Bone regeneration is a complex physiological process that is essential for the successful integration of dental implants into the jawbone. Osseointegration, the direct structural and functional connection between living bone and an implant’s surface, is a critical determinant of implant stability and long-term viability in dental reconstructive therapy. Since excessive levels of circulating parathyroid hormone (PTH) increase osteoclastic activity and accelerate bone resorption, it might seem paradoxical that PTH can also be used as a treatment modality for diseases with bone loss, such as osteoporosis (Jilka, 2007). Administration of PTH analogs can be categorized into two distinct protocols: intermittent and continuous. Intermittent rhPTH(1-34) therapy, typically characterized by daily injections, is clinically used to enhance bone formation and strength. This method leverages the anabolic effects of rhPTH(1-34) without significant bone resorption, which can occur with more frequent or continuous exposure. On the other hand, continuous rhPTH(1-34) exposure, often modeled in research as constant infusion, tends to accelerate bone resorption activities, potentially leading to bone loss (Silva and Bilezikian, 2015; Jilka, 2007). Understanding these differences is crucial for interpreting the therapeutic implications of rhPTH(1-34) in bone health. Intermittent administration of PTH unlikely continuous exposure showed anabolic effects, indicating different responses relating to bone microarchitecture depending on the dose and frequency (Silva and Bilezikian, 2015). However, the underlying mechanisms remain largely unknown, although it was shown that PTH binds through PTH type 1 receptor (PTH1R) and that G-protein-coupled receptors are associated with the protein kinase A-dependent pathway, thereby demonstrating primary anabolic action on bone (Cheloha et al., 2015; Jilka, 2007). The anabolic effect of intermittent PTH administration is mediated by the downregulation of the Wnt/beta-catenin signaling pathway, which upregulates the transcriptional expression of growth factors, such as IGF1, FGF2, and Runx2, which are essential for the proliferation and differentiation of osteoblasts, leading to an increased number of osteoblasts and survival (Krishnan et al., 2006; Lee and Partridge, 2009).

A PTH analog, teriparatide (recombinant human PTH(1-34)), demonstrated its promising anabolic effects in a fracture prevention trial (Neer et al., 2001), leading to its approval by the United States Food and Drugs Administration, making it the first anabolic agent for postmenopausal osteoporotic women. Additionally, its unique anabolic features, which are contrasted with antiresorptive, lead to an increased application of rhPTH(1-34), whereby it was used in both metabolic and pathological bone diseases alongside various other conditions where bone formation occurred (Uusi-Rasi et al., 2005). Conversely, recent concerns regarding the development of osteonecrosis of the jaw (ONJ) have appeared in association with the use of antiresorptive, meaning rhPTH(1-34) has gained attention for its potential to reduce the risk of ONJ and its therapeutic effects in treating ONJ (Jung et al., 2017; Kakehashi et al., 2015). Although in vivo studies on fracture healing, bone augmentation, and titanium osseointegration effects of rhPTH(1-34) have been attempted, they have generally been limited to pilot studies in rodents (Gomes-Ferreira et al., 2020; Jung et al., 2021; Yu and Su, 2020).

Interestingly, only nine mutations have been discovered since the PTH amino acid and nucleotide sequences were confirmed (Lee et al., 2020; Schipani, 1999). Among them, the PTH R25C mutation was discovered in three siblings with familial idiopathic hypoparathyroidism, which consisted of a homozygous arginine to cysteine mutation at residue 25 (R25C) in the mature PTH(1-84) polypeptide and exhibited distinct characteristics from the others (Lee and Lee, 2022). The other mutations located in the prepro-leader region of the hormone resulted in defective synthesis and secretion; however, the PTH R25C mutation is located within the mature bioactive domain of PTH and does not affect synthesis or secretion (Lee and Lee, 2022). Although the capacity of ^R25CPTH(1-34) to bind to the PTH1R and stimulate cAMP production was slightly lower in the human osteoblast-derived SaOS-2 cell line (Lee and Lee, 2022), yet it showed comparable anabolic activity in a mouse model (Bae et al., 2016). Furthermore, the dimeric formation of the ^R25CPTH(1-34) peptide, presumably through disulfide bonding of the cysteine residues, has implied that dimeric ^R25CPTH(1-34) might partake in unique biological actions, which potentiate its clinical applications (Park et al., 2021).

In addition to the limited effectiveness toward certain types of fractures, such as non-vertebral fractures, and the disadvantage of its limited duration of use, the administration of rhPTH(1-34) for osteoporosis has raised concerns about its potential to induce cortical porosity, despite showing favorable results in the treatment of trabecular microarchitecture (Lindsay et al., 2016). This has led to concerns regarding the widespread use of PTH. However, recent notable studies have indicated that cortical porosity is not induced when PTH is administered weekly (Mosekilde et al., 1995), which is in contrast to daily administrations (Yamamoto et al., 2016; Zebaze et al., 2017). These studies suggest that the frequency and dosage of PTH administration can significantly affect the bone response (Hock and Gera, 1992), while different forms of PTH might also induce different biological responses, which means deeper investigations into the therapeutic effects of PTH are required (Bellido et al., 2005).

Therefore, in this study, the authors used a large animal model that mimics postmenopausal osteoporosis to investigate the therapeutic effects of two PTH analogs, rhPTH(1-34) and dimeric ^R25CPTH(1-34), on bone regeneration and osseointegration.

This study investigated the therapeutic effects of rhPTH(1-34) and dimeric ^R25CPTH(1-34) on bone regeneration and osseointegration in a large animal model with postmenopausal osteoporosis. rhPTH(1-34) and dimeric ^R25CPTH(1-34) have shown significant clinical efficacy. Although there have been a few studies investigating their effects on bone regeneration in rodents (Garcia et al., 2013), we aimed to investigate these effects using a large animal model. We chose this model because it more accurately mimics osteoporotic humans (Jee and Yao, 2001). In the evaluation of titanium osseointegration, the rhPTH(1-34) group consistently exhibited enhanced BMD, BV, and other key parameters, thereby indicating superior titanium osseointegration compared to the control and dimeric ^R25CPTH(1-34) groups (Figure 1E). Histological analyses confirmed these results, emphasizing the stronger bone–implant contact observed in the rhPTH(1-34) group. Furthermore, both PTH analogs significantly promoted bone regeneration in artificially created defects, with the rhPTH(1-34) group displaying a more mature trabecular architecture, as evidenced by a notable increase in the TRAP+ cell count during the bone remodeling assessments (Figure 2M and N).

Regarding the results on the effect of dimeric ^R25CPTH(1-34) in the ovariectomy (OVX) mouse model (Noh et al., 2024), bone formation markers were increased in the dimeric ^R25CPTH(1-34) group compared to the rhPTH(1-34) group. Additionally, bone resorption markers were decreased in the rhPTH(1-34) group compared to the control group. However, no significant differences were observed in the dimeric ^R25CPTH(1-34) group. This suggests that the mechanism of action of the dimeric peptide differs from that of the wildtype peptide. Furthermore, based on unpublished data comparing mRNA expression in bone and kidney tissues between the dimeric ^R25CPTH(1-34) and rhPTH(1-34)-treated groups, we strongly believe that dimeric ^R25CPTH(1-34) exhibits distinct biological activity from rhPTH(1-34). These differences may arise from variations in PTH receptor binding, involvement of different G protein subtypes, or downstream intracellular signaling pathways.

The distinct effects of dimeric ^R25CPTH(1-34) and rhPTH(1-34) on osteoblasts and osteoclasts could indicate that while remodeling-based osteogenesis has a limited clinical use period, the dimeric form might promote sustained bone formation and increased bone density over a longer duration. Given that patients with this mutation, who have been exposed to the mutant dimer throughout their lives, exhibit high bone density, this suggests significant potential for dimeric ^R25CPTH(1-34) as a novel therapeutic option alongside wildtype PTH.

Both PTH analogs demonstrated anabolic effects, particularly in the mandible. The distinct pharmacological profile of dimeric ^R25CPTH(1-34) suggests potential for more targeted, long-term applications, especially in conditions requiring sustained bone regeneration (Bae et al., 2016). This biological difference is thought to be due to dimeric ^R25CPTH(1-34) exhibiting a more preferential binding affinity for the RG versus R0 PTH1R conformation, despite having a diminished affinity for either conformation (Lee and Lee, 2022; Park et al., 2021). Additionally, the potency of cAMP production in cells was lower for dimeric ^R25CPTH(1-34) compared to monomeric ^R25CPTH(1-34), consistent with its lower PTH1R-binding affinity (Noh et al., 2024). One of the potential clinical advantages of dimeric ^R25CPTH(1-34) is its partial agonistic effect in pharmacodynamics. This property may allow for a more fine-tuned regulation of bone metabolism, potentially reducing the risk of adverse effects associated with full agonism, such as hypercalcemia and bone resorption by osteolcast activity. Moreover, the dimeric form may offer a more sustained anabolic response, which could be beneficial in the context of long-term treatment strategies (Noh et al., 2024). Also, the impact of dimeric ^R25CPTH(1-34) was notable, as we observed a noticeable improvement in bone formation when compared to the control group. However, these effects were not as strong as those of rhPTH(1-34). Both PTH analogs demonstrated enhanced anabolic effects around the titanium implants, promoting bone regeneration and remodeling.

In addition to the effect of systemic bone mineral gain, the unique anabolic feature of PTH has received clinical attention as an emerging strategy due to the increased risk of ONJ following the use of antiresorptive and the rising need for implantation and bone augmentation in the field of orthopedics and maxillofacial surgery (Ruggiero et al., 2022). Moreover, site-specific differential effects of teriparatide have not been clarified, although it represents an issue often associated with selective concentrations of teriparatide that cause anabolic effects on the central skeleton and possible bone mineral decrease on the peripheral skeleton, including the skull (McClung et al., 2005). Moreover, it can be inferred that facial and jawbones, which have the same developmental origin as the skull through membranous ossification, will show the same bone response as the skull (Setiawati and Rahardjo, 2019). Previous studies have demonstrated that the central skeleton, including the lumbar and thoracic spine and pelvis regions, showed an increase in areal BMD, while the arms, legs, and skull showed a decrease in bone minerals, suggesting an effect of rhPTH(1-34) on the redistribution of bone minerals from the peripheral to the central skeleton (Paggiosi et al., 2018).

However, the results of this study demonstrated that rhPTH(1-34) and dimeric ^R25CPTH(1-34) significantly improved the osseointegration of bone and titanium, as well as jawbone regeneration (Figure 3). The anabolic effects of both PTH analogs in this specific region may have been enhanced by the unique anatomical characteristics of the mandible, which we attribute to these improvements. The authors have attributed this phenomenon to the unique anatomical characteristics observed in the jawbone. The jawbone in the human body undergoes the most rapid bone remodeling and has excellent blood flow (Huja et al., 2006). Since the jawbone is continuously exposed to mechanical stress from mastication and swallowing, this suggests that the net anabolic effect of rhPTH(1-34) in the jawbone, which is not part of the central skeleton, is achieved through mechanical loading. A recent study by Robinson et al., 2021 demonstrated that rhPTH(1-34) and mechanical loading additively stimulate anabolic modeling and synergistically stimulate remodeling in trabecular bone, findings that further support this notion (Robinson et al., 2021). However, further investigation is needed to fully understand this relationship.

The anabolic effects of rhPTH(1-34) have been demonstrated through several large randomized controlled trials (Neer et al., 2001; Tsai et al., 2013). Despite the FDA’s decision to remove the 2-year treatment limit in 2021, which opens possibilities for broader clinical applications, there are still numerous challenges that need to be addressed. There are ongoing concerns about the potential long-term effects of extended use, including accelerated bone remodeling, possible hypercalcemic conditions, and heightened bone resorption (Burr et al., 2001; Fox et al., 2007a; Fox et al., 2007b; Neer et al., 2001; Sato et al., 2004; Tsai et al., 2013). However, recent studies have shown that the frequency and dosing of rhPTH(1-34) administration can lead to different bone responses (Yamamoto et al., 2016; Yamane et al., 2017). An in vivo study by Yamamoto et al. reported that lower doses of rhPTH(1-34) with high-frequency administration resulted in the formation of thin trabeculae, osteoclastogenesis, and accelerated bone remodeling, while low-frequency rhPTH(1-34) administration showed a phenomenon of modeling-based formation through thicker trabeculae, mature osteoblasts, and new bone formation (Yamane et al., 2017). This supports the notion that modeling-based bone gain can be an important axis in PTH anabolism and the primary principle of PTH as bone remodeling-driven bone anabolism.

The use of daily injections in this study was intended to simulate intermittent PTH therapy, a well-established clinical approach for managing osteoporosis and enhancing bone regeneration. Intermittent administration of PTH, as opposed to continuous exposure, is critical for maximizing the anabolic response while minimizing the catabolic effects that are associated with higher frequency or continuous hormone levels. Our findings support the notion that even with daily administration, both rhPTH(1-34) and dimeric ^R25CPTH(1-34) promote bone formation and osseointegration, consistent with the outcomes expected from intermittent therapy. It’s important for future research to consider the dosage and timing of administration to further optimize the therapeutic benefits of PTH analogs (Dempster et al., 2013; Hodsman et al., 2005).

The limitation of this study is that the therapeutic responses of rhPTH(1-34) and dimeric ^R25CPTH(1-34) were focused on local surgical interventions, meaning that we could not investigate the central skeletal responses, such as in the femur and lumbar. Therefore, further research is needed to investigate these different responses by administering the PTH analogs at various frequencies and doses. Additionally, although this study was conducted on large animals, using a larger number of subjects would have yielded more robust results. Implementing randomization of the surgical sites and using guided surgery for implant insertion should also be considered in future studies to achieve more precise results.

Overall, the study demonstrated the therapeutic effects of rhPTH(1-34) and dimeric ^R25CPTH(1-34) on bone regeneration and titanium osseointegration using a beagle model with osteoporosis. Validation of the anabolic effects of rhPTH(1-34) and dimeric ^R25CPTH(1-34) in large animals has resulted in a broader understanding of their physiological and therapeutic functions and further expands their potential applications.

All relevant data has been made publicly available on Dryad at https://doi.org/10.5061/dryad.hmgqnk9t1.

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Author details

1. Jeong-Oh Shin

   Department of Anatomy, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea

   Contribution

   Conceptualization, Resources, Formal analysis, Funding acquisition, Validation, Investigation, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Jong-Bin Lee

   Competing interests

   No competing interests declared

2. Jong-Bin Lee

   Department of Periodontology and Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, Republic of Korea

   Contribution

   Resources

   Contributed equally with

   Jeong-Oh Shin

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6800-4337

3. Sihoon Lee

   Department of Internal Medicine and Laboratory of Genomics and Translational Medicine, Gachon University College of Medicine, Incheon, Republic of Korea

   Contribution

   Conceptualization, Resources, Supervision, Validation, Writing – original draft, Writing – review and editing

   For correspondence

   shleemd@gachon.ac.kr

   Competing interests

   Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0002-9444-5849

4. Jin-Woo Kim

   Department of Oral and Maxillofacial Surgery, Research Institute for Intractable Osteonecrosis of the Jaw, College of Medicine, Ewha Womans University, Seoul, Republic of Korea

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   1. jinu600@gmail.com
   2. jwkim84@ewha.ac.kr

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1672-5730

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