Abaloparatide, a novel osteoanabolic PTHrP analog, increases cortical and trabecular bone mass and architecture in orchiectomized rats by increasing bone formation without increasing bone resorption

被引:32
作者
Chandler, Heidi [1 ]
Lanske, Beate [1 ]
Varela, Aurore [2 ]
Guillot, Martin [2 ]
Boyer, Marilyne [2 ]
Brown, Jeffrey [1 ]
Pierce, Allen [1 ]
Ominsky, Michael [1 ]
Mitlak, Bruce [1 ]
Baron, Roland [3 ]
Kostenuik, Paul [4 ,5 ]
Hattersley, Gary [1 ]
机构
[1] Radius Hlth, Waltham, MA USA
[2] Charles River Labs, Senneville, PQ, Canada
[3] Harvard Sch Dent Med, Boston, MA USA
[4] Phylon Pharma Serv, Newbury Pk, CA USA
[5] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA
关键词
Hypogonadism; Bone loss; Bone formation; PTH1R; Androgen deficiency; Bone mineral density; POSTMENOPAUSAL WOMEN; ANDROGEN-DEPRIVATION; RECEPTOR AGONIST; OLDER MEN; OSTEOPOROSIS; STRENGTH; DENSITY; HISTOMORPHOMETRY; TERIPARATIDE; DEFICIENCY;
D O I
10.1016/j.bone.2018.10.012
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
Male osteoporosis can occur with advanced age and with hypogonadism, with increased bone resorption and/or inadequate bone formation contributing to reduced bone mass and increased fracture risk. Abaloparatide is a selective PTH receptor agonist that increases bone formation and bone mass in postmenopausal women with osteoporosis and in estrogen-deficient animals. The current study evaluated the effects of abaloparatide in orchiectomized (ORX) rats, a model of male osteoporosis. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery; 8 weeks later the ORX groups exhibited relative osteopenia vs sham controls, based on dual X-ray absorptiometry (DXA) and/or peripheral quantitative computed tomography (pQCT) assessments at the total body, lumbar spine, femur, and tibia. ORX rats (n = 10/group) were then injected daily (s.c.) for 8 weeks with vehicle or abaloparatide at 5 (ABL5) or 25 mu g/kg/d (ABL25). Sham controls (n = 10) received s.c. vehicle. DXA and pQCT showed that one or both abaloparatide groups gained more areal and volumetric BMD at all sites analyzed compared with vehicle controls, leading to substantial or complete reversal of ORX-induced BMD deficits. pQCT also indicated greater gains in tibial cortical thickness in both abaloparatide groups versus vehicle controls. Tibial bone histomorphometry showed greater trabecular bone formation and bone volume and improved micro-architecture with abaloparatide, with no increase in osteoclasts. Abaloparatide also led to significant improvements in the balance of biochemical bone formation markers versus bone resorption markers, which correlated with BMD changes. These findings suggest that abaloparatide may have therapeutic benefits in men with osteoporosis.
引用
收藏
页码:148 / 155
页数:8
相关论文
共 38 条
[1]
Bone loss and bone size after menopause [J].
Ahlborg, HG ;
Johnell, O ;
Turner, CH ;
Rannevik, G ;
Karlsson, MK .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (04) :327-334
[2]
[Anonymous], 2011, Guide for the care and use of laboratory animals, DOI DOI 10.17226/12910
[3]
Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025 [J].
Burge, Russel ;
Dawson-Hughes, Bess ;
Solomon, Daniel H. ;
Wong, John B. ;
King, Alison ;
Tosteson, Anna .
JOURNAL OF BONE AND MINERAL RESEARCH, 2007, 22 (03) :465-475
[4]
Mortality after all major types of osteoporotic fracture in men and women: an observational study [J].
Center, JR ;
Nguyen, TV ;
Schneider, D ;
Sambrook, PN ;
Eisman, JA .
LANCET, 1999, 353 (9156) :878-882
[5]
Chandler H, 2017, J BONE MINER RES, V32, pS275
[6]
Chiang C, 2009, J BONE MINER RES, V24, P621, DOI [10.1359/jbmr.081217, 10.1359/JBMR.081217]
[7]
Eighteen Months of Treatment With Subcutaneous Abaloparatide Followed by 6 Months of Treatment With Alendronate in Postmenopausal Women With Osteoporosis: Results of the ACTIVExtend Trial [J].
Cosman, Felicia ;
Miller, Paul D. ;
Williams, Gregory C. ;
Hattersley, Gary ;
Hu, Ming-yi ;
Valter, Ivo ;
Fitzpatrick, Lorraine A. ;
Riis, Bente Juel ;
Christiansen, Claus ;
Bilezikian, John P. ;
Black, Dennis .
MAYO CLINIC PROCEEDINGS, 2017, 92 (02) :200-210
[8]
Standardized Nomenclature, Symbols, and Units for Bone Histomorphometry: A 2012 Update of the Report of the ASBMR Histomorphometry Nomenclature Committee [J].
Dempster, David W. ;
Compston, Juliet E. ;
Drezner, Marc K. ;
Glorieux, Francis H. ;
Kanis, John A. ;
Malluche, Hartmut ;
Meunier, Pierre J. ;
Ott, Susan M. ;
Recker, Robert R. ;
Parfitt, A. Michael .
JOURNAL OF BONE AND MINERAL RESEARCH, 2013, 28 (01) :1-16
[9]
Abaloparatide, a novel PTH receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption [J].
Doyle, N. ;
Varela, A. ;
Haile, S. ;
Guldberg, R. ;
Kostenuik, P. J. ;
Ominsky, M. S. ;
Smith, S. Y. ;
Hattersley, G. .
OSTEOPOROSIS INTERNATIONAL, 2018, 29 (03) :685-697
[10]
Male Osteoporosis [J].
Drake, Matthew T. ;
Khosla, Sundeep .
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA, 2012, 41 (03) :629-+