The effect of starting metformin on bone mineral density among women with type 2 diabetes in the Study of Women's Health Across the Nation (SWAN).

We examined longitudinal changes in BMD among women in the mid-life starting metformin. Study subjects were 57 years old (mean), and 36% were White. Women initiating metformin were similar to noninitiators. During the 3-year follow-up, BMD loss at all anatomic areas was similar between groups and in subgroups including baseline fasting blood glucose. PURPOSE/INTRODUCTION: Women with type 2 diabetes have higher bone mineral density (BMD), experience slower BMD loss, but have increased fracture risk. Data regarding the effect of metformin on BMD remain discordant. We examined longitudinal changes in BMD among women in the mid-life starting metformin. METHODS: Participants in the Study of Women's Health Across the Nation (SWAN), a diverse community-based US cohort, with BMD measurements were evaluated. Propensity score matching helped balance baseline characteristics of metformin initiators versus noninitiators. Mixed model regression tested the change in BMD between groups. RESULTS: Subjects (n = 248) were 57.4 years old (mean), and 35.9% were White. Women initiating metformin (n = 124) were similar to noninitiators (n = 124) in age and race/ethnicity. During the median 3-year follow-up, BMD loss at all anatomic areas was similar between the metformin initiators and nonusers (all p > 0.3). Subgroup analyses including baseline fasting blood glucose showed no between-group differences. Initiation of metformin (vs. not) in peri-menopausal women was not associated with BMD changes. CONCLUSIONS: Women in the mid-life starting metformin had longitudinal changes in BMD very similar to other women not starting metformin.

Changes in collagen type I C-telopeptide and procollagen type I N-terminal propeptide during the menopause transition.

CONTEXT: Collagen type I C-telopeptide (CTX) and procollagen type I N-terminal propeptide (PINP) are reference bone resorption and formation markers, respectively. OBJECTIVE: To characterize CTX and PINP trajectories across the menopause transition (MT). DESIGN: 18-year longitudinal analysis from the Study of Women's Health Across the Nation. SETTING: Community-based cohort. PARTICIPANTS: 541 women (126 Black, 90 Chinese, 87 Japanese, 238 White) who transitioned from pre- to postmenopause. MAIN OUTCOME MEASURES: CTX and PINP. RESULTS: Multivariable mixed effects regression fit piecewise linear models of CTX or PINP relative to years from final menstrual period (FMP); covariates were race/ethnicity, body mass index (BMI), and age at FMP. In the referent participant (White, 52.46 years at FMP, BMI 27.12 kg/m2), CTX and PINP were stable until 3 years pre- FMP (premenopause). During the MT (3 years before to 3 years after the FMP), CTX and PINP increased 10.3% (p<0.0001) and 7.5% (p<0.0001) per year, respectively; MT-related gains totaled 61.9% for CTX and 45.2% for PINP. Starting 3 years post-FMP (postmenopause), CTX and PINP decreased 3.1% (p<0.0001) and 2.9% (p<0.0001) per year, respectively. Compared to White women, during the MT, Chinese participants had larger gains in CTX (p=0.01), and Japanese women experienced greater increases in CTX (p<0.0001) and PINP (p=0.02). In postmenopause, CTX (p=0.01) and PINP (p=0.01) rose more in Japanese relative to White women. CONCLUSIONS: CTX and PINP are stable in premenopause, increase during the MT, and decrease in postmenopause. During the MT and postmenopause, bone turnover change rates vary by race/ethnicity.

Prediabetes and skeletal health.

PURPOSE OF REVIEW: Type 2 diabetes mellitus (T2D) confers a greater risk of skeletal fragility and fracture. Whether prediabetes is detrimental to bone health is uncertain. RECENT FINDINGS: We summarize the current data on the associations of prediabetes with bone turnover, bone mineral density, bone quality, bone material properties and fracture risk. SUMMARY: In cross-sectional studies, prediabetes was associated with lower bone turnover and worse trabecular bone quality. A longitudinal analysis showed that larger increase in insulin resistance (in the absence of T2D) correlated with faster bone loss. Future research to examine the longitudinal associations of prediabetes with bone health parameters is warranted.

Prediabetes and Fracture Risk Among Midlife Women in the Study of Women's Health Across the Nation.

Importance: Whether prediabetes is associated with fracture is uncertain. Objective: To evaluate whether prediabetes before the menopause transition (MT) is associated with incident fracture during and after the MT. Design, Setting, and Participants: This cohort study used data collected between January 6, 1996, and February 28, 2018, in the Study of Women's Health Across the Nation cohort study, an ongoing, US-based, multicenter, longitudinal study of the MT in diverse ambulatory women. The study included 1690 midlife women in premenopause or early perimenopause at study inception (who have since transitioned to postmenopause) who did not have type 2 diabetes before the MT and who did not take bone-beneficial medications before the MT. Start of the MT was defined as the first visit in late perimenopause (or first postmenopausal visit if participants transitioned directly from premenopause or early perimenopause to postmenopause). Mean (SD) follow-up was 12 (6) years. Statistical analysis was conducted from January to May 2022. Exposure: Proportion of visits before the MT that women had prediabetes (fasting glucose, 100-125 mg/dL [to convert to millimoles per liter, multiply by 0.0555]), with values ranging from 0 (prediabetes at no visits) to 1 (prediabetes at all visits). Main Outcomes and Measures: Time to first fracture after the start of the MT, with censoring at first diagnosis of type 2 diabetes, initiation of bone-beneficial medication, or last follow-up. Cox proportional hazards regression was used to examine the association (before and after adjustment for bone mineral density) of prediabetes before the MT with fracture during the MT and after menopause. Results: This analysis included 1690 women (mean [SD] age, 49.7 [3.1] years; 437 Black women [25.9%], 197 Chinese women [11.7%], 215 Japanese women [12.7%], and 841 White women [49.8%]; mean [SD] body mass index [BMI] at the start of the MT, 27.6 [6.6]). A total of 225 women (13.3%) had prediabetes at 1 or more study visits before the MT, and 1465 women (86.7%) did not have prediabetes before the MT. Of the 225 women with prediabetes, 25 (11.1%) sustained a fracture, while 111 of the 1465 women without prediabetes (7.6%) sustained a fracture. After adjustment for age, BMI, and cigarette use at the start of the MT; fracture before the MT; use of bone-detrimental medications; race and ethnicity; and study site, prediabetes before the MT was associated with more subsequent fractures (hazard ratio for fracture with prediabetes at all vs no pre-MT visits, 2.20 [95% CI, 1.11-4.37]; P = .02). This association was essentially unchanged after controlling for BMD at the start of the MT. Conclusions and Relevance: This cohort study of midlife women suggests that prediabetes was associated with risk of fracture. Future research should determine whether treating prediabetes reduces fracture risk.

Leisure time physical activity and bone mineral density preservation during the menopause transition and postmenopause: a longitudinal cohort analysis from the Study of Women's Health Across the Nation (SWAN).

Background: Whether greater leisure time physical activity (LTPA) is associated with less bone mineral density (BMD) loss during the menopause transition (MT) remains an open question. We hypothesized that: 1) larger increases in LTPA from pre-/early perimenopause (period 1) to late perimenopause/postmenopause (period 2) would be associated with a slower period 2 BMD loss rate; and 2) greater entire-study LTPA levels would be associated with better final absolute BMD (g/cm2). Methods: Data were from of the Study of Women's Health Across the Nation (1996-2017). Exclusions were: bone beneficial medications, inability to identify start of the MT, and extreme BMD change rates. LTPA measures were a validated ordinal scale and number of metabolic equivalents per hour per week (MET hr wk-1) from sport/exercise. Multiply adjusted, linear regression models estimated: 1) BMD decline rate (annualized %) as a function of LTPA change; and 2) final BMD as a function of entire-study LTPA. Findings: Median [p25, p75] MET hr wk-1 were 4.2 [0.9, 10.1] and 4.9 [1.4, 11.2] in periods 1 and 2, respectively; walking was the commonest activity. In adjusted models (N = 875), greater increases in LTPA ordinal score and MET hr wk-1 were statistically significantly associated with a slower decline in femoral neck (FN) BMD. Larger entire-study averages of each LTPA measure were statistically significantly related to better final FN and lumbar spine BMD levels. Interpretation: Findings suggest that LTPA, at modest levels, mitigate MT-related BMD decline and even small increases in intensity, duration or frequency of common activities may lessen bone loss at the population level. Funding: US-NIH.

Dietary Inflammatory Index and Fractures in Midlife Women: Study of Women's Health Across the Nation.

CONTEXT: While evidence suggests that chronic, low-grade inflammation is a risk factor for bone loss and fractures, the potential relation between an inflammatory dietary profile and greater fracture risk is uncertain. OBJECTIVE: We examined whether a more inflammatory diet, consumed during pre- and early perimenopause, is associated with more incident fractures starting in the menopause transition (MT) and continuing into postmenopause. METHODS: Dietary inflammatory potential was quantified using 2 energy-adjusted dietary inflammatory index scores: one for diet only (E-DII), and one for diet plus supplements (E-DII-S). We included 1559 women from the Study of Women's Health Across the Nation, with E-DII and E-DII-S scores from the baseline visit (during pre- or early perimenopausal), and up to 20 years of follow-up. We excluded women using bone-beneficial medications at baseline; subsequent initiators were censored at first use. The associations of E-DII or E-DII-S (each tested as separate exposures) with incident fracture were examined using Cox proportional hazards regression. RESULTS: Adjusted for age, BMI, cigarette use, diabetes, MT stage, race/ethnicity, prior fracture, bone-detrimental medication use, aspirin or nonsteroidal anti-inflammatory drug use, and study site, greater E-DII and E-DII-S (tested separately) were associated with more future fractures. Each SD increment in E-DII and E-DII-S predicted 28% (P = .005) and 21% (P = .02) greater fracture hazard, respectively. Associations were essentially unchanged after controlling for bone mineral density. CONCLUSION: A more pro-inflammatory diet in pre- and early perimenopause is a risk factor for incident fracture. Future studies should consider whether reducing dietary inflammation in midlife diminishes fracture risk.

Menopause-Related Changes in Body Composition Are Associated With Subsequent Bone Mineral Density and Fractures: Study of Women's Health Across the Nation.

During the menopause transition (MT), lean mass decreases and fat mass increases. We examined the associations of these body composition changes during the MT (2 years before to 2 years after the final menstrual period) with bone mineral density (BMD) at the end of the MT and fracture after the MT. We included 539 participants from the Study of Women's Health Across the Nation who were not taking bone-beneficial or bone-detrimental medications before or during the MT. Using multivariable linear regression, we assessed the independent associations of % lean mass loss and % fat mass gain during the MT (mutually adjusted) with femoral neck (FN) and lumbar spine (LS) BMD at the end of the MT, adjusted for pre-MT BMD, pre-MT lean and fat mass, race/ethnicity, Study of Women's Health Across the Nation (SWAN) study site, age, and cigarette use. We used Cox proportional hazards regression to quantify the relations of % lean loss and % fat gain during the MT with fracture after the MT. The Cox model was adjusted for the covariates above plus post-MT use of bone-detrimental medications, and censored at the first use of bone-beneficial medications; we further controlled for FN or LS BMD at the end of the MT. Adjusted for covariates, each standard deviation (SD) (6.9%) increment in lean mass loss was associated with 0.010 g/cm2 lower FN BMD (p < 0.0001); each SD (19.9%) increment in fat mass gain was related to 0.026 g/cm2 greater FN (p = 0.009) and LS (p = 0.03) BMD. Each SD increment in lean mass loss and fat mass gain was associated with 63% (p = 0.001) and 28% (p = 0.05) greater fracture hazard after the MT; associations were essentially unchanged by BMD adjustment. MT-related lean mass loss and fat mass gain were associated differentially with BMD; both were independently related to more fractures. Mitigating MT-related body composition changes may reduce fracture risk. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Polypharmacy in Osteoporosis Treatment.

In older adults, polypharmacy and osteoporosis frequently occur contemporaneously. Polypharmacy is increasingly recognized as a risk factor for hip and fall-related fractures. Treatments for osteoporosis include antiresorptive (alendronate, risedronate, zoledronic acid, ibandronate, denosumab) and osteoanabolic (teriparatide, abaloparatide, romosozumab) agents. Polypharmacy is associated with worse adherence to pharmacologic therapy. Thus, the selection of osteoporosis treatment should be individualized and based on a variety of factors, including underlying fracture risk (high vs very high risk), medical comorbidities, medication burden, as well as fracture risk reduction profiles, modes of administration, and side effects of treatment options.

Longitudinal associations of insulin resistance with change in bone mineral density in midlife women.

BACKGROUNDThe effects of insulin resistance on bone mineral density (BMD) are unclear.METHODSIn Study of Women's Health Across the Nation (SWAN) participants, we used multivariable regression to test average insulin resistance (homeostatic model assessment of insulin resistance, HOMA-IR) and rate of change in insulin resistance as predictors of rate of change in lumbar spine (LS) and femoral neck (FN) BMD in 3 stages: premenopause (n = 861), menopause transition (MT) (n = 571), and postmenopause (n = 693). Models controlled for age, average BW, change in BW, cigarette use, race and ethnicity, and study site.RESULTSThe relation between HOMA-IR and BMD decline was biphasic. When average log2HOMA-IR was less than 1.5, greater HOMA-IR was associated with slower BMD decline; i.e., each doubling of average HOMA-IR in premenopause was associated with a 0.0032 (P = 0.01, LS) and 0.0041 (P = 0.004, FN) g/cm2 per year slower BMD loss. When greater than or equal to 1.5, average log2HOMA-IR was not associated with BMD change. In women in whom HOMA-IR decreased in premenopause, the association between the HOMA-IR change rate and BMD change rate was positive; i.e, slower HOMA-IR decline was associated with slower BMD loss. In women in whom insulin resistance increased in premenopause, the association was negative; i.e, faster HOMA-IR rise was associated with faster BMD decline. Associations of average HOMA-IR and HOMA-IR change rate with BMD change rate were similar in postmenopause, but weaker during the MT.CONCLUSIONWhen it decreases, insulin resistance is associated with BMD preservation; when it increases, insulin resistance is associated with BMD loss.FUNDINGThe SWAN has grant support from the NIH of the Department of Health and Human Services (DHHS) through the NIH National Institute on Aging (NIA), National Institute of Nursing Research (NINR), and Office of Research on Women's Health (ORWH) (grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, and U19AG063720).

Program for Reducing Obesity (PRO): An institutional review of an insurance-based weight loss program utilizing shared medical appointments.

Background: Based on CDC estimates in the United States, the prevalence of obesity was 42.4% in 2017-2018, and the annual cost of obesity was $147 billion in 2008. Yet studies estimate that only 20-40% of adults with obesity received counseling from their primary care providers. Recent studies using shared medical appointments (SMA), where patients are seen by a multidisciplinary team, have shown promising results in obesity management. We developed an insurance-based weight loss program incorporating SMA, called the Program for Reducing Obesity (PRO), and report our findings here. Methods: Enrollment began in January 2019 at the UCLA Health Thousand Oaks clinic. Patients age ≥18 years with BMI ≥30 kg/m2 were eligible by referral to PRO, a program consisting of individual visits and SMAs with an obesity medicine board certified endocrinologist and registered dietitian. Primary outcomes were change in weight after 3, 6, and 12 months. Secondary outcomes included proportion that achieved ≥5% weight loss, change in percent body fat, HbA1c, HDL, triglycerides, and blood pressure. Results: 102 patients (mean age 59.7 years, 72% women, mean weight 103.6 kg, mean BMI 36.6 kg/m2) have been analyzed, with 91 patients completing at least 12 months of the program. Patients achieved significant weight loss: 3.0%, 5.0%, and 7.8% of their baseline weight after 3, 6, and 12 months respectively. 52% of patients lost ≥5% of their baseline weight after 12 months. Patients had significant reductions in body fat: 2.1%, 7.4%, and 6.7% of their baseline (all p ≤ 0.01) after 3, 6, and 12 months respectively. Improvements were also seen in HbA1c (p ≤ 0.01), triglycerides (p ≤ 0.04), and systolic blood pressure (p ≤ 0.07) after 12 months although not all results achieved statistical significance. Conclusion: Our institutional review of PRO, an insurance-based obesity program utilizing SMA, demonstrates a successful approach to promoting weight loss in a community-based setting.

Anti-Mullerian Hormone as Predictor of Future and Ongoing Bone Loss During the Menopause Transition.

The menopause transition in women is a period of significant bone loss, with rapid declines in bone mineral density (BMD) commencing a year before the final menstrual period (FMP). Changes in menstrual bleeding patterns cannot reliably tell us if this rapid bone loss has begun or is imminent. We hypothesized that low circulating levels of anti-Mullerian hormone (AMH), which decline as women approach the FMP, would be associated with future and ongoing rapid bone loss. We used data from The Study of Women's Health Across the Nation, a multisite, multi-ethnic, prospective cohort study of the menopause transition to test this hypothesis. Adjusted for age, body mass index, race/ethnicity, and study site, every 50% decrement in AMH level in premenopause and early perimenopause was associated with 0.14% per year faster decline over the following 3 to 4 years in lumbar spine BMD and 0.11% per year faster decline in femoral neck BMD (p < 0.001 for both). AMH in late perimenopause was not associated with the rate of future BMD decline. AMH was also associated with the magnitude of ongoing bone loss, measured as percent of peak BMD lost by the end of the next 2 to 3 years. Every 50% decrement in AMH level was associated with 0.22% additional loss in spine BMD in premenopause, 0.43% additional loss in early perimenopause, and 0.50% additional loss in late perimenopause (p < 0.001 for all three). If a woman will lose more of her peak BMD than the site-specific least significant change (LSC) at either the lumbar spine or femoral neck by the next 2 to 3 years, then AMH below 100 pg/mL will detect it with sensitivity of 50% in premenopause, 80% in early perimenopause, and 98% in late perimenopause. These findings suggest that AMH measurement can help flag women at the brink of significant bone loss for early intervention. © 2022 American Society for Bone and Mineral Research (ASBMR).

Prediabetes and insulin resistance are associated with lower trabecular bone score (TBS): cross-sectional results from the Study of Women's Health Across the Nation TBS Study.

In pre- and early perimenopausal women, prediabetes (with blood glucose ≥ 110 mg/dL) and greater insulin resistance are associated with worse trabecular bone quality (as assessed by trabecular bone score). PURPOSE: Diabetes mellitus (DM) is associated with lower trabecular bone score (TBS) and fracture; less certain is whether the precursor states of prediabetes and increased insulin resistance are also related to adverse bone outcomes. We examined, in women who do not have DM, the associations of glycemic status (prediabetes vs. normal) and insulin resistance with TBS. METHODS: This was a cross-sectional analysis of baseline data collected from 42- to 52-year-old, pre- and perimenopausal participants in the Study of Women's Health Across the Nation (SWAN) TBS Study. Women with prediabetes were categorized as having either high prediabetes if their fasting glucose was between 110 and 125 mg/dL or low prediabetes if their fasting glucose was between 100 and 109 mg/dL. Normoglycemia was defined as a fasting glucose below 100 mg/dL. RESULTS: In multivariable linear regression, adjusted for age, race/ethnicity, menopause transition stage, cigarette use, calcium and vitamin D supplementation, lumbar spine bone mineral density, and study site, women with high prediabetes had 0.21 (p < 0.0001) standard deviations (SD) lower TBS than those with normoglycemia. Low prediabetes was not associated with lower TBS. When HOMA-IR levels were ≥ 1.62, each doubling of HOMA-IR was associated with a 0.11 SD decrement in TBS (p = 0.0001). CONCLUSION: Similar to diabetics, high prediabetics have lower TBS than normoglycemic individuals. Women with greater insulin resistance have lower TBS even in the absence of DM. Future studies should examine the associations of high prediabetes and insulin resistance with incident fracture.

Associations of Age at Menopause With Postmenopausal Bone Mineral Density and Fracture Risk in Women.

CONTEXT: Menopause before age 45 is a risk factor for fractures, but menopause occurs at age ≥45 in ~90% of women. OBJECTIVE: To determine, in women with menopause at age ≥45, whether (1) years since the final menstrual period (FMP) is more strongly associated with postmenopausal bone mineral density (BMD) than chronological age and (2) lower age at FMP is related to more fractures. DESIGN AND SETTING: The Study of Women's Health Across the Nation, a longitudinal cohort study of the menopause transition (MT). PARTICIPANTS: A diverse cohort of ambulatory women (pre- or early perimenopausal at baseline, with 15 near-annual follow-up assessments). MAIN OUTCOME MEASURES: Postmenopausal lumbar spine (LS) or femoral neck (FN) BMD (n = 1038) and time to fracture (n = 1554). RESULTS: Adjusted for age, body mass index (BMI), cigarette use, alcohol intake, baseline LS or FN BMD, baseline MT stage, and study site using multivariable linear regression, each additional year after the FMP was associated with 0.006 g/cm2 (P < 0.0001) and 0.004 g/cm2 (P < 0.0001) lower postmenopausal LS and FN BMD, respectively. Age was not related to FN BMD independent of years since FMP. In Cox proportional hazards regression, accounting for race/ethnicity, BMI, cigarette use, alcohol intake, prior fracture, diabetes status, exposure to bone-modifying medications/supplements, and study site, the hazard for incident fracture was 5% greater for each 1-year decrement in age at FMP (P = 0.02). CONCLUSIONS: Years since the FMP is more strongly associated with postmenopausal BMD than chronological age, and earlier menopause is associated with more fractures.

Pilot Trial of Vitamin D3 and Calcifediol in Healthy Vitamin D Deficient Adults: Does It Change the Fecal Microbiome?

CONTEXT: Experimental studies suggest that vitamin D receptor signaling may benefit the gut microbiome. In humans, whether vitamin D supplementation directly alters the gut microbiome is not well studied. OBJECTIVE: To determine whether correcting vitamin D deficiency with cholecalciferol (vitamin D3, D3) or calcifediol (25-hydroxyvitamin D3, 25(OH)D3) changes gut microbiome composition. METHODS: 18 adults with vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <20 ng/mL) received 60 µg/day of D3 or 20 µg/day of 25(OH)D3 for 8 weeks. Changes in serum 25(OH)D, 1,25-diydroxyvitamin D (1,25(OH)2D), and 24,25-dihydroxyvitamin D (24,25(OH)2D) were assessed. We characterized composition of the fecal microbiota using 16S rRNA gene sequencing, and examined changes in α-diversity (Chao 1, Faith's Phylogenetic Diversity, Shannon Index), ß-diversity (DEICODE), and genus-level abundances (DESeq2). RESULTS: Vitamin D3 and 25(OH)D3 groups were similar. After 8 weeks of vitamin D3, mean 25(OH)D and 24,25(OH)2D increased significantly, but 1,25(OH)2D did not (25(OH)D: 17.8-30.1 ng/mL, P = .002; 24,25(OH)2D: 1.1 to 2.7 ng/mL, P =0.003; 1,25(OH)2D: 49.5-53.0 pg/mL, P = .9). After 8 weeks of 25(OH)D3, mean 25(OH)D, 24,25(OH)2D, and 1,25(OH)2D increased significantly (25(OH)D: 16.7-50.6 ng/mL, P < .0001; 24,25(OH)2D: 1.3-6.2 ng/mL, P = .0001; 1,25(OH)2D: 56.5-74.2 pg/mL, P = .05). Fecal microbial α-diversity and ß-diversity did not change with D3 or 25D3 supplementation. Mean relative abundance of Firmicutes increased and mean relative abundance of Bacterioidetes decreased from baseline to 4 weeks, but returned to baseline by study completion. DESeq2 analysis did not confirm any statistically significant taxonomic changes. CONCLUSION: In a small sample of healthy adults with vitamin D deficiency, restoration of vitamin D sufficiency with vitamin D3 or 25(OH)D3 did not lead to lasting changes in the fecal microbiota.

Faster Lumbar Spine Bone Loss in Midlife Predicts Subsequent Fracture Independent of Starting Bone Mineral Density.

CONTEXT: Bone mineral density (BMD) decreases rapidly during menopause transition (MT), and continues to decline in postmenopause. OBJECTIVE: This work aims to examine whether faster BMD loss during the combined MT and early postmenopause is associated with incident fracture, independent of starting BMD, before the MT. METHODS: The Study of Women's Health Across the Nation, a longitudinal cohort study, included 451 women, initially premenopausal or early perimenopausal, and those transitioned to postmenopause. Main outcome measures included time to first fracture after early postmenopause. RESULTS: In Cox proportional hazards regression, adjusted for age, body mass index, race/ethnicity, study site, use of vitamin D and calcium supplements, and use of bone-detrimental or -beneficial medications, each SD decrement in lumbar spine (LS) BMD before MT was associated with a 78% increment in fracture hazard (P = .007). Each 1% per year faster decline in LS BMD was related to a 56% greater fracture hazard (P = .04). Rate of LS BMD decline predicted future fracture, independent of starting BMD. Women with a starting LS BMD below the sample median, and an LS BMD decline rate faster than the sample median had a 2.7-fold greater fracture hazard (P = .03). At the femoral neck, neither starting BMD nor rate of BMD decline was associated with fracture. CONCLUSION: At the LS, starting BMD before the MT and rate of decline during the combined MT and early postmenopause are independent risk factors for fracture. Women with a below-median starting LS BMD and a faster-than-median LS BMD decline have the greatest fracture risk.

Hormones and bone loss across the menopause transition.

The menopause transition is a critical period for bone health in women, with rapid losses in bone mass and strength occurring over an approximately 3-year window bracketing the date of the final menstrual period. The onset of the rapid bone loss phase is preceded by large changes in sex steroid hormones, measurements of which may be clinically useful in predicting the onset of the rapid loss phase and identifying the women who will lose the most bone mass during this rapid bone loss phase. Here we summarize recent and new findings related to the ability of sex hormone levels to (1) determine if a woman in her 5th decade of life is about to enter or has already entered the rapid phase of bone loss, and (2) if she will lose more than the average amount of bone mass over the menopause transition.

Normocalcaemic primary hyperparathyroidism: An update on diagnostic and management challenges.

Normocalcaemic primary hyperparathyroidism is a condition that can present with intermittent hypercalcemia or may evolve into hypercalcemic primary hyperparathyroidism. This milder biochemical entity remains incompletely understood because of a lack of long-term health outcomes regarding both medical and surgical approaches to its management. Medical therapies have shown some efficacy. A limited number of studies have found that bisphosphonates increase bone mineral density, and calcimimetics may decrease the risk of nephrolithiasis in patients with normocalcaemic primary hyperparathyroidism. Studies have also described patient outcomes after applying the same surgical criteria used for patients with hypercalcaemic primary hyperparathyroidism to those with the normocalcaemic form of the disease. These studies suggest that parathyroid surgery appears to be effective in normalizing elevated serum parathyroid hormone concentrations and decreasing adverse renal and skeletal outcomes in patients with normocalcaemic hyperparathyroidism. Given the available data and overall lack of consensus regarding the optimal management of these patients, a reasonable approach is to tailor treatment to the individual patient by considering their risk factors for new or accelerated bone loss, kidney stones, diminished quality of life, and cardiovascular disease.

Preoperative Vitamin D Repletion in Total Knee Arthroplasty: A Cost-Effectiveness Model.

BACKGROUND: Recent studies have identified vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] < 20 ng/L) as a potentially modifiable risk factor for prosthetic joint infection (PJI) in arthroplasty. The purpose of this study is to determine whether implementation of preoperative 25(OH)D repletion is cost-effective for reducing PJI following total knee arthroplasty (TKA). METHODS: A cost estimation predictive model was generated to determine the utility of both selective and nonselective 25(OH)D repletion in primary TKA to prevent PJI. Input data on the incidence of 25(OH)D deficiency, relative complication rates, and costs of serum 25(OH)D repletion and 2-stage revision for PJI were derived from previously published literature identified using systematic review and publicly available data from Medicare reimbursement schedules. Mean, lower, and upper bounds of 1-year cost savings were computed for nonselective and selective repletion relative to no repletion. RESULTS: Selective preoperative 25(OH)D screening and repletion were projected to result in $1,504,857 (range, $215,084-$4,256,388) in cost savings per 10,000 cases. Nonselective 25(OH)D repletion was projected to result in $1,906,077 (range, $616,304-$4,657,608) in cost savings per 10,000 cases. With univariate adjustment, nonselective repletion is projected to be cost-effective in scenarios where revision for PJI costs ≥$10,636, incidence of deficiency is ≥1.1%, and when repletion has a relative risk reduction ≥4.2%. CONCLUSION: This predictive model supports the potential role of 25(OH)D repletion as a cost-effective mechanism of reducing PJI risk in TKA. Given the low cost of 25(OH)D repletion relative to serum laboratory testing, nonselective repletion appears to be more cost-effective than selective repletion. Further prospective investigation to assess this modifiable risk factor is warranted.

Gut permeability, inflammation, and bone density across the menopause transition.

BACKGROUNDInflammation is implicated in many aging-related disorders. In animal models, menopause leads to increased gut permeability and inflammation. Our primary objective was to determine if gut permeability increases during the menopause transition (MT) in women. Our exploratory objectives were to examine whether greater gut permeability is associated with more inflammation and lower bone mineral density (BMD).METHODSWe included 65 women from the Study of Women's Health Across the Nation (SWAN). Key measures were markers of gut permeability (gut barrier dysfunction, fatty acid binding protein 2 [FABP2]) and immune activation secondary to gut microbial translocation (LPS binding protein [LBP], soluble CD14 [sCD14]), inflammation (high-sensitivity CRP), and lumbar spine (LS) or total hip (TH) BMD.RESULTSIn our primary analysis, FABP2, LBP, and sCD14 increased by 22.8% (P = 0.001), 3.7% (P = 0.05), and 8.9% (P = 0.0002), respectively, from pre- to postmenopause. In exploratory, repeated measures, mixed-effects linear regression (adjusted for BMI, age at the premenopausal visit, race/ethnicity, and study site), greater gut permeability was associated with greater inflammation, along with lower LS and TH BMD.CONCLUSIONGut permeability increases during the MT. Greater gut permeability is associated with more inflammation and lower BMD. Future studies should examine the longitudinal associations of gut permeability, inflammation, and BMD.FUNDINGFunding for this research was provided by NIH, Department of Health and Human Services, through the National Institute on Aging, National Institute of Nursing Research, and NIH Office of Research on Women's Health (U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495).

The Association between Fast Increase in Bone Turnover During the Menopause Transition and Subsequent Fracture.

CONTEXT: Bone turnover increases rapidly during the menopause transition (MT) and plateaus above premenopausal levels in early postmenopause. It is uncertain whether higher bone turnover is associated with fracture in midlife women with near-normal bone mineral density (BMD). OBJECTIVE: Examine whether faster increases in bone turnover during the MT (2 years before to 2 years after the final menstrual period [FMP]), and greater bone turnover during early postmenopause (≥2 years after the FMP) are risk factors for subsequent fracture, accounting for BMD. DESIGN AND SETTING: The Study of Women's Health Across the Nation, a longitudinal cohort study of the MT. PARTICIPANTS: A total of 484 women (initially pre- or early perimenopausal, who transitioned to postmenopause) with bone turnover (urine collagen type I N-telopeptide), BMD, and fracture data. MAIN OUTCOME MEASURE: Incident fracture after the MT. RESULTS: Adjusting for age, race/ethnicity, fracture before the MT, cigarette use, body mass index, and study site in Cox proportional hazards regression, each SD increment in the rate of increase in bone turnover during the MT was associated with 24% greater hazard of incident fracture in postmenopause (P = .008). Accounting for the same covariates, each SD increment in bone turnover during early postmenopause was associated with a 27% greater hazard of fracture (P = .01). Associations remained significant after controlling for MT rate of change and early postmenopausal level of BMD. CONCLUSION: Faster increases in bone turnover during the MT and greater bone turnover in early postmenopause forecast future fractures.