Enhancing Bone Regeneration and Osseointegration using rhPTH(1-34) and Dimeric R25C PTH(1-34) in an Osteoporotic Beagle Model

  1. Jeong-Oh Shin
  2. Jong-Bin Lee
  3. Sihoon Lee
  4. Jin-Woo Kim

  • Curated by eLife

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    eLife assessment

    This work by Shin et al. demonstrated that a different form of PTH (R25C PTH) generated a comparable anabolic signal to rhPTH 1-34 using a large animal model. This valuable finding may have therapeutic potential in promoting bone formation or the healing process, and the methods seem solid.

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Abstract

Introduction

Despite continuous parathyroid hormone (PTH) exposure potentially accelerating bone resorption, intermittent PTH administration has shown anabolic effects on bone microarchitecture. This study investigates the therapeutic impacts of two PTH analogs, rhPTH(1-34) and dimeric R25C PTH(1-34) on bone regeneration and osseointegration in a postmenopausal osteoporosis animal model.

Methods

Twelve female beagles, osteoporotic post-ovariectomy, underwent implant surgeries. Animals were divided into three groups: control, daily rhPTH(1-34) injection, and daily dimeric R25C PTH(1-34) injection. After 10 weeks, bone regeneration and implant osseointegration were evaluated using micro-CT, histological/histomorphometric analyses, and serum biochemical analysis.

Results

While the rhPTH(1-34) group demonstrated improved microarchitectural characteristics, such as BMD, BV, trabecular metrics, and osseointegration degree, the dimeric R25C PTH(1-34) group showed similarly enhanced anabolic effects around the titanium implants, albeit these were less pronounced than the rhPTH(1-34), yet significantly better than the control group. Histologic and TRAP assays revealed that both PTH analogs significantly promoted bone regeneration and remodeling, especially in artificially created bone defects.

Conclusion

This study demonstrated the therapeutic effects of rhPTH(1-34) and dimeric R25C PTH(1-34) on bone regeneration and titanium osseointegration in a beagle model with osteoporosis.

Article activity feed

  1. Version published to 10.1101/2024.02.10.579779v2 on bioRxiv
  2. Version published to 10.7554/elife.93830 on eLife
  3. Version published to 10.7554/elife.93830.1 on eLife
  4. eLife

    eLife assessment

    This work by Shin et al. demonstrated that a different form of PTH (R25C PTH) generated a comparable anabolic signal to rhPTH 1-34 using a large animal model. This valuable finding may have therapeutic potential in promoting bone formation or the healing process, and the methods seem solid.

  5. eLife

    Reviewer #1 (Public Review):

    Summary:

    This study, titled "Enhancing Bone Regeneration and Osseointegration using rhPTH(1-34) and Dimeric R25CPTH(1-34) in an Osteoporotic Beagle Model," provides valuable insights into the therapeutic effects of two parathyroid hormone (PTH) analogs on bone regeneration and osseointegration. The research is methodologically sound, employing a robust animal model and a comprehensive array of analytical techniques, including micro-CT, histological/histomorphometric analyses, and serum biochemical analysis.

    Strengths:

    The use of a large animal model, which closely mimics postmenopausal osteoporosis in humans, enhances the study's relevance to clinical applications. The study is well-structured, with clear objectives, detailed methods, and a logical flow from introduction to conclusion. The findings are significant, demonstrating the potential of rhPTH(1-34) and dimeric R25CPTH(1-34) in enhancing bone regeneration, particularly in the context of osteoporosis.

    Weaknesses:

    There are no major weaknesses.

  6. eLife

    Reviewer #2 (Public Review):

    Summary:

    This article explores the regenerative effects of recombinant PTH analogues on osteogenesis.

    Strengths:

    Although PTH has known to induce the activity of osteoclasts, accelerating bone resorption, paradoxically its intermittent use has become a common treatment for osteoporosis. Previous studies successfully demonstrated this phenomenon in vivo, but most of them used rodent animal models, inevitably having a limitation. In this article, the authors tried to address this, using a beagle model, and assessed the osseointegrative effect of recombinant PTH analogues. As a result, the authors clearly observed the regenerative effects of PTH analogues, and compared the efficacy, using histologic, biochemical, and radiologic measurement for surgical-endocrinal combined large animal models. The data seem to be solid, and has potential clinical implications.

    Weaknesses:

    As PTH's mechanism has already been widely accepted, and the main focus of this article was to compare the preclinical efficacy of PTH analogues, the lack of detail biologic mechanism could be allowed. However, there are some suggestions to enhance the readability of the article:

    First, the authors should clarify why they compared the effects of rhPTH(1-34) and of dimeric R25C2 PTH(1-34)? In most of the parameters, rhPTH(1-34) seems to be superior to dimeric R25C2 PTH(1-34). Why did the authors insist that the anabolic effects of dimer were prominent? Even though implication of dimeric R25C2 PTH(1-34) was drawn from genetic mutation studies, the authors should describe more clearly in the discussion the potential clinical benefits of the dimeric R25C2 PTH(1-34) compared to rhPTH(1-34), especially if dimeric R25C2 PTH(1-34) has just partial agonistic effect in pharmacodynamics.

    Second, please describe the intermittent and continuous application of PTH analogues. Many of the readers may misunderstand that the authors' daily injection of PTHs were actually to mimic the clinical intermittent application or continuous one. Incorporation of the author's intention for experimental design would be more helpful for readers.

    Third, please unify the nomenclature. Ensure consistency in the nomenclature throughout the article. Unify the naming conventions for PTH analogues, such as rhPTH(1-34) vs teriparatide and (Cys25)PTH(1-84) vs R25CPTH(1-34) vs R25CPTH(1-34) vs (1-84). Choose one nomenclature for each analogue and use it consistently throughout the article.

    Overall, this paper is well-written, but these suggestions aim to improve clarity and consistency for a broader readership.

  7. eLife

    Reviewer #3 (Public Review):

    Summary:

    The work submitted by Dr. Jeong-Oh Shin and co-workers aims to investigate the therapeutic efficacy of rhPTH(1-34) and R25CPTH(1-34) on bone regeneration and osseointegration of titanium implants using a postmenopausal osteoporosis animal model.
    In my opinion the findings presented are not strongly supported by the provided data since the methods utilized do not allow to significantly support the primary claims.

    Strengths:

    Strengths include certain good technologies utilized to perform histological sections (i.e. the EXAKT system).

    Weaknesses:

    Certain weaknesses significantly lower the enthusiasm for this work. Most important: the limited number of samples/group. In fact, as presented, the work has an n=4 for each treatment group. This limited number of samples/group significantly impairs the statistical power of the study. In addition, the implants were surgically inserted following a "conventional implant surgery", implying that no precise/guided insertion was utilized. This weakness is, in my opinion, particularly significant since the amount of bone osteointegration may greatly depend on the bucco-lingual positioning of each implant at the time of the surgical insertion (which should, therefore, be precisely standardized across all animals and for all surgical procedures).
    On a minor note: not sure why the authors present a methodology to evaluate the dynamic bone formation (line 272) but do not present results (i.e. by means of histomorphometrical analyses) utilizing this methodology.

  8. Version published to 10.1101/2024.02.10.579779v1 on bioRxiv