Abaloparatide, a Novel PTH Receptor Agonist, Increased Bone Mass and Strength in Ovariectomized Cynomolgus Monkeys by Increasing Bone Formation Without Increasing Bone Resorption

Overview

Journal Osteoporos Int

Specialties Endocrinology
Orthopedics

Date 2017 Dec 21

PMID 29260289

Citations 34

Authors

N Doyle

A Varela

S Haile

R Guldberg

P J Kostenuik

M S Ominsky

S Y Smith

G Hattersley

Affiliations

Soon will be listed here.

Abstract

Introduction: Abaloparatide is a selective PTH1R activator that is approved for the treatment of postmenopausal osteoporosis. The effects of 16 months of abaloparatide administration on bone formation, resorption, density, and strength were assessed in adult ovariectomized (OVX) cynomolgus monkeys (cynos).

Methods: Sixty-five 9-18-year-old female cynos underwent OVX surgery, and 15 similar cynos underwent sham surgery. After a 9-month period without treatments, OVX cynos were allocated to four groups that received 16 months of daily s.c. injections with either vehicle (n = 17) or abaloparatide (0.2, 1, or 5 μg/kg/day; n = 16/dose level), while Sham controls received s.c. vehicle (n = 15). Bone densitometry (DXA, pQCT, micro-CT), qualitative bone histology, serum calcium, bone turnover markers, bone histomorphometry, and bone strength were among the key measures assessed.

Results: At the end of the 9-month post-surgical bone depletion period, just prior to the treatment phase, the OVX groups exhibited increased bone turnover markers and decreased bone mass compared with sham controls. Abaloparatide administration to OVX cynos led to increased bone formation parameters, including serum P1NP and endocortical bone formation rate. Abaloparatide administration did not influence serum calcium levels, bone resorption markers, cortical porosity, or eroded surfaces. Abaloparatide increased bone mass at the whole body, lumbar spine, tibial diaphysis, femoral neck, and femoral trochanter. Abaloparatide administration was associated with greater lumbar vertebral strength, and had no adverse effects on bone mass-strength relationships for the vertebrae, femoral neck, femoral diaphysis, or humeral cortical beams.

Conclusions: Abaloparatide administration was associated with increases in bone formation, bone mass and bone strength, and with maintenance of bone quality in OVX cynos, without increases in serum calcium or bone resorption parameters.

Citing Articles

Histological assessments for anabolic effects in teriparatide/abaloparatide administered rodent models.

Hasegawa T, Yamamoto T, Haraguchi-Kitakamae M, Hongo H, Shi Y, Cui J J Bone Miner Metab. 2024; .

PMID: 39630261 DOI: 10.1007/s00774-024-01562-y.

PTH receptor signalling, osteocytes and bone disease induced by diabetes mellitus.

Marino S, Bellido T Nat Rev Endocrinol. 2024; 20(11):661-672.

PMID: 39020007 DOI: 10.1038/s41574-024-01014-7.

Effects of Abaloparatide on Bone Mineral Density in Proximal Femoral Regions Corresponding to Arthroplasty Gruen Zones: A Study of Postmenopausal Women with Osteoporosis.

Sheth N, Smith J, Winzenrieth R, Humbert L, Wang Y, Boxberger J J Bone Joint Surg Am. 2024; 106(13):1162-1170.

PMID: 38691582 PMC: 11594069. DOI: 10.2106/JBJS.23.01334.

Optimal Intermittent Administration Interval of Abaloparatide for Bone Morphogenetic Protein-Induced Bone Formation in a Rat Spinal Fusion Model.

Abe T, Miyazaki M, Sako N, Kanezaki S, Tsubouchi Y, Kaku N Int J Mol Sci. 2024; 25(7).

PMID: 38612467 PMC: 11011974. DOI: 10.3390/ijms25073655.

Response rates for lumbar spine, total hip, and femoral neck bone mineral density in men treated with abaloparatide: results from the ATOM study.

Dhaliwal R, Kendler D, Saag K, Ing S, Singer A, Adler R JBMR Plus. 2024; 8(2):ziae009.

PMID: 38505522 PMC: 10945712. DOI: 10.1093/jbmrpl/ziae009.

References

Leder B, Tsai J, Uihlein A, Burnett-Bowie S, Zhu Y, Foley K . Two years of Denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial. J Clin Endocrinol Metab. 2014; 99(5):1694-700. PMC: 4010689. DOI: 10.1210/jc.2013-4440. View

Sato M, Westmore M, Clendenon J, Smith S, Hannum B, Zeng G . Three-dimensional modeling of the effects of parathyroid hormone on bone distribution in lumbar vertebrae of ovariectomized cynomolgus macaques. Osteoporos Int. 2001; 11(10):871-80. DOI: 10.1007/s001980070047. View

Ito M, Ikeda K, Nishiguchi M, Shindo H, Uetani M, Hosoi T . Multi-detector row CT imaging of vertebral microstructure for evaluation of fracture risk. J Bone Miner Res. 2005; 20(10):1828-36. DOI: 10.1359/JBMR.050610. View

Varela A, Chouinard L, Lesage E, Guldberg R, Smith S, Kostenuik P . One year of abaloparatide, a selective peptide activator of the PTH1 receptor, increased bone mass and strength in ovariectomized rats. Bone. 2016; 95:143-150. DOI: 10.1016/j.bone.2016.11.027. View

Sato M, Westmore M, Ma Y, Schmidt A, Zeng Q, Glass E . Teriparatide [PTH(1-34)] strengthens the proximal femur of ovariectomized nonhuman primates despite increasing porosity. J Bone Miner Res. 2004; 19(4):623-9. DOI: 10.1359/JBMR.040112. View

Kostenuik P, Capparelli C, Morony S, Adamu S, Shimamoto G, Shen V . OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology. 2001; 142(10):4295-304. DOI: 10.1210/endo.142.10.8437. View

Leder B, ODea L, Zanchetta J, Kumar P, Banks K, McKay K . Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2014; 100(2):697-706. DOI: 10.1210/jc.2014-3718. View

Black D, Greenspan S, Ensrud K, Palermo L, McGowan J, Lang T . The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003; 349(13):1207-15. DOI: 10.1056/NEJMoa031975. View

Tsai J, Uihlein A, Lee H, Kumbhani R, Siwila-Sackman E, McKay E . Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet. 2013; 382(9886):50-6. PMC: 4083737. DOI: 10.1016/S0140-6736(13)60856-9. View

10.

Ominsky M, Stouch B, Schroeder J, Pyrah I, Stolina M, Smith S . Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone. 2011; 49(2):162-73. DOI: 10.1016/j.bone.2011.04.001. View

11.

Body J, Gaich G, Scheele W, Kulkarni P, Miller P, Peretz A . A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002; 87(10):4528-35. DOI: 10.1210/jc.2002-020334. View

12.

Fox J, Miller M, NEWMAN M, Recker R, Turner C, Smith S . Effects of daily treatment with parathyroid hormone 1-84 for 16 months on density, architecture and biomechanical properties of cortical bone in adult ovariectomized rhesus monkeys. Bone. 2007; 41(3):321-30. DOI: 10.1016/j.bone.2007.04.197. View

13.

Parfitt A, Drezner M, Glorieux F, Kanis J, MALLUCHE H, Meunier P . Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987; 2(6):595-610. DOI: 10.1002/jbmr.5650020617. View

14.

Boyce R, Paddock C, Franks A, Jankowsky M, Eriksen E . Effects of intermittent hPTH(1-34) alone and in combination with 1,25(OH)(2)D(3) or risedronate on endosteal bone remodeling in canine cancellous and cortical bone. J Bone Miner Res. 1996; 11(5):600-13. DOI: 10.1002/jbmr.5650110508. View

15.

Fox J, Miller M, Recker R, Turner C, Smith S . Effects of treatment of ovariectomized adult rhesus monkeys with parathyroid hormone 1-84 for 16 months on trabecular and cortical bone structure and biomechanical properties of the proximal femur. Calcif Tissue Int. 2007; 81(1):53-63. DOI: 10.1007/s00223-007-9036-y. View

16.

Burr D, Hirano T, Turner C, Hotchkiss C, Brommage R, Hock J . Intermittently administered human parathyroid hormone(1-34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys. J Bone Miner Res. 2001; 16(1):157-65. DOI: 10.1359/jbmr.2001.16.1.157. View

17.

Lafage M, Balena R, Battle M, Shea M, Seedor J, Klein H . Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study. J Clin Invest. 1995; 95(5):2127-33. PMC: 295812. DOI: 10.1172/JCI117901. View

18.

Fox J, Miller M, Newman M, Turner C, Recker R, Smith S . Treatment of skeletally mature ovariectomized rhesus monkeys with PTH(1-84) for 16 months increases bone formation and density and improves trabecular architecture and biomechanical properties at the lumbar spine. J Bone Miner Res. 2006; 22(2):260-73. DOI: 10.1359/jbmr.061101. View

19.

Miller P, Hattersley G, Riis B, Williams G, Lau E, Russo L . Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial. JAMA. 2016; 316(7):722-33. DOI: 10.1001/jama.2016.11136. View

20.

Finkelstein J, Hayes A, Hunzelman J, Wyland J, Lee H, Neer R . The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med. 2003; 349(13):1216-26. DOI: 10.1056/NEJMoa035725. View