1. 4. Radiation Effects – Salivary
Glands, Bone and Teeth
John Beumer III, DDS, MS
Eric Sung, DDS
Division of Advanced Prosthodontics, Biomaterials and
Hospital Dentistry and
The Jane and Jerry Weintraub Center for Reconstructive
Biotechnology,
UCLA School of Dentistry
All rights reserved. This program of instruction is covered by copyright ©. No
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2. Radiation Effects – Salivary Glands, Bone
and Teeth
Table of Contents
v Salivary glands
v Damage - Mechanism of action
v Oral flora changes and radiation caries fungal infections
v Xerostomia
v Management
v Bone
v Mechanism of damage
v Late effects
v Cellularity
v Remodeling apparatus
v Osteolytic activity
v Periodontal ligament
v Teeth
v Pulpal changes
v Dental development

3. Salivary Damage-Mechanism of Action
v Salivary gland parenchyma Normal salivary gland
consists of acinar cells,
myoepithelial cells, and a ductal
system consisting of striated ducts
and intercalated ducts.
v Primitive glandular stem cells,
found in the ductal elements are
responsible for regeneration of Irradiated salivary gland
these cell populations.
v Reduced production of saliva is
ultimately secondary to the
sterilization of these cell
populations by irradiation (Konings
et al, 2005).

4. Salivary Damage-Mechanism of Action
v Reduction in flow observable the first Normal salivary Gland
Normal Salivary gland
week of therapy.
v Changes occur in volume, viscosity,
pH and buffering capacity, inorganic
and organic constituents after
therapy (Driezen et al, 1977; Brown et al,
1976; Marks et al, 1981; Malkkonen et al,
1986; Valdez et al, 1993; Almstahl et al,
2001). Irradiated salivary gland
v Mean
output can be reduced by from
86-93% (Curtis et al, 1976; Driezen et al,
1977; Marunick et al, 1991)
v These changes predispose to caries,
fungal infections, periodontal disease
v Swallowing and speech are also Irradiated Salivary Gland
impaired.

5. Salivary Damage-Mechanism of Action
v Early
on apoptosis is limited Normal salivary gland
to 2-3% of all cell types
(Paardekoper et al, 1998)
v Howeverfunction of
secretory cells compromised
v Secretory responses are
reduced by 50% by the first
few treatments (Coppes et al, Irradiated salivary gland
2000).
v Probably secondary to
impairment of signal
transduction by the plasma
membrane of the secretory Normal Salivary Gland
cells (Paardekoper et al, 1998;
Coppes et al, 2001)

6. Salivary damage-Mechanism of Action
v During therapy and for a few Normal salivary gland
months thereafter some evidence
of recovery of acinar cells is
observed
v However above 3000 cGy there is
a dramatic reduction of secretory
cells accompanied by progressive
fibrosis and compromise of the
vasculature Irradiated salivary gland
v Function returns to pretreatment levels
if dose is less than 2600 cGy
(Eisbruch et al, 1999; Eisbruch et al,
2003)
v In young patients receiving doses of
35-4500 cGy, damage is reversible Irradiated
v At doses above 55 cGy there is no salivary gland
recovery of function (Franzen et al,
1992; Eisbruch et al, 1999; Roesink et
al, 1999)

7. Salivary damage-Mechanism of Action
v Reduced function is Normal salivary gland
probably due to the
inability of stem cells to
replace aging and
dying parenchymal
cells (Konings et al, Irradiated salivary gland
2005).
Irradiated
salivary gland

8. Salivary Damage - Mechanism of Action
Mean Dose Concept vs the Volume Effect
Irradiated Salivary Gland Normal Salivary Gland
v Mean dose may not be the ultimate predictor of damage to
the salivary glands
v Late damage to salivary gland parenchyma may be
precipitated by secondary events
v Damage can be caused by damage to blood vessels of irradiated
portions of the gland supplying the nonirradiated portions (Konings et
al, 2005; Konings et al, 2006)

9. Radiation Induced Xerostomia
Effects on oral health and function and
quality of life
v Increasedrisk of caries and periodontal
disease and fungal infections
v Oral flora changes
v Difficulty in swallowing
v Impaired speech articulation
v Difficulty in sleeping
v Impaired tolerance of complete dentures (loss
of peripheral seal and lubrication)
v Compromise of taste acuity

10. Radiation caries
This patient received 6800 cGy for a
squamous carcinoma of the tonsil.
Several years prior to radiation she had
several porcelain veneers placed.
Closer exam reveals that several had become
detached and all had become severely
undermined with caries.
These teeth are beyond restoration and the clinician
should direct his/her efforts toward preventing the
infection from developing into an osteoradionecrosis.

11. Clinical significance of radiation • Acute and chronic
induced xerstomia fungal infections
" Changes in the oral flora predispose to:
• Radiation caries
Compromised tolerance of complete dentures
• Increased friction at the denture-mucosal interface
• Difficulty in obtaining and maintaining peripheral seal

12. Changes in the oral flora
Significant population shifts in oral flora
v Cariogenic
organisms gain at the expense of
noncariogenic organisms
v Increasesseen in the relative numbers of
Streptococcus mutans, lactobacillus (Llory et al, 1971;
Brown et al, 1972; Brown et al, 1975; Keene et al, 1981;
Keene and Flemming, 1987; Epstein et al, 1991)
v Significant increases in fungal organisms
(Brown et al, 1975)

13. Changes in the oral flora
Significant increases in the populations of:
v Streptococcus mutans
v Actinomyces
v Lactobacillus
These changes predispose the patient
to radiation caries. The caries
progresses rapidly and in most patients
becomes so extensive that it is
nonrestorable. Eventually, teeth
fracture at the gingival margin.

14. CRT - Radiation fields, xerostomia and and morbidity
High posterior fields
• Risk of caries is high
• Risk of osteoradionecrosis is low
Opposed mandibular fields
• Risk of caries is reduced
• Risk of osteoradionecrosis is high

15. Changes in the oral flora
The numbers of fungal organisms
increase 100 fold
As a result, chronic candidiasis, is
very common after therapy. It
presents in a variety of forms, as
seen here.
Nystatin is drug of choice,
and it can be dispensed in
a number of configurations
including lozenges,
powder, creams and an
oral suspension.

16. Changes in the oral flora
Acute candidiasis is quite rare after the
completion of therapy.
Note the fungal colonies developing on the mucosal surfaces (arrows).
Nystatin remains the least costly and most effective antifungal agent. For
acute forms of candidiasis, vaginal suppositories (100,000 units per
suppository, Sig.- tid), used as an oral lozenge are preferred over the
nystatin oral lozenges because of the latter’s high glucose content.

17. Management of Radiation Induced Xerostomia
Ideal characteristics of a saliva substitute
v Provide a protective coating for the oral mucosa
v Capable of remineralization
v Maintain normal oral flora patterns
v Be long lasting
Saliva substitutes
v Carboxymethylcellulose based
v Mucin based
v Water based
v Glycerin based
Attempts have made to formulate salivary substitutes (Shannon et
al, 1977; Shannon et al, 1978; Visch et al, 1986). Patient responses
have been mixed and most patients prefer increased water intake.

18. Management of Radiation Induced Xerostomia
Saliva substitutes
v Carboxymethylcellulose based
v Mucin based
v Water based
v Glycerin based
These agents have been ineffective for the most part,
although they have been useful in selected patients in
relieving night time discomfort. They also may aid the
severe xerostomic patient who experiences difficulty
with speech articulation.

19. Salivary stimulants
Attempts to stimulate salivary activity after
radiation have been disappointing
v Most common drugs used:
v Pilocarpine
v Cevimeline
v In most studies, measured flow may be increased but
rarely is relief of symptoms noted (Fox et al, 1986;
Greenspan and Daniels, 1989; Johnson et al, 1993; Rieke et
al, 1995)
v Most of the benefit is probably secondary to the
stimulation of minor salivary glands since they are
more resistant to and recover more effectively from the
effects of radiation (Niedemeirer et al, 1998)

20. Salivary stimulants
Pilocarpine
v Requires residual salivary gland parenchyma to
be effective
v Can be dispensed in liquid form used as a mouth
rinse (1 mg per cc) or in tablet form (5 mg)
v Dosage above 20 mg will induce toxic side effects
v Toxic side effects include increased intestinal motility
v Marketed as Salagen
This drug may be useful in patients who have been treated with CRT and with radiation
treatment volumes that spare significant amounts of salivary gland parenchyma but has not
been useful in patients with opposed lateral facial fields that are used to treat tumors of the
soft palate, tonsil, nasopharynx etc. The latter may have little or no residual salivary gland
parenchyma.

21. Salivary stimulants
Cevimeline
v Requires residual salivary gland parenchyma to
be effective
v Toxic side effects include increased intestinal
motility, excessive sweating, nausea
This drug has a similar mechanism of action as pilocarpine and like pilocarpine
may be useful in patients who have been treated with radiation treatment
volumes that spare significant amounts of salivary gland parenchyma (i.e.,
opposed mandibular fields). It has been used in Sjogren’s syndrome patients
with some success. Clinical trials are now being conducted in irradiated
patients.

22. Salivary gland protective agents
v Amifostine (Antonadou et al, 2002)
v Pilocarpine (Roesink et al, 1999, Warde et al,
2002; Burlage et al, 2008)

23. Salivary gland protective agents
Amifostine
v Has been shown to moderately improve subjective
symptoms
v A free radical scavenger
v May limit damage to salivary parenchyma during radiation
v Side effects include hypotension, nausea and vomiting
v Issues
• Questionable rationale
• Questionable study designs
• Possible protective effect on tumor cells (Vissink et al, 2003)
• Cost
Clinical results have been disappointing.

24. Salivary gland protective agents
Pilocarpine
v Administered before and during radiation therapy to limit radiation
damage (Roesink et al, 1999; Warde et al, 2002; Burlage et al, 2008)
v Animal experiments have shown promise but human data is
indeterminate. Some have shown no benefit (Warde et al, 2002) while
others have shown some benefit (Burlage et al, 2008)
v Others (Valdez et al, 1993) have suggested that the drug affects only the
nonirradiated salivary gland parenchyma

25. Stem cell transplantation and enhancement
Reduced saliva production is ultimately secondary to the loss of salivary stem
cells which preclude replacement of aging acinar and ductal cells. Strategies
currently being tested in animal models include:
v Transplants (Lombaert et al, 2008a)
v Secure salivary gland tissue prior to irradiation, retrieve and
culture the stem cells and transplant them back into the subject
after radiation

26. Stem cell transplantation and enhancement
Reduced saliva production is ultimately secondary to the loss of salivary stem
cells which preclude replacement of aging acinar and ductal cells. Strategies
currently being tested in animal models include:
v Stimulate
surviving salivary gland stem cells with bone
marrow cells (Lombaert et al, 2006; Lombaert et al, 2008b)
v This option is limited by the number of stem cells surviving radiation

27. Stem cell transplantation and enhancement
Reduced saliva production is ultimately secondary to the loss of salivary stem
cells which preclude replacement of aging acinar and ductal cells. Strategies
currently being tested in animal models include:
v Increase salivary gland stem cell populations prior to
radiation (Lombaert et al, 2008c)
v This
has been accomplished in an animal model by administering
keratinocyte growth factor (N23-KGF) prior to radiation

28. Maximizing Postradiation Salivary Flow
v Best results achieved by sparing salivary glands from high
dose radiation (Mira et al, 1981; Roesink et al, 2001; Vissink et al,
2003)
v >50% of the parotid glands must be outside the radiation
fields in order to prevent severe xerostomia (Mira et al, 1981)

29. Means of sparing major salivary glands
from high dose radiation with IMRT
Theoretically possible but the results have
been disappointing to date.
Source: www.beaumonthospital.com
Intensity Modulated Radiation Therapy (IMRT) may reduce the
dose to salivary glands. However the dose must be reduced to
less than 40 Gy and this may not be possible in many patients .

30. Radiation Effects – Bone
Mechanism of Damage
(Delanian and LeFaix, 2004; Lyons and Ghazali, 2008)
Damage to bone is the result of dysregulation of
fibroblastic activity
v Initially, endothelial cells damaged that lead
increased cytokine production
v These cytokines in turn promote the release of
inflammatory cytokines
v Loss of small vessel network
v Fibroblasts transformed into myofibroblasts
v Unregulated chronic activation of these
myofibroblasts leads to progressive fibrosis

31. Late Effects – Bone
(Silverman and Chierci, 1965; Rohrer et al, 1979)
v Reduced vasculature
v Loss of osteoprogenitor cells
v Fatty and fibrous degeneration
v Periosteum- Acellular and loss of vasculature
v Occlusion of the inferior alveolar artery
Root Trabecular bone
surface
Marrow
Severity of changes depends on dose

32. Late Effects – Bone
(Silverman and Chierci, 1965; Rohrer et al, 1979)
Severity of tissue changes depends on dose. The
human specimen shown was exposed to in excess
of 70Gy.
Root Trabecular bone
surface
Marrow

33. Late Effects – Bone
Clinical manifestations
v Compromised remodeling and
repair, ie healing of extraction
sites, osseointegration
v Response to infection, ie risk of Lamellar bone
• Loss of central artery in
osteoradionecrosis secondary Haversian systems
to a dental infection. • Death of osteocytes
Root Trabecular bone
surface
Marrow

34. Late effects –Lamellar Bone
v Loss of central artery in Haversian systems (red arrow)
v Loss of osteocytes from their lacunae (yellow arrows)
Such bone is essentially nonvital and lacking
the capacity for repair and remodeling

35. Remodeling apparatus -Osteolytic Activity
Following high dose radiation some
osteoclasts remain as shown in this
human specimen. The mandible in
Osteoclast
this patient received in excess of
70Gy with CRT via opposed lateral
mandible fields.
Isolated osteoclasts represent either the surviving
remnants of the multicellular unit of the remodeling
apparatus or find their way into irradiated bone via
the circulation mediated by macrophages.

36. Remodeling apparatus – Osteolytic Activity
v This patient received 70
Gy to the mandible for an
anterior floor of mouth Sq
Ca.
v Note the dramatic change
Preradiation in the prominence of the
cortical plates (arrows) and
the differences in trabecular
patterns between
preradiaton and
postradiation radiographs.
v Osteolytic activity seems
Postradiation more prominent in patients
treated with chemoRT

37. Remodeling apparatus – Osteolytic Activity
v Spontaneous fractures of the
mandible associated with
concomitant chemotherapy
and CRT. All three patients
received approximately 70
Gy
a b
v All patients received 70 Gy.
a and b: Neither was
associated with dentition. c:
Bilateral fractures through
ramus and angle secondary
to chemoRT. They were not
related to or precipitated by
dentition.
c

38. Clinical significance of compromised remodeling
apparatus
Preradiation extraction of teeth within the clinical treatment volume
When extracting teeth in the field prior to radiation radical
alveolectomies need to performed in order to avoid the
irregular alveolar ridge contours seen below.
Even though the alveolar ridge mucosa is covered with healthy mucosa, its
irregular boney contour precludes the use of complete dentures when the
dose to the mandibular bearing surfaces is high (above 65 Gy).

39. Clinical significance of compromised remodeling
apparatus
Osseointegration
b c
a
a: Normal control specimen. Note both contact and distance osteogenesis.
b: Specimen exposed to equivalent to 52 Gy. Note dramatic reduction is
osteogenesis. c: Specimen exposed to 58 Gy. Note further reduction of
osteogenesis (Courtesy of R. Nishimura).

40. Radiation Effects - Periodontium
Changes in the periodontal ligament
(Silverman and Chierci, 1965; Rohrer et al, 1979; Fugita et al, 1986; Epstein et al, 1998)
v Loss
of cellularity
v Loss of vasculature
v Disorientation of the periodontal ligament fibers
Result: The periodontium is a prime pathway for infection.
50 Gy >70 Gy
This patient developed an
osteoradionecrosis 4 years post
radiation secondary to a periodontal
abscess

41. Radiation Effects - Periodontium
v Lacking blood supply, the bone of the lamina dura becomes
acellular. Note the empty lacunae.
v Cementum likewise, becomes acellular and its capacity for
repair is compromised.
Given cementum’s
compromised capacity of
<70 Gy regeneration and repair,
periodontal procedures,
such as deep scaling and
flap surgery, are therefore
contraindicated in heavily
irradiated dentition.

42. Radiation Effects – Periodontium
(Floral changes?)
v Thereappears to an acceleration of attachment
loss in patients treated with chemoRT

43. Teeth
v Organic component of enamel appears unaffected
(Jansma et al, 1990)
v Microhardness of dentin is affected at the dentin
enamel junction (Keilbassa et al, 1997; Keilbassa et
al, 2006)
v This
phenomenon may be partially responsible for the high
rate of cervical caries in dentitions within the clinical target
volume

44. Teeth - Pulp Changes
v Atrophy of the
odontoblastic layer
and an inability to
fabricate secondary
dentin
v Loss of vasculature
and fibrosis
v Formation of
osteodentin and pulp
stones

45. Teeth - Pulp Changes
v Atrophy of the odontoblastic layer and an inability
to fabricate secondary dentin at levels of
exposure as low as 25 Gy
v Loss of vasculature and fibrosis
v Formation of osteodentin and pulp stones
Osteodentin Pulp stones

46. Clinical Implications of Pulpal Changes
v Response to infectious or mechanical injury to the pulp is
compromised
v Pulp capping is contraindicated. If a pulp exposure is
encountered during cavity preparation a root canal
should be performed
v Pulpal pain mechanisms are altered and patients with
advanced caries are generally asymptomatic

47. Dental development
v Levels as low as 2500 cGy effect tooth development
(Gorlin and Meskin, 1963; Pietrokovski and Menczel,
1966; Dahllof et al, 1994; Kaste et al, 1994)
v Changes reflect a variety of defects that indicate the
several stages of development existing during the
course of radiotherapy
This patient is 16 years of age. He received 3600 cGy of
radiation when he was 4 years of age for treatment of a
rhabdomyosarcoma.

48. Systemic sequellae of Radiation of
Head and Neck Tumors
Radiation induced cancers (Hall, 1995)
v Sarcomas
Carotid atheromas (Zidar, 1997; Freymiller et al, 2000)
Progressive fibrosis may lead to (Eisele, 1991; Kang,
2000; Sharabi, 2003; Nguyen et al, 2006, 2008; Nguyen,
2009)
v Difficulty swallowing
v Vocal cord paralysis
v Aspiration pneumonia
Heart (Basavaraju, 2002; Gyennes, 1998; Kahn, 2001)
v Valve leaflets may thicken and calcify
v Valve orifices narrow
v Acellerated form of athersclerosis
v Compromise of microvasculature

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68. The End
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