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Couto, B.A.D.A.; Fernandes, J.C.H.; Saavedra-Silva, M.; Roca, H.; Castilho, R.M.; Fernandes, G.V.D.O. Antisclerostin Effect on Osseointegration and Bone. Encyclopedia. Available online: https://encyclopedia.pub/entry/41231 (accessed on 15 June 2024).
Couto BADA, Fernandes JCH, Saavedra-Silva M, Roca H, Castilho RM, Fernandes GVDO. Antisclerostin Effect on Osseointegration and Bone. Encyclopedia. Available at: https://encyclopedia.pub/entry/41231. Accessed June 15, 2024.
Couto, Bárbara Alexandra Do Amaral, Juliana Campos Hasse Fernandes, Mariana Saavedra-Silva, Hernan Roca, Rogério Moraes Castilho, Gustavo Vicentis De Oliveira Fernandes. "Antisclerostin Effect on Osseointegration and Bone" Encyclopedia, https://encyclopedia.pub/entry/41231 (accessed June 15, 2024).
Couto, B.A.D.A., Fernandes, J.C.H., Saavedra-Silva, M., Roca, H., Castilho, R.M., & Fernandes, G.V.D.O. (2023, February 14). Antisclerostin Effect on Osseointegration and Bone. In Encyclopedia. https://encyclopedia.pub/entry/41231
Couto, Bárbara Alexandra Do Amaral, et al. "Antisclerostin Effect on Osseointegration and Bone." Encyclopedia. Web. 14 February, 2023.
Antisclerostin Effect on Osseointegration and Bone
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Sclerostin is a glycoprotein encoded in humans by the SOST gene. It is located on chromosome 17q12-q21, with a C-terminal cysteine knot-like (CTCK) domain. It has a similar sequence also to DAN (Differential screening-selected gene Aberrative in Neuroblastoma), an antagonist’s family of the bone morphogenetic protein (BMP). Sclerostin is primarily produced and secreted by osteocytes. Moreover, it is a negative key regulator of osteoblastic functions. It inhibits osteoblast differentiation and bone formation by inhibiting the Wnt signaling pathway after binding with LRP5 and 6 (Wnt-coreceptor). This canonical Wnt signaling (Wnt/β-catenin pathway) is essential in bone healing. It promotes pre-osteoblast proliferation and osteo-induction, enhances survival of all cells of the osteoblast lineage, inhibits differentiation of mesenchymal stem cells (MSCs) into chondrocytes and adipocytes and controls osteoclast maturation by regulating RANKL levels in osteoblast receptors.

antisclerostin bone formation bone remodeling osseointegration

1. Osseointegration of Implants

It was verified that few articles had studied the Scl-Ab effect as a treatment for implant osseointegration and only one [1] verified that Scl-Ab can improve this phenomenon. In general, BIC was higher when the Scl-Ab treatment was performed. This fact was corroborated by Virdi et al. (2012) [2] and Yu et al. (2018) [1], who reached a greater BIC with Scl-Ab at 28 days. Otherwise, Korn et al. (2019) [3] partially agreed with this information. They reported a more significant increase when performing Scl-Ab treatment but decreased BIC after 4 weeks using sandblasted and thermally acid-etched surfaces. This controversial finding must be further investigated because, typically, the BIC is higher when implants have the surface treated.
In general, the Scl-Ab therapies improved the proprieties of implant fixation, providing a significant increase in the newly formed bone [2][4]. An augmented fixation strength was associated with Scl-Ab treatment [5], with a higher enhancement in sham rats.

2. Bone Mineral Density (BMD)

Scl-Ab treatment positively affected BMD around the implants placed [3][6], also showing a positive systemic effect [6]. Ominsky et al. (2011) [7] also reported greater values in different sites. In contrast, Yu et al. (2018) [1] found no differences in BMD between Scl-Ab and control.
To evaluate the effect of Scl-Ab in bone remodeling, it was verified that eight studies included a positive impact on BMD, promoting its increase after administration in animal and human studies. Wu et al. (2018) [8] reported an increase in BMD with the Scl-Ab, but a higher effect was noticed with the combination of Scl-Ab and PTH 1-34. Li et al. (2010) [9] had an increase in BMD with either dose tested. Ominsky et al. (2011) [7] reported a rise of 11% in BMD.
Taut et al. (2013) [10] also reported that the systemic Scl-Ab III treatment trend increased the BMD. On the other hand, the improvement was minimal in the case of local administration. All the evidence corroborates that BMD is increased by Scl-Ab treatment. Even though Ominsky et al.’s (2010) results had a greater increase of volumetric BMD with greater doses in cynomolgus monkeys, they reported that the rise in the BMD area was not significant with the same doses.
McClung et al. (2014) [11], Padhi et al. (2014) [12], and Saag et al. (2017) [13] reported increased BMD with Romosozumab therapy. McClung et al. (2014) [11] also reported the highest growth, administrating 210 mg once a month.
It was noted that the BMC also increased even with different Scl-Ab therapies. Liu et al. (2018) [14] noted a higher effect expression with the combined treatment with Scl-Ab VI and DAB. Moreover, Li et al. (2010) [9] and Ominsky et al. (2010) [15] reported a more significant Scl-Ab effect when used in higher doses.

3. Bone Area (BA)/Total Area (TA) and Bone Volume (BV)/Total Volume (TV)

In Virk et al.’s study [16], authors reported an increase in BA/TA, with a higher result when there was continuous therapy. The BA also increased significantly with the Scl-Ab treatment, with higher effects associated with a continuous period of treatment [16] and higher doses [15][17].
Similar to the increase in BVF, some studies also reported an augmentation in BV. Liu et al. (2018) [14] recognized an increased BV using only Scl-Ab VI; otherwise, the combination of Scl-Ab VI and DAB caused an improved result in the alveolar ridge volume. Virk et al. (2013) [16] referred to higher increases with continuous treatment.
In general, the researchers identified the increase of BVF around the implant after Scl-Ab therapy. This information is supported by Agholme et al. (2010) [6], Liu et al. (2012) [4], Virdi et al. (2012) [2], Virdi et al. (2015) [5] and Korn et al. (2019) [3]. Increases in systemic BFV were also identified (Ominsky et al., 2011) with a higher value in FN and with a higher BV/TV [6].
In general, the BV/TV increased after the Scl-Ab treatment. However, some particularities were noted in some studies. Liu et al. (2018) [14] reported increased BV/TV with Scl-Ab VI treatment alone and combined with DAB. Similar results were identified by Wu et al. (2018) [8], reporting a greater increase in the therapy with Scl-Ab III and PTH. Regarding local use, Taut et al. (2013) [10] showed some effects on the BV/TV improvement compared to systemic administration. Tian et al.’s (2011) [18] study concluded on higher increases in the higher doses after comparing 5 and 25 mg/kg twice a week in rats.

4. Cortical and Trabecular Analysis

A higher trabecular bone (Tb) and cortical bone thickness (Th) was observed after Scl-Ab therapy. There was a systemic increase in Tb.Th after Scl-Ab therapy (Agholme et al. [6], Ominsky et al. [7]).
Several studies in the literature corroborated the information on the increase in Tb.Th around implants. Korn et al.’s (2019) [3] study reported the enhancement of Tb.Th with both implant surfaces analyzed; Liu et al. (2012) [4] referred to this association with a higher value of Scl-Ab; and Agholme et al. (2010) [6] also noticed a better result. Similarly, the cortical (Ct) thickness improved around implants after Scl-Ab treatment. This fact is supported by Virdi et al. (2012 and 2015). Generally, there were better results matched with higher therapeutic doses (25 mg/kg twice a week) [7][9][18]. However, a different effect was obtained by only one study [15], with a higher increase in Ct.Th with a lower dose.
There was an increase in Tb.Th in those studies which tested the effect of Scl-Ab in OVX rats [8][14][19]. The results were higher in OVX rats, compared to the vehicles used in OVX rats and vehicle and drug in Sham rats. Other studies compared the effect of higher and lower doses of Scl-Ab [9][18][20], showing, in general, a higher increase with 25 mg/kg twice a week, with some particularity in Tian et al.’s (2011) [18], who reported a higher increase in the tibia.
The trabecular number (Tb.N) increased with Scl-Ab therapy, but divergent results were found in the literature. Yu et al. (2018) [1] reported a greater Tb.N at 8 weeks around dental implants, Liu et al. (2012) [4] reported a higher increase after Scl-Ab application (25 mg/kg twice a week) and Wu et al. (2018) [8] reported elevated results with all treatment options studied, with higher increases observed for the combination of Scl-Ab with PTH 1-34. On the other hand, different results were reported by other authors. One mentioned that the Scl-Ab treatment had little or no effect in Tb.N [5], whereas the other noticed higher values in the control group [6]. Tian et al. (2010) [20], Tian et al. (2011) [18] and McDonald et al. (2012) [19] also showed different results.
The trabecular separation (Tb.Sp) decreased with the Scl-Ab administration, as referred by Agholme et al. (2010) [6], Li et al. (2010) [9], Tian et al. (2010) [20] and Wu et al. (2018) [8].

5. Bone Formation Rate (BFR)

The BFR increased after the Scl-Ab treatment compared to the control groups. All the studies [9][14][18][20] performed in rats had significantly higher BFR results for the Scl-Ab treatment. There was also an increase in the results of two studies [4][5] observing the BFR around implants, and in one reporting the systemic increase [7].
There were particularities to each study. Liu et al. (2018) [14] reported a significantly higher increase in the basal bone with Scl-Ab with DAB, compared to the Scl-Ab group. Tian et al. (2010) [20], Li et al. (2010) [9], and Tian et al. (2011) [18] reported more significant increases in BFR/BS with higher Scl-Ab treatment doses and Ominsky et al. (2010) [15] obtained a substantial increase in BFR/BS with 30 mg/kg administration once a month of Scl-Ab.
The local rise in BFR/BS was reported by Liu et al. (2012) [4] and Virdi et al. (2015) [5]. Otherwise, Virdi et al. [5] noticed a decreasing result over time. Only Ominsky et al. (2011) [7] reported systemic effects along with BFR/BS increase over time.
In general, some studies [9][18][20] showed similar results in mineral apposition rate, with better outcomes for administering 25 mg/kg of Scl-Ab, twice a week, but Tian et al. (2010) [20] reported no differences in dose administration.

6. Bone Strength and Stiffness

Generally, the Scl-Ab treatment provided an increase in bone strength and stiffness. The researchers identified increased resistance in maximum load in Wu et al.’s (2018) [8] and Li et al.’s (2010) [9] studies. Li et al. (2010) [9] reported that the increased strength in maximum load was related to the dose of Scl-Ab therapy administered.
Moreover, stiffness and energy to fail significantly increased with Scl-Ab treatment [7][8][9][15][16]. Wu et al. (2018) [8] referred to a greater increase in stiffness with the association of Scl-Ab with PTH 1-34. Li et al. (2010) [9] reported some contrasting information for stiffness. They referred to a higher stiffness related to higher treatment doses but reported a more significant effect in stiffness with lower doses in specific sites. However, they reported an increase with higher dose administration at energy necessary to fail. Similarly, Ominsky et al. (2010) [15] reported that increased stiffness and energy to fail were obtained with a higher dose of Scl-Ab treatment.
The high values for stiffness were supported by Virdi et al. (2015) [5], who reported a significant increase over time, with better results in sham rats. On the other hand, Virdi et al. (2012) [2] demonstrated a considerable increase over time for the Scl-Ab group, with apparent results after eight weeks. Ominsky et al. (2011) [7] reported an increase in torsional stiffness of 48%. In contrast, Liu et al. (2012) [4] found the highest stiffness value in the control group.

7. Bone Biomarkers

An increase in the biomarkers associated with bone formation was observed after the beginning of treatment. Liu et al. (2018) [14] reported a rise in BSAP for Scl-Ab and Scl-Ab with DAB and an increase in osteocalcin and P1NP with Scl-Ab. Similar results were obtained by Ominsky et al. (2011) [7], Taut et al. (2013) [10], Virk et al. (2013) [16]. Wu et al. (2018) [8] reported greater increases in osteocalcin and P1NP with the administration of Scl-Ab and a greater increase was reported [8] using Scl-Ab with PTH 1-34.
A decrease in the biomarkers linked to bone resorption was also observed. Liu et al. (2018) [14] reported a reduction in TRACP-5b for both groups studied (Scl-Ab and Scl-Ab + DAB), with a higher effect in the latter. Contrastingly, Li et al. (2010) [9] and Wu et al. (2018) [8] did not report differences in the biomarkers between Scl-Ab and the control group. Ominsky et al. (2010) [15] and Taut et al. (2013) [10] reported that no differences were found in TRACP-5b and CTX serum, respectively.
The disagreement among studies on this topic may have many origins. Different doses and periods of Scl-Ab application can be cited, causing different biological responses, different types of animals and protocols and divergent periods of observation. This topic (bone biomarkers) must still be investigated more deeply.

References

  1. Yu, S.H.; Hao, J.; Fretwurst, T.; Liu, M.; Kostenuik, P.; Giannobile, W.V.; Jin, Q. Sclerostin-Neutralizing Antibody Enhances Bone Regeneration Around Oral Implants. Tissue Eng. Part. A 2018, 24, 1672–1679.
  2. Virdi, A.S.; Liu, M.; Sena, K.; Maletich, J.; McNulty, M.; Ke, H.Z.; Sumner, D.R. Sclerostin antibody increases bone volume and enhances implant fixation in a rat model. J. Bone Jt. Surg. Am. 2012, 94, 1670–1680.
  3. Korn, P.; Kramer, I.; Schlottig, F.; Tödtman, N.; Eckelt, U.; Bürki, A.; Ferguson, S.J.; Kautz, A.; Schnabelrauch, M.; Range, U.; et al. Systemic sclerostin antibody treatment increases osseointegration and biomechanical competence of zoledronic-acid-coated dental implants in a rat osteoporosis model. Eur Cell Mater. 2019, 37, 333–346.
  4. Liu, S.; Virdi, A.S.; Sena, K.; Sumner, D.R. Sclerostin antibody prevents particle-induced implant loosening by stimulating bone formation and inhibiting bone resorption in a rat model. Arthritis Rheum. 2012, 64, 4012–4020.
  5. Virdi, A.S.; Irish, J.; Sena, K.; Liu, M.; Ke, H.Z.; McNulty, M.A.; Sumner, D.R. Sclerostin antibody treatment improves implant fixation in a model of severe osteoporosis. J. Bone Jt. Surg. Am. 2015, 97, 133–140.
  6. Agholme, F.; Li, X.; Isaksson, H.; Ke, H.Z.; Aspenberg, P. Sclerostin antibody treatment enhances metaphyseal bone healing in rats. J. Bone Miner. Res. 2010, 25, 2412–2418.
  7. Ominsky, M.S.; Li, C.; Li, X.; Tan, H.L.; Lee, E.; Barrero, M.; Asuncion, F.J.; Dwyer, D.; Han, C.-Y.; Vlasseros, F.; et al. Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones. J. Bone Miner. Res. 2011, 26, 1012–1021.
  8. Wu, J.; Cai, X.H.; Qin, X.X.; Liu, Y.X. The effects of sclerostin antibody plus parathyroid hormone (1–34) on bone formation in ovariectomized rats. Z Gerontol. Geriatr. 2018, 51, 550–556.
  9. Li, X.; Warmington, K.S.; Niu, Q.T.; Asuncion, F.J.; Barrero, M.; Grisanti, M.; Dwyer, D.; Stouch, B.; Thway, T.M.; Stolina, M.; et al. Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats. J. Bone Miner. Res. 2010, 25, 2647–2656.
  10. Taut, A.D.; Jin, Q.; Chung, J.H.; Galindo-Moreno, P.; Yi, E.S.; Sugai, J.V.; Ke, H.Z.; Liu, M.; Giannobile, W.V. Sclerostin antibody stimulates bone regeneration after experimental periodontitis. J. Bone Miner. Res. 2013, 28, 2347–2356.
  11. McClung, M.R.; Grauer, A.; Boonen, S.; Bolognese, M.A.; Brown, J.P.; Diez-Perez, A.; Langdahl, B.L.; Reginster, J.-Y.; Zanchetta, J.R.; Wasserman, S.M.; et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 2014, 370, 412–420.
  12. Padhi, D.; Allison, M.; Kivitz, A.J.; Gutierrez, M.J.; Stouch, B.; Wang, C.; Jang, G. Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: A randomized, double-blind, placebo-controlled study. J. Clin. Pharmacol. 2014, 54, 168–178.
  13. Saag, K.G.; Petersen, J.; Brandi, M.L.; Karaplis, A.C.; Lorentzon, M.; Thomas, T.; Maddox, J.; Fan, M.; Meisner, P.D.; Grauer, A. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N. Engl. J. Med. 2017, 377, 1417–1427.
  14. Liu, M.; Kurimoto, P.; Zhang, J.; Niu, Q.T.; Stolina, M.; Dechow, P.C.; Feng, J.Q.; Hesterman, J.; Silva, M.D.; Ominsky, M.S.; et al. Sclerostin and DKK1 Inhibition Preserves and Augments Alveolar Bone Volume and Architecture in Rats with Alveolar Bone Loss. J. Dent. Res. 2018, 97, 1031–1038.
  15. Ominsky, M.S.; Vlasseros, F.; Jolette, J.; Smith, S.Y.; Stouch, B.; Doellgast, G.; Gong, J.; Gao, Y.; Cao, J.; Graham, K.; et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J. Bone Miner. Res. 2010, 25, 948–959.
  16. Virk, M.S.; Alaee, F.; Tang, H.; Ominsky, M.S.; Ke, H.Z.; Lieberman, J.R. Systemic administration of sclerostin antibody enhances bone repair in a critical-sized femoral defect in a rat model. J. Bone Jt. Surg. Am. 2013, 95, 694–701.
  17. Li, X.; Ominsky, M.S.; Warmington, K.S.; Morony, S.; Gong, J.; Cao, J.; Gao, Y.; Shalhoub, V.; Tipton, B.; Haldankar, R.; et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 2009, 24, 578–588.
  18. Tian, X.; Jee, W.S.; Li, X.; Paszty, C.; Ke, H.Z. Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. Bone 2011, 48, 197–201.
  19. McDonald, M.M.; Morse, A.; Mikulec, K.; Peacock, L.; Yu, N.; Baldock, P.A.; Birke, O.; Liu, M.; Ke, H.Z.; Little, D.G. Inhibition of sclerostin by systemic treatment with sclerostin antibody enhances healing of proximal tibial defects in ovariectomized rats. J. Orthop. Res. 2012, 30, 1541–1548.
  20. Tian, X.; Setterberg, R.B.; Li, X.; Paszty, C.; Ke, H.Z.; Jee, W.S. Treatment with a sclerostin antibody increases cancellous bone formation and bone mass regardless of marrow composition in adult female rats. Bone 2010, 47, 529–533.
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