see also:

• osteoporosis;
• hypercalcaemia;
• bone physiology

• bisphosphonates inhibit the resorption of bone by osteoclasts and may have an effect on osteoblasts. They are structurally similar to pyrophosphate, a normal product of human metabolism. This structure gives the drugs a high affinity for bone and they probably remain in bone for many years.
• Bisphosphonates can reduce progression of osteoporosis by inhibiting the resorption of bone.
• Bisphosphonates can reduce the hypercalcaemia of malignancy by inhibiting the resorption of bone.

• patients who are on bisphosphonate Rx are at a ~3-5% risk of triggering osteonecrosis if they have a dental extraction or an implant placement¹⁾
• this is defined as a necrotic bone area with or without an area of exposed avascular necrotic bone in the maxillofacial region
• it is usually associated with bone that has been exposed for at least 8 weeks, in a patient who received and/or is receiving bisphosphonates, with no previous history of irradiation to the maxillofacial region - over 2/3rd of BRONJ cases reported in literature up to 2012 show a strong correlation with dental extractions and/or oral surgical procedures²⁾
• because the jaws have a greater blood supply than other bones and a faster turnover rate related to their daily activity and presence of teeth, bisphosphonates are highly concentrated in jaws and are at especial risk due to there being only thin mucosa covering the bone
• occurs twice as frequently in mandible than in maxilla and areas with thin mucosa such as torus mandibularis and mylohyoid ridge³⁾
• typically occurs around 18 months (ranging from 4 to 35 months) after starting therapy or around 3 months after a dental extraction whilst on Rx
• risk increases with:⁴⁾
  • the cumulative dose of bisphosphonates
    • higher cumulative dosing used in oncology patients rather than just osteoporosis Rx dosing is a particular risk
  • potency and IV dosing vs oral (they are poorly absorbed orally)
    • most cases of BRONJ have been reported with alendronic acid
  • dental procedures especially dental extraction, implant placement but also periodontal Rx
  • chemotherapy and corticosteroids
  • older patients
  • females
  • possible Causasians
  • possibly smoking and genetic factors
  • some other possible risk factors include anaemia, hypocalcaemia, secondary hyperPTH, dialysis, etc
  • low serum CTx (C-telopeptides) ⁵⁾
• clinical features
  • typical presentation is in the form of non-healing extraction socket, presence of exposed bone, gingival swelling or purulent discharge, when local debridement and antibiotics are ineffective⁶⁾
  • they may become secondary infected with actinomyces
• possible pathophysiologic theories:
  • an excess of osteoclast activity, resulting in an alteration of normal bone turnover
  • inhibition of osteoclastic activity
  • inhibition of angiogenesis, which is essential for the healing process of a fresh extraction socket
    • bisphosphonates reduced endothelial cell proliferation by inducing apoptosis, which consequently resulted in lower vessel densities due to a reduction in the formation of new capillaries
  • toxic effects of bisphosphonates on the oral mucosa (similar to its effects on gastric mucosa) causing suppressed cell proliferation, leading to the inhibition of oral wound healing
• preventive strategies
  • ensure all dental work is completed prior to commencing Rx with elimination of any potential infection sites (eg. search for caries, dental cracks, loose fillings via OPG and dental inspection)
    • hopeless teeth should be removed prior to Rx
    • subgingival scaling should be performed
    • poorly fitting dentures should be replaced to avoid soft tissue trauma
    • stress importance of good oral hygiene, regular dental checkups (+/- screening X-rays)
  • if the patient has been taking medicine for more than 3 years it has been recommended to stop the medicine for at least 3 months before carrying out any surgical procedure and once the healing is complete the drug can be re-started ⁷⁾
  • if dental work is needed after Rx, then avoid extraction if at all possible via root can Rx / crown
    • consider root canal Rx followed by coronal amputation and leave the roots ⁸⁾
  • if extraction is required after Rx then consult with faciomax surgeon
    • consider possible temporary cessation of bisphosphonate Rx
    • avoid flap raising⁹⁾
    • bd chlorhex mouthwash for 2 months post-op
    • 2 month follow up
    • ? role of Plasma Rich in Growth Factor (PRGF) ¹⁰⁾
• DDx of a non-healing extraction socket
  • local infection
  • a trapped food particle/foreign body
  • BRONJ
  • in rare cases, an underlying or undiagnosed oral malignancy/cancer.
• diagnosis
  • OPG + clinical Dx
• Mx
  • swab m/c/s
  • if possible, avoid further dental work as it may delay wound healing
  • chlorhex mouth washes
  • optimally adjust dentures if used
  • antibiotics according to swab results
  • may need surgical debridement to reduce sharp edges or if advanced, to reduce volume of necrotic bone

• A once-yearly iv bisphosphonate which is given as a 5mg iv infusion (1st infusion should be given usually in a hospital) to Mx osteoporosis in patients with osteoporotic fractures (not to be confused with the 4mg monthly infusions to Rx hypercalcaemia in malignancies).
• has a high affinity for mineralized bone and a very long skeletal retention time (it is slowly released from bone over years)
• Similar adverse event profile to oral bisphosphonates but less oesophageal/GIT adverse effects.
• Thus there may be a role for ED short stay units to be giving 1st iv infusion for those patients who cannot tolerate oral bisphosphonates or do not wish to take weekly doses of these, and who have an osteoporotic fracture. Oral bisphosphonates must be ceased, and max. of 3 infusions over 3 years permitted on PBS.
• See NPS RADAR Dec 2008

• mainly used for osteoporosis or Paget's disease rather than for bone mets, myeloma or cancer-related hypercalcaemia

• usually once weekly dosing
• mainly causes GIT side effects - GORD, dysphagia, stomach ulcers
• can rarely cause BRONJ