Gender and ISQ TABELA

Curriculum Vitae
Name: Marissa Thi Matthews

Contact: marissa.matthews@umaryland.edu
Degree and Date to be Conferred: M.S., 2014
Collegiate Institutions Attended:
University of Maryland, Baltimore
School of Dentistry
M.S. in Biological Sciences 2011-2014
New York University

College of Dentistry
D.D.S. 2007-2011
OKU 2011
Swarthmore College
B.A. in Biology and Religion 2003-2007
ITA Scholar Athlete 2011
Professional Publications:
Alvero A, Brown D, Montagna M, Matthews M, Mor G. Phenoxodiol-Topotecan Co-
Administration Exhibit Significant Anti-Tumor Activity Without Major Adverse Side
Effects. Cancer Biology & Therapy 6:4, e1-e6, April 2007.
Professional Positions Held:

Resident
University of Maryland, Baltimore
School of Dentistry
Current Committee Memberships:

Dr. Mark Reynolds
Dr. Mary-Elizabeth Aichelmann-Reidy
Dr. Glen Minah
Title of Dissertation: The Impact of Gender on Dental Implant Stability assessed using
Resonance Frequency: A Systematic Review
Marissa Matthews, Master of Science, 2014
Thesis Directed by: Dr. Mary-Elizabeth Aichelmann-Reidy
Resonance Frequency Analysis (RFA) is a non-invasive surrogate method of
measuring implant stability and measuring changes in the bone implant interface over
time. Factors that can influence this value include bone density, preparation of the
osteotomy, the length and diameter of the implant, and design of the implant. There
are inherent gender differences in bone density, particularly with respect to post-
menopausal women. The purpose of this systematic review was to determine if there
was a difference in RFA value based on patient gender. A comprehensive literature
search up to March 15, 2014 was performed using Medline and Embase for all
literature related to implant stability as measured by RFA in humans. Inclusion
criteria consisted of controlled studies including healthy men and women, RFA value
at the time of placement, and the mean and standard deviation separately for gender.
Exclusion criteria excluded studies where implants were not placed in alveolar bone,
and studies where implants were placed in conjunction with sinus lifts, biologics, or
grafting. A comprehensive search yielded 2712 articles; 2591 articles failed to meet
the inclusion criteria, and of the remaining 131, 117 were excluded based on a lack of
data with regard to gender, leaving 14 articles for review and 7 for meta-analysis. The
meta-analysis showed no significant difference in RFA value with respect to gender.
These results must be interpreted with caution, given the limited available data. Two
studies reported females having higher RFA values than males, although one study
reported more mandibular implants were placed in women than men. Research
stratified by age is necessary to determine whether age-related changes in bone density
are related to RFA values. Such an association would necessitate changes in
recommendations for ISQ stability values based on age and gender.
The Impact of Gender on Dental Implant Stability Assessed Using Resonance Frequency:
A Systematic Review
By
Marissa Thi Matthews
Thesis submitted to the Faculty of the Graduate School of the

University of Maryland, Baltimore in partial fulfillment
of the requirements for the degree of
Master of Science
2014
Table of Contents
Chapter Page
Introduction ......................................................................................................................... 1
I. Long Term Studies On Tooth Loss .............................................................................. 1

II. Modes of Tooth Replacement..................................................................................... 2
III. History of The Dental Implant and Osseointegration ............................................... 3
IV: Definitions of Implant Success and The Role of Primary Stability .......................... 5
V. Methods of Measuring Implant Stability.................................................................... 6
VI. The Osstell Unit ........................................................................................................ 7
VI. Bone In Health, Alveolar Bone, and The Definition of Bone Density ..................... 9
VII. Gender and Bone Density ...................................................................................... 10
VIII. Osteoporosis and The Role of Hormone Replacement Therapy .......................... 12
IX: Implant Survival In Males vs. Females .................................................................. 13
Purpose.............................................................................................................................. 14
Materials and Methods ...................................................................................................... 15
Search Protocol ............................................................................................................. 15

Selection Criteria ........................................................................................................... 16
Data Collection And Analysis ....................................................................................... 19
Results ............................................................................................................................... 21
Characteristics of Interventions ..................................................................................... 30

Characteristics of Outcome Measures ........................................................................... 30
Discussion ......................................................................................................................... 36
Conclusions ....................................................................................................................... 40
References ......................................................................................................................... 41
iii
List of Tables
Table 1. List of Excluded Studies ..................................................................................... 21
Table 2. Study Characteristics .......................................................................................... 25
Table 3. Characteristics of Outcome Measure .................................................................. 26
iv
List of Figures
Figure 1. Osstell readings range from 1-100, indicating level of stability. A value
of 65 indicates stability adequate to immediately load.. ......................................................8
Figure 2. Picture of Osstell wand emitting a vibration to magnetic peg placed in implant
to generate an RFA value. ....................................................................................................8
Figure 3. Data Flowchart depicting initial search results to final studies included. .........18
Figure 4. The Basis For Strength of Recommendation From JEBDT. .............................20
Figure 5. The Basis For Grading The Quality of Evidence From JEBDT. ......................20
Figure 6. Average ISQ and standard deviation for females, as reported. .........................32
Figure 7. Average ISQ and standard deviation for males, as reported. ............................33
Figure 8. RFA findings (ISQ) with respect to gender by study…………………...……..34
Figure 9. Forest plot of meta-analysis results for mean difference of ISQ for male versus
female.................................................................................................................................35
v
Introduction
I. Long Term Studies On Tooth Loss
While causes of tooth loss are multi-factorial and can vary based on geographic
location, a systematic review published in 2007 on populations in Europe reveal the most
common cause of tooth extraction is dental caries1. The etiology of dental caries is also
multi-factorial, and risk factors include diet, microbiota, tooth anatomy, and oral hygiene.
Other reasons teeth are lost include periodontal disease, treatment planning for
orthodontics or prosthodontics, traumatic injury, tooth impaction, and pain1. The
systematic review by Mueller et al reveals the disparity in tooth loss based on geography
and access to care. Also highlighted is the future need for treatment because, in spite of
improving dental technologies and longer life expectancies, the need to treat edentulous
patients will increase due to the growing proportion of elderly in the population. Mueller
et al. also found that institutionalized individuals have more tooth loss than independently
living individuals, suggesting that independently living individuals are better able to care
for themselves, which extends to oral health.
In a systematic review by Zhang et al. in Chinese adults, rural populations had
higher decayed teeth, missing teeth and filled teeth, compared to their urban
counterparts2. The authors attributed this to low dental IQ and lack of knowledge of
preventative practices such as fluoridated toothpaste. As the Chinese population aged, the
DMFT score increased, a trend consistent with previous reports. Additional notable
findings included the filled component to the DMFT score was consistently low with the
decayed component on the rise, which the authors attributed to a lack of access to care2.
A common thread to these reviews is an aging population and an increasing need for
tooth replacement.
1
II. Modes of Tooth Replacement
Traditionally, options for tooth replacement include removable prosthetic
appliances and fixed appliances, such as tooth-supported fixed partial dentures and
implant-supported crowns and prostheses. Options for tooth replacement have improved
and expanded with the advent of dental implants. In a Cochran review by Abt et al.,
interventions for replacement of the partially absent dentition were explored3. Regarding
removable partial dentures, differences in designs, minor connectors, and materials used
revealed no significant differences; however, using a sublingual bar compared to a
lingual plate resulted in significantly more tooth mobility3. In fixed dental prostheses that
were tooth supported, there was insufficient evidence that material, connector type nor
cement made a difference in success and retention of the dental prosthesis. However, the
authors admit that challenges to this review include few randomized controlled trials and
differences in interventions and outcome measures, making direct comparisons
inconclusive3. This review did not take into account patient desires--most patients
strongly prefer a fixed restoration over a removable one.
In contrast to the results of Abt et al., Scheuber et al. provided a systematic review
on the economic aspects of implants versus short span fixed bridges and found dental
implants to be more cost effective, given that healthy proximal teeth were spared invasive
preparation in the case of a single tooth replacing implant4. What makes this review
unique is that the outcome measures for success of the implant or the fixed partial denture
were combined with cost utility analysis in order to facilitate a better patient driven
outcome measure. This review found that in a young patient, based on average cost and
average longevity, after 7 years of use, the dental implant would become more cost
effective than the fixed partial denture4. However, the equation shifts based on the
2
condition of the adjacent teeth, the state of the remaining alveolar bone, the physical and
emotional costs of a surgical procedure, and the patient’s medical history.
Zitzmann further expanded on cost effectiveness of dental implants versus fixed
partial prostheses and concluded that while patient satisfaction was similar in both
treatment options, the lower initial costs with regard to laboratory fees resulted in the
favoring of implant supported crowns over fixed partial dentures5. This review also
highlights the advantages and disadvantages of both forms of therapy. In fixed partial
dentures, improvement of esthetics of the abutment teeth is possible with the prosthesis.
While a single unit implant doesn’t affect the esthetics of the adjacent teeth, the
surrounding soft tissue may be altered, due to changes in the morphology of the dental
papilla 5.
Dental implants are becoming increasingly popular for tooth replacement. The
advantages to dental implant therapy over removable partial dentures or fixed partial
dentures include enhanced esthetics, no preparation of adjacent teeth, a fixed restoration
where hygiene can be performed similar to natural teeth, and a high success rate that has
been well established in the literature6.
III. History of The Dental Implant And Osseointegration

Branemark is credited as the primary scientist responsible for the development of
dental implants. His research goal was to define criteria that would enable bone and
tissue healing around a material that was clinically implanted7. Initial studies were
performed on the rabbit fibula that revealed thin bone around the titanium implant,
provided the implant was properly immobilized. Under high-resolution light microscopy,
once sectioned, the slide revealed the pattern of the implant observed histologically in the
3
surrounding bone. The animal studies progressed to dogs, and the titanium implants were
maintained over 10 years with healthy bone tissue surrounding them7.
Branemark also highlighted the principles of dental implant osseointegration in
this same publication. These recommendations included minimal bone removal and
trauma during preparation of the implant site, allowing for healing time for the bony
tissue components which was dependent upon the healing capacities of the tissues, the
quality of the bone, and prevention of early loading. Branemark described fibrous
encapsulation if motion was introduced prematurely or the implant overloaded with
force7. The osteoblast, a bone forming cell, is anchorage dependent, which is why it is
critical that no micromotion is introduced in the early healing of the implant.
The implant bone interface was further explored. Osseointegration at the light
microscope level was described as functional ankylosis. Aside from the peri-implant
sulcus, the rest of the implant is in direct contact with bone. Linder et al. later observed
the bone implant interface under scanning electron microscope and transmission electron
microscope and found a proteoglycan layer 20-50nm thick around the implant, then a
collagen layer 100-500nm thick finally surrounded by bone that was mature8. Hansson et
al further elucidated the implant connective tissue interface (the peri-implant sulcus) with
a 20nm thick proteoglycan layer separating the collagen fibrils from the oxide layer over
the titanium implant9.
Titanium as a material for dental implants is an ideal choice for numerous
reasons. Titanium is highly biocompatible, resistant to corrosion, and is strong. Parr
described an oxide layer that develops spontaneously when titanium is exposed to air.
4
This oxide layer is 100 A thick, and this oxide layer is what interacts with collagen fibrils
and fibroblasts10.
IV: Definitions of Implant Success and the Role of Primary Stability

The success rates of dental implants vary based on the criteria evaluating the
implants. The latter was highlighted in Albrektsson et al. review of criteria of success11.
The NIH published the earliest success criteria in 1978, which included less than 1mm of
mobility, partial radiolucency, no more than 1/3 of the implant length of bone loss,
treatable gingival inflammation, and service of at least 5 years in 75% of cases12.
Albrektsson et al. provided more stringent guidelines, including no mobility of the
implant, no radiolucency, less than 0.2 mm of vertical bone loss after the first year,
absence of pain and or irreversible symptoms and 85% success as defined by these
guidelines after 5 years, 80% at 10 years11.
While these criteria helped define implant success after a period of function, they
did not provide factors for future osseointegration at the time of implant placement. One
of the most important factors in determining future osseointegration and implant success
is primary stability at the time of placement, because absence of primary stability has
been demonstrated to impair osseointegration13. Primary stability is the absence of
movement in bone after the implant is placed into the prepared osteotomy; this is based
solely on the implant mechanically engaging the walls of the osteotomy. Factors that
impact primary stability include bone quantity and quality, surgical protocol and design
of the implant13.
While the original Branemark research stated no motion should be introduced
immediately after implant placement, as research progressed, it was possible to load
5
implants, provided the micromotion was below the threshold to interfere with
osseointegration. When an implant has a prosthetic connection within 48 hours of the
implant surgery, this is referred to as immediate loading. Advantages to immediate
loading include delivery of a fixed restoration (as opposed to a removable one) at the
time of surgery, which has been suggested to improve esthetic outcomes14. As a clinician,
the decision to immediately load or not to load is based on the risk of introducing motion
beyond the threshold for successful osseointegration. Having noninvasive, predictable
methods as an unbiased measure to aid in the decision of whether to load or not can
greatly improve clinical outcomes.
V. Methods of Measuring Implant Stability

There are multiple methods for determining initial, or primary, implant stability.
The implant can be removed, and the torque value that allows for removal can be used as
a measure of dental implant stability; however, this method doesn’t allow for integration.
The insertion torque value is the amount of torque it takes (based on the implant driver or
motor) for the implant to be inserted into the prepared osteotomy. The resultant values
correlate with the density of bone and the resistance of the implant to rotation.
The Periotest was originally designed to determine the mobility of teeth based on
the ability of the periodontium to withstand a controlled impact15. The Periotest uses a
rod to tap the tooth at a controlled speed. The less mobility a tooth exhibits, the less the
rod slows as it recoils from tapping the tooth, and this is translated into a measurement
displayed by the Periotest. The values range from -8 to -50, with a higher value
corresponding to decreased stability. Olive et al. applied the Periotest to dental implants
in order to have an objective measure of stability, and the ability of the bone surrounding
6
the implant to dampen a controlled impact load16. The Periotest is a reliable means of
non-invasive measuring to determine implant stability at the time of placement and
throughout the healing process. However, studies suggest that the Periotest has greater
variability in clinical scenarios than Resonance Frequency Analysis using the Osstell
unit17.
Barewal et al. discussed two methods of quantitative measure of implant
stability: the Insertion Torque Value (ITV) and Resonance Frequency Analysis (RFA).
Insertion torque value is determined by the resistance of the bone to preparation, the
energy required by the motor to create the osteotomy, and these values correlate with the
density of the bone18. ITV is a better measure of the implant’s resistance to rotation,
whereas RFA is a better measure of axial stability. RFA is measured by the Osstell unit
and expressed in a value known as the Implant Stability Quotient(ISQ).
VI. The Osstell Unit

Meredith et al. performed the initial research regarding the Osstell unit. The
Osstell unit was introduced as another method of non invasive implant stability over time.
An advantage over the Periotest (as reported by Meredith et al.) is that while the value
may give a measure of implant stability, the relationship to osseointegration is not as
clear19.
Resonance Frequency Analysis (RFA) was introduced as a non-invasive method
of measuring rigidity of the bone implant interface at the time of placement and during
healing20. RFA is the basis for the Osstell unit. A magnetic peg (the transducer) is placed
inside the implant, and a wand connected to the Osstell unit (the resonance frequency
analyzer) emits a vibration until a signal is received when flexural bending of the implant
7
takes place21. A numerical value, the Implant stability quotient (ISQ) is displayed that
corresponds to an algorithm based upon the dampening of the harmonic frequency
relative to the implant it is connected. These values range from 1-100, with a value of 65
or higher considered necessary for successful immediate loading22.
Figure 1. Osstell readings range from 1-100, indicating level of stability. A value of 65
indicates stability adequate to immediately load an implant.22.
Figure 2. Picture of Osstell wand emitting a vibration to magnetic peg placed in implant
to generate an RFA value.
8
While the RFA values provide a point of reference, numerous factors play a role
in determining the RFA value, including bone density, preparation of osteotomy, length
and diameter of the implant, and patient gender23.
In a review of factors influencing primary dental implant stability, Mesa et al
determined that while the site of implant insertion was the most strongly associated with
lack of primary stability, the next most associated variable with lack of primary stability
was gender. Females were 1.54 times more likely to lack primary stability than men24.
Linden provides an excellent commentary regarding issues with the study, including the
fact that the authors used primary stability as a measure of osseointegration and, while
this is strongly correlated, the two are not the same25. Additionally, Mesa et al used the
Periotest to measure initial stability of the implants, and, as previously discussed, the
Periotest can introduce more error than other methods of measuring implant stability. As
for gender, one of the purposes of this systematic review is to explore whether there are
inherent sex related differences in RFA values, another measure of implant stability.
VI. Bone In Health and Alveolar Bone

In health, skeletal bone is constantly turned over. In a very simplified model of
bone formation, osteoclasts are the cells that resorb bone, while osteoblasts are the cells
that form bone, maintaining homeostasis of bone mass. Many factors can tip this
balance, including, but not limited to: mechanical usage, central homeostatic factors
(hormone related), diseases, and physiologic aging 26. After the age of 40, the balance of
bone maintenance favors resorption, leading to osteoporosis. The reduced bone mass and
9
degradation of bony architecture results in reduced quality bone more susceptible to
fracture26.
Alveolar bone is the bone that contains teeth and their supporting structures. This
bone has cortical components exteriorly, while the interior components are typically
cancellous. Bundle bone is the bone that lines the tooth alveolus and contains the fibers
necessary for attachment via the periodontal ligament to the tooth. Alveolar bone is
unique in that the turnover is much more rapid, however the remodeling process is
similar to bone in other anatomical sites27.
VII. Gender And Bone Density

Gender plays a significant role in influencing bone density. When age is
considered, there are significant sex-related differences in bone mineral density. In a
study of human cadavers by Baker et al., men and women had a similar amount of protein
matrix per unit of segment volume, yet women had significantly less bone mineral to
their skeletons28. The authors suggest the difference is due to lower calcium content per
skeleton, and possible post-menopausal changes, as most of the cadavers were over the
age of 45.
Osteoporosis affects over 30 million post-menopausal women in the United States
alone26. Post-menopausal women are particularly vulnerable to osteoporosis because of
the loss of estrogen associated with menopause. As estrogen decreases, there is an
increase of cytokines (either directly or indirectly) that regulate osteoclasts, including
RANK ligand, TNF alpha, IL-1, IL-6 and IL-11 and M-CSF and prostaglandin E426.
Rank ligand binds to RANK, found on osteoclasts, which causes them to activate and
proliferate, leading to an increase in bone resorption26.
10
Nordin reported on the clinical significance and pathogenesis of osteoporosis,
which represents a reduced volume bony tissue per unit volume of anatomical bone29.
Clinical osteoporosis is more commonly observed in women. Nordin attributes this
difference in risk to increased sensitivity to parathyroid hormone, which stimulates bone
resorption and, more importantly, the loss of protective estrogen hormones that prevent
parathyroid hormone induced bone resorption. Nordin makes a point to state that
estrogens do not prevent parathyroid hormone from stimulating calcium absorption by
the gut or renal tubule; rather, estrogens prevent parathyroid hormone’s action of
releasing calcium from the skeleton29. Shiraki et al. further expanded on estrogen and its
important role in maintaining bone mineral density in elderly women. The role of
estrogen may be even more important in elderly women than post-menopausal women.
Androgens are also decreased in patients with osteoporosis, and androgens promote
osteoblastic proliferation; therefore, androgens also play an important role in maintaining
bone mineral metabolism in older women30.
Yamashita-Mikami further elucidated the changes that occur on the microscopic
level in the alveolar bone of post-menopausal women. Cores of bone were removed in
preparation for implant placement and analyzed by microCT and tested for markers of
systemic bone turnover. In the alveolar bone, the bone volume/turnover volume ratio
was significantly decreased in late post-menopausal women. At the onset of menopause,
systemic bone metabolic activity increases, and these changes were reflected in the
microCT of samples from early post-menopausal women. This brief increase in metabolic
bone activity correlated with bone loss with altered trabecular morphology31.
11
Bone density describes the quality of bone; clinically, various methods have been
proposed in implant dentistry. The most common is the Lekholm and Zarb classification,
which is based on radiographic appearance and resistance to drilling when preparing an
implant osteotomy. Type 1 bone is almost entirely compact bone; Type 2 bone has a
surrounding layer of thick cortical bone covering cancellous bone; Type 3 bone has a thin
layer of cortical bone covering dense cancellous bone; and Type 4 bone has a thin layer
of cortical bone that encases low-density trabecular bone32. Bone density varies based on
anatomical location, and physiologic factors. Bone density can have significant
ramifications on implant success and healing, with most failures happening in Type 4
bone, and healing taking the longest in Type 4 bone32.
VIII. Osteoporosis And The Role of Hormone Replacement Therapy

Oral estrogen replacement therapy has been recommended to combat the effects
of menopause. Not only does estrogen replacement therapy ease the vasomotor symptoms
of menopause, such as “hot flashes”, it also has benefits in combating osteoporosis33.
Orally administered estrogen can prevent rapid loss of bone mineral mass. The possible
mechanisms behind the prevention of estrogen related osteoporosis is unclear. It has been
suggested that estrogens prevent parathyroid hormone activity, which, by inhibition,
results in a decreased rate of bone resorption. It has also been suggested that estrogens
stimulate calcitonin activity, which promotes bone mineralization29. Vaughn suggests
timing is critical in administering hormone replacement therapy--estrogen should be
administered prior to extensive losses in bone density occur.
12
IX: Implant Survival In Males vs. Females
No clinical trials have documented differences in implant success based on
gender. In a retrospective analysis, Cha reported no significant difference in implant
survival in men versus women34. While there was no difference in implant success based
on gender, there were differences in implant complications--there was a statistically
significant difference in coronal fractures of the fixtures, and they speculated this
difference was due to differences in occlusal forces based on gender33. Osteoporosis and
osteopenia are not contraindications to dental implant therapy, and have not been
demonstrated to increase risk of implant failure35. While Chai et al. didn’t report on
implant survival, they did report at the time of implant placement, insertion torque value
was correlated to implant site bone density, which is risk factor for implant failure36.
August et al. discussed the effect of post-menopausal estrogen status being significant;
without hormone replacement therapy (HRT), the authors found decreased implant
healing affecting the maxilla but not the mandible37. However, this difference did not
manifest in a significant difference in implant success.
There is evidence that post-menopausal women have decreased bone quality when
compared to men of a similar age cohort28,29, and there is evidence that RFA values are
affected by bone density23. However, the question remains: With inherent sex related
differences in bone, is there a sex related difference in RFA values?
13
Purpose
The primary objective of this systematic review was to assess RFA values for
men and women to determine whether there was a difference in numeric RFA value in
assessing primary stability. The purpose was to address the following question: Among
patients with dental implants, does gender affect the RFA value?
14
Materials and Methods
A comprehensive search of the literature was performed as part of this systematic review.
Search Protocol
The electronic database Pubmed was searched for studies up to March 15, 2014,
where data were collected regarding resonance frequency analysis of implants in relation
to gender.
Field 1: Dental implant OR endosseous implant OR implant
(AND) Field 2: Gender OR male OR female OR sex
(AND) Field 3: Resonance Frequency Analysis OR RFA OR Osstell OR Implant
Stability
All search terms were used with a *, indicating the root word would be searched for all
possible identification of search terms. Search results were restricted to human studies
and the English language.
All years of the database EMBASE was searched for studies, where data were
collected regarding resonance frequency analysis with respect to gender in dental implant
placement with more restricted search terms.
Field 1: Dental implant OR endosseous implant OR implant
(AND) Field 2: Gender OR male OR female OR sex
(AND) Field 3: Resonance Frequency Analysis OR RFA OR Osstell OR Implant
Stability
Studies were restricted to human studies, and restricted by Journal: Clinical Oral Implants
Research, The international journal of oral and maxillofacial implants, Journal of Oral
and Maxillofacial Surgery, Clinical Implant Dentistry and Related Research,
International Journal of Oral and Maxillofacial Surgery, Clinical Oral Implant Research,
15
and the International Journal of Oral and Maxillofacial Implants.
The International Journal of Oral and Maxillofacial Implants, the Journal of Oral
Implantology, Implant Dentistry, Clinical Oral Implants Research, and the Journal of
Oral Rehabilitation were hand searched from 2005 to present for additional articles
concerning gender and Resonance Frequency Analysis. The European Journal of
Implantology was searched from 2008 to present for articles concerning gender and RFA.
Finally, a search was completed based on the references of the included articles for
additional articles to review.
Selection Criteria
Inclusion Criteria: Publications included were limited to in vivo human studies published
in the English language. To be included, the studies must have endosseous dental
implants placed into native or previously grafted alveolar bone. Studies included should
report mean RFA data (Osstell) at the time of placement, the number of patients, number
of implants, and patient gender. The studies must have more than 1 patient, and subjects
should be systemically healthy.
Exclusion Criteria: Studies were excluded if they did not report RFA by gender.
Manuscripts without RFA at the time of implant placement were excluded. Implants
placed in non-alveolar bone sites (i.e. zygoma, palate, heart, orbit) were excluded as well.
Studies reporting implant stability measured by a methodology other than resonance
frequency were excluded (i.e.. Periotest). Studies were excluded if implants were placed
in conjunction with bone grafting or sinus lifts or biologics (i.e. PRP, BMP, PDGF) to
avoid undue influence on RFA. Studies were excluded if they were case reports. Finally,
16
studies were excluded if the number of male and female subjects were not reported
separately for implants and RFA values.
17
Figure 3. Data Flowchart depicting initial search results to final studies included.
18
Data Collection And Analysis
Selection of Studies: The titles and abstracts of all studies identified meeting the
inclusion and exclusion criteria were reviewed by 2 independent reviewers. If the abstract
did not provide enough data to decide whether the study qualified, the full report was
obtained and reviewed. Study characteristics were identified and recorded in a table.
Characteristics recorded included a study description, inclusion and exclusion criteria,
number of subjects, age, assessment interval, implant type, number of implants placed,
and whether implants were immediate implants or immediately loaded.
Data Extraction: The data were extracted by 2 independent reviewers using a data
extraction table. Data included subject-related information on smoking, diabetes, bone
metabolic disorders, and bisphosphonate use as well as ISQ by gender, findings of the
study, ISQ by arch, Insertion Torque value by gender, implant survival, quality
assessment, and whether there was an association with ISQ and gender. Subsequent to
data abstraction, study authors were contacted by email for raw data (mean and standard
deviation) where unavailable by subjects for gender and RFA. There were 7 articles with
incomplete data for inclusion in the meta-analysis.
Quality Assessment of Evidence: The protocol for grading the level of evidence of
included studies was based on the strength of recommendation taxonomy (SORT) from
the Journal of Evidence-Based Dental Practice38. Assessment was based on Strength-of-
Recommendation (Figure 4) and Quality of Evidence (Figure 5). While other assessment
systems are available, the JEBDT was used because it is clear, easy to use, and thorough
in evaluating evidence.
19
Figure 4. The Basis For Strength of Recommendation From JEBDT38.
Figure 5. The Basis For Grading The Quality of Evidence From JEBDT38.
20
Results
The search strategy yielded a combined 243 articles, which were screened to meet
inclusion criteria. Of the articles that met the inclusion criteria, 115 were eliminated
based on the exclusion criteria, leaving 13 articles for this review.
Table 1. List of Excluded Studies
Reference Rationale For Exclusion*

Al-Khaldi et al.39 2011 No data provided regarding gender with
Al-Nawas et al.40 2007 respect to ISQ value
Akca et al. 41 2006
Alsaadi et al. 422007
Alsabeeha et al.43 2010
Balleri et al.44 2002
Balshi et al.45 2007
Barewal et al.46 2003
Barewal et al.47 2012
Becker et al.48 2005
Becker et al.49 2013
Bergkvist et al.502010
Bergkvist et al.512009
Bilbao et al.52 2009
Bischof et al. 532004
Bogaerde et al. 542010
Bornstein et al. 552009
Boronat-Lopez et al.56 2006
Brechter et al. 572005
Calvo Guirado et al.58 2008
Calvo Guirado et al. 592011
Calvo Guirado et al. 2009
Cannizzaro et al. 602008
Cannizzaro et al.61 2008
Cannizzaro et al.62 2008
Chang et al. 632007
Cornelini et al.642004
Cornelini et al. 652006
21
Table 1. cont.
Da Cunha et al.66 2004
Da Silva et al.67 2012
Degidi et al. 682007
Dursin et al.72 2012
Ersanli et al.73 2005
Farre-Pages et al. 742011
Farzad et al. 752004
Fischer et al.76 2009
Fischer et al.77 2008
Friberg et al. 781999
Friberg et al. 791999
Gallucci et al.80 2004
Garcia Morales et al.81 2009
Gonzalez-Garcia et al.82 2011
Guncu et al. 832008
Hallman et al. 842005
Han et al.85 2010
Ho et al. 862013
Ibanez et al.87 2005
Kahraman et al.88 2009
Karabuda et al. 892011
Kokovic et al.902014
Lachmann et al.91 2007
Lai et al. 922008
Lang et al93 2007
Lee et al.94 2012
Liddelow and Henry 95 2010
Liddelow and Henry 96 2007
Lindgren et al.97 2012
Makary et al. 982012
Marcovic et al. 992011
Melo et al. 1002009
Merheb et al. 1012010
Miyamoto et al. 1022005
Monje A et al. 1032014
22
Table 1. cont.
Nedir et al. 1042004
O’Sullivan et al. 1052004
Oates et al. 1062007
Oh and Kim107 2012
Olsson et al. 1082003
Ostman et al. 1092005
Ostman et al. 1102008
Okzan et al. 1112007
Pae et al. 1122010
Park et al. 1132010
Payne et al.114 2004
Pieri et al. 1152012
Portmann et al. 1162006
Rabel et al.1172007
Rasmusson et al.118 1999
Rocci et al. 1192003
Rossi et al. 1202010
Roze et al.121 2009
Sencimen et al. 1222011
Sennerby et al.123 2012
Siadat et al.124 2012
Simunek et al. 1252012
Simunek et al. 1262010
Sjostrom et al. 1272005
Stephan et al.128 2008
Tallarico et al.129 2011
Tozum et al. 1302008
Turkyilmaz et al.133 2008
Turkyilmaz and McGlumphy134 2008
Turkyilmaz et al. 1352007
Turkyilmaz et al. 1362006
Turkyilmaz et al.137 2006
Valderrama et al. 1382007
Vanden Bogaerde et al.139 2005
Veltri et al. 1402008
23
Table 1. cont.

West and Oates143 2007
Zix et al. 1442008
Crismani et al.145 2006

Jackson et al.146 2008 Palatal implants were placed for
Schatzle et al.147 2009 orthodontic anchorage, not for tooth
Shiigai T. 1482007 replacement
Stacci et al. 1492011
Stoker et al. 1502011
Zhou et al. 1512009
Al-Juboori et al.152 2013 No RFA value provided at time of surgery
Kessler-Liecht et al.153 2008
Yamaguchi et al. 1542008
Zix et al. 1552005
*More than one exclusion criterion may apply
24
25
26
27
28
Summary of Findings: Of the included studies, 13 were prospective
cohort157,158,159,160,161,163,164,165,166,167,168,169 and 1 was a retrospective cohort study162.
Characteristics of Participants: The ages of participants of the included studies ranged
from 18-76 (Table 2). Some trials failed to report the mean age (three studies)159,161,167
while others failed to report a range of the ages of participants (seven)156,160,162,164,165,

166,169
. In one study, the mean age under 50 and over 50 was reported, but no overall mean
was reported162. The number of males and females were not specified in one trial163.
Sample Size: The sample size ranged from 10 participants to 267 participants (Table 2).
Implants were placed in both the maxilla and mandible in the majority of studies
(twelve)156,157,158,159,162,162,163,164,165,166,167,169. In two studies, implants were placed only in
the anterior mandible161,168.
Assessment Interval: The time the ISQ was taken ranged from time of surgery to 90 days
after surgery (Table 2). The number of intervals the ISQ was recorded ranged from one
time (6 studies)156,157,162,165,166,168 to thirteen times (1 study)169.
Main Inclusion Criteria: All studies required patients seeking tooth replacement. Plaque
control had to be adequate in one study164, and another study required good oral
hygiene167. Four studies mentioned that patients had to be in good general health in the
inclusion criteria158,159,160, 168. Three studies mentioned there had to be adequate bone
volume prior to implant placement161,163,167. One study mentioned female fertile patients
had to confirm via pregnancy test that they were not pregnant164.
Main Exclusion Criteria: Four studies did not include smokers156,157,159,163 and one study
specified that smokers could only smoke less than 10 cigarettes a day164. Four studies
specified that uncontrolled diabetics were excluded157,158,161,169, whereas three studies
29
generalized to exclude patients with systemic disorders158,162,167. Four studies excluded
patients with bone metabolism disorders156,158,161,169 four studies excluded patients with
active periodontal disease157,164,167,169 and three studies excluded patients with
parafunctional habits157,164,169. Two studies did not mention specific exclusion
criteria165,166, one study excluded patients with radiation therapy168, and one study
excluded patients with osteoporosis161.
Characteristics of Interventions
(1) Implant Systems and Sizes: Three studies placed Nobel Biocare® implants,161,165,169
two placed Straumann® implants,157,163 two studies placed Branemark implants,158,168 one
study placed Biohorizons®,159 and two studies placed DEFCON implants,160,162. One
study placed Straumann®, Astratech, and Thommen,164, one study placed Branemark and
ITI166, one study placed Zimmer,156, and one study placed Nobelbiocare® and ITI
implants167. Implant diameters ranged from 3.3mm to 5mm. Implant lengths ranged from
7-18mm. One study did not specify implant diameter and length166 and one study did not
specify implant length169.
(2) Immediate versus Conventional Placement: One study performed immediate
placement implants where possible158, seven placed implants into healed grafted or native
bone157,159,160,161,163,167,168 and six studies did not specify if they placed immediate
implants or conventional implants156,162,164,164,166,169.
(3) Immediate versus Conventional Loading: One study performed immediate loading
exclusively158, two studies performed both immediate and conventional loading,161,168 one
study performed early loading at 8 weeks,164 eight reported conventional
loading,156,157,159,160,163,166,167,169 and two did not specify loading protocols162,165.
30
Characteristics of Outcome Measures
(1) ISQ By Gender: The findings of each of the studies included regarding ISQ relative to
gender is depicted in Table 3. Three studies found that females have significantly higher
ISQ values than males156,159,160. The average values for ISQs in females at the time of
implant placement was generated with the studies that provided numerical data (Figure
6). Five studies stated males had significantly higher ISQ values than
females157,158,164,164,165. The average values for ISQs in males at the time of implant
placement was generated with the studies that provided numerical data (Figure 7). Six
studies reported no significant difference in ISQ value relative to gender161,162,167,167,168,

169
. These study findings are depicted in Figure 8.
(2) ISQ By Arch: The ISQ relative to location in the maxilla compared to the mandible is
depicted in Table 3. Six studies reported mandibular implants had higher ISQ values than
maxillary implants, a difference that was statistically significant158,159,160,165,165,166,167. One
study reported a significantly higher ISQ in the anterior mandible than the posterior
maxilla162. Four studies reported no significant difference in maxillary ISQ versus
mandibular ISQ157,164,169. One study did not report ISQ by arch163. Two studies placed
implants exclusively in the mandible, so no comparison was made161,168.
(3) Gender and Insertion Torque Value: Insertion Torque value by Gender is reported in
Table 3, if the studies reported this value. Two studies reported no statistically
significant difference in ITV based on gender,157,168 one reported significantly higher ITV
in males than in females162, and 11 studies did not report these
values156,158,159,160,161,163,164,165,166,169.
31
(4) Implant Survival: Implant survival, when reported, is depicted in Table 3. Three
studies reported no implant failures157,164,167. Two studies reported success rates above
95%158,169. One study reported 2 implants failures166, and the remaining studies did not
report success rates156,159,160,161,162,163,165,168.
Quality of Evidence: Two independent examiners rated the quality of evidence based on
the JEBDT criteria38, and these assessments are reported in Table 3. The majority of the
studies were classified as 2C156,157,159,160,161,162,163,164,165,166,167,168,169 and two studies was
classified as 2B158,162.
Alghamdi H et al.,
ISQ (Female) 2011
Boeriu S, 2011
100
Fuster-Torres MA et
80 al., 2011
Liaje A et al., 2012
60
ISQ
77.63 Ostman PO et al., 2006

40 75.84 75.7
64.3973.1 64 66.573.3 Turkyilmaz I et al.,
20 2006
Yang SM et al., 2007
0
Study Aksoy et al., 2009
Figure 6. Average ISQ and standard deviation for females, as reported. denotes no
standard deviation reported
32
Alghamdi H et al.,
ISQ (Male) 2011
Boeriu S, 2011
100
Fuster-Torres MA et
80 al., 2011
Liaje A et al., 2012
60
Ostman PO et al.,
ISQ
40 2006
70.26 77.5668.5 75 75.6 70.2
68.27 Turkyilmaz I et al.,
61
20 2006
Yang SM et al., 2007
0
Study Aksoy et al., 2009
Figure 7. Average ISQ and standard deviation for males, as reported. denotes no
standard deviation reported
33
Study Female
Male ISQ>Female
No Difference ISQ>Male
ISQ
ISQ
Aksoy U et al. 2009 X
Alghamdi H et al. 2011 X
Balshi S et al. 2005 X
Boeriu 2011 X
Boronat Lopez et al.

X
2008
Brochu J et al. 2005 X
Fuster-Torres M et al.
X
2011
Guler A et al. 2013 X
Liaje A et al. 2012 X
Ostman P et al. 2006 X
Park K et al. 2012 X
Rokn A et al. 2011 X
Turkyilmax I et al. 2006 X
Yang S et al. 2007 X
Figure 8. RFA findings (ISQ) with respect to gender by study
34
Meta-Analysis:
A meta-analysis of studies that reported mean and standard deviation ISQ values
for men and women was performed. The statistical software Open MetaAnalyst
(Providence, RI) was used to generate a Forest plot, seen in Figure 9. A Continuous
Random-Effects model was used because this is the best model to synthesize
heterogenous research. RFA values are a continuous measure, which is why a continuous
model was used. Of the 7 studies included, 3 found males had significantly higher RFA
values than females157, 164, 165 , three studies found no difference162, 168, 169,and one study
found women had significantly higher RFA values than men156. After completing the
meta-analysis, there was an overall weighted mean difference of 0.806 with a 95%
confidence interval ranging from -1.295 to 2.906. This indicates that of the studies
analyzed, there was no significant difference in RFA value with respect to gender. The
analysis was tested for heterogeneity (P-value of .047,Q value 12.781, I2 of 53%)
indicating no significant difference, with moderate heterogeneity.
Figure 9. Forest plot of meta-analysis results for mean difference of ISQ for male versus
female.
35
Discussion
One of the most important factors in predicting implant success is obtaining
primary stability at the time of implant placement. Primary stability is based on a number
of factors, including quality of bone, bone density, arch location, and to some extent,
operator technique. One measure of implant stability commonly used is RFA analysis,
which produces an ISQ value. Clinicians can use this ISQ value to objectively assess
whether or not to load an implant at the time of placement or not based on research-
derived values. The purpose of this review was to assess whether there was a difference
in the ISQ value based on gender. The prediction was females would have a lower ISQ
value than men, given the quality of bone deteriorates as women age due to post-
menopausal changes.
(1) ISQ by Gender
The results of this review regarding ISQ with respect to gender are inconclusive.
While the majority of studies stated there was no difference in ISQ with respect to
gender, of the studies that did report a difference, the majority stated males had a higher
ISQ value than females. This is consistent with previous reports of females having lower
ISQ values than males. Zix et al reported this and attributed the findings to the
postmenopausal status of female patients leading to compromises in bone density156. This
change in bone density can potentially put implants in females at higher risk of failure,
which, to date, has yet to be corroborated with research.
Ostman reports that differences found in RFA value with respect to gender are not
clinically relevant because there is no difference in failure rate of implants when
comparing men and women165. Balshi reported that while males had significantly higher
ISQ values than females at the time of placement, at the 90 day follow up, this difference
36
was no longer significant158. Future studies stratified by age with multiple ISQ readings
throughout the osseointegration process could determine when this difference is no
longer significant. The ramifications of this finding could affect the treatment of the post-
menopausal women, particularly with respect to immediate implant loading, since a
longer healing period may be necessary.
While proposed by a few studies, post-menopausal females without hormone
replacement therapy tend to have lower bone density values, and as a result, may have
lower ISQ values. This could impact therapy and treatment decisions related to
immediate loading in the post-menopausal women, hence the interest in looking at gender
differences with respect to ISQ. This review could be improved if more studies were
completed and stratified by age and gender.
(2) ISQ by Location
The results of this review regarding ISQ by location, in studies that did report this
statistic, mandibular ISQ values are higher than maxillary ISQ values. This is consistent
with the quality of bone typically found in each respective location, which is a major
contributing factor to the ISQ value. This finding is consistent with the literature
regarding ISQ value by arch--the maxilla is typically a lesser quality bone than bone of
the mandible, and the ISQ values reflect this46,171.
Quality of Evidence:
The JEBDT guidelines provide a clear and succinct method of classifying the
strength and quality of evidence. Strength is given an A, B or C rating. An A denotes
consistent, quality patient oriented evidence, B is limited quality or inconsistent patient
37
oriented evidence, and C denotes disease oriented evidence or expert opinions38. When
assessing the quality of evidence, the JEBDT guidelines first distinguish the nature of a
study: whether it is a diagnostic study, a treatment/prevention/screening study, or a
prognosis study. The types of studies that qualify for each level vary depending on the
nature of the study, as seen in Figure 5.
The majority of studies evaluated (eleven) were grade 2C-all cohort studies using
disease-oriented evidence. This disease oriented evidence (RFA) is a surrogate measure
that may or may not reflect improvements that matter to patients, the crux of the JEBDT
guidelines38.
Meta-Analysis:
The results of the meta-analysis suggest that there is a trend for men to have a
higher ISQ values than women; however, no significant difference was found. This lack
of association is not consistent with the common finding of post-menopausal women
having poorer bone quality than men, and bone quality being a major determinant of RFA
value; however, the studies used did not stratify based on pre-menopausal versus post
menopausal status. While age was not controlled in the studies included, there were more
studies consistent with the trend of males having higher RFA values than females.
One limitation of this meta-analysis was that the analysis was weighted based on
the number of subjects rather than implants. This is a common limitation described in the
periodontal literature, as the results vary greatly depending on whether one uses the
implants or the patients as the computational unit. Of the studies included in the meta-
analysis, two deviated from the trend of males having higher ISQ values than females156,
172
. In the study by Aksoy et al., the deviation from the trend may be related to the
38
distribution of implant sites, as they report women had more mandibular implant sites
compared to the men. In the study by Fuster-Torres et al., the deviation from the trend is
not explained; however, there were more female subjects than male subjects, more
implants were placed in females than males, and the distribution of the arch where the
implants were placed was not disclosed. It is possible that this difference may be
explained by where the implant was placed, if the implant was placed in previously
grafted bone, or this difference could be an anomaly.
39
Conclusions
The topic of ISQ with respect to gender is relatively unexplored, and this review
confirms the need for future research. The results of this meta-analysis found no
significant difference in RFA values with respect to gender. Further studies are necessary
stratifying the study population by age, in order to control for potential differences related
to menopausal status. The future application of this information may change the
recommendations for ISQ stability values based on age and gender and may help
minimize the risk of implant failures.
40
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Gender and ISQ TABELA

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Curriculum Vitae

Name: Marissa Thi Matthews

New York University

Professional Positions Held:

Current Committee Memberships:

Thesis submitted to the Faculty of the Graduate School of the

I. Long Term Studies On Tooth Loss .............................................................................. 1

Materials and Methods ...................................................................................................... 15

Search Protocol ............................................................................................................. 15

Characteristics of Interventions ..................................................................................... 30

Table 1. List of Excluded Studies ..................................................................................... 21

Table 2. Study Characteristics .......................................................................................... 25

Table 3. Characteristics of Outcome Measure .................................................................. 26

Figure 4. The Basis For Strength of Recommendation From JEBDT. .............................20

Figure 8. RFA findings (ISQ) with respect to gender by study…………………...……..34

orthodontics or prosthodontics, traumatic injury, tooth impaction, and pain1. The

for themselves, which extends to oral health.

In a systematic review by Zhang et al. in Chinese adults, rural populations had

revealed no significant differences; however, using a sublingual bar compared to a

differences in interventions and outcome measures, making direct comparisons

strongly prefer a fixed restoration over a removable one.

emotional costs of a surgical procedure, and the patient’s medical history.

Zitzmann further expanded on cost effectiveness of dental implants versus fixed

dentures include enhanced esthetics, no preparation of adjacent teeth, a fixed restoration

been well established in the literature6.

III. History of The Dental Implant And Osseointegration

maintained over 10 years with healthy bone tissue surrounding them7.

Branemark also highlighted the principles of dental implant osseointegration in

encapsulation if motion was introduced prematurely or the implant overloaded with

critical that no micromotion is introduced in the early healing of the implant.

the titanium implant9.

Titanium as a material for dental implants is an ideal choice for numerous

reasons. Titanium is highly biocompatible, resistant to corrosion, and is strong. Parr

IV: Definitions of Implant Success and the Role of Primary Stability

treatable gingival inflammation, and service of at least 5 years in 75% of cases12.

Albrektsson et al. provided more stringent guidelines, including no mobility of the

guidelines after 5 years, 80% at 10 years11.

been demonstrated to impair osseointegration13. Primary stability is the absence of

While the original Branemark research stated no motion should be introduced

immediately after implant placement, as research progressed, it was possible to load

osseointegration. When an implant has a prosthetic connection within 48 hours of the

implant surgery, this is referred to as immediate loading. Advantages to immediate

beyond the threshold for successful osseointegration. Having noninvasive, predictable

greatly improve clinical outcomes.

V. Methods of Measuring Implant Stability

non-invasive measuring to determine implant stability at the time of placement and

Barewal et al. discussed two methods of quantitative measure of implant

and expressed in a value known as the Implant Stability Quotient(ISQ).

VI. The Osstell Unit

may give a measure of implant stability, the relationship to osseointegration is not as

Resonance Frequency Analysis (RFA) was introduced as a non-invasive method

corresponds to an algorithm based upon the dampening of the harmonic frequency

or higher considered necessary for successful immediate loading22.

to generate an RFA value.

and diameter of the implant, and patient gender23.

In a review of factors influencing primary dental implant stability, Mesa et al

VI. Bone In Health and Alveolar Bone

similar to bone in other anatomical sites27.

VII. Gender And Bone Density

considered, there are significant sex-related differences in bone mineral density. In a

Osteoporosis affects over 30 million post-menopausal women in the United States

alone26. Post-menopausal women are particularly vulnerable to osteoporosis because of

the loss of estrogen associated with menopause. As estrogen decreases, there is an

increase of cytokines (either directly or indirectly) that regulate osteoclasts, including