Serum-Stable and Selective Backbone-N-Methylated Cyclic Peptides That Inhibit Prokaryotic Glycolytic Mutases.

N-Methylated amino acids (N-MeAAs) are privileged residues of naturally occurring peptides critical to bioactivity. However, de novo discovery from ribosome display is limited by poor incorporation of N-methylated amino acids into the nascent peptide chain attributed to a poor EF-Tu affinity for the N-methyl-aminoacyl-tRNA. By reconfiguring the tRNA's T-stem region to compensate and tune the EF-Tu affinity, we conducted Random nonstandard Peptides Integrated Discovery (RaPID) display of a macrocyclic peptide (MCP) library containing six different N-MeAAs. We have here devised a "pool-and-split" enrichment strategy using the RaPID display and identified N-methylated MCPs against three species of prokaryotic metal-ion-dependent phosphoglycerate mutases. The enriched MCPs reached 57% N-methylation with up to three consecutively incorporated N-MeAAs, rivaling natural products. Potent nanomolar inhibitors ranging in ortholog selectivity, strongly mediated by N-methylation, were identified. Co-crystal structures reveal an architecturally related Ce-2 Ipglycermide active-site metal-ion-coordinating Cys lariat MCP, functionally dependent on two cis N-MeAAs with broadened iPGM species selectivity over the original nematode-selective MCPs. Furthermore, the isolation of a novel metal-ion-independent Staphylococcus aureus iPGM inhibitor utilizing a phosphoglycerate mimetic mechanism illustrates the diversity of possible chemotypes encoded by the N-MeAA MCP library.

Urine methanol concentration and alcohol hangover severity.

BACKGROUND: Congeners are substances, other than ethanol, that are produced during fermentation. Previous research found that the consumption of congener-rich drinks contributes to the severity of alcohol hangover. Methanol is such a congener that has been related to alcohol hangover. Therefore, the aim of this study was to examine the relationship between urine methanol concentration and alcohol hangover severity. METHODS: N = 36 healthy social drinkers (22 females, 14 males), aged 18-30 years old, participated in a naturalistic study, comprising a hangover day and a control day (no alcohol consumed the previous day). N = 18 of them had regular hangovers (the hangover group), while the other N = 18 claimed to be hangover-immune (hangover-immune group). Overall hangover severity was assessed, and that of 23 individual hangover symptoms. Urine methanol concentrations on the hangover and control days were compared, and correlated to hangover (symptom) severity. RESULTS: Urine methanol concentration was significantly higher on hangover days compared to control days (p = 0.0001). No significant differences in urine methanol concentration were found between the hangover group and hangover-immune group. However, urine methanol concentration did not significantly correlate with overall hangover severity (r = -0.011, p = 0.948), nor with any of the individual hangover symptoms. These findings were observed also when analyzing the data separately for the hangover-immune group. In the hangover group, a significant correlation with urine methanol concentration was found only with vomiting (r = 0.489, p = 0.037). CONCLUSION: No significant correlation was observed between urine methanol concentration and hangover severity, nor with individual core hangover symptoms.

Effects of Two Years of Teriparatide, Denosumab, or Both on Bone Microarchitecture and Strength (DATA-HRpQCT study).

CONTEXT: In postmenopausal osteoporosis, combining denosumab and teriparatide increases hip and spine bone mineral density more than either monotherapy. OBJECTIVE: The objective of the study was to determine the effects of 2 years of combination therapy on bone microarchitecture and estimated strength. DESIGN: This was an open-label, randomized controlled trial. PARTICIPANTS AND METHODS: We performed high-resolution peripheral quantitative computed tomography at the distal tibia and radius in 94 postmenopausal osteoporotic women randomized to 2 years of teriparatide 20 µg sc daily, denosumab 60 mg sc every 6 months, or both. RESULTS: Total volumetric bone mineral density (vBMD) at the radius and tibia, trabecular vBMD at the radius, and cortical vBMD at the tibia all increased more in the combination group than both monotherapy groups (P < .002 for all comparisons with combination). Cortical thickness at the tibia also increased more in the combination group (8.1% ± 4.3%) than both other groups (P < .001). Cortical porosity at both the radius and tibia increased progressively over the 24-month treatment period in the teriparatide group but was stable in both other groups (P < .001 teriparatide vs both other groups). Trabecular vBMD at the tibia increased similarly in all groups, whereas radius trabecular vBMD increased more in the combination group than the other groups (P < .01 for both comparisons). Finite element analysis-estimated strength improved or was maintained by all treatments at both the radius and tibia. CONCLUSIONS: Two years of combined teriparatide and denosumab improves bone microarchitecture and estimated strength more than the individual treatments, particularly in cortical bone. These findings suggest that this regimen may be beneficial in postmenopausal osteoporosis.

Endogenous hormones and bone turnover markers in pre- and perimenopausal women: SWAN.

We tested the hypothesis that higher serum osteocalcin and urinary N-telopeptide of type I collagen (NTx) concentrations would be found in women with increasing cycle irregularity or increased follicle stimulating hormone concentrations. We studied 2,375 pre- and early perimenopausal women from the Study of Women's Health Across the Nation (SWAN), aged 42-52 years, who self-identified their race/ethnic origin as African-American (28.3%), Caucasian (49.4%), Japanese (10.5%) or Chinese (11.8%). Outcome measures were serum osteocalcin, a measure of bone formation, and NTx, a measure of bone resorption. The explanatory variables were menopausal status, based on self-reported regularity of menstrual bleeding, and circulating endogenous hormone concentrations including estradiol (E(2)), testosterone (T), sex hormone binding globulin (SHBG) and follicle stimulating hormone (FSH) concentrations. Additionally, we evaluated the association of the bone turnover markers with the Free Androgen Index (FAI) and the Free Estradiol Index (FEI), ratios of total testosterone and estradiol concentrations to SHBG, respectively. Higher FSH concentrations were associated with higher NTx concentrations ( beta=0.003, partial r2=2.1%, p<0.0001), both before and after adjusting for other covariates (total explained variability of 9%). Higher FSH concentrations were also associated with higher osteocalcin concentrations ( beta=-0.216, partial r2=4.1%, p<0.0001, total explained variability of 15.4%). There were no significant associations of the bone turnover markers with other endogenous hormones, following adjustment for covariates. Mean osteocalcin and NTx values were not significantly different in premenopausal women compared to early perimenopausal women. In these pre- and early perimenopausal women, higher FSH concentrations, but not other serum reproductive hormone concentrations, are positively associated with greater bone turnover prior to the last menstrual period.

The association of endogenous hormone concentrations and bone mineral density measures in pre- and perimenopausal women of four ethnic groups: SWAN.

We evaluated bone mineral density (BMD), hormone concentrations and menstrual cycle status to test the hypothesis that greater variations in reproductive hormones and menstrual bleeding patterns in mid-aged women might engender an environment permissive for less bone. We studied 2336 women, aged 42-52 years, from the Study of Women's Health Across the Nation (SWAN) who self-identified as African-American (28.2%), Caucasian (49.9%), Japanese (10.5%) or Chinese (11.4%). Outcome measures were lumbar spine, femoral neck and total hip BMD by dual-energy X-ray densitometry (DXA). Explanatory variables were estradiol, testosterone, sex hormone binding globulin (SHBG) and follicle stimulating hormone (FSH) from serum collected in the early follicular phase of the menstrual cycle or menstrual status [premenopausal (menses in the 3 months prior to study entry without change in regularity) or early perimenopause (menstrual bleeding in the 3 months prior to study entry but some change in the regularity of cycles)]. Total testosterone and estradiol concentrations were indexed to SHBG for the Free Androgen Index (FAI) and the Free Estradiol Index (FEI). Serum logFSH concentrations were inversely correlated with BMD (r = -10 for lumbar spine [95% confidence interval (CI): -0.13, -0.06] and r = -0.08 for femoral neck (95% CI: -0.11, -0.05). Lumbar spine BMD values were approximately 0.5% lower for each successive FSH quartile. There were no significant associations of BMD with serum estradiol, total testosterone, FEI or FAI, respectively, after adjusting for covariates. BMD tended to be lower (p values = 0.009 to 0.06, depending upon the skeletal site) in women classified as perimenopausal versus premenopausal, after adjusting for covariates. Serum FSH but not serum estradiol, testosterone or SHBG were significantly associated with BMD in a multiethnic population of women classified as pre- versus perimenopausal, supporting the hypothesis that alterations in hormone environment are associated with BMD differences prior to the final menstrual period.

Body mass index in mid-life women: relative influence of menopause, hormone use, and ethnicity.

OBJECTIVE: To assess the relative influence of menopausal status and hormone use on body mass index (BMI) among a multiethnic sample of mid-life women. DESIGN: Cross-sectional telephone survey conducted at seven sites where each site targeted an ethnic minority group and Caucasians as part of Study of Women's Health Across the Nation (SWAN). SUBJECTS: A total of 7181 Caucasians, 3949 African-Americans, 1660 Hispanics, 562 Chinese Americans, and 803 Japanese Americans between ages of 40 and 55 y residing in or near Boston, Chicago, Detroit, Los Angeles, Newark, NJ, Oakland, CA, and Pittsburgh, PA. MEASUREMENTS: Self-reported BMI based on weight in kg divided by height in m(2) menopausal status, physical inactivity, postmenopausal hormone use, ethnicity, and age in years. RESULTS: Compared to premenopausal women (covariate adjusted M=27.3), women reporting a surgical menopause (M=28.2) or being in the perimenopausal transition (M=27.7 for early and 27.9 for late perimenopause) had higher BMI. Women reporting a natural menopause (M=27.4) did not have a higher BMI than premenopausal women, after adjusting for chronological age and other covariates. Hormone use was associated with lower BMI (M=26.5 vs 27.3). A comparison of effect sizes showed that menopausal status (F=13.1), followed by chronological age (F=24.0), were the least powerful predictors of BMI, whereas the more powerful predictors were physical activity level (F=1377.1) and ethnicity (F=400.5). CONCLUSIONS: The menopausal transition affects body mass index in mid-life, but the effect is small relative to other influences. Interventions to increase physical activity are highly recommended to prevent increases in adiposity common in mid-life.

Molecular analysis of defect healing in rat diaphyseal bone.

Spatial expression of messenger ribonucleic acid (mRNA) for osteoblastic marker in drill hole defect healing of adult male rats was analyzed by in situ hybridization. The defect was filled with hematoma 3 days after surgery, expressing Type I collagen mRNA. Hematoma was replaced with fibrous tissue on day 7, and then with new trabecular bone on day 10, originated from the intra-medullary space, respectively. mRNA for Type I collagen, parathyroid hormone 1 receptor (PTHIR), and alkaline phosphatase (ALP) were expressed in the same cell population of fibrous tissue adjacent to newly-formed trabecular bone, and in osteoblasts lining the newly-formed trabecular bone. Hematopoietic marrow with osteoclasts subsequently invaded the region, also from the intra-medullary space, replacing all the new trabecular bone by day 21, except for a thin sub-periosteal layer. mRNA for Type I collagen, PTH1R and ALP was expressed on the periosteal surface of thin layer. Although cartilage formation was not histologically visible, mRNA for Type II collagen was weakly detected in the majority of osteoblasts lining the newly-formed trabecular bone.

Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

BACKGROUND: Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. METHODS: We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. RESULTS: New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). CONCLUSIONS: Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

Prevention of estrogen deficiency-related bone loss with human parathyroid hormone-(1-34): a randomized controlled trial.

CONTEXT: Short-term intermittent administration of parathyroid hormone (PTH) prevents bone loss from the spine in women treated with a gonadotropin-releasing hormone (GnRH) analog. However, the effects of a longer period of PTH administration on bone mass in estrogen-deficient women, particularly on the hip and on cortical bone of the total body, are unknown. OBJECTIVE: To determine whether more prolonged PTH administration can prevent estrogen deficiency bone loss from the hip, spine, and total body in young women with endometriosis receiving GnRH analog (nafarelin acetate) therapy. DESIGN: Randomized controlled trial. SETTING: General Clinical Research Center of a tertiary care, university-affiliated hospital. PATIENTS: Forty-three women between the ages of 21 and 45 years with symptomatic endometriosis. INTERVENTION: Nafarelin alone (200 microg intranasally twice daily) or nafarelin plus human parathyroid hormone-(1-34) (hPTH-[1-34]) (40 microg subcutaneously daily). MAIN OUTCOME MEASURES: The primary end points were bone mineral density (BMD) of the anterior-posterior and lateral spine, femoral neck, trochanter, radial shaft, and total body at 12 months of treatment. RESULTS: In the women who received nafarelin alone, the mean (SEM) BMDs of the anterior-posterior spine, lateral spine, femoral neck, trochanter, and total body were 4.9% (0.6%) (P<.001), 4.9% (0.8%) (P<.001), 4.7% (1.1%) (P<.001), 4.3% (0.9%) (P<.001), and 2.0% (0.6%) (P= .003) lower than at baseline after 12 months of therapy. In contrast, coadministration of hPTH-(1-34) increased BMD of the anterior-posterior spine by 2.1% (1.1%) (P=.09) and lateral spine by 7.5% (1.9%) (P=.002) and prevented bone loss from the femoral neck, trochanter, and total body, despite severe estrogen deficiency. Radial shaft BMD did not change significantly in either group. Serum bone-specific alkaline phosphatase and osteocalcin concentrations and urinary excretion of hydroxyproline and deoxypyridinoline increased 2-fold to 3-fold during the first 6 to 9 months of therapy in the women who received nafarelin plus hPTH-(1-34) and then declined. Changes in urinary deoxypyridinolone excretion were strongly predictive (r= 0.85) of changes in spinal BMD in the women who received nafarelin plus hPTH-(1-34). CONCLUSIONS: Parathyroid hormone prevents bone loss from the proximal femur and total body and increases lumbar spinal BMD in young women with GnRH analog-induced estrogen deficiency.

Evaluation of bone mineral density using three-dimensional solid state phosphorus-31 NMR projection imaging.

A solid state magnetic resonance imaging technique is used to measure true three-dimensional mineral density of synthetic hydroxyapatite phantoms and specimens of bone ex vivo. The phosphorus-31 free induction decay at 2.0 T magnetic field strength is sampled following application of a short, hard radiofrequency excitation pulse in the presence of a fixed amplitude magnetic field gradient. Multiple gradient directions covering the unit sphere are used in an efficient spherical polar to Cartesian interpolation and Fourier transform projection reconstruction scheme to image the three-dimensional distribution of phosphorus within the specimen. Using 3-6 Gauss/cm magnetic field gradients, a spatial resolution of 0.2 cm over a field of view of 10 cm is achieved in an imaging time of 20-35 minutes. Comparison of solid state magnetic resonance imaging with dual energy X-ray absorptiometry (DXA), gravimetric analysis, and chemical analysis of calcium and phosphorus demonstrates good quantitative accuracy. Direct measurement of bone mineral by solid state magnetic resonance opens up the possibility of imaging variations in mineral composition as well as density. Advantages of the solid state magnetic resonance technique include avoidance of ionizing radiation; direct measurement of a constituent of the mineral without reliance on assumptions about, or models of, tissue composition; the absence of shielding, beam hardening, or multiple scattering artifacts; and its three-dimensional character. Disadvantages include longer measurement times and lower spatial resolution than DXA and computed tomography, and the inability to scan large areas of the body in a single measurement, although spatial resolution is sufficient to resolve cortical from trabecular bone for the purpose of measuring bone mineral density.

Sequential effects of chronic human PTH (1-84) treatment of estrogen-deficiency osteopenia in the rat.

Although daily injections of parathyroid hormone (PTH) can rapidly reverse estrogen-deficiency bone loss in rats, PTH treatment of osteoporotic humans has to date produced more modest increases in bone mass. To explore the reasons for this important difference, we evaluated the dose- and time-dependence of human PTH 1-84 treatment effects on bone mass and biochemical markers of bone metabolism in rats with estrogen-deficiency bone loss. The highest doses of PTH increased spinal, femoral, and total skeletal mass to supra-normal levels and stimulated cortical endosteal bone formation. Spine and whole skeleton mass and density increased rapidly at first, but then increased more slowly; the rate of change decreased significantly (p < 0.01) during continued treatment with the highest doses of PTH. The effects of PTH treatment on biochemical markers also were both dose-dependent and time-dependent. Serum osteocalcin, a marker of osteoblast function, increased with the highest doses of PTH (p < 0.001), but reached an early plateau and later returned toward baseline. Urinary excretion of pyridinolines, a marker of osteoclast function, increased in a time-dependent fashion throughout treatment (p < 0.001). Serum 1,25(OH)2 vitamin D levels increased in a dose-related fashion, but then decreased toward control levels despite continued treatment. We demonstrate that both osteoblast and osteoclast function are increased during daily PTH therapy in the rat. The pattern of response depends on both the dose of PTH and the duration of therapy. These dose- and time-related effects should be taken into account when designing experimental PTH treatments for osteoporosis, and they deserve intensive study.

A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty.

We have previously demonstrated that men with histories of constitutionally delayed puberty have significantly lower spinal and radial bone mineral density than normal men. Because these men were in their mid-twenties, it is possible that bone density was decreased because bone development was still incomplete. In addition, there is no information on the bone density of the proximal femur, the most important clinical site for osteoporotic fractures, in men with histories of delayed puberty. To address these issues, we performed repeat measurements of radial and spinal bone mineral density 2 yr after the initial evaluations in 18 men with histories of delayed puberty. Bone mineral density of the femoral neck was also measured at the time of follow-up evaluations. The mean radial bone mineral density at the time of the repeat evaluations was similar to the mean value from the initial evaluations (0.74 +/- 0.08 vs. 0.74 +/- 0.07 g/em2) and the mean change was 0.00 +/- 0.04 g/cm2. Similarly, the mean spinal bone mineral density at the time of the repeat evaluations was similar to the mean value from the initial evaluations (1.02 +/- 0.10 vs. 1.01 +/- 0.10 g/cm2) and the mean change was -0.01 +/- 0.04 g/cm2. Bone mineral density of the femoral neck was significantly lower in the men with histories of delayed puberty than in normal men (0.88 +/- 0.11 vs. 0.98 +/- 0.14 g/cm2 P < 0.02). These data indicate that bone accretion is complete by the mid-twenties in men with histories of constitutionally delayed puberty and that their bone mineral density does not improve with time. In addition, these men have decreased bone density of the femoral neck, which might increase their risk for hip fractures when they are older.

Skeletal safety of tiludronate.

The medical uses of bisphosphonates derive from their exceptional ability to inhibit bone resorption. However, bone resorption is essential for the healing of fractures, the repair of microscopic fatigue cracks in bone, nad the internal reorientation of trabecular and cortical bone in response to altered mechanical strains. In theory, overdose with bisphosphonates might interfere with the repair of fractures or weaken bone strength (by forcing bones to accumulate and propagate fatigue cracks or by abolishing the skeleton's adaptive powers). Regulatory agencies (particularly in the USA) have, therefore, set comprehensive and stringent safety criteria before the marketing of bisphosphonates can be approved. Some bisphosphonates can also inhibit bone mineralization, alter hepatic function, or cause gastritis/esophagitis. The safety profile of tiludronate will be described from this perspective, emphasizing the results of prolonged treatment in animals, and studies in humans.

Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency.

BACKGROUND: Analogues of gonadotropin-releasing hormone (GnRH) are often given to induce hypogonadism in women who have estrogen-dependent disorders such as endometriosis and uterine leiomyomas. Because estrogen deficiency causes bone loss, concern about premature osteoporosis has prevented long-term therapy with GnRH analogues. We conducted a study to determine whether parathyroid hormone could prevent bone loss in women receiving therapy with GnRH analogues. METHODS: We administered human parathyroid hormone (40 micrograms subcutaneously daily) to 20 of 40 women with endometriosis who were being treated with nafarelin (200 micrograms intranasally twice daily) for six months; the remaining 20 women received only nafarelin. Cortical and trabecular bone density and biochemical markers of bone turnover were measured every three months during the six-month study period. RESULTS: Serum estradiol concentrations fell to postmenopausal values in 36 of the 40 women. In the women who received nafarelin alone, the mean (+/- SE) bone density in the lumbar spine decreased by 2.8 +/- 0.5 percent (P < 0.001) when measured in the anteroposterior projection and by 3.5 +/- 0.8 percent (P < 0.001) when measured in the lateral projection. In contrast, bone density in the lumbar spine did not change when measured in the anteroposterior projection and increased by 3.4 +/- 1.2 percent when measured in the lateral projection (P = 0.01) in the women who also received parathyroid hormone. Bone density at the femoral neck decreased slightly and similarly in both groups. Radial bone density did not change in either group. Serum alkaline phosphatase and osteocalcin concentrations and urinary hydroxyproline and pyridinoline excretion increased (P < 0.001) in the women who received nafarelin plus parathyroid hormone. CONCLUSIONS: Parathyroid hormone can prevent bone loss in the lumbar spine in young women with estrogen deficiency caused by treatment with GnRH analogues.

Comparison of four methods for cross-calibrating dual-energy X-ray absorptiometers to eliminate systematic errors when upgrading equipment.

Dual-energy x-ray absorptiometry (DXA) is a widely employed technique for making noninvasive measurements of bone mineral density (BMD). Advances in DXA technology have resulted in the development of new densitometers that offer increased scan speed, improved spatial resolution, and the ability to make measurements at additional skeletal sites. However, changing from a first to a second-generation DXA system generates two additional potential sources of error. First, if the densitometers produce results that are substantially different, diagnostic errors occur if the results from both instruments are compared to the same normative database. Second, even if the densitometers produce results that are nearly identical, small systematic errors may influence interpretation of serial bone density measurements in individual patients. To assess the impact of changing from a first- to a second-generation DXA scanner, we made measurements using the standard "pencil beam" mode on 133 consecutive patients using both a Hologic QDR-1000 and a QDR-2000 densitometer when the latter instrument was calibrated according to the manufacturer's routine procedure using a single anthropomorphic spine phantom. We then recalculated the results for the QDR-2000 densitometer using cross-calibration factors based on (1) a regression line generated by scanning three anthropomorphic spine phantoms whose BMD ranged from osteoporotic to high normal on each instrument, (2) an adult human lumbar spine embedded in tissue-equivalent plastic, or (3) a regression line derived from scans of the first 83 patients that was then applied to the last 50 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of lateral versus anterior-posterior spine dual energy x-ray absorptiometry for the diagnosis of osteopenia.

Because bone mineral density (BMD) measurements at various sites differ in the relative amounts of cortical and trabecular bone that they assess, they also differ in their sensitivity for detecting osteopenia. Lateral spine dual energy x-ray absorptiometry (DXA) allows measurement of BMD of the vertebral bodies, which contain mainly trabecular bone, without contribution from the posterior vertebral elements, which are rich in cortical bone. Thus, we hypothesized that lateral spine DXA would detect osteopenia more frequently than anterior-posterior (AP) spine DXA. To assess the ability of DXA to estimate trabecular bone mass, we compared AP and lateral DXA spine measurements with trabecular bone measurements by quantitative computed tomography (QCT) in 58 patients. We then compared AP vs. lateral spine DXA measurements in 1) 300 women referred for routine bone densitometry, 2) 30 glucocorticoid-treated women, and 3) 44 women with vertebral compression fractures. To compare short term reproducibility, we performed repeat AP and lateral DXA scans in 50 women. The association between QCT and DXA measurements was stronger when DXA measurements were made in the lateral (r = 0.784) or midlateral (r = 0.823) projection than in the AP (r = 0.571) projection. The association of BMD with age was stronger when DXA measurements were made in the lateral (r = 0.536) or midlateral (r = 0.536) projection than in the AP (r = 0.382) projection. The declines in BMD with age for AP, lateral, and midlateral DXA measurements were 0.48%, 0.60%, and 0.88%/yr, respectively. In the women referred for routine densitometry, lateral DXA measurements were significantly (P < 0.05) more abnormal than AP measurements compared with those in young women. This was also true in the women treated with glucocorticoids and women with vertebral compression fractures. Lateral DXA often detected osteopenia in patients whose AP DXA was normal. The 95% confidence limits for changes in BMD attributable to measurement error for AP, lateral, and midlateral DXA were 0.027, 0.038, and 0.057 g/cm2, respectively. These results indicate that lateral DXA measurements identify patients with osteopenia more often than AP DXA measurements, probably because lateral DXA more accurately estimates trabecular bone mass. Short term reproducibility of lateral DXA is nearly as good as that for AP DXA.

Accuracy, precision, and utility of spine and whole-skeleton mineral measurements by DXA in rats.

We evaluated the precision and accuracy of dual-energy x-ray bone densitometry (DXA) in 38 male and female rats aged 1-10 months. The coefficients of variation (CV) estimated from same-day paired measurements of bone mineral content (BMC) were 1.26% at the lumbar spine and 0.69% at the whole skeleton, and the corresponding CV for BMC corrected for projected bone area (i.e., bone mineral density, BMD) were 0.57 and 0.66%. BMC, measured in vivo, correlated closely with the subsequently determined ash weights (spine r2 = 0.94, whole-skeleton r2 = 0.97). The long-term CV for BMC measurements, assessed by measuring a frozen animal daily for 4 weeks, were 1.28% for the spine and 1.03% for the whole skeleton; for BMD the corresponding CV were 0.88 and 1.15%. To examine the utility of serial DXA measurements we followed female rats subjected to ovariectomy (OVX) or sham operation at 10 months of age and male rats given daily subcutaneous injections of hPTH-(1-34) or vehicle starting at 10 months of age every 3 weeks for 15 weeks. In the OVX rats a progressive decrease in spine BMC was observed that was most rapid during the first 6 weeks. By 15 weeks the mean spine BMC decreased by 17% in the OVX rats (p < 0.007 versus sham operation). OVX did not affect the accuracy of DXA measurements as assessed by comparison with the ash weight at the end of the 15 week study. PTH treatment increased spine BMC by a mean of 32% and increased whole-skeleton BMC by a mean of 19% within 15 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Intermittent administration of bovine PTH-(1-34) increases serum 1,25-dihydroxyvitamin D concentrations and spinal bone density in senile (23 month) rats.

We examined the effect of intermittent administration of bovine parathyroid hormone (1-34) (bPTH) on spinal bone mineral content (BMC) and bone mineral density (BMD), serum 1,25-dihydroxyvitamin D concentrations, and serum markers of osteoblast function in senile male and female rats (23 and 24 months of age, respectively). Sexually mature young (3 month) male rats were similarly treated for comparison. bPTH administration increased serum osteocalcin concentrations without changing serum inorganic phosphate or calcium concentrations in either group of old animals. In young animals, PTH administration increased the serum calcium and inorganic phosphate concentrations significantly (p less than 0.05), although values remained within the normal range. In the vehicle-treated male rats, serum 1,25-dihydroxyvitamin D concentrations were lower in the senile than in the young animals (18 +/- 5 versus 47 +/- 6 pg/ml, p less than 0.05). PTH administration resulted in significantly increased serum 1,25-dihydroxyvitamin D concentrations in the senile and young male animals (both, p less than 0.05) and the final mean serum 1,25-dihydroxyvitamin D concentrations were not statistically different (68 +/- 9 versus 85 +/- 6 pg/ml respectively; p = NS). Serum 1,25-dihydroxyvitamin D concentrations were significantly (p less than 0.05) higher in the PTH-treated senile female rats than the sex-matched, vehicle-treated controls. The pretreatment spinal BMC and BMD as assessed by dual-energy x-ray absorptiometry (DEXA) were significantly higher in the senile male animals than in the young animals. Spinal BMC and BMD decreased in the vehicle-treated senile male rats (p less than 0.05) over the 3 weeks of the study despite a gain in weight.(ABSTRACT TRUNCATED AT 250 WORDS)