7.4 Drugs Affecting Haemostasis, Bone (MRONJ) & Drug Interactions

7.4 Drugs Affecting Haemostasis, Bone (MRONJ) & Drug Interactions

Modern dental practice frequently involves managing medically complex patients who are prescribed long-term antithrombotic medications, bone-modifying agents, or polypharmacy regimens. Dental practitioners must possess a thorough understanding of haemostatic pharmacology, the Scottish Dental Clinical Effectiveness Programme (SDCEP) guidelines for minor oral surgery, the prevention and staging of Medication-Related Osteonecrosis of the Jaw (MRONJ), and key drug-drug interactions.

Pharmacology of Antithrombotic Medications & Surgical Management

Antithrombotic drugs comprise antiplatelet agents (which prevent platelet activation/aggregation) and anticoagulants (which inhibit the coagulation cascade).

Antiplatelet Medications

• Aspirin (Acetylsalicylic Acid): Irreversibly acetylates a specific serine residue ($Ser^{529}$) on the $COX-1$ enzyme, abolishing platelet thromboxane $A_2$ ($TXA_2$) synthesis. Because platelets lack nuclei and cannot synthesize new enzymes, the antiplatelet effect lasts for the entire 7–10 day lifespan of the platelet. Prophylactic dose is 75 mg daily.
• $P2Y_{12}$ ADP Receptor Antagonists: Clopidogrel (75 mg OD), Prasugrel, and Ticagrelor. These agents prevent adenosine diphosphate (ADP) from binding to the $P2Y_{12}$ platelet receptor, blocking ADP-mediated activation of the glycoprotein IIb/IIIa complex.
• Dual Antiplatelet Therapy (DAPT): Combination of Aspirin plus a $P2Y_{12}$ inhibitor, routinely prescribed following percutaneous coronary intervention (PCI) with coronary stent placement to prevent stent thrombosis.
• SDCEP Surgical Guidance: Antiplatelet monotherapy and dual antiplatelet therapy (DAPT) should NEVER be interrupted prior to minor oral surgery. Stopping antiplatelet therapy dramatically elevates the risk of fatal thromboembolic events (myocardial infarction, ischemic stroke, acute stent thrombosis), which far outweighs the localized bleeding risk. Local haemostatic measures must be rigorously employed.

Anticoagulant Medications

Vitamin K Antagonists (Warfarin)

• Mechanism of Action: Warfarin competitively inhibits Vitamin K epoxide reductase complex subunit 1 (VKORC1). This blocks the regeneration of active reduced Vitamin $K_1$, preventing $gamma$-carboxylation of glutamate residues on Factors II, VII, IX, and X, as well as endogenous anticoagulant Proteins C and S.
• Monitoring: Monitored via the International Normalised Ratio (INR). Target therapeutic ranges are 2.0–3.0 for atrial fibrillation and deep vein thrombosis, and 2.5–3.5 for mechanical heart valves.
• SDCEP Surgical Guidance:
  • Measure the INR within 24 hours prior to surgery (up to 72 hours if the patient has a stably maintained INR).
  • If the INR is $< 4.0$, proceed with minor oral surgery (e.g., 1–3 teeth extractions, scaling) without altering the Warfarin dose.
  • If the INR is $ge 4.0$, defer treatment and consult the patient's anticoagulant clinic.

Direct Oral Anticoagulants (DOACs)

• Direct Factor Xa Inhibitors: Apixaban (5 mg BD), Rivaroxaban (20 mg OD), Edoxaban (60 mg OD). Rapidly bind and inhibit free and clot-bound Factor Xa.
• Direct Thrombin (Factor IIa) Inhibitor: Dabigatran (150 mg BD). Direct competitive inhibitor of thrombin.
• Pharmacokinetic Profile: Rapid onset (1–3 hours) and short elimination half-lives (10–14 hours). DOACs do not require routine INR monitoring.
• SDCEP Risk-Stratified Management:
  • Low Bleeding Risk Procedures (1–3 teeth extractions, periodontal scaling, endodontics): Do NOT interrupt DOAC therapy. The patient takes their normal morning dose.
  • Higher Bleeding Risk Procedures ($> 3$ extractions, surgical flap reflection, bone recontouring):
    • Once-Daily DOACs (Rivaroxaban, Edoxaban): Advise the patient to delay their morning dose on the day of surgery until haemostasis is successfully established post-procedure.
    • Twice-Daily DOACs (Apixaban, Dabigatran): Advise the patient to omit their morning dose on the day of surgery, taking their next scheduled dose that evening once a stable clot has formed.

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Local Haemostatic Protocols in Dental Surgery

For all patients taking antithrombotic medications, meticulous local haemostasis is mandatory:

1. Atraumatic Surgery: Minimize tissue trauma, preserve bony walls, and perform smooth socket debridement.
2. Local Haemostatic Agents: Pack the extraction socket with oxidized regenerated cellulose (Surgicel) or a gelatin sponge (Gelatamp), providing a mechanical matrix for fibrin attachment.
3. Suturing: Place resorbable sutures (3-0 Vicryl) under firm tension to compress the socket margins.
4. Topical Antifibrinolytic Application: Apply firm pressure over the socket for 10–20 minutes using a gauze swab soaked in 5% Tranexamic Acid solution. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation to plasmin, preventing premature clot lysis.
5. Postoperative Instructions: Advise the patient to avoid rinsing, spitting, drinking hot liquids, using straws, smoking, or engaging in strenuous physical exertion for 24 hours.

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Medication-Related Osteonecrosis of the Jaw (MRONJ)

Diagnostic Criteria (AAOMS / SDCEP)

MRONJ is diagnosed when all three of the following criteria are met:

1. Exposed Bone or Fistula: Exposed bone in the maxillofacial region, or bone that can be probed through an intraoral or extraoral fistula, persisting for more than 8 weeks.
2. Drug Exposure: Current or previous treatment with antiresorptive (bisphosphonates, denosumab) or antiangiogenic therapies.
3. No Radiotherapy: No history of radiation therapy to the jaws or obvious metastatic disease of the jaws.

Causative Pharmacological Agents

• Bisphosphonates (Oral: Alendronic acid 70 mg weekly, Risedronate, Ibandronate; IV: Zoledronic acid 5 mg yearly, Pamidronate):
  • High affinity for hydroxyapatite crystals in bone matrix. During osteoclast-mediated bone resorption, bisphosphonates are internalized by osteoclasts and inhibit farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway.
  • FPPS inhibition disrupts prenylation of small GTPase proteins, inducing osteoclast apoptosis, suppressing bone remodeling, and inhibiting angiogenesis. Bisphosphonates persist in bone matrix for decades ($t_{1/2} > 10$ years).
• Denosumab (SC: Prolia 60 mg 6-monthly for osteoporosis; Xgeva 120 mg monthly for oncology):
  • Fully human monoclonal antibody that binds with high specificity to RANKL (Receptor Activator of Nuclear Factor $kappa$B Ligand).
  • Prevents RANKL from binding to its receptor RANK on pre-osteoclasts, inhibiting osteoclast maturation, function, and survival.
  • Unlike bisphosphonates, Denosumab does not integrate into bone matrix; its bone-suppressive effects reverse within 6 months of discontinuation.
• Antiangiogenic Agents (Bevacizumab, Sunitinib, Aflibercept): Reversibly inhibit vascular endothelial growth factor (VEGF) signaling, impairing capillary sprouting, microvascular repair, and bone healing.

SDCEP MRONJ Risk Stratification

• Low-Risk Category:
  • Patients treated with oral bisphosphonates for osteoporosis, osteopenia, or Paget's disease for less than 5 years (without concurrent systemic corticosteroid use).
  • Patients treated with quarterly IV bisphosphonates for osteoporosis for $< 5$ years.
• High-Risk Category:
  • Patients receiving antiresorptive or antiangiogenic drugs for oncology management (e.g., IV zoledronic acid monthly or SC denosumab monthly for bone metastases/myeloma).
  • Patients taking oral bisphosphonates for longer than 5 years.
  • Patients taking antiresorptive drugs for any duration combined with systemic corticosteroids or potent immunosuppressants.

Clinical Management & Surgical Guidelines

• Pre-Treatment Dental Optimization: Prior to initiating oncology-dose IV bisphosphonates or denosumab, patients must undergo comprehensive dental examination. All unrestorable teeth and active dental infections must be extracted and mucosal healing achieved before starting drug therapy.
• Preventive Surgical Management: In high-risk patients needing dental care, explore non-surgical alternatives where possible (e.g., root canal treatment, coronal decoronation leaving roots in situ to avoid extraction).
• Extraction Protocol for High-Risk Patients: If extractions are unavoidable, perform atraumatic surgery, smooth sharp bony projections, achieve primary mucosal closure, pack with local haemostatics, and review healing at 4 and 8 weeks.
• Drug Holiday Guidance: Routine drug holidays are NOT recommended by SDCEP guidelines prior to dental extractions. Discontinuing bisphosphonates provides no immediate benefit due to long bone matrix retention. Discontinuing Denosumab (Prolia) carries a grave risk of rebound hypercalcemia and multiple vertebral fractures.

MRONJ Clinical Staging System

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Critical High-Risk Drug Interactions in Dental Practice

Dental prescribers must remain vigilant against hazardous drug-drug interactions that can lead to severe morbidity or mortality.

Top 5 Hazardous Dental Drug Interactions

1. Warfarin + Miconazole Oral Gel / Metronidazole / Macrolides:
   • Mechanism: Miconazole, metronidazole, and clarithromycin potently inhibit hepatic CYP2C9 or CYP3A4, preventing warfarin clearance.
   • Clinical Result: Massive INR elevation, uncontrolled bleeding, severe internal or intracranial hemorrhage.
2. Local Adrenaline + Non-Selective Beta-Blockers (Propranolol):
   • Mechanism: Propranolol blocks $eta_2$ vasodilatory receptors in skeletal muscle. Injected adrenaline acts on $alpha_1$ receptors without $eta_2$ opposition.
   • Clinical Result: Severe hypertensive emergency accompanied by compensatory reflex bradycardia.
3. NSAIDs + ACE Inhibitors / ARBs + Diuretics ("The Triple Whammy"):
   • Mechanism: NSAIDs constrict afferent renal arterioles (blocking $PGE_2$), ACE inhibitors dilate efferent renal arterioles (blocking Angiotensin II), and diuretics deplete volume.
   • Clinical Result: Catastrophic reduction in glomerular filtration rate (GFR), precipitating Acute Kidney Injury (AKI).
4. NSAIDs + Selective Serotonin Reuptake Inhibitors (SSRIs):
   • Mechanism: SSRIs block platelet serotonin reuptake (depleting intracellular serotonin required for aggregation), while NSAIDs erode gastric mucosa.
   • Clinical Result: 3 to 6-fold increase in the incidence of severe upper gastrointestinal ulceration and bleeding.
5. NSAIDs + Methotrexate:
   • Mechanism: NSAIDs competitively inhibit renal tubular secretion of methotrexate and reduce renal blood flow.
   • Clinical Result: Methotrexate accumulation and toxicity, causing severe bone marrow suppression, pancytopenia, and fatal stomatitis.