Clinical characteristics of pregnancy and lactation associated osteoporosis: An online survey study.

Pregnancy and lactation associated osteoporosis is a rare and often severe osteoporosis presentation. Little information is available about etiology, clinical characteristics, risk factors and predictors of severity. Using an anonymized questionnaire, we defined clinical characteristics and potential risk factors for disease severity in PLO including primiparity, heparin exposure and celiac disease. PURPOSE: Pregnancy and lactation associated osteoporosis (PLO) is a rare form of early-onset osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. Little information is available about etiology, clinical characteristics, risk factors and predictors of disease severity. METHODS: PLO patients were recruited to complete an anonymized online questionnaire. Disease severity was defined as total number of fractures during or after the first pregnancy associated with a fracture(s). Analyses related disease severity to potential predictors including diseases/conditions or medication exposures. RESULTS: 177 completed surveys were received between 5/29/2018 and 1/12/2022. Average age at initial PLO fracture event was 32 ± 5 years. The majority were primiparous with singleton pregnancy and 79% fractured during lactation. Subjects reported 4.7 ± 2.7 total PLO fractures, with 48% reporting ≥ 5 fractures. Vertebral fractures, reported by 164/177 responders (93%), were the most common fracture type. Conditions and medications most commonly reported included vitamin D deficiency, amenorrhea unrelated to pregnancy, nephrolithiasis, celiac disease (CD), oral steroid use, heparin products during pregnancy and progestin only contraceptive after pregnancy. CD and heparins exposure during pregnancy were significantly related to disease severity. CONCLUSION: This is the largest study characterizing clinical features of PLO to date. The large number of participants and broad range of clinical and fracture characteristics queried has yielded novel information on the characteristics of PLO and potential risk factors for its severity, including primiparity, exposure to heparin and CD. These findings provide important preliminary data that can help target future mechanistic investigations.

Smoking Is Associated with Sex-Specific Effects on Bone Microstructure in Older Men and Women.

BACKGROUND: Smoking is a risk factor for fracture, but the mechanism by which smoking increases fracture risk is unclear. METHODS: Musculoskeletal health was compared with dual energy X-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HR-pQCT), trabecular bone score, and vertebral fracture assessment in current and past smokers and nonsmokers from a multiethnic study of adults ≥ age 65. Skeletal indices were adjusted for age and weight. RESULTS: Participants (n = 311) were mean age (±SD) 76.1 ± 6.5 years, mostly female (66.0%) and non-white (32.7% black/39.4% mixed race/26.3% white). Mean pack-years was 34.6 ± 20.4. In men (n = 106), weight and BMI were lower (both p < 0.05) in current vs past smokers. Male smokers consumed half the calcium of never and past smokers. BMD by DXA did not differ by smoking status at any skeletal site in either sex. Current male smokers had 13.5%-15.3% lower trabecular bone score vs never and past smokers (both p < 0.05). By HR-pQCT, trabecular volumetric BMD was 26.6%-30.3% lower and trabeculae were fewer, thinner and more widely spaced in male current vs past and never smokers at the radius (all p < 0.05). Cortical indices did not differ. Tibial results were similar, but stiffness was also 17.5%-22.2% lower in male current vs past and never smokers (both p< 0.05). In women, HR-pQCT trabecular indices did not differ, but cortical porosity was almost twice as high in current vs never smokers at the radius and 50% higher at the tibia (both p < 0.05). CONCLUSIONS: In summary, current smoking is associated with trabecular deterioration at the spine and peripheral skeleton in men, while women have cortical deficits. Smoking may have sex-specific skeletal effects. The consistent association with current, but not past smoking, suggests the effects of tobacco use may be reversible with smoking cessation.

Multivariate approaches for the development of quality control in-situ fiber optics dissolution methods for fixed-dose combination tablets.

The purpose of this research was to develop a fiber optic (FO) dissolution method for quantification of multiple actives in combination pharmaceutical tablets. FO dissolution allows direct API quantification in the vessel, obviating the need for error-prone facets of traditional dissolution methods. However, FO dissolution is potentially challenged by overlapping UV spectra, matrix effects, UV-active excipients, API interactions with excipients and media, and undissolved components attenuating the UV signal. These obstacles might render FO dissolution method development more complex than LC-end dissolution. The case study in this manuscript has the added complexity of a triple combination product (Midol), where acetaminophen, caffeine, and pyrilamine maleate exhibit similar release kinetics, share largely overlapping UV spectra and span an order of magnitude difference in concentration. Single-wavelength quantification required unique features for the actives of interest, which were not available for the formulation of interest without preprocessing. The methods employed for the quantification of actives were a partial least squares multivariate calibration and a peak area calibration, both using prepared mixtures as reference data. The selected combination tablet demonstrated collinear API release; therefore, individual quantification required a design of experiments for mixture design. The advantages of FO dissolution will be discussed in the context of the formulation under investigation. Additionally, some general guidelines will be suggested for the development of other FO methods.

Fractures in women with type 2 diabetes are associated with marked deficits in cortical parameters and trabecular plates.

The basis for increased fracture risk in type 2 diabetes (T2DM) is not well understood. In this multi-ethnic, population-based study (n = 565), we investigated bone microstructure, trabecular plate/rod morphology, and mineralization in women with T2DM (n = 175) with and without fracture using a second-generation HRpQCT and individual trabecula segmentation and mineralization (ITS; ITM). Covariate-adjusted aBMD was 3.0%-6.5% higher at all sites (all p<.005) in T2DM vs controls. By HRpQCT, T2DM had higher covariate-adjusted trabecular vBMD (5.3%-6.4%) and number (3.8%-5.1%) and greater cortical area at the radius and tibia. Covariate-adjusted cortical porosity was 10.0% higher at the tibia only in T2DM vs controls, but failure load did not differ. Among women with T2DM, those with adult atraumatic fracture (n = 59) had 5.2%-8.5% lower adjusted aBMD at all sites by DXA compared with those without fracture (n = 103). By HRpQCT, those with fracture had lower adjusted total vBMD and smaller cortical area (10.2%-16.1%), lower cortical thickness (10.5-15.8%) and lower cortical vBMD associated with 18.1 and 17.2% lower failure load at the radius and tibia, respectively (all p<.05); plate volume and thickness were 5.7% and 4.7% lower, respectively, (p<.05) while rod volume fraction was 12.8% higher in the fracture group at the tibia only. Sodium glucose cotransporter 2 inhibitor users (SGLT2i; n = 19), tended to have lower radial rod tissue mineral density by ITS (p=.06). GLP1 agonist users (n = 19) had trabecular deficits at both sites and higher cortical porosity and larger pores at the distal tibia. In summary, T2DM is associated with increased cortical porosity while those with T2DM and fracture have more marked cortical deficits and fewer trabecular plates associated with lower failure load.

Reasons for increased fracture risk in type 2 diabetes (T2DM) are not well-understood. We used a multi-ethnic, population-based cohort (n = 565), to study bone structure in women with T2DM (n = 175) using advanced imaging and analysis techniques. Participants with T2DM tended to have higher bone density and better structure by DXA and HRpQCT, respectively, at the radius and tibia; only cortical porosity was higher (worse) in participants with diabetes compared with those without diabetes but there was no difference in bone strength. Participants with T2DM and fracture had lower cortical parameters and bone strength compared with participants with T2DM without fracture at both sites. In summary, T2DM is associated with increased cortical porosity while those with T2DM and fracture have more marked cortical deficits associated with lower failure load.

Bisphosphonates Maintain BMD after Sequential Teriparatide and Denosumab in Premenopausal Women with Idiopathic Osteoporosis.

CONTEXT: We previously reported that sequential teriparatide followed by denosumab substantially increases BMD in premenopausal idiopathic osteoporosis (PremenIOP). OBJECTIVE: To determine whether administration of bisphosphonates after denosumab cessation is associated with stable BMD in PremenIOP. DESIGN: Open-label extension study. PARTICIPANTS: 24 PremenIOP Teriparatide-Denosumab Study participants. INTERVENTIONS: Oral alendronate (ALN), 70mg weekly, or IV zoledronic acid (ZOL), 5mg once (patient choice), was administered 7 months (M) after final denosumab dose. OUTCOMES: BMD by DXA and serum C-telopeptide (CTX) q6M; vertebral fracture assessment (VFA) and HR-pQCT q12M. RESULTS: 24 women with PremenIOP (aged 43 ± 8 years), severely affected with low trauma adult fractures (range 0-12; 9 with vertebral fractures) and/or very low BMD, had large BMD increases on sequential teriparatide-denosumab (spine: 25 ± 9%; total hip: 11 ± 6%). During the Bisphosphonate Extension, mean BMD and CTX changes in the entire group were small and not statistically significant at 6 or 12M.Women choosing ZOL (n = 6) versus ALN (n = 18) did not differ by baseline age, BMI, fractures, BMD, or CTX. On ZOL, there were small LSBMD declines and CTX increases, particularly between 6M and 12M, while greater stability was observed on ALN.Changes in BMD and CTX did not differ by duration of denosumab (36M vs <36M) or between 20 women who remained premenopausal and 4 who transitioned into menopause. Higher pre-teriparatide CTX, likely reflecting baseline remodeling status, predicted more spine and hip bone loss. No new vertebral (clinical or VFA screening) or non-vertebral fractures occurred. CONCLUSION: BMD remained stable in women with PremenIOP who received bisphosphonates after sequential teriparatide-denosumab therapy.

Trabecular and cortical microarchitecture in postmenopausal HIV-infected women.

Our objective was to assess the effects of HIV infection and antiretroviral therapy on trabecular and cortical microarchitecture in postmenopausal minority women. A subgroup of 106 (46 HIV-infected, 60 uninfected) postmenopausal Hispanic and African American women from an established cohort had areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry and trabecular and cortical volumetric BMD (vBMD) and microarchitecture measured by high-resolution peripheral quantitative computed tomography (HRpQCT) at the radius and tibia. HIV-infected women were slightly younger (58 ± 1 vs. 61 ± 1 years, p = 0.08), and had lower body mass index (BMI; 28 ± 1 vs. 32 ± 1 kg/m(2), p < 0.01). BMI-adjusted aBMD Z scores were lower in HIV-infected women at the lumbar spine, total hip, and ultradistal radius. Serum N-telopeptide and C-telopeptide levels were also higher in HIV-infected women. Trabecular and cortical vBMD were similar at the radius, but cortical area (105.5 ± 2.4 vs. 120.6 ± 2.0 mm(2), p < 0.01) and thickness (956 ± 33 vs. 1,075 ± 28 µm, p < 0.01) at the tibia were approximately 11-12 % lower in HIV-infected women. Differences remained significant after adjusting for age, BMI, and race/ethnicity. In contrast, cortical porosity was similar in the two groups. Although HIV-infected postmenopausal women had lower aBMD at the spine, total hip, and ultradistal radius and higher levels of bone resorption markers, the only differences detected by HRpQCT were lower cortical thickness and area at the tibia.

Skeletal Microstructure in Caribbean Hispanic Women.

Hispanic individuals are underrepresented in skeletal research. Bone mineral density (BMD) and fracture data are conflicting. We investigated skeletal health in elderly Caribbean Hispanic (HW), non-Hispanic white (NHW), and non-Hispanic black (NHB) women in a population-based study in New York City. We utilized high-resolution peripheral quantitative CT (HRpQCT), dual-energy X-ray absorptiometry (DXA), and finite element analysis (FEA). Of 442, 48.4% were HW, 21.3% NHW, and 30.3% NHB. Adjusted analyses are shown. Compared to NHW, HW had 8.5% (p < 0.01) lower spine areal BMD (aBMD) and 5.1% lower trabecular bone score (TBS). The frequency of morphometric vertebral fractures did not differ between HW and NHW. By HRpQCT, HW had 2.9% higher cortical (Ct) volumetric BMD (vBMD), 7.9% greater Ct area (Ct.Ar) and 9.4% greater Ct thickness (Ct.Th) at the radius compared to NHW. Results were similar at the tibia but trabecular microstructure tended to be worse. Ultimately, failure load (FL) did not differ between HW and NHW at either site. aBMD was 3.8% to 11.1% lower at the spine, femoral neck, and radius in HW compared to NHB (all p < 0.001) and vertebral fractures were twice as common. Compared to NHB, HW had 7.7% to 10.3% lower Ct.Ar at both the radius and tibia as well as 8.4% lower total vBMD, 6.3% lower trabecular number, and 10.3% lower Ct.Th at the tibia associated with 18.2% and 12.5% lower FL at both sites, respectively. In conclusion, HW had lower spine aBMD and TBS versus NHW women, whereas microstructural differences at the radius and tibia were small and not associated with differences in FL. In contrast, HW had lower aBMD, as well as deteriorated radial and tibial microstructure associated with worse FL compared to NHB women. Our results provide insight into racial/ethnic differences in skeletal health, adding to data that may be used to improve osteoporosis screening and treatment in HW. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Bone microstructure in proton pump inhibitor users.

OBJECTIVES: We assessed skeletal microstructure and stiffness in proton pump inhibitor (PPI) users compared to non-users with high resolution peripheral quantitative computed tomography (HRpQCT) and microfinite element analysis (µFEA) and other modalities. Relationships between PPI dose/frequency and bone parameters were evaluated. METHODS: We cross-sectionally assessed skeletal health in 601 older (≥age 65 years) adults (130 PPI users and 471 non-users) participating in a multi-ethnic population-based study of aging. RESULTS: PPI users tended to have more comorbidities and take more medications than non-users. Female PPI users (n = 100) were more likely to be non-Caucasian, shorter with higher BMI, and more likely to have diabetes, lower physical activity and be using anti-depressants and thiazide diuretics compared to non-users (n = 302). Male PPI users (n = 30) were more likely to have liver disease than non-users (n = 169). In women, historical fractures (53.0 % vs. 43.4 %, p = 0.05) and falls (38 % vs. 26.8 %, p = 0.04) tended to be more frequent in PPI users compared to non-users. Number of falls was higher in women reporting daily rather than intermittent PPI use (1.8/year vs. 1.0/year, p < 0.001). In women, there were no differences in any HRpQCT or µFEA parameter. By HRpQCT, covariate-adjusted cortical volumetric bone density (Ct.vBMD) was 4.2 % lower in male PPI users vs. non-users at the tibia (p = 0.04), but this did not result in reduced stiffness. There were no other differences by HRpQCT at the tibia or radius. CONCLUSIONS: PPI use was not associated with altered skeletal microstructure or stiffness in elderly men and women. The results do not support a relationship between PPI use and microstructure.

Thiazide use and skeletal microstructure: Results from a multi-ethnic study.

Background: Thiazide diuretics, a commonly used class of anti-hypertensives, have been associated with increased areal bone mineral density (aBMD). Data regarding effects on fracture are conflicting and no information is available regarding effects on skeletal microstructure and mechanical competence. Methods: We compared skeletal microstructure, volumetric BMD (vBMD), stiffness and prevalent fractures in current thiazide diuretic users and non-users from a population-based multiethnic cohort of elderly adults age ≥ 65 years (N = 599) with high resolution peripheral quantitative computed tomography (HR-pQCT) and micro-finite element analysis. Results: Female current thiazide diuretic users had higher weight and BMI and were more likely to be non-Caucasian compared to non-users. There were no differences in age, historical fractures or falls between female users and non-users. Female thiazide users tended to have lower calcium and vitamin d intake compared to non-users. After adjusting for age, weight, race and other covariates, 1/3-radius mean aBMD by dual energy x-ray absorptiometry (DXA) was 3.2% (p = 0.03) higher in female users vs. non-users. By HRpQCT, adjusted mean cortical vBMD was 2.4% (p = 0.03) higher at the radius in female users vs. non-users, but there was no difference in stiffness. DXA results were similar in the subset of Black females. There was no difference in any adjusted aBMD or cortical skeletal parameters by DXA or HRpQCT respectively in males. Conclusions: Thiazide use was associated with a modestly higher aBMD at the predominantly cortical 1/3-radius site and radial cortical vBMD by HRpQCT in females. The effect on cortical bone may offer skeletal benefits in women taking thiazides for other indications such as hypertension, hypercalciuria or recurrent nephrolithiasis.

Current anti-depressant use is associated with cortical bone deficits and reduced physical function in elderly women.

BACKGROUND: Anti-depressants, particularly selective serotonin reuptake inhibitors (SSRIs), are associated with an increased risk of fracture. The mechanism is unclear and may be due to effects on bone metabolism, muscle strength, falls or other factors. It is unknown if serotonin norepinephrine reuptake inhibitors (SNRIs) have similar effects. METHODS: We compared musculoskeletal health in current female anti-depressant users and non-users from a population-based multiethnic (35.6% black, 22.3% white and 42.1% mixed) cohort study of adults ≥65 years old in New York (N = 195) using dual x-ray absorptiometry (DXA), trabecular bone score (TBS), vertebral fracture assessment (VFA), high resolution peripheral quantitative computed tomography (HR-pQCT), body composition, and grip strength. RESULTS: Current anti-depressant users were more likely to be white than non-white (OR 1.9, 95% CI 1.2-2.9) and were shorter than non-users, but there were no differences in age, weight, BMI, physical activity, calcium/vitamin D intake, falls or self-rated health. There were more pelvic fractures in current vs. non-users (7.1% vs. 0%, p = 0.04). Age- and weight-adjusted T-score by DXA was lower in current users at the 1/3-radius (-1.6 ± 1.1 vs. -1.0 ± 1.4, p = 0.04) site only. There was no difference in TBS, vertebral fractures or fat/lean mass by DXA. Age- and weight-adjusted grip strength was 13.3% lower in current users vs. non-users (p = 0.04). By HR-pQCT, age- and weight-adjusted cortical volumetric BMD (Ct. vBMD) was 4.8% lower in users vs. non-users at the 4% radius site (p = 0.007). A similar cortical pattern was seen at the proximal (30%) tibia. When assessed by anti-depressant class, deteriorated cortical microstructure was present only in SSRI users at the radius and only in SNRI users at the proximal tibia. CONCLUSIONS: Anti-depressant use is associated with cortical deterioration and reduced physical function, but effects may be class-specific. These findings provide insight into the mechanism by which anti-depressants may contribute to the increased fracture risk in older women.

Effect of vitamin D3 and calcium carbonate supplementation on muscle strength in postmenopausal women living with HIV.

BACKGROUND: Both falls and fractures are increased in older persons living with HIV (PLWH). Low serum total 25-hydroxyvitamin D (25-OHD) levels have been associated with falls, fractures and poor muscle strength. We hypothesized that vitamin D (VitD) supplementation would improve muscle strength in postmenopausal PLWH. METHODS: In a 12-month prospective, randomized, double-blind, study of 69 African American and Hispanic postmenopausal PLWH on antiretroviral therapy with 25-OHD ≥10 ng/ml and ≤32 ng/ml, we investigated the effects of daily low (1,000 IU; n=31) and moderate (3,000 IU; n=38) cholecalciferol doses on lean mass and strength. Change in lean body mass was assessed by dual-energy X-ray absorptiometry (DXA), and isometric and isokinetic muscle strength in the dominant lower extremity was assessed using the Biodex System 4 Pro. RESULTS: Mean age was 56 ±5 years, median CD4+ T-cell count 722 cells/mm3 and 74% had HIV RNA≤50 copies/ml. Serum 25-OHD did not differ at baseline, but was higher in the moderate than low VitD group at 6 and 12 months. In both groups, there were significant increases in lower extremity isokinetic torque, work and power at 12 months, with no change in lean mass. CONCLUSIONS: VitD supplementation was associated with a modest increase in lower extremity strength in postmenopausal PLWH, without a concomitant increase in muscle mass. Magnitude of increase in strength were similar with 3,000 IU and 1,000 IU daily. Future larger studies will be required to determine the optimal dose of VitD to improve muscle strength and to determine whether supplementation reduces the risk of falls and fractures in PLWH.

A Randomized Placebo-Controlled Trial of Low- Versus Moderate-Dose Vitamin D3 Supplementation on Bone Mineral Density in Postmenopausal Women With HIV.

BACKGROUND: Prevalence of osteoporosis and fracture is increased among older people with HIV. We compared the effects of low (1000 IU) vs moderate (3000 IU) vitamin D3 (VitD) supplementation on areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) in African American and Hispanic postmenopausal women with HIV on antiretroviral therapy. METHODS: We performed a 12-month prospective, randomized, double-blind, placebo-controlled study with primary outcomes of change in aBMD by dual-energy X-ray absorptiometry (DXA) and secondary outcomes of change in vBMD by quantitative computed tomography and bone turnover markers. An intent-to-treat analysis was performed on 85 randomized subjects (43 low and 42 moderate) for primary DXA outcomes, and complete case analysis was performed for secondary outcomes. RESULTS: Mean age was 56 ± 5 years, median CD4 count was 722 cells/mm, and 74% had HIV RNA ≤ 50 copies/mL. Serum 25-OHD was higher in the moderate than low VitD group at 6 months (33.1 ± 10.3 vs 27.8 ± 8.1 ng/mL, P = 0.03) and 12 months, but parathyroid hormone levels remained similar. Percent change in aBMD, vBMD, and bone turnover markers did not differ between low and moderate VitD groups before or after adjustment for baseline aBMD. CONCLUSIONS: VitD supplementation at 3000 IU daily increased mean total 25-OHD levels in postmenopausal women with HIV, but we did not find evidence of an effect on BMD beyond those observed with 1000 IU daily. Future studies are necessary to determine whether VitD supplementation is beneficial in this patient population, and if so, what dose is optimal for skeletal health.

Women With Pregnancy and Lactation-Associated Osteoporosis (PLO) Have Low Bone Remodeling Rates at the Tissue Level.

Pregnancy and lactation-associated osteoporosis (PLO) is a rare, severe, early form of osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. In studies of idiopathic osteoporosis (IOP) in premenopausal women, we enrolled 78 women with low-trauma fractures and 40 healthy controls, all with normal menses and no secondary cause of bone loss. In 15 of the affected women, the PLO subgroup, fractures had occurred during late pregnancy or lactation. We hypothesized that clinical, bone structural, and metabolic characteristics would differ between women with PLO and those with (non-PLO) IOP and controls. All were evaluated > 12 months postpartum, when structural and remodeling characteristics would be expected to reflect baseline premenopausal status rather than transient postpartum changes. As previously reported, affected subjects (PLO and IOP) had BMD and microarchitectural deficiencies compared to controls. Women with PLO did not differ from those with IOP in terms of age, BMI, body fat, menarcheal age, parity, or age at first pregnancy. However, women with PLO had a more severe clinical presentation than those with IOP: more fractures (5.5 ± 3.3 versus 2.6 ± 2.1; p = 0.005); more vertebral fractures (80% versus 17%; p < 0.001); and higher prevalence of multiple fractures. BMD deficits were more profound and cortical width tended to be lower in PLO. PLO subjects also had significantly lower tissue-level mineral apposition rate and bone formation rates (0.005 ± 0.005 versus 0.011 ± 0.010 mm2 /mm/year; p = 0.006), as well as lower serum P1NP (33 ± 12 versus 44 ± 18 µg/L; p = 0.02) and CTX (257 ± 102 versus 355 ± 193 pg/mL; p = 0.01) than IOP. The finding that women with PLO have a low bone remodeling state assessed more than a year postpartum increases our understanding of the pathogenic mechanism of PLO. We conclude that women with PLO may have underlying osteoblast functional deficits which could affect their therapeutic response to osteoanabolic medications. © 2019 American Society for Bone and Mineral Research.

Determination of triphenylphosphine oxide in active pharmaceutical ingredients by hollow-fiber liquid-phase microextraction followed by reversed-phase liquid chromatography.

A versatile procedure has been developed and validated for the determination of triphenylphosphine oxide (TPPO) at low levels in various active pharmaceutical ingredients (APIs). This procedure incorporates the use of the novel hollow-fiber liquid-phase microextraction (LPME) for the measurement of this potential process-related impurity in aqueous solutions of APIs. A small volume (40 microL) of 1-octanol contained within a hollow polypropylene fiber is used for the extraction of TPPO from low pH aqueous API solutions. More than a 100-fold increase in the TPPO concentration is obtained without additional evaporation of the extract. Experimental parameters of the extraction procedure were investigated to optimize extraction efficiency and minimize sample matrix interference. Using HPLC/UV as the end analysis technique, the procedure was validated for TPPO in the concentration range of 3-16 microg/L with an API present at 1500 mg/L. The versatility of the method was demonstrated by applying the procedure to the analysis of APIs with different molecular structures. This simple LPME procedure is inexpensive and offers appropriate sensitivity for the intended use while providing several advantages over other analysis methods for pharmaceutical samples.

Determination of methyl and ethyl esters of methanesulfonic, benzenesulfonic and p-toluenesulfonic acids in active pharmaceutical ingredients by solid-phase microextraction (SPME) coupled to GC/SIM-MS.

The development, optimization and validation of an extraction method for methyl and ethyl esters of various sulfonic acids is presented. The extraction and determination of these esters in active pharmaceutical ingredients (APIs) was accomplished using solid-phase microextraction coupled to GC/MS in the SIM mode. The factors affecting the extraction efficiency are discussed. This method was validated as a limits test and allows the determination of the sulfonic esters at the 5 ppm level in APIs. The method proved to be reproducible (%R.S.D.s less than 6%) and suitable for use with external standard quantitation, and also met basic validation requirements. This method offers numerous advantages over liquid-liquid extraction methods and was also compared to other extraction techniques such as solid-phase extraction (SPE) and liquid-phase microextraction (LPME) also being developed in our laboratories.

Standardized test mixture for the characterization of comprehensive two-dimensional gas chromatography columns: the Phillips mix.

A novel column characterization test mixture is developed for use in comprehensive two-dimensional gas chromatography (GC x GC). This mixture has been named the "Phillips mix" in honor of the late professor John B. Phillips, the father of GC x GC. The mixture comprises a series of homologous compounds from structural groups that cover a volatility and polarity range that is similar to the Grob mix, and includes saturated hydrocarbons (alkanes), unsaturated hydrocarbons (alkenes and alkynes), carbonyls (ketones and aldehydes), primary alcohols, fatty acid methyl esters, alkyl ethers, carboxylic acids, aromatics, as well as other unique functional groups (such as amines, etc.). Similarly to the Grob mix in conventional one-dimensional GC, the Phillips mix can be used as a standardized test for performance characterization of GC x GC column sets. Unlike the Grob mix, however, the Phillips mix's most important use is as a practical guideline for column users. This paper addresses some qualitative aspects of the use of the Phillips mix through an investigation of the chromatographic fingerprints of two different GC x GC column combinations.

Higher rates of bone loss in postmenopausal HIV-infected women: a longitudinal study.

CONTEXT AND OBJECTIVE: The objective of the study was to assess the effects of HIV infection and antiretroviral therapy on change in bone mineral density (BMD) in postmenopausal minority women. DESIGN, SETTING, AND PATIENTS: We report a longitudinal analysis of change in BMD with a median duration of 15.4 (interquartile range 13.1, 20.7) months in a prospective cohort study of 128 (73 HIV+, 55 HIV-) postmenopausal Hispanic and African-American women. MAIN OUTCOME MEASURES: Annualized change in BMD by dual-energy x-ray absorptiometry and correlation with baseline markers of bone turnover and serum levels of inflammatory cytokines were measured. RESULTS: HIV+ women were younger (56 ± 1 vs. 59 ± 1 yr, P < 0.05) and had lower body mass index (BMI; 28 ± 1 vs. 31 ± 1 kg/m(2), P < 0.01). The majority of HIV+ women were on established antiretroviral therapy for more than 3 yr. At baseline, BMD, adjusted for age, race, and BMI, was lower in HIV+ women at the lumbar spine (LS), total hip, and radius and serum C-telopeptide was higher. Annualized rates of bone loss adjusted for baseline BMD were higher in HIV+ women by 2.4-fold at the LS (-1.2 ± 0.3% vs. -0.5 ± 0.3%, P = 0.0009), 3.7-fold at the one third radius (-1.1 ± 0.2% vs. -0.3 ± 0.2, P = 0.006) and 1.7-fold at the ultradistal radius (-1.2 ± 0.2% vs. -0.7 ± 0.2%, P = 0.02). In multivariate analysis, HIV+ status predicted bone loss at the LS, total hip, and ultradistal radius. Among HIV+ women, lower BMI, higher markers of bone turnover levels, and tenofovir were associated with more bone loss. CONCLUSION: HIV+ postmenopausal minority women had lower BMD, increased bone turnover, and higher rates of bone loss than HIV- women. These features may place these women at increased risk for fracture as they age.

Improving the hardness of dry granulated tablets containing sodium lauryl sulfate.

The impact of the addition of a wetting agent, the surfactant sodium lauryl sulfate (SLS), on the tablet hardness of a dry granulated, solid oral dosage form was investigated. In three batches, SLS was added concurrently with: (1) a poorly soluble, highly hydrophobic active pharmaceutical ingredient (API) and the other excipients prior to the initial blending step, (2) magnesium stearate prior to roller compaction, or (3) magnesium stearate prior to tableting. A fourth batch, which did not contain SLS, served as a control. The maximum hardness of 100 mg, 1/4″-SRC tablets for the four batches--SLS added initially, prior to roller compaction, prior to tableting, and no SLS--were 61±3, 71±3, 89±5, and 86±3N, respectively, suggesting reduced processing of SLS improves tablet hardness by ∼50%. Dissolution of the tablets in 900 ml of simulated gastric fluid with paddles at 75 rpm showed that: (1) there was no impact on the insertion point of SLS into the process on API dissolution, and (2) that the presence of SLS improved dissolution by 5% compared to the control tablets. Adding SLS just prior to tableting can improve tablet hardness and yield similar dissolution performance relative to SLS addition prior to the initial blending step.

Low bone mass and high bone turnover in postmenopausal human immunodeficiency virus-infected women.

CONTEXT: Low bone mineral density (BMD) is commonly reported in young men and women with HIV infection, and fracture rates may be higher. With effective antiretroviral therapy (ART), the HIV population is aging. However, little is known about the skeletal status of postmenopausal women. OBJECTIVE: We aimed to assess the effects of HIV infection and ART on BMD and bone turnover in postmenopausal minority women. DESIGN, SETTING, AND PATIENTS: A prospective cohort study was performed in 92 HIV+ and 95 HIV- postmenopausal Hispanic and African-American women. MAIN OUTCOME MEASURES: We measured BMD by dual-energy x-ray absorptiometry, fracture prevalence, serum levels of inflammatory cytokines (TNFalpha, IL-6), bone turnover markers, calciotropic hormones, and estrone. RESULTS: HIV+ women were younger (56 +/- 1 vs. 60 +/- 1 yr; P < 0.01) and had lower BMI (28 +/- 1 vs. 30 +/- 1 kg/m(2); P < 0.01) and estrone levels. Prevalence of T scores below -1.0 was greater in HIV+ women at the spine (78 vs. 64%; P < 0.05), total hip (45 vs. 29%; P < 0.05), and femoral neck (64 vs. 46%; P < 0.05), and Z scores adjusted for BMI were lower in HIV+ women at the same sites. Serum TNFalpha, N-telopeptide, and C-telopeptide were significantly higher in HIV+ than HIV- women, particularly those receiving ART. HIV+ status was independently and negatively associated with spine and hip BMD after adjustment for age, ethnicity, BMI, and alcohol. CONCLUSION: The lower BMD, higher prevalence of low BMD, and higher levels of bone turnover markers detected in HIV+ postmenopausal minority women could place them at high risk for future fractures.

High-throughput analysis of phthalate esters in human serum by direct immersion SPME followed by isotope dilution-fast GC/MS.

Solid-phase microextraction (SPME) coupled to gas chromatography/mass spectrometry (GC/MS) was applied to the determination of phthalate esters in human serum. The present method decreased the sample preparation time by a factor of 50 by using direct immersion SPME with an 85-microm polyacrylate fiber to extract phthalate esters from the matrix. The use of fast GC/MS further improves total analysis time when compared to other techniques. Isotope dilution was successfully applied to improve the precision, reproducibility, and repeatability of the SPME method. The linear dynamic range spans several orders of magnitude from low ppb to ppm levels, and the LOD for the method is 15 pg microL(-1) on average with RSDs less than 4% for the six phthalate esters included in this study.