Journal of Dental Implants

REVIEW ARTICLE
Year
: 2022  |  Volume : 12  |  Issue : 1  |  Page : 10--16

Systemic medications and implant success: Is there a link? part one: The effects of antihypertensives, oral hypoglycaemic agents and insulin 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

Correspondence Address:
Dr. Prema Sukumaran
Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603
Malaysia

Abstract

Dental implants require healthy bone for successful osseointegration. However, bone health can become compromised by ageing 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 antihypertensives, oral hypoglycaemic agents (OHAs)/insulin, hormones (corticosteroid, thyroxin and tamoxifen) and anti-resorptive agents including bisphosphonates and anti-angiogenic agents. Part One of this paper reviews the current knowledge regarding the effects of antihypertensives, OHAs and insulin on the outcome of implant therapy.



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 one: The effects of antihypertensives, oral hypoglycaemic agents and insulin on the outcome of implant therapy.J Dent Implant 2022;12:10-16


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 one: The effects of antihypertensives, oral hypoglycaemic agents and insulin on the outcome of implant therapy. J Dent Implant [serial online] 2022 [cited 2022 Jul 7 ];12:10-16
Available from: https://www.jdionline.org/text.asp?2022/12/1/10/347664


Full Text

 Introduction



Dental implants require healthy bone for successful osseointegration. Osseointegration is the formation of a direct structural and functional bony adherence to the surface of a load-bearing fixture.[1],[2] Successful osseointegration depends on implant properties (i.e., material and design), aseptic and good surgical techniques and proper loading protocol as well as patient related factors including bone health, underlying medical conditions and the medications used to treat these conditions.

The effect of these therapies on osseointegration is not well understood. So far, our understanding of the medications' implication towards osseointegration is indirect (i.e., based on the status of medical health rather than medication based). Some uncontrolled systemic diseases may elicit pro-inflammatory host responses that lead to bone loss and peri-implant disease.[3] Systemic intake of medications to manage these underlying conditions have demonstrated the ability to modulate bone metabolism leading to many uncertainties with regards to the provision of endosseous implants. In 2006, Mombelli and Cionca[4] reported that there is lack of clear evidence supporting the absolute and relative contraindications for implant therapy in patients suffering from the more common systemic diseases. Dawson and Jasper[5] also noted the lack of randomised controlled studies comparing implant outcomes in healthy versus medically compromised patients. This is because the mechanisms through which systemic diseases and their various therapies modulate bone homeostasis is still not fully understood. Some medications that may affect the success of implant therapy include antihypertensive drugs, oral hypoglycaemic agents (OHAs)/insulin, hormone-based therapy (corticosteroid, thyroxin and tamoxifen), antiresorptive agents and anti-angiogenic agents. This paper reviews the current knowledge on the effects of the first two groups of medications on the success of implant therapy.

 Antihypertensive Medication



Approximately 45% of the global population is affected by hypertension and these estimates increase with age.[6] Anti-hypertensive medications, such as beta-blockers, thiazide diuretics, angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin II receptor blockers are the most commonly prescribed drugs used to treat hypertension. Beta-blockers act by blocking the β-2 receptor in the sympathetic nervous system resulting in a decrease in blood pressure; thiazide diuretics control hypertension by blocking the thiazide-sensitive Na-Cl symporter and inhibiting reabsorption of sodium and chloride ions from the distal convoluted tubules in the kidneys; ACE inhibitors and angiotensin II receptor blockers block the renin-angiotensin system to reduce blood pressure.[7] Following implant placement, the peri-implant soft and hard tissues undergo a series of changes as the four phases of osseointegration unfold; namely homeostasis, inflammation, proliferation and remodelling.[8] Anti-hypertensive medications may interfere in central pathways and bone cell interactions, affecting any of these phases of wound healing.[9]

To date, the influence of anti-hypertensive medications on dental implant-related outcomes remains rather speculative, as reported in a limited number of human and preclinical studies. Morrison and Tamimi[10] observed the association between subjects with treated hypertension and the presence of ectopic oral bone growth (i.e., tori), whereby this may reduce the necessity for bone augmentation surgeries. García-Denche et al.,[11] found that patients on antihypertensive medication had significantly higher implant survival rate after sinus augmentation.

These findings were echoed by Wu et al. in 2016.[7] The retrospective cohort study with a mean follow-up of 17.1 months, showed improved survival rates of osseointegrated dental implants associated with oral anti-hypertensive medications. The exploratory analysis included a retrospective cohort of 1499 dental implants in 728 patients (327 implants in 142 antihypertensive-drugs-users and 1172 in 586 nonusers) in Canada. The implant failure rate was almost seven folds lower in patients using anti-hypertensive medications (0.6%) than in nonusers (4.1%). Hypertensive patients not taking anti-hypertensive medications had a failure rate of 4.7% although this was not statistically significant. The study also found that bone augmentation was performed less often in anti-hypertensive drugs users than in nonusers; but we have to caution that the procedure may have been avoided in some patients due to their underlying medical status. Adjusted for potential confounders, it was reported that age, gender, implant length, implant torque, implant loading and bone augmentation did not affect the implant survival rate.[7]

It must be noted that the length and dosage of anti-hypertensive therapy were not reported by the authors, and the specific influence of each anti-hypertensive medications could not be identified due to the limited sample size in each sub-category. In addition, the retrospective design of the study did not allow the determination of a direct “cause-and-effect relationship” between osseointegration, bone healing and antihypertensive medications. Lastly, these findings could also be limited by recall bias as the study relied on self-reported exposures by the patients in the clinic database subject to how recent the event, social desirability of the drugs, and data collection methodology.

An animal model study by Al-Subaie et al.[12] reported that propranolol, a commonly prescribed nonselective β-blocker accelerated bone healing and implant osseointegration in rats' tibiae in-vivo. Following titanium rod implantation, propranolol (5 mg/kg, subcutaneous, daily) was administered in the experimental group while rats in the control group were injected with saline (0.1 mL, subcutaneous, daily) for 2 weeks. Osseointegration was more pronounced in propranolol-treated rats with higher bone-implant-contact and higher peri-implant bone volume/tissue volume.

In yet another rodent model study, Mulinari-Santos et al.,[13] demonstrated that an angiotensin II receptor blocker, losartan, reversed impaired osseointegration in spontaneously hypertensive rats compared to untreated controls, revealing higher bone per tissue volume and trabecular thickness on micro-computed tomographic analysis. Histomorphometric analysis also showed that losartan significantly increased the thickness of newly formed bone. These findings may suggest that, prior to implant placement, losartan may exert anabolic effects on peri-implant bone in hypertensive subjects, thereby supporting the quality of the alveolar bone.[14],[15] After implant placement, losartan supports bone remodelling and contributes to better biomechanical stability in the long-term.[15]

Several hypotheses were outlined by Wu et al.,[7] to explain the biological plausibility of the beneficial effects of anti-hypertensive medications on bone metabolism and osseointegration. Anti-hypertensive therapy can affect bone metabolism by inhibiting osteoclasts' catabolic effects on bone either by blocking their β2 adrenergic receptors (beta-blockers), enhancing bone formation through increasing calcium absorption at the distal convoluted tubule (thiazides) or via inhibition of the renin-angiotensin system (ACE inhibitors).[3],[7] It was also hypothesised that losartan improves microcirculation in fracture healing and graft consolidation in preclinical models, possibly through an anabolic shift in bone remodelling via the ACE2/Angiotensin 1–7/Mas pathway.[16],[17],[18]

Anti-hypertensive drugs have also been reported to be beneficial in preventing osteoporosis and subsequent fragility fractures.[19],[20] Bone metabolism is regulated by the highly dynamic relationship between osteoclasts, osteoblasts and an array of hormonal and regulatory influences. The sympathetic nervous system inhibits bone formation through adrenergic receptors present in all bone cells.[19],[21] Accordingly, anti-hypertensive medications have been shown to inhibit activity of the sympathetic nervous system by blocking adrenergic receptors. By inhibiting the normal physiologic function of osteoclasts, these drugs may counteract this catabolic state, shifting the balance toward increased bone formation and bone mineral density.[10],[22],[23],[25]

All in all, most studies confirm the positive effect of anti-hypertensive medication on bone and osteointegration. However, careful monitoring of patients on anti-hypertensives and constant update on their systemic medication intake is highly recommended at pre-and peri-implant placement as well as during review appointments.

 Anti-Diabetic Drugs



Bone can be thought of as a pleiotropic endocrine organ that secretes at least three hormones, namely fibroblast growth factor 23 (FGF23), osteocalcin and lipocalin 2. The former regulates phosphate metabolism in kidneys, while the latter two osteoblast-secreted hormones regulate glucose homeostasis. Osteocalcin, in particular, promotes energy expenditure, insulin secretion and glucose homeostasis while lipocalin 2, maintains glucose homeostasis by inducing insulin secretion and improving glucose tolerance and insulin sensitivity.[26] The cascade of molecular events triggered by chronic hyperglycaemia in diabetes mellitus impairs bone metabolism. Numerous studies have shown that persistent hyperglycaemia negatively affects bone homeostasis leading to increased bone fragility and increased risk of fractures.[27],[28]

It is no surprise then, that diabetes mellitus has long been considered a relative contraindication for dental implant treatment.[29] Several clinical and animal studies have looked into the effects of diabetes and its various permutations on osteointegration. A reduction in the quantity and quality of osteoblasts as well as increased osteoclast recruitment can be observed around implants during the early phase of healing in diabetics. These factors can delay healing by up to 6 months and compromise bone-to-implant contact.[30] This is thought to be caused by advance glycation end-products (AGEs), a class of irreversible glucose metabolites that accumulate as a result of hyperglycaemia. Changes in the extracellular matrix caused by AGEs lead to diminished collagen production, reduced osteoblastic secretion of alkaline phosphatase (ALP) and reduced serum levels of osteocalcin. Its impact on FGF23 and lipocalin 2 is currently being investigated. It has also been suggested that AGEs competitively inhibit the attachment of bone forming proteins to the implant surface thereby jeopardising normal bone formation.[31]

Upregulation of genes expressing pro-inflammatory cytokines such as interleukin (IL)-6, IL-8 and tumour necrosis factor–α as well as chemokines such as monocyte chemotactic protein-1 and C-C chemokine receptor-2 and-4 are also marked in poorly controlled diabetics. These factors are known to worsen the severity of peri-implantitis. The fibrosis caused by these factors favours a less stable fibrointegration rather than osteointegration.[30]

Therefore, good glycaemic control is imperative to the management of diabetes mellitus as persistent hyperglycaemia not only leads to altered bone metabolism but also to long term serious complications of macrovascular and microvascular disease.[28] Anti-diabetic medication is often prescribed to help diabetic patients control glucose levels. The more commonly prescribed drugs are OHAs such as biguanides, sulphonylureas, thiazolidinidiones and the newer integrin-based therapies and sodium-glucose co-transporter 2 (SGLT2) inhibitors, as well as injectable therapies, namely insulin. However, studies looking into the relationship between these drugs and bone homeostasis have yielded inconsistencies. It is important to consider the effect these treatment modalities have on bone health as this, by extension, may have an impact on osteointegration and implant survival.

Oral hypoglycaemic agents

Biguanides

Biguanides are a synthetic derivative of galegine, a natural guanine compound extracted from the Galega officinalis plant. Unlike other biguanides such as Phenformin and Buformin (which have been withdrawn from use due to their side effects), only Metformin remains in use today.[32] Metformin helps control blood glucose levels by reducing hepatic glucose production and increasing glucose uptake in muscle.[27],[33] It does this via the action of AMP-activated protein kinase (AMPK) which suppresses fatty acid synthesis, increases glucose uptake in muscle and decreases sterol regulatory element-binding-protein 1 (SREBP 1) expression. SREBP 1 has been implicated in the pathogenesis of insulin resistance, dyslipidemia and diabetes.[27]

The effect of AMPK on bone metabolism is not well understood but studies suggest that it positively affects osteoblast differentiation. The reverse appears to be true for osteoclast differentiation.[28] A study conducted by Serrão et al.,[33] looked specifically at the impact of metformin on bone healing around implants in a rat model. Metformin appeared to enhance bone metabolism by stimulating osteoblast expression of osteoprotegrin (OPG) and inhibiting the expression of receptor activator of nuclear factor kB-ligand (RANKL). OPG was able to suppress osteoclast formation and bone resorption by interfering with RANK/RANKL interactions thus providing a protective effect to bone around implants.[27],[33]

Sulphonylureas

Sulphonylureas, are a group of secretogogues that have been around for more than 50 years. They act by binding to receptors on the surface of pancreatic β-cells thereby stimulating the secretion of insulin. They also act on insulin-sensitive tissues by enhancing glucose uptake.[27] Their mechanism of action is mediated through the inhibition of ATP-dependant potassium channels by binding to specific receptors of pancreatic β-cells. The resultant depolarisation of the cell membranes cause an influx of calcium into the cytocol, causing a chain of physiological process which eventually leads to an increase in insulin secretion. Currently, second generation sulphonylureas such are gliclazide, glipizide and glibenclamide are used in the treatment of Type 2 diabetes mellitus (T2DM).[34]

This class of drugs are generally considered to have a minimal or at least neutral effect on bone.[27] Glimepiride has been shown to stimulate proliferation and differentiation of rat osteoblasts via the PI3K/Akt pathway. Activation of this pathway also enhanced osteocalcin and ALP activities and protected rat mandibular osteoblasts from the effects of hyperglycaemia. However, due to the limited number of studies available, the best conclusion to be drawn is that this group of drugs does not appear to have a detrimental effect on bone.[28] While studies on the effects of sulphunylureas on osseointegration and implant survival are almost nonexistent, one such study showed that gliclazide may contribute to reduction in linear bone loss in ligature induced periodontitis in rodents.[35]

Thiazolidinediones

Thiazolidinediones (TZDs) are a class of oral hypoglygaemic agents used in the treatment of T2DM. They activate peroxisome proliferator-activated receptor-gamma (PPARγ) to increase peripheral uptake of glucose and reduce hepatic glucose production. Activation of PPARγ modifies transcription of genes involved in glucose and lipid metabolism. TZDs also reduce insulin resistance of muscle, liver and adipose tissue.[36] As PPARγ agonists, TZDs also suppress osteoblastic differentiation and enhance osteoclastic differentiation of mesenchymal and hematopoietic stem cells respectively. In animal studies, they alter bone remodelling to favour bone resorption and cause massive accumulation of adipocytes in the bone marrow cavity.[37] Reduction in bone formation markers such as bone specific ALP, and procollagen type I N propeptide (PINP) and an increase in C-terminal telopeptide of type I collagen (CTX), a bone resorption marker, have been associated with rosiglitazone in women.[27] The negative effect of rosiglitazone and pioglitazone on bone mass and increase fracture risk (especially in women) is well documented.[37] Although there are no studies investigating the impact on TZDs on implants specifically, its negative effect on bone turnover might serve as an indicator to its possible effect on osseointegration.

Sodium-glucose co-transporter 2 inhibitors

SGLT2 channels are responsible for 90% of renal glucose resorption. They are expressed almost exclusively by proximal convoluted tubular cells and are independent of insulin action. SGLT2 inhibitors are a novel class of oral hypoglycaemic drugs that targets these channels resulting in reduced glucose resorption and glycosuria. Current findings on the effects of SGLT2 inhibitors on bone are mixed. SGLT2 inhibition may affect bone metabolism indirectly by altering calcium/phosphate metabolism.[27] It is thought that the knock-on effect from SGLT2 inhibition as well as concomitant sodium loss increases phosphate reabsorption (via sodium-phosphate co-transporters) and renal calcium excretion.[38] Elevated serum phosphate levels stimulate FGF 23, a regulator of phosphate and Vitamin D metabolism, which inhibits 1,25-dihydroxyvitamin D. This in turn reduces calcium absorption from the gut. Coupled with urinary loss, the resultant lowered calcium concentration can trigger parathyroid hormone (PTH) secretion. To suggest that this may possibly induce secondary hyperparathyroidism might be a stretch. However, Blau et al. demonstrated that there was an increase in serum phosphate, FGF23 (which is secreted by bone) and PTH whereas a reduction in 1,25-dihydroxyvitamin D was seen with the administration of canagliflozin in healthy volunteers.[39] However, they did concede that the changes were observed in the short term and whether there is a sustained and detrimental effect on bone remains to be seen. These negative effects, if persistent may be ameliorated by the positive effects of lowering blood glucose levels.[38],[39] In negating the deleterious effect hyperglycaemia has on bone, SGLT2 inhibitors may prove beneficial to bone metabolism in the long run. Similar to TZDs, the direct effect of SGLT2 inhibitors on bone metabolism and implant may not be fully understood at this point in time although there seems to be scarce evidence pointing towards an indirect positive effect of bone metabolism, which is turn could be advantageous for osseointegration.

Incretin-based therapies

Incretin-based therapies are named so because of their effect on incretin hormones. Incretion hormones are released from gut endocrine cells in response to nutrient ingestion in order to modulate glucose homeostasis. Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptides 1 and 2 (GLP 1 and GLP 2) are incretins that stimulate pancreatic β-cells to secrete insulin and suppress α-cell release of glucagon. Once released incretin hormones (GIP and GLP 1) are rapidly inactivated by dipeptidyl peptidase 4 (DPP4) enzymes. GLP 1 receptor agonists such as exenatide and liraglutide and DPP4 inhibitors such as sitogliptin and vidagliptin are incretin-based drugs that are currently in use for T2DM treatment.[28]

Incretin receptors found on both osteoblasts and osteoclasts seem to allude to the fact that they may have important roles in bone homeostasis. GIP has been shown to have an anabolic effect on bone by increasing ALP activity and Type I collagen synthesis while suppressing osteoclastic bone resorption. GLP-1 receptors on osteoblast also produce a similar anabolic reaction on osteoblasts while GLP-2 reduces osteoclast activity. GLP 1 may also indirectly suppress bone resorption by stimulating the release of calcitonin via activation of GLP 1 receptors on thyroid C-cells.[27] Besides that, decreased bone quality, osteopenia, thinner trabeculae bone and decreased collagen maturity seen in animals knocked-out for GIP and/or GLP 1 receptors, further support the role incretins play on bone homeostasis.[40]

Despite these findings, the skeletal effects of incretin-based therapies are not well established although several in vitro and in vivo studies suggest that they have a positive effect on bone.[37] The GLP-1 receptor agonists exenatide and liragutide were shown to increase trabeculae, but not cortical bone mass in normoglycaemic ovariectomised mice while the effects on DPP4 inhibitors on bone are inconsistent.[40] Based on current evidences available, it may be acceptable to agree that there are no obvious contraindications to placing implants in patients on incretin-based therapies. However, more robust clinical studies are needed before we can emphatically conclude the effects of this group of medication on osseointegration and survival of implants.

Insulin

The discovery of insulin in 1921 transformed the management T1DM, which up until then was considered a fatal condition. Initially, insulin was extracted from the pancreases of cows and pigs which was then purified before use. However, nowadays, recombinant DNA technology has enabled the large-scale production of human insulin.[41]

Insulin appears to have an anabolic effect on bone. This effect is exerted when insulin binds to insulin receptors on osteoblasts. Through the action of intercellular signalling molecules known as insulin receptor substrate (IRS-1 and IRS-2), osteoblast proliferation and differentiation are enhanced, and bone formation increases.[28] Osteopenia and low bone turnover were demonstrated on IRS-1 and IRS-2 deficit mice.[42]

Fiorellini et al.[31] investigated the role of insulin on osteointegration using an animal model and reported that bone regulation was increased when insulin was administered to diabetic rats. In fact, bone density was greater in insulin-controlled rats compared to their nondiabetic counterparts. However, bone-to-implant contact was reduced when the same comparison was made. In other studies, insulin has been shown to have an anabolic effect on bone metabolism due to its structural resemblance to IL-1 and IL-2. Insulin also appears to neutralise the inhibitory effect of uncontrolled diabetes on somatomedin production. Somatomedin stimulates cartilage production and skeletal growth.[31] Animal studies using rat model have shown that the combination of Vitamin D3 and insulin therapy promotes titanium implant osseointegration.[43]

Diabetes mellitus has long been considered a relative contraindication to dental implant therapy. However, despite many changes to bone metabolism and osseointegration, several studies have reported success rates close or similar to normal subjects. When analysed collectively, global implant failure rates in diabetics fall within a wide range (0%–14.3%).[30],[44] Despite the variable results, most authors agree that the key to ensuring success of implant therapy in diabetics is good glycaemic control. The role anti-diabetic medications play in controlling hyperglycaemia may enhance the positive effects or ameliorate some the possible negative effects these therapies have on bone metabolism and osseointegration. The importance of careful patient selection coupled with additional measures such good oral hygiene, antibiotics and a longer healing phase may ensure better success in diabetic patients.[30]

 Conclusions



The effects of medications on osseointegration are not always clearly defined, as they may exert both positive and negative impact on both bone homeostasis and osseointegration. However, polypharmacy, especially in the ageing population, may further complicate the effect of medications on tissue healing postimplant placement.

In part 2 and 3 of this series, we will delve more closely into the effects of hormone therapies, as well as anti-resoprtive agents such as bisphosphonates and anti-angiogenic drugs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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