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Endocrinology. 2017 Sep 1;158(9):2722-2740. doi: 10.1210/en.2017-00355.

Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism.

Author information

1
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
2
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
3
Department of Orthopedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202.
4
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
5
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
6
Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
7
Center for Translational Musculoskeletal Research, School of Health and Rehabilitation Sciences, Indiana University, Indianapolis, Indiana 46202.
8
Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, Indianapolis, Indiana 46202.
9
Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida 33136.
10
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
11
Richard A. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana 46202.

Abstract

Combining anticatabolic agents with parathyroid hormone (PTH) to enhance bone mass has yielded mixed results in osteoporosis patients. Toward the goal of enhancing the efficacy of these regimens, we tested their utility in combination with loss of the transcription factor Nmp4 because disabling this gene amplifies PTH-induced increases in trabecular bone in mice by boosting osteoblast secretory activity. We addressed whether combining a sustained anabolic response with an anticatabolic results in superior bone acquisition compared with PTH monotherapy. Additionally, we inquired whether Nmp4 interferes with anticatabolic efficacy. Wild-type and Nmp4-/- mice were ovariectomized at 12 weeks of age, followed by therapy regimens, administered from 16 to 24 weeks, and included individually or combined PTH, alendronate (ALN), zoledronate (ZOL), and raloxifene (RAL). Anabolic therapeutic efficacy generally corresponded with PTH + RAL = PTH + ZOL > PTH + ALN = PTH > vehicle control. Loss of Nmp4 enhanced femoral trabecular bone increases under PTH + RAL and PTH + ZOL. RAL and ZOL promoted bone restoration, but unexpectedly, loss of Nmp4 boosted RAL-induced increases in femoral trabecular bone. The combination of PTH, RAL, and loss of Nmp4 significantly increased bone marrow osteoprogenitor number, but did not affect adipogenesis or osteoclastogenesis. RAL, but not ZOL, increased osteoprogenitors in both genotypes. Nmp4 status did not influence bone serum marker responses to treatments, but Nmp4-/- mice as a group showed elevated levels of the bone formation marker osteocalcin. We conclude that the heightened osteoanabolism of the Nmp4-/- skeleton enhances the effectiveness of diverse osteoporosis treatments, in part by increasing hyperanabolic osteoprogenitors. Nmp4 provides a promising target pathway for identifying barriers to pharmacologically induced bone formation.

PMID:
28637206
PMCID:
PMC5659666
DOI:
10.1210/en.2017-00355
[Indexed for MEDLINE]
Free PMC Article

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