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Weber, Thomas Joseph

Overview:

Osteoporosis, with current studies that focus on advances in diagnosis and natural history of male and postmenopausal osteoporosis. The study on male osteoporosis include a collaborative study with outside investigators is examining the utility of lateral spine bone densitometry in identifying men with osteoporosis and low trauma fractures.

Hypophosphatemic disorders, including X-link hypophosphatemic rickets and tumor-induced osteomalacia. My ongoing research study, in collaboration with Dr. L Darryl Quarles at the University of Kansas, seeks to further confirm and extend our understanding of the role of FGF-23 in human disorders of phosphate homeostasis, including patients with chronic kidney disease. Pending studies include primary and sub-investigator directed Phase 1 / 2 first in human studies examining the effects of a monoclonal antibody and enzyme replacement therapy for X-linked hypophosphatemic rickets and hypophosphatasia, respectively.

Positions:

Associate Professor of Medicine

Medicine, Endocrinology, Metabolism, and Nutrition
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1989

M.D. — University of Chicago

Medical Resident, Medicine

Yale University

Instructor, Medicine

Yale University

Fellow In Endocrinology, Medicine

Duke University

Grants:

Endocrinology and Metabolism Training Program

Administered By
Medicine, Endocrinology, Metabolism, and Nutrition
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2014
End Date
June 30, 2019

UX023-CL303 XLH Study

Administered By
Duke Clinical Research Institute
AwardedBy
Ultragenyx Pharmaceutical
Role
Principal Investigator
Start Date
September 15, 2015
End Date
December 31, 2018

UX023-CL203 Adult Extension Study

Administered By
Duke Clinical Research Institute
AwardedBy
Ultragenyx Pharmaceutical
Role
Principal Investigator
Start Date
March 15, 2015
End Date
June 30, 2018

UX023T-CL201 TIO Study

Administered By
Duke Clinical Research Institute
AwardedBy
Ultragenyx Pharmaceutical
Role
Principal Investigator
Start Date
July 15, 2015
End Date
March 31, 2018

An integrated and diverse genomic medicine program for undiagnosed diseases

Administered By
Pediatrics, Medical Genetics
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 01, 2014
End Date
March 31, 2018

UX023-CL304 XLH Study

Administered By
Duke Clinical Research Institute
AwardedBy
Ultragenyx Pharmaceutical
Role
Principal Investigator
Start Date
November 01, 2015
End Date
April 30, 2017

HIV and Asthma in the Post- ART Era

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
September 13, 2014
End Date
August 31, 2016

Clinically vs. pathologically negative lymph nodes in patients with papillary thyroid cancer

Administered By
Surgery, Advanced Oncologic and Gastrointestinal Surgery
AwardedBy
Endocrine Fellows Foundation
Role
Mentor
Start Date
May 01, 2015
End Date
April 30, 2016
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Publications:

Impaired calcium sensing distinguishes primary hyperparathyroidism (PHPT) patients with low bone mineral density.

A subset of PHPT patients exhibit a more severe disease phenotype characterized by bone loss, fractures, recurrent nephrolithiasis, and other dysfunctions, but the underlying reasons for this disparity in clinical presentation remain unknown.We sought to identify new mechanistic indices that could inform more personalized management of PHPT.Pre-, peri-, and postoperative data and demographic, clinical, and pathological information from patients undergoing parathyroidectomy for PHPT were collected. Univariate and partial Spearman correlation was used to estimate the association of parathyroid tumor calcium sensing capacity with select variables.An unselected series of 237 patients aged >18years and undergoing parathyroidectomy for PHPT were enrolled.Calcium sensing capacity, expressed as the concentration required for half-maximal biochemical response (EC50), was evaluated in parathyroid tumors from an unselected series of 74 patients and assessed for association with clinical parameters. The hypothesis was that greater disease severity would be associated with attenuated calcium sensitivity and biochemically autonomous parathyroid tumor behavior.Parathyroid tumors segregated into two distinct groups of calcium responsiveness (EC50<3.0 and ≥3.0mM). The low EC50 group (n=27) demonstrated a mean calcium EC50 value of 2.49mM [95% confidence interval (CI): 2.43-2.54mM], consistent with reference normal activity. In contrast, the high EC50 group (n=47) displayed attenuated calcium sensitivity with a mean EC50 value of 3.48mM [95% CI: 3.41-3.55mM]. Retrospective analysis of the clinical registry data suggested that high calcium EC50 patients presented with a more significant preoperative bone mineral density (BMD) deficit with a t-score of -2.7, (95% CI: -3.4 to -1.9) versus 0.9, (95% CI: -2.1 to -0.4) in low EC50 patients (p<0.001). After adjusting for gender, age, BMI, 25 OH vitamin D level and preoperative iPTH, lowest t-score and calcium EC50 were inversely correlated, with a partial Spearman correlation coefficient of -0.35 (p=0.02).Impaired calcium sensing in parathyroid tumors is selectively observed in a subset of patients with more severe bone mineral density deficit. Assessment of parathyroid tumor biochemical behavior may be a useful predictor of disease severity as measured by bone mineral density in patients with PHPT.

Authors
Weber, TJ; Koh, J; Thomas, SM; Hogue, JA; Scheri, RP; Roman, SA; Sosa, JA
MLA Citation
Weber, TJ, Koh, J, Thomas, SM, Hogue, JA, Scheri, RP, Roman, SA, and Sosa, JA. "Impaired calcium sensing distinguishes primary hyperparathyroidism (PHPT) patients with low bone mineral density." Metabolism: clinical and experimental 74 (September 2017): 22-31.
PMID
28764845
Source
epmc
Published In
Metabolism
Volume
74
Publish Date
2017
Start Page
22
End Page
31
DOI
10.1016/j.metabol.2017.06.004

Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is characterized by lower extremity deformities that lead to bone and/or joint pain that result from decreased renal tubular reabsorption leading to hypophosphatemia caused by elevated levels of fibroblast growth factor 23 (FGF23).Validate the use of SF-36v2 Health Survey (SF-36v2) and the Western Ontario and McMaster Osteoarthritis Index (WOMAC) to measure previously unstudied health-related quality of life (HRQoL) in XLH patients and determine the change in HRQoL before and after treatment with KRN23, a human monoclonal anti-FGF23 antibody.Twenty-eight adult outpatients with XLH received up to four doses of KRN23 administered subcutaneously every 28 days. General HRQoL was measured with the SF-36v2 and condition-related HRQoL with the WOMAC at baseline and study endpoint as a secondary outcome of a Phase 1/2, open-label, multicenter, dose-escalation trial.Testing for scale discriminant validity and convergent-divergent validity supported the use of these scales in the assessment of HRQoL in XLH. Both instruments indicated impairment of physical function at baseline with all mean scores showing a trend to improved health at study endpoint compared to baseline. When corrected for multiple comparisons, the score for Role Limitations due to physical health on the SF-36v2 which measures the patient's perception of their own chronic functional impairments due to poor physical health remained significantly improved (P < 0.05), increasing to the mean score of US adults. For the WOMAC, Physical Functioning and Stiffness scores were significantly improved (P < 0.05).KRN23 administration was associated with significantly improved patient perception of their Physical Functioning and Stiffness due to their disease. This study demonstrates that the SF-36v2 and WOMAC are valid tools for assessing HRQoL in XLH.

Authors
Ruppe, MD; Zhang, X; Imel, EA; Weber, TJ; Klausner, MA; Ito, T; Vergeire, M; Humphrey, JS; Glorieux, FH; Portale, AA; Insogna, K; Peacock, M; Carpenter, TO
MLA Citation
Ruppe, MD, Zhang, X, Imel, EA, Weber, TJ, Klausner, MA, Ito, T, Vergeire, M, Humphrey, JS, Glorieux, FH, Portale, AA, Insogna, K, Peacock, M, and Carpenter, TO. "Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia." Bone reports 5 (December 2016): 158-162.
PMID
28326356
Source
epmc
Published In
Bone Reports
Volume
5
Publish Date
2016
Start Page
158
End Page
162
DOI
10.1016/j.bonr.2016.05.004

Case series: Odontohypophosphatasia or missed diagnosis of childhood/adult-onset hypophosphatasia? - Call for a long-term follow-up of premature loss of primary teeth.

Hypophosphatasia, a metabolic bone disease caused by a tissue-nonspecific alkaline phosphatase deficiency, leads to undermineralization of bone and/or teeth, impaired vitamin B6 metabolism, and a spectrum of disease presentation. At the mild end of the spectrum, it presents as pathologic fractures in later adulthood. Patients with isolated dental manifestations, typically presenting as premature loss of primary teeth, are classified as having odontohypophosphatasia (odontoHPP). A subset of patients diagnosed with odontoHPP in childhood can later develop extra-dental manifestations that constitute childhood- or adult-onset hypophosphatasia.Retrospective data related to onset, detailed clinical course, and method of diagnosis were collected as part of a natural history of adult patients with hypophosphatasia. Of 9 initial patients, all had low serum alkaline phosphatase levels for their age and gender at adult presentation (Table 2). The majority (8/9) demonstrated childhood dental signs of hypophosphatasia as the initial clinical manifestation: premature loss of primary teeth (7/9), absent primary teeth (1/9), and delayed loss of primary teeth (1/9). Despite childhood dental presentation and/or other signs/symptoms, diagnosis of hypophosphatasia was delayed 20-54 years (median = 46) since the primary tooth problems and 8-45 years (median = 27) since the first fracture or onset of a major adult tooth problem.Patients with primary tooth loss in childhood were often diagnosed with hypophosphatasia later in life. Pediatric patients classified as having odontoHPP under present practice can manifest significant disease burden later in life.

Authors
Mori, M; DeArmey, SL; Weber, TJ; Kishnani, PS
MLA Citation
Mori, M, DeArmey, SL, Weber, TJ, and Kishnani, PS. "Case series: Odontohypophosphatasia or missed diagnosis of childhood/adult-onset hypophosphatasia? - Call for a long-term follow-up of premature loss of primary teeth." Bone reports 5 (December 2016): 228-232.
PMID
28580391
Source
epmc
Published In
Bone Reports
Volume
5
Publish Date
2016
Start Page
228
End Page
232
DOI
10.1016/j.bonr.2016.08.004

Burden of disease in adult patients with hypophosphatasia: Results from two patient-reported surveys.

Hypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutation(s) in the tissue-nonspecific alkaline (TNSALP) phosphatase gene, which manifests as rickets and/or osteomalacia with systemic complications and affects patients of all ages. The burden of disease is poorly characterized in adult patients.We assessed patient-reported burden of disease using two surveys reasonably specific for HPP symptomatology, the Hypophosphatasia Impact Patient Survey (HIPS) and the Hypophosphatasia Outcomes Study Telephone interview (HOST).Patients with HPP were invited to participate via patient advocacy groups or their medical provider. Survey questions captured demography, HPP-related medical history, mobility, and health-related quality of life (using Short Form 12 [version 2] Health Survey [SF-12v2]) via internet report (HIPS) or telephone interview (HOST).One hundred twenty-five adults responded (mean [standard deviation, SD] age: 45 [14.3] years). Eighty-four patients (67%) reported pediatric-onset of their symptoms. Common clinical features in the study population included pain (95% of patients), fractures (86% of patients) muscle weakness (62%) and unusual gait (52%). Use of assistive devices for mobility (60%) was also prevalent. Twenty-six percent of patients reported more than 10 fractures. Seventy-four percent of patients had undergone orthopedic/dental surgical procedures. The health profile of patients responding on the SF-12 showed a broad and substantial impact of HPP on health-related quality of life, with domains related to physical ability showing the greatest decrement compared to normative data.In aggregate, these data indicate that HPP can confer a high burden of illness in adulthood.

Authors
Weber, TJ; Sawyer, EK; Moseley, S; Odrljin, T; Kishnani, PS
MLA Citation
Weber, TJ, Sawyer, EK, Moseley, S, Odrljin, T, and Kishnani, PS. "Burden of disease in adult patients with hypophosphatasia: Results from two patient-reported surveys." Metabolism: clinical and experimental 65.10 (October 2016): 1522-1530.
PMID
27621187
Source
epmc
Published In
Metabolism
Volume
65
Issue
10
Publish Date
2016
Start Page
1522
End Page
1530
DOI
10.1016/j.metabol.2016.07.006

Battle of the sex steroids in the male skeleton: and the winner is....

Male osteoporosis is a multifactorial disease, although it is often in part related to hypogonadism. While testosterone replacement therapy has been shown to improve bone mineral density, studies have also linked bone loss and higher fracture risk in men to low estrogen levels. In this issue of the JCI, Finkelstein and colleagues report the results of a clinical study in a cohort of healthy adult men aimed at further discerning the specific roles of androgen and estrogen deficiency in bone loss. The results of their study support previous findings that estrogen deficiency has a dramatic effect on bone homeostasis in men. Future studies to corroborate and expand on these findings have potential to influence the clinical management of male osteoporosis.

Authors
Weber, TJ
MLA Citation
Weber, TJ. "Battle of the sex steroids in the male skeleton: and the winner is.." Journal of Clinical Investigation 126.3 (March 2016): 829-832.
PMID
26901810
Source
epmc
Published In
Journal of Clinical Investigation
Volume
126
Issue
3
Publish Date
2016
Start Page
829
End Page
832
DOI
10.1172/jci85006

Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia.

In X-linked hypophosphatemia (XLH), serum fibroblast growth factor 23 (FGF23) is increased and results in reduced renal maximum threshold for phosphate reabsorption (TmP), reduced serum inorganic phosphorus (Pi), and inappropriately low normal serum 1,25 dihydroxyvitamin D (1,25[OH]2 D) concentration, with subsequent development of rickets or osteomalacia. KRN23 is a recombinant human IgG1 monoclonal antibody that binds to FGF23 and blocks its activity. Up to 4 doses of KRN23 were administered subcutaneously every 28 days to 28 adults with XLH. Mean ± standard deviation KRN23 doses administered were 0.05, 0.10 ± 0.01, 0.28 ± 0.06, and 0.48 ± 0.16 mg/kg. The mean time to reach maximum serum KRN23 levels was 7.0 to 8.5 days. The mean KRN23 half-life was 16.4 days. The mean area under the concentration-time curve (AUCn ) for each dosing interval increased proportionally with increases in KRN23 dose. The mean intersubject variability in AUCn ranged from 30% to 37%. The area under the effect concentration-time curve (AUECn ) for change from baseline in TmP per glomerular filtration rate, serum Pi, 1,25(OH)2 D, and bone markers for each dosing interval increased linearly with increases in KRN23 AUCn . Linear correlation between serum KRN23 concentrations and increase in serum Pi support KRN23 dose adjustments based on predose serum Pi concentration.

Authors
Zhang, X; Imel, EA; Ruppe, MD; Weber, TJ; Klausner, MA; Ito, T; Vergeire, M; Humphrey, J; Glorieux, FH; Portale, AA; Insogna, K; Carpenter, TO; Peacock, M
MLA Citation
Zhang, X, Imel, EA, Ruppe, MD, Weber, TJ, Klausner, MA, Ito, T, Vergeire, M, Humphrey, J, Glorieux, FH, Portale, AA, Insogna, K, Carpenter, TO, and Peacock, M. "Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia." Journal of clinical pharmacology 56.2 (February 2016): 176-185.
PMID
26073451
Source
epmc
Published In
Journal of Clinical Pharmacology
Volume
56
Issue
2
Publish Date
2016
Start Page
176
End Page
185
DOI
10.1002/jcph.570

Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23.

In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia.The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH.Two sequential open-label phase 1/2 studies were done.Six academic medical centers were used.Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05-0.6 mg/kg); 22 entered a 12-month extension study (0.1-1 mg/kg).KRN23 was injected sc every 28 days.The main outcome measure was the proportion of subjects attaining normal serum Pi and safety.At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3-7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9-85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile.Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH.

Authors
Imel, EA; Zhang, X; Ruppe, MD; Weber, TJ; Klausner, MA; Ito, T; Vergeire, M; Humphrey, JS; Glorieux, FH; Portale, AA; Insogna, K; Peacock, M; Carpenter, TO
MLA Citation
Imel, EA, Zhang, X, Ruppe, MD, Weber, TJ, Klausner, MA, Ito, T, Vergeire, M, Humphrey, JS, Glorieux, FH, Portale, AA, Insogna, K, Peacock, M, and Carpenter, TO. "Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23." The Journal of clinical endocrinology and metabolism 100.7 (July 2015): 2565-2573.
PMID
25919461
Source
epmc
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
100
Issue
7
Publish Date
2015
Start Page
2565
End Page
2573
DOI
10.1210/jc.2015-1551

Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH.Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days.KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P<0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine.KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.

Authors
Carpenter, TO; Imel, EA; Ruppe, MD; Weber, TJ; Klausner, MA; Wooddell, MM; Kawakami, T; Ito, T; Zhang, X; Humphrey, J; Insogna, KL; Peacock, M
MLA Citation
Carpenter, TO, Imel, EA, Ruppe, MD, Weber, TJ, Klausner, MA, Wooddell, MM, Kawakami, T, Ito, T, Zhang, X, Humphrey, J, Insogna, KL, and Peacock, M. "Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia." Journal of Clinical Investigation 124.4 (April 2014): 1587-1597.
PMID
24569459
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
4
Publish Date
2014
Start Page
1587
End Page
1597
DOI
10.1172/jci72829

Comparison of cost-effectiveness of vitamin D screening with that of universal supplementation in preventing falls in community-dwelling older adults.

OBJECTIVES: To compare the cost-effectiveness of population screening for vitamin D insufficiency with that of universal vitamin D supplementation in community-dwelling older adults. DESIGN: A Markov decision model simulating follow-up over a 36-month period. Published data were used to estimate values for the model, including costs (measured in 2011 U.S. dollars), utilities (measured in quality-adjusted life years (QALYs)), and probabilities. SETTING: Decision analysis simulation from a societal perspective. PARTICIPANTS: Hypothetical cohort of community-dwelling women and men aged 65 to 80. MEASUREMENTS: Net monetary benefit (NMB) was calculated by subtracting the incremental cost of the strategy from the product of incremental QALYs and willingness-to-pay threshold. A higher NMB indicates greater cost-effectiveness. RESULTS: In women aged 65 to 80, population screening was slightly more cost-effective than universal supplementation, with an incremental NMB of $224 compared with $189 (P < .001). Population screening in men was also more cost-effective than universal supplementation (incremental NMB $298 vs $260, P < .001). Results differed according to age group. In those aged 65, population screening had cost-effectiveness similar to that of universal supplementation in women ($59 vs $71) and men ($114 vs $120), whereas in those aged 80, population screening was substantially more cost-effective than universal supplementation in women ($563 vs $428) and men ($703 vs $571). CONCLUSION: Population screening and universal supplementation for vitamin D insufficiency are cost-effective strategies in community-dwelling older women and men. In the oldest old, population screening may be more cost-effective than universal supplementation.

Authors
Lee, RH; Weber, T; Colón-Emeric, C
MLA Citation
Lee, RH, Weber, T, and Colón-Emeric, C. "Comparison of cost-effectiveness of vitamin D screening with that of universal supplementation in preventing falls in community-dwelling older adults." J Am Geriatr Soc 61.5 (May 2013): 707-714.
PMID
23631393
Source
pubmed
Published In
Journal of American Geriatrics Society
Volume
61
Issue
5
Publish Date
2013
Start Page
707
End Page
714
DOI
10.1111/jgs.12213

Tumor-induced osteomalacia masking primary hyperparathyroidism.

Authors
Elfenbein, DM; Weber, TJ; Scheri, RP
MLA Citation
Elfenbein, DM, Weber, TJ, and Scheri, RP. "Tumor-induced osteomalacia masking primary hyperparathyroidism." Surgery 152.6 (December 2012): 1256-1258.
PMID
23158192
Source
pubmed
Published In
Surgery
Volume
152
Issue
6
Publish Date
2012
Start Page
1256
End Page
1258
DOI
10.1016/j.surg.2012.08.062

Cost-effectiveness of oral bisphosphonates for osteoporosis at different ages and levels of life expectancy.

OBJECTIVES: To evaluate the cost-effectiveness of oral bisphosphonate therapy for osteoporosis in women at different ages and life expectancies. DESIGN: A Markov model was used to analyze oral bisphosphonate treatment for 5 years compared to no intervention. Women at each age were divided into life expectancy quartiles: the lowest 1% to 25% (sickest group), the two middle 26% to 75% (average health group), and the highest 76% to 100% of life expectancy (healthiest group). Simulations were performed for hypothetical cohorts at 5-year intervals with starting ages between 50 and 90 and for each life expectancy group and followed for up to 100 years or until death. Data sources included published fracture rates, costs, utility values, and mortality risks. SETTING: Computer simulation using a societal perspective. PARTICIPANTS: Hypothetical cohort of women with various life expectancies beginning osteoporosis treatment between the age of 50 and 90 years. MEASUREMENTS: Cost per quality-adjusted life years (QALY) gained for 5 years of bisphosphonate therapy compared to no treatment. Cost-effectiveness was defined at a willingness-to-pay of $50,000. RESULTS: In the healthiest group, all costs were less than $18,000 per QALY. In the median quartiles of life expectancy, lifetime costs per QALY were less than $27,000 for patients at all ages; treatment became cost-saving at a starting age of 75 and remained so through a starting age of 85. Even in the sickest group, although osteoporosis treatment was not cost-saving, it remained cost-effective through a starting age of 90 with lifetime costs of less than $43,000 per QALY. CONCLUSION: Treatment with an oral bisphosphonate for 5 years was cost-effective for all women, regardless of quartile of life expectancy. Advanced age should not prevent consideration of osteoporosis treatment based on cost effectiveness, and strategies to improve care, such as nurse-led screening programs or electronic medical record tools, are needed.

Authors
Pham, AN; Datta, SK; Weber, TJ; Walter, LC; Colón-Emeric, CS
MLA Citation
Pham, AN, Datta, SK, Weber, TJ, Walter, LC, and Colón-Emeric, CS. "Cost-effectiveness of oral bisphosphonates for osteoporosis at different ages and levels of life expectancy." J Am Geriatr Soc 59.9 (September 2011): 1642-1649.
PMID
21883116
Source
pubmed
Published In
Journal of American Geriatrics Society
Volume
59
Issue
9
Publish Date
2011
Start Page
1642
End Page
1649
DOI
10.1111/j.1532-5415.2011.03571.x

Older men's explanatory model for osteoporosis.

PURPOSE: To explore the nature of men's experiences of osteoporosis by developing an understanding of men's explanatory models. DESIGN AND METHODS: This descriptive study invited community-residing male osteoporosis patients aged 50+ to participate in interviews about osteoporosis. Participants were recruited from a hospital-affiliated bone clinic. Men completed a questionnaire on demographic, medication, and fracture-related information, and descriptive statistics were calculated using Statistical Package for the Social Sciences. Interviews elicited the 5 domains of men's explanatory model (Kleinman, 1987) and open-ended information regarding men's experiences living with this disorder. Narrative data were analyzed both for content and inductively. RESULTS: Men's narratives demonstrate that an osteoporosis diagnosis is accompanied by negative psychosocial sequelae in this population. Men defined it as a disease of the bone that may increase the likelihood of fracture and that may cause pain. Participants reported that osteoporosis is diagnosed by bone mineral density (BMD) score and that disease progression is measured by a decrease in BMD and an increase in pain or new fractures. Men described a reluctance to take medications, dissatisfaction with side effects, and a perception that osteoporosis treatment in men had little basis in long-term medication efficacy or safety data. They viewed osteoporosis as a degenerative chronic disease with an overall stable course. IMPLICATIONS: Participants' explanatory models for osteoporosis are substantively different than clinical models. These differences provide a foundation for exploring the importance of gender to osteoporosis outcomes, a context for making sense of men's bone health behavior, and a clear case for an increase in advocacy and educational efforts for men who have or are at risk for osteoporosis.

Authors
Solimeo, SL; Weber, TJ; Gold, DT
MLA Citation
Solimeo, SL, Weber, TJ, and Gold, DT. "Older men's explanatory model for osteoporosis." Gerontologist 51.4 (August 2011): 530-539.
PMID
21310768
Source
pubmed
Published In
The Gerontologist
Volume
51
Issue
4
Publish Date
2011
Start Page
530
End Page
539
DOI
10.1093/geront/gnq123

Osteoporosis in lung transplant candidates compared to matched healthy controls.

PURPOSE: Advanced lung disease increases the risk for diminished bone mineral density (BMD). The prevalence and severity of osteoporosis in lung transplant candidates is unclear. METHODS: We retrospectively evaluated BMD of subjects screened for lung transplant at our institution. Observed prevalence of osteoporosis and osteopenia within our cohort was compared to the expected prevalence of each from the Third National Health and Nutrition Examination Survey (NHANES III) data matched for age, gender, and race. Lateral chest radiographs were evaluated for vertebral fractures. RESULTS:   High prevalence rates of osteoporosis (37%) and combined osteoporosis/osteopenia (86%) were observed. Subjects with pulmonary fibrosis had higher BMD and T-scores compared to all other subgroups. All subjects within the cohort had a higher observed combined rate of osteoporosis/osteopenia at all bone sites compared to expected rates from healthy, matched controls. Vertebral fractures were present in 23% of subjects but did not correlate with BMD or the diagnosis of osteoporosis. CONCLUSIONS: Abnormal BMD was prevalent in most pre-lung transplant subjects, with striking differences noted in comparison with a healthy, matched cohort. Lateral chest radiographs in combination with BMD data give a more complete picture of bone abnormalities. Osteoporosis screening prior to lung transplantation should be performed to identify high-risk subjects for fracture and allow for intervention.

Authors
Lakey, WC; Spratt, S; Vinson, EN; Gesty-Palmer, D; Weber, T; Palmer, S
MLA Citation
Lakey, WC, Spratt, S, Vinson, EN, Gesty-Palmer, D, Weber, T, and Palmer, S. "Osteoporosis in lung transplant candidates compared to matched healthy controls." Clin Transplant 25.3 (May 2011): 426-435.
PMID
20482557
Source
pubmed
Published In
Clinical Transplantation
Volume
25
Issue
3
Publish Date
2011
Start Page
426
End Page
435
DOI
10.1111/j.1399-0012.2010.01263.x

Disorders of phosphorus homeostasis.

PURPOSE OF REVIEW: The study of phosphorus physiology and investigations into clinical disorders of phosphorus metabolism has blossomed over the past decade. Recent work has confirmed and further extended our knowledge of basic mechanisms of phosphorus metabolism. RECENT FINDINGS: This review will focus on FGF-23 and Klotho, and on the recent further dissection of their roles in phosphorus and skeletal metabolism. Additionally, this review will detail recent studies that implicate a role for these phosphaturic and vitamin D regulating factors in extraskeletal calcification, including that occurring in soft tissue and vascular beds. SUMMARY: These findings in total provide fertile ground for investigations into the cause and treatment of abnormal skeletal and extraskeletal calcification in patients with inherited hypophosphatemic disorders. More importantly, and certainly with wider potential clinical application, these studies likewise imply a role for these factors in the pathogenesis of accelerated cardiovascular disease that occurs in patients with the most common hyperphosphatemic disorder, chronic kidney disease. Future studies are needed to confirm a harmful or possibly even beneficial role for FGF-23 and other factors in these disease states, and to determine whether therapeutic manipulation of these factors does truly affect clinical outcomes in patients with hypophosphatemia and hyperphosphatemia.

Authors
Lee, R; Weber, TJ
MLA Citation
Lee, R, and Weber, TJ. "Disorders of phosphorus homeostasis." Curr Opin Endocrinol Diabetes Obes 17.6 (December 2010): 561-567. (Review)
PMID
20962635
Source
pubmed
Published In
Current Opinion in Endocrinology, Diabetes and Obesity
Volume
17
Issue
6
Publish Date
2010
Start Page
561
End Page
567
DOI
10.1097/MED.0b013e32834041d4

Hypovitaminosis D in glycogen storage disease type I.

Glycogen storage disease type I (GSD I) is caused by inherited defects of the glucose 6-phosphatase complex, resulting in fasting hypoglycemia, lactic acidosis, hyperuricemia and hyperlipidemia. Sixteen out of 26 (61.5%) GSD I patients in our study had suboptimal levels (<30 ng/ml) of 25-hydroxyvitamin-D (25(OH)D) despite supplementation of vitamin D and/or vitamin D + calcium based on WHO standards in 24/26 (92.3%) patients. The restrictive nature of the GSD I diet, metabolic derangements and intestinal malabsorption seen in GSD I are possible reasons for the observed hypovitaminosis D. Our results suggest that measurement of 25(OH)D should be considered in the routine evaluation of GSD I patients.

Authors
Banugaria, SG; Austin, SL; Boney, A; Weber, TJ; Kishnani, PS
MLA Citation
Banugaria, SG, Austin, SL, Boney, A, Weber, TJ, and Kishnani, PS. "Hypovitaminosis D in glycogen storage disease type I." Mol Genet Metab 99.4 (April 2010): 434-437.
PMID
20060350
Source
pubmed
Published In
Molecular Genetics and Metabolism
Volume
99
Issue
4
Publish Date
2010
Start Page
434
End Page
437
DOI
10.1016/j.ymgme.2009.12.012

Following the forgotten phosphorus.

Authors
Nair, LT; Dodd, L; Weber, TJ
MLA Citation
Nair, LT, Dodd, L, and Weber, TJ. "Following the forgotten phosphorus." Am J Med 122.12 (December 2009): 1093-1095.
PMID
19958885
Source
pubmed
Published In
American Journal of Medicine
Volume
122
Issue
12
Publish Date
2009
Start Page
1093
End Page
1095
DOI
10.1016/j.amjmed.2009.07.006

Osteoporosis in older women

Authors
Pham, AN; Colón-Emeric, CS; Weber, TJ
MLA Citation
Pham, AN, Colón-Emeric, CS, and Weber, TJ. "Osteoporosis in older women." Clinical Geriatrics 17.10 (2009): 20-28.
Source
scival
Published In
Clinical geriatrics
Volume
17
Issue
10
Publish Date
2009
Start Page
20
End Page
28

Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f®): long-term treatment in azoospermic men with hypogonadotropic hypogonadism

Objective: To demonstrate the efficacy and safety of follitropin alfa administered with hCG on spermatogenesis in adult male hypogonadotropic hypogonadism (HH) patients. Design: Phase III, multicenter, open-label, noncomparative. Setting: Seven US medical centers. Patient(s): A total of 36 adult males with severe HH. Intervention(s): A total of 1,000 U hCG on alternate days for 3 to 6 months, with dose adjustments after 2 months, if necessary, to normalize T levels, followed by follitropin alfa 150 U and hCG on the same alternate days for 18 months, with dose adjustments as necessary. Main Outcome Measure(s): Proportion of patients with sperm density ≥1.5 × 106/mL. Pubertal advancement and long-term safety and tolerability were also evaluated. Result(s): In total, 22 of 29 patients (75.9%) who received ≥1 dose of follitropin alfa and 20 of 25 patients (80%) who completed 18 months of hCG + follitropin alfa treatments achieved a sperm concentration ≥1.5 × 106/mL. A sperm concentration >20 × 106/mL was achieved by 8 of 29 men (27.5%). Median sperm concentration at 18 months was 5.2 × 106/mL. Pubertal development continued during the study, and testis volumes increased. Five clinical pregnancies were achieved. Acne (52% of patients) was the most common side effect, and gynecomastia was reported in 10% of patients. Conclusion(s): Long-term treatment of azoospermic HH men using follitropin alfa and hCG is effective for stimulating spermatogenesis and is well-tolerated. © 2009 American Society for Reproductive Medicine.

Authors
Matsumoto, AM; Snyder, PJ; Bhasin, S; Martin, K; Weber, T; Winters, S; Spratt, D; Brentzel, J; O'Dea, L
MLA Citation
Matsumoto, AM, Snyder, PJ, Bhasin, S, Martin, K, Weber, T, Winters, S, Spratt, D, Brentzel, J, and O'Dea, L. "Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f®): long-term treatment in azoospermic men with hypogonadotropic hypogonadism." Fertility and Sterility 92.3 (2009): 979-990.
PMID
18930190
Source
scival
Published In
Fertility and Sterility
Volume
92
Issue
3
Publish Date
2009
Start Page
979
End Page
990
DOI
10.1016/j.fertnstert.2008.07.1742

Fibrogenesis imperfecta ossium: MR imaging of the axial and appendicular skeleton and correlation with a unique radiographic appearance.

We describe a distinctly unusual MR appearance of the cancellous bone never before described in a patient with biopsy-proven fibrogenesis imperfecta ossium.

Authors
Coursey, C; Weber, T; Dodd, L; Martinez, S
MLA Citation
Coursey, C, Weber, T, Dodd, L, and Martinez, S. "Fibrogenesis imperfecta ossium: MR imaging of the axial and appendicular skeleton and correlation with a unique radiographic appearance." Skeletal Radiol 36.11 (November 2007): 1077-1084.
PMID
17618434
Source
pubmed
Published In
Skeletal Radiology
Volume
36
Issue
11
Publish Date
2007
Start Page
1077
End Page
1084
DOI
10.1007/s00256-007-0334-2

Fractures in children with Pompe disease: a potential long-term complication.

BACKGROUND: Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Classic infantile-onset disease, characterized by cardiomegaly and profound weakness, leads to death in the first year of life from cardiorespiratory failure. Reversal of cardiomyopathy and improved motor function have been shown in clinical trials of rhGAA enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme), recently approved for clinical use. Increased survival potentially unmasks long-term complications of this previously lethal disease, including risk of skeletal fracture, recently identified at our institution and not previously reported in children with Pompe disease. OBJECTIVE: To report the risk of fracture in children with Pompe disease with increased survival with ERT. MATERIALS AND METHODS: We present four cases of fracture in patients with classic infantile Pompe disease treated with ERT at our institution, and review a study database for additional reports of fracture in this population. RESULTS: We review 19 fractures in 14 children with Pompe disease on ERT. CONCLUSION: Radiologists should be familiar with and vigilant for the association of fractures and increased survival on ERT in children with Pompe disease. We discuss potential mechanisms, implications for radiographic surveillance, potential intervention, and needs for further research.

Authors
Case, LE; Hanna, R; Frush, DP; Krishnamurthy, V; DeArmey, S; Mackey, J; Boney, A; Morgan, C; Corzo, D; Bouchard, S; Weber, TJ; Chen, Y-T; Kishnani, PS
MLA Citation
Case, LE, Hanna, R, Frush, DP, Krishnamurthy, V, DeArmey, S, Mackey, J, Boney, A, Morgan, C, Corzo, D, Bouchard, S, Weber, TJ, Chen, Y-T, and Kishnani, PS. "Fractures in children with Pompe disease: a potential long-term complication." Pediatr Radiol 37.5 (May 2007): 437-445.
PMID
17342521
Source
pubmed
Published In
Pediatric Radiology
Volume
37
Issue
5
Publish Date
2007
Start Page
437
End Page
445
DOI
10.1007/s00247-007-0428-y

Update on male osteoporosis

PURPOSE: Fragility fractures are increasingly recognized as an important cause of morbidity and mortality in men. This review focuses on the potential causes, means of diagnosis, and available treatment for male osteoporosis. EPIDEMIOLOGY: More than 2 million men in the United States have osteoporosis, and approximately 1 in 5 fractures occur in men. Moreover, it is estimated that there will be 800 000 hip fractures in men worldwide in 2025, reflecting a greater rate of increase in men (89%) than that in women (69%). REVIEW SUMMARY: Male osteoporosis is a multifactorial disorder with testosterone deficiency, excessive glucocorticoids, and excess alcohol intake the most commonly observed causes. Although the lifetime risk of fracture is lower in men than in women, men have higher mortality rates after hip and other types of osteoporotic fracture. Diagnostic assessment of osteoporosis in men generally should be more comprehensive than that in women, given that more than half of men will have an identifiable secondary disorder that contributes to their disease. Treatment with pharmacologic agents does have favorable effects on bone mineral density in men, though definitive evidence of antifracture benefit is lacking to date. TYPE OF AVAILABLE EVIDENCE: Systematic reviews, prospective cohort studies, randomized-controlled trials, meta-analyses. GRADE OF AVAILABLE EVIDENCE: Fair. CONCLUSION: Male osteoporosis is a common disorder associated with significant morbidity and mortality. An approach of lifestyle modification, appropriate nutrition (with calcium/vitamin D), and selective use of pharmacologic agents appears to confer skeletal benefit to men similar to that in women.

Authors
Weber, TJ; Gold, DT
MLA Citation
Weber, TJ, and Gold, DT. "Update on male osteoporosis." Advanced Studies in Medicine 6.4 (2006): 171-181.
Source
scival
Published In
Advanced Studies in Medicine
Volume
6
Issue
4
Publish Date
2006
Start Page
171
End Page
181

New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men.

A new mucoadhesive testosterone buccal system (Striant), 30 mg testosterone (T), was applied twice daily in 82 hypogonadal men for 3 months. Serum T, free T, and 5alpha-dihydrotestosterone were measured during this period. T pharmacokinetics were determined from the data obtained during a 24-h sampling at wk 12. Physiological mean serum T concentrations were steady and consistently maintained. The mean percentage of time over a 24-h period that total serum T concentrations were above the lower limit of adult male range was 80.1%. During treatment, mean serum 5alpha-dihydrotestosterone, free T, and estradiol concentrations paralleled serum T. T pharmacokinetics were not significantly affected by body mass index, age, food or beverage, gum abnormalities, or medications known to cause dry mouth. Gum-related adverse events occurred in 16.3% of subjects. Except for three subjects, the gum adverse effects occurred early during treatment, did not cause interruption of treatment, and resolved rapidly and completely. The T buccal system is a novel T formulation that offers a safe, effective, and convenient alternative to existing formulations for physiological T replacement therapy in hypogonadal men.

Authors
Wang, C; Swerdloff, R; Kipnes, M; Matsumoto, AM; Dobs, AS; Cunningham, G; Katznelson, L; Weber, TJ; Friedman, TC; Snyder, P; Levine, HL
MLA Citation
Wang, C, Swerdloff, R, Kipnes, M, Matsumoto, AM, Dobs, AS, Cunningham, G, Katznelson, L, Weber, TJ, Friedman, TC, Snyder, P, and Levine, HL. "New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men." J Clin Endocrinol Metab 89.8 (August 2004): 3821-3829.
PMID
15292312
Source
pubmed
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
89
Issue
8
Publish Date
2004
Start Page
3821
End Page
3829
DOI
10.1210/jc.2003-031866

Long-Term Testosterone Gel (AndroGel) Treatment Maintains Beneficial Effects on Sexual Function and Mood, Lean and Fat Mass, and Bone Mineral Density in Hypogonadal Men

Transdermal testosterone (T) delivery represents an effective alternative to injectable androgens. We studied 163 hypogonadal men who applied 5, 7.5, or 10 g AndroGel (T gel) 1% CIII per day for up to 42 months. Efficacy data were presented in 123 subjects considered evaluable. Continuous AndroGel treatment normalized mean serum T and free T levels. Mean serum 5α -dihydrotestosterone concentrations and 5α-dihydrotestosterone/T ratio slightly increased, mean serum estradiol/T ratio doubled, and mean serum FSH and LH levels were suppressed by T replacement. Sexual function and mood parameters improved rapidly and were maintained throughout T treatment. Lean body mass increased (P = 0.0001) and fat mass decreased (P = 0.0001), and these changes were maintained with treatment but were not accompanied by significant increases in muscle strength. Increases in serum bone markers suggestive of increased bone formation were followed by gradual and progressive increases in bone mineral density more in the spine (P = 0.0001) than the hip (P = 0.0004). Mild local skin irritation occurred in 12 subjects, resulting in discontinuation in only one subject. Except for the anticipated increase in hematocrit and hemoglobin, there were no clinically significant changes in blood counts or biochemistry. In three subjects with elevated serum prostate-specific antigen, prostate biopsies showed cancer. We conclude that con. tinued application of AndroGel resulted in beneficial effects similar to those with injectables and other transdermal preparations. This study was neither placebo controlled nor powered to determine the effects of T treatment on prostate cancer risk. Thus, monitoring for prostatic disease and assessment for erythrocytosis are strongly advised to reduce the risk of adverse events with T treatment of hypogonadal men.

Authors
Wang, C; Cunningham, G; Dobs, A; Iranmanesh, A; Matsumoto, AM; Snyder, PJ; Weber, T; Berman, N; Hull, L; Swerdloff, RS
MLA Citation
Wang, C, Cunningham, G, Dobs, A, Iranmanesh, A, Matsumoto, AM, Snyder, PJ, Weber, T, Berman, N, Hull, L, and Swerdloff, RS. "Long-Term Testosterone Gel (AndroGel) Treatment Maintains Beneficial Effects on Sexual Function and Mood, Lean and Fat Mass, and Bone Mineral Density in Hypogonadal Men." Journal of Clinical Endocrinology and Metabolism 89.5 (2004): 2085-2098.
PMID
15126525
Source
scival
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
89
Issue
5
Publish Date
2004
Start Page
2085
End Page
2098
DOI
10.1210/jc.2003-032006

Serum FGF23 levels in normal and disordered phosphorus homeostasis.

UNLABELLED: We investigated if the circulating levels of the phosphaturic factor FGF23 are elevated in subjects with XLH. Although we failed to find a statistically significant increase, FGF23 levels were significantly correlated with the degree of hypophosphatemia in XLH. In contrast, FGF23 levels were markedly increased in subjects with ESRD and correlated inversely with the degree of hyperphosphatemia. INTRODUCTION: Inactivating mutations of PHEX cause renal phosphate wasting in X-linked hypophosphatemic rickets (XLH) because of the accumulation of a phosphaturic hormone called phosphatonin. The recent discovery that FGF23 is the circulating phosphaturic factor in autosomal dominant hypophosphatemia raises the possibility that FGF23 is phosphatonin. METHODS: Fasting serum FGF23 levels and serum biochemical parameters were measured using a human FGF23 (C-terminal) ELISA assay in 11 subjects with XLH and 42 age-matched controls, 5 subjects with hypophosphatemia of unknown cause, and 14 hyperphosphatemic subjects with end stage renal disease (ESRD). Associations between variables were examined using the Spearman's correlation coefficient and linear regression analysis. RESULTS AND CONCLUSIONS: FGF23 (RU/ml) concentrations were not different (p = 0.11) between control and hypophosphatemic XLH subjects, but were significantly increased in hyperphosphatemic subjects with ESRD (p < 0.001). Western blot analysis found the presence of both full-length and C-terminal FGF23 fragments in serum from ESRD subjects. There was a strong inverse correlation between FGF23 and serum phosphorus (r = -0.60) and calcium and phosphorus (Ca x P) product (r = -0.65) in XLH, and a strong positive relationship between FGF23 and Pi (r = 0.50) and Ca x P product (r = 0.62) in ESRD. FGF23 levels were variably elevated in subjects with hypophosphatemia of unknown cause, one of which had tumor-induced osteomalacia (TIO). Removal of the tumor resulted in rapid reduction in serum FGF23 levels. These findings suggest that FGF23 has a possible role in mediating hypophosphatemia in XLH and TIO, but the overlapping levels of FGF23 in hypophosphatemic disorders and normal subjects indicate that serum phosphorus and FGF23 can also be independently regulated.

Authors
Weber, TJ; Liu, S; Indridason, OS; Quarles, LD
MLA Citation
Weber, TJ, Liu, S, Indridason, OS, and Quarles, LD. "Serum FGF23 levels in normal and disordered phosphorus homeostasis." J Bone Miner Res 18.7 (July 2003): 1227-1234.
PMID
12854832
Source
pubmed
Published In
Journal of Bone and Mineral Research
Volume
18
Issue
7
Publish Date
2003
Start Page
1227
End Page
1234
DOI
10.1359/jbmr.2003.18.7.1227

Effect of alendronate on bone mineral density in male idiopathic osteoporosis.

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.

Authors
Weber, TJ; Drezner, MK
MLA Citation
Weber, TJ, and Drezner, MK. "Effect of alendronate on bone mineral density in male idiopathic osteoporosis." Metabolism 50.8 (August 2001): 912-915.
PMID
11474478
Source
pubmed
Published In
Metabolism
Volume
50
Issue
8
Publish Date
2001
Start Page
912
End Page
915
DOI
10.1053/meta.2001.24925

Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men

OBJECTIVE: Androgen replacement has been reported to increase bone mineral density (BMD) in hypogonadal men. We studied the effects of 6 months of treatment with a new transdermal testosterone (T) gel preparation on bone turnover markers and BMD. DESIGN: This was a prospective, randomized, multicentre, parallel clinical trial where 227 hypogonadal men, mean age 51 years (range: 19-68 years) were studied in 16 academic and research institutions in the USA. Subjects were randomized to apply 1% T gel containing 50 or 100 mg T (delivering approximately 510 mg T/day) or two T patches (delivering 5 mg T/day) transdermally for 90 days. At day 91, depending on the serum T concentration, the T gel dose was adjusted upward or downward to 75 mg T/day until day 180. No dose adjustment occurred in the T patch group. MEASUREMENTS: Serum T, free T and oestradiol, bone turnover markers and BMD were measured on days 0, 30, 90 and 180 before and after treatment. RESULTS: Application of T gel 100 mg/day resulted in serum T concentrations 1.4 and 1.9-fold higher than in the T gel 50 mg/day and the T patch groups, respectively. Proportional increases occurred in serum oestradiol. Urine N-telopeptide/crestinine ratio, a marker for bone resorption, decreased significantly (P = 0.0019) only in the T gel 100 mg/day group. Serum bone osteoblastic activity markers (osteocalcin, procollagen and skeletal alkaline phosphatase) increased significantly during the first 90 days of treatment without intergroup differences but declined to beseline thereafter. BMD increased significantly both in the hip (+1.1 ± 0.3%) and spine (+2.2 ± 0.5%) only in the T gel 100 mg/day group (p = 0.0001 ). CONCLUSIONS: Transdermal testosterone gel application for 6 months decreased bone resorption markers and increased osteoblaetlc activity markers for a short period, which resulted in a small but significant increase in BMD. Ongoing long-term studies should answer whether the observed increases in BMD are sustained or continue to be dependent on the dose of testosterone administered.

Authors
Wang, C; Swerdloff, RS; Iranmanesh, A; Dobs, A; Snyder, PJ; Cunningham, G; Matsumoto, AM; Weber, T; Berman, N
MLA Citation
Wang, C, Swerdloff, RS, Iranmanesh, A, Dobs, A, Snyder, PJ, Cunningham, G, Matsumoto, AM, Weber, T, and Berman, N. "Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men." Clinical Endocrinology 54.6 (2001): 739-750.
PMID
11422108
Source
scival
Published In
Clinical Endocrinology
Volume
54
Issue
6
Publish Date
2001
Start Page
739
End Page
750
DOI
10.1046/j.1365-2265.2001.01271.x

How bone density testing influenced osteoporosis treatment in a community hospital.

Authors
Weber, TJ; Green, JB; Chow, H; Spitz, A; Wagner, GS
MLA Citation
Weber, TJ, Green, JB, Chow, H, Spitz, A, and Wagner, GS. "How bone density testing influenced osteoporosis treatment in a community hospital." N C Med J 61.6 (November 2000): 321-324.
PMID
11103606
Source
pubmed
Published In
North Carolina Medical Journal
Volume
61
Issue
6
Publish Date
2000
Start Page
321
End Page
324

Preventing bone loss after renal transplantation with bisphosphonates: we can... but should we?

Authors
Weber, TJ; Quarles, LD
MLA Citation
Weber, TJ, and Quarles, LD. "Preventing bone loss after renal transplantation with bisphosphonates: we can.. but should we?." Kidney Int 57.2 (February 2000): 735-737.
PMID
10652053
Source
pubmed
Published In
Kidney international
Volume
57
Issue
2
Publish Date
2000
Start Page
735
End Page
737
DOI
10.1046/j.1523-1755.2000.00900.x

Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men

Testosterone (T) therapy for hypogonadal men should correct the clinical abnormalities of T deficiency, including improvement of sexual function, increase in muscle mass and strength, and decrease in fat mass, with minimal adverse effects. We have shown that administration of a new transdermal T gel formulation to hypogonadal men provided dose proportional increases in serum T levels to the normal adult male range. We now report the effects of 180 days of treatment with this 1% T gel preparation (50 or 100 mg/day, contained in 5 or 10 g gel, respectively) compared to those of a permeation-enhanced T patch (5 mg/day) on defined efficacy parameters in 227 hypogonadal men. In the T gel groups, the T dose was adjusted up or down to 75 mg/day (contained in 7.5 g gel) on day 90 if serum T concentrations were below or above the normal male range. No dose adjustment was made with the T patch group. Sexual function and mood changes were monitored by questionnaire, body composition was determined by dual energy x-ray absorptiometry, and muscle strength was measured by the one repetitive maximum technique on bench and leg press exercises. Sexual function and mood improved maximally on day 30 of treatment, without differences across groups, and showed no further improvement with continuation of treatment. Mean muscle strength in the leg press exercise increased by 11 to 13 kg in all treatment groups by 90 days and did not improve further at 180 days of treatment. Moderate increases were also observed in arm/chest muscle strength. At 90 days of treatment, lean body mass increased more in the 100 mg/day T gel group (2.74 ± 0.28 kg; P = 0.0002) than in the 50 mg/day T gel (1.28 ± 0.32 kg) and T patch groups (1.20 ± 0.26 kg). Fat mass and percent fat were not significantly decreased in the T patch group, but showed decreases in the T gel groups (50 mg/day, -0.90 ± 0.32 kg; 100 mg/day, -1.05 ± 0.22 kg). The increase in lean mass and the decrease in fat mass were correlated with the changes in average serum T levels attained after transdermal T replacement. These beneficial effects oft replacement were accompanied by the anticipated increases in hematocrit and hemoglobin but without significant changes in the lipid profile. The increase in mean serum prostate-specific antigen levels (within the normal range) was correlated with serum levels of T. The greatest increases were noted in the 100 mg/day T gel group. Skin irritation was reported in 5.5% of subjects treated with T gel and in 66% of subjects in the permeation-enhanced T patch group. We conclude that T gel replacement improved sexual function and mood, increased lean mass and muscle strength (principally in the legs), and decreased fat mass in hypogonadal men with less skin irritation and discontinuation compared with the recommended dose of the permeation-enhanced T patch.

Authors
Wang, C; Swerdloff, RS; Iranmanesh, A; Dobs, A; Snyder, PJ; Cunningham, G; Matsumoto, AM; Weber, T; Berman, N
MLA Citation
Wang, C, Swerdloff, RS, Iranmanesh, A, Dobs, A, Snyder, PJ, Cunningham, G, Matsumoto, AM, Weber, T, and Berman, N. "Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men." Journal of Clinical Endocrinology and Metabolism 85.8 (2000): 2839-2853.
PMID
10946892
Source
scival
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
85
Issue
8
Publish Date
2000
Start Page
2839
End Page
2853
DOI
10.1210/jc.85.8.2839

Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men

Transdermal delivery of testosterone (T) represents an effective alternative to injectable androgens. Transdermal T patches normalize serum T levels and reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin irritation and/or lack of adherence. T gels have been proposed as delivery modes that minimize these problems. In this study we examined the pharmacokinetic profiles after 1, 30, 90, and 180 days of daily application of 2 doses of T gel (50 and 100 mg T in 5 and 10 g gel, delivering 5 and 10 mg T/day, respectively) and a permeation-enhanced T patch (2 patches delivering 5 mg T/day) in 227 hypogonadal men. This new 1% hydroalcoholic T gel formulation when applied to the upper arms, shoulders, and abdomen dried within a few minutes, and about 9-14% of the T applied was bioavailable. After 90 days of T gel treatment, the dose was titrated up (50 mg to 75 mg) or down (100 mg to 75 mg) if the preapplication serum T levels were outside the normal adult male range. Serum T rose rapidly into the normal adult male range on day i with the first T gel or patch application. Our previous study showed that steady state T levels were achieved 48-72 h after first application of the gel. The pharmacokinetic parameters for serum total and free T were very similar on days 30, 90, and 180 in all treatment groups. After repeated daily application of the T formulations for 180 days, the average serum T level over the 24-h sampling period (Cavg) was highest in the 100 mg T gel group (1.4- and 1.9-fold higher than the Cavg in the 50 mg T gel and T patch groups, respectively). Mean serum steady state T levels remained stable over the 180 days of T gel application. Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the Cavg, whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the normal range for most patients. Serum free T levels paralleled those of serum total T, and the percent free T was not changed with transdermal T preparations. The serum dihydrotestosterone Cavg rose 1.3-fold above baseline after T patch application, but was more significantly increased by 3.6- and 4.6-fold with T gel 50 and 100 mg/day, respectively, resulting in a small, but significant, increase in the serum dihydrotestosterone/T ratios in the two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed proportionately with serum T in all study groups; serum sex hormone-binding globulin showed small decreases that were significant only in the 100 mg T gel group. We conclude that transdermal T gel application can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range. Transdermal T gel provided flexibility in dosing with little skin irritation and a low discontinuation rate.

Authors
Swerdloff, RS; Wang, C; Cunningham, G; Dobs, A; Iranmanesh, A; Matsumoto, AM; Snyder, PJ; Weber, T; Longstreth, J; Berman, N
MLA Citation
Swerdloff, RS, Wang, C, Cunningham, G, Dobs, A, Iranmanesh, A, Matsumoto, AM, Snyder, PJ, Weber, T, Longstreth, J, and Berman, N. "Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men." Journal of Clinical Endocrinology and Metabolism 85.12 (2000): 4500-4510.
PMID
11134099
Source
scival
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
85
Issue
12
Publish Date
2000
Start Page
4500
End Page
4510
DOI
10.1210/jc.85.12.4500

Erratum: Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men (Journal of Clinical Endocrinology and Metabolism 85 (2839-2853))

Authors
Wang, C; Swerdloff, RS; Iranmanesh, A; Dobs, A; Snyder, PJ; Cunningham, G; Matsumoto, AM; Weber, T; Berman, N
MLA Citation
Wang, C, Swerdloff, RS, Iranmanesh, A, Dobs, A, Snyder, PJ, Cunningham, G, Matsumoto, AM, Weber, T, and Berman, N. "Erratum: Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men (Journal of Clinical Endocrinology and Metabolism 85 (2839-2853))." Journal of Clinical Endocrinology and Metabolism 85.10 (2000): 3525--.
Source
scival
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
85
Issue
10
Publish Date
2000
Start Page
3525-

Secondary osteoporosis. Diagnostic considerations.

This article discusses the important secondary causes of osteoporosis that contribute significantly to bone loss and that seem to increase fracture risk, including hypogonadism, endogenous and exogenous thyroxine excess, hyperparathyroidism, malignancies, gastrointestinal diseases, medications, vices, and connective tissue diseases.

Authors
Harper, KD; Weber, TJ
MLA Citation
Harper, KD, and Weber, TJ. "Secondary osteoporosis. Diagnostic considerations." Endocrinol Metab Clin North Am 27.2 (June 1998): 325-348. (Review)
PMID
9669141
Source
pubmed
Published In
Endocrinology & Metabolism Clinics of North America
Volume
27
Issue
2
Publish Date
1998
Start Page
325
End Page
348

Steroidogenic factor 1 plays multiple roles in endocrine development and function.

The nuclear hormone receptor family comprises a group of structurally related transcriptional regulators that mediate the actions of diverse ligands, including steroid hormones, thyroid hormone, vitamin D, and retinoids. The nuclear receptor family also contains members for which activating ligands have not been identified-the orphan nuclear receptors. One of these orphan nuclear receptors, steroidogenic factor 1 (SF-1), has emerged as an essential regulator of steroidogenic cell function within the adrenal cortex and gonads; SF-1 also plays important roles in reproduction at all three levels of the hypothalamic-pituitary-gonadal axis. First identified as a tissue-specific regulator of the transcription of the cytochrome P450 steroid hydroxylases, considerably broader roles for SF-1 were revealed by genetic studies in mice lacking SF-1 due to targeted gene disruption. These SF-1-knockout mice had agenesis of their adrenal glands and gonads, male-to-female sex reversal of their internal and external genitalia, impaired gonadotrope function, and agenesis of the ventromedial hypothalamic nucleus. These studies delineated essential roles of SF-1 in regulating endocrine differentiation and function at multiple levels. Despite these insights into roles of SF-1, the precise mechanisms by which SF-1 exerts its multiple effects remain to be determined. This review highlights experiments that have established SF-1 as a pivotal determinant of endocrine differentiation and function and identifies areas in which additional studies are needed to expand our understanding of SF-1 action.

Authors
Wong, M; Ikeda, Y; Luo, X; Caron, KM; Weber, TJ; Swain, A; Schimmer, BP; Parker, KL
MLA Citation
Wong, M, Ikeda, Y, Luo, X, Caron, KM, Weber, TJ, Swain, A, Schimmer, BP, and Parker, KL. "Steroidogenic factor 1 plays multiple roles in endocrine development and function." Recent Prog Horm Res 52 (1997): 167-182. (Review)
PMID
9238852
Source
pubmed
Published In
Recent progress in hormone research
Volume
52
Publish Date
1997
Start Page
167
End Page
182

Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development.

Mutations of the orphan nuclear receptors, steroidogenic factor 1 (SF-1) and DAX-1, cause complex endocrine phenotypes that include impaired adrenal development and hypogonadotrophic hypogonadism. These similar phenotypes suggest that SF-1 and DAX-1 act in the same pathway(s) of endocrine development. To explore this model, we now compare directly their sites of expression. In mouse embryos, SF-1 expression in the urogenital ridge and brain either preceded or coincided with Dax-1 expression, with coordinate expression thereafter in the adrenal cortex, testis, ovary, hypothalamus, and anterior pituitary. The striking colocalization of SF-1 and Dax-1 supports the model that they are intimately linked in a common pathway of endocrine development. The slightly earlier onset of SF-1 expression and its ability to bind specifically to a conserved sequence in the Dax-1 5'-flanking region suggested that SF-1 may activate Dax-1 expression. However, promoter activity of Dax-1 5'-flanking sequences did not require this potential SF-1-responsive element, and Dax-1 expression was unimpaired in knockout mice lacking SF-1, establishing that SF-1 is not required for Dax-1 gene expression in these settings. Although the precise mechanisms remain to be established and may be multifactorial, our results strongly suggest that these two orphan nuclear receptors interact in a common pathway of endocrine development.

Authors
Ikeda, Y; Swain, A; Weber, TJ; Hentges, KE; Zanaria, E; Lalli, E; Tamai, KT; Sassone-Corsi, P; Lovell-Badge, R; Camerino, G; Parker, KL
MLA Citation
Ikeda, Y, Swain, A, Weber, TJ, Hentges, KE, Zanaria, E, Lalli, E, Tamai, KT, Sassone-Corsi, P, Lovell-Badge, R, Camerino, G, and Parker, KL. "Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development." Mol Endocrinol 10.10 (October 1996): 1261-1272.
PMID
9121493
Source
pubmed
Published In
Molecular endocrinology (Baltimore, Md.)
Volume
10
Issue
10
Publish Date
1996
Start Page
1261
End Page
1272
DOI
10.1210/mend.10.10.9121493
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