Parathyroid Hormone-Related Protein for the Treatment of Postmenopausal Osteoporosis: Defining the Maximal Tolerable Dose

被引:73
作者
Horwitz, Mara J. [1 ]
Tedesco, Mary Beth [1 ]
Garcia-Ocana, Adolfo [1 ]
Sereika, Susan M. [3 ]
Prebehala, Linda [1 ]
Bisello, Alessandro [2 ]
Hollis, Bruce W. [4 ]
Gundberg, Caren M. [5 ]
Stewart, Andrew F. [1 ]
机构
[1] Univ Pittsburgh, Sch Med, Div Endocrinol & Metab, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA
[3] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA
[4] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA
[5] Yale Univ, Sch Med, Dept Orthoped, New Haven, CT 06520 USA
基金
美国国家卫生研究院;
关键词
BONE TURNOVER MARKERS; HUMORAL HYPERCALCEMIA; HUMAN VOLUNTEERS; MINERAL DENSITY; WOMEN; 1,25-DIHYDROXYVITAMIN-D; HEALTHY; PEPTIDE; PTHRP; MASS;
D O I
10.1210/jc.2009-0233
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
Context: PTH is the only approved skeletal anabolic agent for the treatment of human osteoporosis. Unlike PTH, which is a mixed anabolic and catabolic agent, PTHrP displays features suggesting that it may be a pure anabolic agent when intermittently administered. The full dose range of PTHrP is unknown. Objectives: The primary objective of the study was to define the complete therapeutic window and dose-limiting toxicities of PTHrP. The secondary objective was to determine whether PTHrP retains a pure anabolic profile at the highest usable doses. Design: This was a single-blinded, two-part, dose-escalating clinical trial. Setting: The study was conducted in a university academic setting. Patients or Other Participants: Participants included 41 healthy postmenopausal women between the ages of 45 and 75 yr. Intervention: Interventions included PTHrP(1-36) or placebo in a dose-escalating design for 3 wk. Main Outcome Measures: Safety measures (hypercalcemia, nausea, vomiting, hemodynamics, flushing, miscellaneous) and bone turnover markers were measured. Results: Intermittent PTHrP was administered safely and without serious adverse events in subjects receiving 500 and 625 mu g/d for 3 wk. Subjects receiving 750 mu g/d developed mild hypercalcemia. Bone turnover markers suggested that even at the highest doses, daily sc PTHrP may not activate bone resorption, i.e. may be purely anabolic. Interestingly, when hypercalcemia occurred, it may have resulted not from bone resorption but from activation of intestinal calcium absorption by 1,25 dihydroxyvitamin D. Conclusions: In doses as high as 750 mu g/d, in contrast to PTH, intermittently administered PTHrP appears to act as a pure skeletal anabolic agent. Surprisingly, PTHrP in the high doses studied activates 1,25 dihydroxyvitamin D production. Dosing information obtained herein can be used to design a longer term head-to-head comparative efficacy trial of PTHrP vs. PTH. (J Clin Endocrinol Metab 95: 1279-1287, 2010)
引用
收藏
页码:1279 / 1287
页数:9
相关论文
共 33 条
[1]
Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development [J].
Amizuka, N ;
Karaplis, AC ;
Henderson, JE ;
Warshawsky, H ;
Lipman, ML ;
Matsuki, Y ;
Ejiri, S ;
Tanaka, M ;
Izumi, N ;
Ozawa, H ;
Goltzman, D .
DEVELOPMENTAL BIOLOGY, 1996, 175 (01) :166-176
[2]
The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis [J].
Black, DM ;
Greenspan, SL ;
Ensrud, KE ;
Palermo, L ;
McGowan, JA ;
Lang, TF ;
Garnero, P ;
Bouxsein, ML ;
Bilezikian, JP ;
Rosen, CJ .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (13) :1207-1215
[3]
Cosman F, 2007, J BONE MINER RES, V22, pS210
[4]
Daily and cyclic parathyroid hormone in women receiving alendronate [J].
Cosman, F ;
Nieves, J ;
Zion, M ;
Woelfert, L ;
Luckey, M ;
Lindsay, R .
NEW ENGLAND JOURNAL OF MEDICINE, 2005, 353 (06) :566-575
[5]
A cross-sectional study of bone turnover markers in healthy premenopausal women [J].
de Papp, Anne E. ;
Bone, Henry G. ;
Caulfield, Michael P. ;
Kagan, Risa ;
Buinewicz, Anna ;
Chen, Erluo ;
Rosenberg, Elizabeth ;
Reitz, Richard E. .
BONE, 2007, 40 (05) :1222-1230
[6]
Altered selectivity of parathyroid hormone (PTH) and PTH-Related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor [J].
Dean, Thomas ;
Vilardaga, Jean-Pierre ;
Potts, John T., Jr. ;
Gardella, Thomas J. .
MOLECULAR ENDOCRINOLOGY, 2008, 22 (01) :156-166
[7]
Parathyroid hormone (PTH)-related protein(1-36) is equipment to PTH(1-34) in humans [J].
EverhartCaye, M ;
Inzucchi, SE ;
GuinnessHenry, J ;
Mitnick, MA ;
Stewart, AF .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1996, 81 (01) :199-208
[8]
The effects of parathyroid hormone, alendronate, or both in men with osteoporosis [J].
Finkelstein, JS ;
Hayes, A ;
Hunzelman, JL ;
Wyland, JJ ;
Lee, H ;
Neer, RM .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (13) :1216-1226
[9]
Establishing a Reference Interval for Bone Turnover Markers in 637 Healthy, Young, Premenopausal Women From the United Kingdom, France, Belgium, and the United States [J].
Glover, Sarah J. ;
Gall, Martin ;
Schoenborn-Kellenberger, Oliver ;
Wagener, Michael ;
Garnero, Patrick ;
Boonen, Steven ;
Cauley, Jane A. ;
Black, Dennis M. ;
Delmas, Pierre D. ;
Eastell, Richard .
JOURNAL OF BONE AND MINERAL RESEARCH, 2009, 24 (03) :389-397
[10]
Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis - A randomized trial [J].
Greenspan, Susan L. ;
Bone, Henry G. ;
Ettinger, Mark P. ;
Hanley, David A. ;
Lindsay, Robert ;
Zanchetta, Jose R. ;
Blosch, Consuelo M. ;
Mathisen, Annette L. ;
Morris, Stephen A. ;
Marriott, Thomas B. .
ANNALS OF INTERNAL MEDICINE, 2007, 146 (05) :326-339