|Year : 2022 | Volume
| Issue : 1 | Page : 17-23
Systemic medications and implant success: Is there a link? Part two: The effects of therapeutic hormones on the outcome of implant therapy
Prema Sukumaran1, Dionetta Delitta Dionysius2, Wei Cheong Ngeow3, Chuey Chuan Tan3, Mohd Zamri Hussin1
1 Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
2 Department of Oral and Maxillofacial Surgery, Hospital Sultanah Nora Ismail, Johor, Malaysia
3 Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
|Date of Submission||09-Oct-2021|
|Date of Acceptance||27-Feb-2022|
|Date of Web Publication||16-Jun-2022|
Dr. Prema Sukumaran
Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Dental implants require healthy bone for successful osseointegration. However, bone health can become compromised by aging and/or the presence of underlying medical conditions. The severity and complications associated with these medical conditions usually indicate that they require medication for successful management. Some of these medications may undoubtedly exert effects on bone through direct or indirect mechanisms and, therefore, may also affect osseointegration. These include antihypertensive drugs, oral hypoglycemic agents/insulin, hormones (corticosteroid, thyroxin, and tamoxifen), and anti-resorptive agents including bisphosphonates and anti-angiogenic agents. Part two of this paper reviews the current knowledge regarding the effects of corticosteroids, thyroxin, and tamoxifen on the outcome of implant therapy.
Keywords: Bone-to-implant interface, medical conditions, medications, osseointegration, review, success rate, systemic conditions
|How to cite this article:|
Sukumaran P, Dionysius DD, Ngeow WC, Tan CC, Hussin MZ. Systemic medications and implant success: Is there a link? Part two: The effects of therapeutic hormones on the outcome of implant therapy. J Dent Implant 2022;12:17-23
|How to cite this URL:|
Sukumaran P, Dionysius DD, Ngeow WC, Tan CC, Hussin MZ. Systemic medications and implant success: Is there a link? Part two: The effects of therapeutic hormones on the outcome of implant therapy. J Dent Implant [serial online] 2022 [cited 2023 Jun 8];12:17-23. Available from: https://www.jdionline.org/text.asp?2022/12/1/17/347665
| Introduction|| |
The maxilla and mandible consist of a mixture of dense outer cortical bone and inner trabecular bone which provides skeletal support and muscle attachments. Residing within the lacunar-canalicular network are the bone-forming osteoblasts which produce organic bone matrix and aid in its mineralization. Osteoblasts produce bone by synthesizing and secreting type I collagen (~90% of bone matrix protein) and some minor types of collagen, proteoglycans, fibronectin, and specific bone proteins (e.g., osteopontin, bone sialoprotein, and osteocalcin (~9%) to form the unmineralized flexible osteoids within which they reside., Mineralization of bone is achieved by the local release of phosphate, generated by phosphatases present within the osteoid. Together with calcium in the extracellular fluid, they grow into hydroxyapatite (Ca10[PO4]6[OH] 2) crystals. The proportion of organic matrix to mineral in adult human cortical bone is approximately 60% mineral, 20% organic material, and 20% water.
Apart from osteoblasts, bone also consists of unique exocrine cells called (i) osteoclasts that dissolve bone mineral and enzymatically degrade extracellular matrix proteins during bone resorption, (ii) osteocytes, which are osteoblast-derived postmitotic cells that have mechanosensor and endocrine secreting features, and (iii) bone lining cells, which have a specific role in coupling bone resorption to bone formation by physically defining bone remodeling compartments.
Bone is a metabolically active tissue. Normal growth and homeostasis of the jawbones are always in dynamic balance and are highly sensitive to factors such as hormone fluctuations. In part one of this series, we discussed insulin and several hormones secreted by osteocytes (fibroblast growth factor 23, osteocalcin, and lipocalin 2), as well as their effect on bone homeostasis. In part two of this series, we delve into the effects of other forms of therapeutic hormones on the bone metabolism and osseointegration of implants.
| Corticosteroid Therapy|| |
Glucocorticoids are widely prescribed to treat various allergic and autoimmune diseases. It is also commonly used to reduce inflammation for postoperative pain and improve the soft-tissue swelling after surgical procedures. In bone, it suppresses many osteoclastogenic pro-inflammatory cytokines and causes a reduction in bone-specific alkaline phosphatase serum levels. As a result, long-term use causes disturbances in bone homeostasis, characterized by consistent changes in bone remodeling with decreased bone formation as well as increased bone resorption. There is a reduction of preosteoblasts formation, inducing osteoblasts/osteocytes apoptosis and promoting the differentiation of bone marrow into adipocytes. Corticosteroids also favor osteoclastogenesis where it promotes the longevity of osteoclasts and reduces bone density. The most debilitating side effect of long-term high-dose corticosteroid therapy is bone loss, also termed glucocorticoid-induced osteoporosis. Current evidence indicates that autophagy and apoptosis induced by glucocorticoids can regulate bone metabolism through complex mechanisms that will lead to bone loss. In addition, prolonged use of corticosteroids results in higher blood glucose and lower serum insulin levels, a systemic condition which has been addressed in part one of this series.
The reduction in osteogenesis, increased bone resorption, and impaired bone healing affect the outcome of implant osseointegration., Unfortunately, the gold standard for prevention and treatment of corticosteroid-induced osteoporosis are anti-resorptive medications. The effects of anti-resorptive therapy on osseointegration are addressed in part three of this series. Significant diversity exists among the studies reviewed over corticosteroid therapy in implant osseointegration, hence the conflicting results., Many animal studies examined the effects of corticosteroid on the long bones, which may differ structurally and embryologically from the human jawbones. Most animal studies on the effects of short- or long-term corticosteroids in tibia bone supported the finding that administration of corticosteroids resulted in significantly reduced bone-to-implant and bone volume.,,,
On the contrary, Fujimoto et al. demonstrated no difference in implant removal torque and significant bone-to-implant contact in the mandible of a female rabbit model compared to the tibia. Werner et al. reported no significant difference in the amount of implant osseointegration between the dexamethasone-tested group and control group besides increased peri-implant bone volume in a rat model. The small sample size of animal studies might not represent the real clinical scenario in human samples, therefore, the generalization of their results to implant osseointegration in humans must be done with caution.
Several human studies including case reports and case series on this subject are summarized in [Table 1].,,,,,,,, All these reports support excellent implant osseointegration and survival rates in patients on corticosteroid therapy which are similar to normal healthy patients. Bencharit et al. proposed that the long-term implant success rate was favorable once the implant osseointegration is established despite prolonged usage of corticosteroids, while a retrospective study by Carr et al. found that corticosteroid therapy would not increase the risk of implant failure after 1st year of implant placement.
In conclusion, there is no strong evidence to indicate that corticosteroid is contraindicated for implant therapy. In fact, the current review has been shown that successful survival of implants between corticosteroid users and healthy subjects is comparable.
| Thyroxine Therapy (Thyroid Replacement Therapy)|| |
Thyroxine (T4) (tetraiodothyronine/3, 5, 3',5' tetraiodothyronine) and triiodothyronine (T3) (3, 5, 3' triiodothyronine) are two important therapeutic hormones used in the management of hypothyroidism. Physiologically, these hormones are crucial to regulate bone mineral homeostasis, bone density, and the basal metabolic rate. In addition, thyroid hormones also play a significant role in hard- and soft-tissue wound healing.,,
Literature shows that poorer soft-tissue healing is more prevalent in humans and animals with untreated hypothyroidism when compared to those on thyroid replacement therapy. It is believed the hypothyroid state reduces the production of type IV collagen and hydroxyproline from the inflammatory to proliferative phase of wound healing. Thyroid hormones have also demonstrated their ability to induce angiogenesis via the activation of the mitogen-activated protein kinase pathway.,,, However, there are also studies which show no significant changes in the wound tensile strength for hypothyroid animals or humans.,
Thyroid hormones act on nuclear T3 receptors, predominantly the thyroid receptor-α-1. These receptors are commonly found on human osteoblast and osteoclast cell lines and can therefore stimulate osteoblast proliferation by converting preosteoblasts to mature osteoblasts, subsequently inducing direct bone matrix formation. On the other hand, thyroid hormones, particularly T3, can also stimulate osteoclasts indirectly by acting on osteoblasts or osteoblast-like cells in the process of bone resorption. Many researchers have found that there is no difference in the bone mineral density in patients receiving thyroid replacement therapy compared to matched controls, underlying the importance that thyroid hormones play in bone homeostasis.,,,,
However, other studies have observed a noticeable reduction in bone mineral density at various sites of the skeletal system in hypothyroid patients undergoing T4 replacement, especially in long bones (tibia and femur) and lumbar spine., An animal study by Talaeipour et al. reported a significantly higher degree of bone density loss in the mandible compared to the hard palate, skull, and alveolar bone after administration of levothyroxine. Therefore, the evidence on adverse skeletal effects from hormone replacement therapy remains inconclusive.
Feitosa et al. have shown that changes in thyroid hormone levels influenced cortical and cancellous bone response toward dental implant osseointegration in a rat model. Cortical bone was found to be more sensitive to the changes of serum T3 and T4 levels than cancellous bone. Hypothyroidism is associated with a lower degree of osseointegration while bony formation around dental implants is generally better in hyperthyroidism. A review paper by Zahid et al. suggested that thyroid diseases could have an influence on the health of periodontal tissue, particularly in hypothyroid status. Overzealous thyroid hormone replacement in hypothyroid patients may lead to impaired homeostasis of the periodontium. Hence, the prudent administration of thyroid hormone therapy is important for better management of soft tissue as well as for improved success of osseointegration.
At present, only a handful of researchers have looked into the outcome of implant osseointegration in patients on thyroid replacement therapy, shown in [Table 2].,,, These results suggest that neither medically well-controlled hypothyroid patients nor thyroid-stimulating hormone suppression therapy was responsible for failure of implant osseointegration. However, given the limited number of studies available, the outcomes outlined in the table should be interpreted cautiously although all studies seem to suggest that there are no absolute contraindications to place implants in this group of patients.
|Table 2: Effects of thyroid hormone replacement therapy in dental implant osseointegration|
Click here to view
| Tamoxifen/Raloxifene (Selective Estrogen Receptor Modulator)|| |
There are three agents that are available as selective estrogen receptor modulators (SERMs). They are tamoxifen, raloxifene, and toremifene. Tamoxifen is the oldest and most common nonsteroidal hormonal therapy used in the treatment of estrogen-receptor-sensitive breast cancer in premenopausal patients. It is also used as chemoprevention therapy in patients with high breast cancer risk. Tamoxifen competitively binds to the estrogen receptor (ER) (ERα and ERβ) on osteoblasts, to induce differentiation and proliferation, and osteoclasts, to increase apoptosis.
Although tamoxifen is well known for its antiestrogenic effects, it also displays estrogen agonistic properties with long-term usage by increasing circulating estrogen and its effects on target tissues. Zidan et al. showed that tamoxifen has an osteoprotective effect, preserving and even increasing bone mineral density in some cases. This finding is consistent with other human studies in which tamoxifen preserves the bone mineral density of trabecular and, to a lesser extent, cortical bone, especially in postmenopausal women.,,
The mechanism of action for SERMs and estrogen in preserving bone mineral density is still not well understood. Tamoxifen is found to increase the production of osteoprotegerin (OPG). OPG diminishes the binding of receptor activator of NFkB ligand (RANKL) to its receptors (RANK). Bone resorption is suppressed by the low circulating RANKL/OPG ratio. In addition, tamoxifen also attenuates osteoclastogenesis by inhibiting osteoclast formation and differentiation. Hence, tamoxifen preserves and increases bone density through either direct or indirect actions on osteoblastic and osteoclastic cells.,, A literature search found no reports available on the outcome of implant osseointegration in patients prescribed with tamoxifen.
A benzothiophene analog is a second-generation SERM widely used for the prevention and treatment of osteoporosis. It has estrogenic effects on bone remodeling, lipid metabolism, and blood coagulation while exhibiting anti-estrogenic effects on breast and endometrial tissue. Ramalho-Ferreira et al. found that oral administration of raloxifene improved peri-implant bone mass density, bone-implant contact, and resistance to reverse torque in osteoporotic rats compared to the control group. They also suggested that raloxifene enhanced implant osseointegration compared to the usage of oral alendronate (see subsequent sub-topic on Bisphosphonates and anti-resorptive agents). Several other studies have also reported similar results, indicating that raloxifene can significantly increase bone volume, mineral deposition, and implant osseointegration in animal models., Rarely, raloxifene may cause osteonecrosis of the jaw which could adversely affect implant osseointegration.,
Currently, there are insufficient data to contraindicate or discourage implant placement in patients receiving SERMs. On the contrary, the findings, although limited, suggest that SERMs are particularly beneficial for osteoporotic patients who require dental implant rehabilitation.
| Conclusion|| |
Although the relationship between successful implant osseointegration with concurrent use of therapeutic hormones requires more research, the current data do not seem to contraindicate their concurrent use. Careful case selection, taking into account various other factors, is the key to success. Understanding the effect of various medications on osseointegration is an added layer of invaluable information to the clinician. In part three of this series, we will present the current understanding of anti-resorptive agents and their effect on implant success.
| References|| |
Crockett JC, Rogers MJ, Coxon FP, Hocking LJ, Helfrich MH. Bone remodelling at a glance. J Cell Sci 2011;124:991-8.
Boskey AL. Bone composition: Relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep 2013;2:447.
de Paula FJ, Rosen CJ. Bone remodeling and energy metabolism: New perspectives. Bone Res 2013;1:72-84.
Ngeow WC, Lim D, Ahmad N. 66 years of corticosteroids in dentistry: And we are still at a cross road? In: Corticosteroids. London: InTech; 2018. Available from: http://dx.doi.org/10.5772/intechopen 0.71540
. [Last accessed 2020 Jul 31].
Ngeow WC, Lim D. Do corticosteroids still have a role in the management of third molar surgery? Adv Ther 2016;33:1105-39.
Wang T, Liu X, He C. Glucocorticoid-induced autophagy and apoptosis in bone. Apoptosis 2020;25:157-68.
Fu JH, Bashutski JD, Al-Hezaimi K, Wang HL. Statins, glucocorticoids, and nonsteroidal anti-inflammatory drugs: Their influence on implant healing. Implant Dent 2012;21:362-7.
Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia LJ, et al.
Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest 2006;116:2152-60.
Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: Pathophysiology and therapy. Osteoporos Int 2007;18:1319-28.
Ouanounou A, Hassanpour S, Glogauer M. The influence of systemic medications on osseointegration of dental implants. J Can Dent Assoc 2016;82:g7.
Smith RA, Berger R, Dodson TB. Risk factors associated with dental implants in healthy and medically compromised patients. Int J Oral Maxillofac Implants 1992;7:367-72.
Yaghini J, Abed AM, Izadi M, Birang R, Torabinia N. Effect of short-term steroid use (Prednisolone) on bone healing around implants: An experimental study on dogs. OHDM 2017;16:2-5.
Almagro MI, Roman-Blas JA, Bellido M, Castañeda S, Cortez R, Herrero-Beaumont G. PTH [1-34] enhances bone response around titanium implants in a rabbit model of osteoporosis. Clin Oral Implants Res 2013;24:1027-34.
Carvas JS, Pereira RM, Caparbo VF, Fuller P, Silveira CA, Lima LA, et al.
A single dose of zoledronic acid reverses the deleterious effects of glucocorticoids on titanium implant osseointegration. Osteoporos Int 2010;21:1723-9.
Keller JC, Stewart M, Roehm M, Schneider GB. Osteoporosis-like bone conditions affect osseointegration of implants. Int J Oral Maxillofac Implants 2004;19:687-94.
Fujimoto T, Niimi A, Sawai T, Ueda M. Effects of steroid-induced osteoporosis on osseointegration of titanium implants. Int J Oral Maxillofac Implants 1998;13:183-9.
Werner SB, Tessler J, Guglielmotti MB, Cabrini RL. Effect of dexamethasone on osseointegration: A preliminary experimental study. J Oral Implantol 1996;22:216-9.
Alsaadi G, Quirynen M, Komárek A, Van Steenberghe D. Impact of local and systemic factors on the incidence of late oral implant loss. Clin Oral Implants Res 2008;19:670-6.
Yokokoji M, Fujimoto T, Ohya M, Ueda M. Dental implants for an elderly patient with rheumatoid arthritis taking long-term steroids. Asian J Oral Maxillofac Surg 2009;21:123-6.
Bencharit S, Reside GJ, Howard-Williams EL. Complex prosthodontic treatment with dental implants for a patient with polymyalgia rheumatica: A clinical report. Int J Oral Maxillofac Implants 2010;25:1241-5.
Krennmair G, Seemann R, Piehslinger E. Dental implants in patients with rheumatoid arthritis: Clinical outcome and peri-implant findings. J Clin Periodontol 2010;37:928-36.
Weinlander M, Krennmair G, Piehslinger E. Implant prosthodontic rehabilitation of patients with rheumatic disorders: A case series report. Int J Prosthodont 2010;23:22-8.
Ergun S, Katz J, Cifter ED, Koray M, Esen BA, Tanyeri H. Implant-supported oral rehabilitation of a patient with systemic lupus erythematosus: Case report and review of the literature. Quintessence Int 2010;41:863-7.
Zigdon H, Gutmacher Z, Teich S, Levin L. Full-mouth rehabilitation using dental implants in a patient with scleroderma. Quintessence Int 2011;42:781-5.
Petsinis V, Kamperos G, Alexandridi F, Alexandridis K. The impact of glucocorticosteroids administered for systemic diseases on the osseointegration and survival of dental implants placed without bone grafting – A retrospective study in 31 patients. J Craniomaxillofac Surg 2017;45:1197-200.
Drew A, Bittner N, Florin W, Koch A. Prosthetically driven therapy for a patient with systemic lupus erythematosus and common variable immunodeficiency: A case report. J Oral Implantol 2018;44:447-55.
Carr AB, Revuru VS, Lohse CM. Risk of dental implant failure associated with medication use. J Prosthodont 2019;28:743-9.
Safer JD, Crawford TM, Holick MF. Topical thyroid hormone accelerates wound healing in mice. Endocrinology 2005;146:4425-30.
Burch WM, Lebovitz HE. Triiodothyronine stimulates maturation of porcine growth-plate cartilage in vitro
. J Clin Invest 1982;70:496-504.
Lewinson D, Harel Z, Shenzer P, Silbermann M, Hochberg Z. Effect of thyroid hormone and growth hormone on recovery from hypothyroidism of epiphyseal growth plate cartilage and its adjacent bone. Endocrinology 1989;124:937-45.
Safer JD, Crawford TM, Holick MF. A role for thyroid hormone in wound healing through keratin gene expression. Endocrinology 2004;145:2357-61.
Natori J, Shimizu K, Nagahama M, Tanaka S. The influence of hypothyroidism on wound healing. An experimental study. Journal of Nippon Medical School 1999;66:176-80.
Davis PJ, Davis FB, Mousa SA. Thyroid hormone-induced angiogenesis. Curr Cardiol Rev 2009;5:12-6.
Safer JD. Thyroid hormone and wound healing. J Thyroid Res 2013;2013:124538.
Cannon CR. Hypothyroidism in head and neck cancer patients: Experimental and clinical observations. Laryngoscope 1994;104:1-21.
Ladenson PW, Levin AA, Ridgway EC, Daniels GH. Complications of surgery in hypothyroid patients. Am J Med 1984;77:261-6.
Klaushofer K, Varga F, Glantschnig H, Fratzl-Zelman N, Czerwenka E, Leis HJ, et al.
The regulatory role of thyroid hormones in bone cell growth and differentiation. J Nutr 1995;125:1996S-2003S.
Britto JM, Fenton AJ, Holloway WR, Nicholson GC. Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone resorption. Endocrinology 1994;134:169-76.
Moser E, Sikjaer T, Mosekilde L, Rejnmark L. Bone indices in thyroidectomized patients on long-term substitution therapy with levothyroxine assessed by DXA and HR-pQCT. J Thyroid Res 2015;2015:796871.
Quan ML, Pasieka JL, Rorstad O. Bone mineral density in well-differentiated thyroid cancer patients treated with suppressive thyroxine: A systematic overview of the literature. J Surg Oncol 2002;79:62-9.
Hanna FW, Pettit RJ, Ammari F, Evans WD, Sandeman D, Lazarus JH. Effect of replacement doses of thyroxine on bone mineral density. Clin Endocrinol (Oxf) 1998;48:229-34.
Fowler PB, McIvor J, Sykes L, Macrae KD. The effect of long-term thyroxine on bone mineral density and serum cholesterol. Clin Med (Lond) 1996;30:527.
Franklyn JA, Betteridge J, Daykin J, Holder R, Oates GD, Parle JV, et al.
Long-term thyroxine treatment and bone mineral density. Lancet 1992;340:9-13.
Kung AW, Lorentz T, Tam SC. Thyroxine suppressive therapy decreases bone mineral density in post-menopausal women. Clin Endocrinol (Oxf) 1993;39:535-40.
Diamond T, Nery L, Hales I. A therapeutic dilemma: Suppressive doses of thyroxine significantly reduce bone mineral measurements in both premenopausal and postmenopausal women with thyroid carcinoma. J Clin Endocrinol Metab 1991;72:1184-8.
Talaeipour AR, Shirazi M, Kheirandish Y, Delrobaie A, Jafari F, Dehpour AR. Densitometric evaluation of skull and jaw bones after administration of thyroid hormones in rats. Dentomaxillofac Radiol 2005;34:332-6.
Feitosa Dda S, Bezerra Bde B, Ambrosano GM, Nociti FH, Casati MZ, Sallum EA, et al.
Thyroid hormones may influence cortical bone healing around titanium implants: A histometric study in rats. J Periodontol 2008;79:881-7.
Zahid TM, Wang BY, Cohen RE. The effects of thyroid hormone abnormalities on periodontal disease status. J Int Acad Periodontol 2011;13:80-5.
Attard NJ, Zarb GA. A study of dental implants in medically treated hypothyroid patients. Clin Implant Dent Relat Res 2002;4:220-31.
de Souza JG, Neto AR, Filho GS, Dalago HR, de Souza Júnior JM, Bianchini MA. Impact of local and systemic factors on additional peri-implant bone loss. Quintessence Int 2013;44:415-24.
Neves J, de Araújo Nobre M, Oliveira P, Martins Dos Santos J, Malo P. Risk factors for implant failure and peri-implant pathology in systemic compromised patients. J Prosthodont 2018;27:409-15.
Rey JR, Cervino EV, Rentero ML, Crespo EC, Alvaro AO, Casillas M. Raloxifene: Mechanism of action, effects on bone tissue, and applicability in clinical traumatology practice. Open Orthop J 2009;3:14-21.
Lum SS, Woltering EA, Fletcher WS, Pommier RF. Changes in serum estrogen levels in women during tamoxifen therapy. Am J Surg 1997;173:399-402.
Zidan J, Keidar Z, Basher W, Israel O. Effects of tamoxifen on bone mineral density and metabolism in postmenopausal women with early-stage breast cancer. Med Oncol 2004;21:117-21.
Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, et al.
Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992;326:852-6.
Powles TJ, Hickish T, Kanis JA, Tidy A, Ashley S. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 1996;14:78-84.
Neal AJ, Evans K, Hoskin PJ. Does long-term administration of tamoxifen affect bone mineral density? Eur J Cancer 1993;29A: 1971-3.
Ho TY, Santora K, Chen JC, Frankshun AL, Bagnell CA. Effects of relaxin and estrogens on bone remodeling markers, receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG), in rat adjuvant-induced arthritis. Bone 2011;48:1346-53.
Khosla S, Atkinson EJ, Dunstan CR, O'Fallon WM. Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men. J Clin Endocrinol Metab 2002;87:1550-4.
Michael H, Härkönen PL, Kangas L, Väänänen HK, Hentunen TA. Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro
. Br J Pharmacol 2007;151:384-95.
Ramalho-Ferreira G, Faverani LP, Prado FB, Garcia IR Jr., Okamoto R. Raloxifene enhances peri-implant bone healing in osteoporotic rats. Int J Oral Maxillofac Surg 2015;44:798-805.
Faverani LP, Polo TO, Ramalho-Ferreira G, Momesso GA, Hassumi JS, Rossi AC, et al
. Raloxifene but not alendronate can compensate the impaired osseointegration in osteoporotic rats. Clin Oral Investig 2018;22:255-65.
Heo HA, Park S, Jeon YS, Pyo SW. Effect of raloxifene administration on bone response around implant in the maxilla of osteoporotic rats. Implant Dent 2019;28:272-8.
Baur DA, Altay MA, Teich S, Schmitt Oswald M, Quereshy FA. Osteonecrosis of the jaw in a patient on raloxifene: A case report. Quintessence Int 2015;46:423-8.
Pontes HA, Souza LL, Uchôa DC, Cerqueira JM. Mandibular osteonecrosis associated with raloxifene. J Craniofac Surg 2018;29:e257-9.
[Table 1], [Table 2]