Effect of Topical Melatonin Application on Dental Implant Osseointegration and Marginal Bone Level (Clinical and Radiographic Evaluation)
Phase: PHASE3
Conditions: Alveolar Bone Loss
Sponsor: University of Baghdad

 
 
 
 
October 21, 2019 
Effect of topical melatonin 
application on dental implant 
osseointegration and marginal bone 
level (Clinical and Radiographic 
Evaluation)
 
 

Republic of Iraq 
Ministry of Higher Education                                                         
And Scientific Research 
University of Baghdad 
College of Dentistry 
 
 
 
 
Title 
Effect of topical melatonin application on dental 
implant osseointegration and marginal bone level 
(Clinical and Radiographic Evaluation) 
 
 
 
Proposal thesis 
Submitted to the Department of Periodontics, College of 
Dentistry/University of Baghdad in Partial Fulfillment of the 
Requirements for Master's Degree in Periodontics. 
 
 
By 
Zaid Mohannad Yasser 
B.D.S. 
 
Supervised by:  
Prof. Dr. Saif S.Saliem 
B.D.S., M.Sc. (Periodontics) 
 
2019-2020 

Introduction:- 
 
   Melatonin (N-acetyl-5-methoxy-tryptamine) is an indoleamine synthesized and 
secreted by the pineal gland and other organs, such as the retina, bone marrow, 
and intestines in a circadian pattern. Extrapineal sites contribute poorly, or only 
upon specific stimuli to circulating melatonin(Hardeland et al., 2006). Melatonin 
influences numerous physiological actions that may be mediated by the binding of 
the indoleamine to membrane receptors in all tissues(Girgert et al., 2009). 
Because of its lipophilic properties, melatonin passes through cell membranes to gain 
access to subcellular organelles (Hevia et al., 2008), being capable to bind to some 
cytosolic proteins like kinase-C (Macías et al., 2003). Currently, melatonin is not 
considered a hormone in the classical sense of the term, because it is synthesized 
in several organs and does not exert effects on a specific target (Tan et al., 2003), 
but it is rather a powerful cell protector against molecular damage. For the 
synthesis of melatonin, the pineal cells take up tryptophan from the blood and, 
through hydroxylation and a decarboxylation process, turn it into serotonin. 
Serotonin is then converted into N-acetylserotonin through N-acetyltransferase 
and subsequently methylated to the final form of melatonin by the enzyme 
hydroxy indole-O-methyltransferase (Reiter, 1991) (Figure 1). In healthy 
individuals, the maximum secretion of melatonin occurs between midnight and 2 
a.m., then it decreases to a minimum during the day(Simonneaux and Ribelayga, 
2003). Melatonin has numerous physiological functions in different parts of the 
body, such as the control of circadian rhythms (McArthur et al., 1997), regulation 
of body temperature(Dollins et al., 1994), and activation of the immune 
system(Guerrero and Reiter, 2002).In the oral cavity, melatonin has been 
recognized as an important substance with paracrine effects on nearby 
cells(Tresguerres et al., 2002), it also acts as an antioxidant and an anti-
inflammatory and plays an important role in bone formation and in the reduction 
of bone resorption(Peyrot et al., 2008, Hardeland et al., 2009). 
 
 
 

 
Figure 1. Melatonin synthesis and representation of its molecule (Reiter, 1991)
 
 
Osseointegration defined as a direct connection between living bone tissues and a 
titanium implant without any connective tissues. Osteoblasts are bone formative 
cells, and osteoclasts are bone resorptive cells. When these cells work together 
physiologically, the formation and resorption processes of bone tissue is known 
as bone remodelling. The remodeling of bone tissues is regulated by the action of 
systemic hormones (estradiol, parathyroid, growth, and melatonin) and by the 
bone marrow and osteoid matrix-derived growth factors(Tresguerres et al., 
2012, Wulandari).Insufficient bone quality and quantity can be seen frequently 
in elderly populations with atrophic and osteoporotic bones, and this situation 
stems 
from 
increased 
osteoclastic 
activity 
due 
to 
a 
reduction 
in 
osteoblastogenesis. In addition, local free radical concentrations in all body cells, 
including osteoblasts, can reduce osteoblastic activity in aged patients. This 
process could lead to a reduction in bone regeneration capacity(Cao et al., 2005). 
Melatonin can also suppress osteoclastogenesis, and therefore inhibit bone tissue 

resorption(Cutando et al., 2008, Witt‐Enderby et al., 2006). In addition to this, 
in vitro research has reported that melatonin can increase osteoblast proliferation 
and differentiation(López-Martínez et al., 2012, Muñoz et al., 2012). So was 
proposed that the local application of melatonin during surgical implant 
placement procedures would be an effective treatment technique for dental 
implant osseointegration(Dundar et al., 2016). Worthy osseointegration is a 
prerequisite for dental implants. Optimal osseointegration depends on the 
formation of new bone around implants, which may be stimulated by the 
application of biomimetic agents(Ramazanoglu et al., 2011). Considering the 
bone metabolism, melatonin acts directly on the osteoclast, a multinucleated cell, 
which resorbs the extracellular matrix through various mechanisms, including the 
production of free radicals(Roth et al., 1999). Moreover, in pre-osteoblast 
cultures from rats, melatonin, in a dose-dependent manner, promoted the 
development of bone sialoprotein and other protein bone markers, including 
alkaline phosphatase, osteopontin, and osteocalcin, and speeds up their period of 
differentiation into osteoblasts from the normal rate, which is 21 days, to 12 days, 
this reaction is mediated by the membrane receptors for the indole(Roth et al., 
1999). Also, melatonin, may interfere with the function of the osteoclast and 
thereby inhibit bone resorption(Cardinali et al., 2003). (Cutando et al., 2008) 
conducted an experimental study using melatonin with dental implants in dogs. 
Two weeks after implant insertion, melatonin significantly increased all 
parameters of osteointegration. It has been observed that melatonin, increases 
bone mass by suppressing resorption through down-regulation of the RANKL-
mediated osteoclast formation and activation(Cutando et al., 2007). These data 
point towards an osteogenic effect of melatonin that may be of clinical importance, 
as it could be used as a therapeutic agent in situations in which bone formation 
would be advantageous, such as in the treatment of fractures or of osteoporosis 
(Cardinali et al., 2003). 
 
 
  
 

Toxicology of Melatonin:-
 
The physiological functions of the pineal hormone melatonin are extremely 
diverse. The functions include direct and indirect modulations of anti-oxidative 
defense, blood pressure, body temperature, cortisol rhythm, reproduction and 
immune function (Claustrat and Leston, 2015). Correspondingly, exogenous 
melatonin has been investigated as a treatment for a number of medical and 
surgical diseases, demonstrating encouraging results (Andersen et al., 2014, 
Gitto et al., 2011). In the USA, melatonin is available as an over-the-counter non-
prescription drug. In most European countries, however, melatonin remains a 
prescription drug (Circadin) and has only been approved as a treatment for 
primary insomnia in people over 55 years of age. However, a recent Norwegian 
register study documented a 3- to 5-times increase in off-label use among children 
and adolescents in the time period 2004 to 2012 (Hartz et al., 2015). Melatonin 
is generally considered safe (Yousaf et al., 2010), but the increasing clinical use 
with potentially increasing doses necessitates further investigations of the risks 
of both mild and serious adverse effects. In experimental animal studies, 
exogenously administered melatonin has been given in doses up to 800 mg/kg 
without any acute toxic effects (Barchas et al., 1967). A number of studies in 
preterm infants have investigated the anti-oxidative/anti-inflammatory and 
clinical effects of exogenous melatonin in different conditions, such as pain during 
tracheal intubation (10 mg/kg  x 10 doses, randomized)(Gitto et al., 2012), 
asphyxia (10 mg x 8 doses, randomized) (Fulia et al., 2001), respiratory distress 
(10 mg/kg x 10 doses, randomized)(Gitto et al., 2004b). Despite repeated high 
doses of intravenous melatonin, no signs of adverse effects were observed (Gitto 
et al., 2004c, Gitto et al., 2004a). Oral melatonin in doses of 0.5–10 mg was 
administered daily from 10 days to 12 weeks to improve sleep quality (Wright et 
al., 2011, Cortesi et al., 2012). The studies performed detailed registration of 
possible adverse effects, demonstrating a number of mild adverse effects, such as 
agitation, dizziness, headache, nausea, and sleepiness (Wasdell et al., 2008, Jain 
et al., 2015). Another study was to assess the toxicology of melatonin (10 mg), 
administered for 28 days to 40 volunteers randomly assigned to groups receiving 
either melatonin (N_30) or placebo (N_10) in a double-blind fashion, according to 

the parameters analyzed, there is no toxicological effect that might compromise 
the use of melatonin at a dose of 10 mg for the period of time utilized in this 
study(Seabra et al., 2000). A randomized, double-blind, placebo-controlled study 
including 54 female patients undergoing breast cancer surgery were given 6 mg 
of oral melatonin or placebo to improve depressive symptoms and anxiety during 
a three month investigational period (Hansen et al., 2014). Finally, a randomized, 
double-blind, placebo-controlled study was conducted in elderly patients 
suffering from Alzheimer’s disease who were administered 2 mg of melatonin or 
placebo for a 24-week period (Wade et al., 2014). A substantial number of both 
animal and human studies document that short-term use of melatonin is safe, even 
in extreme doses. No studies indicate that exogenous melatonin possesses any 
serious adverse effects. Also, randomized clinical studies indicate that long-term 
administration only induces mild adverse effects comparable to placebo 
treatment. (Andersen et al., 2016).                                                                                       
 
Periotest M device:-
 
Periotest device was developed to measure the damping characteristics of natural 
teeth and has been used to evaluate implant (Cehreli et al., 2009). It was 
developed by Schulte in 1983 to quantify TM (Shulte et al., 1983), and then 
utilized by Teerlinck et al. (1991), to measure implant stability and to overcome 
destructive methods in measuring the implant stability like histologic analysis, 
tensional test, push-out/pull-out test and removal torque analysis. The 
(Classic/Wired) Periotest device has been the subject of several studies with 
generally favorable results. These results showed that the Periotest device 
generally demonstrated a high degree of repeatability and reliability. A wireless 
version of the Periotest (Periotest “M”) has been introduced to the profession. 
According to information provided by the electronic page of the Periotest M 
/wireless device manufacturer (Medizintechnik Gulden, Modautal, Germany), 
Periotest M is simpler to perform an objective evaluation of an implant's stability 
compared to classic Periotest. In Periotest M wireless design, the user can benefit 
from maximum freedom of movement. The device can be used for taking 
measurements on a wide variety of implants, without the need for any special 
accessories, such as a smart peg (Pang et al., 2014). The Periotest has an 

important advantage against the others like the Osstell device: it can be applied 
directly to the implant superstructure (Geckili et al., 2009). 
The limitations of Periotest are the inability of the instrument to measure the 
mesiodistal mobility, the possible effect of position and angle of the rods on the 
measured value (Satwalekar et al., 2015). The readings of PTV are from (−8 to 
+50) according to information provided by the device manufacturer 
(Medizintechnik Gulden, Modautal, Germany) (Pang et al., 2014), (Table 1). 
These readings are displayed digitally on a monitor as (PTVs), (Aparicio et al., 
2006). 
 
(Table 1): Interpretation of readings of implant stability in periotest (Pang et 
al., 2014). 
 
Reading 
Interpretation 
−8 to 0.0 
Good osseointegration, the implant can be loaded. 
+0.1 to +9.9 
Clinical examination is required, in most cases, 
loading is not possible. 
+10 to +50 
Osseointegration is not sufficient, the implant 
cannot be loaded. 
 
 
  
Cone-beam computed tomography (CBCT):-
 
Cone-beam computed tomography (CBCT) is an imaging modality that offers 
significant advantages for the evaluation of implant patients (Hatcher et al., 
2003, Schulze et al., 2005). The field of view (FOV) is an important feature that 
describes the extent of the imaged volume from large FOV (greater than 15 cm) to 
medium FOV (8 to 15 cm) and limited FOV (less than 8 cm). Limited FOV units 
image a small area, delivering less radiation and producing a higher-resolution 
image (Newman et al., 2018). CBCT allows for defining with elevated accuracy 
the quality (cortical/medullar ratio) and the quantity (height and thickness) of 
bone available for the implant, providing the essential information of performing 
or not a preimplant bony graft (Garlaschi et al., 2014). when compared to 
medical CT, CBCT can be recommended as a dose reducing technique for dental 

implant applications(Okano et al., 2009, Qu et al., 2010). The effective dose from 
CBCT examinations ranges from 13 µ Sv with the 3D Accuitomo CBCT machine 
using the 4 x4 cm FOV to 479 µ Sv with the CB Mercury CBCT machine (Table 2). 
For comparison, the effective dose from one panoramic radiograph is 
approximately 10 to 14µSv(Ludlow et al., 2006). Furthermore, the exposure 
from a maxillomandibular medical CT ranges from 474 to 1160 µSv(Loubele et 
al., 2009). The average background radiation in the United States is 3000 µSv (3 
mSv) per year or 8 µSv per day (Table 2). It is important to understand that every 
effort must be made to reduce the effective radiation dose to the patient. By using 
the smallest possible FOV, the lowest mA setting, the shortest exposure time, and 
a pulsed exposure mode of acquisition, it is possible to accomplish effective dose 
reduction to the patient(Sur et al., 2010). 
 
  
  
 

Aim and objectives:- 
 
Aim: - To evaluate the osseointegration following the application of melatonin 
around dental implants.
 
Objectives: -
 
 1- Measuring primary and secondary stability of the dental implant by Periotest 
M device.
 
2- Measuring marginal bone level around the dental implant in baseline and after 
6 months follow up using a cone-beam computed tomography (CBCT).
 
Research Hypothesis:-
 
The topical application of melatonin powder in the osteotomy site has an effect 
on osseointegration around the dental implant and minimize marginal bone loss.
 
Null hypothesis:- 
 
The topical application of melatonin powder in the osteotomy site has no effect 
on osseointegration around the dental implants and in minimizing marginal 
bone loss.
 
Methodology:-
 
Study design: - a split-mouth clinical trial.
 
Setting & Subjects:
 
 The study will be conducted in a split-mouth design on patients male with 
subjects 
 
the
 ,)
molar area
 
st
1 
lower jaw (canine to
 
upper or
the 
 
teeth in
 
missing
will be selected depending on bone density and from those attending to the 
department of periodontics.
 
Inclusion criteria:
 
1. Patients male have good oral hygiene. 
 
2. Patients were periodontally healthy. 
 
 
st
to 1
 
canine
( 
lower jaw
 
upper or
 
Patients had at least two missing teeth in the
. 
3
molar area) indicated for the dental implant.
 

Exclusion criteria:
 
1-Patients with any systemic diseases that influence bone healing such as 
osteoporosis and diabetes mellitus.
 
2-Fully edentulous.
 
3-Patients who had parafunctional habits. 
 
4-Smokers.
 
5-Patients who were not able to follow the treatment protocol.
 
Sample Size:
 
Twenty single-piece endosseous implants use for patients with at least two 
.)
area
 s
molar
 
st
lower jaw (canine to 1
 
upper or
the 
 
teeth in
 
missing
 
Materials:-
 
-
from (Sigma
) 
methoxytryptamine
-
5
-
Acetyl
-
N
( 
Melatonin powder
-
1
Aldrich/Germany).
 
2-Periotest M device (Medizintechnik Gulden, Germany).
 
3-Dentium implant surgical kit system and DI fixtures (Dentium Co., Korea).
 
Procedure:
 
Twenty single-piece endosseous implants (Dentium Co, Korea) will use to restore 
missing teeth in the upper or lower jaw (canine to 1st molars area) from both sides. 
The study will be split-mouth technique, each patient serves as his own control 
(served into 2 groups), the study side (topical application of melatonin in the 
implant side), and the control side (no melatonin in the other implant side of the 
same patients). According to the study reported by (Cutando et al., 2008) the 
estimated dose of melatonin required to enhance osseointegration of dental 
implant and minimize the marginal bone resorption is 1.2 mg of melatonin powder 
for each implant. CBCT for all patients before implant placement to determine 
bone density, dimension, and anatomical landmarks. Prior to surgery, all patients 
will instruct to use chlorhexidine 0.12% mouthwash as antiseptic. After local 
anesthesia, a mucoperiosteal flap will reflect. The manufacturer’s instructions 
should be followed for the preparation of the implant osteotomy site. For the study 

side, 1.2 mg of melatonin powder will place in the osteotomy site before the 
insertion of the implant. For the control side, no melatonin powder will be used 
and implants will be inserted directly in the prepared implant site. After dental 
implant installation, the gingival former will insert into the body of the fixture, 
then the Periotest M device will use to measure the primary stability of the DI 
fixture. After that, the gingival former will be removed and cover screw place and 
tightened into the fixture. Sutures will place after flap replacement. Patients 
should be instructed to use antibiotics amoxicillin 500mg and metronidazole 
500mg 3 times/day for 5 days after surgical procedure, soft diet and proper oral 
hygiene measures. Also, CBCT immediately after implant placement to record 
baseline bone level, CBCT after 6 months follow up to measure marginal bone level 
around implant comparing with baseline measurement, and measure the 
secondary stability using periotest M device. 
 
Stopping rules
 
The occurrence of an unexpected include implant failure...
 
Budget and funding
 
This study is self-funded.
 
Justification for ethical approval:-
 
According to the college of the dentistry/university of Baghdad following the 
Declaration of Helsinki / Tokyo on medical protocol and ethics.
 
Dissemination
 
Postgraduate Thesis.
 
 
 
 
 

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