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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 12  |  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


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 Submission09-Oct-2021
Date of Acceptance27-Feb-2022
Date of Web Publication16-Jun-2022

Correspondence Address:
Dr. Prema Sukumaran
Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdi.jdi_23_21

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   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 2022 Jul 7];12:17-23. Available from: https://www.jdionline.org/text.asp?2022/12/1/17/347665


   Introduction Top


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.[1],[2] 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.[1]

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.[1]

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.[3] 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 Top


Glucocorticoids are widely prescribed to treat various allergic and autoimmune diseases.[4] It is also commonly used to reduce inflammation for postoperative pain and improve the soft-tissue swelling after surgical procedures.[5] In bone, it suppresses many osteoclastogenic pro-inflammatory cytokines and causes a reduction in bone-specific alkaline phosphatase serum levels.[6] 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.[7] 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.[6] 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.[7],[9] 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.[10],[11] 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.[12],[13],[14],[15]

On the contrary, Fujimoto et al.[16] 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.[17] 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].[18],[19],[20],[21],[22],[23],[24],[25],[26] 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.[20] 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.[27] found that corticosteroid therapy would not increase the risk of implant failure after 1st year of implant placement.
Table 1: Effects of corticosteroids in dental implant osseointegration

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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) Top


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.[28],[29],[30]

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.[31],[32],[33],[34] However, there are also studies which show no significant changes in the wound tensile strength for hypothyroid animals or humans.[35],[36]

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.[37] 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.[38] 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.[39],[40],[41],[42],[43]

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.[44],[45] An animal study by Talaeipour et al.[46] 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.[47] 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.[48] 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].[18],[49],[50],[51] 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

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   Tamoxifen/Raloxifene (Selective Estrogen Receptor Modulator) Top


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.[52]

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.[53] Zidan et al.[54] 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.[55],[56],[57]

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.[58],[59],[60] 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.[38] 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).[61] Several other studies have also reported similar results, indicating that raloxifene can significantly increase bone volume, mineral deposition, and implant osseointegration in animal models.[62],[63] Rarely, raloxifene may cause osteonecrosis of the jaw which could adversely affect implant osseointegration.[64],[65]

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 Top


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.



 
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