ORIGINAL ARTICLE
Effect of intraoral administration of parathyroid hormone on osseous and soft tissue healing around implants in ovariectomized rat maxillae
Farah A. Al-Omari,
Shinichiro Kuroshima,
Yusuke Uto,
Yusuke Uchida,
Takashi Sawase,
Farah A. Al-Omari
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Search for more papers by this authorCorresponding Author
Shinichiro Kuroshima
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Correspondence
Shinichiro Kuroshima, Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-City, Nagasaki 852-8588, Japan.
Email: [email protected]
Search for more papers by this authorYusuke Uto
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Search for more papers by this authorYusuke Uchida
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Search for more papers by this authorTakashi Sawase
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Search for more papers by this authorFarah A. Al-Omari,
Shinichiro Kuroshima,
Yusuke Uto,
Yusuke Uchida,
Takashi Sawase,
Farah A. Al-Omari
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Search for more papers by this authorCorresponding Author
Shinichiro Kuroshima
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Correspondence
Shinichiro Kuroshima, Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-City, Nagasaki 852-8588, Japan.
Email: [email protected]
Search for more papers by this authorYusuke Uto
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Search for more papers by this authorYusuke Uchida
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Search for more papers by this authorTakashi Sawase
Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Search for more papers by this authorFirst published: 21 December 2023
Farah A. Al-Omari and Shinichiro Kuroshima contributed equally to this work.
Abstract
Objectives
Intermittent administration of parathyroid hormone (PTH) increases systemic bone mass. However, the effect of PTH on osseous and soft tissue healing around implants in osteoporosis patients remains unclear. This study aimed to investigate the effects of PTH on tissue healing around implants in ovariectomized rats and to compare systemic and intraoral administration routes.
Material and Methods
Implants were placed at the healed sites of ovariectomized rats 3 weeks after maxillary first molar extraction. Rats were randomly divided into two groups that received either daily systemic subcutaneous or local intraoral PTH administration. Maxillae were dissected to examine bone architectures with micro-computed tomography images. Histomorphometric and immunohistochemical analyses were performed to evaluate osseous and soft tissue healing around the implants.
Results
Regardless of the administration route, PTH significantly increased bone area and the numbers of osteoblasts, osteoclasts, and osteocytes in the first and second inside and outside areas of implant threads, in addition to decreasing the number of sclerostin+ osteocytes. However, the intraoral PTH administration route was superior to the systemic route by significantly improving bone quality and promoting collagen production in the connective tissue around implants.
Conclusions
Parathyroid hormone administration promoted both osseous and soft tissue healing around implants, irrespective of administration route. Interestingly, intraoral administration improved the evaluated parameters more than systemic administration. Thus, the intraoral route could become a useful treatment strategy for implant treatment in osteoporosis patients.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
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| clr14227-sup-0001-FigureS1.zipZip archive, 1.8 MB |
Figure S1 |
| clr14227-sup-0002-FigureS2.zipZip archive, 6.1 MB |
Figure S2 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- Almagro, M. I., Roman-Blas, J. A., Bellido, M., Castañeda, S., Cortez, R., & Herrero-Beaumont, G. (2013). PTH [1-34] enhances bone response around titanium implants in a rabbit model of osteoporosis. Clinical Oral Implants Research, 24, 1027–1034. https://doi.org/10.1111/j.1600-0501.2012.02495.x
- Bellido, T., Ali, A. A., Plotkin, L. I., Fu, Q., Gubrij, I., Roberson, P. K., Weinstein, R. S., O'Brien, C. A., Manolagas, S. C., & Jilka, R. L. (2003). Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. The Journal of Biological Chemistry, 278, 50259–50272. https://doi.org/10.1074/jbc.M307444200
- Bouxsein, M. L., Boyd, S. K., Christiansen, B. A., Guldberg, R. E., Jepsen, K. J., & Müller, R. (2010). Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. Journal of Bone and Mineral Research, 25, 1468–1486. https://doi.org/10.1002/jbmr.141
- Camacho, P. M., Petak, S. M., Binkley, N., Diab, D. L., Eldeiry, L. S., Farooki, A., Harris, S. T., Hurley, D. L., Kelly, J., Lewiecki, E. M., Pessah-Pollack, R., McClung, M., Wimalawansa, S. J., & Watts, N. B. (2020). American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update. Endocrine Practice, 26, 564–570. https://doi.org/10.4158/GL-2020-0524
- Cho, S. W., Pirih, F. Q., Koh, A. J., Michalski, M., Eber, M. R., Ritchie, K., Sinder, B., Oh, S., Al-Dujaili, S. A., Lee, J., Kozloff, K., Danciu, T., Wronski, T. J., & McCauley, L. K. (2013). The soluble interleukin-6 receptor is a mediator of hematopoietic and skeletal actions of parathyroid hormone. The Journal of Biological Chemistry, 288, 6814–6825. https://doi.org/10.1074/jbc.M112.393363
- Cohn Yakubovich, D., Eliav, U., Yalon, E., Schary, Y., Sheyn, D., Cook-Wiens, G., Sun, S., McKenna, C., Lev, S., Binshtok, A. M., Pelled, G., Navon, G., Gazit, D., & Gazit, Z. (2017). Teriparatide attenuates scarring around murine cranial bone allograft via modulation of angiogenesis. Bone, 97, 192–200. https://doi.org/10.1016/j.bone.2017.01.020
- Cohn-Schwartz, D., Schary, Y., Yalon, E., Krut, Z., Da, X., Schwarz, E. M., Gazit, Z., Pelled, G., & Gazit, Z. (2022). PTH-induced bone regeneration and vascular modulation are both dependent on endothelial signaling. Cell, 11, 897. https://doi.org/10.3390/cells11050897
- Dayer, R., Brennan, T. C., Rizzoli, R., & Ammann, P. (2010). PTH improves titanium implant fixation more than pamidronate or renutrition in osteopenic rats chronically fed a low protein diet. Osteoporosis International, 21, 957–967. https://doi.org/10.1007/s00198-009-1031-x
- Donos, N., Kostopoulos, L., & Karring, T. (2002). Alveolar ridge augmentation using a resorbable copolymer membrane and autogenous bone grafts. An experimental study in the rat. Clinical Oral Implants Research, 13, 203–213. https://doi.org/10.1034/j.1600-0501.2002.130211.x
- Gao, X., Meng, Y., Hao, D., & Liu, H. (2022). Parathyroid hormone enhances gap healing and osseointegration in orthopedic porous coated titanium implants: A correlative micro-computed tomographic, histomorphometric and biomechanical analysis. BMC Musculoskeletal Disorders, 23, 17. https://doi.org/10.1186/s12891-021-04917-y
- Hock, J. M., Gera, I., Fonseca, J., & Raisz, L. G. (1988). Human parathyroid hormone-(1-34) increases bone mass in ovariectomized and orchidectomized rats. Endocrinology, 122(6), 2899–2904. https://doi.org/10.1210/endo-122-6-2899
- Jilka, R. L. (2007). Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone, 40, 1434–1446. https://doi.org/10.1016/j.bone.2007.03.017
- Kanzawa, M., Sugimoto, T., Kanatani, M., & Chihara, K. (2000). Involvement of osteoprotegerin/osteoclastogenesis inhibitory factor in the stimulation of osteoclast formation by parathyroid hormone in mouse bone cells. European Journal of Endocrinology, 142, 661–664. https://doi.org/10.1530/eje.0.1420661
- Keller, H., & Kneissel, M. (2005). SOST is a target gene for PTH in bone. Bone, 37(2), 148–158. https://doi.org/10.1016/j.bone.2005.03.018
- Kuroshima, S., Entezami, P., McCauley, L. K., & Yamashita, J. (2014). Early effects of parathyroid hormone on bisphosphonate/steroid-associated compromised osseous wound healing. Osteoporosis International, 25, 1141–1150. https://doi.org/10.1007/s00198-013-2570-8
- Kuroshima, S., Kaku, M., Ishimoto, T., Sasaki, M., Nakano, T., & Sawase, T. (2017). A paradigm shift for bone quality in dentistry: A literature review. Journal of Prosthodontic Research, 61, 353–362. https://doi.org/10.1016/j.jpor.2017.05.006
- Kuroshima, S., Kovacic, B. L., Kozloff, K. M., McCauley, L. K., & Yamashita, J. (2013). Intraoral PTH administration promotes tooth extraction socket healing. Journal of Dental Research, 92, 553–559. https://doi.org/10.1177/0022034513487558
- Kuroshima, S., Nakano, T., Ishimoto, T., Sasaki, M., Inoue, M., Yasutake, M., & Sawase, T. (2017). Optimally oriented grooves on dental implants improve bone quality around implants under repetitive mechanical loading. Acta Biomaterialia, 48, 433–444. https://doi.org/10.1016/j.actbio.2016.11.021
- Kuroshima, S., Yasutake, M., Tsuiki, K., Nakano, T., & Sawase, T. (2015). Structural and qualitative bone remodeling around repetitive loaded implants in rabbits. Clinical Implant Dentistry and Related Research, 17(Suppl 2), e699–e710. https://doi.org/10.1111/cid.12318
- Kwon, T., Wang, C. W., Salem, D. M., & Levin, L. (2020). Nonsurgical and surgical management of biologic complications around dental implants: Peri-implant mucositis and peri-implantitis. Quintessence International, 51, 810–820. https://doi.org/10.3290/j.qi.a44813
- Lelovas, P. P., Xanthos, T. T., Thoma, S. E., Lyritis, G. P., & Dontas, I. A. (2008). The laboratory rat as an animal model for osteoporosis research. Comparative Medicine, 58, 424–430.
- Lemos, C. A. A., de Oliveira, A. S., Faé, D. S., Oliveira, H. F. F. E., del Rei Daltro Rosa, C., Bento, V. A. A., Verri, F. R., & Pellizzer, E. P. (2023). Do dental implants placed in patients with osteoporosis have higher risks of failure and marginal bone loss compared to those in healthy patients? A systematic review with meta-analysis. Clinical Oral Investigations, 27, 2483–2493. https://doi.org/10.1007/s00784-023-05005-2
- Li, X., Qin, L., Bergenstock, M., Bevelock, L. M., Novack, D. V., & Partridge, N. C. (2007). Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. The Journal of Biological Chemistry, 282, 33098–33106. https://doi.org/10.1074/jbc.M611781200
- Liu, S., Broucek, J., Virdi, A. S., & Sumner, D. R. (2012). Limitations of using micro-computed tomography to predict bone-implant contact and mechanical fixation. Journal of Microscopy, 245, 34–42. https://doi.org/10.1111/j.1365-2818.2011.03541.x
- Mair, B., Tangl, S., Feierfeil, J., Skiba, D., Watzek, G., & Gruber, R. (2009). Age-related efficacy of parathyroid hormone on osseointegration in the rat. Clinical Oral Implants Research, 20, 400–405. https://doi.org/10.1111/j.1600-0501.2008.01658.x
- McCauley, L. K., Dalli, J., Koh, A. J., Chiang, N., & Serhan, C. N. (2014). Cutting edge: Parathyroid hormone facilitates macrophage efferocytosis in bone marrow via proresolving mediators resolvin D1 and resolvin D2. Journal of Immunology, 193, 26–29. https://doi.org/10.4049/jimmunol.1301945
- Miller, S. C., Hunziker, J., Mecham, M., & Wronski, T. J. (1997). Intermittent parathyroid hormone administration stimulates bone formation in the mandibles of aged ovariectomized rats. Journal of Dental Research, 76, 1471–1476. https://doi.org/10.1177/00220345970760080901
- Nakano, T., Kaibara, K., Tabata, Y., Nagata, N., Enomoto, S., Marukawa, E., & Umakoshi, Y. (2002). Unique alignment and texture of biological apatite crystallites in typical calcified tissues analyzed by microbeam X-ray diffractometer system. Bone, 31, 479–487.
- Neer, R. M., Arnaud, C. D., Zanchetta, J. R., Prince, R., Gaich, G. A., Reginster, J. Y., Hodsman, A. B., Eriksen, E. F., Ish-Shalom, S., Genant, H. K., Wang, O., & Mitlak, B. H. (2001). Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. The New England Journal of Medicine, 344, 1434–1441. https://doi.org/10.1056/NEJM200105103441904
- NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. (2001). Osteoporosis prevention, diagnosis, and therapy. JAMA, 285, 785–795. https://doi.org/10.1001/jama.285.6.785
- Ohkawa, Y., Tokunaga, K., & Endo, N. (2008). Intermittent administration of human parathyroid hormone (1-34) increases new bone formation on the interface of hydroxyapatitecoated titanium rods implanted into ovariectomized rat femora. Journal of Orthopaedic Science, 13, 533–542. https://doi.org/10.1007/s00776-008-1275-x
- Okamoto, T., & de Russo, M. C. (1973). Wound healing following tooth extraction. Histochemical study in rats. Revista da Faculdade de Odontologia de Araçatuba, 2, 153–169.
- Oki, Y., Doi, K., Makihara, Y., Kubo, T., Oue, H., & Tsuga, K. (2016). Intermittent administration of parathyroid hormone enhances primary stability of dental implants in a bone-reduced rabbit model. Journal of Oral Science, 58, 241–246. https://doi.org/10.2334/josnusd.15-0717
- On, J. S., Chow, B. K., & Lee, L. T. (2015). Evolution of parathyroid hormone receptor family and their ligands in vertebrate. Frontiers in Endocrinology, 6, 28. https://doi.org/10.3389/fendo.2015.00028
- Onyia, J. E., Helvering, L. M., Gelbert, L., Wei, T., Huang, S., Chen, P., Dow, E. R., Maran, A., Zhang, M., Lotinun, S., Lin, X., Halladay, D. L., Miles, R. R., Kulkarni, N. H., Ambrose, E. M., Ma, Y. L., Frolik, C. A., Sato, M., Bryant, H. U., & Turner, R. T. (2005). Molecular profile of catabolic versus anabolic treatment regimens of parathyroid hormone (PTH) in rat bone: An analysis by DNA microarray. Journal of Cellular Biochemistry, 95, 403–418. https://doi.org/10.1002/jcb.20438
- Onyia, J. E., Miles, R. R., Yang, X., Halladay, D. L., Hale, J., Glasebrook, A., McClure, D., Seno, G., Churgay, L., Chandrasekhar, S., & Martin, T. J. (2000). In vivo demonstration that human parathyroid hormone 1-38 inhibits the expression of osteoprotegerin in bone with the kinetics of an immediate early gene. Journal of Bone and Mineral Research, 15, 863–871. https://doi.org/10.1359/jbmr.2000.15.5.863
- Park, J. Y., Heo, H. A., Park, S., & Pyo, S. W. (2020). Enhancement of peri-implant bone formation via parathyroid hormone administration in a rat model at risk for medication-related osteonecrosis of the jaw. Journal of Periodontal and Implant Science, 50, 121–131. https://doi.org/10.5051/jpis.2020.50.2.121
- Park, S., Heo, H. A., Kim, K. W., Min, J. S., & Pyo, S. W. (2017). Intermittent parathyroid hormone improves bone formation around titanium implants in osteoporotic rat maxillae. The International Journal of Oral & Maxillofacial Implants, 32, 204–209. https://doi.org/10.11607/jomi.5037
- Rhee, Y., Allen, M. R., Condon, K., Lezcano, V., Ronda, A. C., Galli, C., Olivos, N., Passeri, G., O'Brien, C. A., Bivi, N., Plotkin, L. I., & Bellido, T. (2011). PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling. Journal of Bone and Mineral Research, 26, 1035–1046. https://doi.org/10.1002/jbmr.304
- Salari, N., Ghasemi, H., Mohammadi, L., Behzadi, M. H., Rabieenia, E., Shohaimi, S., & Mohammadi, M. (2021). The global prevalence of osteoporosis in the world: A comprehensive systematic review and meta-analysis. Journal of Orthopaedic Surgery and Research, 16, 609. https://doi.org/10.1186/s13018-021-02772-0
- Sasaki, M., Kuroshima, S., Aoki, Y., Inaba, N., & Sawase, T. (2015). Ultrastructural alterations of osteocyte morphology via loaded implants in rabbit tibiae. Journal of Biomechanics, 48, 4130–4141. https://doi.org/10.1016/j.jbiomech.2015.10.025
- Sato, Y., Kitagawa, N., & Isobe, A. (2020). Current consensus of dental implants in the elderly—What are the limitations? Current Oral Health Reports, 7, 321–326. https://doi.org/10.1007/s40496-020-00268-0
10.1007/s40496-020-00268-0 Google Scholar
- Shen, Y. F., Huang, J. H., Wang, K. Y., Zheng, J., Cai, L., Gao, H., Li, J. F., & Li, J. F. (2020). PTH derivative promotes wound healing via synergistic multicellular stimulating and exosomal activities. Cell Communication and Signaling: CCS, 18, 40. https://doi.org/10.1186/s12964-020-00541-w
- Shibamoto, A., Ogawa, T., Duyck, J., Vandamme, K., Naert, I., & Sasaki, K. (2018). Effect of high-frequency loading and parathyroid hormone administration on peri-implant bone healing and osseointegration. International Journal of Oral Science, 10, 6. https://doi.org/10.1038/s41368-018-0009-y
- Shirota, T., Tashiro, M., Ohno, K., & Yamaguchi, A. (2003). Effect of intermittent parathyroid hormone (1-34) treatment on the bone response after placement of titanium implants into the tibia of ovariectomized rats. Journal of Oral and Maxillofacial Surgery, 61, 471–480. https://doi.org/10.1053/joms.2003.50093
- Silva, B. C., & Bilezikian, J. P. (2015). Parathyroid hormone: Anabolic and catabolic actions on the skeleton. Current Opinion in Pharmacology, 22, 41–50. https://doi.org/10.1016/j.coph.2015.03.005
- Skripitz, R., Böhling, S., Rüther, W., & Aspenberg, P. (2005). Stimulation of implant fixation by parathyroid hormone (1-34)-A histomorphometric comparison of PMMA cement and stainless steel. Journal of Orthopaedic Research, 23, 1266–1270. https://doi.org/10.1016/j.orthres.2005.04.006.1100230605
- Suzue, M., Kuroshima, S., Uto, Y., Uchida, Y., & Sawase, T. (2022). Controlled mechanical early loads improve bone quality and quantity around implants: An in vivo experimental study. Clinical Oral Implants Research, 33, 1049–1067. https://doi.org/10.1111/clr.13989
- Tang, Y., Wu, X., Lei, W., Pang, L., Wan, C., Shi, Z., Zhao, L., Nagy, T. R., Peng, X., Hu, J., Feng, X., van Hul, W., Wan, M., & Cao, X. (2009). TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nature Medicine, 15, 757–765. https://doi.org/10.1038/nm.1979
- Uchida, Y., Kuroshima, S., Uto, Y., Kanai, R., Inoue, M., Suzue, M., & Sawase, T. (2020). Intermittent administration of parathyroid hormone improves bone quality and quantity around implants in rat tibiae. Journal of Oral Biosciences, 62, 139–146. https://doi.org/10.1016/j.job.2020.03.001
- United Nations Department of Economic and Social Affairs. (2022). World population prospects 2022: Summary of results [Dataset]. https://www.un.org/development/desa/pd/content/World-Population-Prospects-2022
- Uto, Y., Kuroshima, S., Nakano, T., Ishimoto, T., Inaba, N., Uchida, Y., & Sawase, T. (2017). Effects of mechanical repetitive load on bone quality around implants in rat maxillae. PLoS One, 12, e0189893. https://doi.org/10.1371/journal.pone.0189893
- van Eenige, R., Verhave, P. S., Koemans, P. J., Tiebosch, I. A. C. W., Rensen, P. C. N., & Kooijman, S. (2020). RandoMice, a novel, user-friendly randomization tool in animal research. PLoS One, 15, e0237096. https://doi.org/10.1371/journal.pone.0237096
- Xu, L., Mei, L., Zhao, R., Yi, J., Jiang, Y., Li, R., Zhao, Y., Pi, L., & Li, Y. (2020). The effects of intro-oral parathyroid hormone on the healing of tooth extraction socket: An experimental study on hyperglycemic rats. Journal of Applied Oral Science, 28, e20190690. https://doi.org/10.1590/1678-7757-2019-0690
