adverse oral and dental manifestations of medications

lecture given 4/21/2026

what are adverse oral and dental manifestations of medications?

gingival hyperplasia, burning mouth syndrome, candidiasis, xerosomia, dental stains, allergic reaction, meth mouth syndrome, medication related osteonecrosis of the jaws (MRONJ)

what drugs can cause gingival hyperplasia and how commonly does it do so?

anticonvulsants (dilantin)- 15-50% incidence

calcium antagonists (procardia, cardizem, amlodipine)- 10-20%

immunosuppressants (cyclosporine)- 27%

hormonal contraceptives

pregnancy (pyogenic granuloma)

gingival hyperplasia

non-inflammatory enlargement of the gingiva produced by factors other than local irritation

characteristically due to an increase in the number of cells

what is the pathophysiology of gingival hyperplasia?

interaction of phenytoin, nifedipine, and cyclosporine with epithelial keratinocytes, fibroblasts, and collagen can lead to an overgrowth of gingival tissue in susceptible individuals

drug induced- firm, fibrotic

inflammatory/chronic gingivitis- red, edematous, bleeds easily

what differential diagnoses are needed for gingival hyperplasia?

gingivitis and medication hyperplasia, leukemia (esp acute lymphocytic leukemia), pregnancy and puberty (hormonal exaggeration of plaque response) granulomatous diseases like wegner’s and sarcoidosis

what is the treatment for gingival hyperplasia?

surgial excision, improved oral hygiene will decrease recurrence

burning mouth syndrome

ongoing or recurrent oral burning pain

commonly involves the tongue, but also lips, gingiva, oral mucosa, in the absence of visible mucosal abnormalities

burning or scalding sensation

dry mouth sensation (often with normal salivary flow)

dysgeusia (altered taste, metallic, bitter, sour)

tingling or numbness sensation

symptoms may worsen throughout the day

if you cannot find an underlying cause of burning mouth syndrome, your pt is crazy

no! consider neuropathic dysfunction

if identifiable condition triggers the burning sensation, differential diagnosis is needed between…

xerostomia (medications, sjogren’s diabetes), denture irritation, infection (candidiasis), geographic tongue, GERD, nutritional deficiencies (vitamin and minerals), chemotherapy, menopause

what is the treatment for burning mouth syndrome?

diagnosis of exclusion-

history, oral examination, lab testing CBC/iron/zinc/B vitamins/glucose/oral swab for candidiasis

if cause is identified, elimiate the cause

if no known etiology, treat as neuropathic pain with amitriptyline, gabapentin, tricyclic antidepressants, or alpha-lipoic acid 600mg/day

candidiasis

a yeast infection of the mucous membranes of the mouth and tongue

candida albicans

the organism that causes oral candidiasis and other forms of infection

an opportunistic organism meaning that it invades only when the conditions for its growth are optimal

what are the systemic and local factors that affect candidiasis?

systemic- xerostomia, antibiotics, diabetes, steroids, chemotherapy, HIV, malnutrition

local- ill fitting dentures, lip licking habit, overuse of antiseptic or antibiotic mouth washes, decrease in VDO

what are the treatments for candidiasis?

nystatin and fluconazole

what are common causes of dry mouth?

medications, radiation, medical conditions like diabetes/increased blood glucose levels/autoimmune diseases/sjogren’s syndrome/surgical removal of salivary glands, smoking, mouth breathing

what medications can induce xerostomia?

anticholinergics, tricyclic antidepressants, antispasmodics, neuroleptics, MAO inhibitors, antiparkinsonian agents, lithium, central adrenergic antagonists, diuretics, decongestants, antihistamines, bronchodilators

xerostomia sequelae

dental caries, altered taste, bacterial sialadenitis, dysphagia, candidiasis

consider fluroride mouth rinse prevention

what are the different kinds of tooth staining and what can cause it?

external- chlorohexidine

internal- tetracycline, fluoride

allergic reaction

contact drug reaction, angioedema, oral lichenoid drug reaction, erythema multiforme (EM), erythema multiforme major

contact drug reaction

direct drug toxicity, direct injury caused by acidic pH or chemical

white fibrinous base with erythema, no immune reaction

aspirin burn

angiogenic edema

smooth diffuse swelling of the lips, chin, eyes, and tongue

associated with angiotensin converting enzyme inhibitors (ACE) like lisinopril

airway problems

release of histamine

non-allergic drug reactions

treatment is airway observation, antihistamines, stop ACE inhibitor

loss of taste or diminished perception in 2-4% of pts

oral lichenoid drug reaction

oral lesions in the mouth

direct contact with irritating substance, common with some components of toothpastes like cinnamon or mint, chewing gum like big red

what is the presentation of oral lichenoid drug reactions?

erosions or ulcerations, papular lesion, asymptomatic, white striations (commonly unilateral)

what medications can caue oral lichenoid drug reactions?

NSAIDs, pencillins, allopurinol, diuretics, gold salts, methyldopa, ACE inhibitors, sulfamethoxazole, synthroid, beta blockers

erythema multiforme (EM)

young adults

drug induced cases ~25-50% of reported casess

skin (target lesions)/oral lesions (hemorrhagic ulcers)

lasts 2-4 weeks

what drugs can cause drug induced EM?

sulfonamides, including hypoglycemics

nonsteroidal anti-inflammatory drugs (NSAIDs)

anticonvulsants (lamictall, keppra, neurontin, tegretol, depakote)

barbituates (phenobarbital, seconal, butalbital)

antibiotics

salicylates

erythema multiforme major

stevens- johnson syndrome, children under 15, quick onset (24 hrs)

pathogenesis- antibody based hypersensitivity

what types of lesions may appear in erythema multiforme major?

skin- macules that progress to skin necrosis

oral- hemorrhagic crusting ulcers of lips and labial mucosa

eye- conjunctival and corneal necrosis that could lead to blindness

what is the mechanism of action of methamphetamine?

stimulates release and blocks re-uptake of monoamine neurotransmitters (dopamine, norepinephrine, and serotonin)

what systemic effects does methamphetamine have?

increase in systolic and diastolic BP

shortness of breath

nausea and vomiting

diarrhea

meth mouth

rampant caries (commonly on the buccal surface and interproximal surface)

acidic nature of the drug, xerostomia, cravings for high calorie carbonated beverages, poor oral hygiene, and clenching/grinding all contribute

BRONJ or MRONJ

MRONJ bc bisphosphonates are not the only medication that can cause

bisphosphonate

structurally resemble pyrophosphates (naturally occurring polyphosphates)

PCP bond instead of a POP bond

have marked affinity for hydroxyapatite

2 lateral side chains: R1 determines binding affinity to hydroxyapatite, R2 determines antiresorptive potency

what are the oral bisphosphonates?

alendronate, risedranate, ibandronate, skelid, didronel

what are the IV bisphosphonates?

pamedronate, zolendronic acid, bonefos

what are the IV bisphosphonates for osteoporosis?

once yearly infusion of zolendronate

IV ibandronate administered every 3 months, have FDA approval for management of osteoporosis

denosumab

a RANKL inhibitor- fully humanized antibody against RANKL and inhibits osteoclast function and associated bone resorption

does not bind to bone, and its effects on bone remodeling are mostly diminished within 6 months of treatment cessation

RANKL binds to its receptor on osteoclast precursors and mature osteoclasts driving osteoclast differentiation, osteoclast activation, and osteoclast survival

RANKL is the central driver of bone resorption

denosumab for osteoporosis

administered subcut ever 6 mo

denosumab for metastatic bone disease

administered monthly

romosozumab

new monoclonal antibody used for fracture prevention in osteoporotic women

administered subcut

works by inhibiting sclerostin resulting in increased bone formation and decreased bone resorption

sclerostin is secreted by osteocytes, acting as a key inhibitor of bone formation

bisphosphonate pharmacokinetics

highly polar compounds, and are poorly absorbed after oral administration thus having a low bioavailability

maximum serum concentration is reached in 30-60min

virtually all of the absorbed dose is either taken up into the bone or eliminated in the urine

bone uptake and renal clearance account for the rapid clearance from plasma

bisphosphonates are sequestered and therefore are retained in bone for extended durations of time

this results in a prolonged plasma terminal elimination half life that reflects the gradual dissociation of drug from the bone back into circulation following exposure at the bone surface during the remodeling process

what bisphosphonate has a plasma terminal elimination half life of over 10 years?

alendronate (fosamax)

angiogenesis inhibitors

decrease capillary tube formation

inibit VEGF and vessel sprouting

stops tumors from growing new blood vessels, starving them of nutrients and oxygen

what meds are angiogenesis inhibitors?

VEGF inhibitors, tyrosine kinase receptor inhibitors, disease modifying antirheymatic drugs

pts with multiple myeloma may receive both _____ and _____ medications have a higher incidence of MRONJ

increased MRONJ severity or prevalence if _____ are also combined with the drugs above

antiresorptive, antiangiogenic

DMARDs

osteonecrosis of the jaw

normally bone resorption and formation are tightly coupled

osteocytes act as mechanosensors detecting stress and translating it into signals to osteoblasts or osteoclasts

exposed bone is the result of action of drugs on the daily remodeling and replenishment of bone

antiresorptive medications have direct effects on osteoclast formation, differentiation, or function

what are the unique characteristics of the jaw?

greater blood supply than other bones

higher turnover rate→ higher BP concentration

chornic invasive dental diseae and treatments

thin overlying mucosa

what are indications for use of bisphosphonates?

malignancy- hypercalcemia, breast cancer bone metastasis, bone lesions (multiple myeloma), bone prophy for solid tumors of prostate/lungs/kidneys/colorectal/GI

treatment and prevention of osteoporosis

treatment and prevention of osteopenia

pagets diease, chronic steroid therapy, osteogenesis imperfecta, giant cell tumors

why are bisphosphonates used for bone metastasis?

they irreversibly inhibit osteoclasts- results in inability by malignancies to resorb bone and proliferate

what are skeletally related events secondary to bone metastasis?

bone pain, pathologic facture, spinal cord nerve root compression, hypercalcemia of malignancy

MRONJ

all must be present to establish diagnosis

current or previous treatment with antiresorptive therapy alone or in combination with immune modulators or antiangiogenic medications

exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for more than 8 weeks

no previous history of radiation therapy to the maxillofacial region

how common is MRONJ in cancer pts with placebo groups?

how common is MRONJ if cancer pts exposed to zoledronic acid or denosumab

0-0.019%

0.017-0.04%

what is the risk of MRONJ in osteoporosis pts?

oral bisphosphonates- 0.02-0.05

IV zoldronate- 0.02

RANKL inhibitors- 0.04-0.3

roomszoumab- 0.03-0.05

what regions of the jaw are most affected by MRONJ?

mandible- 68%

maxilla- 27.7%

both- 4.2%

what is the clinical presentation of MRONJ?

pain, exposed bone, soft tissue swelling and infection, loosening of teeth, drainage

radiographically- changes are not evident until there is significant bone involvement, may appear similar to osteomyelitis (motteled bone, sequestrum, areas of new periosteal bone, widening of PDL), sclerotic and radiolucent pattern

what are the microscopic findings of MRONJ?

empty lacunae, inflammatory cells, absence of osteoclasts, no tumor at site

what are drug related risk factors for MRONJ?

potency, reason for treatment, duration of therapy

what are local risk factors for MRONJ?

concomitant oral disease (periodontal disease, dental infections, ill fitting dentures), local anatomy (mandibular/palatal tori, mylohyoid ridge), precipitating event (dentoalveolar surgery like dental extractions, periodontal surgery, dental implants, periapical surgery)

what are demographic/systemic risk factors for MRONJ?

age, cancer diagnosis (multiple myeloma > breast cancer > other), race (caucasians)

what are other co-morbidities for MRONJ?

chemotherapy, steroid therapy, alcohol, smoking

what are treatment recommendation for pts on bisphosphonates bc of malignancy?

prophy treatment prior to IV bisphosphonates therapy

routine clinical and radiographic exam

eradicate infections

remove teeth (healing period of 6 weeks)- nonrestorable, severe periodontal disease, remove teeth with poor long term prognosis

avoid dental implant placement

stabilize and treat perio disease

functional rehab of salvageable dentition

educate on oral hygiene and signs of disease

avoid invasive dental procedures if possible, maintain routine dental cleanings, ensure good fit of dentures (avoid soft tissue injury), aggressibely manage dental infections non-surgically, regular dental assessment needed

what are treatment recommendation for pts on bisphosphonates bc of osteoporosis?

comprehensive oral evaluation, patient education, review needed treatment and alternative treatments and how any treatment relates to MRONJ

alternative treatment, conservative approach, antibiotics, chlorhexidine mouth rinse, follow up

what should you do if a patient has been taking oral bisphosphonates for less than 4 years and has no clinical risk factors?

no alteration to planned treatment, inform pt about possible low risk of MRONJ

what should you do if a patient has been taking oral bisphosphonates for less than 4 years and has clinical risk factors?

drug holiday- stopping the oral bisphosphonate for 3 months prior to the procedure and restart after healing is complete

obvi consult w prescribing physician

DO NOT DRUG HOLIDAY FOR DENOSUMAB- bc of rebound resorption, elective surgery after 3-4 months of the last dose administration will allow for waning effects of medications and allow 6-8 weeks before the next dose

stage 0 of MRONJ

pts with no clinical evidence of necrotic bone, but present with non-specific symptoms or clinical and radiographic findings

stage I of MRONJ

exposed bone, asymptomatic, no evidence of significant infection

stage II of MRONJ

exposed bone, pain, infection

most common presentation

stage III of MRONJ

exposed necrotic bone extending beyond the region of alveolar bone, pathologic fracture or extraoral fistula, oral antral/oral nasal communication, osteolysis extending to the inferior border of the mandible or sinus floor

what are the treatment goals for MRONJ?

presevation of quality of life

how should pts with established MRONJ be treated?

superficial bony debridement to reduce sharp surfaces and prevent trauma to adjacent soft tissue (controversial)

remove appliance or protective stent may be used to protect exposed bone or adjacent soft tissue

avoid invasive dental procedures where possible

biopsy is NOT recommended unless metastisis is suspected

how should pts with established MRONJ stage I be treated?

non-surgical approach recommended to prevent futher osseosus injuries

daily irrigations and oral antimicrobial rinses

clinical follow up every 3 months

how should pts with established MRONJ stage II be treated?

culture directed antibiotic therapy

pain control

daily irrigations and oral antimicrobial rinses

clinical follow up ever 3 months

what oral antibiotics should be given to stage II MRONJ pts?

not allergic to penicllin- amoxicillin with metronidazole, both pills 500mg 3x a day

allergic to penicillin- clindamycin (300mg 3x a day) or azithromycin (250mg 1x per day)

what IV antibiotics should be given to stage II MRONJ pts?

no allergic to penicillin- unasyn (1.5g every 6 hrs) AND metronidazole (500mg 3x a day)

allergic to penicillin- ciprofloxacin (500mg 2x a day) AND metronidazole (500mg 3x a day)

how should pts with established MRONJ stage III be treated?

culture directed antibiotic therapy

pain control

daily irrigations and oral antimicrobial rinses

surgical debridement / resection to reduce volume of necrotic bone

serum CTx

C telopeptide

type I collagen C telopeptide a product of bone degration

measures inhibition of osteoclast activity

can be used to measure suppression of osteoclastic activity, or recovery of osteoclastic activity after stopping bisphosphonate treatment

not really used anymore

value increases approx 25 pg/ml for each month of drug holiday

high risk serum CTX value

less than 100 pg/ml

medium risk serum CTX value

between 100-150 pg/ml

low risk serum CTX value

above 150 pg/ml