Bone Mineral Density During and After Lactation: A Comparison of African American and Caucasian Women.

During lactation, changes in maternal calcium metabolism are necessary to provide adequate calcium for newborn skeletal development. The calcium in milk is derived from the maternal skeleton through a process thought to be mediated by the actions of parathyroid hormone-related protein (PTHrP) in combination with decreased circulating estrogen concentrations. After weaning, bone lost during lactation is rapidly regained. Most studies of bone metabolism in lactating women have been performed in Caucasian subjects. There are well-documented differences between African American (AA) and Caucasian (C) bone metabolism, including higher bone mineral density (BMD), lower risk of fracture, lower 25-hydroxyvitamin D (25(OH) D), and higher PTH in AA compared to C. In this prospective paired cohort study, BMD and markers of bone turnover were compared in self-identified AA and C mothers during lactation and after weaning. BMD decreased in both AA and C women during lactation, with similar decreases at the lumbar spine (LS) and greater bone loss in the C group at the femoral neck (FN) and total hip (TH), demonstrating that AA are not resistant to PTHrP during lactation. BMD recovery compared to the 2 week postpartum baseline was observed 6 months after weaning, though the C group did not have complete recovery at the FN. Increases in markers of bone formation and resorption during lactation were similar in AA and C. C-terminal telopeptide (CTX) decreased to 30% below post-pregnancy baseline in both groups 6 months after weaning, while procollagen type 1 N-terminal (P1NP) returned to baseline in the AA group and fell to below baseline in the C group. Further investigation is required to determine impacts on long term bone health for women who do not fully recover BMD before a subsequent pregnancy.

A novel long-acting formulation of oral buprenorphine/naloxone produces prolonged decreases in fentanyl self-administration by rhesus monkeys.

BACKGROUND: Due to the poor oral bioavailability of buprenorphine, an oral formulation has not been thought possible. Lyndra Therapeutics is developing a once-weekly long-acting oral product containing buprenorphine. We evaluated the efficacy of this formulation in reducing intravenous (i.v.) fentanyl self-administration by three male and three female rhesus monkeys. METHODS: Buprenorphine HCl and naloxone HCl were co-formulated using an 11:1 ratio of buprenorphine:naloxone in a controlled-release gastric residence formulation administered in an oral capsule (LYN-013). Naloxone was included to determine the feasibility of combining naloxone with buprenorphine in the formulation as an abuse deterrent. Complete fentanyl dose-response functions were determined during each session. The efficacy of single doses of 56/5, 112/10 and 168/15 mg buprenorphine/naloxone in reducing fentanyl self-administration was examined over 13 days. RESULTS: LYN-013 significantly decreased the rate of responding for fentanyl for 3 days and significantly reduced total intake of fentanyl for 8 days. Time to maximal buprenorphine levels (Tmax) ranged between 56 and 68 h for all 3 doses. The maximal buprenorphine level (Cmax) following 168 mg was 2.3 ng/ml which was significantly greater that those observed for 56 mg (1.22 ng/ml) and 112 mg (1.35 ng/ml). Finally, the area-under-curves (AUCtau) were buprenorphine dose-dependently increased from 88 to 127-265 h*ng/ml. There were no signs of non-specific changes in behavior. CONCLUSIONS: A once-weekly oral buprenorphine/naloxone formulation produced sustained suppression of fentanyl self-administration in monkeys suggesting that oral delivery of buprenorphine with this formulation could provide a new opportunity to treat opioid use disorders (OUD).

Characterization of Device-Related Malfunction, Injury, and Death Associated with Using Elastomeric Pumps for Delivery of Local Anesthetics in the US Food and Drug Administration MAUDE Database.

PURPOSE: To characterize medical device reports about elastomeric pumps delivering local anesthesia made to the US Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database. PATIENTS AND METHODS: We conducted a retrospective review of medical device reports submitted to MAUDE from January 2010 to July 2018. A systematic, computerized algorithm was used to identify records pertaining to elastomeric pumps using local anesthesia. Included records indicated the use of local anesthesia or were determined to involve the use of local anesthetics (if they did not contain specific information on drug use). Reports were analyzed within the MAUDE event type categories of malfunction, injury, death, other, and missing. Possible cases of liver injury or surgical site infection were also identified. Manual review of narratives provided in MAUDE was performed by 2 reviewers to identify possible or probable cases of local anesthetic system toxicity (LAST). RESULTS: From a pool of 384,285 reports about elastomeric pumps from the MAUDE database, 4093 met inclusion criteria for involving elastomeric pumps to deliver local anesthetics, with the peak number of reports occurring in 2014. Of these identified reports, 3624 (88.5%) were categorized as malfunctions, 292 (7.1%) as injuries, and 8 (0.2%) as involving death. We identified 13 cases (0.3%) of possible liver injury and 51 cases (1.2%) of possible surgical site infection; 139 reports (3.4%) were determined to be probably (n=53) or possibly (n=86) associated with LAST. CONCLUSION: Malfunction of elastomeric pumps delivering local anesthetics leaves patients vulnerable to injury or death. Our study indicates that reports of malfunction, injury, and death have been reported to the MAUDE database. These reports likely reflect an underrepresentation of cases in the real-world population, emphasizing the need for more comprehensive medical device reporting.

Longitudinal changes in hip geometry in relation to the final menstrual period: Study of Women's Health Across the Nation (SWAN).

BACKGROUND: In SWAN, we showed that accelerated loss of bone mineral density (BMD) begins 1 year before the final menstrual period (FMP) to 2 years after the FMP and slows thereafter. However, the risk of fracture depends on both BMD and bone geometry. The hip structural analysis (HSA) measures important geometric properties of bone. Changes in HSA parameters across the menopausal transition have not been previously assessed. METHODS: The current analysis uses data from SWAN, 5 years before to 5 years after FMP (N = 900, Age (mean(SD)) = 46.85(2.60), 44% White). HSA parameters at the femoral narrow neck were obtained from 2D DXA scans and normalized to baseline values. FMP was determined from annual interviews. Changes in HSA were assessed over 3 periods, 5 to 2 years before FMP (pre-transmenopausal), 2 years before to 1 years after FMP (transmenopausal), 1 to 5 years after FMP (postmenopausal). Mixed linear models with random slopes were used to estimate the rate of change in HSA parameters relative to FMP. RESULTS: Loss of BMD, cross-sectional area (CSA), and section modulus (SM) and increases in outer diameter (OD) were greatest in the transmenopausal period (p for all<0.05). Changes continued in the postmenopausal period but were not statistically significant. The cumulative percentage changes over 10 years in BMD (-10.67%), CSA (-9.01), SM (-7.03) and OD (+1.95) were statistically significant. CONCLUSION: Changes in hip geometry across the menopause transition parallel changes in BMD and provide insight into mechanisms that may increase risk of fragility fracture.

Associations Between Lean Mass, Muscle Strength and Power, and Skeletal Size, Density and Strength in Older Men.

Studies examining the relationship between muscle parameters and bone strength have not included multiple muscle measurements and/or both central and peripheral skeletal parameters. The purpose of this study was to explore the relationship between lean mass, muscle strength and power, and skeletal size, bone density, and bone strength. We studied the association between appendicular lean mass (ALM), grip strength, and leg power, and central quantitative computed tomography (QCT) parameters in 2857 men aged 65 years or older; peripheral QCT was available on a subset (n = 786). ALM, grip strength, and leg power were measured by dual-energy X-ray absorptiometry (DXA), Jamar dynamometer, and the Nottingham Power Rig, respectively. Multivariable models adjusting for potential confounders including age, race, study site, BMI, and muscle measurements were developed and least squares means were generated from linear regression models. For the multivariable model, percent differences of bone parameters between lowest (Q1) and highest quartiles (Q4) of ALM, grip strength, and leg power were reported. ALM was significantly associated with central and peripheral QCT parameters: percent higher values (Q4 versus Q1) ranging from 3.3% (cortical volumetric bone mineral density [vBMD] of the femoral neck) to 31% (vertebral strength index of the spine). Grip strength was only significantly associated with radial parameters: percent higher values (Q4 versus Q1) ranging from 2.5% (periosteal circumference) to 7.5% (33% axial strength index [SSIx]). Leg power was associated with vertebral strength and lower cross-sectional area with percent lower values (Q4 versus Q1) of -11.9% and -2.7%, respectively. In older men, stronger associations were observed for ALM compared to muscle strength and power. Longitudinal studies are needed to examine the relationship between independent changes in muscle measurements and skeletal size, density and strength. © 2018 American Society for Bone and Mineral Research.

Complement proteins and arterial calcification in middle aged women: Cross-sectional effect of cardiovascular fat. The SWAN Cardiovascular Fat Ancillary Study.

BACKGROUND: CVD risk increases in women after menopause. Recent data suggest higher levels of complement protein C3 and cardiovascular fat (CF) in postmenopausal women. Whether complement proteins are associated with early markers of atherosclerosis in healthy midlife women has never been evaluated. Additionally, the potential impact of the local CF on these associations has never been assessed. METHODS: Participants (n = 100, age (mean(SD)):50.48(2.63), 50% premenopausal) were from the Study of Women's Health Across the Nation (SWAN). Arterial calcification (aortic-AC and coronary-CAC) and CF volumes around the heart and aorta (total heart-TAT and aortic perivascular adipose tissue-PVAT) were quantified using EBCT scans. AC and CAC were each evaluated as presence (Agatston scores >0) and extent of calcification (log (Agatston scores+1)). Logistic and linear regression models were used for statistical analysis. RESULTS: Adjusting for age, race, menopausal status and lipids, C3 was significantly associated with both presence and extent of AC and CAC, all P values <0.05. Associations between C3 and presence and extent of AC and CAC were explained by additional adjustment for log TAT and log PVAT, respectively. Association between C3 and log(AC+1) was more pronounced at higher volumes of log TAT (interaction-P = 0.013) adjusting for study variables. No associations were found with C4. CONCLUSIONS: Higher C3 was significantly associated with presence and greater extent of arterial calcification in midlife women. These associations were explained by higher volumes of CF, suggesting CF as a potential source of C3. C3 could be a potential non-invasive biomarker of early diagnosis of atherosclerosis. These findings need to be replicated in larger studies.