Implant Prosthodontic Management of Medicaüv Treated

Hvpothvroid Patients

Nikolai J. Attard B.Ch.D.

A thesis subrnitted in conformity with the requirements for the degree of Master of Science Graduate Department of Dentistry

Faculty of Dentistry University of Toronto 2001

O Copyright by Nikolai John Attard, 2001

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Abstract: Implant Prosthodontic Management of Medicaiiv Treated Hypothvroid Patients. mast ter of Science, 200 1. Nikolai John Attard Graduate Department of Dentistry, Specialty of Prosthodontics, Faculty of Dentistry, University of Toronto.

A retrospective analysis of implant treated patients with a history of medically managed

hypothyroidism was conducted to investigate its impact on (i) survival / loss of osseointegated

Brhemark implants, (ii) marginal bone behavior and (iii) prosthodontic management,

The charts of patients treated between 1979 and June 2000 were reviewed and patients with

reported histones of thyroid disease at the a m e of surgery were selected.

The total patient population group consisted of 27 female patients. They were matched with a

control by age, gender, location (jaw and zone) of implants, type of prosthesis and dental status

of the opposing arch. Additional factors studied were medical history, rnedications. smoking

habits, and bone quality and quantity.

There was no statistical difference in the nurnber of implant failures, The hypothyroid patients

had more soft tissue complications and more bone loss in year one of loading when compared to

their matched controls. The implant suntival outcornes did not influence the prosthodontic

treatment plan.

This preliminary study suggests that medically controlled hypothyroid female patients treated

with implants were not at higher risk of implant failure when compared to matched controls and

that a history of controlled hypothyroidism is not a contra-indication for implant therapy with

endosseous implants.

Acknowledgments:

1 would Like to thank my supervisor and mentor. Dr, George Zarb for his guidance,

encouragement, cnticism and support throughout this research project and during my cLinical

training in the specidty of Prosthodontics.

1 thank the members of my advisory cornmittee, Drs. Howard Tenenbaum, Gerald Baker and

Herenia Lawrence, for their interest and valuabIe direction in this project.

Special thanks to the staff in the Department of Prosthodontics for their assistance during this

research project.

Finally, 1 would like to express gratitude to my family, especiaily my parents, for their

encouragement, love and persona1 sacrifice throughout this odyssey.

Table of Contents

Abstract

Acknowledgments

List of Tables

List of Figures

Chapter 1

Introduction

Local and Systemic Determinants of Implant Failure

Thyroid Disorders and Medications

Chapter 2

The Thyroid Gland

Age-related Changes in Thyroid Function

Chapter 3

Bone Tissue

Wound Healing Response at the Implant Site

Bone Response following Osseoîntegration

Chapter .4

Impact of Thyroid Hormone on Wound Healing

The role of Thyroid Homione in Sofi Tissue Wound Healing

Thyroid Hormone and Dental Development

Chapter 5

Hyperthyroidism and Skeletal Integrïty

The effects of Thyroid Hormone Replacement on Skeletail Integrity

Hypothyroidism

Bone Minerai Density Changes in the Hypothyroid State

TSH Suppression Related Changes in the Bone Mineral Density

Fracture Risk in Patients with Thyroid Disorders

Chapter 6

Staternent of the Problem

Objectives of the Study

Hypotheses

Materials and Methods

Methods

Statistical Methods

Chapter 7

Results

Chapter 8

Discussion

References

List of Tables:

Table 1 : A s u m q of factors controlhg the secretion of thyroid homones.

Table 2: Effect of Hyperthyroidisrn on Bone.

Table 3 : Summary of effect of Replacement Thyroxine Therapy on Bone.

Table 4: Summary of effect of Suppressive Thyroxine Therapy on Bone.

Table 5: Inclusion and exclusion miteria for patients to be treated with complete implant supported prostheses.

Table 6: Inclusion and exclusion criteria for patients to be treated with fked partial implant supported prostheses.

Table 7: Inclusion and exclusion crïterÏa for patients to be treated with single tooth implant supported prostheses.

Table 8: Comparative analyses of characteristics between the Hypotbyroid and Control Groups.

Table 9: Comparative analyses of various characteristics between the Hypothyroid and Control Groups.

Table 10: Outcome analyses at the hplant Level.

Table 11: Kaplan Meier Average Survival Time of Dental Implants.

Table 12: Lifetables for the Survival of Implants in the Hypothyroid and Control Groups.

Table 13: Prosthodontic outcome at the Implant Level.

Table 14: Prosthodontic outcome at the Patient Level.

Table 15: Intra-observer agreement for the Mesial and Distal Marginal Bone Level Measurements.

Table 16: Inter4bsewer agreement for the Mesial and Distal Marginal Bone Level Measurements.

Table 17: Bone Loss /milErneters (Mean -f- S.E.) around Dental Implants for Mesial and Distal Sites-

Table 18: Bone Loss /milLimeters (Mean + S.E.) around Dental Implants for Hypothyroid md Control Patients.

Table 19: Linear Regression Mode1 for Mean Bone Loss at Year 1.

Table 20: Linear Regression Model for Mean Bone Loss at Year 1.

Table 21: Linear Regression Model for Mean Bone Loss at Year 1 in Hypothyroid Patients.

Table 22: Final Logistic Regession mode1 for Soft Tissue Complications post-stage 1 S urgery.

Table 23: Categorïes of Medications used by the patients.

List of Figures:

Figure 1: The hypothalamic-hypophyseai-thyroid mis.

Figure 2: Follow-up Period of Patients since Stage I surgery.

Figure 3: Cumulative Survival Probabilities of Implants in the Hypothyroid and Control Groups.

Chapter L

Introduction

Oral rehabilitation of patially edentulous and edentulous patients with endosseous implants is a

welI-recognized alternative prosthodontic therapy. The initial successful treatrnent outcomes

reported by Swedish researchers have been confirrned by Toronto studies (1-7) and have

spawned diverse cornrnercidly and dentist drïven research initiatives. The thrust of these

initiatives has emphasized different macro- and micro-desigs, some aspects of the role of

patient-mediated systemic and behavioral aspects, as well as optimized healing responses-

It could be a r~ued that the favorable treatrnent outcomes reported with the Brhemark system ( 1-

11) have precluded an evidentiary basis for patient selection with different systemic disease

background. Consequently research into implant failures is a recently emerging area of

significant interest. (12, 13) Past and ongoing studies in the Implant Prosthodontic Unit (PU) at

the University of Toronto have focused on the impact of rnedical conditions (osteoporosis,

diabetes and cardiovascular disease) and patient behavior (smoking) on implant treatment

outcomes. Each one of these studies contributes to the overall database required to ensure

informed decision making by professional and patient m e .

This study is a preliminary investigation of the possible effects of thyroid disorders and

medications alone, or in combinatian, on treatment outcomes for implant-supported prostheses.

Local and ~vsternic Determinants of Implant Failure

Success or failure rate of dental implants can be theoretically classified as being due to local or

systernic factors. Moreover the implant failure can be categorized as occumng early and late,

depending on the time when failure is diagnosed.

Local determinants of implant faiiures: early implant failure occurs at. or pnor to. stage II

sugery when the fixture is exposed to the oral environrnent while late implant failure occurs

after that surgery. Sennerby et al. ( I l ) reported that most of implant failures are detected at stage

II surgery or during the ensuing prosthetic phase. They suggest that this may be due to soft tissue

encapsulation as a response to micro-movements in the implant-bone interface. Failure during

the prosthetic phase may be due to inadequate healing penods following stage 1 surgery,

especially when the host site consists of poor quality or so-called soft bone. This latter situation

in which the host-bed for an implant is classified as bone quality type NT by Lekholm and Zarb

( 14), is regarded as unfavorable for osseointegation. It has been reported to be associated with a

higher failure rate than that in bone qualities type 1 to m. (15, 16) Other local factors that appear

to have an impact on the success/failure rates of dental implants have d s o been described and

include:

1. Strict adherence to the treatment protocol: Close scmtiny of the results fiom the early

developmental phase of the Brhemark system show a s i=~f icant relationship between

expenence of the surgeon and implant failure. ( 12) ( L 7)

II. Jaw site: Implant success in zone 1 (an area defined as Hying between the mental foramina) is

higher than in zone II, while the maxilla demonstrates a Lower 15-year osseointegration success

rate (80-9096) when compared to the mandible (95%), (1%)-

m. Implant lenoth and diameter: Clinical evidence has indicated that short implants have a lower

success rate than longer implants (8, 9, 15) and that wider fixtures might be more successful

than standard 3-75mm wide ones (12). However, recernt evidence suggests that this may be

incorrect. Ivanoff et al (19) observed a higher failure rate for 5mm pIatform implants in a

retrospective study. They report 18% failure rate for wide platform implants with a cumulative

success rate of 73% for 5.0rnm wide-diameter Brinemark implants.

IV. Host bed: Sennerby and Roos (12) reviewed studies which suggest that implant fuilure is

hisher in the grossly resorbed maxilla when fixtures are placed simultaneously in the Iiost bed

with a bone gaft . It ais0 appears that the success rate in irradiated bone is generally lower,

although adjuvant hyperbaric oxygen treatment c m reduce the failures rates. (30) Different

facial bones exhibited different rates of implant loss with the Frontal bone showing the highest

failure rate. ( 2 1 )

V. Forces: Overloading of osseointegrated implants c m also result in impiant loss. This was

confirrned in an animai study that showed excessive loading on oral implants could result in

complete or partial loss of osseointegration at the histo4ogical level. (22) Both, retrospective

( 2 3 ) and prospective (9) clinical studies, and a review (24) have confimed that mechanical

overloading adversely effects implant survival.

VI. Plaque: Mombelli et al. (25) reported that the oral rnicrobiota around implants are comparable

in both healthy and perïodontally comprornised teeth- However, this cross-sectional study

f d e d to indicate if the microbiota are the cause of, as opposed to the predictable sequel, of the

failing impIants, In fact, i t is more probable that a f a i h g implant rnight be due to other causes

with secondary involvement of microorganisms which maintain the destructive process

occurring around it- It is possible that rnicrobiota may very well play a minor role in the

initiation of bone loss. (26)

Systernic determinants of succesd failure rate: Other factors, such as age and general health of

the patient, or chronic diseases, may play a role in the outcome of the survival of dental implants-

Age does not appear to effect osseointegration. However, this observation applies to elderly

patients exclusively since long-term studies on implants in young adults are inconclusive. Bryant

(18) concluded that age per se does not impact on success of osseointegration, unless extensive

residual rid,oe resorption is present. This would preclude placement of an adequate number and

size of implants for the proposed restoration.

General health: general health may play a role in the outcome of osseointegration. Factors which

may affect bone physiolo,ay, and consequently affect the bone implant interface, are Likely to

impact on implant survival. These could include systernic diseases and certain bone conditions

such as osteoporosis. In a retrospective study, no statisticdy si,onificant correlation was found

between medical conditions and osseointegation.(27) Unfortunately, the small population

(n=104) studied and grouping of the medical conditions in the analysis, may have missed out on

any potential link between a particular condition and implant success rate. Another survey study

by Weyant (28) reported a statistically significant impact of the rnedicai history and the use of

medicinals on the outcomes of osseointegation. The nature of the design of this study precluded

a more detailed analysis of health factors criteria involved and the results do not establish a

causal-effect relationship between the health factors and osseointegation. As a result these

factors end up as only risk markers,

Other authors have looked at specific conditions that may have an impact on implant success

rate. A preliminary report surveyed implant-treatment outcomes in patients with cardiovascular

diseases. No correlation between cardiovascular disease and implant success could be found.

However the small population investigated only sugests that cardiovascular disease is not a risk

factor for osseointegration. (29) A suni1a.r survey of patients with a history of osteoporosis in

other parts of the skeleton failed to reved an association with the outcome of osseointegration.

(30) Two papers investigated the roie of female hormones on the outcome of osseointegration.

No correlation was found between success of osseointegration and fluctuations of ovulatory

hormone levels(3 l), while postmenopausal women on hormone replacement therapy (HRT) did

not have a better survival outcome of implant survival when compared to a sirnilar control group

of patients not on HRT. (32) However the authors did find that smoking appeared to significantly

increase the failure rate in the s o u p of menopausal women undergoing hormone replacement

therapy, thus potentiaily clustering failures in this group of patients.

The impact of diabetes mellitus on osseointegration (33) was found not to be significant, and is

not considered a contraindicatian for implants therapy as long as the systemic condition is well

controlled, Diabetic patients were more likely to demonstrate an increased Ioss of bone loss

during the first year of loading when compared to the controls though this difference disappeared

in subsequent years. A hisher incidence of paraesthesia was also reported in diabetic patients and

the use of other medications contributed to increased soft tissue complications. (33)

Behavioral deterrninants: Smoking has been shown to affect healing. Since osseointegration is

basically a healing process, it is tempting to hypothesize that smoking can influence its course. A

ten-year longïtudind study of patients treated with Branemark implants in anterior mandibular

zone reported that more bone loss was observed in smokers, when compared to non-smokers;

and that this trend was exacerbated with poor oral hygiene in the multivariate analysis

perforrned- (34) Another retrospective study (35) on the effect of smoking on osseointegation

concluded that cigarette smoking has a negative effect on implant survival even after accounting

for potential confounding variables. It also concluded that cigarette smoking per se should not be

a contraindication for implant therapy, but that patients should be informed that they are at a

slightly higher risk of implan~ failures if they continue smoking dunng the initial phase of

healing following surgery. Habsha's study showed oniy a 2.2 times greater risk than in non-

smokers at the time of stage 1 surgery, or if they have a ~i~pif icant smoking history. The latter

was described as a history of more than 25 pack-years smoking history. (35)

Thvroid Disorders and Medications

The literature pertaining to implant successf failure rate in medically comprornised patients is

lirnited both in design, and number of patients studied- This precludes reaching definite

conclusions. It therefore seems reasonable to presume that conditions which impact on bone

metabolism may alter the success/failure rate of osseointegration- ClearIy these conditions must

be investigated to understand their impact on the osseointegration process and to better predict

the outcome in patients seeking treatment with dental implants.

Thyroid disorders and thyroid hormone medication have been shown to influence bone

metabolism. Thyroid disease is certainly a cornmon problem in the U.S. While sirnilar statistics

are not available for Canada, the prevdence of thyroid hormone replacement therapy in an

unselected population of adults older than 65years (n=2575) was reported as 6.995, 10% in

women and 2 3 % in males. (36) However Synthroid, a registered hypothyroidism therapy dnig

was one of the most prescribed medicines during 1999 (37). Given these observations, an

investigation of this group seemed appropriate.

The Thvroid Gland

The thyroid gland is the Iargest endocrine organ, whose function is to secrete a suffkient arnount

of thyroid horrnone, primarily thyroxine (T4) and a lesser quantity of 3', 3. 5-tri-iodothyronine

(T3)- These hormones are important for normal growth and development and also replate a

number of homeostatic functions, including ener,ay and heat production. The thyroid gland

concentrates iodine, synthesizes and stores thyroid hormones as thyroglobulin. The iodinated

thyronines are derived from iodination of the phenolic s o u p s of tyrosine residues in

thyroglobulin to form mono- or diiodo-tyrosine, which are coupled to form T3 or T.4. Thymid

hormones are transported in semm bound to carrier proteins. It is the fiee fraction of T3 and T4

ulat is responsible for hormonal activity. Only 0.04% of T4 and 0.4% of T; are free. The rest of

the thyroid hormones circulating the plasma are protein-bound and have no physiologie activity.

However this pool of bound hormone is in equilibrium with fiee thyroid hormone. The three

major thyroid hormone transport molecules are thyroxine binding globulin, thyroxine binding

predburnin and albumin.

The growth and function of the thyroid gland (38) is controlled by at Ieast four mechanisms:

(Table 1 at the end of the section)

1) The hypothaiamic-pituitary -thyroid axis

The hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and release of

anterior pituitary TSH. which in tum stimulates growth and horrnone secretion by the thyroid

gland. This hypothalarnic-hypophyseal-thyroid axis is regulated by a negative feedback

mechanism, whereby in both the hypothalamus and the pituitary, it is primarily T3 that inhibits

10

TRH and TSH secretion. In the antenor pituitary, TRH binds to specific membrane receptors on

thyrotrophs and prolactin-secreting ceus, stimulating synthesis and rdease of both TSH and

prolactin- Thyroid hormones cause a slow depletion of pituitary TFM receptors thus dirninishing

TRH response. The pituitary thyrotrophs respond to the T M in two ways, stimulating the

release of stored hormone and stimulating gene activity, which increase hormone synthesis.

(Figure 1 )

Figure 1: The Hvpothalamic-Hv~o~hvsea1-Th~yroid Axis.

f /fl Anterior Pituitary Gland

// /t\ Thyroid Gland

1 The h_vpothalamic-hypophyseal-thyroid axis. In both the hypothalamus and the pituitary gland, it is primarily Tj that inhibits TRH and TSH secretion. T4 undergoes rnonoiodonation to T3 in neural, p i tu i tq , as well as in peripheral tissues. 1

2 ) Pituitary and peripheral deiodinases.

These enzymes modify the effects of T4 and T5 Pituitary type 2 5'- deiodinases are enzymes that

convert T4 to T; in the brûïn and pituitary, providing the main source of intraceIlular Tj. This

enzyme's activity is increased in hypothyroidism to help maintain the T3 levels and decreased in

hyperthyroidism to prevent overloading of neural tissues with thyroid hormone. Another

enzyme. 1 5'-deiodinase, acts in the reverse way- Ft is decreased in hypothyroidism and elevated

in hyperthyroidism accelerating the T4 metabolism.

3) Autoregdation of hormone synthesis by the thyroid gland itself in relationship to its

iodine supply.

Autoreplation is defined as the capacity of the thyroid gland to modify its funchon to adapt to

the changes in the availability of iodine, independent of pituitary TSH, thus maintaining a stable

secretion of the hormone with varying iodide concentrations- The major adaptation to low iodide

intdce is the preferential synthesis of T; rather than T.4, increasing the metabolic effectiveness of

the secreted hormone. Iodide excess inhibits many thyroidal functions, including iodide

transport, CAMP formation, HDz generation, hormone synthesis and secretion, and the binding

of TSH and TSH-R antibody to the TSH receptor.

4) Stimulation or inhibition of thyroid function by TSH receptor autoantibodies.

The antibodies to TSH receptor can either block the action of TSH or rnimic TSH activity by

binding to different areas on the TSH receptors. This provides a form of thyroid regdation by the

immune system.

Table 1: Summaw of Factors con troll in^ the Secretion of Thvroid Hormones

1. HYPOTHALAMIC: Synthesis and release of TRI3

Stimularo~: Decreased serum T4 and T3, and intraneuronal T; Neurogenic: Pulsatile secretion and circadian rhythm Exposure to cold (animais and human newbom) Alpha-adrenergic catecholamines Arginine vasopressin X~thibitory : hcreased serum T4 and T3, and intraneuronal T3 Alp ha-adrenergîc bIoc kers Hypothalamic tumors

1. ANTERIOR PITUITARY: Synthesis and release of TSH stimulatory: TRH Decreased serum T4 and T;, and intrathyrotrope T3 Decreased activity Type 2 5'-deiodinase Estrogen: increased TRH binding sites Inhibitory : Increased serum T4 and T3, and intrathyrouope T3 Increased activity Type 2 5'-deiodinase Somatostatin Dopamine, dopamine agonis ts: bromocriptine Glucocorticoids Chronic illness P i tu i tq tumors

3. THYROID: Synthesis and release of thyroid hormone stintulatory: TSH TSH-R stimulating antibodies Inhibitory : TSH-R blocking antibodies Iodide excess Lithium therapy

Age-related Chanees in Thvroid Function

The hypophyseal portal system develops by the 11" week of gestation when measurable TSH

and TRH are detectable. The secretion of thyroid hormone probably begins in mid gestation,

with TSH increasing rapidly to peak 1eveIs at 24-28 weeks, and TA levels peaking at 35-40

weeks. T; levels remain low during gestation since TJ is converted to reverse T; by a deiodinase

during fetal developrnent. At birth, there is a sudden marked rise in TSH, a r ise in T4, a rise in T3

and a fall in reverse T;.

Thyroxine turnover is highest in infants and children and gradually falls to adult Levels after

puberty. T.4 is stable until after the sixth decade, when it drops again. T3 also decreases with age.

Consequentiy, any replacement doses of levothyroxine should be titred very carefully since this

will Vary with age, because thyroxine turnover decreases with age. Thus the average replacement

dose of levothyroxine is 10% to 15% lower in a patient oider than 65 years. (36) Since many

patients on replacement therapy are managecl for many decades, inadvertent over-replacement

may occur as patients age. In adults, a change occurs during pregnancy. when total TJ and T3

levels rise passively in response to an estrogen- induced rise in thyroxine binding globulin. The

contraceptive pi11 produces a similar change. In stress or illness, hepatic conversion of TA to T3 is

reduced and reverse T; is increased. (38)

Chapter 3

Bone Tissue

Bone is a cornplex tissue containing many ceUs lying in a non-cellular connective tissue

component consisting of both an inorganic and organic matrix. Bone is one of the few tissues in

the adult human that totally regenerates its form and function after injury. It is a unique structure

and performs several fùnctions. It serves as a reservoir of calcium, supports and protects organs

and tissues and plays an important role in locomotion.

Typical larnellar bone is composed of approximately 8% water and 92% solid material. The

latter is divided into 31% organic phase and 7 1% inorganic phase. (39) The inorganic maaix

consists largely of calcium salts, with hydroxyapatite making up the largest portion- The organic

matrix consists of collagen (90% to 95% Type I), glycoproteins, and proteoglycans. It supplies

the form to the bone and supporting structure for the deposition and crystallization of the

inorganic salts.

There are three principle bone cells identified during the formation and remodeling of bone.

These are osteoblasts, osteocytes and osteoclasts. Osteoblasts, specialized cells that line the

surface of the bone, synthesize bone matrix, and are derived from osteoprogenitor cells in

adjacent mesenchymd tissues. Osteocytes are found bwed deep within mineralized bone matrix

in lacunae and form an extensive intercellular network connection via canaliculi through which

they provide nutrition to bone. (39) The osteocyte may participate in the bone remodeling

process by being responsible for a direct perilacunar resorption or as part of a coupled resorptive

function with the osteoclast- (40) The osteoclasts are a heterogeneous group of multinuclear

16

cells. They are found where bone is resorbed, forming a ruffled border that appears to penetrate

the bone. (39)

NormaI Bone Remodeling

Bone modeling and remodeling are two different processes which should be recognized. Bone

modeLing is the process associated with growth of the bones in childhood and adolescence while

bone remodeling constitutes a cellular process throughout Iife allowing continuous replacement

of old bone tvith new bone. (41)

Bone remodeling takes place in three different phases. It is initiated by the nctiitntion of

precursor ceils to osteoclasts that resoi-6 bone until they have reached a final resorption depth.

Osteoblasts then invade the resorbed space and start depositing or foiming new bone. This whole

phenornenon is known as the bone structural unit or BSU, characterized by a certain stnictural

thickness. In cortical bonr, a BSU consists of a Haversian system or an osteon. A trabecular BSU

is less definable, consisting of irregular plates bordering the marrow spaces and separated from

the remaining bone by a cernent line. (42)

This whole process is known as the nctivntion-resorption-fonnntioiz sequence and the concept

implies that that there is tempord and spatiai coupling between the resorption and formation

phases in normal bone.

Activation defines the process whereby precursors of osteoclasts are induced to mature to

multinuclear c e l k Cells Lining the bone surface, probably of osteoblastic lineage, activate the

osteoclast precursors, by exposing the bone surface to the osteoclasts. This process is regulated at

a paracrine and hormonal level. (42) Normal trabecular bone is activated with an interna1 of 2 to

3 years whereas the activation frequency in cortical bone is slower. Bone mass is preserved via

the coupling of the two processes. At the periosteal surface, bone formation exceeds bone

resorption resulting in a net increase of the outer diameter of bone with age. The opposite is true

for the endosteal surface. Net resorption results in expansion of the marrow spaces. (41 )

Bone loss c m be defined as being reversible or irreversible. Reversible bone loss occurs when

there is:

1. A high activation frequency,

2. Increased final resorption depth,

3. Prolongation of the resorptive period and

4. Prolongation of the formative phase,

Irreversible bone loss occurs when there is an irnbalance between the final resorption depth md

the mean thickness of newly formed bone. Another mechanism for irreversible loss is

disintegration of the trabecular bone structure due to perforation of the trabeculae. (41, 42) This

could occur via:

1. Enhanced activation frequency,

2. Increased final resorption depth and

3. Reduced trabecular thickness.

Wound Healing Response at the Implant Site

A surgically prepared bone host site for an alloplastic cornrnercialiy pure titanium tooth root

initiates a series of healing events at the site that results in osseointegation- This biomechanical

event is described as:

.'A pr-oces rvhere.hy clÏizically asynptmzntic 1-igid fixatiorz of nlloplnstic rnnterirrls is aclzieved,

and maii~ta Nt ed. in bune during jïinctional loadiizg ". (43 )

The healing response, which occurs following injury to a bone, aises irrespective of the

traumaac cause, be it a fracture, surgical intervention or placement of an oral endosseous

implant. The biocompatible implant is reported as having an adherent, self-repairing oxide layer.

which has excellent resistance to corrosion. (44)

The conditions for favorable bone healing to occur include the presence of adequate cells,

adequate nutrition to these cells plus an adequate stimulus for bone repair. There are different

phases of healing described following injury to bone. The fxst is the inflamrnatory phase, which

leads to the release of gowth factors and sensitizing of cells to the healing process. The second

is the granulation or proliferative phase that occurs a few days after injury, and the third and final

phase, the callus phase, whereby a delicate balance is established arnong the several tissues that

leads to eventual maturation of the wound. The healing continuum is described in distinct steps

but is really an uninterrupted process. The phases are summarized in the following pages.

Phase 1. The Inflamrnatow response:

Albrektsson, in 1983, stated that treatment with implants consists of preparation of the recipient

bony site for the placement of an implant. This surgery results in a thin layer of necrotic bone in

the peri-implant region, even if the strictest surgical protocol is followed. There is also the

formation of dead space around the fixture that is filled with plasma proteins that are released

corn the tissues surrounding the surgical site. (45) The resultant ischernia results in the death of

osteocytes and subsequent release of lysosomal enzymes, which leads to the destruction of both

the collagenous and non-collagenous matrix. A hematoma foms and initiates an elaborate

sequence of biochemical and cellular events in a tirne dependent pattern that constitutes the

heaiing cascade. Platelet damage and contact with qvnthetic materials causes their activation and

the release of intracellular granules resulting in the release of adenosine nucleotide, serotonin and

histamines, leading to further platelet aggregation and local thrombosis. (46) Local ce11

proliferation begins and continues for approximately 3 days, until induced mesenchymal cells

condense- By day 5, polymorphonuclear ieukocytes, histiocytes, lymphocytes, and rnast cells

migrate into the wound. (47) Shortly afier the inflamrnatory phase is established, precursor

mesenchymal cells and osteoproge~tor cells proiiferate and migrate into the fracture site- The

sources of these cells are the bone marrow, endosteum, periosteum, and surrounding soft tissues,

Phase II. The granulation or proMerative phase:

The second phase is characterized with the maturation of precursor cells and early bone

formation. The initial process is neovascularization, or the vascular ingrowth from the

surrounding tissues. This process is induced by the relative hypoxia that develops due to the

rnetabolism of the inflammatory cells. This hypoxic state stimulates angiogenesis. As new

vascular ingrowtb proceeds, the blood supply to the site is improved leading to further cellular

ingrowth- Undifferentiated mononuclear cells enter the area and differentiation produces cellular

elements needed - to provide bone formation such as fibroblasts, chondroblasts and osteoblasts.

Consequently, the initial process involves sensitization of cells to provide definitive new bone

formation: fibr~b~lasts, which produce collagen and proteoglycans; chondroblasts, which lay

down new cartila=ge and osteoid-producing osteoblasts. Albreksston described the process that

results in the repair of the cortical necrotic border zone around the fixture as creeping

substitution involwing the coordinated action of osteoblasts and osteoclasts. Vessels penetrate the

necrotic border zone of the wound according to the path of least resistance. Osteoclasts resorb

the necrotic bon= and osteoblasts forrn new bone around the vessel. A s a result of vascular

ingrowth, the newly laid bone around the vessels will be in an unordered fashion. However, with

time, the area is reorganized with vessels gradually growing in a more orderly pattern and

creeping substituttion dong these vessels results in remodeling of the bone. The prcduction of

osteoblasts, fibroblasts, and chondroblasts fonn a mixture of fibrous tissue, cartilage and loosely

woven bone known as the soft callus. The soft callus is transfonned into bone as the process of

endochondral ossiification replaces the cartilaginous components. (39, 46) The calcification of

the organic matrix proceeds as calcium hydroxyapatite is deposited, and leads to the formation of

calcified matnx interconnected by newly fonning blood vessels. Further ossification occurs as

immature woven bone is produced and results in filling of the bony defect around the fmture.

Phase III. The maturation stage:

The hard callus that is forrned replaces the sofi callus that surrounds the implant. Modeling and

remodeling take place to restore normal bone architecture and re-establish the marrow cavity.

Hard callus contains woven bone that follows the pattern of vascular ingrowth. A balance of

osteoclastic resorption and osteoblastic deposition results in replacement of woven bone with

layers of mature lameliar bone, organized by functional stresses applied to the bone. For years

after placement of implants, there will be an increased activity of coupted

osteoclastic/osteoblastic function in the form of gradua1 replacement of the interfacial hard tissue

to neuf more orderly mature bone, resulting in healing without scar tissue.

Albrektsson (45) used a rabbit animal mode1 to inveshgate the peri-implant healing process

around fixtures placed in long bones. The results revealed that there is initial vascular ingrowth

appearing and maturing dunng the first 3 weeks after implantation. Ossification is at a peak

during the third and fourth week, reaching a steady state by the sixth to the eighth week. The

author also demonstrated that at one-year folluw-up of unloaded fixtures, there was little change

of the bony picture when cornpared to that seen in the sixth or eighth week.

Although described as distinct steps, the above processes or phases occur as a continuum. The

replation of bone repair is a complex process that requires interplay between hormones,

systernic, and local factors. Bone-inductive proteins, iike Bone Morphogenic Protein (BMP).

trigger the initiation of the healing cellular cascade in bone. They induce the differentiation of

pluripotential cells into cartilage- and bone- forrning cells. BMP mts in synchrony with growth

factors that modulate and regdate the induced progenitor cells. Examples of growth factors are

platelet derived growth factor (PDGF). transforming growth factor-beta (TGF-P), epidermal

growth factor (EGF). insuIin growth factor-1 (IGF-O. and basic fibroblastic growth factor (bFGF

or FGF-2). (47) These have potential to promote osseous wound healing and act during the callus

formation and also during bone formation, remodeling. (39) Other proteins involved are nerve

growth factor, which is mitogenic during callus formation and also interleukins 1 and 2. The

latter are produced by monocytes and induce fibroblastic proliferation, the production of

collagenases and prostaglandins (IL-1) and the stimulation of bone resorption (IL-2). Insulin has

a synergistic effect with growth factors during the bone formation/remodeling phase. (39)

Davies (48) summarized the bone response to endosseous implants as consisting of two distinct

phenomena by which bone c m become juxtaposed on an implant surface. He calls these

phenomena distance osteogenesis, and contact osteogenesis.

Distance osteogenesis is a process whereby new bone is formed on the surface of the bone in the

pen-implant area. Thus an osteogenic ceil h e a g e exists on the bone surface and this la- down

new bone that eventually encroaches on the implant itself.

The second process, or contact osteogenesis, consists of three steps. The first is osteoconduction,

whereby osteogenic cells migrate to the implant surface through a t e m p o r q connective tissue

surface. The second is de novo %one formation, and results in a mineralized interfacial matrïx

being laid on the implant surface itself and comprises a four-stage process. Differentiating

osteogenic cells initidly secrete a collagen-free organic mamx that is rich in osteopontin and

bone sialoprotein, and acts as a nucleation site for calcium phosphate minerakation resulting in

crystal growth. Concurrently, collagen is laid and subsequently mineralized. In the third or

remodeling phase results in a long-term stability of the transcortical portion of the endosseous

implant via remodehg of the osteons takes place.

Bone Response following Osseointeeration

Nurnerous clinical studies addressed both the success of implant therapy as well as the mwejnd

bone response around implants. I n general. bone loss around implants appears to Vary both in

patients and also within the same patient.

Adell et al (2) reviewed 3768 fixtures placed in 371 patients. The authors reported that 8 1% of

the maxillary and 91% of the mandibular fixtures remained stable. They reported a marginal

bone loss of 1 Srnm for the first year following implant placement which then tapered down to an

ongoing annual loss of O.lmm. Lindquist et ai (49) reviewed 47 patients treated with fixed

tissue-integated prostheses in the anterior mandible and observed similar results. The mean bone

loss was 0.06mm annually after the first year of loading. The sarne authors (3) subsequently

reported marginal bone loss averagïng 1Smm during the first year. This progressed at a slow

rate, reaching 0.9- 1 .?mm after 10 and 15 years respectively.

These European studies were further corroborated in North Arnerica by the Toronto prospective

studies. The sarne crestal bone response was reported for the edentulous patient, mean bone loss

of less than O. lrnrn per year after the initial year of loading were an average loss of 1.5mm was

reported. (4, 50, 5 1) Henry et al's report (5) was in agreement with previous studies and

identified a mean marginal bone loss of O to 1.2mrn before a steady state was reached after the

thïrd year of loading,

Sirnilar figures were reported for overdenture therapy of the edentulous jaws. Zarb et al (5 1 )

found that bone loss was less than 0.2rnrn per year, while Bergendal et al (52) reported that the

marginal bone loss was around 0.5 to 0,7mm in the mandible and somewhat higher in the maxilIa

over a 5 year penod with a first year marginal bone loss of around 0.3mrn.

Avivi-Arbor et al (IO) reported that the for single tooth implant-supported restoration, marginai

bone loss during the first year of Ioading was between 0.36 and 0.4mrn and the mean annual

bone loss following year one was 0.03 to O. 1 Imm. The marginal bone levels around single tooth

implant-supported restorations were well within the annual 0.2rnm per year guidelines proposed

in a multicenter study published in 1996. (1 1)

In partially edentulous patients, a mean bone loss of less than O.2m.m annually following the first

year of function was reported in all studies where the partial denture was supported by implants

only (9, 53, 54, 55, 56) as well as in a combination scenario of tooth implant supported fixed

partial denture. (57)

However, Wyatt's research on the outcomes of implant supported fixed partial dentures (58),

reported that 15% of the patients experienced bone loss exceeding O.lrnm per year. These

observations applied to younger male patients, in the mandible when compared to the maxilla

after one year of Ioading, and also when the design inciuded a distal cantilevered pontic. (8,5S)

Al1 of these studies, with the exception of Lindquist (34) and Accursi's f33), have not identified

any factor that may have contributed to bone loss.

Lindquist (34) concluded that over a ten-year period about lmrn of crestal bone was lost, being

siagd5cantly greater in smokers. If the patients had poor oral hygiene, more bone loss was noted;

patients with a combined history of smoking and poor oral hygiene, had three times geater bone

loss after ten years than non-smokers. Accursi (33) found that diabetic goup lost more bone

dunng the first year of function when compared to the control goup of patients. However bone

loss after year one was not statistically different between the two groups.

Taken together, these cited papers show that most of the bone ioss occurs in the first year

following loading and then stabilizes irrespective of site, jaw and type of prosthesis provided.

This is o d y true for the adult populations studied, as there is still no long-terrn evidence to

predict what happens in the very young or growing patient. It therefore seems prudent to not

extrapolate these results to the young patient. ( 18)

Chapter 4

Impact of Thvroid Hormone on Wound Healing

There are a number of studies indicating that th-vroid hormones are important in regulating the

wound-healing phenornenon in soit tissues and in bone fracture healing. They al1 suges t that an

imbdance of thyroid hormone upsets the healing process since both hypothyroid and

hyperthyroid States altered healing rates. Thyroid hormone plays an important role in bone

gowth and maturation m d functions as a systernic regdatory factor for chondrogenesis and

endochondral ossification and so has a r d e in fracture healing.

Burch et ai have showed the importance of thyroid hormone on chondrogenesis and

endochondral ossification, in their in-vitro studies on ce11 cultures from chick embryos and fetal

porcine cartilage. (59-6 1 ) Chicken embryo cartilage incubated with T3 demonstrated microscopic

changes in maturation, with development of large numbers of hypertrophieci chondrocytes, and

biochemical evidence of maturation, with increased alkaline phosphatase activity. There was a

dose-response range for Tj for stimulation of growth and to a lesser degree, stimulation of

akaline phosphatase activity. This study demonstrates that Tj in physiological concentrations

directly affects cartilage growth and maturation, pnmarily through stimulating chondrocyte

hypertrophy. (60) These results were confirmed in another study (6 1) in which the effect of

thyroid hormone on growth-hormone-dependent serum factors (somatomedins) role in growth

was investigated. The authors found that thyroid hormone promotes cartiIage growth by

promoting the activity of the growth hormones (synergistic effect) rather than increasing their

synthesis and through acceleration of cartilage ce11 prolifention.

28

The same authors obtained similar results in another study on porcine cartilage. (59) There was a

dose response increase in akaline phosphatase, a marker of hypertrophied chondrocytes, specific

to triiodotllyronine only and not to other hormones like cortisol, bovine parathyroid, insulin and

5% fetal calf serum. This was confirmed by histological examinations that showed increased

alkaline phosphatase activity in the zone of maturation, the site where mature chondrocytes

would be present, (59)

Another study investigated the interaction of thyroid hormone and growth hormone in a

hypothyroid rat model. (62) Sprause-Dawley female rats were sacrificed to see the response of

articular cartilage, epiphyseal growth cartilage, epiphyseal trabecular bone and metaphyseal

trabecular bone in the proximal tibia. Pnor to sacrifice, replacement therapy with hurnan growth

hormone or L-T4 or combination of both was introduced for a penod of two weeks, The width of

the articular and epiphyseal growth plate cartilage and the bone volume of the epiphyseal

trabecular bone and metaphyseal trabecular bone were reduced in the hypothyroid rats when

compared to their controls. Thyroid hormone treatrnent restored these parameters to different

magnitudes. The epiphysed trabecular bone was restored and surpassed the control. The articular

cartilage and epiphyseal trabecular bone volume was returned to control volume while ùiat of the

metaphyseal trabecular bone was restored to 68% of the control values. Growth hormone only

restored the epiphyseal trabecular bone to near control levels and the metaphyseal trabecular

bone to a lesser but si,onificant extent. Combination of thyroid and growth hormone restored and

further enlarged the width of the epiphyseal growth plate cartiIage and metaphyseal trabecular

bone. This study confirm that thyroid hormone is involved in the health of the epiphyseal growth

plates and its remodeling in metaphysed trabecular bone since the darnaged epiphyseal growth

plate cartilage in the hypothyroid rats was restored. Since growth hormone therapy alone did not

induce recovery of the growth plate, the authors suggest that thyroid hormones must exert their

effects through other pathways besides its action through gowth honnone. The same group of

researchers, Lewinson 1994, conducted the same type of studies in the mandibles of hypothyroid

Spngue-Dawley rats. They investigated the response of the cartilage and subchondral spongiosa

of the mandibular condyles with morphological, morphometric parameters and

irnrnunohistochernical localization of the growth hormone receptor and insulin-like growth

factor-1 (IGF-1). This study shows that the mandibular condyle of the rat reacts to

hypothyroidism differently from other sites, specifically the tibia, the site previously investigated

by the authors. The hypothyroid mandibuIar condyle, exhibited hyperostosis of the subchondral

bone, probably due to aiteration of the endochondral ossification processes. The cellularity of the

cartilage in the hypothyroid condyles was reduced but was restored following administration of

thyroxine. lmmunohistochemistry revealed that growth hormone was present in ail the condylar

sites irrespective of the thyroid state of the rats. However, IGF-1 decreased in the hypothyroid

condyle, even when growth honnone was administered. This su,ogests that the hypothyroid

cartilage in the condyle is refractory and compromised in response to the induction of IGF-1 by

growth hormone. These results demonstrate that condylar cartilage reacts differently fiom other

sites and suggests that the jawbones are distinct £Yom other skeletal sites.

The impact of thyroid hormone and the role of hypothyroidism on fracture healing in the fernora,

were investigated in a rat mode1 by Urabe et al (63) using histological, biological and

biomechanical methods. Seventy-six female Long-Evans rats were divided in three groups. The

study groups received methimazole only or methimazole and L-thyroxine. three weeks pnor to

fracture of the femora. Methimazole inhibits iodination of thyroglobulin, iodothyrosine coupling

and also thyroglobulin synthesis, thus leading to development of hypothyroidism in the rats.

Six fractured femora (3 animals) corn each group were harvested on days 4,7, 10, 12 and 14

after the closed fractures were done. A unilateral femoral fracture was produced in the remaining

3 1 rats, Of these, eleven and twenty rats were sacrificed on day 14 and 21 respectively after

fracture.

The histological results showed that intrarnembranous bone formation tended to be smaller in the

rats that were rendered hypothyroid but not replace with L-thyroxine. At day 11, vascularization

was less in the hypothyroid rats ( 3 3 % ~ ~ 92%) compared to the rats that were replaced. Biolo,oical

observation showed that bene expression of matrix proteins in replaced rats was restored to

normal levels comparable to the controls on day 10 onwards. The rats that were replaced with L-

thyroxine had similar peak force to failure and stiffness of the fractured femora in biomechanical

observations performed on the fracture sites. This study showed that hypothyroidism led to a

decreased intrarnembranous ossification on day 4 thoush this was not statistically significant.

Thus the effects of hypothyroidism on the differentiation of chondrocytes and osteoblasts in the

fracture callus may result in an inhibition of endochondral ossification during the early phase of

fracture healing repair. It also provides evidence that the hypothyroidism can influence

mechanical properties of the fracture callus and sug-g-ests tiiat thyroid hormone is one of the

critical systernic factors for fracture healing. Important to note was that replacement with L-

thyroxine in the hypothyroid rats mainly led to recovery of the impaired repair process which

then reverted to a normal level.

Thus these studies confirm that thyroid hormones are required for the proliferation and

maturation of cartilage and also emphasize its role in bone healing. This activity is important in

other tissues as will be discussed shortly.

The Role of Thvroid Hormone in Soft Tissue Wound Healine,

Mehregan and Zamick (64) using a rat animal model, showed that TI< therapy improved the

healing response in rats that had sustained deep demal burns when compared to controls.

Kistology showed bener wound organization as evidenced by the presence of fibroblasts and the

amount of collagen in the rats that were receiving the thyroid hormone. The sarne results were

obtained for the healing of the split skin gaft placed afier the initial scar was removed for

histological investigation. The authors did not state clearly if the rats were rendered hyperthyroid

with this therapy, though they did mention that they were hypermetabolic.

In a similar study, Hendron et al (65) examined the effect of L-thyroxine on wound healing in

guinea pigs following a 50% full thickness scald burn. In this study, guinea pigs underwent

thyroidectomy a month prier to the burn and then received daily graded doses of L-thyroxine.

FoUowix-g injury, oxygen consumption was de tedned at a 4-day interval in closed metabolic

chambers. The results showed that the level of thyroid replacement had an important effect on

the rate of healing of burn wounds in the thyroidectomized guinea pigs- Very low or very high

doses of thyroid hormone replacement therapy to the thyroidectornized guinea pigs had an

adverse effect on the healing of the wounds, whilst replacement at a physiologie level,

au,omented wound closure when compared to matched controls.

This finding is also consistent with the results of Kiviriklio et al. (66) In this study. isotopic '"c

labeled proline was injected in male Wistar rats that had been rendered hypothyroid or

hyperthyroid. Collagen rnetaboiism was investigated by monitoring the levels of hydroxyproline

14 C in skin and in urine sarnples. The results of this study suggested that the rates of synthesis

and breakdown of collagen are altered in both hyperthyroidism and hypothyroidism. The rates of

sqnthesis of collagen were decreased in both conditions. The study further indicated that in

hyperthyroidism, the rates of catabolism of collagen were increased whiIst in hypoth-woidism it

was decreased.

This is also corroborated in another animal study. (67) Lennox and Johnston studied healing

rates and tensile stren,oth of wounds in rats that undenvent thyroidectomy. A group of rats

received high doses of L-thyroxine and rendered hyperthyroid whilst another group was not

administered thyroid hormone and left hypothyroid. Wound healing was accelerated by a mean

of 2.5 days in the hyperthyroid group and delayed by 2 days in the hypothyroid group when

compared to the control group. Both results were statisticdly significant. The tensile strena@ of

wounds was significantly greater at ten days in the hyperthyroid group and the basal nitrogen

turnover increased, correlating with accelerated wound healing.

L-thyroxine and zinc therapy effects on wound healing were investigated in a rat model that had

laparotomy. (68) A group of ten rats served as control (group A). The other 40 were administered

5-propyl 2-thiouracil ( P m ) for 21 days and rendered hypothyroid. Immediately after this

surgical intervention, the hypothyroid rats were divided as follows: B was hypothyroid, C was

hypothyroid and adrninistered L-thyroxine, D receiving zinc hypothyroid and E, hypothyroid rats

receiving L-thyroxine and zinc. The rats were sacrificed 7 and 14 days after the laparotomy

intervention and blood sarnples were obtained. The results showed that group E had the highest

breaking stren,g.h of the wound when compared to the other groups. The hypothyroid goup (B)

had the lowest rnean breaking point of ail groups. This study is important in confirming that a

hypothyroid rat model c m be readily established as evidenced by the low thyroxine T; and T.4

Ievels and high TSH Ievels in the hypothyroid rats at baseline. The results are also interesting

because such a state has an -impact on zinc levels, which were reduced at baseline in the

hypothyroid rats and corrected in groups C , D and E foilowing zinc supplementation. This study

dso shows that zinc probably is important only in cross linkage of nascent colhgen molecules

since there was no si,gificant increase in hydroxyproline leveis following zinc administration,

however there was a significant increase in the breaking strength of the wound scar.

Case reports on patients that were rendered hypothyroid have dso indicated that a hypothyroid

state inhibits wound healing and that once corrected, wounds heal. Four men treated for

carcinoma of the larynx who subsequently developed hypothyroidism had delayed wound

heaiing of pharyngeal fistulae that were refractory to conservative and surgical care. Correction

of their hypothyroid state with replacement therapy resulted in rapid healing of the wounds. (69)

Alexander et al (70) in a retrospective five-year review of twenty-nine patients trerited for cancer

of the larynx disclosed that seven patients had hypothyroidism develop in the post-treatment

period (zero to two years) whilst another five patients treated with a combination of surgery and

radiation had hypothyroidism develop during treatment. Of the latter, two had fistulae develop

that were resistant to intensive local care. They closed promptly after treatrnent of the

hypothyroidisrn. Of the two patients who had hypothyroidism develop after surgery alone, one

had fistulae develop that were resistant to local care, but responsive to thyroid hormone

replacement.

The role of thyroid hormones on collagen metabolism was also studied in a ciinical study (7 1 ) in

a group of 19 patients (4 males and 15 females) with untreated thyrotoxicosis, and 20 pre-, and

20 postmenopausal women taking T4 100-200 micrograms daily for autoimrnune

hypothyroidism. Urinary excretion of the bone collagen derived pyridinium cross-links

pyridinoline and deoxypyridinoline was measured and both were significantly elevated in the

thyrotoxic patients compared to 287 controls.

In premenopausal women mean urinary p-vridinium cross-link excretion and semm osteocalcin

levels were similar in both Ta-treated and matched control groups, even though most patients had

TSH suppression. In postmenopausal women, mean excretion of pyridinium cross-links

pyridinoline was significantly raised in those taking T.4, relative to euthyroid controls. Sub-group

analysis of T4-treated women with suppressed TSH levels indicated that both pyridinium cross-

Links pyridinoline and deoxypyridinoline excretion were si3anificantly elevated. This study

suggests that bone collasen breakdown is increased in thyrotoxicosis, and in postmenopausal

women who have TSH suppression.

Thvroid Hormone and DentaI Development

Literature pertaining to dentistry and thyroid hormone function is sparse. Most of the recent

literature is from Orthodonties studies, which show an interest in the relation of thyroid hormone

and accelerated tooth movement and prevention of root resorption.

An early study (72) on lambs indicated that hypothyroidism affects ameloblastic activity, though

there was no characteristic alteration of the tooth morphology. Biggerstaff and Rose showed that

enamel of hypothyroid larnbs was poorly calcified suggesting that hypothyroidism alters the

ameloblastic activity. Though observation of ground sections of enarnel indicated that

differences in the quaiity of normal and cretin lamb enarnel existed, no statistical differences

were evident.

These morphological changes are usually localized defects in the enarnel and have been

described in animai (73) and clinicai(74) reports.

Gavin examined the incisor teeth of rats and found that in the thyroparathyroidectornized goup

there was a sigificantly higher proportion of defects narnely enarnel hypoplasia and fractures.

However, one should note that the rats had their parathyroid removed and this rnay have played a

role in the defects.

Knrichs investigated dental changes in juvenile hypothyroidism in a group of thirty-six patients

over a period of 15 years. The author showed that in cases where the hypothyroidism was not

diagnosed early in Iife, there were more developmental defects in the teeth. He also noted that in

such cases, there was also delayed exfoliation and eruption of the permanent dentition.

Animal studies have shown that hypothyroidism causes degeneration of the penodontal ligament

collagen fibers. Delayed organization of collagen fibers and decrease in the amount of fibers in

the periodontal ligament were observed. Thyroidectomy in newborn rats has been reported to

produce a reduction in the ceilularity of the incisor periodontal ligament. In the rabbit rnodel,

there was a decrease in cellularity of the ligament and also retarded alveolar bone apposition

around teeth. (75)

Case reports in the dental literature have discussed the impact of undiagnosed hypothyroidism on

craniofacial development. In al1 these cases, after treatment wiih thyroid hormone, the

progression of the dental age and facial development improved. (76-79) The different response

of localized areas in the mandible to thyroxine suggests that growth regulation by different

classic endocrine hormones may act locally at different sites through growth factors via paracrine

mechanisms. (76) It was suggested hat craniofacial growth is affected by retardation in velocity

nther than modification in pattern in hypothyroidism. (77) Garn et al (80) suggested that in

juvenile hypothyroidism, dental age was delayed by as much as S years. Dental delay was far

less pronounced however than skeletal delay being approximately a third as much as skeIetal

delay.

It was suggested that th-yroid hormone supplementation during orthodontic treatrnent may

improve alveolar bone remodeling and prevent root resorption.

Shirazi et al (81) studied the effects of different doses of thyroxine on the rate of orthodontic

tooth movement and force-induced root resorption. Fifty male Sprague-Dawley rats were divided

into five groups: a normal group that received no intervention and was designated as the normal

group; a control group in which appliances were placed and injected with saline solution, and

three groups in which appliances were placed and 5, 10 and 20/micro,sram/kg L- thyroxin was

adrninistered intraperitoneally (i .p.) every day.

The appliance was a fixed orthodontic appliance consisting of a 5 mm closed-coi1 spring that was

figated between the maxillary incisor and maxiiIary first molar to deliver a tooth movement force

without causing increased amounts of resorptive activiy.

The tooth movement was determined by measuring set points. The rnaxiI1a.y frrst molars were

extracted after the animais were sacrificed and examined under electron rnicroscopy. The results

showed that administration of 2O/micro=rn/kg i.p. /day L-thyroxine only sipificantly increased

the amount of orthodontic tooth movernent

(p 0.001). Thus no dose-response effect was found. Orthodonticaily treated rats showed more

resorptive lacunae than the normal group. In other groups, the extent of root resorption as seen

fiorn scanning electron rnicrographs decreased with thyroxine administration, though no

statistical analysis of these findings were discussed. Bone densitometry andysis of comparative

radiographs taken at the start and finish of the experiment indicated that in the group that

received 2O/mïcro~arn/kg i.p. / day L-thyroxine, bone density decreased during treatment and

was sipificant. This study suggests that administration of thyroid hormone increases the rate of

dveolar bone remodeling and indirectly au,ments tooth movement in conjunction with reduced

root resorption. Poumpros et al better explained external root resorption in another study (82)

Forty-eight male Sprague-Dawley rats were divided into three groups: a group of normal rats, a

control group in which appliances were placed, and an experimental group in which appliances

were placed and 5 microgramsAcg body weight L-thyroxine was administered for 13 days. Root

resorption was induced by orthodontie force on the maxiilary incisors and was measiired by

using a calibrated

This study found that fewer force-induced root resorption lesions occurred in the thyroxine g o u p

than in the control goup. When compared to the previous study, this dosage was low and

compares to the results of Shirazi et al. (8 1)

Akaiine phosphatase activity in the thyroxine group was sia~ficantly different from the normal

and control groups- Thus, the decrease of resorptive lesions in the thyroxine group seemed

correlated to a change in the bone rnodeling process. The authors suggested that this is related to

a change in the rernodeling of bone, especially to the resorption activity, making the process

more efficient.

These resuIts have aiso been reported in a case senes in a group of three patients (83). These

three patients were undergoing orthodontic treatrnent and were adrninistered daily thyroid

hormone due to radiographie s i p s of root resorption. Though this is a case series, one may

consider that thyroxine administration may improve alveolar bone resorption and thus indirectly

decrease root resorption. It is obvious that a well-controlled chnical trial is indicated to show that

thyroxine therapy may help reduce root resorption and at what dosage and dso to verify that this

practice does not harrn the patients.

These articles show that thyroid imbaiance has an influence on the dental maturation and skeletal

growth of the jawbones especially in the young patient. This indirectly suggests that in the adult,

thyroid imbaiance rnay influence the jawbones and should be further investigated.

Chapter 5

Hvperthvroidism and Skeletal Integritv

Hyperthyroidisrn is the clinical syndrome resulting fiom the effect on the tissues of excess

circulating T3 and T4 with a resultant increase in the metabolic rate- Hyperthyroidism may result

from three main pathologïcal Iesions: Graves' disease, functioning adenoma and toxic nodular

goiter. The cornmonest cause is Graves' thyroiditis in which there is a long-acting thyroid

stimulating immunoglobulins- These antibodies to the TSH receptor stimulate the thyroid gland

in ways analogous to the normal action of TSH. This disorder usually presents in the third and

fourth decade of life- Graves' disease is found more often in women thm in men.

A functioning adenoma is usually an autonomous nodule and it secretes an increasing amount of

thyroid hormone until TSH is switched off completely. This results in thyrotoxicosis.

Toxic multinodular goiter usually develops in the fi* decade after a long history of non-toxic

goiter, usually in areas of endemic goiter. Diffuse or focal autonomous nodular formation

develops in the enlarged thyroid dons with thyrotoxicosis that is generally mild in nature and

associated with suppressed TSH.

Architectural changes in bone due to hvperthvroidism

The hyperthyroid state is characterized by a reduction of the trabecular bone mass. The changes

in trabecular bone volume may be caused by expansion of the remodeling space, increased

occurrence of perforations and a negative balance between resorption.formation, specifically an

increased resorption rate. In fact there is a marked shortening of both the resorptive and

formative phases of the remodeling cycle in the trabeculcir bone cornpartment, resulting in a

42

reduction of 220 days per cycle in a normal person to around 110 days in a hyperthyroid person.

(42) The hyperthyroid state is charxterized by enhanced active resorption leadins to irreversible

bone Ioss with increased risk of disintegation or reduction in the thickness of the trabecular

network resulting in increased cortical porosity (4 1) and bone minerd mobilization. (42)

Changes in Bone minerd densitv and content due to hvperthvroidism

There are various studies in the literature that indicate that a state of hyperthyroidism has a

negative impact on the bone metabolisrn with a resultant loss of the bone architecture- A

longitudinal study on 23 male patients with Graves' disease reported on changes in the BMD

over a period of 2 years. (84)The study showed a si,onificant difference in the BMC and BMD

between the subjects and their matched controls, In fact a 17% reduction in the baseline BMD of

the hyperthyroid patients was reported at the site measured, the forearm. The study also reported

k s t a drop and then a rise in the BMD as treatrnent progressed. The data showed a sipificant

reduction from baseiine at one-year treatment followed by a si,onificant increase at 3 years, back

to the original baseline for hyperthyroid patients. The 2-year BMD value for the subjects was

still 16.7% less than the baseline for the controls. This suggests that treatment improves the

BMD and that this recovery is gradual. However though the BMD was improved, it did not

return to the level of the rnatched controls. This study also did not find any difference the method

of treatment had on restoration of the bone content. This is also consistent with the resuIts

reported by Kroher et al. (85) these authors reported that the BMD in a group of 25 patients (30

fernales and 5 males) with untreated thyrotoxicosis, the lumbar BMC was 13.6% Iower than Siat

of the controis- Age did not impact on this resuk Treatment of the thyrotoxicosis over a period

of a year, showed a significant increase in the lumbar BMC. The loss appeared to be at least

partially reversibly during the duration of the investigation.

In a cross sectionai study (86) measurements of BMD were performed in premenopausd and

postmenopausal women categorized as follows: patients with a history of non-toxic nodular

goiter, another with subclinical hyperthyroidism and a final group with toxic autonomous thyroid

nodule (overtly hyperthyroid). Compared to healthy controls, the toxic nodular goiter group had

Iower BMD at the lumbar spines. This was more evident in the postrnenopausal soup , though

the premenopausal group also reached statistical si,onificance. At the femoral neck as well as the

rnidshaft radius, the BMD was also ~i~gificantly lower in the hyperthyroid group. Kndeed in

hyperthyroidism the duration of the disease rather than its severity seems to be more dangerous

for bone. (87)

Campos-Pastor et al (88) reported that in twenty-eight fernale subjects with active thyrotoxicosis,

there was a s i a~f i can t reduction in the BMD values at the lumbar spine, femoral neck and Ward

triangle when compared to controls. In patients undersoing treatment, there was no si,anificant

difference in the BMD at the studied sites when compared to the controls. However the values

for postmenopausal patients showed significant decreases in al1 three sites. A si,gificant negative

correlation between the BMD and duration of thyroid hyperfunction was found in the femoral

neck and Ward's triangle.

Lee et al. (89) studied the changes in the BMD and osteoblastic activity in 109 patients with

Graves' disease. 86 were wornen and the rest men. 75 patients were treated whilst the other 34

were undergoing treatment during the study. When compared to controls, the BMD of femde

patients with hyperthyroidisrn was Iower than that of normal controls in both the spine and

femur, where trabecular and cortical bone predominate respectively. Age and presumably

menopause had no impact on this reported reduction. The si,onificant negative correlation

between the serurn osteocalcin and BMD of the spine and hip sites suggests that osteoblastic

activity was set in motion due to the resorption process reflected as an increase in the semm

ionized calcium level.

In a cross-sectional study of 202 Caucasian women, the authors (90) also showed that a history

of thyrotoxicosis was associated *th a tendency towards a decrease in BMD at the spine and the

femoral neck, trochanter and Ward's triangle. This study also indicated that in patients on

thyroxine therapy, a previous history of thyrotoxicosis may impact on the BMD levels.

Two M e r studies investigated if a history of thyrotoxicosis influenced the BMD in patients on

thyroxine therapy. (91) (92) Grant et al. e x d n e d 106 postmenopausal women with a previous

history of hyperthyroidism. These women were subdivided into 4 goups according to treatment.

The patients were grouped into surgically rnanaged or treated with radioiodine and further

subdivided into those that remained euthyroid or those that required thyroxine therapy.

Measurements were obtained at distal and ultra distal forearm, sites that are predominantiy

cortical and trabecular respectively. At the ultra distal site, differences were statistically

si,onificant for di groups compared to controls except for the goup that was surgically treated

only- At the distal site, predominantly cortical, the same results were obtained. This suggests that

patients treated surgically are at Iower risk for BMD reduction. It further susgests that

postmenopausal women treated with radioiodine for thyrotoiucosis have si,onificant reduction,

whether or not they are on thyroxine therapy and are still at risk of osteoporosis.

Adlin et al (92) studied 19 postmenopausal patients who had been on thyroxine therapy for an

average of 15 years. In general a 17% decrease in the BMD at the lumbar and hip sites was found

in the treated group. Further analysis of 7 patients with a tustory of thyrotoxicosis showed a loss

of bone density in the hip despite the smalI number of the subgroup. One concludes from these

studies that thyrotoxicosis while active is significant in causing bone loss and even in

perpetuating the loss when it is controLled. Franklyn et al (93) in a cross-sectional study of 27

premenopausal and 60 postmenopausal with a previous history of thyrotoxicosis showed a

si,anificant decrease in BMD only in the postrnenopausal women, specifically in various spinal

sites and trochanter. Interestingly, Franklyn et al (94) found that estrogen therapy in patients with

a history of previous thyrotoxicosis and subsequent thyroxine therapy may be beneficial in

reducing the loss in fernoral and vertebral BMD. These results also indirectly confinn that

thyrotoxicosis itself has a negative impact on bone minera1 density,

Langdahl et al. suggested in two studies, that patients with a previous history of thyrotoxicosis

treated either medicaliy (95) or surgically (96) had no impact on the BMD for the total body or

regionaily, thus contradicting previous studies. In both cross-sectional studies, age and BMD

were inversely correlated, Markers for bone metabolisrn were al1 in the norrnd range except for

the patients treated medicdly where a marker for resorption, U-PYR, was elevated. (9.5) Other

markers for resorption were normal and the authors suggest that t h i s deviation has no impact.

However, in both studies, there was a ~i~gnificant change in the fat cornpartment in the treated

patients suggesting t!!at the period of hyperthyroidism might have irreversibly changed the

trabecular bone microarchitecture and thereby reduced the biomechanical cornpetence of this

cornpartment.

A surnmary of the articles discussed is presented as Table 3 in the following pages.

Table 3: Effect of Hvperthvroidism on Bone

Stud- (Reference)

Patient Control Shrdy Design

Menopausal Staîus

Patients (n)

males 20 females 5 males 23 13

Site Change in BMD Characteristics

Toh et al (84) Krolner et al (85)

Grave's disease Yes Yes

Long- Cross-

/ Not specified

Radius

Long- Cross-

Spine Spine Femonl neck Forearm Spine Femoral neck Forearm Spine Femoral neck Forearm

Spine Femur

Yes Subciïnical hyperthyroidism

Post-

Tosic nodules Yes

Yes

Pre- Post-

Hyperthyroidism Cross- Pre- Post

32 females 20 males

Campos Pastor et al (88)

Grave's disease. Nodular toxic coiter and - mu1tinodular goiter Grave's disease

Yes

Yes

Cross- Pre-

Post-

Spine FemoraI neck Ward's triangle

Spine Femonl sites

Long- Pre- Post-

1 .i. NS in males L L

f revious hyperthyroidism

Duncan et al (90)

Cross- Pre-/ Post-

Spine Femoral neck Ward's trian_ole Trochanter

Previous hyperthyroidism

Yes. except for surgical group

Cross- Post- Forearm

NS: Non significant; reduction.

Table 2 Cont: Effect of Hvperthvroidism on Bone

Study (Re fer ence) Fnnklyn er al

Patient Characteristics Previous hyperthyroidism

Previous hyperthyroidism

previous-- hyperthyroidism

Control

Yes

Yes

Yes

Study

Cross-

Cross-

Post-

Pre- Post-

Pre- Post-

Patients

15 1 S 6 males 11 28 23males

Site

Spine Fernoml neck Troc hanter Ward's triangle Spine Femoral neck Trochanter Ward-s tnangie Spine Hip Forearm Spine H~P Forearm

Change in BMD NS NS

NS: Non significant; reduction.

The effects of Thvroid Hormone Replacement on Skeletal Integrity

Thyroid hormone is used in clinicd practice for two reasons, correction of a hypothyroid state

and for TSH suppression.

Hvpothvroidism

Hypothyroidisrn may develop in early or adult life. Early hypothyroidism may be congenital or

else may develop in childhood, in this case being defined as juvenile. Causes of congenital

hyp~th~vroidisrn include:

failure of thyroid development; endemic cretinism; pituitary or hypothalamic insufficiency;

iodine or antithyroid treatment of the mother, defects in thyroid hormone biosynthesis, and

thyroid hormone resistance. (97)

Hypothyroidism with onset in adult life is ctlmost always due to autoimmunity, unless it resuIts

from previous treatment of thyrotoxicosis. Thus, causes of hypothyroidism can be Hashimoto's

thyroiditis, idiopathic thyroid atrophy, previous radioactive iodine therapy, neck irradiation and

thyroidectomy. Hypothyroidism is a cornmon condition, with a prevalence of 2.4 to 3.4% in

adults. (98) In persons over 60 years of age, the prevalence of primary hypothyroidisrn increases

to S.OS%, 3.9% in men and 6.75% in women. (36)

Bone Architectural Chan~es in the Hvpothvroid State

The hypothyroid state is characterized by a decreased rate of the remodeling cycle. In the

hypothyroid state, the activation frequency is reduced and the phases of remodeling are

prolonged, being characterized by a reduced final resorption depth, and increased wall thickness

in the trabecular cornpartment. Changes in bone mass are very slow in hypothyroidism being

exemplified by a remodeling cycle of around 620 days when cornpared to 15 1 days in age and

sex matched controls. (41. 41) In the hypothyroid state, matnx synthesis and rninerdization are

influenced and cellular function is decreased. (41) This rnay suggest that since the bone

physiology is disrupted, nomai healing around endosseous implants may be affected, thus

comprornising osseointegration.

Bone Minerai Densitv Chances in the Hv~othvroid State

There are various studies investigating the changes in BMD in hypothyroid patients. In some of

these, it is apparent that the patients were over-replaced with the therapy and so their TSH levels

were suppressed. These will be discussed in the section under TSH suppression. Some articles

however present analyses of patients that were maintained on replacement therapy only.

Ribot (99) evduated the femord and vertebral Bone Mineral Density (BMD) in a group of

hypothyroid patients, The results showed that replacement therapy with L-thyroxine is associated

with a statistically significant decrease in BMD in both the vertebrae and femora during the first

year of treatrnent. This loss was not related to menopause or age. When patients exhibiting the

largest bone loss were excluded, the results still rernained si,onificant, This is also consistent with

the results reported b y Krolner et al. (85)

Twenty-six prernenopausal fernale adults with a history of Hashimoto's thyroiditis and on

replacement therapy (as detemiined by normal TSH levels) had total body and regiond BMD

determined in a cross-sectional study. The wornen on long-term physiologc dose of

levothyroxine had normal total body BMD but lower BMD at different anatomical sites

including the femoral neck, femoral trochanter, Ward's triangle, the pelvis and both arms. These

were statistically si,gnificant when compared to the cont.rol group. No correlation was established

between the total or regional BMD and the duration or dosage of levothyroxine. (100)

Greenspan et al who exarnined 28 premenopausal and 38 postmenopausal women maintained

within a physiologie range of thyroxine therapy, over a penod of at least 5 years, also obtained

similar results. Both premenopausal and postrnenopausaf patients had decreased spinal and

hipbone density. Though statistically significant, the authors deemed that the changes were not

clinically relevant with respect to the long-term outcome of fracture morbidity- ( 10 1 )

In another cross sectional analysis of forty premenopausal females, the BMD at the femoral neck

and greater trochanter was related negatively to thyroxine dose. In the same group the urinary

cross-link excretion correlated positively with thyroxine dose, and negatively with duration of

treatrnent. A longitudinal study of these patients also sugested that annual changes in BMD

were inversely related to thyroxine dose at ail sites but achieved statistical significance only at

the femoral neck and Ward's area. (102) Campos-Pastor et al (88) reported that in twenty-four

femde subjects (9 postmenopausal and 15 premenopausal) on replacement doses of L-T.+, there

was a significant difference in the BMD values between the postrnenopausal patients and

controls in the lumbar spine and Ward triangle, In the sarne postrnenopausal subjects the femoral

site hrid a significant negative correlation between the total cumulative dose of L-T4 and BMD.

At a tissue level, there is evidence that hypophyseal sensitivity to the administration of L-

thyroxine may be different from that of other tissues. (103) A state of euthyroidism from the

hypophyseal viewpoint does not completely rule out the possibility of hyperthyroidism in other

tissues. (104, 105) Hypothyroid patients receiving customary replacement doses of L-thyroxine

may have abnorrnal systolic time intervals (105) and elevations in liver-derived plasma

glutathione-S-transferase concentrations (104) similar to those seen in hyperthyroid paaents.

Gow et at also demonstrated in hypothyroid subjects treated with L-thyroxine the iack of

agreement between the plasma TSH level and the increase in one or several biological indicators

of tissue hyperthyroidism. ( 106)

Ciondre et al evaluated biopsy specimens of undecalcified transiliac bone obtained from a group

of thirty-six hypothyroid patients at different stages of management of their disorder and

compared with normative data obtained from a historical cohort, Their results showed that

during the first month of treatment, trabecular and cortical hyper-resorption was present leading

to cortical porosity. At six months, a total bone volume Ioss of 36% of their trabecular bone

occurred and after more than six months, osteopenia was present both in trabecular and in

corncal bone. (107) Though these results indicate at a tissue level that bone resorption occurs,

one musc be careful as only five patients were followed longitudinally and no correlation to the

menopausal state of the female subjects was made.

Recently, quantitative ultrasonmetry (QUS) of bone has been introduced to predict changes in

bone. Both cross-sectional and prospective studies have shown that QUS is capable of predicting

hip and vertebral fracture as BMD determination and even provides additional information. 156

had non-toxic goiter or hypothyroidism and had been on non-suppressive LT4 therapy for at least

5 years. (108) These were matched with 5 1 I patients for age, weight, height. body mass index,

rnenopausal status and KRT use. Investigation with QUS indicated that women on long-term

replacement therapy were associated with a sIight reduction in QUS values. However correction

for menopausal status indicated that QUS values were more pronounced in postrnenopausal

patients. These results show that long-term replacement therapy led to accelerated bone loss,

although absolute values were not in the osteoporotic range-

Other sixdies were not able to corroborate the previously discussed results. that is the negative

impact of thyroxine replacement therapy on the bone mineral density at various anatomicai sites.

Franklyn et al. (93) reported in a cross sectional study that in 22 matched postrnenopausal

females treated for primary hypothyroidism there was no significant differences in the BMD at

nny site exarnined (femur, trochanter, Ward's triangle and lumbar spines). They concluded that

T4 therapy alone did not represent a siaonificant risk factor for loss of bone mineral density and

hence osteoporotic fracture.

There was no reduction in the bone density of L7 postmenopausal women in a short-terni

randornized trial. In this study, patients with subclinical hypothyroidism (normal serum free

thyroxine an elevated TSH) on replacement dosages for an average of 14 rnonths did not incur a

loss in BMD at the wrist and lumbar spine when compared to controls. (109) In a cross-sectional

study of 202 Caucasian women, the authors (90) concluded that the deleterious effect of thyroid

hormone therapy should be considered d o n g with other risk factors such as age. bone mass index

and previous history of the thyroid disorder (especially thyrotoxicosis). A dose response

reduction of the BMD at the radius indicated that a nsk existed only at suppressive leveIs of

thyroid hormone,

Campos-Pastor et al (88) as aforementioned reported the only significant difference in the BMD

values of postrnenopausal patients. In the case of the premenopausal women, no reduction of

BMD was found to be signïficant indicatimg that perhaps only postrnenopausal women may be at

risk of excessive loss of bone-

A sumrnary of the effect of replacement thyroxine-therapy on bone is presented in the following

table 3.

Table 3: Summary of Effect of Replacement Thvroxine Therapv on Bone

1 Study

Campos Pastor

Ribot et al

Kung et al

Garton et al L

Patients Characteristics Primary hypothyroiclism

Thyroid cancer. Goiter Previous hypothyroidism or hyperthyroidism

Goiter nodule

Autoimmune thyroiditis

Controh

Yes

Yes

No

Yes

Yes

Study Design Cross- Loris- Cross-

Cross-

Cross-

Cross-

Lon%-

Menopausal

Pre-

Post-

Post-

Pre-

Pre-

Re-

Patients (n) S Spine

Spine

Spine Ward's triangle Fernord neck Spine Ward's aiangle Fe moral neck Spine

Spine Total body Femoral neck Trochanter Ward's triangle

Spine Femoral neck Trochanter Ward's aiangle Spine Fe mord neck Trochanter Ward's triangle

Change

NS: Non significant; reduction.

Table 3 Cont: Summarv of Effect of Replacement Thvroxïne Therapv on Bone

Study 1 Patient (Reference) 1 Characteristics

Ross et a1 ( Hypothyroidisrn

Coindre et al (107)

Control 1 Study 1 Menopausal

Hypothyroidism correlated to

state.

Patients Site 1 Change

neck Trochanter NS Ward's N S trian& Hie I * S ine

NS: Non sipificant: reduction.

TSH Suppression Reiated Changes in the Bone Minerai Density

Thyroid stirnulating hormone (TSH) suppression results when there is excess thyroid homone

circulating in the body. It c m be achieved wjth exogenous administration of 1;-thyroxine to fully

suppress TSH. This is advocated for inhibition of progression or recurrence of thyroid cancer.

Partial TSH suppression by tiiyroid hormone treament, also known as exogenous subclinical

hyperthyroidisrn, has been advocated to inhibit the growth of benign thyroid nodules and goiters.

Partial TSH suppression can also result from endogenous causes sucb as a functioning nodule,

nodular goiter, early Graves' disease, or spontaneously resolving hyperthyroidism resulting from

subacute thyroiditis. In this case endogenous subclinical hyperthyroidism would be present and

is characterized by normal free thyroxine Ievels and triiodothyronine levels and partially

suppressed TSH levels. ( 1 10)

The introduction of sensitive serum TSH assays in the mid-1980s enabled a distinction to be

made between reduced TSH concentrations i n hyperthyroidism and normal values in a euthyroid

state. These tests also revealed that patients supposedly on L- thyroxine replacement therapy for

the management of hypothyroidism had reduced TSH leveIs and were being over-replaced. This

state of euthyroidism with reduced serum TSH concentration but normal T4 and T; values had

been designated as subclinical hyperthyroidisrn.

Although patients on thyroid therapy present as a spectrum, the literature pertaining to these

conditions may be very difficult to separate. As will be described patients with different

disorders have either been combined in studies or else some originally on replacement therapy

were found over-replaced thus leading t~ suppression of TSH and associated subclinical

hyperthyroidisrn. (1 11) Over-treatment with thyroid hormone is common, in fact 59% of 1180

Scottish patients receiving T4 replacement therapy had their TSH suppressed. (1 12)

There are numerous papers in the literature discussing bone changes following TSH suppression.

In a short longitudinal study, Stail et al. (1 13) reported on the rates of bone mineral loss in a

group of 18 postmenopausal women with primary hypothyroidism. Of these, 10 were over

treated with thyroxine and had their TSH suppressed. The sites measured were the spine, radius

and fernoral neck. It was concluded that compared to healthy controls, these posmienopausal

women had statistically si,onificant accelerated bone loss from the spine. A sirnilar trend, though

not statistically si,onificant was measured at the other two sites. The chronic use of thyroxine

indicated that the adverse effect of excess thyroxine on bone loss is not transient and the dosage

of the thyroxine did not predict the rate of bone loss.

In another cross sectional study (1 14). a homogenous group of fifty-four postrnenopausal women

on long-term thyroxine treatment for primary hypothyroidism were examined. A11 had their TSH

suppressed, indicating that they were over-replaced Like in the previous study. The mean BMD at

the radius of treated patients were ~i~gi f icant ly lower than those of the controls, with a reductioa

of 9.6%. The authors also showed a Linear decrease in the mean BMD with increasing number of

pars of treatrnent. In fact a reduction in radial BMD of 4-396 and 11.3% afier 5 and 10 years of

treatrnent respectively was noted. Unlike the previous study by Stall, ail these patients had a

higher level of markers for bone turnover. Markers of bone formation (osteocalcin and alkaline

phosphatase) and of bone resorption ( u r i n q hydroxyprolinelcreatinine and calcium/creatinine)

were significantly higher in the treated patients- This paper is important since the group was

homogeneous with a negative history of hyperthyroidism and so the changes in BMD are

attributable to thyroxine therapy alone. In another cross-sectional study of 120 postrnenopausal

women, the BMD at the distal and rnidshafi radius, hip and lumbar spine was less than in

controls. This effect was dose related with a suppressive dose of 1.6mgkg of body weight or

greater yielding a significantly lower BMD. Estrogen use in this group appeared to protect

against thyroid associated bone loss. (1 15)

Moreover, Pines et a l (1 1 6 ) found that the effects of HRT on BMD in women with sub-clinical

hypothyroidism treated with L-thyroxine were reduced thus preventing the beneficial effects of

HRT. The postmenopausal women were divided into three groups, one g o u p on HRT only, the

other on HRT and L-T4 therapy and the last group not receiving any medications and matched to

a euthyroid control on HRT. Al1 patients were followed longitudinally for three years. Lumbar

measurements were taken at the start and termination of the study. Compared to baseline

measurements, euthyroid and hypothyroid patients on HRT only, had an increase in BMD after

three years. As for the other groups, both hypothyroid patients on no medications and those on L-

T4 and HRT had a reduced BMD, especially for the latter group. This study suggests two things,

that patients with subclinical hypothyroidism continue to loss BMD if untreated and also that L-

Thyroxine seems to inhibit the beneficial effect of the HRT on BMD.

Kung et al (1 17) studied 34 postmenopausal women with a history of thyroid carcinoma on life-

long thyroxine suppressive therapy- This cross sectionai study showed that the total body mineral

content was lower in the treated group in both cortical and trabecular regions as evidenced by

lower BMD in the lumbar spine and the hip region. Also, increased osteoblast activity was

reflected by elevation of alkaline phosphatase and osteocalcin level, whereas increased bone

resorption was evidenced by increased urinary hydroxyproline.

There are studies that focus on the bone metabolism in premenopausal women on TSH

suppression. Paul et al. (1 18) found that in thirty-one matched premenopausal patients. the BMD

at the fernoral neck and at the femoral trochanter was 12.8% and 10.1% lower respectively. No

significant reduction was observed at the lumbar spine. The women had been receiving L-

thyroxine suppressive therapy for a variety of thyroid disorders for an averase of 9.6 years (5-

23years). The greatest reduction in the bone rnineral density was observed in women 35 years

and older, suggesting that they rnight be at a greater nsk for bone loss whenon

supraph ysiological doses of L-thyroxine.

Fourteen premenopausal women who had undergone thyroidectomy for thyroid carcinoma but

were otherwise healthy, were investigated over a penod of one to three years. Compared to

controls, these patients had a linear decrease (2.6% annually) in BMD in the vertebrd spinal

bone- However no statistical ciifference was found in the radial bone, suggesting that the lumbar

spine may more sensitive to changes induced by the thyroxine suppressive therapy. (1 19)

In another longitudinal assessment of bone densitometry, the same results were obtained, with

the exception of the radius site, The study had 24 patients on aggressive suppressive treatment

for thyroid cancer and 44 patients on conservative suppressive therapy for benign thyroid

disease. Compared with the control group, the thyroid cancer goup had significantly decreased

bone density at the midradius and the other group on conservative suppression had reduced bone

density in the Iurnbar spine- Moreover, the rate of bone Ioss at al1 sites (rnidradius, distal radius,

femoral neck and lumbar spine) was greater in the suppression group than in the control group.

The rates of bone loss in the cancer goup was also greater in al1 sites than in the control and

were greater than those of the suppression group in the radius and femoral neck (sites consisting

of 50 to 95% cortical bone) but not for the lumbar spine which is predominantly trabecular bone.

(120)

In a heterogeneous group of 28 premenopausal women on suppressive therapy for a variety of

thyroid disorders (Hashimoto's thyroiditis, multinodular goiter, solitary thyroid nodules, thyroid

cancer and ectopic thyroid tissue), a 9% .reduction in the cortical BMD was rneasured at the

proximai and distal radius, in patients who had taken the medication for at least 10 years. This

cross sectional study also established that this reduction in the BMD in the non-dominant radius

was related to the duration of the suppressive therapy rather than the dosage used. ( 12.1 )

A 20% deficit was reported in f o r e m bone minera1 content (BMCA3W) in postmenopausal

women with euthyroid goiter under chronic suppressive treatment with modest doses of thyroid

hormone- A lesser but still signifiant 5% reduction in the premenopausal patients was observed

when cornpared to controls. (122) This study had 87% of the patients treated with Tj, and it

demonstrated a more substantial reduction in bone mass reduction in the distd radius than that

seen in patients treated with L-T4 and raises the question as to whether T; has a more detrimental

effect on bone mass than T4.

Mudde et al ( 123) investigated wornen with a history of spontaneous subclinical hyperthyroidism

due to multinodular goiter. They rneasured BMD in the forearm and conchded that women with

untreated multinodular goiter and signs of subclinical hyperthyroidism had reduced bone density.

They also suggest that the degree of reduction in bone mass seems to be correlated with duration

rather than severity of thyroid hormone excess. However this study did not present any results

that show the impact, if any, of the menopausal state on the measurements. Another study by

Foldes et d (56) also investigated patients with endogenous subclinical hyperthyroidism. In this

cross sectional study measurements of BMD were performed in premenopausal and

postmenopausal women categorized as follows: patients with a history of non-toxic nodular

goiter, another with subclinicai hyperthyroidism and a final group with toxic autonomous thyroid

nodule (that is overtly hyperthyroid). Cornpared to hedthy controls, the toxic nodular goiter

group had lower BMD at the lumbar spines. This was more evident in the postmenopausal group,

though the premenopausd group d s o reached statistical sig-nificance. The BMD was lower only

in the femoral neck and radius in postmenopausal subclinical hyperthyroid group compared with

the control. Thus these two articles indicate that active subclinical hyperthyroidism is associated

with changes in the BMD and also suggested that this may be time dependent (L23).

Lehmke et al studied (124) patients with subclinical hyperthyroidism due to suppressive doses of

thyroxine, These fifty patients with a history of thyroid cancer had their BMD measured at

different appendicular sites of the skeleton, the radius, calcaneus, and the lumbar spine. Group

analysis, that included nine men, resulted in a sigificant decrease in the BMD at the calcaneus, a

site that is predominantly trabecular (80%). Moreover in post-menopausal women a decrease of

13% in BMD was measured whilst no statistically significant reduction was found in the

premenopausal women. At the mid shaft of the forearm, a predominantiy cortical measurernent

site, the average BMD value was significantly lower in the post-rnenopausal women but not in

premenopausal wonien. This study had a moderate correlation between the duration of TSH-

suppressive treatment and BMD in the calcaneus and also suggests that subclinical

hyperthyroidism affects BMD in certain parts of the skeleton since a nonuniform response of

axial and appendicular sites were reported.

The effect of TSH suppression on BMD was investigated in 18 pre and 9 postmenopausal

women with dual-energy X-ray absorptiometry. (125) When matched to their controls (54 age-

matched), postmenopausal women had reduced BMD at the vertebral and fernord sites with the

exception of Ward's triangle. No significant reduction was registered for the premenopausal

women.

In another longitudinal spread (126) over a two-year penod sixty-four postmenopausal women

were exarnined to determine the relationship between bone turnover and TSH levels and to see

whether adjustment of T4 dosage to correct TSH suppression altered the BMD measured by dual-

energy X-ray absorptiometry, The women were divided in three groups, the first with nomai

TSH levels, the second with suppressed TSH levels and the third on TSH suppression therapy for

thyroid cancer management and matched with thirty-six controls. Over a two-year penod there

was no corretation in BMD and bone turnover in ail groups. Correction of TSH suppression in

the second goup oniy. resulted in less bone turnover and improvement in BMD in this group

su~gesting indirectly that TSH suppression may result in Iower BMD levels.

Forty white fernales (19 premenopausal and 31 postmenopausal) started on L-T4 suppression

therapy were studied longitudinally over a one-year penod. (127) Compared to their matched

controls, the premenopausai wornen had reduced BMD only at the femoral neck as measured by

dual-energy X-ray absorptiometry. On the other hand, postrnenopausal women showed a

significant decrease at all sites measured both femoral and lumbar sites. Markers for bone

turnover were elevated only at the three-month follow-up in both groups. Based on the sites

measured, this study suggests that TSH suppressive therapy with L-TA increases the bone mineral

turnover and may contribute to a BMD reduction, Moreover, this BMD reduction may be more

marked in cortical bone.

Other studies in the literature disagree with these previously discussed articles. Grant et al

reported in a cross sectionai study (128) of 78 postmenopausal female patients with primary

hypothyroidisrn and on thyroxine replacement and in several of them with their TSH suppressed.

They found no significant reduction in the BMD at the proximal and distal f o r e m when

compared to the controls. However in their sub-group analysis a decrease in the BMD, of at rnost

5%, was present in the suppressed patients. Unfortunately, this study failed to study other

standard sites such as the spine or femur and as such their conclusion is iimited.

Another cross-sectional study reported on a group of 23 patients with non-toxic goiter and

another 27 with a history of well-differentiated thyroid carcinoma. (129) Menopausal status was

mixed and measurements were taken at the lumbar spine, femoral neck, tmnk and the

extremities. As a whoIe group, there was no difference in the BMD when compared to the

controls. However, the cancer patients had on average, lower bone mass than their controls of 2-

5% of a l l bone sites, though this reached significance at the extrernities only- Moreover, when

the cancer patients were compared to the goiter patients, with bone mass adjusted for age and

height, a si,gnificant reduction of 12% was observed in the calcium body index as weil as 7%

reduction in the BMD of the extremities, which is predominantly cortical though the authors

state that the reduction in the BMD is not relevant with respect to risk for fracture.

Franklyn et al (130) in a study of cancer patients found no skgnificant bone loss in the lumbar

spine or femoral neck- In this cross-sectiond study, 49 patients with well-differentiated cancer

on long-term suppressive thyroxine treatment were matched with controls obtained from a single

practice. This might have led to selection bias. Marcocci et al. obtained the same results in a

cross-sectional study of a heterogeneous group of 47 females with a history non-toxic goiter or

afier thyroidectorny, differentiated cancer and non-toxic goiter. ( 13 1 ) The dumtion of

suppressive treatrnent was on average a decade and no si,anificant difference were found in BMD

at any site of measurement (total body and regional analysis of the femur and lumbar spines).

A homogenous group of twenty-five thyroidectomized patients with a history of thyroid cancer

and on iong-tem suppressive doses of thyroxine were investigated. (132) This cross sectional

study found no difference in bone density at the spine for the whole group when compared to the

controls. However, postmenopausal patients showed a significant lower BMD and a higher level

of bone alkaline phosphatase than premenopausal patients. Moreover. as a group,

thyroidectomized patients had a si,onificantly higher level of aLkaline phosphatase and urine

hydroxyproline than the controls indicating an increased bone turnover in patients treated with

TSH-suppressive doses of thyroxine. The pronounced decrement in spine BMD in the post-

menopausal subgroup dong with a greater increase in markers of bone remodeling supports the

hypothesis that postmenopausd changes in bone turnover can be enhanced by thyroxine

treatment. One could speculate that the menopausal state could consequently lead to an

imbalance in the bone resorption and remodeling leading to an increased trend of bone loss in

these sensitized patients.

rable 4: Sumrnarv of effect of Suppressive Thvrorrine Therapv on Bone

Menopausai Status

Study (Reference)

Patients Site I Change In BMD

Patient Characteristics

Controi

Long- ~ ~ Cross-

Cross-

Hashimoto's hypothyroidism Graves disease

Post- Yes Femoral neck Spine

Radius +--- ( L 14) Schneider Precious hypo- et al ( 1 15)

Post-

Post-

Long- Pines et al ( 116) Kung et al

Post- 1

34 Spine Femoral nec k Trochanter Ward's triangle Arms

Subclinical hypothyroidism Thyroid cancer ' Cross-

Yes

Yss Post-

Paul et al (1 18)

Cross- Previous hypo- or hyperthyroidism Thyroid cancer,

Post- Yes Spine Femoral neck Trochanter

Forearm Spine Forearm Spine Femoral neck

Pioli et al Long- Pre- Goiter Goiter

( 1 19) 1 Thyroid cancer 1 Yes

Long-

Cross-

Cross-

Cross-

McDermott et a1 (120)

Pre-/ Post-

Hashimoto's hypoth_vroidism. Goiter, nodules, Thyroid cancer Goiter

Goiter. noduIes Thyroid cancer

Ross et al (121)

Yes

Pre- F o r e m

Taelman et al ( 1 22) PvIudde et aI (123)

Pre-/ Post- Pre-/ Post-

Goiter Yes

Table 4 Cont: Summarv of effect of Suppressive Thvroxine Therapv on Bone

Study (Reference) Foldes et a1 ( S 6 )

Lehmke et ai ( 134)

Ongphiph adhanahl et al (15 )

Guo et al i 126)

De Rosa et a1 (127)

Grant et ai (138)

Patient Characteristics Subclinical hypothyroidism

Th yroid cancer

cancer

Goiter

Hypothyroidism

Control

Yes

-

Yes

Yes

-

Yes

Y es

Yes

stÜdY

Cross-

Cross-

Cross-

Long-

Long-

Cross-

Meno pausai Status Pre-/

Post-

Pre4

Post-

fie-/

Post-

Post-

Pre-

Post-

Post-

Patients (N) 13

24

25

16

1 S

9

64

19

2 1

Site

Spine Femo ml neck Fo re'm Spine Femoral neck F o r e m

Forearm Calcaneus Spine Forearrn Calcaneus Spine

Spine FernoraI neck Trochanter Ward's triangle Spine Femoral neck Troc hanter Ward' s trian@e Spine Femoral neck Femoral neck Spine ïrochanter Ward's triangle Femoral neck Spine Trochanter Ward's triangle Forearm

Change In BMD NS NS

NS .L L

.L NS NS NS L .L L NS NS

NS NS

L L

L L

NS NS

L NS NS NS L L L L

NS: Non significant; reduction.

Table 4 Cont: Summarv of effect of Suppressive Thvroxine-therapv on Bone

Study 1 Patient 1 Control

cancer 1 Goiter

(Reference) Muller et

Marcocci Thyroid

Goiter Giannini Thyroid et ai (132) cancer

Characteristics Thyroid

Franklyn et al (130)

Study 1 Menopausal ( Patients 1 Site 1 Change

Yes

Thyroid cancer

Design Cross-

Cross- Post- Femoral neck

Trochanter NS W d s trianole

Cross- Pre-

Cross- Total Body NS

Pre- 11 Spine NS I - 1 Post- 1 13 1

NS: Non significant: -.. reduction.

Fracture Risk in Patients with Thvroid Disorders

There are studies indicating that a history of previous hyperthyroidism or active hyperthyroidism

leads to increased nsk of fracture. A case control study on 116 postmenopausal women

concluded that the odds ratio for presence of hyperthyroidisrn in hip fracture patients is 7.5.

suggesting an increased risk for hip fracture in this group. No increased nsk for hip b c t u r e

could be detected in patients who used thyroid hormone supplements. (133) In a study of

Osteoporotic Fractures ( 134) ( 1 35), postmenopausal women with a history of hyperthyroidism

had an increased risk of subsequent hip fracture- After adjustments for age and weight, women

with a past history of hyperthyroidism who were not taking thyroid hormone had an increased

relative risk of hip fracture (R.R= 3.4; C.1 1.5-4.1 ).

Thyroid hormone use in patients without a history of hyperthyroidism was also associated with

an increased risk (R.R 1.9; C.1 1.2-3-l), even after adjustments for age, weight and hip BMD.

(135) However in the latter paper by the same group, afier adjustment for previous

hyperthyroidism, the increased risk of fracture was no longer statistically significant for thyroid

hormone use. ( 134) In another retrospective interview-based study, posaenopausal patients with

a history of thyroid disease had no increase in fracture rate. However, there was a tendency for

women with a history of hyperthyroidisrn to experience fracture earlier in life. (136) It can be

argued that the this lower number of fractures may be due to the design of the study, since 15-

20% of patients die within the first year of a hip fracture. This may have Ied to selection bias

resulting in under-reporting of a correlation between thyroid disorder and fractures. ( 136) A case

report published in 1979 (137), indicated that a female patient who had sustained a mmdibular

fracture had delayed healing and non-union of the fracture. This may have been caused by

inadequate immobilization and an active state of hypothyroidism. Upon correction of the

hypothyroid state with thyroid supplement, a bony union and remodeling ensued without the

placement of intermaxillary fixation. Though this is only a case report, this indicates the

importance of thyroid hormone in the process of bone healing.

Taken al1 together. this evidence presented suggests that hyperthyroidism clearly adversely

affects bone and is associated with hip fracture. Snidies on replacement or suppressive therapy

suggest thar thyroid hormone therapy for suppression of TSH for thyroid cancer, goiter. or

nodules seems to have an adverse effect on the bone. It also seems to be greater in cortical than

trabecular bone. Thyroid replacement therapy resulting in nomal serum TSH levels seems to

have minimal or no effect on bone in the context of weakening of the skeleton. It seems that this

bone loss is multifactorial and other factors such as age and menopausal status may contribute to

the overall picture. Hypothetically. it is possible that thyroxine therapy may sensitize the

skeleton. Moreover, the bone changes may be site specific. Why some authors reported

conflicting results is hard to explain. Besides the aforementioned differences, there are other

dissirnilarities such as the method used to measure bone density. dosage of thyroxine and type of

patient investigated and the previous medical history. AU these factors make it hard for one to

combine and compare the results. Even though longitudinal studies were presented, no definite

conclusion can be reached. As stated by most authors. a well-controlled randomized study is

required to solve these questions. This literature was generated to answer the concerns that

patients on thyroxine therapy are at a nsk of reduction of bone rnass and potentiaily at risk of

fracture. None of the authors have looked at the jawbones and so one has to be careful when

extrapolating their conclusions to Our area of interest. The individuality of the jawbones when

compared to the rest of the skeleton c m be gleaned from the osteoporosis iiterature. Various

authors have investigated the role of osteoporosis on residual ridge resorption and have

suggested that a positive correlation exists between residual ridge resorption (138) ( 139) andor

jawbone mass ( 140, 14 1 ) and skeletal bone mass. On the other hand, some authors have failed to

show any correIation between the jawbones and skeletal bone changes. (142-144) Evidence also

exists that the jawbones behave differently with time due to their different content of cortical and

trabecular bone. ( 145-147) This further reinforces the argument that literature pertaining to other

skeletal sites should not be appiied to the jawbones and emphasizes the fact that the jawbones

should be investigated separately. It is obvious then, that the effect of th-yroxine therapy on the

jawbones should be exarnined so that we can better understand if thyroid hormone therapy has an

impact on osseointegration since changes reported in the BMD, even if rnaybe very low in the

context of the whole skeleton, may still be relevant in osseointegration.

Chapter 6

Statement of the Problem

A normal or optimal wound healing response is required for successful osseointegation of

implants placed in the jawbones. A history of hypothyroidism, and medications required for

management of the disorder, may be expected to alter the bone host site's heaiing response

potenhal and its bone density. It therefore seems appropriate and prudent to investigate if a

patient's history of hypothyroidism and medications taken for its control impact on

osseointegation. This concem included implant outcornes both pre- and post- loading, together

with other factors such as gender. age, menopausal status, implant lenad and diameter, site of

fixture placement, design of the prosthesis and occlusal considerations. The question 1 wish to

investigate in this study is the following:

Do implants in parients rvho have been dingnosed ivitlz hypothyroidism and are i-eceiving

r-eplncernerzt tlzerapy have rvoi-se or trcornes as defin ed by srr rvival/ Zoss of implants and iricreased

mat-ginal boize loss nrorrizd inzplants rharz patients ivho are not beerz hypothyroid nizd have iiot

received thyi-oid replacement therapy?

O biectives of the studv:

1. To determine retrospectively the survival of Brhemark dental implants plsced in the

jawbones in patients with a history of hypothyroidism, and treatment with thyroxine

replacement therapy alone or in combination with other medical and behavioral factors.

2- To determine retrospectively if marginal bone toss around B&nemark dental implants

placed in the jawbones is associated with a history of h_vpothyroidisrn, and

hypothyroidisrn and thyroxine replacement therapy alone or in combination with other

medical and behavioral factors.

3. To determine retrospectively if implant failure in the patients resulted in a change of the

proposed prosthodontic treatment plan.

Hvpotheses :

1. A history of hypothyroidism and treatment with thyroxine replacement therapy reduces

the survival of Brhemark endosseous dental implants.

2. A history of hypothyroidisrn and treatment with thyroxine replacement therapy increases

the marginal bone loss around osseointegrated endosseous Brhemark dental implants.

3. Loss of implants will result in adverse changes in prosthodontic treatment plans.

Materials and Methods

Materials

Al1 the charts of the patient population treated at the Implant Prosthodontic Unit (PU) at the

University of Toronto were reviewed. These patients had been treated with Brhemark dental

implants and al1 of them fonn part of an ongoing prospective study which was initiated in the

late nineteen seventies. Once treated, patients' information is stored in a central database and

updated regularly according to the frequency of recall visits. In total, 464 consecutive patients

treated up to June 2000 were surveyed, and patients with reported histories of thyroid disease

were selected. The latter goup consisted of 27 patients.

Patients were treated at the P U if they showed a history of maladaptive prosthetic experience, or

due to their desire to avoid conventional removable prosthetic solutions, Patients were excluded

if (i) they had a brittle medical condition or a condition that prechxded minor oral surgery, (ii) if

their expectations were unredistic with respect to outcorne, (iii) if they suffered from a serious

psychiatrie disorders, (iv) if they had a history of substance abuse or (v) if the quantity of the

r e m a i ~ n g bone was unable to accommodate an implant measuring 7mrn in length and 3.75m.m

in width. Tables 5, 6.7 show the inclusion and exclusion cnteria for treatment of partially and

complete edentulous patients and also single tooth implant supported restorations.

Table 5: Inclusion and exc:usion criteria for patients to be treated with complete implant

INCLUSION CRITERIA 1. Self reported and demonstrated

prosthodontic rndadaptive experience

EXCLUSION CRITERIA 1. hability to undergo a rninor oral surgical procedure

2, Systemicdly hedthy enough to undergo a rninor oral surgery procedure

2. History of substance abuse

3. Proposed sites of edentulous jawbones that couId accommodate at least a lOrnm Brhemark implant

3. Unredistic patient expectations of the treatment with respect to esthetics

4 Redistic esthetic expectations of the patient

4. Insufficient bone quantity or comprornised hedth of the proposed surgicd edentulous site

5. Gave informed consent 5. Psychoses

Table 6: Inclusion and exclusion criteria for patients to be treated with fixed partial implant supported prostheses (Sl

INCLUSION CRITERIA

edentulous space but less than ail teeth per arc h)

3. The adjacent teeth are structurally sound and esthetically acceptable to the patient

3. Restored adjacent teeth preclude fixed partial dentures

denture

- - - -

5. Maladaptive experience or refusai to wear a removable prosthesis

6. Adequate or modifiable bone dimensions for Brkemark fixture placement

7. Absence of vital anatomic structures in close proxirnity to the proposed implant sites

8. Adequate interarch space for implant surgical placement

9. Adequate interarch space for abutments. prosthetic components and prosthesis

10. Adequate control of occlusal load distribution to implants and teeth

- -

1 1. Realistic esthetic expectations

EXCLUSION CRITERIA

1 - Inability to undergo a minor oral surgical procedure

2.A h i s t o ~ of substance abuse

4, Unredistic patient expectations of the treatment with respect to esthetics

5. hsufficient bone quality or compromised health of the proposed surgical edentulous site

6. Insufficient bone dimensions for Brhernark implant placement

7. Incornplete facial growth and eruption of adjacent teeth

8. Inability to provide written consent to treatment

Table 7: Inclusion and exclusion criteria for patients to be treated with single tooth implant supported prostheses (10)

1 INCLUSION CRITERIA

1- Single tooth space

Adjacent teeth: intact, restored with

restorations, restored prostheses precluding the addition of the missing tooth

3. Patient reluctant of preparation of adjacent teeth

4. Demonstrated maladaprive experience. or psychoIogicd reluctance to W e a r a removable partial denture

close proximity to a proposed implant site

EXCLUSION CRITERIA

1. inability to undergo a rninor surgicd procedure

2.A history of substance abuse

3. Psychoses

4. Unredistic patient expectations of the treatment with respect to esthetics

5. insufficient bone qudity or compromised hedth of the proposed surgical edentulous site

6. hsufficient bone dimensions for Brânemark implant placement

7. Incornplete facial growth and eruption of adjacent teeth

8. hadequate mouth opening to accomrnodate the minimum 4cm of hardware dimensions necessary for implant placement

9. Insufficient vertical interarch space to accommodate the prosthodontic components available, together with a pontic and occasional gingival analogue

Patient management at the IPU follows a set protocol. The patient is first screened by a

prosthodontist. The medicai history is reviewed with the patient and the presenting prosthodo ntic

complaint is investigated, The patient is then presented with different options and an informed

decision is obtained. If the implant option is chosen, another appointment with an oral surgeon is

organized. During both consultations, the patient is presented with treatment options; the nature

of the surgical intervention is discussed, including possible risks and complications that rnay

arise.

Al1 patients are treated sur@cally ad modum Branemark, that is two stage surgery. (2) with the

duration of the healing phase varying with the location of the implant. The number of Branemark

fixtures placed depends on the jaw morphology and health plus the proposed prosthodontic

treatment. For a fixed tissue integrated prosthesis in an edentulous patient, 5 and 6 implânts are

placed in the mandible and maxiila respectively. In partially edentulous patients 2 to 3 implants

are placed depending on the dimensions of the available site, Surgery is usually performed under

local anesthesia and oral sedation, though some patients opt for general anesthetic. The

performing surgeon graded the bone quantity and quaiity at the tirne of the surgery according to

the Lekholm and Zarb classification. (14)

After placement of the implants, four to six months are allowed for healing. In the case of site

a~~g-nentation, more implants are placed and the healing penod is extended up to nine months.

Durin% this healins period. the patient is asked not to Wear the interim prosthesis for the first two

weeks and after the interim prosthesis is relined regularly with a soft reline to rninimize any

loading of the healing bone and soft tissues.

At stage II surgery the fixture is exposed to the oral environment and a transepithelia1 abutment

is attached to it. The prosthadontic treatment is c d e d out by prosthodontic staff and graduate

residents under staff supervision. Success or failure of osseointegation is evaluated initially

during stage II surgery and then is monitored clinically and radiogaphically on an annual basis

when the prosthesis is removed. Foilowing completion of the prosthodontic phase, follow-up

visits are scheduled on an mnual basis, although a number of patients do not reguhrly attend the

annual recalls. These recall visits consist of an updating of the medical history plus a clinical

examination, and where possible the prosthesis is removed and standardized periapical films are

taken. The individual implant is then exaniined for pain and mobility. The health of the pen-

implant tissues is also assessed.

The proposed criteria are those first proposed in 1986 and subsequently reiterated at the Toronto

consensus conference in 1998. ( 148)

1. Implant therapy is presclibed to resolve prosthodontic problems by permitting diverse

prosthodontic treatrnents, which may in turn impact upon the economics of the service. Such

prostheses should meet the clinically evolved standards of function, cornfort and esthetics.

They should also aiiow far routine maintenance and should permit planned or unplanned

revision of the existing design. Treatment outcornes success criteria for implant- supported

prostheses should also be assessed in the context of time-dependent considerations for any

required retreatment.

II. Criteria for implant success apply to individual endosseous implants, and

a- At the time of testing, the implants have been under functiond loadin,o.

b. AI1 implants under investigation must be accounted for-

c. Since a gold standard for mobility assessment is currently unavailable, the method

employed must be specifically described in operative terms.

d. Radiographs to measure bone loss should be standard periapical films with specified

reference points and angulation.

The success criteria comprise the following deterrninants:

1. The resultant implant support does not preclude the placement of a planned functional

and esthetic prosthesis that is satisfactory to both patient and dentist.

3. There is no pain, discornfort, altered sensation, or infection attributable to the implants.

3. Individual unattached implants are immobile when tested clinically.

4. The mean vertical boqe loss is less than 0.2mm annually following the first year of

function.

Methods

The study was conducted in the Implant Prosthodontic Unit at the Faculty of Dentistry,

University of Toronto. The design of the study is retrospective, specificaliy an Ex Post Facto

retrospective study. In this type of investigation, the outcome is already present (survival or loss

of implant and marginal bone loss around the fixtures) at the tirne of sampiing with the groups-

h-vpothyroid and control groups respectively identified from the patient pool at the Implant

Prosthodontic Unit,

Partially and fully edentulous patients who had oral implant therapy and who had or have a

history of hypothyroidism and are on replacement rnedications, prior to implant therapy, were

included as the study group. These patients developed hypothyroidism before having implant

therapy. These patients are already part of an ongoing data base collection from previously

initiated prospective studies in the Implant Prosthodontic Unit since the late seventies.

A control group was matched to the study population with respect to ase, gender, site of implant

placement, prosthesis design and bone characteristics (as deterrnined radiographically by the

surgeon at the time of stage 1 surgery). An attempt was also made to match the number of

implants, zone and presence or absence of other medical conditions and smoking habits.

The hierarchy of matching was as following:

1. Gender: this was rnatched for every single patient

2. Abe: this was matched as closely as possible so that the patients and control did not differ

in respect to their menopausal status.

4. Si,onificant medical history apart from thyroid: an attempt was made to approximate the

medical history. Though medical conditions will only be presented under the umbrella of

"other medical condition", where possible controls with the sarne condition were

selected.

5 . Number and location of the implant: the location of the fixtures was always matched. In

the majority of the patients the number were also matched. In a few patients with multiple

locations of implants, two controls were matched to approximate the number and

location. This was done because no single control was found matching the number and

Iocation of implants in the patient.

6. Prosthesis type: this was always matched in every control selected and

7. Smoking habits: Where possible the smoking habits, as reported in the dental chart. were

matched in the control selected.

Data. on the survivaVfailure and complications were compiled from the dental charts and at each

scheduled patient recall.

During this recall visit, a summer student at the Department of Prosthodontics reviewed each of

the groups' patients' medical history so that the main investigator was blinded to a patient's

presence or absence of a history of hypothyroidism. Al1 patients were asked about their medical

history, medications and smoking habits. If the patient was hypothyroid, the duration of the

condition and the medications taken was obtained. Permission was also asked to allow the

investigator to contact the patient's physician. The type of prosthesis and the dental status of the

opposing arch were noted. The number of years of partial or complete edentulism prior to

implant placement was confirmed.

The prosthesis was then removed and the condition of the soft tissue was assessed for s i g s of

inflammation, swelling and suppuration. Individual implants were evaluated for mobility by

applying a calibrated bucco-lingual force with the end of a rnirror handle. It was then percussed

apically to assess any pain or sensitivity. AU the abutment screws were torqued to a force of

20Ncm via a torque wrench to determine if the abutment screw was tight and also to assess if any

pain was elicited. Any mobility or painful response to the induced torquing and tapping was

designated as a failed implant.

Foilowing this examination. standardized radiographs were taken, utilizing a locating jig that

controlied for angulation and focus to film distance were taken at abutment placement. This was

done to establish bone heights and to confinn proper seating of the abutment. The distance

selected is 10 cm as measured fiom the edge of the periapical film to the border of the ring of the

Rinn holder that is placed to the cone of the X-ray machine, (33, 50.58, 149, 150)

Bone loss measurements as previously described by Co* l49), Chaytor (50), Wyatt (58), Avivi-

Arber (150) and Accursi (33), were carried out on the patients using their initial films as a

quantitative starting point, and comparing them to the current films made as integral part of the

recall maintenance protocol.

The standard periapicai films were scanned into an Apple Macintosh Quadra 800 computer

(Apple Canada Inc. 7495, Mârkharn Road, Markharn, OntarÏo L3R SG2 utilizing a Microtex

scanner (Microtek Scanmaker 35T, Microtek Lab Inc., 3715 Doolittle Dr., Redondo Beach, CA

90178). They were standardized as to the contrast, and scale using the public domain software

MH Image program 1.54 ( 151) (58) (33) The image created was at a resolution of 968 dpi, scale

of 100%, height and width of image were 15.05cm and 9.96cm respectively. The size of the

image created was 213KB per individual implant scanned. The image was then assigned a code

and saved.

The code for every image was as follows:

Chart number-year (image was taken)/montb/day-implant nurnber E (meaning enhanced image).

Measurements of the bone height were obtained. The height was measured front the shoulder of

the implant, adjacent to the abutment, to the crest of the lowesr plate of bone visible. This was

recorded for both the mesial and disrd of each implant. Ail measurements were repeated on two

separate occasions and a mean was calculated between the nvo measurements for each site. This

measurement was then utilized for statistical analysis of bone loss. If any measurement was more

than two standard deviations different fiom the mean, a third rneasurement was obtained and a

new measure was calculated and recorded- Al1 scanning procedures were carried out in a random

fashion with the investigator being blinded to the health status of the patient. Similady. al1

calculations with respect to bone loss were conducted in a blind fashion to prevent any bias in

the results obtained. Calibracion of the investigator was done by measuring 36 radiogaphs and

comparing to the results of a previous investigator in the department.

S tatistical Methods

Clinical data were collected with aid of a questionnaire and then input in an Excel worksheet and

transferred to an SPSS statisticd package for analysis. Variables were coded and two work

sheets were created one at the patient level and another at the implant level, the latter having a

dental implant as a unit of measure.

The independent variables were as foLlows:

1. Continuous variables: Age at stage 1 surgery in years, the years followed since insertion

of the prostheses, the number of implants per person, the years edentulous prior to implant

placement, duration of hypothyroidism prior to implant treatment. In the SPSS worksheets

utiLized in the muitivariate analysis some continuous variables were recoded into new

categorical variables. Specifically, the variables recoded and the new variables were:

Age at stage 1 was recoded into O= Lowest age to 45 years and 1= 46 years through the

highest.

Duration of hypothyroidism prior to implant placement into O=lowest to 10 years and l= 1 1

years through highest.

Duration of edentulism pnor to implant placement into O= lowest to 10 years and l= I I years

tht-ough highest,

Age at stage I surgery into O= lowest to 45 and l= 46 through highest.

2. Nominal variables: Group was as coded as O=control patients and l= hypothyroid group.

Menopausal status coded as 1= premenopausal and i=postmenopausal. The medical

conditions other than hypothyroidisrn were coded as O= no medical condition other than

hypothyroidism and l= other medical condition present. Medications other than

thyroxine replacement therapy were coded as O=no medications used and l=other

medications used. The smoking status was coded as l=active and former smokers and

?=non-smokers (never smoked). The jawbones where the implants were placed were

coded as l=maxiIIa and 2=mandible. The zones in the jawbones were coded as 1= zone 1

(interforaminal space) and 'l=posterior to the mental foramina. Bone quality was coded as

l= quality 1,3= quaiity 3,3= quality 3 and 4= quality 4 and bone quantity was coded as

1= quantity A, 2= quantity B, 3= quantity C, 4= quantity D and 5= quantity E. Implant

lenaa were coded in millimeters. The type of the implant-supported prostheses were

coded as 1= hI1y edentulous fixed, 3= fuUy edentulous-overdenture, 3- partially

edentulous-fixed, 4= single tooth, 5= partially edentulous-removable overdenture. The

state of the opposing dentition was coded as l= natural dentition, 3= removable partial

denture, 3= fixed partial denture, 4= complete denture, 5=complete fixed (natural or

tissue integrated prosthesis) and 6=unopposed. The implant site was coded according to

the designated tooth number. The sites where the bone rneasurements were calculated,

were coded as folIows: l= mesial site of measurement and 2= distal site of measurement.

The dependent variables of interest were as follows:

1. Continuous variables: Time to Failure measured in years and calculated by subtracting

the date when the implant was loaded fiom the date when the implant failed. If failure

never occurred during follow-up, then the observation was censored and time was equal

to the last follow-up examination minus the date the implant was loaded. The bone loss

for year 1 following loading was measured in millimeters. Slopes of bone loss measured

in millimeters between year L of loading and 4,10 years and overall post insertion of

prostheses. These slopes were calculated in an Excel worksheet and then transferred to

the SPSS package for analyses.

2. Nominal variables: Implant status coded as 1= loaded, 2= failure and 3= sleeper implant.

Soft tissues complications at post stage I and last visit recall were coded as 1= complications

present and 3= no complications present.

Bivariate analysis to explain the association between the independent variables and the outcornes

were carried out. The success/failure data were compared between the two study groups to

determine if hypothyroidism had an impact on survival rate of oral implants. The tests carried out

were Student's t-test for continuous variables and the Chi-square test for categorical data to test

for statisticd significance.

Multivariate analyses were performed to identiQ factors in combination with hypothyroidisrn

that affect the success/failure of Bribemark endosseous dental implants.

Specifically, multiple linear regression was used to test the joint effect of independent variables

on continuous dependent variables such as bone loss outcornes,

Multiple logistic regression was used to cdculate the adjusted odd ratios of independent

variables impacting on nominal dependent outcornes.

An intra-class correiation study was done prior to bone measurements to calibrate the main

investigator and also to assess- the degree-of agreement between the investigator and an other

experienced investigator in the Department of Prosthodontics.

Chapter 7

Results

The charts of the patient population treated at the Implant Prosthodontic Unit, University of

Toronto were reviewed. These patients have been treated tvith Brhemark dental implants and al1

form part of an ongoing prospective study, initiated in the late seventies.

In total, 464 consecutively treated patients up to June 2000 were surveyed and patients with

reported histories of hypothyroid disease were selected. The latter consisted of 27 patients.

Therefore the prevalence of hypothyroidism in the patient population was 5.8%. This is

comparable to the population at large. Dependin3 on the age cohort, hypoth_vroidism has a

prevalence of 3.4 to 3.4% in adults (98), or 6.75% as demonstrated in a study of 3575 patients-

(36)

The hypothyroid patients were matched to control patients, except with the case of two patients.

The latter were matched to two patients each because no control patient was found that had the

sarne number and distribution of dental implants as in their cases. Thus 56 patients were asked to

come for a recall visit. Al1 29 control patients and 21 hyp~th~yroid patients attended resulting in

an overall recall rate of 89.2%.

Six hypothyroid patients did not attend the recall visit for the following reasons: 4 had moved

away and could not be located, whilst two other patients were not interested in the recall visit.

The mean duration of hypothyroidism in the study group was 15.38 years with a Standard

deviation of 14.44 years. This is a large standard deviation because of a wide range from O years

to 48 years (O=hypothyroidism was diagnosed the year the dental implants were placed).

Analyses of Confounding Variables

Potential confounding variables that could bias the outcome measures of this study were

identified and matched as closely as possible between the study and control patients. Bivariate

analyses consisting of Student's t-test and Chi-square test were carried out at a si,anificance level

of p>0.05 to assess the level of matching.

The potential confoundinq variables are as follows:

Age at stage 1 surgery, the years edentulous pnor to implant placement, the years followed since

insertion of the prostheses, the nurnber of implants per person, menopausal status, medical

conditions other than hypothyroidism, medications other than thyroxine replacement therapy, the

smoking status, the type of the implant-supported prosthesis, bone quality and quantity, implant

len,oth, number of implants per zone, the jawbone where the implants were placed and the state

of the opposing dentition.

)S.

p-value 1 Table 8: Comparative analvses of characteristics between the Hvpothvroid and Control Grou

Student's t-test for analysis performed at a patient level.

Variables

Age at stage 1

Years edentulous pnor to imptant placement

Years followed since insertion

Number of implants per person 1 Controi 1 13 1 3.52 1 1-50 1 1

Group

S tudy Control

Study

Control

Smdy Control

Study

Std. Dev

10.40 10.66

3.69

9.97

6.07 5.05

2.05

Patients

11 23

11

13

3 1 33

2 1

Mean

59.19 56.17

11.64

13.83

7.90 8.57

3.90

Minimum Value

34 37

I

1

0.3 0.3

1

Masimum Value

7s 74

30

31

19.0 17.0

1 O

Table 9: Comparative analvses of various characteristics between Hvpothwoid and Control Groups.

Variable Menopausal status Premenopausal Postmenopausal

1 Medical condition other 1 than hyp~th~vroidism Present None Total

[ Medications other than 1 th yroid replacement therap y Present None Total Smoking Status Active and former smokers Non-smokers Totd Type of implant restoration. TIP-FPD ' Overdenture TIP-FPD' Single tooth Total State of the opposing

Shidy Group

dentition Natural or resrored teeth

Complete Denture

a=Chi-square test; b= Fisher's Exact test.

Control Group

l= fixed-tissue integrated prosthesis in an edentulous patient.

p-value

0.188 'b'

2= fixed-tissue intepteci prosthesis in a partiaiiy edentulous patient.

Table 9 Cont: Comparative analvses of various characteristics between Hvpothyroid and Control Groups.

Variable

Number of irnpIants per person 1 implant 2 irnpIants 3 implants 4 implants 5 implants 6 implants 10 implants

Study Group Control Group p-value

Number of implants per zone ' Zone 1 Zone 3

~awbone l

MaxiIla Mandible

Implant length ' 7.0mm 8.5mm 1O.Ornr-n 1 1 . 5 m 13 .Omm 15.0mm l8.Omrn 20.0mm

Bone qualityl Quality I

Quality 2 Quality 3 Quality 4

Bone quantityL Quantity A Quantity B Quantity C Quantity D Quantity E

test. 1= Bivariate level.

Figure 2: Follow-up Period of Patients since Stage 1 Surgerv.

Follow-up Period Of Hypothyroid Patients

21 1 1

OP reioad Xme 1 19 I Loaded Period 1 17 I

15

(d 13

C c 2 11 - Q a

9

7

5

3

I Follow-up Period of Control Patients I 23

m~re load Period 1 21

19

17

15

g '3 œ G Il Q 0,

9

7

5

3

1

O IO 1s 20 TimeNears 2s

1 I Follow-up period:Years since insertion o f prostheses (black line on graphs) not significant, p=0.690. Student's r-test.

As s h o w in Tables 8 and 9 there was no statistically significant difference between the

hypothyroid and control groups for age at stage 1 surgery, the years edentulous prior to implant

placement, the years followed since insertion of the prostheses, the number of implants per

person, menopausal status, medical conditions other than hypothyroidism, medications other

than thyroxine replacement therapy, the smoking status, implant len,gth, the jawbone. the type of

the implant-supported prosthesis and the state of the opposin,o dentition. Table 9 aiso shows that

the distribution of implants placed was statistically different in zone I and 3. More implants were

placed in zone 1 in the hypothyroid group whilst the control group received more implants in

zone 2- Overall, more implants were placed in zone 1 than in zone 2. Bone quality and quantity

as classified by Lekholm and Zarb (14) were also found to be statistically different between the

groups. More implants were placed in bone of qualities 1 and 3 in controls and in bone qudity 4

in hypothyroid patients. As regards to bone quantity, hypothyroid subjects received more

implants in bone quantity B, whilst the controls had more implants placed in bone quantities A,

D and E. Figure 2 shows the follow-up penod of the patients that was not significant (p=û.690).

Table 10 sumrnarizes the outcorne analyses at the implant level for absolute loss of implants and

the soft tissue outcorne, as subjectively assessed by the oral surgeon.

In total, 163 implants were placed, 82 in the hypothyroid group and 8 1 in the control group. Five

implants were Iost out of a total of 163. This is equivalent to a 3% failure, or a 97% success, rate.

This loss was not statistically si30nificant at a p-value of 1.00.

Out of the five dental implants lost, four were early failures, two in each group and another was a

late failure in the hypothyroid group. This was diagnosed at an annual recall visit, 5 years after

loading of the implant. Al1 lost implants were placed in zone 1, with 4 early failures in the

mandible and 1 late failure in the maxiIla.

Table 10: Outcome anahses at the Implant Level.

1 Variable 1 Hypothyroid Group ( Control 1 p-value

1 Lost implants 1 3 (3.7%) 1 2 (2.5%) I Implant success outcome. Loaded and sleepers 79 (96,396)

Soft tissue complications post-stage 1 surgery No complication Complication

1 1 I

a= Chi-square test; b= Fisher Exact test.

Soft tissue complications at rem11 No compiication Complication

Table 10 also shows the soft tissue response at post stage 1 surgery recall and at the last recall

visit in June 3-000. The oral surgeons reported in the visit following stage 1 surgery that more soft

tissue complications around dental implant sites were present in the hypothyroid group (21%)

when compared to the control group (8.6%). This was statistically sipificant at a p-value of

0.018. However, these complications were of a minor nature and easily rectified with proper

care. The soft tissue appearance at the last recall visit, in June 2000 was not statistically

~i~gnificantly different between the hypothyroid and control groups. The analysis presented in

Table 10 does not account for different follow-up times. To account for tirne of follow-up

survivai analysis was performed and presented in the following Table 1 1. Implants not used in

the prosthesis design (so-called sleepers) were deleted from the anaiysis and not included in the

Group

79 (97.5%)

64 (78.0%) 18 (33.0%)

1.00 'b'

78 (95- 1%) 4 (4.9%)

74 (9 1.4%) 7 (8.6%)

0.018 '"

79 (97.5%) 2 (2.5%)

0.683 '"

success or failure grououps. It was felt that their inclusion would have no ment in assessing if

hypothyroidism does have an impact on osseointegration.

Table Il: Kaplan Meier A v e r a ~ e Survival Time of Dental Imalants.

Variable 1 Mean 1 S.E. 1 Log Rank test ( Breslow Test

Thyroid Group ConuoI Group

1 l I Zone 1

Smoking Group 1 (active and former srnokers) Group 2 (non-smokers)

Zone 1 Zone 2**

18.3 16.6

I I 1

Jawbone 1 1 1

14.7 18.4

Maxïlla Mandi ble

0-4 0.3

Bone Quality Quality 1 ** QuaLity 1 QuaLity 3** Quaiïty 4

0.3 0.3

Bone Quantity Quantity A 14.4 Quantity B** - Quantity C 16.6 Quantity D 16.7 Quantity E 9.3

p-value

0.670

p - d u e

0-78 1

0.752 0,795

Yrs edentulous Group I (lowest to 10 yrs)** Group 2 ( 1 1 to the highest)

Menopausa1 status Premenopausal Postrneno pausa1

-- 16.2

12.6 1 S.5

- 0.4

0.4 0.3

0.078 O-os2

0.792 0.9 16

Table 11 Cont: Kaplan Meier Average Survival Time of Dental Implants,

Variable

Medical conditions Other medical conditions No other medical conditions

Medications Other medications No other medications

Type of Implant supported restoration, TIP-FPD (cdentulous) Overdenture TIP-FPD

State of the opposing dentition

Naturd or restores teeth RPD Complete Denture

S.E. Log Rank test p-value

Breslow Test p-value

censored.

As indicated in the survival tables, there are no statistically significant differences for the

variables accountin,a for the implant survivaUfailure. A life-table for the outcorne. which is

survivaYfailure of the dental implants. was c d e d for the main expianatory variable that is a

history of hypothyroidism and is also presented as a figure. (Table 12 & Figure 3)

As shown in the life-table there was no statistical difference in the survivai rate of the dental

implants between the hypothyroid and control goups with p= 0.78 1 1 (Table 12). The cumulative

success rate of dental implants was 97.52% for controls and 95.49% for the hypothyroid group

respective1 y (Figure 3).

Table 12: Life-tables for the Survival of Dental Implants in the Hvpothvroid and Control Croups.

ControI Patients

Interval start time/yrs

No. Implants No. Implants No- Implants Number of Cumulative entering this withdrawn rit exposed to failures Proportion interval the interval risk surviving at

End 81 1 80.5 2 0.9752 78 3 76 -5 O 0,9752 67 6 64 O 0,9752 49 O 49 O 0,9752 47 O 47 O 0.9752 40 6 37 O 0.9752 29 6 26 O 0,9752 11 9 16.5 O 0.9752 9 O 9 O 0.9752 9 9 4.5 O 0.9752

Hvpothvroid Patients

Lnterval start 1 No. implants No. implants No. implants Number of Cumulative - tirne/yrs 1 entering this withdrawn at exposed to failures Proportion

1 interval the interval risk surviving at

O End

82 I 81.5 2 0.9755 I 3 5 7 9 I l 13 15 17 19

79 14 72 O 0.9755 57 5 54.5 O 0-9755 52 9 47 -5 1 0.9549 40 2 39 O 0.9549 38 5 35.5 O 0.9549 28 4 26 O 0.9549 19 O 19 O 0.9549 19 9 14.5 O 0-9549 10 5 7.5 O 0.9549 5 5 2.5 O 0.9549

Wilcoxon test; p=0.78 1 1. Number of implants withdrawn is due to either being sleepers ( 1 in control and 1 in hypothyroid group) or not being followed for the Ume interval presented.

Figure 3: Cumulative Survivai Probabilities of Dental Implants in the Hvpothvroid and Control Groups

Survival Analysis of Dental Implants

r I - C o n t r o l Group

Hypothyroid gr ou^

, 1

5 10 15

Time in Years

20 Wilcoxon Test; p=0.7S 1

The following gaph presents the same cumulative '30 success with a different scale, focusing between the 94 to 98% proportions on the y-axis and startXng from year 1 post-loading.

Survival Analysis of Dental Implants

1 3 5 7 9 1 1 13 15 17 19

Time in Years

- C o n t r o l Group Hypothyroid Group

Wilcoxon Test; p=0-78 1

Table 13: Prosthodontic outcome at the Implant Level.

1 1 Absolute status of Im~lant 1 1 1 1 Loaded implants 1 Failed implant or 1 Total number of 1 1 1 '6sleeper" implants ( implants

Table 14: Prosthodontic outcome at the Patient Level.

Prosthodontic treatment main tained Prosthodontic treatment modified

Fisher's Exact Test, p= 1.000

15 1 (95.6%)

5 ( 100%)

Total nurnber of Patients

Absolute status of Implant per Subject

Prosthodontic treatment 1 maintained

Tables 13 and 14 present the Prosthodontic outcome in a l l the patients, irrespective of the study

group at the implant and patient-level, respectively. In these analyses, so-called "sleeper"

implants were grouped with the failed implants, since they were not included in the final

7 (3.4%)

----

Loaded implants

36 (83-7%)

Prosthodontic treatrnent modified

prosthesis design. As indicated in the tables, the failed implants did not impact in any way

prosthodontic outcome. In other words, the failed implants did not result in a change

proposed prosthodontic treatment both at the implant and at the patient level.

15s ( 100%)

5 (100%)

Failed implant or "sleeper" implants

on the

Fisher's Exact Test, p=1.000

1 (100%)

the

---- 1 (100%)

Validation of Marginal Bone Measuremenk

The intra- and inter-obsenrer reliability of the cornputer-assisted bone measurements around the

dental implant was assessed using the Intra-Class Correlation Coefficient. This coefficient is

based on the analysis of the quantitative data obtained fiom the mesial and distal marginal bone

level measurements. These measurements were made fkom the infenor d a c e of the implant

collar to the lowest observed level of bone contacting the dental implant. Measurements were

excluded fkom the analysis when the bone levels could not be identified assertively.

A total of 36 standardized periapical radiographs of dental implants were randomly selected. The

marginal bone levels on the mesial and distal surface were measured twice- The mean of these 72

sites measured were then compared to establish the calibration of the main investigator and also

the intra- and inter-observer variability between the principal investigator and ano ther

experienced investigator (B).

Table 15: Intra-observer agreement for the Mesial and Distal Marginal Bone Level Measurements.

1 Investigator 1 Intra-class Correlation Coefficient 1

Table 16: Inter-bserver agreement for the Mesial and Distal Marginal Bone Level Measurements.

Main hvestigator Investigator B

- - - -

Lntra-Class correlation Coefficient 1

Mesial 0.89 0-89

Distal 0.95 0.88

t

Mesial Distal

0.89 0.83

Table 15 shows the intra-class correlation coefficient for the mesial and distal sites of implant

measurements- The degree of intra-class correlation for both observers is "very good" since a

value more than 0.8 was obtained. Table 16 presents the intra-class correlation coefficient for

inter-observer agreement of peri-implant bone measurements between the two investisators for

both the mesial and distal sites of measurernents. This also shows that there is "very good'.

agreement between the investigators, indicating that the main investigator in this study was

properly calibrated with the previous investi, =ator.

Bone Measurement Results

The bone measurements for the mesial and distal sites were analyzed to see if there was a

statistical difference between the two sites. A Student's t-test showed no statistical difference

bettveen the sites at year one or for any of the slopes calculated, (Table 17) Thus, the mesial and

distal measurements were pooled together in a data sheet and used for the analysis of the bone

measurements. The final results for the bone measurements in hypothyroid and control patients

are presented in Table 18. Since the hypothyroid patients were matched to controls, a paired

Student's t-test was carried out to test for any significant difference in the change in bone levels

between the groups. There was a significant difference in the arnount of bone loss during the first

year of implant loading as indicated. There was more bone loss in the hypothyroid group, being

si+pificant at a p-value of 0.017- There was no statistical difference in the slopes measuring bone

loss between the first year of loading and year 4, year 10 and the overall years followed.

Table 17: Bone Loss /rnillimeters (Mean + S.E.) around Dental Implants for Mesial and Distal Sites.

YEAR OF

loading 1 Slope of bone loss from 1 0.087M.0 15 yearl to 4 N=(63 ) Slope of bone loss from 0,WH.O 10 year 1 co year 1 O i k ( 6 5 ) Overall slope of bone 0.038H.009 loss N=( 70)

- - -

Student's r-test: N= number of implants involved in the analysis.

Table 18: Bone Loss hnillirneters (Mean + S.E.) around Dental Implants for Hvpothvroid and Control Patients.

YEAR OF INVESTIGATION

HYPOTHYROID PATIENTS

Bone loss during ye& 1 loading SIope of bone loss from yearl to 4 Slope of bone loss from year 1 to year 10

CONTROL p-value PATIENTS

0.308M.082 N=(4 1 ) 0.I33kO.027 N=(47) 0.076M.014 N=(50)

Overall slope of b o n e loss - . - - y I

ysis. N= number of implants involved in the paired

0.05 1kû.O 15 N=(52)

analysis. Paired Student's r-test at an implant level of ana

Multivariate Analvses

The bivariate analyses for the outcomes indicated that sol? tissue complications post-stage 1 and

bone loss for year 1 were both statisticdly ~i~gpificant at p-values of 0.018 and 0.017.

respective1 y.

Multivariate analyses were carried out to test the joint effect of the variables on the soft tissue

complications and also on the year 1 bone loss. Multivariate analyses consisted of multiple linear

regression for bone loss in year one and logistic regression for the soft tissue complications.

Tablel9: Linear Regression Mode1 for Mean Bone Loss at Year 1

l=Active and former smoker ?=Non-smoker Medical condition other than Thyroid condition. O= No medical condition i = Medical condition

Variable Constant Group. O= Control 1 = Hypothyroidism Smoking

Medications taken other than for

Parameter Estimate (fi) 0.568

O. 187

hypothyroid. O= No medications 1= Medications taken Bone quality in site of implant placement? Bone quantity."' 1 -0.05 1

F=0.905; p=0.494; ~'=0.032;* As classified by Lekholm and

Table 19 presents the linear regression mode1 for bone loss in Year 1 loading. The factor most

strongly associated with bone loss in year 1 is the group variable, with hypothyroidism being

borderline at p= 0.052. AU other factors are not si,pificant. The mode1 R'= 0.031 indicating that

this model explains only 3.2% of the amount of variance in bone loss measured in year I of

loading. Another regession model to explain bone loss in year 1 of loading is presented in Table

70. This model does not include bone quality and quantity because the bivariate analyses showed

that though both independent variables were significant, the distributions of implants were highly

skewed.

Table 20: Linear Rearession Mode1 for Mean Bone Loss at Year 1

Variable Constant Group. O= Control l= Hypothyroidism Smoking l=Active and former srnoker ?=Non-smo ker Medical conditions other than Thyroid condition. O= No medical condition 1 = Medical condition Medications taken other than for hypothyroid. O= No medications 1= Medications taken.

Parameter Estimate (fi) 1 Standard Error 0.131 1 0.077

I

p-value 0.094

In this model, none of the independent variables x e siagpificant in explaining the bone loss in

year 1. The model's R' is 0.028.

Another linear regression model was constructed to try and explain which independent variables

may impact on the bone loss in year I for the hypothyroid group only. In this model both bone

quality and quantity are included since this analysis was only cmied out in the hypothyroid

patients. (See Table 2 1 )

Table 21: Linear Regression Mode1 for Mean Bone Loss at Year 1 in Hvpothvroid Patients

1 Variable 1 Parameter Estimate ($) 1 Standard Error ( p-value 1 Constant 1 -0,198 1 0.627 1 0,753

1 Duration of edentulism pnor to ] 1 1

Medications taken other than for hypothyroid. O= No medications l= Medications taken. Duration of hypothyroidism prior to Implant placement O= less than lOyears 1 = more than 10 years Bone QuaLity** Bone Quantitv**

implant placement O= less than lOyears

1 1= more than 10 years 1 F=2.82; p=0.026; ~'=0.220; **B one as classified b y Lekholm and Zarb.

0.593

0.3 19

O. 139 -0.07 1

This multiple regression model reveals that medications that were taken by the hypothyroid

patients, other than for the hypothyroidism, have an impact on bone loss measured in year 1 of

loading. This was si,anificant at p=û-025. Although not staastically significant at the 5% level,

duration of hypothyroidism prior to implant placement was perhaps clinically significant at

pS.087. The mode1 is si,~ficant at p=0.026 and ~ 3 . 2 2 . This means that the model explains

22% of the amount of variance in bone loss measured in year 1 of loading in the hypothyroid

patients only.

0.256

O. 183

O. 138 O. 10 1

-

0 - 0 3

0.057

0.33 1 0.484

Table 22: Final Logistic Reeression Mode1 for Soft Tissue CompIications Post-Stage 1 surgery.

1 Variable 1 Adiusted Odds Ratio 1 95% Confidence Interval 1 D-value

l= Active and former smokers

Group O= ControI 1-Hypothyroid Smoking status

1 Asze at Stage I 1 1.1 1 1-03-1-17 1 0.006 -3 Log Likelihood =122,65; Chi-square=25.13; df=3; pc0.00 1

5.83

The logistic regession model is presented in Table 33 and this shows the variables group,

smoking status and age as ail being si,onificant in explainkg soft tissue complication post stage 1

1 -85-18.39

surgery. Hypothyroid patients were 5.83 times likely as non-hypothyroid patients to develop soft

0.003

tissue complications post-stage 1 surgery. Non-smoking in this model is a risk factor. The reason

for this is that there were more non-smokers in both the hypothyroid and control group which

rnight have biased this analysis. In addition, the risk of developing soft tissue complications was

associated with 1.1 times increased odds per unit change in age. The model was highly

Chap ter 8

Discussion

Bone is a complex dynarnic tissue, which constantly remodels in response to both functional

needs and to injury. This remodeiing process is regulated locally and systematicdiy, and is

harnessed in the implant surgicd protocol so as to elicit an intimate contact between bone and

altoplastic material,

Recently, a new research concern regarding failed outcornes has surfaced in the field of dental

implants. What causes failure has become a compelIing concern. It appears that both local and

systernic factors play a role since bone is a dynamic reservoir that is influencced by changes

happening in the body. The body of evidence pertaining to the systeniic impact on

osseointegation is still in its initial phases because it is hard to organize well-designed studies

that reach meanin,oful results. Nonetheless, emerging evidence sheds sorne light om the impact of

various metabolic and behavioral factors on osseointegration.

The rationale of thk preliminary study was to investigate if hypothyroidism. a coondition known

to influence bone, could impact on osseointegration, which is basically a wound healing response

to a surgical intervention.

Al1 the patients studied in this study were females and results are only applicable t ~ o women, No

male hypothyroid patient was treated with dental implants between 1979 and June 2000, the cut -

off point for incIusion in the study. The recall rate for the entire group of patients nsked to

participate in this study was 89%. Unfortunately the dropouts occurred only in the hypothymid

patients and this may result in rneasurernent bias. Six hypothyroid patients did not attend the

I l 3

recall visits in surnmer 2000. This was due to four having moved out of city of Toronto, whiIe

the other two were not interested in the recall visit, and were therefore dropped ftom the study-

The prevalence of hypothyroidism in the patient population treated at the InipIant Prosthodontic

Unit was 5.8%, which is very close to the prevalence reported by Sawin et ai. (36) In this study

the overall prevalence of thyroid hormone use in a population of 2575 elderiy patients was 6.9%

specifically 10% in women. Of these wornen, 68% were taking for definite or probable

hypothyroidism. This equate to 104 female patients or 6.7596, which is sirrrilar to this study.

Analysis of the confounding variables showed that most of the independent variables were weH

matched between the hypothyroid group and controls, as evidenced by the statistical analysis

both at patient level and also implant level. There was no statisticd difference in the sirbjects'

ages at stage 1. This is also evident in the rnenopausal status matching. This is an important

observation since the literature relating to the impact of thyroid disorders on bone suggests that

there is difference between pre- and post-menopausal patients, with more bone loss reported in

postmenopausal rather than in premenopausal women, The matching used in this study

eliminated possible bias that could have resulted for both the absolute failure of implants and

also the changes in the marginal bone changes measured around the dental implants.

Medical condition and use of medications were also matched closely. Wherever possible, hedth

conditions of patients and controls were matched. The types of medications were not matched in

this study nor were there an attempt to group them, consequently, the impact of specific

categones of medications on the outcome measures was not determined.

The smoking status was reevaluated at the last recall visit in June 2000. Patients were

specifically asked if they were smokers. If they denied an active history of smoking they were

asked if they were former smokers. No attempt was made to quantify the amount of tobacco

srnoked. In the statistical analyses smoking status was dichotomized. The first group consisted of

non-smokers done whilst the second group consisted of both active and former smokers. The

latter was done since there is evidence that aryl hydrocarbons, active components of cigarette

smoke have a negative effect on wound healing. The half-life of these aryl hydrocarbons has

been reported to exceed ten years in the environment (152) and between four to twelve years in

human blood and fat. (153) Since their half-iife can be so long, it was decided that former

srnokers should be grouped with active smokers, as aryl hydrocarbons may still be present in the

body afier cessation of smoking and possibly impact on osseointegration. In this study, there

were more non-smokers in both groups and the smokins habits were not statistically differ ent.

Overloading of dental implants has an adverse effect on osseointegration and c m lead to failure.

This was shown both in animal studies (22). clinical studies (9, 23) and in a review (24)- The

clinical objectives of the Prosthodontic department at the University of Toronto is to prevent

untoward loadinp of dental implants by carefully distributing occlusal forces according to

Beyron's principles. (154-156) In this study the nurnber of implants. type of prosthesis and

dental state of the opposing dentition, were matched so that the study and connol goups would

be comparable in this respect. There was no statistical ~i~gif icance for al1 the three independent

factors. It is therefore ternpting to state that these factors did not impact on the outcome of the

results.

The distribution of the dental implants in the jawbones was the sarne for both groups. However

more dental implants were placed in the mandible than in the rnaxilla. One hundred forty

implants were placed in the mandible and 23 in the maxiIIa. As regards the specific zone in the

jawbones, there was a statistical difference, with more implants pIaced in zone 1 in the

hypothyroid group whilst in the controi group, more implants were placed in zone II. Overall,

more implants were phced in zone 1, totaling 11 1; the rest, 52,were placed in zone II. Both bone

quality and quantity, as classified by Lekholm and Zarb (14) were statistically different.

However the distribueon was skewed as shown in table 2. Only one implant was placed in bone

quality type1 and none placed in bone quantity type E in the hypothyroid group. Although both

parameters were si,gmificant, the statistical consultant suggested their exclusion from the

multivaciate analysis s o as to avoid skewing the results.

Outcornes:

The first hypothesis sought to test the effect a history of hypothyroidism would have on the

survival of Brgnemark dental implants.

Five implants failed in total in the hypothyroid and control groups. Three failures occurred in the

hypothyroid group and two in the control subjects. Four of these failures were recorded as early

failures in the mandible with the only late failure, which happened £ive years afier loading,

occurring in the maxilla in the hypothyroid group. All failures occurred in patients who had been

edentulous for at least ten years prior to implant failure.

The overall success rate was 97 %. On a group level the success rate was 95.49 % for the

hypothyroid group and 97.51 % for the control group. This was not statistically different. The

sunival analysis accounting for the different foilow-up times showed no difference for any of

the potential confounding variables impact on the failure of the implants reported. Thus the

overalI success rate is very high and the first hypothesis was disproved since there was no

difference in the number of dental implant failures between the groups.

Unfortunately there are no studies reporthg success rates of osseointegration in patients with

hypothyroidism and so these results cannot be compared to other studies. Yet it can be matched

to those reported in the international literature for different implant treatment options available.

(3-8, 10, 1 1, 33, 5 1,56, 157)

Esposito et al in a meta-anaiytical study reported that overail 7.7% of implants failed over a

period of 5 years (or 92.3% success rate), the majority being early failures prior to prostheses

connection. In this study 2.45% of the implants had early failure. This is consistent with results

reported by Esposito et al, who reported an overail 3.4% early failure in cases of complete

edentulism and 2% in partially edentulous patients. (1 58)

Soft tissue complications post-stase 1 surgery were different between the groups with more

complications being reported in the hypothyroid group- This was a subjective assessrnent by the

oral surgeons and included wound breakdown due to loosening of the sutures or due to "delayed

healing". Hypothetically, the so-called delayed healing may have been due to the presence of

granulation tissue at a penod when maybe a better soft tissue picture was expected. This could be

due to the different rates of tissue healing in different subjects. However, this difference could

also be explained in the context of altered healing response in animal modeIs with thyroid

disorders, (65, 66) and also as reported in a clinical study (71)- These studies suggest that both

hyperthyroidism and hypothyroidism alter the healing response. Hendron et al (65) showed that

both hypo- and hyperthyroidism had an effect on the healing of burn wounds in guinea pigs, with

evidence of inhibited epithelialjzation in boùi disorders. It is therefore tempting to speculate that

the higher proportions of soft tissue complications observed in this study may have been due to

an imbalance in the thyroid levels. Hypothetically these patients may have been over-replaced

with thyroxine therapy. This assumption is based on the fact that over-replacement is common in

patients on thyroxine therapy unless the dosage is monitored diLigently. However, the study

design did not allow a thorough investigation of the thyroxine dosage and its impact cannot be

definitely ascertained. A multivariate analysis indicates that these soft tissue complications c m

be explained by the grouping, smoking and age while ai1 were highly significant. it should be

noted that a non-smoking status had actually an adjusted odds ratio of 3.87 of having soft tissue

complications post stage 1 sursery in this study. This anomaIy c m be explained because there

were more non-smokers in this study. Roughly 75% of al1 the patients in both groups were non-

smokers, and this distorts the results in the multivariate analysis. The odds of having soft tissue

complications in a hypothyroid patient were 5.83. The factor of age was significant in explaining

the complications. However the odds ratio was quite small at 1.1, meaning that the chances of

being older and having sofi tissue complications were reaIly quite slender-

In the last r e c d visit in surnrner 2000, the soft tissue complications present were found in only 6

peri-implant sites and were of minor nature, They were identified as a rninor gîn,oivitis due to

poor hygiene and al1 resolved following adequate hy,oiene implementation. This corresponds to

what has been reported in the literature (4, 159 andl60).

The second hypothesis was designed to investigate if a history of hypothyroidism and thyroxine

replacement therapy increased marginal bone loss arolind dental implants.

The mean bone loss measured in first year was more pronounced in the hypothyroid group

(0.308mm k 0.08) when compared to the control group (0.04mm & 0.05). This result was based

on measurements obtained from forty-one pairs of sites. The slopes of the mean bone loss for the

other years were not statistically different. A trend in reduction of the mean bone loss c m be

observed for the hypothyroid group foliowing the first year of loading. This can be explained in

terms of the bone stabilizing after the first year of heaiing and adaptation to loading. The slopes

for the overall bone l o s over the years followin,o loading shows a reduction in bone loss. This

c m be interpreted as stabilization of the bone followimg the initial heaiing phase, This

stabilization and the overall bone loss reported for both year L, and the dopes in the following

years are weil within the 0.2m.m annually proposed in the Woronto consensus report. (148) This

is in accordance with values described in the literature, where more bone loss was reported in the

first year and then a reduction and stabilization in the rate of loss was reported after rehabilitation

of both edentulous (2-5) (52) and partially edentulous patiemts (9, 10. 55. 56, 58). These studies

reported a wide range of bone loss measurements and did mot discuss the medical status of the

patients, which lirnits a direct comparison with resuIts obtaimed in this study. However, it can be

concluded that sirnilar trends in the bone picture were c-mparable to those described in the

literature.

Harvey et al's (71) retrospective study reported that th._e bone markers of bone collagen

breakdown were higher in patients wïth thyrotoxicosis, and in postmenopausal women on TSH

suppression. Moreover, other authors ( 104- 106) have suggested that that a state of euthyroidism

fiom the hypophyseal viewpoint does not rule out hyperthyroidism in other tissues, This could

mean that the hyperthyroid state expressed at a bone tissue level durins the vulnerable early

healing period could lead to more bone turnover. This wo-uld in turn be characterized by the

observed increased bone loss in the f i s t year. Clearly t h ï s is a speculative suggestion but

deserves further investigation.

The multivariate regession models for bone loss in year o n e could not thorou,ohly explain what

factors were contributing to the measured Ioss, aithou@ in the first model a history of

hypothyroidism was found to be barely significant. However in a second model (table 20), the

role of the group is lost when bone quality and quantity are excluded. A further model for the

mean bone loss in year one for just the hypothyroid group was constructed to see if the duration

of hypothyroidism had an impact on the outcome but the duration of hypothyroidism was not

significant. In the same model, the use of medications, other than thyroxine replacement therapy,

was observed to be si,onificant. More bone Ioss was recorded in the patients with a history of

medication use. The differènt categories of medications used by patients in this study are

presented in the following table 23. The scope of this thesis precluded any attempt to seek

correlation between the medications taken and bone behavior around the implants. However, the

reported observation appears to suggest that certain medications couId indeed play a role in bone

changes around dental implants. This observation underscores the need for further studies in this

field.

Table 23: Categories of Medications used bv the patients

Anti-depressants

Type of Medications

Hormone replacement thenpy Anti-asthmatics

cGeory of Medications Examptes of Medications iisted by Patients

hti-diabetic medications

Ace-inhibitor, Calcium blockers, * Diuretics, * Selective serotonin re-uptake inhibitors. TncycLic and related antidepressants.

Estrogens.

Selective Bz-adrenoreceptor stimulant. Antimuscarinic bronchodiIators. NSAIDs. Cox-inhibitor. Non-narcotic analgesic. Insulin. Sulp honylureas. Biguanides. Bone Metabolism regulator.

Fluoxetine. Amitriptyline. Trazodone Hydrochloride. Estrodial,

Sdbutamol. Ipratropium Brornide. Aspirin, Diclofenac Sodium. Celecoxib. Acetaminophen. Lnsulin. Giibenclamide- Me tfo nnin. Etidronate Disodium

medications 1 Calcium carbonate. * Medications not specified by patient.

The third hypothesis was designed to explore if implant loss results in changes in the proposed

prosthodontic treatrnent plans.

The impact of implant failure on the prosthodontic outcome was not ~ i~gi f icant . The failed

implants had no impact on the proposed prosthodontic thenpy outcome. This result on al1

patients met the success criteria proposed in the Toronto consensus report. (L48) None of the

patients who lost an implant ended up with a change in the prosthesis design. In one patient who

had been treated with a fixed full-arch mandibular tissue integrated prosthesis, recurrent crew

fncture associated with the biomechanical design of the prosthesis necessitated its conversion to

an overdenture. No further screw Gactures were observed and patient reported complete

satisfaction with the altered treatment plan. This raises an important question relating to

prosthesis design and patient satisfaction. Although not properly explored. all patients reported

satisfaction with their prostheses irrespective of the design. This area of research will be

readdressed in future research since it has a very important impact on treatment planning.

Limitations of the studv

A number of Limitations are conceded:

1. Gender. Al1 hypothyroid and control patients were females and reported results are

therefore not applicable to males.

2- The sample size was small. However the patients were closely matched with the

controls, and potential confounding variables were accounted for as reported in the

results. The problem could be improved by organizing a multi-center study to incïease

the number of patients.

3. Study design. Although patients selected in this study were part of an ongoing

prospective study initiated in the late seventies in Toronto, the study lookcd at the

hypothyroid patients retrospectively. The study specifically is an ex post-facto

retrospective design. Blinding of the main investigator at various stages of the study

added strength to the study.

4. Dosage of thyroxine replacement therapy. This was not monitored because of the

different duration of the disorder prior to implant therapy, hence precluding a definite

determination of the dosages prescribed and establishing a relation to the outcomes

measured.

In conclusion, the results of this prelirninary study cannot be considered as definite ones. They

are an initial atternpt to investigate factors in the patients' medical history that may have an

impact on osseointegation. Recognizing the Limitations of my research design. this study looks

at hypothyroidism and sugests that:

1. Medically controlled hypothyroid female patients treated wîth Brhemark dental implants

in the Implant Prosthodontic Unit were not at higher risk of implant faiIure when

compared to matched controls.

2. Hypothyroid female patients rnay have more bone loss in the fxst year of loading,

especially if additional medications for other disorders are taken. However, this tapers off

after year one of loading to levels that are not different thm those registered in controls.

Moreover, the measurernents are still wi thin the sugested guidelines in the international

fiterature.

3. Hypothyroid female patients may have more soft tissue compiications in the early healing

phase. However, these are minor and readily rectified with proper care.

4. Failed implants did not preclude the patients fiom receiving the proposed prosthodontic

therap y planned for them.

5. A history of controlled hypothyroidism does not appear to be a contra-indication for

implant therapy with Brihernark endosseous dental implants.

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