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• Central to androgenic PCOS are persistent, rapid GnRH pulses of myriad • Rapid LH pulses stimulate androgens, tonically high estrogens, and low progesterone • Progesterone normally slows GnRH and LH pulses (if androgens not elevated). • With normalized GnRH/LH pulses, androgen excess and hyperinsulinemia recover. • Cyclic progesterone for PCOS lowers androgens and restores estradiol-progesterone balance. To examine the pathophysiology of androgenic PCOS as a model of androgen excess with estradiol (E2) - progesterone (P4) imbalance; to assess therapy with Cyclic P4. Brain or hypothalamic origins of PCOS were drawn from basic science, animal, and clinical data, with a focus on the pulse rate of gonadotrophin releasing hormone (GnRH) and effects on luteinizing hormone (LH) pulsatility and ovarian androgen production. PCOS occurs for 10% of reproductive-aged women from a myriad of potential etiologies, including the central pathophysiology of rapidly pulsing GnRH consequent to increased kisspeptin and GABA A. The inhibitory progesterone feedback that normally slows LH is decreased or absent with PCOS, resulting in chronic LH stimulation of ovarian theca cells and hyperandrogenism. Standard PCOS therapy with combined hormonal contraceptives (CHC) induces predictable flow and lower androgens but does not correct neuroendocrine disturbances and increases already tonically high E2 levels. In contrast, Cyclic P4 provides predictable withdrawal flow and symptom relief but also decreases LH and androgens. Vaginal progesterone with other therapies appears to improve fertility outcomes. Although non-randomized controlled studies of single-cycle progesterone therapy are available, there is no evidence that longer-duration Cyclic P4 reverses the clinical and/or metabolic PCOS disturbances. Longer studies and RCTs are needed. Ovulatory disturbances, androgen excess, and E2 > P4 imbalance are central to androgenic PCOS. Cyclic P4 therapy, by slowing GnRH pulse rate, may improve both PCOS symptoms and fertility. [ABSTRACT FROM AUTHOR]

• Estrogen is the current hormonal focus for Women's Health—Progesterone is ignored. • Estradiol, in all cells/tissues, causes important proliferation and necessary growth. • Progesterone inhibits proliferation, causes tissue differentiation and maturation. • Balanced estradiol and progesterone actions are necessary for premenopausal health. • Reproductive life estradiol-progesterone balance could prevent age-related diseases. This review is to challenge current concepts of women's reproduction with its cultural over-emphasis on estrogen and positive actions, while progesterone tends to be ignored or associated with negative effects. To explore the physiology, and the clinical implications of understanding that progesterone and estradiol interact in counterbalancing and complementary ways within a complex system that is Women's Reproductive Health. Fundamental, descriptive, quantitative and experimental data all show that estradiol's important cellular action is to promote growth and proliferation; by contrast, despite short-term proliferative effects, progesterone's dominant actions are to inhibit proliferation, to enhance differentiation and promote maturation. Estradiol and progesterone variably interact in every cell and tissue in women's bodies and across the life cycle. Since ovulation and thus progesterone's presence is subclinical in normal-length cycles, we urgently need a convenient, home, once/cycle, inexpensive test of normal ovulation. Major funding is needed for ovulation-testing cycle-by-cycle over months or years in large population-based cohorts of adolescent, premenopausal and perimenopausal women. These women need to be followed for fertility and their later-life experiences of osteoporotic fracture, myocardial infarction, breast and endometrial cancers. In addition, all research with menstruating women participants and female mammals needs cycle-phase specific testing. It is difficult to perceive, much less to change, a current paradigm. With this journal issue, however, we have begun the important tasks of transforming concepts about women's health, and setting the research agenda to advance the innovative understanding that women's reproductive and overall health becomes optimal when premenopausal menstrual cycle estradiol and progesterone actions are balanced within this complex system. [ABSTRACT FROM AUTHOR]

• Withdrawal from high brain estrogen (E2) causes neuroendocrine stress hormone spikes. • Norepinephrine (NE) causes thermoneutral narrowing of vasomotor symptoms (VMS). • VMS and psychosocial stress (anxiety, depression) bidirectionally relate and to NE. • Progesterone suppresses central NE and decreases VMS in peri- and menopausal women. • Progesterone therapy may allow women to stop E2 for VMS without rebound symptoms. It was previously thought that estrogen deficiency caused hot flushes and night sweats or vasomotor symptoms (VMS). However, VMS also present in women in the Late Reproductive Transition or "Very Early Perimenopause" who still have regular menstrual cycles and whose estrogen levels have not decreased. Social emotional stresses increase VMS that, in turn, increase stress hormones and mood changes. Evidence suggests that downward swings of estradiol (E2) cause the dramatic neuroendocrine/cytokine release with elevated central norepinephrine levels leading to thermoneutral zone narrowing and VMS. There are aspects of the physiology of VMS that resemble "estrogen addiction ". The aim of this review is to integrate scientific and clinical VMS knowledge in a new paradigm within the model of balanced estradiol and progesterone levels for women's optimal health. We reviewed studies focusing on VMS and its risk factors, pathophysiology and treatment on PubMed, MEDLINE, and EMBASE. Estrogen withdrawal stimulates release of a host of cytokines and neurotransmitters most important of which is increased NE. Downward E2 levels are also associated with anxiety and depression. Initially premenopausal women made menopausal by bilateral ovariectomy/chemotherapy with rapid E2 decline are more likely to report severe VMS than those with natural reproductive aging. When E2 levels drop, increased central NE neuroendocrine-thermal dysregulation triggers hot flushes/night sweats. Although E2-based menopausal hormone therapy relieves VMS, its discontinuation often produces a VMS rebound. P4 relieves VMS in both menopausal and perimenopausal women likely by decreasing or stabilizing NE. We hypothesize that the rebound on discontinuing E2 therapy could be prevented by first adding P4 and then gradually weaning off E2. The effects—of E2 withdrawal, and high E2 levels to increase, and of full dose P4 to suppress central NE levels—need further documentation. Several primate studies and clinical and controlled trials are needed to test this new model. High brain E2 exposure followed by E2 withdrawal rather than low estrogen per se is the underlying cause of VMS; P4 counterbalances the varying E2 levels in the premenopausal years. P4 therapy in perimenopause/menopause may effectively decrease or prevent hot flushes/night sweats without the risk of withdrawal VMS increases that are related to stopping E2 therapy. [ABSTRACT FROM AUTHOR]

Progesterone, estradiol's partner hormone, is commonly ignored, as in a figure depicting menstrual cycle hormones in a Nature Reviews Disease Primer review of menopause [3]! She goes on to show that estradiol is a powerful growth and proliferation-inducing hormone that needs progesterone's proliferation suppressing and maturation stimulating effects for optimal hormonal balance and ultimately Health. Another illustration of the progesterone-estradiol balance paradigm shift is in women's bone health across the lifecycle [15]. Cyclic progesterone treatment might facilitate the development of normal ovulation, and potentially spontaneous fertility, in women with PCOS as well as reversing its unwanted oligomenorrhea, weight gain, acne and hirsutism effects. [Extracted from the article]

Background Population-based incident fracture data aid fracture prevention and therapy decisions. Our purpose was to describe 10-year site-specific cumulative fracture incidence by sex, age at baseline, and degree of trauma with/without consideration of competing mortality in the Canadian Multicentre Osteoporosis Study adult cohort. Methods Incident fractures and mortality were identified by annual postal questionnaires to the participant or proxy respondent. Date, site and circumstance of fracture were gathered from structured interviews and medical records. Fracture analyses were stratified by sex and age at baseline and used both Kaplan–Meier and competing mortality methods. Results The baseline (1995–97) cohort included 6314 women and 2789 men (aged 25–84 years; mean ± SD 62 ± 12 and 59 ± 14, respectively), with 4322 (68%) women and 1732 (62%) men followed to year-10. At least one incident fracture occurred for 930 women (14%) and 247 men (9%). Competing mortality exceeded fracture risk for men aged 65 + years at baseline. Age was a strong predictor of incident fractures especially fragility fractures, with higher age gradients for women vs. men. Major osteoporotic fracture (MOF) (hip, clinical spine, forearm, humerus) accounted for 41–74% of fracture risk by sex/age strata; in women all MOF sites showed age-related increases but in men only hip was clearly age-related. The most common fractures were the forearm for women and the ribs for men. Hip fracture incidence was the highest for the 75–84 year baseline age-group with no significant difference between women 7.0% (95% CI 5.3, 8.9) and men 7.0% (95% CI 4.4, 10.3). Interpretation There are sex differences in the predominant sites and age-gradients of fracture. In older men, competing mortality exceeds cumulative fracture risk. [ABSTRACT FROM AUTHOR]

Abstract: The WHO fracture risk assessment tool (FRAX®) estimates an individual’s 10-yr major osteoporotic and hip fracture probabilities. When bone mineral density (BMD) is included in the FRAX calculation, only the femoral neck measurement can be used. Recently, a procedure was reported for adjusting major osteoporotic fracture probability from FRAX with femoral neck BMD based on the difference (offset) between the lumbar spine and the femoral neck T-score values. The objective of the current analysis was to independently evaluate this algorithm in a population-based cohort of 4575 women and 1813 men aged 50yr and older from the Canadian Multicentre Osteoporosis Study. For women and men combined, there was a 15% (95% confidence interval 7–24%) increase in major osteoporotic fracture risk for each offset T-score after adjusting for FRAX probability calculated with femoral neck BMD. The effect was stronger in women than men, but a significant sex interaction was not detected. Among the full cohort, 5.5% had their risk category reclassified after using the offset adjustment. Sex- and age-dependent offsets (equivalent to an offset based on Z-scores) showed improved risk classification among individuals designated to be at moderate risk with the conventional FRAX probability measurement. In summary, the T-score difference between the lumbar spine and femoral neck is an independent risk factor for major osteoporotic fractures that is independent of the FRAX probability calculated with femoral neck BMD. [Copyright &y& Elsevier]

Background: The relationship between kidney function and bone loss is unclear.Study Design: A prospective observational study.Setting& Participants: 191 men and 444 women aged > or = 50 years participating in a population-based observational study designed to determine risk factors for bone loss and fractures.Predictors: The primary predictor of change in bone mineral density (BMD) was estimated creatinine clearance (using the Cockcroft-Gault formula) measured at baseline and stratified by quartiles. Our secondary predictor was estimated glomerular filtration rate using the Modification of Diet in Renal Disease Study equation, also stratified by quartiles.Outcomes& Measurements: Changes in BMD at the lumbar spine, total hip, and femoral neck during 5 years.Results: Compared with participants in the first quartile of estimated creatinine clearance (>101.2 mL/min), those in remaining quartiles were older (quartile 1, 50.0 years; quartile 2 [101.2-83.4 mL/min], 54.7 years; quartile 3 [83.4-68.3 mL/min], 60.5 years; and quartile 4 [<68.3 mL/min], 68.3 years); weighed less; reported more sedentary hours; were less likely to report excellent, very good, or good self-reported health; consumed less caffeine; and had lower serum calcium and phosphate and higher serum parathyroid hormone levels. After adjusting for age, weight, sex, baseline BMD, and these differences, compared with those in the first quartile, those in the fourth quartile had decreases in BMD of 0.08 g/cm(2) (95% CI, 0.04-0.1) at the lumbar spine, 0.08 g/cm(2) (95% CI, 0.06-0.1) at the femoral neck, and 0.09 g/cm(2) (95% CI, 0.07-0.1) at the total hip. Bone loss did not increase with worsening kidney function (P for trend > 0.05). Results were not substantially different using estimated glomerular filtration rate.Limitations: Observational study design and indirect measures of kidney function.Conclusions: Men and women with impaired kidney function are at increased risk of bone loss, even with minimal reduction in kidney function. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To assess computerised least-squares analysis of quantitative basal temperature (LS-BT) against urinary pregnanediol glucuronide (PdG) as an indirect measure of ovulation, and to evaluate the stability of LS-QBT to wake-time variation. Study design: Cross-sectional study of 40 healthy, normal-weight, regularly menstruating women aged 19–34. Participants recorded basal temperature and collected first void urine daily for one complete menstrual cycle. Evidence of luteal activity (ELA), an indirect ovulation indicator, was assessed using Kassam''s PdG algorithm, which identifies a sustained 3-day PdG rise, and the LS-QBT algorithm, by determining whether the temperature curve is significantly biphasic. Cycles were classified as ELA+ or ELA−. We explored the need to pre-screen for wake-time variations by repeating the analysis using: (A) all recorded temperatures, (B) wake-time adjusted temperatures, (C) temperatures within 2h of average wake-time, and (D) expert reviewed temperatures. Results: Relative to PdG, classification of cycles as ELA+ was 35 of 36 for LS-QBT methods A and B, 33 of 34 (method C) and 30 of 31 (method D). Classification of cycles as ELA− was 1 of 4 (methods A and B) and 0 of 3 (methods C and D). Positive predictive value was 92% for methods A–C and 91% for method D. Negative predictive value was 50% for methods A and B and 0% for methods C and D. Overall accuracy was 90% for methods A and B, 89% for method C and 88% for method D. The day of a significant temperature increase by LS-QBT and the first day of a sustained PdG rise were correlated (r =0.803, 0.741, 0.651, 0.747 for methods A–D, respectively, all p <0.001). Conclusion: LS-QBT showed excellent detection of ELA+ cycles (sensitivity, positive predictive value) but poor detection of ELA− cycles (specificity, negative predictive value) relative to urinary PdG. Correlations between the methods and overall accuracy were good and similar for all analyses. Findings suggest that LS-QBT is robust to wake-time variability and that expert interpretation is unnecessary. This method shows promise for use as an epidemiological tool to document cyclic progesterone increase. Further validation relative to daily transvaginal ultrasound is required. [Copyright &y& Elsevier]

Abstract: Purpose: Studies from around the world indicate a trend toward younger ages of menarche. The extent of this trend in the Canadian population is unknown, and the relationship to later-life health indicators has not yet been fully elucidated. The objective of this study is to estimate the trend in age at menarche (AAM) in the Canadian population and evaluate the relationship between AAM and adult body mass index (BMI). Methods: Our data source was a nationally representative survey (the Canadian Community Health Survey, 2.2), and analyses included 8080 women, aged 15 and older, who self-reported AAM. Height and weight were measured by the interviewers for the calculation of current BMI. We modeled the secular trend in AAM over time, and the relationship between current BMI and AAM. Results: We found a statistically significant decline in AAM in successive age cohorts, indicating a 0.73-year (8.8-month) decrease in AAM between the oldest and youngest age cohorts in the sample. A 1-year increase in AAM was associated with a decrease in mean BMI of approximately 0.5 kg/m2, after adjustment for covariates. A current age–AAM interaction term was nonsignificant, indicating that the relationship was stable throughout increasing temporal separation from puberty. Conclusion: The observed trend toward earlier menarche could be an indicator of a change in insulin-related metabolism, possibly mediated by behavioral and environmental variables. This study suggests that AAM may be an important clinical and public health indicator of susceptibility to overweight and obesity and attendant morbidity. [Copyright &y& Elsevier]

Abstract: At the 2007 Position Development Conference, the Dual-Energy X-ray Absorptiometry Technical Task Force investigated three major areas of bone density testing. Although bone mineral density (BMD) testing in men had previously been reviewed at the 2005 Position Development Conference, we reviewed the most recent data in men to develop appropriate indications for bone density testing in men. We continue to recommend screening at age 70 and discuss the clinical risk factors that may be an appropriate indication for earlier BMD testing. Menopausal transition (perimenopause) was considered an important time to consider BMD evaluation because bone loss may be significant prior to menopause. However, because fracture risk is inherently low in women of this age without other risk factors, screening BMD testing is not appropriate. We discuss the risk factors that are strong indicators of fracture risk that may be increased during the menopause transition. The presence of these risk factors are appropriate indications for BMD testing with applicability of WHO diagnostic categorization. The issue of establishing a high threshold for BMD was investigated thoroughly and the current literature was reviewed. Despite the fact there is agreement that all BMD values greater than T-score -1.0 are not normal, it was felt that because of the paucity of sensitivity data and confounding factors such as high body mass index, an upper threshold could not be established or recommended at this time. This was felt to be an important area for further research. [Copyright &y& Elsevier]

Abstract: Routine bone mineral densitometry (BMD) screening has been recommended for women aged ≥65 yr (Osteoporosis Canada [OC], International Society for Clinical Densitometry [ISCD], Canadian and United States Task Forces on Preventative Healthcare, and National Osteoporosis Foundation) and for men ≥65 yr (OC) or ≥70 yr (ISCD). We estimated the number of older Canadians needed to screen (NNS) by BMD to detect an undiagnosed case of osteoporosis, using prospective, multicenter, population-based data from the Canadian Multicentre Osteoporosis Study (CaMos). We included participants aged ≥65 yr with baseline dual-energy X-ray absorptiometry (DXA) BMDs at the femoral neck and lumbar spine (L1–L4). Osteoporosis was defined by a T-score ≤2.5 at either site. Patients were questioned about a prior diagnosis of osteoporosis. We studied 2699 women and 1032 men aged ≥65 yr. The percentage prevalence and 95% confidence intervals were determined. In individuals aged ≥65 yr, the prevalence of osteoporosis was 25.6% in women (95% confidence interval, 24.0%, 27.3%) and 8.9% in men (7.3%, 10.8%). In 652 men aged ≥70 yr, the prevalence of osteoporosis was 11.3% (9.1%, 14.0%). Of the participants with BMD-defined osteoporosis, 76.6% of woman aged ≥65 yr (73.2%, 79.6%; 516 of 674 women), 93.4% of men aged ≥65 yr (86.4%, 96.9%; 85 of 91), and 93.2% of men ≥70 yr (84.9%, 97.0%; 68 of 73) were not aware of it. Thus, the minimum NNS by BMD testing to detect one previously undiagnosed case of osteoporosis in Canada is: 6 women aged ≥65 yr, 13 men aged ≥65 yr, and 10 men aged ≥70 yr. [Copyright &y& Elsevier]

Introduction: For many years, individual women and doctors have experimented with extending the duration of active oral contraceptive (OC) pills between pill-free intervals (long OC) to control menstruation. The U.S. approval of an OC with 84 active days and 7 pill-free days in 2003 has attracted considerable media attention. In this review we consider the published evidence on the effectiveness, side effects, and risks of menstrual suppression with long OC. Methods: We performed a systematic review of published literature on long OC, up to April 2003. Results: Ten papers were located; two were randomized trials comparing long OC to standard OC; the remaining studies were single-group observational studies. Women on long OC schedules had fewer days of scheduled bleeding during days without pills but more days of unscheduled bleeding and spotting than those on standard OC. These problems were worse for women new to OC and diminished over time. Women on long OC were more likely to discontinue due to poor control of bleeding; women on standard OC were more likely to stop because of problems with headaches. Women on long OC and standard OC both showed increases in physiological factors related to clotting, with a nonsignificant tendency for those on long OC to be more affected. No studies considered the effects of long OC on breast tissue, breast density, endometrial safety, or adolescent maturation and reproductive development. No systematic data were available on the return to reproductive function and fertility after taking long OC. There were no placebo-controlled trials and no information on how long OC compares to normal, unmedicated menstrual cycles. Therefore we believe scientific evidence for safety of long OC use is presently lacking. [Copyright &y& Elsevier]

Background: Cognitive dietary restraint, assessed by the Three-Factor Eating Questionnaire restraint subscale, is associated with subclinical menstrual cycle disturbances. This association may be mediated by stress-activated cortisol release. Objective: We assessed whether 24-h urinary cortisol excretion differs between women with high and low restraint scores. Design: Participants (aged 21.6 ± 2.5 y; n = 62) with normal-length menstrual cycles and high (n = 33) or low (n = 29) restraint scores completed a questionnaire describing weight history, dietary practices, and exercise. Cortisol, calcium, and creatinine were measured in urine collected over 24 h on a day when all food and beverages were provided and measured. Previously, 3-d food records and anthropometric measurements were obtained. Results: Age, height, weight, body mass index, and length of menstrual cycle were similar between groups. The reported amount of exercise was higher (3.4 ± 1.7 compared with 2.2 ± 1.8 h/wk; P < 0.05) and energy intakes (assessed from 3-d and 24-h food records) were lower in the high- than in the low-restraint group. Ratios of urinary cortisol (nmol) to creatinine (mmol) were higher in the high-restraint than in the low-restraint group (42.9 ± 12.9 compared with 36.3 ± 8.9; P < 0.05), whereas ratios of urinary calcium (mmol) to creatinine were lower (0.3 ± 0.1 compared with 0.4 ± 0.2; P < 0.05) in the high-restraint group. Urinary cortisol was not associated with exercise, nutrient intakes, or anthropometric measurements. Conclusions: High dietary restraint scores are associated with urinary cortisol, a biological marker of stress, and high cortisol excretion may affect bone health. Our results suggest that further research is warranted to clarify these associations and to determine whether they persist over time. [ABSTRACT FROM AUTHOR]

Examines the spinal bone mineral density (BMD) in premenopausal vegetarian and nonvegetarian women. Information on vegetarianism; Design of the study; Analyses performed in the study; Assessment of food intake and dietary restraint; Details on the association between BMD and baseline variables.

Ovulatory function was prospectively assessed over 6 mo in 23 vegetarians and 22 nonvegetarians with clinically normal menstrual cycles. Subjects were 20-40 y of age, of stable weight (body mass index, in kg/m², of 18-25), on current diets for ≥ y, and not using oral contraceptives. Quantitative analysis of basal body temperature records classified cycles as normally ovulatory, short luteal phase (< 10 d), or anovulatory. Subjects completed the Three-Factor Eating Questionnaire (subscales for restraint, hunger, and disinhibition) and kept three 3-d food records. Vegetarians had lower BMIs (21.1 ± 2.3 vs 22.7 ± 1.9, P < 0.05), percentage body fat (24.0 ± 5.5% vs 27.4 ± 5.1%, P < 0.05), and restraint scores (6.4 ± 4.4 vs 9.5 ± 3.7, P < 0.05). Mean cycle lengths were similar, but vegetarians had longer luteal phase lengths (11.2 ± 2.6 vs 9.1 ± 3.8 d, P < 0.05). Cycle types also differed (χ² = 9.64, P < 0.01): vegetarians had fewer anovulatory cycles (4.6% vs 15.1% of cycles). Compared with those with restraint scores below the median, highly restrained women had fewer ovulatory cycles (3.6 ± 2.3 vs 5.0 ± 1.4, P < 0.05) and shorter mean luteal phase lengths (7.4 ± 4.1 vs 10.7 ± 3.1 d, P < 0.05). We conclude that ovulatory disturbances and restrained eating are less common among vegetarians, and that restraint influences ovulatory function. [ABSTRACT FROM AUTHOR]

We assessed the relationship between dietary restraint and menstrual cycle characteristics in 27 ovulatory women, previous participants in a longitudinal study of spinal cancellous bone mineral density (BMD). Subjects completed the restraint scale of the Three Factor Eating Questionnaire, recorded basal temperature and exercise for at least three menstrual cycles, and completed a 3-d food record. Cycle lengths of women in the upper and lower tertiles of scores for restraint were similar [27.8 ± 1.0 (x¯ ± SE) vs 27.6 ± 0.8 d], but luteal phase length was shorter in the former group (8.6 ± 0.9 vs 10.8 ± 0.5 d, P < 0.05). Age, body mass index, percent body fat, waist-hip ratio, reported energy intake, and activity were similar between groups. Because the previous longitudinal study found associations between ovulatory disturbances and bone loss, we assessed spinal BMD using dual-energy x-ray absorptiometny (DXA) and quantitative computed tomography (QCF). BMD of women in upper and lower restraint tertiles, respectively, did not differ: DXA, 1.15 ± 0.05 vs 1.20 ± 0.06 glcm²; and OCT. 140 ± 7 vs 133 ± 7 mg/cm³. Additional prospective studies, however, appear warranted. In conclusion, this study's results provide evidence that high dietary restraint is associated with a shortened luteal phase length. [ABSTRACT FROM AUTHOR]

For many years, osteoporosis in women was equated with estrogen deficiency. The recent articles by Zaidi and colleagues offer a new challenge to the estrogen-deficiency–osteoporosis hypothesis by showing that follicle-stimulating hormone (FSH) stimulates osteoclastic bone resorption perhaps through tumor necrosis factor-α (TNF-α). These authors, however, neglected to mention bone abnormalities and high testosterone levels that were previously shown in FSH-receptor knockout and other modified mice. It is also possible that they have overemphasized potential relationships of these new data with human bone loss. Despite these fascinating data, the paradigm of FSH causing hypogonadal bone loss is not yet ready to displace the estrogen-deficiency–osteoporosis paradigm, although that model already faces considerable challenge. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article about the bone formation effects of progesterone and progestins.

We hypothesized that diet would have direct effects on glucose metabolism with direct and indirect effects on bone metabolism in a cohort of Canadian adults. We assessed dietary patterns (Prudent [fruit, vegetables, whole grains, fish, and legumes] and Western [soft drinks, potato chips, French fries, meats, and desserts]) from a semiquantitative food frequency questionnaire. We used fasting blood samples to measure glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR), 25-hydroxyvitamin D (25OHD), parathyroid hormone, bone-specific alkaline phosphatase (a bone formation marker), and serum C-terminal telopeptide (CTX; a bone resorption marker). We used multivariate regression models adjusted for confounders and including/excluding body mass index. In a secondary analysis, we examined relationships through structural equations models. The Prudent diet was associated with favorable effects on glucose metabolism (lower insulin and HOMA-IR) and bone metabolism (lower CTX in women; higher 25OHD and lower parathyroid hormone in men). The Western diet was associated with deleterious effects on glucose metabolism (higher glucose, insulin, and HOMA-IR) and bone metabolism (higher bone-specific alkaline phosphatase and lower 25OHD in women; higher CTX in men). Body mass index adjustment moved point estimates toward the null, indicating partial mediation. The structural equation model confirmed the hypothesized linkage with strong effects of Prudent and Western diet on metabolic risk, and both direct and indirect effects of a Prudent diet on bone turnover. In summary, a Prudent diet was associated with lower metabolic risk with both primary and mediated effects on bone turnover, suggesting that it is a potential target for reducing fracture risk. [ABSTRACT FROM AUTHOR]

With the advent of combined antiretroviral therapy (cART), life expectancy has increased among persons living with HIV, but so too has risk for comorbidities including osteoporosis and fragility fracture. To explore whether HIV status and cART influence three-dimensional measures of BMD, bone microarchitecture and strength we aimed to compare these outcomes between women living with HIV (WLWH; n = 50; 50.4 ± 1.2 years, 44% postmenopausal) and without HIV (controls; n = 50; 51.8 ± 1.2 years, 52% postmenopausal). Outcomes were lumbar spine, total hip and femoral neck areal BMD by DXA; distal radius and tibia trabecular BMD, thickness and number, and cortical BMD and area by HR-pQCT; and finite element analysis-derived bone strength (failure load). Multivariable regression analysis compared bone outcomes between groups adjusting for known osteoporosis risk factors. Within WLWH, we examined associations between bone outcomes and HIV-related factors including disease severity and cART duration. WLWH were diagnosed 20 ± 4 years ago, were on cART for 123 ± 37 months and 80% had HIV plasma viral load <40 copies/mL. For women ≥50 years (n = 61), total hip aBMD T-Score was lower among WLWH than controls. Adjusted distal radius trabecular BMD and thickness and distal tibia trabecular BMD and failure load were 8–19% lower in WLWH than controls (p < 0.05). Cortical BMD and area did not differ between groups at either site. Lifetime cART duration and current plasma viral load were not associated with bone outcomes in WLWH; however, previous treatment with tenofovir was negatively associated with distal radius trabecular BMD and trabecular number and LS aBMD T-score. WLWH have compromised BMD, bone microarchitecture and strength vs. controls of similar age and reproductive status. Treatment with tenofovir may contribute to bone deficits in WLWH. • Women living with HIV have compromised trabecular bone density, structure and strength. • Duration of antiretroviral therapy is not associated with bone outcomes in women with HIV. • Tenofovir may have a lasting negative influence on trabecular bone in women living with HIV even after discontinuation. [ABSTRACT FROM AUTHOR]