John P Bilezikian

Columbia University, New York, New York, United States

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Publications (586)3520.12 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The microstructural skeletal phenotype of Hypoparathyroidism (HypoPT), a disorder of inadequate parathyroid hormone secretion, is altered trabecular microarchitecture with increased trabecular bone volume and thickness. Using 2-D histomorphometric analysis, we previously found that 2 years of PTH(1-84) in HypoPT is associated with reduced trabecular thickness (Tb.Th) and an increase in trabecular number (Tb.N). We have now utilized direct 3-D microstructural analysis to determine the extent to which these changes may be related to bone strength. Iliac crest bone biopsies from HypoPT subjects (n = 58) were analyzed by microcomputed tomography (µCT) and by microfinite element (µFE) analysis. Biopsies were performed at baseline and at 1 or at 2 years of recombinant human PTH(1-84) [rhPTH(1-84)]. In a subset of subjects (n = 13) at 3 months, we demonstrated: a reduction in trabecular separation (Tb.Sp, 0.64 ± 0.1 to 0.56 ± 0.1 mm; p = 0.005) and in the variance of trabecular separation (Tb.SD, 0.19 ± 0.1 to 0.17 ± 0.1 mm; p = 0.01), along with an increase in bone volume/total volume (BV/TV, 26.76 ± 10.1 to 32.83 ± 13.5%; p = 0.02), bone surface/total volume (BS/TV, 3.85 ± 0.7 to 4.49 ± 1.0 mm(2) /mm(3) ; p = 0.005), Tb.N (1.84 ± 0.5 vs 2.36 ± 1.3 mm(-1) ; p = 0.02) and Young's modulus (649.38 ± 460.7 to 1044.81 ± 1090.5 N/mm(2) ; p = 0.049). After 1 year of rhPTH(1-84), Force increased (144.08 ± 102.4 to 241.13 ± 189.1 N; p = 0.04) and Young's modulus tended to increase (662.15 ± 478.2 to 1050.80 ± 824.1 N/m(2) ; p = 0.06). The 1 year change in cancellous mineralizing surface (MS/BS) predicted 1 year changes in µCT variables. The biopsies obtained after 2 years of rhPTH(1-84) showed no change from baseline. These data suggest that administration of rhPTH(1-84) in HypoPT is associated with transient changes in key parameters associated with bone strength. The results indicate that rhPTH(1-84) improves skeletal quality in HypoPT early in treatment. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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    ABSTRACT: Primary hyperparathyroidism (PHPT) was originally described as a symptomatic disease with overt radiological skeletal manifestations. When the multichannel biochemical screening test became widely used in the early 1970s in the Western world, the predominant presentation of PHPT became an asymptomatic one. Radiological signs were relegated to a vanishingly small percentage of patients. In the late 1980s, when dual-energy X-ray absorptiometry (DXA) became widely used, skeletal manifestations could be readily demonstrated with this more sensitive imaging technology. With the application of even more sensitive imaging technologies, such as high resolution peripheral quantitative computed technology (HRpQCT), applications such as the trabecular bone score (TBS) to DXA, individual trabecula segmentation (ITS), and finite element analysis (FEA) modeling to HRpQCT, a more complete profile of skeletal involvement in PHPT has emerged. This chapter reviews this skeletal profile in asymptomatic PHPT, as assessed by these imaging approaches.
    No preview · Chapter · Dec 2015
  • Natalie E. Cusano · Shonni J. Silverberg · John P. Bilezikian
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    ABSTRACT: Primary hyperparathyroidism (PHPT) is a common endocrine disorder traditionally defined by hypercalcemia and elevated parathyroid hormone (PTH) levels. A newer presentation of PHPT has been described over the past decade in which PTH is elevated in the setting of consistently normal serum calcium levels and in the absence of secondary causes of hyperparathyroidism such as renal disease or vitamin D deficiency. Recognition of this newer phenotype of PHPT, normocalcemic PHPT, supports a biphasic chronological time course in which PTH levels are first elevated but serum calcium is normal, followed by the development of frank hypercalcemia in some but not all individuals. Although much remains unknown, this chapter reviews the literature regarding this newly described phenotype of PHPT. © 2015 John P. Bilezikian, Robert Marcus, and Michael A. Levine Published by Elsevier Inc. All rights reserved..
    No preview · Chapter · Dec 2015
  • Mishaela R. Rubin · Claudio Marcocci · John P. Bilezikian
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    ABSTRACT: The effects of chronic parathyroid hormone (PTH) deficiency on the human skeleton are profound. In normal adults, bone mass is regulated by a precise balance between bone resorption and formation in the tightly regulated process of bone remodeling. PTH is a key regulator of the rate and extent of this process, which characteristically decreases with a reduction or absence of circulating PTH with a consequent increase in bone mass. Numerous lines of evidence employing biochemical, imaging, and histomorphometric methodologies have all demonstrated major abnormalities in a skeleton that is deprived of PTH. More recent studies have demonstrated that many of these abnormalities are reversible with PTH treatment.
    No preview · Chapter · Dec 2015
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    John P. Bilezikian · Robert Marcus · Michael A. Levine

    Full-text · Chapter · Dec 2015
  • Dorothy A. Fink · Natalie E. Cusano · Aline G. Costa · John P. Bilezikian
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    ABSTRACT: Hypercalcemia is a common endocrine problem. The most common causes of hypercalcemia are primary hyperparathyroidism in the outpatient and malignancy in the inpatient settings. Together, these two causes of hypercalcemia account for approximately 90% of all cases. Both primary hyperparathyroidism and malignancy have easily recognized laboratory patterns with the proviso that renal function is normal and the patient is not concomitantly taking vitamin D supplementation. It is important to note that although PTH and PTHrP share intense homology at their N-termini, primary hyperparathyroidism is typically associated with levels of 1,25(OH)2D that are in the upper range of normal or frankly elevated. PTHrP-mediated hypercalcemia does not usually cause elevations in 1,25(OH)2D concentrations. This chapter focuses on less common etiologies of hypercalcemia including local and ectopic hormone syndromes. © 2015 John P. Bilezikian, Robert Marcus, and Michael A. Levine Published by Elsevier Inc. All rights reserved..
    No preview · Chapter · Dec 2015
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    ABSTRACT: Primary hyperparathyroidism is a common endocrine disease that has undergone a series of changes in its clinical presentation over the past 60 years. The form of primary hyperparathyroidism (PHPT) that is seen most often in countries where biochemical screening is routine is described as “asymptomatic” because these individuals do not have classical signs and symptoms that are typically associated with hypercalcemia or high levels of parathyroid hormone. Four international workshops on the management of this form of PHPT have been held: 1991, 2002, 2008, and 2013. In this chapter, we present the results of the 2013 conference that led to a revision of the 2008 guidelines. It constitutes an update of evidence-based information about diagnostics, clinical features, and management of this disease. The conference also highlighted areas for which research is needed to clarify issues that remain uncertain or controversial.
    No preview · Chapter · Dec 2015
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    John P. Bilezikian · Robert Marcus · Michael A. Levine

    Full-text · Chapter · Dec 2015

  • No preview · Chapter · Dec 2015
  • Barbara C. Silva · John P. Bilezikian
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    ABSTRACT: Parathyroid hormone (PTH) is essential for the maintenance of the serum calcium concentration within narrow, normal limits, a feat that is achieved, in part, by its ability to regulate bone resorption. In addition to this traditional catabolic role, the osteoanabolic actions of PTH are also well known. Clinically, the catabolic effect of PTH is best represented by primary hyperparathyroidism (PHPT), whereas its osteoanabolic effect is best seen when PTH or its biological amino-terminal fragment [PTH(1-34)] is used as a therapy for osteoporosis. At the cellular level, PTH favors bone resorption, mostly by affecting the RANKL-OPG-RANK system and ultimately increasing both osteoclast recruitment and osteoclast activity. On the osteoanabolic level, PTH increases bone formation, a feat mediated, in part, by control of sclerostin, a regulator of the osteoanabolic Wnt signaling pathway. This chapter focuses on the cellular bases by which PTH exerts these dual anabolic and catabolic actions on the skeleton. © 2015 John P. Bilezikian, Robert Marcus, and Michael A. Levine Published by Elsevier Inc. All rights reserved..
    No preview · Chapter · Dec 2015
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    ABSTRACT: Primary hyperparathyroidism (PHPT) is a relatively common disorder that is often asymptomatic in the western world. Reports of the devastating effects of excess parathyroid hormone (PTH) secretion on the skeleton are both part of the history of the disease and seen now in settings where routine biochemical screening tests are not widespread and vitamin D deficiency is prevalent. Severe bone involvement is now distinctly uncommon. However, the question of bone involvement and fracture risk in PHPT, as part of the current phenotypic presentation of the disease, is an important issue. The introduction of bone densitometry helped to focus attention on the extent and sites of bone loss in mild, asymptomatic PHPT, especially with regard to involvement of the two major skeletal compartments, cortical and cancellous bone. Application of the technique of bone histomorphometry to the percutaneous bone biopsy has also provided much new insight into the effects of mild PHPT on the skeleton. Furthermore, the biopsy sample can be used to investigate the material properties of both the mineral and organic components of the bone matrix. This chapter reviews the histomorphometric characteristics of bone involvement in PHPT and the effects of the disease on the material properties of bone matrix.
    No preview · Chapter · Dec 2015
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    ABSTRACT: Insulin, proinsulin, and C-peptide levels increase with sulfonylurea exposure but the acuity of increase has not been described in dialysis patients. We present a case of a dialysis patient who presented with hypoglycemia and was found to have accidental sulfonylurea ingestion. This is a 73-year-old man with ESRD on peritoneal dialysis, without history of diabetes, who presented with hypoglycemia. Past medical history includes multiple myeloma, congestive heart failure, and hypertension. At initial presentation, his blood glucose was 47 mg/dL, with concomitant elevations in the following: C-peptide 30.5 (nl: 0.8–3.5 ng/mL), insulin 76 (nl: 3–19 μ IU/mL), and proinsulin 83.3 (nl: ≤8.0 pmol/L). During the 72-hour fast, which he completed without hypoglycemia, insulin declined to be within normal limits (to 12 μ IU/mL); proinsulin (to 12.1 pmol/L) and C-peptide (to 7.2 ng/mL) levels decreased but remained elevated. The sulfonylurea screen ultimately returned positive for glipizide, clinching the diagnosis. This is the first reported case which characterizes the chronic elevation of proinsulin in a patient with ESRD, as well as its dramatic increase after a presumed solitary exposure to sulfonylurea. The 72-hour fast conducted gives insight into the clearance of insulin, proinsulin, and C-peptide after sulfonylurea ingestion in ESRD.
    Preview · Article · Dec 2015 · Case Reports in Endocrinology
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    ABSTRACT: The 2015 Santa Fe Bone Symposium was a venue for healthcare professionals and clinical researchers to present and discuss the clinical relevance of recent advances in the science of skeletal disorders, with a focus on osteoporosis and metabolic bone disease. Symposium topics included new developments in the translation of basic bone science to improved patient care, osteoporosis treatment duration, pediatric bone disease, update of fracture risk assessment, cancer treatment-related bone loss, fracture liaison services, a review of the most significant studies of the past year, and the use of telementoring with Bone Health Extension for Community Healthcare Outcomes, a force multiplier to improve the care of osteoporosis in underserved communities.
    No preview · Article · Dec 2015 · Journal of Clinical Densitometry
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    ABSTRACT: Context: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). Objective: To describe the effects of canagliflozin on bone mineral density (BMD) and bone biomarkers in patients with T2DM. Design: Randomized study, consisting of a 26-week, double-blind, placebo-controlled period and a 78-week, double-blind, placebo-controlled extension. Setting: 90 centers in 17 countries. Patients: Aged 55-80 years (N = 716) with T2DM inadequately controlled on a stable antihyperglycemic regimen. Interventions: Canagliflozin 100 or 300 mg or placebo once daily. Outcome: measures: BMD was assessed using dual-energy x-ray absorptiometry at weeks 26, 52, and 104. Bone strength was assessed using quantitative computed tomography and finite element analysis at week 52. Serum collagen type-1 beta-carboxy-telopeptide (beta-CTX), osteocalcin, and estradiol were assessed at weeks 26 and 52. Results: Canagliflozin doses of 100 and 300 mg were associated with a decrease in total hip BMD over 104 weeks, (placebo-subtracted changes: -0.9% and -1.2%, respectively), but not at other sites measured (femoral neck, lumbar spine, or distal forearm). No meaningful changes in bone strength were observed. At week 52, canagliflozin was associated with an increase in beta-CTX that was significantly correlated with a reduction in body weight, an increase in osteocalcin, and, in women, a decrease in estradiol. Conclusions: In older patients with T2DM, canagliflozin showed small but significant reductions in total hip BMD and increases in bone formation and resorption biomarkers, due at least in part to weight loss.
    No preview · Article · Nov 2015 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Context: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). Objective: To describe the effects of canagliflozin on bone fracture risk. Design and setting: Randomized phase 3 studies in patients with T2DM. Patients and interventions: Canagliflozin 100 and 300 mg were evaluated in the overall population of patients from 9 placebo- and active-controlled studies (N=10194), as well as in separate analyses of a single trial enriched with patients with a prior history/risk of cardiovascular disease (ie, CANagliflozin cardioVascular Assessment Study [CANVAS]; N=4327) and a pooled population of 8 non-CANVAS studies (N=5867). Outcome: Measures: Incidence of adjudicated fracture adverse events (AEs), fall-related AEs, and volume depletion-related AEs were assessed. Results: The incidence of fractures was similar with canagliflozin (1.7%) and non- canagliflozin (1.5%) in the pooled non-CANVAS studies. In CANVAS, a significant increase in fractures was seen with canagliflozin (4.0%) versus placebo (2.6%) that was balanced between upper and lower limbs. The incidence of fractures was higher with canagliflozin (2.7%) versus non-canagliflozin (1.9%) in the overall population that was driven by the increase of fractures in CANVAS. The incidence of reported fall-related AEs was low, but significantly higher with canagliflozin in CANVAS, potentially related to volume depletion-related AEs, but not significantly different in the pooled non-CANVAS studies and the overall population. Conclusions: Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with prior history/risk of cardiovascular disease, and with lower baseline eGFR and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown.
    No preview · Article · Nov 2015 · The Journal of Clinical Endocrinology and Metabolism

  • No preview · Article · Nov 2015 · Osteoporosis International
  • Aline G Costa · John P Bilezikian
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    ABSTRACT: Chronic diseases typically require long-term treatment. Osteoporosis is a chronic disease in which fracture risk is high, and treatment is required to prevent fragility fractures. Denosumab is a fully human monoclonal antibody that inhibits RANK ligand, a powerful bone-resorbing cytokine. It is approved for individuals with osteoporosis who are at high risk for fracture. Clinical trial results confirm that denosumab is effective over the long term and has an excellent safety profile. In patients at high risk for osteoporotic fracture, therefore, long-term treatment with denosumab appears to present an attractive benefit profile.
    No preview · Article · Oct 2015 · Current Osteoporosis Reports

  • No preview · Article · Sep 2015
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    ABSTRACT: In hypoparathyroidism, areal bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) is above average and skeletal indices by bone biopsy are abnormal. We used high resolution peripheral quantitative computed tomography (HRpQCT) and finite element analysis (FEA) to further investigate skeletal microstructure and estimated bone strength. We studied 60 hypoparathyroid subjects on conventional therapy using DXA, HRpQCT and FEA of the distal radius and tibia compared to normative controls from the Canadian Multicentre Osteoporosis Study. In hypoparathyroid women and men, areal BMD was above average at the lumbar spine and hip sites by DXA; radial BMD was also above average in hypoparathyroid women. Using HRpQCT, cortical volumetric BMD was increased in the hypoparathyroid cohort compared to controls at both the radius and tibia. Cortical porosity was reduced at both sites in pre- and postmenopausal women and at the tibia in young men with a downward trend at the radius in men. At the tibia, trabecular number was increased in premenopausal women and men and trabecular thickness was lower in women. Ultimate stress and failure load at both sites for the hypoparathyroid subjects were similar to controls. Using a linear regression model, at both radius and tibia, each increment in age decreased ultimate stress and failure load while each increment in duration of hypoparathyroidism increased these same indices. These results provide additional evidence for the critical role of parathyroid hormone in regulating skeletal microstructure. Longer disease duration may mitigate the adverse effects of age on estimated bone strength in hypoparathyroidism. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
  • Aline G Costa · John P Bilezikian · E Michael Lewiecki
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    ABSTRACT: Sclerostin is a regulator of the osteoanabolic canonical Wnt signaling pathway, and thus helps to govern rates of bone formation. The Wnt pathway is also recognized as playing an important role in the pathophysiology of the chronic kidney disease - mineral and bone disorder (CKD-MBD). It also may serve as an interface between bone and the vascular system. Pharmacological inhibition of sclerostin has shown promise as an osteoanabolic approach to the treatment of osteoporosis. Inhibition of sclerostin is a potentially useful but unproven strategy in the management of CKD-MBD. Clinical trials with humanized monoclonal sclerostin antibodies (Scl-Ab) have shown a rapid initial increase in bone formation and a marked increase in bone mineral density. Although clinical data, to this point, in CKD are not available, animal models of low bone turnover CKD show that Scl-Ab improves trabecular bone volume and mineralization without affecting biochemical indices. Targeted clinical trials are needed to evaluate the potential effectiveness of Scl-Ab in CKD. Based upon the available data, there is potential not only for this new therapeutic class to improve skeletal health but perhaps also to have substantial cardiovascular benefits in CKD.
    No preview · Article · Jul 2015 · Current Opinion in Nephrology and Hypertension

Publication Stats

24k Citations
3,520.12 Total Impact Points

Institutions

  • 1978-2015
    • Columbia University
      • • College of Physicians and Surgeons
      • • Division of Endocrinology
      • • Department of Pharmacology
      • • Department of Medicine
      New York, New York, United States
    • CUNY Graduate Center
      New York, New York, United States
  • 2010
    • Università degli Studi di Brescia
      • Department of Medicine and Surgery
      Brescia, Lombardy, Italy
  • 1984-2009
    • New York Medical College
      • Department of Medicine
      New York City, NY, United States
  • 2003-2007
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2006
    • University of Cincinnati Medical Center
      Cincinnati, Ohio, United States
  • 2005
    • Indiana University-Purdue University Indianapolis
      • Department of Medicine
      Indianapolis, IN, United States
    • University of California, San Francisco
      • Department of Epidemiology and Biostatistics
      San Francisco, CA, United States
    • Università degli Studi di Siena
      • Department of Medicine, Surgery and Neuroscience
      Siena, Tuscany, Italy
  • 1990-2001
    • Helen Hayes Hospital
      West Haverstraw, New York, United States
    • Gracie Square Hospital, New York, NY
      New York, New York, United States
  • 1990-1997
    • Albert Einstein College of Medicine
      • Department of Pathology
      New York City, NY, United States
  • 1995
    • Temple University
      Philadelphia, Pennsylvania, United States
  • 1987
    • National Institutes of Health
      • Branch of Metabolic Diseases Branch (MDB)
      베서스다, Maryland, United States