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1.
Osteoporos Int ; 26(5): 1655-60, 2015 May.
Article in English | MEDLINE | ID: mdl-25572049

ABSTRACT

UNLABELLED: Substantial variability exists in the serum 25(OH)D increase observed in response to vitamin D supplementation. Measurement of circulating cholecalciferol and 24,25(OH)2D, as indicators of vitamin D absorption and degradation, respectively, account for approximately half of the variation in serum 25(OH)D observed following supplementation. INTRODUCTION: Vitamin D supplementation produces a variable response in serum 25(OH)D. This variability likely reflects, in part, differences in vitamin D absorption and/or degradation. Despite this variation in response, virtually all expert recommendations endorse a fixed vitamin D supplementation dose, an approach also used in most prospective studies. Such utilization of a single vitamin D dose does not assure attaining any pre-specified target 25(OH)D level, thereby compromising clinical care and prospective supplementation trials. This study begins addressing this weakness by exploring the feasibility of vitamin D metabolite measurements to predict serum 25(OH)D level attained following supplementation. METHODS: Ninety-one community-dwelling postmenopausal women with baseline 25(OH)D of 10-30 ng/mL received oral vitamin D3, 2300 or 2500 IU, daily for 4-6 months. Serum 25(OH)D, cholecalciferol (D3), and 24,25(OH)2D were measured before and at the end of supplementation to determine if metabolite concentrations allow prediction of the 25(OH)D level attained. RESULTS: From baseline and follow-up data, we derived a multiple linear regression model predicting posttreatment 25(OH)D as follows: final 25(OH)D = 8.3 + (1.05*initial 25(OH)D) - (7.7*initial 24,25(OH)2D) + (0.53*final D3) + (4.2*final 24,25(OH)2D). This model has an adjusted R(2) = 0.55, thus accounting for approximately half of the observed variance in the final 25(OH)D level. CONCLUSIONS: The contributions of circulating cholecalciferol and 24,25(OH)2D to this predictive model can be considered as indicators of intestinal absorption and clearance, respectively. This paradigm requires further study; it may allow efficient "treat-to-25(OH)D-target" strategies useful in optimizing prospective studies and clinical practice.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Cholecalciferol/therapeutic use , Dietary Supplements , Osteoporosis, Postmenopausal/drug therapy , 24,25-Dihydroxyvitamin D 3/blood , Aged , Drug Monitoring/methods , Female , Follow-Up Studies , Humans , Middle Aged , Osteoporosis, Postmenopausal/blood , Vitamin D/analogs & derivatives , Vitamin D/blood
2.
J Clin Endocrinol Metab ; 96(4): 981-8, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21289249

ABSTRACT

CONTEXT: Whether ergocalciferol (D(2)) and cholecalciferol (D(3)) are equally effective to increase and maintain serum 25-hydroxyvitamin D [25(OH)D] concentration is controversial. OBJECTIVE: The aim of the study was to evaluate the effect of daily and once monthly dosing of D(2) or D(3) on circulating 25(OH)D and serum and urinary calcium. DESIGN, SETTING AND PARTICIPANTS: In a university clinical research setting, 64 community dwelling adults age 65+ were randomly assigned to receive daily (1,600 IU) or once-monthly (50,000 IU) D(2) or D(3) for 1 yr. MAIN OUTCOME MEASURES: Serum 25(OH)D, serum calcium, and 24-h urinary calcium were measured at months 0, 1, 2, 3, 6, 9, and 12. Serum PTH, bone-specific alkaline phosphatase, and N-telopeptide were measured at months 0, 3, 6, and 12. RESULTS: Serum 25(OH)D was less than 30 ng/ml in 40% of subjects at baseline; after 12 months of vitamin D dosing, levels in 19% of subjects (n = 12, seven receiving daily doses and five monthly doses) remained low, despite compliance of more than 91%. D(2) dosing increased 25(OH)D(2) but produced a decline (P < 0.0001) in 25(OH)D(3). Substantial between-individual variation in 25(OH)D response was observed for both D(2) and D(3). The highest 25(OH)D observed was 72.5 ng/ml. Vitamin D administration did not alter serum calcium, PTH, bone-specific alkaline phosphatase, N-telopeptide, or 24-h urine calcium. CONCLUSIONS: Overall, D(3) is slightly, but significantly, more effective than D(2) to increase serum 25(OH)D. One year of D(2) or D(3) dosing (1,600 IU daily or 50,000 IU monthly) does not produce toxicity, and 25(OH)D levels of less than 30 ng/ml persist in approximately 20% of individuals. Substantial between-individual response to administered vitamin D(2) or D(3) is observed.


Subject(s)
Cholecalciferol/administration & dosage , Ergocalciferols/administration & dosage , Osteoporosis/drug therapy , Aged , Aged, 80 and over , Bone Density Conservation Agents/administration & dosage , Calcium/blood , Calcium/urine , Circadian Rhythm , Dosage Forms , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Humans , Male , Osteoporosis/blood , Osteoporosis/urine , Placebos , Vitamin D/blood
3.
J Clin Endocrinol Metab ; 93(5): 1804-8, 2008 May.
Article in English | MEDLINE | ID: mdl-18319318

ABSTRACT

CONTEXT: Measurement of circulating 25-hydroxy-vitamin D [25(OH)D]) is the accepted clinical indicator of vitamin D status. However, between-laboratory differences in measurement of this analyte exist, which may confound clinical care. OBJECTIVES: We investigated the current agreement of 25(OH)D measurement in clinical laboratories and explored the possibility that simple calibration would improve between-laboratory agreement. DESIGN AND PARTICIPANTS: Serum obtained from healthy volunteers (age 20-60 yr) and one "calibrator," selected to have a 25(OH)D value near 30 ng/ml, were sent for 25(OH)D measurement in four clinical laboratories (laboratories A-D) using HPLC, liquid chromatography tandem mass spectroscopy, and RIA methodologies. MAIN OUTCOME MEASURES: Serum 25(OH)D. Based upon self-report, the laboratory with the lowest interassay percent coefficient of variation was assigned as the reference to which the others were compared using linear regression and Bland-Altman analyses (Analyse-it; Analyse-it Software, Ltd., Leeds, UK). RESULTS: Good correlation was observed for 25(OH)D measurement between laboratory A and laboratories B-D (R(2) = 0.99, 0.81, and 0.95, respectively). Modest between-laboratory variation was noted; the mean bias ranged from 2.9-5.2 ng/ml. Consistent with a systematic offset, each value in laboratory B was higher than in laboratory A, and 89% of values from laboratories B-D were higher than laboratory A. The use of a single calibrator and correction factor reduced mean between-laboratory bias for laboratories B and D. CONCLUSIONS: Measurement of 25(OH)D by clinical laboratories yields similar results. The use of even a single calibrator will improve, but not resolve, between-laboratory variability. Based upon these data, in combination with reported within-individual variability, we recommend that clinicians aim for values greater than 30 ng/ml in their patients.


Subject(s)
Vitamin D/analogs & derivatives , Adult , Calibration , Chromatography, High Pressure Liquid , Female , Humans , Linear Models , Male , Mass Spectrometry , Middle Aged , Vitamin D/blood
4.
J Clin Endocrinol Metab ; 92(6): 2130-5, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17426097

ABSTRACT

CONTEXT: Lack of sun exposure is widely accepted as the primary cause of epidemic low vitamin D status worldwide. However, some individuals with seemingly adequate UV exposure have been reported to have low serum 25-hydroxyvitamin D [25(OH)D] concentration, results that might have been confounded by imprecision of the assays used. OBJECTIVE: The aim was to document the 25(OH)D status of healthy individuals with habitually high sun exposure. SETTING: This study was conducted in a convenience sample of adults in Honolulu, Hawaii (latitude 21 degrees ). PARTICIPANTS: The study population consisted of 93 adults (30 women and 63 men) with a mean (sem) age and body mass index of 24.0 yr (0.7) and 23.6 kg/m(2) (0.4), respectively. Their self-reported sun exposure was 28.9 (1.5) h/wk, yielding a calculated sun exposure index of 11.1 (0.7). MAIN OUTCOME MEASURES: Serum 25(OH)D concentration was measured using a precise HPLC assay. Low vitamin D status was defined as a circulating 25(OH)D concentration less than 30 ng/ml. RESULTS: Mean serum 25(OH)D concentration was 31.6 ng/ml. Using a cutpoint of 30 ng/ml, 51% of this population had low vitamin D status. The highest 25(OH)D concentration was 62 ng/ml. CONCLUSIONS: These data suggest that variable responsiveness to UVB radiation is evident among individuals, causing some to have low vitamin D status despite abundant sun exposure. In addition, because the maximal 25(OH)D concentration produced by natural UV exposure appears to be approximately 60 ng/ml, it seems prudent to use this value as an upper limit when prescribing vitamin D supplementation.


Subject(s)
Skin/metabolism , Sunlight , Vitamin D Deficiency/diagnosis , Vitamin D Deficiency/metabolism , Vitamin D/analogs & derivatives , Cohort Studies , Environmental Exposure , Female , Hawaii , Humans , Male , Middle Aged , Skin/radiation effects , Ultraviolet Rays , Vitamin D/blood
5.
Osteoporos Int ; 17(5): 768-74, 2006.
Article in English | MEDLINE | ID: mdl-16435075

ABSTRACT

INTRODUCTION: Changes in bone mineral density are used to monitor osteoporosis therapy. To determine whether a change in bone mass is clinically significant, the precision of bone mineral density measurements must be known. METHODS: We therefore measured the impact of vertebral body exclusion on dual energy X-ray absorptiometry (DXA) precision. At one university and one Veterans Affairs DXA center, three radiology technologists each scanned 30 participants twice, with repositioning between scans, to estimate DXA precision. Three International Society for Clinical Densitometry-certified physicians reviewed all lumbar spinal scans to note the presence of focal structural defects. We calculated precision for subsets of vertebrae, and for virtual samples of patients with and without physician-identified vertebral focal structural defects. We graphed the reciprocal of least significant change versus bone area to determine the dependence of precision on interpreted scan area. RESULTS: Within each sample, greater interpretable bone area improved precision. The contribution of interpreted bone area to precision differed among the samples, ranging from 57 to 94%. Greater population bone mineral density heterogeneity and presence of focal structural defects each decreased precision. CONCLUSION: All bone densitometry centers must determine precision using a sample representative of their served populations. Failure to do so may lead to incorrect determination of least significant change. Population heterogeneity, vertebral body exclusion and presence of focal structural defects each decreases precision.


Subject(s)
Absorptiometry, Photon/standards , Lumbar Vertebrae/diagnostic imaging , Osteoporosis/diagnostic imaging , Absorptiometry, Photon/methods , Aged , Bone Density , Female , Humans , Lumbar Vertebrae/physiopathology , Male , Middle Aged , Reproducibility of Results , Sensitivity and Specificity
6.
Ann Rheum Dis ; 65(5): 654-61, 2006 May.
Article in English | MEDLINE | ID: mdl-16339289

ABSTRACT

BACKGROUND: Reducing bisphosphonate dosing frequency may improve suboptimal adherence to treatment and therefore therapeutic outcomes in postmenopausal osteoporosis. Once-monthly oral ibandronate has been developed to overcome this problem. OBJECTIVE: To confirm the 1 year results and provide more extensive safety and tolerability information for once-monthly dosing by a 2 year analysis. METHODS: MOBILE, a randomised, phase III, non-inferiority study, compared the efficacy and safety of once-monthly ibandronate with daily ibandronate, which has previously been shown to reduce vertebral fracture risk in comparison with placebo. RESULTS: 1609 postmenopausal women were randomised. Substantial increases in lumbar spine bone mineral density (BMD) were seen in all treatment arms: 5.0%, 5.3%, 5.6%, and 6.6% in the daily and once-monthly groups (50 + 50 mg, 100 mg, and 150 mg), respectively. It was confirmed that all once-monthly regimens were at least as effective as daily treatment, and in addition, 150 mg was found to be better (p<0.001). Substantial increases in proximal femur (total hip, femoral neck, trochanter) BMD were seen; 150 mg produced the most pronounced effect (p<0.05 versus daily treatment). Independent of the regimen, most participants (70.5-93.5%) achieved increases above baseline in lumbar spine or total hip BMD, or both. Pronounced decreases in the biochemical marker of bone resorption, sCTX, observed in all arms after 3 months, were maintained throughout. The 150 mg regimen consistently produced greater increases in BMD and sCTX suppression than the 100 mg and daily regimens. Ibandronate was well tolerated, with a similar incidence of adverse events across groups. CONCLUSIONS: Once-monthly oral ibandronate is at least as effective and well tolerated as daily treatment. Once-monthly administration may be more convenient for patients and improve therapeutic adherence, thereby optimising outcomes.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Diphosphonates/therapeutic use , Osteoporosis, Postmenopausal/drug therapy , Administration, Oral , Aged , Aged, 80 and over , Bone Density/drug effects , Bone Density Conservation Agents/adverse effects , Diphosphonates/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Femur/physiopathology , Hip Joint/physiopathology , Humans , Ibandronic Acid , Lumbar Vertebrae/physiopathology , Middle Aged , Osteoporosis, Postmenopausal/physiopathology , Treatment Outcome
7.
Osteoporos Int ; 16(12): 1513-8, 2005 Dec.
Article in English | MEDLINE | ID: mdl-15834512

ABSTRACT

Although many vertebral fractures are clinically silent, they are associated with increased risk for subsequent osteoporotic fractures. A substantial number of these fractures are demonstrable using instant vertebral assessment with Hologic densitometers. Whether similar recognition is possible using dual-energy lateral vertebral assessment (LVA) with GE Lunar densitometers remains uncertain. Thus, we evaluated the ability of clinicians using LVA to detect prevalent vertebral fractures. Dual-energy LVA and conventional thoracic and lumbar spine radiographs were concurrently obtained in 80 postmenopausal women. Using an established visual semiquantitative system, vertebral fractures were identified individually by two non-radiologist clinicians on LVA images, and the results were compared with spinal radiograph evaluation by an expert radiologist. Using LVA, 95% of vertebral bodies from T7 through L4 were evaluable, but a majority (66%) of vertebrae from T4 to T6 were not adequately visualized. In the LVA-evaluable vertebrae, prevalent fractures were identified in 40 vertebral bodies by radiography. In this regard, the clinicians using LVA detected 17 of 18 radiographically evident vertebral fractures of grade 2 or 3, a false negative rate of 6%. They identified 50% (11/22) of grade 1 fractures. Additionally, the vast majority of evaluable non-fractured vertebrae, (764/794, 96.2%) were correctly classified as normal by LVA. Thus, clinicians utilizing LVA correctly identified the vast majority of grade 2 or 3 vertebral compression fractures and normal vertebral bodies, although detection of grade 1 fractures was less effective. In conclusion, the low-radiation, dual-energy LVA technique provides a rapid and convenient way for clinicians to identify patients with, and without, grade 2 or 3 vertebral fractures, thereby enhancing care of osteoporotic patients.


Subject(s)
Spinal Fractures/diagnosis , Spine/pathology , Aged , Aged, 80 and over , Densitometry/methods , Female , Humans , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/pathology , Middle Aged , Osteoporosis, Postmenopausal/complications , Osteoporosis, Postmenopausal/diagnostic imaging , Radiography , Spinal Fractures/diagnostic imaging , Spinal Fractures/etiology , Spine/diagnostic imaging , Thoracic Vertebrae/diagnostic imaging , Thoracic Vertebrae/pathology
8.
J Clin Endocrinol Metab ; 89(7): 3152-7, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15240586

ABSTRACT

Endemic hypovitaminosis D contributes to osteoporosis development. However, variation in 25-hydroxyvitamin D (25OHD) measurement is reported and confounds the diagnosis of vitamin D insufficiency/deficiency. This report emphasizes the marked variability observed in serum 25OHD measurements between laboratories.Initially, postmenopausal women had serum 25OHD determinations: 42 in laboratory A, 20 in laboratory B. Their mean (sem) serum 25OHD concentrations were 46 (2.1) and 21 (2.3) ng/ml in laboratories A and B, respectively. Furthermore, there was little overlap in serum 25OHD among these clinically similar individuals. Specifically, 17% of those measured in laboratory A but 90% in laboratory B were below an arbitrary threshold value of 32 ng/ml.Subsequently, serum was obtained from 10 healthy adults. Two aliquots from each individual, one of which was spiked with 20 ng/ml 25OHD, were sent to six laboratories. Substantial variability was noted between these six laboratories. The mean serum 25OHD concentration ranged from 17.1-35.6 ng/ml. Similarly, the mean increase produced by spiking with 20 ng/ml ranged from 7.7-18.0 ng/ml.In conclusion, 25OHD assays yield markedly differing results; whether an individual is found to have low or normal vitamin D status is a function of the laboratory used. If the medical community is to make progress in correcting widespread hypovitaminosis D, 25OHD measurement must be standardized.


Subject(s)
Hematologic Tests/standards , Vitamin D Deficiency/blood , Vitamin D Deficiency/diagnosis , Vitamin D/analogs & derivatives , Aged , Aged, 80 and over , Clinical Laboratory Techniques/standards , Female , Humans , Middle Aged , Osmolar Concentration , Reference Standards , Reproducibility of Results , Vitamin D/blood
9.
Bone ; 34(2): 303-19, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14962809

ABSTRACT

Matrix extracellular phosphoglycoprotein (MEPE) is expressed exclusively in osteoblasts, osteocytes and odontoblasts with markedly elevated expression found in X-linked hypophosphatemic rickets (Hyp) osteoblasts and in oncogenic hypophosphatemic osteomalacia (OHO) tumors. Because these syndromes are associated with abnormalities in mineralization and renal phosphate excretion, we examined the effects of insect-expressed full-length human-MEPE (Hu-MEPE) on serum and urinary phosphate in vivo, (33)PO(4) uptake in renal proximal tubule cultures and mineralization of osteoblast cultures. Dose-dependent hypophosphatemia and hyperphosphaturia occurred in mice following intraperitoneal (IP) administration of Hu-MEPE (up to 400 microg kg(-1) 31 h(-1)), similar to mice given the phosphaturic hormone PTH (80 microg kg(-1) 31 h(-1)). Also the fractional excretion of phosphate (FEP) was stimulated by MEPE [65.0% (P < 0.001)] and PTH groups [53.3% (P < 0.001)] relative to the vehicle group [28.7% (SEM 3.97)]. In addition, Hu-MEPE significantly inhibited (33)PO(4) uptake in primary human proximal tubule renal cells (RPTEC) and a human renal cell line (Hu-CL8) in vitro (V(max) 53.4% inhibition; K(m) 27.4 ng/ml, and V(max) 9.1% inhibition; K(m) 23.8 ng/ml, respectively). Moreover, Hu-MEPE dose dependently (50-800 ng/ml) inhibited BMP2-mediated mineralization of a murine osteoblast cell line (2T3) in vitro. Inhibition of mineralization was localized to a small (2 kDa) cathepsin B released carboxy-terminal MEPE peptide (protease-resistant) containing the acidic serine-aspartate-rich motif (ASARM peptide). We conclude that MEPE promotes renal phosphate excretion and modulates mineralization.


Subject(s)
Extracellular Matrix Proteins/pharmacology , Glycoproteins/pharmacology , Osteogenesis/physiology , Phosphates/metabolism , Phosphoproteins/pharmacology , Amino Acid Sequence , Animals , Blotting, Western , Cells, Cultured , Dose-Response Relationship, Drug , Electrophoresis, Polyacrylamide Gel , Humans , Kidney Tubules/drug effects , Kidney Tubules/metabolism , Mice , Molecular Sequence Data , Osteoblasts/drug effects , Osteogenesis/drug effects , Parathyroid Hormone/pharmacology , Recombinant Proteins/pharmacology , Sequence Homology, Amino Acid
10.
Calcif Tissue Int ; 71(2): 112-20, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12200644

ABSTRACT

Many studies have been done involving exercise, impact loading, and the effect on BMD. In some of these studies, particularly those involving outpatient activity, compliance and the specific parameters of an individual's impact loading have been difficult to monitor effectively. In this study, an individual, home-use platform was used to record daily, specific, and reproducible impact forces generated during a heel drop exercise. At three centers over 24 months, we conducted a randomized, prospective study of 157 osteoporotic and osteopenic women, aged 60-85 years. A total of 99 patients used the home Osteocare device (OrthoGenesis Incorporated, Northborough, Massachusetts USA) to generate a reproducible and specific daily impact program (active group). Controls (32) performed a similar motion on the unit but without trying to trigger an impact force (sham group), and 26 patients did no prescribed heel drop exercise (control group). All groups had the same calcium and vitamin D supplementation. Hip DXA was performed at baseline and every 6 months during the entire study duration. Compliance with the 3-5 min routine was high, and patients were able to consistently achieve the specific targeted impact range. Pooled BMD results showed no significant differences between groups in overall BMD measurements. However, a classification model that looked at individual site-specific BMD changes showed that more than 75% of the active group responded (versus 62% for both the sham and the control groups) by maintaining or increasing site-specific hip BMD over the 2-year trial. In fact, at the end of the study, 45% of the actives were gainers versus 12% and 22% in the sham and control groups, respectively. This study suggests that hip BMD may be maintained through a brief, safe, at-home, monitored impact loading program.


Subject(s)
Bone Diseases, Metabolic/therapy , Exercise Therapy , Hip Joint/physiology , Osteoporosis, Postmenopausal/therapy , Postmenopause/physiology , Absorptiometry, Photon , Aged , Aged, 80 and over , Bone Density , Bone Diseases, Metabolic/metabolism , Female , Femur/diagnostic imaging , Femur/metabolism , Humans , Middle Aged , Osteoporosis, Postmenopausal/metabolism , Patient Compliance , Treatment Outcome , Weight-Bearing/physiology
11.
J Bone Miner Res ; 17(2): 311-20, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11811562

ABSTRACT

PHEX, a phosphate-regulating gene with homologies to endopeptidases on the X chromosome, is mutated in X-linked hypophosphatemia (XLH) in humans and mice (Hyp). Although recent observations indicate that Phex protein is expressed primarily in bone and may play an important role in osteoblast function and bone mineralization, the pattern of the Phex protein expression in the developing skeleton and its subcellular localization in osteoblasts remain unknown. We examined the ontogeny of the Phex protein in the developing mouse embryo and its subcellular localization in osteoblasts using a specific antibody to the protein. Immunohistochemical staining of mouse embryos revealed expression of Phex in osteogenic precursors in developing vertebral bodies and developing long bones on day 16 postcoitum (pc) and thereafter. Calvaria from day 18 pc mice showed Phex epitopes in osteoblasts. No Phex immunoreactivity was detected in lung, heart, hepatocytes, kidney, intestine, skeletal muscle, or adipose tissue of mouse embryos. Interestingly, embryonic mouse skin showed moderate amounts of Phex immunostaining. In postnatal mice, Phex expression was observed in osteoblasts and osteocytes. Moderate expression of Phex was seen in odontoblasts and slight immunoreactivity was observed in ameloblasts. Confocal microscopy revealed the presence of immunoreactive PHEX protein in the Golgi apparatus and endoplasmic reticulum of osteoblasts from normal mice and in osteoblasts from Hyp mice transduced with a human PHEX viral expression vector. PHEX protein was not detected in untransduced Hyp osteoblasts. These data indicate that Phex protein is expressed in osteoblasts and osteocytes during the embryonic and postnatal periods and that within bone, Phex may be a unique marker for cells of the osteoblast/osteocyte lineage.


Subject(s)
Gene Expression Regulation, Developmental , Osteoblasts/metabolism , Proteins/metabolism , Amino Acid Sequence , Animals , Animals, Newborn , Endoplasmic Reticulum/metabolism , Female , Golgi Apparatus/metabolism , Growth Plate/metabolism , Humans , Hypophosphatemia, Familial/genetics , Hypophosphatemia, Familial/physiopathology , Mice , Mice, Inbred Strains , Molecular Sequence Data , PHEX Phosphate Regulating Neutral Endopeptidase , Proteins/genetics , Proteins/immunology , Skin/embryology , Skin/metabolism , Skull/embryology , Skull/metabolism
13.
Obes Res ; 9(9): 544-51, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11557835

ABSTRACT

OBJECTIVE: On the basis of the clinical observations that bupropion facilitated weight loss, we investigated the efficacy and tolerability of this drug in overweight and obese adult women. RESEARCH METHODS AND PROCEDURES: A total of 50 overweight and obese (body mass index: 28.0 to 52.6 kg/m(2)) women were included. The core component of the study was a randomized, double-blind, placebo-controlled comparison for 8 weeks. Bupropion or placebo was started at 100 mg/d with gradual dose increase to a maximum of 200 mg twice daily. All subjects were prescribed a 1600 kcal/d balanced diet and compliance was monitored with food diaries. Responders continued the same treatment in a double-blind manner for an additional 16 weeks to a total of 24 weeks. There was additional single-blind follow-up treatment for a total of 2 years. RESULTS: Subjects receiving bupropion achieved greater mean weight loss (last-observation-carried-forward analysis) over the first 8 weeks of the study (p = 0.0001): 4.9% +/- 3.4% (n = 25) for bupropion treatment compared with 1.3% +/- 2.4% (n = 25) for placebo treatment. For those who completed the 8 weeks, the comparison was 6.2% +/- 3.1% (n = 18) vs. 1.6% +/- 2.9% (n = 13), respectively(p = 0.0002), with 12 of 18 of the bupropion subjects (67%) losing over 5% of baseline body weight compared with 2 of 13 in the placebo group (15%; p = 0.0094). In the continuation phase, 14 bupropion responders who completed 24 weeks achieved weight loss of 12.9% +/- 5.6% with fat accounting for 73.5% +/- 3.7% of the weight lost and no change in bone mineral density as assessed by DXA. Bupropion was generally well-tolerated in this sample. DISCUSSION: Bupropion was more effective than placebo in achieving weight loss at 8 weeks in overweight and obese adult women in this preliminary study. Initial responders to bupropion benefited further in the continuation phase.


Subject(s)
Anti-Obesity Agents/therapeutic use , Bupropion/therapeutic use , Dopamine Uptake Inhibitors/therapeutic use , Obesity/drug therapy , Adult , Anti-Obesity Agents/adverse effects , Bupropion/adverse effects , Dopamine Uptake Inhibitors/adverse effects , Double-Blind Method , Drug Administration Schedule , Energy Intake , Female , Follow-Up Studies , Humans , Middle Aged , Treatment Outcome , Weight Loss
14.
Metabolism ; 50(8): 912-5, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11474478

ABSTRACT

Idiopathic osteoporosis in men is an increasingly recognized disorder accounting for up to 200,000 hip fractures worldwide each year. Although there is no widely accepted or proven efficacious treatment for men with idiopathic osteoporosis, we attempted to examine the effectiveness of alendronate in this disorder. We retrospectively compared the clinical records of male patients with osteopenia (hip or spine T scores less than -1.0, with or without low-trauma fractures) treated either with alendronate 10 mg orally/day and calcium and vitamin D replacement versus conservative treatment with calcium and vitamin D alone. Review included analysis of laboratory studies and bone turnover markers in a subset of patients. We documented bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) and repeated BMD after an average follow-up of 1.9 and 2.7 years in the alendronate-treated and conservative treatment groups, respectively. At baseline, conservatively-treated and alendronate-treated patients had similar BMD at the lumbar spine and hip. Over the period of observation, the conservatively-treated patients exhibited insignificant changes in BMD at all measured sites. In contrast, alendronate treatment resulted in a significant increase in BMD of the spine (+4.6%, P =.002), trochanter (+6.4%, P =.002), and total hip (+4.7%, P =.002). Indeed, compared with conservative treatment, alendronate-treated patients sustained a significant annualized percent increment of the BMD in the spine (2.7 +/- 0.6 v 1.1 +/- 0.3, P =.025), trochanter (4.7 +/- 1.7 v 0.7 +/- 0.6, P =.025), and total hip BMD (3.3 +/- 0.9 v 0.1 +/- 0.4, P =.0009). These data are among the first that illustrate the potential efficacy of alendronate in the management of idiopathic osteoporosis in men.


Subject(s)
Alendronate/pharmacology , Bone Density/drug effects , Osteoporosis/physiopathology , Absorptiometry, Photon , Alendronate/therapeutic use , Humans , Male , Middle Aged , Osteoporosis/diagnostic imaging , Osteoporosis/drug therapy
16.
Kidney Int ; 57(1): 9-18, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10620182

ABSTRACT

PHEX gene and hypophosphatemia. X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) are diseases that have in common abnormal proximal renal tubular function resulting in increased renal clearance of inorganic phosphorus and hypophosphatemia. The recent discovery of the PHEX gene has provided new insights to these disorders. In this regard, identification of the PHEX gene product as a membrane-bound endopeptidase suggests that the pathophysiologic cascade underlying XLH likely involves inactivation mutations of the gene causing a failure to clear an active hormone, phosphatonin, from the circulation. The presence of this hormone through unknown mechanisms decreases the sodium-dependent phosphate cotransporter in the kidney, resulting in impaired phosphate transport. In contrast, TIO likely evolves secondary to tumor overproduction of the putative phosphatonin, which exerts physiologic function despite efforts to counteract the resultant hypophosphatemia with overproduction of PHEX transcripts that are insufficient to accommodate the enhanced substrate load. These potential pathophysiologic mechanisms for XLH and TIO provide valuable inroads to understanding phosphate homeostasis, as well as vitamin D metabolism, bone mineralization, and calcium metabolism.


Subject(s)
Hypophosphatemia/genetics , Proteins/genetics , Humans , PHEX Phosphate Regulating Neutral Endopeptidase , Phenotype
18.
J Bone Miner Res ; 14(12): 2027-35, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10620061

ABSTRACT

The mechanism by which inactivating mutations of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) cause X-linked hypophosphatemia remains unknown. However, recent reports suggest errant PHEX activity in osteoblasts may fail to inactivate a phosphaturic factor produced by these cells. To test this possibility, we examined coordinated maturational expression of PHEX and production of phosphate transport inhibitory activity in osteoblasts from normal and hyp-mice. We assessed the inhibitory activity in conditioned medium by examining the effects on opossum kidney cell phosphate transport and osteoblast PHEX expression by reverse transcriptase-polymerase chain reaction during a 17-day maturational period. Inhibitory activity increased as a function of osteoblast maturational stage, with no activity after 3 days and persistent activity by 6 days of culture. More significantly, equal phosphate transport inhibitory activity in conditioned medium from normal and hyp-mouse osteoblasts (control 1.90 +/- 0.12, normal 1.48 +/- 0.10, hyp 1.45 +/- 0.04 nmol/mg of protein/minute) was observed at 6 days. However, by 10 days hyp-mouse osteoblasts exhibited greater inhibitory activity than controls, and by 17 days the difference in phosphate transport inhibition maximized (control 2.08 +/- 0.09, normal 1.88 +/- 0.06, hyp 1.58 +/- 0.06 nmol/mg of protein/minute). Concurrently, we observed absent PHEX expression in normal osteoblasts after 3 days, limited production at 6 days, and significant production by day 10 of culture, while hyp-mouse osteoblasts exhibited limited PHEX activity secondary to an inactivating mutation. The data suggest that the presence of inactivating PHEX mutations results in the enhanced renal phosphate transport inhibitory activity exhibited by hyp-mouse osteoblasts.


Subject(s)
Carrier Proteins/antagonists & inhibitors , Proteins/genetics , Symporters , Animals , Biological Transport , Cell Line , Culture Media, Conditioned , Disease Models, Animal , Gene Expression Regulation , Hypophosphatemia/genetics , Kidney , Mice , Mice, Transgenic , Mutation , Opossums , Osteoblasts , PHEX Phosphate Regulating Neutral Endopeptidase , Phenotype , Phosphates/metabolism , Protein Biosynthesis , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Sodium-Phosphate Cotransporter Proteins
20.
Am J Physiol ; 275(4): E700-8, 1998 10.
Article in English | MEDLINE | ID: mdl-9755091

ABSTRACT

X-linked hypophosphatemia (XLH) is caused by inactivating mutations of PEX, an endopeptidase of uncertain function. This defect is shared by Hyp mice, the murine homologue of the human disease, in which a 3' Pex deletion has been documented. In the present study, we report that immortalized osteoblasts derived from the simian virus 40 (SV40) transgenic Hyp mouse (TMOb-Hyp) have an impaired capacity to mineralize extracellular matrix in vitro. Compared with immortalized osteoblasts from the SV40 transgenic normal mouse (TMOb-Nl), osteoblast cultures from the SV40 Hyp mouse exhibit diminished 45Ca accumulation into extracellular matrix (37 +/- 6 vs. 1,484 +/- 68 counts . min-1 . microgram protein-1) and reduced formation of mineralization nodules. Moreover, in coculture experiments, we found evidence that osteoblasts from the SV40 Hyp mouse produce a diffusible factor that blocks mineralization of extracellular matrix in normal osteoblasts. Our findings indicate that abnormal PEX in osteoblasts is associated with the accumulation of a factor(s) that inhibits mineralization of extracellular matrix in vitro.


Subject(s)
Calcification, Physiologic/physiology , Extracellular Matrix/physiology , Osteoblasts/physiology , Alkaline Phosphatase/analysis , Animals , Cell Division , Cell Line, Transformed , Cells, Cultured , Heterozygote , Humans , Hypophosphatemia/genetics , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Mice, Transgenic , Osteoblasts/cytology , Reverse Transcriptase Polymerase Chain Reaction , Simian virus 40/genetics
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