipated energy (Int), mineral and organic maturities than Tb BSUs, without difference in hardness. Although those differences are relatively small compared to those found between Ost and Int BSUs, they may influence bone strength at macroscale.

Clinical Significance of the Cardio-Ankle Vascular Index in Postmenopausal Women With Hypercholesterolemia

Background: The cardio-ankle vascular index (CAVI) is a physiological indicator of arterial elasticity. However, limited information regarding the clinical significance of the CAVI in patients with hypercholesterolemia is available. This cross-sectional study aimed to elucidate the clinical significance of the CAVI for the primary prevention of cardiovascular disease (CVD) among postmenopausal women with hypercholesterolemia. Methods: A total of 168 untreated postmenopausal hypercholesterolemic women (low-density lipoprotein cholesterol levels ≥ 140 mg/dL, mean age ± standard deviation, 63 ± 10 years) with no history of CVD events were enrolled. The CAVI was measured using commercial devices, after which, its relationships with various clinical parameters, such as carotid artery ultrasonography findings and CVD biomarkers, were examined. Results: A significant positive correlation was observed between the CAVI and maximum intima-media thickness of the common carotid artery (max-C-IMT), which was evaluated using carotid artery ultrasonography (r = 0.49, P < 0.001). Regarding CVD biomarkers, the CAVI was significantly correlated with estimated glomerular filtration rate (r = -0.18, P < 0.001), high-sensitivity C-reactive protein (r = 0.36, P < 0.001), whole blood passage time as a marker of blood rheology (r = 0.41, P < 0.001), and skin autofluorescence as a marker of advanced glycation end products in tissues (r = 0.46, P < 0.001), although no significant correlation was noted between serum lipid parameters and the CAVI. Multiple regression analysis identified max-C-IMT (β = 0.35, P < 0.001), whole blood passage time (β = 0.18, P = 0.007), skin autofluorescence (β = 0.17, P = 0.011), and age (β = 0.16, P = 0.018) as variables independently associated with CAVI. Conclusion: The present study indicated that the CAVI is an essential CVD risk factor among postmenopausal women with hypercholesterolemia. Moreover, impaired blood rheology and increase of skin autofluorescence were associated with elevated CAVI in such patients. J Clin Med Res. 2021;13(5):276-282 doi: https://doi.org/10.14740/jocmr4509

Clinical Significance of the Cardio-Ankle Vascular Index in Postmenopausal Women With Hypercholesterolemia.

BackgroundThe cardio-ankle vascular index (CAVI) is a physiological indicator of arterial elasticity. However, limited information regarding the clinical significance of the CAVI in patients with hypercholesterolemia is available. This cross-sectional study aimed to elucidate the clinical significance of the CAVI for the primary prevention of cardiovascular disease (CVD) among postmenopausal women with hypercholesterolemia.MethodsA total of 168 untreated postmenopausal hypercholesterolemic women (low-density lipoprotein cholesterol levels ≥ 140 mg/dL, mean age ± standard deviation, 63 ± 10 years) with no history of CVD events were enrolled. The CAVI was measured using commercial devices, after which, its relationships with various clinical parameters, such as carotid artery ultrasonography findings and CVD biomarkers, were examined.ResultsA significant positive correlation was observed between the CAVI and maximum intima-media thickness of the common carotid artery (max-C-IMT), which was evaluated using carotid artery ultrasonography (r = 0.49, P < 0.001). Regarding CVD biomarkers, the CAVI was significantly correlated with estimated glomerular filtration rate (r = -0.18, P < 0.001), high-sensitivity C-reactive protein (r = 0.36, P < 0.001), whole blood passage time as a marker of blood rheology (r = 0.41, P < 0.001), and skin autofluorescence as a marker of advanced glycation end products in tissues (r = 0.46, P < 0.001), although no significant correlation was noted between serum lipid parameters and the CAVI. Multiple regression analysis identified max-C-IMT (β = 0.35, P < 0.001), whole blood passage time (β = 0.18, P = 0.007), skin autofluorescence (β = 0.17, P = 0.011), and age (β = 0.16, P = 0.018) as variables independently associated with CAVI.ConclusionThe present study indicated that the CAVI is an essential CVD risk factor among postmenopausal women with hypercholesterolemia. Moreover, impaired blood rheology and increase of skin autofluorescence were associated with elevated CAVI in such patients.

Mitochondrial and redox dysfunction in post-menopause as risk factor of neurodegenerative disease: a pilot study testing the role of a validated Japanese functional food.

During the menopause women may experience increased oxidative stress and decreased antioxidant capacity and, together with the decline of neurosteroids, this represents a risk factor for Alzheimer's disease. The aim of the present study was to test a functional food (FPP-ORI, Osato Research Institute, Gifu, Japan) on redox and mitochondrial efficiency in post-menopausal women. The study population consisting of 69 untreated post-menopausal women were given supplements as follows: Group A was given a multivitamin (MV) 1c 2 times a day, and group B was given FPP 4.5 g 2 times a day. Group C consisted of 23 fertile premenopausal women as the control group. The tests carried out on entry, and at 3 and 6 months were erythrocyte redox parameters, plasma oxidated proteins, brain-derived neurotrophic factor (BDNF) and peripheral blood mononuclear cell (PBMC) mitochondria cytochrome c oxidase Vmax activity. Menopausal women showed an increased malondialdehyde (MDA) (p<0.05 vs control) which was normalized by both treatments (p<0.05), but MV failed to do so in the BMI ≥26 subgroup (p<0.05). All other redox enzymes and BDNF were significantly lower in menopausal women and they responded only to FPP (p<0.05). Carbonyl protein level was higher in "BMI ≥ 26" subgroup (p<0.05) and reduced only by FPP (p<0.05). The PBMC cyclooxygenase to citrate synthase activity was reduced (<40%) in the menopausal group (p<0.01) and only FPP caused a significant restoration (p<0.05). Although preliminary, these data confirm the redox and mitochondrial dysfunction occurring in post-menopause and responsive to FPP but very poorly to high dosage antioxidants. This may lead to potential preventive opportunities in menopause-associated neurodegenerative disease.

Dehydroepiandrosterone and/or its metabolites: possible androgen receptor antagonistic effects on digitized mammographic breast density in normal breast tissue of postmenopausal women.

Background Androgens, notably testosterone inhibit breast cell proliferation and negative correlations between free testosterone (fT) and breast cell proliferation as well as mammographic density have been described. Dehydroepiandrosterone (DHEA) is reported to be a partial androgen antagonist in breast tumor cells in vitro. Our aim was to investigate if circulating DHEA had any effects on the association between circulating fT and mammographic density in vivo in the normal postmenopausal breast. Methods We measured visual and digitized mammographic density and serum DHEA, testosterone, sex-hormone-binding globulin and calculated fT in 84 healthy untreated postmenopausal women. Results Significant negative correlations between fT and both visual and digitized mammographic density were strengthened when the median DHEA level decreased from 10.2 to 8.6 nmol/L. Thereafter, correlations became weaker again probably due to decreasing fT levels and/or sample size. There were no correlations between mammographic density and DHEA, at any of the DHEA concentration ranges studied. Serum levels of fT and DHEA were positively correlated. Conclusion Our findings demonstrate that circulating DHEA and/or its metabolites counteract the inhibitory action of fT on mammographic breast density.

Pharmacoeconomic and associated cost savings among women who were prescribed systemic conjugated estrogens therapy compared with those without menopausal therapy.

To explore changes in healthcare costs among postmenopausal women in a commercial population who were prescribed conjugated estrogens for menopausal symptoms. Using the MarketScan dataset from April 1, 2008 through September 30, 2012, postmenopausal women aged ≥45 years, who were prescribed conjugated estrogen tablets (Premarin), were identified. A comparative cohort of postmenopausal women with vasomotor symptoms without any menopause therapy was also identified. Women included were required to have continuous medical and pharmacy benefits for 6 months before and 12 months after index date, with baseline characteristics compared using chi-square and t tests. The 6 and 12-month change (difference in follow-up and baseline costs) in direct healthcare costs was calculated and a difference-in-differences model was used to compare the incremental change at 6 and 12 months in healthcare costs between the cohorts, adjusting for demographic and clinical characteristics. The study included 1,404 women who were prescribed conjugated estrogens, and 3,096 untreated women. Women prescribed conjugated estrogens were significantly younger (52 vs 54 years; P < 0.0001) and had a lower Charlson comorbidity index score (0.29 vs 0.41; P < 0.001) compared with the untreated women. After adjusting for baseline characteristics, women treated with conjugated estrogens showed a greater difference in the change in total healthcare costs (-$1,601 vs -$503; P = 0.044), including inpatient stay costs (-$1,431 vs -$28; P < 0.0001), between the baseline and follow-up periods compared with untreated women. Women who were prescribed oral conjugated estrogens had a significantly greater reduction in healthcare costs after treatment initiation compared with untreated postmenopausal women.

Reasons for Not Treating Women with Postmenopausal Osteoporosis with Prescription Medications: Physicians' and Patients' Perspectives.

In the United States, between one-third and two thirds of postmenopausal women do not begin treatment with a prescription osteoporosis medication after a diagnosis of osteoporosis. The objective of this study was to understand the reasons for this lack of treatment. Online physician and patient surveys were administered in 2013. The physician survey included a chart review of untreated postmenopausal women recently diagnosed with osteoporosis and gathered data on physicians' practices regarding the management of osteoporosis in postmenopausal women. The patient survey was given to untreated postmenopausal women with a recent osteoporosis diagnosis. The physician survey was completed by 224 physicians, who also reviewed 811 patient charts. A total of 165 patients completed the patient survey. In the chart review, physicians reported that 19% of the postmenopausal women they diagnosed with osteoporosis were not prescribed an osteoporosis medication. The patient declined a physician's recommendation for pharmacological treatment in 81% and 52% of cases in the physician and patient surveys, respectively. The most frequent reasons for physicians not recommending treatment were: low calcium and/or vitamin D levels, patients potentially at risk of medication side effects, pre-existing gastrointestinal problems, and polypharmacy. The most frequent reasons for patients deciding against treatment were: concerns about side effects, considering nonprescription options and behavioral modifications, and questioning the potential benefit of taking the medication. Patients decided against pharmacological treatment of newly diagnosed osteoporosis in at least half of the cases of nontreatment. The principal reasons for not being treated with a prescription medication, given by both physicians and patients, were that there were alternatives and concern about the risks of prescription medications.

Intervertebral disc height in premenopausal women treated and untreated postmenopausal women and postmenopausal women with osteoporotic vertebral fractures

Intervertebral disc height in premenopausal women treated and untreated postmenopausal women and postmenopausal women with osteoporotic vertebral fractures

Study of the Effects of the Age at Menopause and Duration of Menopause on Bone Mineral Density in Postmenopausal Women in Uzbekistan

The aim of the present study was to determine whether an association exists between the duration of menopause and the age of menopause onset, and the differences in bone mineral density (BMD) in postmenopausal women. Materials and Methods: We have reviewed medical records of 112 postmenopausal women who had not taken any antiosteoporosis treatment and/or hormone replacement therapy at the time of BMD measurement. The mean age of the postmenopausal women was 53.5±1.1 years, and the mean menopausal period was 4.5 years. The women were evaluated according to the duration of menopause at the time of BMD measurement and age at menopause onset. BMD was measured anteroposteriorly at the L1–L4 level by the dual-energy X-ray absorptiometry method. Results: According to WHO criteria, osteoporosis and osteopenia were identified in 18(16.2%) and 44(39.2%) cases, respectively; overall, 50(44.6%) women had normal BMD.At the time of BMD measurement, osteoporosis was determined in 10.3% and 29.1% of the women with menopause duration of 0–3 years and >7 years, respectively (P=0.047). The percentages for osteopenia were similar among the three different menopause durations (36.2%, 43.3% and 41.6% for 0-3 years, 4-7 years and >7 years, respectively). No differences were determined in the prevalence of osteopenia and osteoporosis in women with menopause duration of >7 years. Thirty-three percent of women with the age of menopause onset of 52 years, respectively). The frequency of osteopenia did not differ between the groups according to the age of menopause onset. Conclusion: According to our results, osteoporosis is related to the duration of menopause at the time of BMD measurement more than to the age of menopause onset among untreated postmenopausal women. (Int J Biomed. 2016;6(1):38-40.).

Are Biochemical Markers of Bone Turnover Representative of Bone Histomorphometry in 370 Postmenopausal Women?

The levels of bone formation and resorption can be assessed at the tissue level by bone histomorphometry on transiliac bone biopsies. Systemic biochemical markers of bone turnover reflect the overall bone formation and resorption at the level of the entire skeleton but cannot discriminate the different skeletal compartments. Our aim was to investigate the correlations between the serum biochemical markers of formation and resorption with histomorphometric parameters. We performed post hoc analysis of a previous clinical study. Patients were selected from the general population. A total of 371 untreated postmenopausal osteoporotic women aged 50 to 84 years with a lumbar T-score ≤ -2.5 SD or ≤ -1 SD with at least one osteoporotic fracture. Transiliac bone biopsies were obtained after a double tetracycline labeling, and blood samples were collected. The static and dynamic parameters of formation and bone resorption were measured by histomorphometry. Serum biochemical markers of formation (bone alkaline phosphatase [ALP]; procollagen type I N-terminal propeptide [PINP]) and resorption (C-terminal crosslinking telopeptide of collagen type 1 [sCTX]) were assessed. The mean values of biochemical markers were: bone ALP, 15.0 ± 5.2 ng/mL; PINP, 56.2 ± 21.9 μg/mL; and sCTX, 0.58 ± 0.26 ng/mL. Bone ALP and PINP were significantly correlated with both the static and dynamic parameters of formation (0.21 ≤ r' ≤ 0.36; 0.01 ≥ P ≥ .0001). sCTX was significantly correlated with all resorption parameters (0.18 ≤ r' ≤ 0.24; 0.02 ≥ P ≥ .0001). Bone turnover markers were significantly but modestly associated with bone turnover parameters measured in iliac cancellous bone. The iliac crest bone may not represent perfectly the whole bone turnover.

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis

Among 97 postmenopausal women with primary osteoporosis, adequate calcium and vitamin D supplementation, and good compliance to a 36-month bisphosphonate treatment, the 25.8% of patients are inadequate responders. Current smoking and a bone turnover in the upper part of the normal range increase the risk of treatment failure. To evaluate the prevalence of the bisphosphonate treatment failure and its possible associated factors in women with primary osteoporosis (PO). We studied 97 previously untreated postmenopausal women with PO and fragility fractures and/or a FRAX® 10-year probability of a major osteoporotic fracture ≥ 7.5%, before and after a 36-month treatment with alendronate or risedronate and adequate vitamin D supplementation with good compliance. At baseline and after 36 months, lumbar spine (LS) and femoral bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and vertebral fractures by spinal radiographs. Spinal deformity index (SDI) was calculated. Treatment failure was defined by the presence of ≥ 2 incident fragility fractures and/or a BMD decrease greater than the least significant change. Bisphosphonate treatment failure was observed in 25.8% of patients. Age, body mass index, years since menopause, familiar history of hip fracture, number of falls, type of bisphosphonate used, 25-hydroxyvitamin D levels (25OHVitD), BMD, SDI, and FRAX® score at baseline were not different between responders and inadequate responders. Treatment failure was associated with current smoking (OR 3.22, 95% CI 1.10-9.50, P = 0.034) and baseline alkaline phosphatase total activity levels ≥ 66.5 U/L (OR 4.22, 95% CI 1.48-12.01, P = 0.007), regardless of age, number of falls, LS BMD, and baseline SDI. The 25.8 % of PO postmenopausal women inadequately responds to bisphosphonates, despite a good compliance to therapy and normal 25OHVitD levels. The current smoking and bone turnover in the upper part of the normal range are associated with the inadequate response to bisphosphonates.

Estrogen Can Modulate Menopausal Women’s Heart Rate Variability

The aim of our study was to compare the responses of heart rate variability (HRV) with two different types of hormonal substitution therapy (HT) in post-menopausal women (cross-sectional study) and to reveal an effect of HT shortly after beginning of its administration (follow-up study). To elucidate the influence of menopause and effects of different protocols of a HT on autonomic control of heart rate, we evaluated the heart rate variability (HRV) in 5 groups: premenopausal women (n=140), postmenopausal women without HT (n=360), women on HT with conjugated estrogen only (n=168), women on continuous combined estrogen-progesterone HT (n=117), and men (n=140). Frequency-domain of short-term stationary R-R intervals was performed to evaluate the total variance, low frequency power (LF; 0.04-0.15 Hz), high frequency power (HF; 0.15-0.40 Hz), portion of low frequency power (LF%) and ratio of LF to HF (LF/HF). Significantly lower portion of the LF was found in premenopausal women [46.9 (+/-2.7) nu] when compared to untreated postmenopausal women [54.3 (+/-2.9) nu] and men [55.2 (+/-3.0) nu]. Treatment by estrogen only was proved to decrease the LF% [40.1 (+/-2.1) nu] while no effect on HRV was observed in women treated with combination of estrogen and progesterone [57.2 (+/-3.1) nu]. Also the HF was lower in postmenopausal women [4.16 (+/-0.16) ms(2)] than in premenopausal women [4.79 (+/-0.22) ms(2)] and women treated with estrogen only [4.98 (+/-0.25) ms(2)] while in women treated with combined hormonal therapy the average value [3.99 (+/-0.21) ms(2)] did not significantly differ from that of untreated postmenopausal women. The follow-up study also proved increase of high frequency power already after two months of estrogen substitution therapy [4.86 (+/-0.14) ms(2) vs. 4.19 (+/-0.15) ms(2)]. These results suggest that higher vagal modulation of heart rate that seems typical for younger women becomes after menopause similar to that of men. We also proved a positive shift of HRV parameters toward more beneficial values as for a cardiovascular risk in postmenopausal women treated with estrogens but not in those treated by combined estrogen - progesterone substitution therapy.

Testosterone implants in women: Pharmacological dosing for a physiologic effect

ObjectivesThe objectives of this study were to determine therapeutic serum testosterone (T) levels/ranges and inter-individual variance in women treated with subcutaneous T implants. Study designIn study group 1, T levels were measured at two separate time intervals in pre- and post-menopausal women treated with subcutaneous T for symptoms of androgen deficiency: (i) four weeks after pellet insertion, and (ii) when symptoms of androgen deficiency returned.In a separate pharmacokinetic study (study group 2), 12 previously untreated postmenopausal women each received a 100mg T implant. Serum T levels were measured at baseline, 4 weeks and 16 weeks following T pellet implantation.In study ‘group’ 3, serial T levels were measured throughout a 26h period in a treated patient. ResultsIn study group 1, serum T levels measured at ‘week 4’ (299.36±107.34ng/dl, n=154), and when symptoms returned (171.43±73.01ng/dl, n=261), were several-fold higher compared to levels of endogenous T. There was significant inter-individual variance in T levels at ‘week 4’ (CV 35.9%) and when symptoms returned (CV 42.6%). Even with identical dosing (study group 2), there was significant inter-individual variance in T levels at ‘week 4’ (CV 41.9%) and ‘week 16’ (CV 41.6%). In addition, there was significant intra-individual circadian variation (CV 25%). ConclusionsPharmacologic dosing of subcutaneous T, as evidenced by serum levels on therapy, is needed to produce a physiologic effect in female patients. Safety, tolerability and clinical response should guide therapy rather than a single T measurement, which is extremely variable and inherently unreliable.

Iliac vessel wall thickness in menstrual and hormone treated and untreated postmenopausal women

Objective: To assess iliac vessel wall thickness in different groups of women. Method: Three groups of women were menopausal and were classified by hormone replacement therapy (HRT) (n = 32), atherosclerotic risk factors (n = 14) and an untreated group of postmenopausal women (n = 29), two groups of menstrual women, above 35 years (N = 35) and below 35 years (n = 16). In these groups of women, a 3.5 MHz ultrasound was used to assess the combined vessel wall thickness of the right iliac artery inner wall and vein outer wall. Results: The iliac vessel wall thickness was found significantly high in the menopausal group of women possessing high risk factors for atherosclerosis (4.3 ± 0.08 mm) and the untreated menopausal group of women (3.9 ± 0.08 mm) compared to the other three groups (p < 0.0001) (Mann–Whitney U test). The vessel wall thickness of the HRT group was 2.96 ± 0.09 mm, the older menstrual group 2.61 ± 0.07 mm, and 2.0 ± 0.06 mm in the young menstrual group. The HRT group had a significantly thicker iliac vessel wall compared to the young menstrual group (p < 0.001). Conclusion: These results confirm the significant impact of high risk factors, such as smoking, hyperlipidaemia and diabetes, on the vessel wall thickness due to accelerated atherosclerosis. This study also suggests that the oestrogenaemic state of a woman may affect the health of the vessel wall.

Age determines longitudinal changes in body composition better than menopausal and bone status: The OFELY study

Long-term body composition (BC) changes and their determinants have been rarely explored. We aimed to evaluate BC changes in French women from the Os des Femmes de Lyon (OFELY) cohort and to explore several determinants of those changes. At baseline, premenopausal (PreM) women (n = 145) had lower fat body mass (FM) and greater lean body mass (LM), relative skeletal muscle mass index (RASM), and total body bone mineral content (TBBMC) compared with untreated postmenopausal (PostM) women (n = 412). During a 6-year follow-up, LM and RASM did not change, whereas a significant increase of FM and a decrease of TBBMC were observed in PreM (n = 88) and PeriM women (n = 44; women who became PostM during the follow-up). In untreated PostM women, FM increased, whereas LM, RASM, and TBBMC decreased (p < 0.0001). Age was a significant determinant of the changes in BC. After controlling for age, menopausal status was still a significant determinant only for changes in TBBMC. FM, LM, RASM, and TBBMC were higher in women with normal bone mineral density (BMD) compared with women with osteopenia or osteoporosis (p < 0.0001), but after adjusting for age, changes of BC were not significantly different according to the bone status. After controlling for age and menopausal status, levels of P1NP in the highest quartile were associated with a greater decrease of LM and RASM compared with lower levels. In conclusion, BC changes in French women over a 6-year follow-up showed a high interindividual variability. Aging may be the most important determinant of changes in body composition, rather than menopausal and bone status.

Bone remodeling in postmenopausal women who discontinued denosumab treatment: Off-treatment biopsy study

Denosumab is a fully human monoclonal antibody that neutralizes the activity of RANKL, leading to the inhibition of osteoclast maturation, bone-resorbing activity, and survival. Evaluation of trans-iliac crest bone biopsy specimens in the phase 3 pivotal fracture study with denosumab in postmenopausal women with osteoporosis showed evidence of reduced bone turnover at the tissue level in subjects receiving denosumab, and up to one-third of subjects did not have evidence of tetracycline labeling in trabecular or cortical bone. Discontinuation of denosumab therapy has demonstrated that the effects of denosumab are reversible, as assessed by biochemical markers of bone turnover (BTM) and BMD. The precise nature of changes that occur at the tissue level with denosumab discontinuation have not been explored. Fifteen subjects were enrolled in a cohort study to evaluate the effects of denosumab discontinuation at the tissue level. Subjects had discontinued osteoporosis treatment for a mean time of 25.1 months (range 21 to 29 months). Bone histomorphometry results were compared with results from placebo-treated women with osteoporosis in the denosumab phase 3 pivotal fracture bone biopsy substudy, and BTMs were compared with subjects' pretreatment values. The results of this study showed normal histology and bone remodeling similar to those observed in untreated postmenopausal women with osteoporosis. With treatment cessation, 100% of biopsy specimens had evidence of tetracycline labels. Biochemical markers were comparable to and highly correlated with pretreatment levels. These data confirm that the effects of denosumab on bone turnover at the tissue level are fully reversible.

Respective roles of organic and mineral components of human cortical bone matrix in micromechanical behavior: An instrumented indentation study

Bone is a multiscale composite material made of both a type I collagen matrix and a poorly crystalline apatite mineral phase. Due to remodeling activity, cortical bone is made of Bone Structural Units (BSUs) called osteons. Since osteon represents a fundamental level of structural hierarchy, it is important to investigate the relationship between mechanical behavior and tissue composition at this scale for a better understanding of the mechanisms of bone fragility. The aim of this study is to analyze the links between ultrastructural properties and the mechanical behavior of bone tissue at the scale of osteon. Iliac bone biopsies were taken from untreated postmenopausal osteoporotic women, embedded, sectioned and microradiographed to assess the degree of mineralization of bone (DMB). On each section, BSUs of known DMB were indented with relatively high load ( ∼ 500 mN) to determine local elastic modulus ( E ), contact hardness ( H c ) and true hardness ( H ) of several bone lamellae. Crystallinity and collagen maturity were measured by Fourier Transform InfraRed Microspectroscopy (FTIRM) on the same BSUs. Inter-relationships between mechanical properties and ultrastructural components were analyzed using multiple regression analysis. This study showed that elastic deformation was only explained by DMB whereas plastic deformation was more correlated with collagen maturity. Contact hardness, reflecting both elastic and plastic behaviors, was correlated with both DMB and collagen maturity. No relationship was found between crystallinity and mechanical properties at the osteon level.

Neutrophil Count for the Identification of Postmenopausal Hypertensive Women at Increased Cardiovascular Risk

High white blood cell and neutrophil counts identify patients at increased cardiovascular risk in various clinical settings. However, the prognostic value of white blood cell and neutrophil counts in hypertensive postmenopausal women is unknown. We tested the independent prognostic value of total white blood cell and neutrophil counts for cardiovascular events in hypertensive postmenopausal women. We examined 298 initially untreated postmenopausal women with essential hypertension who were part of Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA). Mean duration of follow-up was 8 years (range 1-20 years). Treatment was tailored to each individual. Mean age at entry was 59 years. Diabetic women comprised 9.1% of the group, and current smokers comprised 17.5% of the group. During follow-up, 31 new major cardiovascular events occurred. In univariable analyses, age, diabetes, serum creatinine, blood pressure, left ventricular hypertrophy, and neutrophil count showed an association with the risk of events (all P<.05). In a multivariable Cox analysis, after adjustment for traditional cardiovascular risk factors, for each 1.25x10 (1 standard deviation) increase in neutrophil count there was a 67% higher risk of cardiovascular events (hazard ratio 1.67, 95% confidence interval 1.32-2.07; P<.001). Furthermore, neutrophil count showed robust incremental predictive value for cardiovascular events, in addition to traditional risk factors. Total white blood cell count did not show any association with cardiovascular events. A high peripheral neutrophil count identifies postmenopausal hypertensive women at increased risk of cardiovascular disease. Such relation appears to be independent of traditional risk factors. III.

Excretion of estrogens, catecholestrogens and phytoestrogens in carriers of BRCA1 gene mutations: effects of metformin

BRCA1 gene mutation is associated with a combination of excessive aromatase activity/expression, predominantly estrogen receptor-negative phenotypes of tumors, and only scarce information about estrogen contents in body fluids. In the present work, isotope dilution capillary gas chromatography/mass spectrometry was used to study urinary excretion of estrogens, their catechol metabolites, and phytoestrogens in 22 women (11 with BCRA1 gene mutations and 11 without these mutations) in average 5.1+/-0.4 years before surgery for breast cancer. BCRA1 mutation carriers (including 3 premenopausal females) compared with respective controls showed significantly higher urinary estradiol and estrone excretion and a trend to an increased 2-OH-E2 excretion. In the subgroup of untreated postmenopausal women, BCRA1 mutation carriers showed a trend to increased estradiol and estrone excretion and to a higher value of the mean levels of all estrogen metabolites tested. The treatment after the baseline laboratory investigation of 6 women from postmenopausal group with the antidiabetic biguanide metformin for 3 months was associated with decreases in the excretion rates of 4-hydroxyestradiol, 2-methoxyestradiol, and 16-epiestriol and did not influence phytoestrogen excretion. The decrease in 2-methoxyestrogen excretion was more consistent in women without BCRA1 mutations than in BCRA1 mutation carriers. The data suggest the possibility that aromatase complex activation in BCRA1 mutation carriers is combined with increases in both, estrogen metabolism into catecholestrogens and their inactivation by methoxylation, and that metformin may affect both of these pathways.

Cinacalcet Treatment of Primary Hyperparathyroidism: Biochemical and Bone Densitometric Outcomes in a Five-Year Study

Primary hyperparathyroidism (PHPT) is characterized by chronically elevated serum calcium and inappropriately normal or increased PTH. Our objective was to evaluate long-term tolerability, safety, and efficacy of cinacalcet in PHPT patients. A 4.5-yr open-label extension study was conducted at 14 study centers in the United States. Forty-five subjects with PHPT from a double-blind, placebo-controlled, 1-yr trial were continued into this study. After the parent study, all subjects were treated with 30 mg cinacalcet twice daily, increasing to 50 mg twice daily during the 12-wk titration if serum calcium levels were 10.3 mg/dl or higher and then maintained on cinacalcet for up to 4.5 yr. Assessments included serum calcium, PTH, phosphate and alkaline phosphatase, and areal bone mineral density (aBMD). Vital signs, safety chemistries and hematology, and adverse events were monitored throughout. Compared with baseline, cinacalcet treatment improved biochemical measures of PHPT including reducing serum calcium and PTH and increasing serum phosphate with slight increases in alkaline phosphatase. No changes in z-scores of aBMD at spine, hip, or wrist were seen with annual percent changes, consistent with reports for untreated postmenopausal women or PHPT patients. Safety biochemistries remained normal, and adverse events (most commonly arthralgia, myalgia, diarrhea, respiratory infection, and nausea) were mild to moderate in severity. Treatment of PHPT patients with cinacalcet for up to 5.5 yr maintained normocalcemia, reduced plasma PTH, increased serum phosphate and alkaline phosphatase with no significant effects on aBMD, and was well tolerated.