Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism

Yu Shao, Selene Hernandez-Buquer, Paul Childress, Keith R. Stayrook, Marta B. Alvarez, Hannah Davis, Lilian Plotkin, Yongzheng He, Keith W. Condon, David Burr, Stuart J. Warden, Alexander Robling, Feng Chun Yang, Ronald Wek, Matthew Allen, Joseph Bidwell

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2722-2740
Number of pages19
JournalEndocrinology
Volume158
Issue number9
DOIs
StatePublished - Sep 1 2017

Fingerprint

zoledronic acid
Parathyroid Hormone
Osteoporosis
Osteogenesis
Therapeutics
Bone and Bones
Alendronate
Thigh
Adipogenesis
Osteocalcin
Raloxifene Hydrochloride
Osteoblasts
Skeleton
Transcription Factors
Biomarkers
Bone Marrow
Genotype

ASJC Scopus subject areas

  • Endocrinology

Cite this

Shao, Y., Hernandez-Buquer, S., Childress, P., Stayrook, K. R., Alvarez, M. B., Davis, H., ... Bidwell, J. (2017). Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism. Endocrinology, 158(9), 2722-2740. https://doi.org/10.1210/en.2017-00355

Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism. / Shao, Yu; Hernandez-Buquer, Selene; Childress, Paul; Stayrook, Keith R.; Alvarez, Marta B.; Davis, Hannah; Plotkin, Lilian; He, Yongzheng; Condon, Keith W.; Burr, David; Warden, Stuart J.; Robling, Alexander; Yang, Feng Chun; Wek, Ronald; Allen, Matthew; Bidwell, Joseph.

In: Endocrinology, Vol. 158, No. 9, 01.09.2017, p. 2722-2740.

Research output: Contribution to journalArticle

Shao, Y, Hernandez-Buquer, S, Childress, P, Stayrook, KR, Alvarez, MB, Davis, H, Plotkin, L, He, Y, Condon, KW, Burr, D, Warden, SJ, Robling, A, Yang, FC, Wek, R, Allen, M & Bidwell, J 2017, 'Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism', Endocrinology, vol. 158, no. 9, pp. 2722-2740. https://doi.org/10.1210/en.2017-00355
Shao Y, Hernandez-Buquer S, Childress P, Stayrook KR, Alvarez MB, Davis H et al. Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism. Endocrinology. 2017 Sep 1;158(9):2722-2740. https://doi.org/10.1210/en.2017-00355
Shao, Yu ; Hernandez-Buquer, Selene ; Childress, Paul ; Stayrook, Keith R. ; Alvarez, Marta B. ; Davis, Hannah ; Plotkin, Lilian ; He, Yongzheng ; Condon, Keith W. ; Burr, David ; Warden, Stuart J. ; Robling, Alexander ; Yang, Feng Chun ; Wek, Ronald ; Allen, Matthew ; Bidwell, Joseph. / Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism. In: Endocrinology. 2017 ; Vol. 158, No. 9. pp. 2722-2740.
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