OSTEITIS DUE TO BIPHOSPHONATES AND ANTIRESORBERS
Introduction:
- Antiresorbents are drugs that act as inhibitory agents of osteoclasts responsible for bone resorption. This is the reason for their wide use in recent years in improving the quality of life of patients with benign and malignant bone pathologies.
- Besides their proven effect in improving the quality of life of patients, the use of antiresorptive drugs has been linked to the appearance of a major side effect which is osteonecrosis of the jaws (ONJ).
Historical
Bisphosphonates, formerly called diphosphonates, appeared in Germany towards the end of the 19th century . More precisely in 1865. They were mainly used as corrosion inhibitors in the textile and oil industries.
Since the 1960s, bisphosphonates have begun to be used in the treatment of certain pathologies of bone metabolism.
2003 (Marx et al), the use of bisphosphonates has been linked, based on clinical case reports and retrospective studies, to the occurrence of a major side effect which is osteonecrosis of the jaws.
In 2005, the AFSSAPS (French Agency for the Safety of Health Products) published an information letter intended for practitioners likely to prescribe bisphosphonates (BPs) or to have to perform surgical intervention on patients treated
In 2010, AFSSAPS and the MHRA (Medicines and Healthcare Products Regulatory Agency) reported on the occurrence of cases of ONJ in cancer patients treated with antiangiogenic drugs.
- Bisphosphonates (BPs)
- Definitions:
Bisphosphonates (BPs) are structural analogues of inorganic pyrophosphates; they are synthetic molecules prescribed primarily to decrease bone resorption.
- Chemical structure of BPs:
The central oxygen atom of the POP bond of inorganic pyrophosphate is replaced by a carbon atom (PCP bond), making the BPs molecule resistant to enzymatic hydrolysis.
The R1 radicals increase the affinity of BPs for hydroxyapatite. The R2 radicals determine the potency.
OSTEITIS DUE TO BIPHOSPHONATES AND ANTIRESORBERS
- BPS classification:
- Non-amino BPs: 1st generation ; containing CH, CH3 or H in position R2, they do not contain a nitrogen atom (clodronate, etidronate and tiludronate)
- Amino BPs: 2nd and 3rd generation : have a nitrogen atom in their R2 radical (Alendronate, Pamidronate, Ibandronate, Zoledronate)
- The pharmacokinetics of BPs:
Orally administered BPs are poorly absorbed. Their bioavailability varies from 1 to 5%.
Intravenous administration ensures better bioavailability (40 to 61%).
The plasma half-life is short, of the order of a few hours (6h). On the other hand, their bone half-life lasts several years.
Elimination is via the kidneys.
1.5 Mechanism of action:
It is the result of 2 main chemical properties:
- Affinity for hydroxyapatite and
– Inhibitory effect on osteoclasts.
- Mode of action of BPs:
-Inhibition of calcification in soft tissues.
– Inhibition of bone resorption.
-Other effects:
-Antiangiogenic action: some BPs (Zoledronic acid).
-Pro-inflammatory effect
- Directions:
1-Malignant pathologies:
- Multiple myeloma
- Osteolytic metastases of certain malignant tumors,
- Malignant hypercalcemia.
2-benign pathologies:
- Paget’s disease,
- Osteoporosis (postmenopausal or male, corticosteroid-induced,
- (SAPHO) syndrome,
- Aseptic necrosis of the hip,
- Osteogenesis imperfecta,
- Fibrous dysplasia of bones.
- Side effects
– Short-term side effects: They are well known and for the most part minor and transient:
-Nausea, vomiting, diarrhea, abdominal pain, anemia, thrombocytopenia, leukopenia, sometimes pancytopenia, dysphagia, esophagitis, as well as esophageal ulcers, flu-like syndrome and headaches.
-Dry mouth and ulceration, rare cases of immediate hypersensitivity and erythema multiforme
-Long-term side effects: osteonecrosis of the jaws
- Denosumab (Prolia®, Xgeva®):
Denosumab, an antibody (made in a laboratory by genetic engineering) neutralizes the Rank-ligand protein, which mediates the main pathway stimulating the different stages of osteoclast differentiation. By blocking their formation.
Denosumab prevents the destruction of bone tissue by these cells. It therefore acts on bone remodeling but unlike BPs, it does not remain in the bone and its action ceases quickly once the treatment is eliminated.
- Antiangiogenics: Sunitinib (Sutent®) and bevacizumab (Avastin®)
Sunitinib and bevacizumab are respectively indicated for the treatment of advanced cancers not amenable to surgical resection and for the treatment of metastatic cancers of the colon, rectum, pancreas, breast, lung and kidney.
- OSTEONECROSIS OF THE MAXILLA
1-Definition of Osteonecrosis of the Jaw (ONJ) and ( BRONJ ) in English Bisphosphonates-Related Osteonecrosis of the Jaw:
The AFSSAPS defines ONM as follows:
- Previous or current treatment with BPs.
- Lesion of the mucosa in the maxillofacial region exposing necrotic bone, and persisting for more than 8 weeks.
- No history of radiotherapy in the maxillary region.
- Absence of metastatic localization at the ONM area
2 – Pathophysiology:
– The binding of BPs to bone hydroxyapatite crystals is proportional to the intensity of bone remodeling at the time of their administration.
– Their concentration is therefore higher in growth zones, bone sites in the process of healing, tumor sites and those which naturally present a higher rate of physiological remodeling such as the alveolar bone of the jaws.
– At the level of the jaws, remodeling is significant due to constant demands by functions and parafunctions such as chewing and muscular demands during speech, facial expressions, bruxism, etc., which would explain the locations of osteonecrosis at the maxillary and mandibular level.
1. Hypocellularity theory :
BPs induce apoptosis of bone cells, especially osteoclasts. There is also a potential effect of BPs on osteocytes and osteoblasts
Which is the cause of a decrease in bone remodeling in areas of high BP concentrations.
2. Hypovascularization theory:
The antiangiogenic effect of certain BPs (zoledronate, pamidronate) leads to a reduction in intraosseous vascularization.
3. Theory of direct toxicity of BPs:
The accumulation of BPs at the level of the jaw is directly toxic for the overlying mucosa, any trauma (dental avulsion, prosthetic irritation, etc.) would cause an increase in the local concentration of Bps, responsible for the failure of healing of soft tissues and promotes superinfection and bone necrosis.
4. Micro-fracture theory:
High-dose BP treatment could lead to “frozen” bone whose remodeling is inhibited too significantly. This inert bone has lost all capacity to repair physiological micro-fractures induced by function (zoledronate, pamidronate and alendronate).
5. Infectious theory:
In the oral cavity, the maxillae are subjected, during function (mastication) and parafunctions (bruxism), to regular stress that would stimulate remodeling activity leading to greater absorption of BPs. This accumulation of BPs could induce a drastic reduction in remodeling promoting bone necrosis.
The vascularization of the overlying mucosa is then reduced and any minor trauma could lead to exposure of the underlying necrotic bone. Secondary colonization by oral flora of the exposed necrotic bone can be responsible for pain or infectious accidents often revealing osteonecrosis.
3- Clinical study :
Several classifications
Three successive stages are described
- Stage I: simple asymptomatic bone exposure with normal peripheral tissues.
- Stage II: Exposure of infected bone associated with functional symptoms and inflammation of peripheral tissues
- Stage III: bone fracture with extraoral fistulization.
Based on the DOESAK scale
Stage 0: no symptoms of necrotic bone with intraoral exposure.
Stage I: Asymptomatic intraoral exposure of necrotic bone or small asymptomatic intraoral fistula.
Stage II: Intraoral exposure of necrotic bone associated with pain and symptoms of concomitant infection.
Stage III: Intraoral exposure of necrotic bone associated with pain, swelling and cellulitis formation (abscess), multiple fistulas and radiological signs of extensive osteolysis.
Stage IV: intraoral exposure of necrotic bone associated with pain, swelling and cellulitis formation (abscess), appearance of an extraoral fistula or pathological fracture or bucco-sinus communication and radiological signs of extensive osteolysis at the edge of the mandible or large parts of the maxilla.
The intraoral examination
There is a mucosal breach exposing avascular and atonic bone with 1 or more uninhabited dental alveoli. The presence of a bone sequestrum (responsible for pain) and inflammation of the gum and peripheral soft tissues. In the event of superinfection, there is suppuration with mucosal and/or cutaneous fistula.
Spontaneous tooth mobility and loss are associated with this clinical picture. General signs are exceptional.
The clinical aspect of ONJ combines functional signs such as pain of variable intensity, throbbing, non-systematic, paresthesia or anesthesia of the area concerned (labiomental region), halitosis, cacosmia (maxillary location with sinus repercussions).
OSTEITIS DUE TO BIPHOSPHONATES AND ANTIRESORBERS
Radiological aspects
- Orthopantomogram/Retroalveolar:
Radiological signs of ONJ are absent early in the course of the disease even if ONJ is clinically visible; a loss of 30% to 50% of the bone mineral phase is required for ONJ to be detected. In advanced cases, sequestration is noted within an environment of radiological osteodensification.
- Computed tomography (CT):
Allows to individualize the cortical bone from the spongy bone, the evaluation of the extent of a possible bone sequestrum in formation, the periosteal proliferation at the mandibular level gives a double contour image
- Magnetic resonance imaging (MRI):
allows to specify the involvement of adjacent soft tissues, sinuses and mandibular canal. It would also allow to detect subclinical ONJ
- CT scanner: allows images to be seen even before clinical signs appear
- Sintigraphy: is positive in patients with clinical ONJ
Histological examination
Histological analysis is not necessary for diagnosis but allows to eliminate other pathologies, in particular cancer metastases, and tumor involvement. The necrotic bone shows no signs of bone remodeling, there is a dense lympho-plasmacytic inflammatory infiltrate with polymorphonuclear neutrophils in the medullary spaces. In most cases, an infection is distinguished with demonstration of germs of the oral flora and sometimes an actinomyces infection.
Biological tests:
1. Blood test: FNS, VS, CRP is useful in monitoring, possibly in differential diagnosis
2. Bone remodeling markers:
2.1/ Urinary NTx: Urinary cross-linked N-telopeptides of collagen I (NTx) levels are persistently elevated in a significant number of patients during bisphosphonate treatment.
2.2/C-terminal telopeptide (CTX):The most widely used serological biochemical marker to stratify the risk of ONJ in bisphosphonate users is the cross-linked C-terminal telopeptide (CTX) of type I collagen. When bone turnover increases, osteoclasts degrade type I collagen, releasing CTX molecules.
4. risk factors
- They are related to BPs treatment and oral factors.
1. Molecule and route of administration:
- Molecules administered IV are more responsible for ONJ than orally.
- The most potent molecules and the highest bioavailability are more often the cause of ONJ. The molecules: zoledronate-pamidronate by IV route.
2. Treatment duration and cumulative dose:
- The cumulative risk increases on average from 1% after 12 months of treatment to 11% after 48 months.
- Exposure to the molecule (number of infusions and cumulative number of hours of infusion is directly correlated with the risk of developing ONJ).
3. Oral factors:
- Intraoral invasive procedures or dento-periodontal pathologies are found in 50% to 85% of ONJ triggers.
4. Other factors: are corticosteroid therapy, anticancer treatments (no formal proof).
5.Diagnosis
1. Positive diagnosis:
- These are the criteria set out in the ONM definition.
2. Differential diagnosis:
- all other types of osteitis (ORN, chronic and acute secondary osteitis, osteomyelitis, primary osteitis, corticosteroid-induced osteitis) and a primary location or metastasis of cancer.
THERAPEUTIC MANAGEMENT:
-The French Agency for the Safety of Health Products (AFSSAPS), in 2007, in collaboration with a group of experts including clinicians, stomatologists, maxillofacial surgeons and dental surgeons, developed recommendations concerning the oral care of patients treated with BP.
-These recommendations concern three situations:
*Patients candidates for treatment with bisphosphonates.
*Patients treated with bisphosphonates without evidence of osteonecrosis.
*Patients with proven osteonecrosis.
- ONJ continues to evolve even with treatment.
- Prevention
- Preventive measures before treatment: clinical and radiological oral health assessment.
- Elimination of proven or potential infectious foci by extraction or conservative treatment.
- Periodontal sanitation (scaling and rigorous oral hygiene).
- Elimination of all possible causes of mucosal trauma.
- Inform the patient of the risks involved and their role in preventing ONJ.
- After treatment: clinical follow-up to intercept any problems and management in the least invasive way.
1. Patients candidates for bisphosphonate treatment:
a. In patients requiring BP for malignant pathologies :
*it is essential to carry out an oral-dental assessment: this will be carried out by a dental surgeon or a stomatologist.
*To carry out a radiological assessment: the dental panoramic scan must be supplemented by retro-alveolar images or even a dental scanner or CT scan in case of doubt concerning an infectious focus.
*It is preferable to start treatment with BP, if the patient’s clinical condition allows it, only once the dental situation has cleared up: it is necessary to carry out the necessary dental care, eliminate all infectious foci, wait for the mucous membranes to heal and, if possible, for the bone to heal completely (120 days).
b. In patients requiring BP for osteoporosis/Paget’s disease
*an oral health check-up and follow-up of necessary dental care are recommended. This care should not delay the initiation of BP treatment in patients at high risk of fractures.
2. Patients treated with bisphosphonate without evidence of osteonecrosis:
a. In patients receiving bisphosphonate for malignant diseases ,
*it is essential to carry out an oral-dental follow-up. This will be carried out by a specialist every 4 months and at the slightest oral-dental symptom, in collaboration with the oncologist.
– Detect and treat infectious foci using procedures that are as non-invasive as possible for the bone, periodontium and mucosa. Extractions should be limited to teeth that cannot be preserved (stage 3 mobility or presence of an active infectious focus) without stopping BP treatment, under local or locoregional anesthesia, without vasoconstrictor, under antibiotic treatment the day before extraction and then until complete healing (assessed clinically and radiologically),
– To regularize the alveolar crest and suture the edges hermetically, to consider making a periodontal splint to stabilize teeth whose mobility is stage 1 to 2, rather than extraction;
– To avoid extraction in the presence of a tooth with decaying caries but without pathological mobility, by performing root treatment (by cutting the crown of the tooth flush with the gum), and by reconstructing the tooth with conventional techniques, taking precautions not to alter the surrounding tissues;
– To contraindicate surgical periodontal treatments;
– To contraindicate implantology. On the other hand, the presence of implants already integrated into the bone structure does not increase the risk of ONJ; they must be preserved.
b. In patients receiving a bisphosphonate for osteoporosis/disease Page
*it is recommended:
-To carry out oral-dental monitoring, at least once a year.
-To perform dental extractions, when necessary, under antibiotic treatment and in the least traumatic way possible.
-The necessary surgery will be performed while avoiding lifting one or more full-thickness flaps; if there are problems closing the wound, a partial-thickness flap will be preferred to best preserve the vascularization of the underlying bone.
*Currently available data do not allow us to consider that taking BP for osteoporosis is a contraindication to the placement of a dental implant.
Tooth extraction protocols:
- Stop or not treatment with BPs by discussing with the prescribing doctor.
- Radiological assessment to assess the severity of the necrosis and the presence of sequestra
- Strict oral hygiene
- Local analgesic and antiseptic treatment (chlorhexidine mouthwash 0.1%) at stage 1
- Under 24-hour antibiotic treatment (AFSSAPS; Amoxicillin
02g/day) or 48 hours (DOESAK: German-Austrian-Swiss scientific working group on tumors of the mandible and the cervico-facial region; recommends the use of: Augmentin ®/in case of allergy it recommends clindamycin) of the extraction and then until complete healing.
- Under local or locoregional anesthesia, without vasoconstrictor.
- Avoid intraligamentous, intraseptal and intraosseous anesthesia.
- Tooth extraction followed by ridge regularization and hermetic sutures
- Flexible gutter
- ATB post op: 7 to 14 days.
- -Liquid to soft feeding
- Daily rinses with 0.2% chlorhexidine post-surgery.
- Removal of sutures after 10 to 14 days
- Remove the prostheses for at least 3 weeks.
- Patients with proven osteonecrosis:
-Care in a hospital department for maxillofacial surgery, ENT or dentistry.
-Radiological assessment (OPT) to assess the extent of the necrosis and the possible presence of a sequestrum.
-Avoid any surgical procedure
-Treat pain medically
-Strict oral hygiene: daily rinses with an antiseptic solution – 0.1% aqueous chlorhexidine – in the presence of ulcers with visible areas of necrotic bone in the mouth.
-Minimal surgical treatment (clean surgery with regularization of traumatic edges, elimination of mobile sequestrum).
-In case of fracture and significant bone necrosis of the mandible, reconstructions using free or pedicled bone grafts should be avoided.
-Resection of the necrotic bone in the vicinity of the fracture and external fixator or better reconstruction plate with screw anchors as far as possible from the area of necrosis.
1-Management of proven maxillary osteonecrosis:
a-Conservative treatment:
*Limited ONM : long-term broad-spectrum antibiotic therapy (penicillins-macrolides or tetracycline) + multiple daily antiseptic rinses + analgesics lead to a cure in the majority of cases.
*Otherwise minimal surgery : regularization of bone edges traumatic to soft tissues or if painful symptoms.
b-Invasive treatment:
-Medical treatment + surgery allow lasting mucosal closure to isolate the bone from the oral cavity to avoid secondary superinfections (good results if surgery is performed quickly after the appearance of ONJ).
-Conservative laser treatment + early excision surgery
Therapeutic window: to suspend or not treatment with BPs???
* Procedure for treating proven ONJ:
-Start preoperative antibiotic therapy with Augmentin® or failing that with clindamycin 48 hours before surgery per os or 24 hours before by intravenous injection.
-Postoperative antibiotic therapy for 10 to 14 days by IV route if the patient is hospitalized and per os if the patient is an outpatient.
-Subperiosteal section with wide exposure of the surgical site in case of endotracheal anesthesia.
-Complete manual or electrical excision of osteonecrosis until macroscopic detection of bleeding points.
-Regularization of bone ridges with diamond burs.
-Osteosynthesis in accordance with the surgeon’s decision.
-Possibility of closing the wound with “multi-layer” mucosal flaps.
-(a) With soft tissues of the floor of the mouth for cases of “boxed” loss of substance of the mandible.
-(b) With Bichat’s fatty ball in case of opening of the maxillary sinus.
– Hermetic sutures with separate stitches and protective gutter in soft, non-compressive silicone.
-Nasogastric tube feeding for 3 to 5 days for extensive surgeries; then liquid and soft diet for 10 to 14 days.
-Daily rinses with antiseptics (Chlorhexidine 0.2%) after surgery.
-Hospitalization for at least 7 days.
-Removal of the sutures after 10 to 14 days.
-Remove the prosthesis for at least 3 weeks.
BPs and dental implantology
- The risk of osteonecrosis associated with implant placement is low, but cannot be completely ruled out, in patients treated for a benign condition with oral BPs.
- Implantology is therefore possible, however it is necessary to rigorously assess the risk; it is also authorized in patients with osteoporosis and treated with intravenous BPS, however the patient must be informed that at present there is no data to assess the risk.
- The risk associated with implant placement is higher, and the occurrence of osteonecrosis is faster in patients treated with intravenous BPs for a malignant disease. The AFFSAPS considers that dental implants are formally contraindicated in patients treated with intravenous BPs.
Support for patients with dental implants or candidates for dental implants
- Patients with dental implants and candidates for BPs treatment:
- The recommendations are the same as for patients without dental implants.
- The presence of implants already integrated into the bone does not increase the risk of osteonecrosis, so their removal is not necessary.
a)- Patients on oral BPs and candidates for implant placement:
- The risk of osteonecrosis is low but should not be neglected. It increases even more if the duration of treatment is greater than 2 years.
- The patient should be informed of alternative solutions to implantology and the associated risks; some recommendations suggest that an informed consent form should be signed by the patient.
- The prescribing physician should be contacted to discuss the benefit/risk ratio of surgery and to adapt or even temporarily stop treatment if necessary.
- No data in the literature have established surgical protocols for implant placement in a patient on oral BPs. However, professional organizations recommend:
– Carry out hygiene measures before the procedure.
– Prescribe antiseptic mouthwashes (chlorhexidine) before and during the days following the procedure.
– Prescribe antibiotics the day before the operation and until complete healing (Amoxicillin 2g/day or Clindamycin 600mg/day).
– Start with a localized area and wait 2 months before the next intervention when there are multiple surgical sites, so as not to immediately expose the patient to extensive osteonecrosis.
– Avoid intra-ligamentous, intra-septal and intra-osseous anesthesia. Although debated, no validated data contraindicate the use of vasoconstrictors.
– Avoid lifting full thickness flaps.
– Smooth out sharp bone edges.
– Suture the edges without tension and in a hermetic manner.
– Perform a surgical procedure that is as non-traumatic as possible.
– Monitor healing and continue hygiene measures.
– Monitor the patient regularly (minimum twice a year).
b)- Patients on BPs and with dental implants
- Several complications can arise:
1- Peri-implantitis: Peri-implantitis is likely to increase the risk of ONJ, so it should be treated as quickly as possible. Non-surgical measures based on a mechanical approach that is as non-traumatic as possible (curettage, surface disinfection) and pharmacological (antibiotic therapy) with follow-up every 4 to 6 weeks should be preferred.
- Implant failure : If these surgical revision measures fail, the implant will have to be removed.
The recommendations for implant removal are similar to the protocol recommended for tooth extraction.
OSTEITIS DUE TO BIPHOSPHONATES AND ANTIRESORBERS
- Peri-implant osteonecrosis: In case of peri-implant osteonecrosis, the OSTEITIS DUE TO BIPHOSPHONATES AND
ANTI-RESORBERS
Introduction:
Antiresorbants are drugs that act as inhibitory agents of osteoclasts responsible for bone resorption. This is the origin of their wide use in recent years in improving the quality of life of patients with benign and malignant bone pathologies.
In addition to their proven effect in improving the quality of life of patients, the use of antiresorbants has been linked to the appearance of a major side effect which is osteonecrosis of the jaws (ONJ).
History
Bisphosphonates, formerly called diphosphonates, appeared in Germany towards the end of the 19th century . More precisely in 1865. They were mainly used as corrosion inhibitors in the textile and oil industries.
From the 60s bisphosphonates began to be used in the treatment of certain pathologies of bone metabolism.
2003 (Marx et al), the use of bisphosphonates was linked on the basis of clinical case reports and retrospective studies, to the appearance of a major side effect which is osteonecrosis of the jaws.
In 2005, AFSSAPS (French Agency for the Safety of Health Products) published an information letter intended for practitioners likely to prescribe bisphosphonates (BPs) or to have to surgically intervene on patients treated
In 2010, AFSSAPS and the MHRA (Medicines and Healthcare Products Regulatory Agency); communicated on the occurrence of cases of ONJ in cancer patients treated with antiangiogenics.
Bisphosphonates (BPs)
Definitions:
Bisphosphonates (BPs) are structural analogues of inorganic pyrophosphates; they are synthetic molecules prescribed primarily to decrease bone resorption.
Chemical structure of BPs: The central oxygen atom of the POP bond of inorganic pyrophosphate is replaced by a carbon atom (PCP bond), making the BP molecule resistant to enzymatic hydrolysis. The R1 radicals increase the affinity of BPs for hydroxyapatite. The R2 radicals determine the potency. Classification of BPS:
Non-amino BPs: 1st generation; containing CH, CH3 or H in the R2 position, they do not contain a nitrogen atom (clodronate, etidronate and tiludronate) Amino BPs: 2nd …3rd generation; containing CH , CH3 or H in the R2 position, they do not contain a nitrogen atom (clodronate, etidronate and tiludronate) Amino BPs: 4th
generation; containing CH, CH3 or H in the R2
position
, they do not contain a nitrogen atom (clodronate, etidronate and tiludronate ) Amino BPs: 5th generation; containing CH, CH3 or H in the R2 position, they do not contain a nitrogen atom (clodronate, etidronate and tiludronate) Amino BPs: 6th generation; containing CH, CH3 or H in the R2 position, they do not contain a nitrogen atom (clodronate, etidronate and tiludronate) Amino BPs: 7th generation; containing CH, CH3 or H in the R2 position, they do not contain a nitrogen atom (clodronate, etidronate and tiludronate) Amino BPs: 8
th and 3rd generation : have a nitrogen atom in their R2 radical (Alendronate, Pamidronate, Ibandronate, Zoledronate)
Pharmacokinetics of BPs:
BPs administered orally are poorly absorbed. Their bioavailability varies from 1 to 5%.
Intravenous administration ensures better bioavailability (40 to 61%).
The plasma half-life is short, of the order of a few hours (6h). On the other hand, their bone half-life lasts several years.
Elimination is via the kidneys.
1.5 Mechanism of action:
This is the result of 2 main chemical properties:
Affinity for hydroxyapatite and
– Inhibitory effect on osteoclasts.
Mode of action of BPs:
-Inhibition of calcification in soft tissues.
– Inhibition of bone resorption.
-Other effects:
-Antiangiogenic action: some BPs (Zoledronic acid).
-Pro-inflammatory effect
Indications:
1-Malignant pathologies:
Multiple myelomas
Osteolytic metastases of certain malignant tumors,
Malignant hypercalcemia.
2-benign pathologies:
Paget’s disease,
Osteoporosis (postmenopausal or male, corticosteroid-induced,
(SAPHO) syndrome,
Aseptic necrosis of the hip,
Osteogenesis imperfecta,
Fibrous dysplasia of the bones.
Adverse effects
– Short-term adverse effects: They are well known and for the most part minor and transient:
– Nausea, vomiting, diarrhea, abdominal pain, anemia, thrombocytopenia, leukopenia, sometimes pancytopenia, dysphagia, esophagitis, as well as esophageal ulcers, flu-like syndrome and headaches.
– Dry mouth and ulceration, rare cases of immediate hypersensitivity and erythema multiforme –
Long-term adverse effects: osteonecrosis of the jaws
Denosumab (Prolia®, Xgeva®):
Denosumab, antibodies (manufactured in the laboratory by genetic engineering) neutralizes the Rank-ligand protein mediator of the main pathway stimulating the different stages of osteoclast differentiation. By blocking their formation.
Denosumab prevents the destruction of bone tissue by these cells. It therefore acts on bone remodeling but unlike BPs, it does not remain in the bone and its action quickly ceases once the treatment is eliminated.
Antiangiogenics: Sunitinib (Sutent®) and bevacizumab (Avastin®)
Sunitinib and bevacizumab are respectively Indicated for the treatment of advanced cancers not amenable to surgical resection and for the treatment of metastatic cancers of the colon, rectum, pancreas, breast, lung and kidney.
OSTEONECROSIS OF THE MAXILLA
1-Definition of osteonecrosis of the jaw (ONJ) and ( BRONJ ) in English Bisphosphonates-Related Osteonecrosis of the Jaw:
AFSSAPS defines ONJ as follows:
Previous or current treatment with BPs.
Mucosal lesion in the maxillofacial region exposing necrotic bone, and persisting for more than 8 weeks.
No history of radiotherapy in the maxillary region.
No metastatic localization in the ONJ zone
2 – Pathophysiology:
– The fixation of BPs on bone hydroxyapatite crystals is proportional to the intensity of bone remodeling at the time of their administration.
– Their concentration is therefore higher in growth zones, bone sites in the process of healing, tumor sites and those which naturally present a higher rate of physiological remodeling such as the alveolar bone of the maxilla.
– At the level of the jaws, remodeling is important due to constant demands by functions and parafunctions such as chewing and muscular demands during speech, facial expressions, bruxism, etc., which would explain the locations of osteonecrosis at the maxillary and mandibular levels.
1. Hypocellularity theory :
BPs induce apoptosis of bone cells, especially osteoclasts. There is also a potential effect of BPs on osteocytes and osteoblasts,
which is the cause of a decrease in bone remodeling in areas of high BP concentrations.
2. Hypovascularization theory:
The antiangiogenic effect of certain BPs (zoledronate, pamidronate) leads to a decrease in intraosseous vascularization.
3. Theory of direct toxicity of BPs:
The accumulation of BPs at the level of the maxilla is directly toxic for the overlying mucosa, any trauma (tooth avulsion, prosthetic irritation, etc.) would cause an increase in the local concentration of Bps, responsible for the failure of healing of soft tissues and promotes superinfection and bone necrosis.
4. Micro-fracture theory:
A high-dose BP treatment could lead to a “frozen” bone whose remodeling is inhibited too much. This inert bone has lost all capacity to repair physiological micro-fractures induced by the function (zoledronate, pamidronate and alendronate).
5. Infectious theory:
In the oral cavity, the maxillae are subjected, during function (mastication) and parafunctions (bruxism), to regular stress which would stimulate the remodeling activity leading to a greater absorption of BPs. This accumulation of BPs could induce a drastic reduction in remodeling promoting bone necrosis.
Therefore, the vascularization of the overlying mucosa is reduced and any minor trauma could lead to exposure of the underlying necrotic bone. Secondary colonization by oral flora of the exposed necrotic bone can be responsible for pain or infectious accidents often revealing osteonecrosis.
3- Clinical study :
Several classifications
We describe 3 successive stages
Stage I: simple asymptomatic bone exposure with normal peripheral tissues.
Stage II: exposure of infected bone associated with functional symptoms and inflammation of peripheral tissues
Stage III: bone fracture with extraoral fistulization.
Based on the DOESAK scale
Stage 0: no symptoms of necrotic bone with intraoral exposure.
Stage I: asymptomatic intraoral exposure of necrotic bone or small asymptomatic intraoral fistula.
Stage II: Intraoral exposure of necrotic bone associated with pain and symptoms of concomitant infection.
Stage III: Intraoral exposure of necrotic bone associated with pain, swelling and cellulitis (abscess) formation, multiple fistulas and radiological signs of extensive osteolysis.
Stage IV: intraoral exposure of necrotic bone associated with pain, swelling and cellulitis formation (abscess), appearance of an extraoral fistula or a pathological fracture or a bucco-sinus communication and radiological signs of extensive osteolysis at the edge of the mandible or large parts of the maxilla.
Intraoral examination
A mucosal breach is found exposing avascular and atonic bone with 1 or more uninhabited dental alveoli. The presence of a bone sequestrum (responsible for pain) and inflammation of the gum and peripheral soft tissues. In the event of superinfection, there is suppuration with mucosal and/or cutaneous fistula.
Spontaneous tooth mobility and loss are associated with this clinical picture. General signs are exceptional.
The clinical aspect of ONJ combines functional signs such as pain of variable intensity, throbbing, non-systematic, paresthesia or anesthesia of the area concerned (labiomental region), halitosis, cacosmia (maxillary location with sinus repercussion).
Radiological aspects
Orthopantomogram/Retroalveolar:
The radiological signs of ONJ are absent at the beginning of the evolution even if ONJ is clinically visible; a loss of 30% to 50% of the bone mineral phase is required for ONJ to be detected. In advanced cases, sequestration is noted within an environment of radiological osteodensification
Computed tomography (CT):
Allows the cortical bone to be individualized from the cancellous bone, the evaluation of the extent of a possible bone sequestrum in formation, the periosteal proliferation at the mandibular level gives a double contour image
Magnetic resonance imaging (MRI):
allows the involvement of adjacent soft tissues, sinuses and the mandibular canal to be specified. It would also allow the detection of subclinical ONJ
CT-scan: allows images to be seen even before the appearance of clinical signs
Sintigraphy: is positive in patients with clinical ONJ
Histological examination
Histological analysis is not necessary for diagnosis but allows the elimination of other pathologies, in particular cancer metastases, and tumor involvement. The necrotic bone shows no signs of bone remodeling, a dense lympho-plasmacytic inflammatory infiltrate with polymorphonuclear neutrophils is found in the medullary spaces. In most cases, an infection with evidence of oral flora germs and sometimes an actinomyces infection is distinguished.
Biological tests:
1. Blood tests: FNS, ESR, CRP are of interest in monitoring, possibly in differential diagnosis
2. Bone remodeling markers:
2.1/ Urinary NTx: A urinary cross-linked N-telopeptides of collagen I (NTx) level is persistently elevated in a significant number of patients during treatment with bisphosphonates
2.2/ C-terminal telopeptide (CTX): The most widely used serological biochemical marker to stratify the risk of ONJ in bisphosphonate users is the cross-linked C-terminal telopeptide (CTX) of type I collagen. When the bone turnover rate increases, osteoclasts degrade type I collagen, which has the effect of releasing CTX molecules.
4. Risk factors
They are related to treatment with BPs and oral factors.
1.Molecule and route of administration:
Molecules administered by IV are more responsible for ONJ than orally.
The most potent molecules and the highest bioavailability are more often the cause of ONJ. Molecules: zoledronate-pamidronate by IV route.
2.Duration of treatment and cumulative dose:
The cumulative risk increases on average from 1% after 12 months of treatment to 11% after 48 months.
Exposure to the molecule (number of infusions and cumulative number of hours of infusion is directly correlated with the risk of developing ONJ). 3.Oral-dental factors: Intra-oral invasive procedures or dento-periodontal pathologies are found in 50% to 85% of the triggering of ONJ. 4.Other factors: are corticosteroid therapy, anticancer treatments (no formal proof). 5.Diagnosis 1.Positive diagnosis: These are the criteria set out in the ONM definition. 2.Differential diagnosis: all other types of osteitis (ORN, chronic and acute secondary osteitis, osteomyelitis, primary osteitis, corticosteroid-induced osteitis) and a primary location or metastasis of cancer. THERAPEUTIC MANAGEMENT: -The French Agency for the Safety of Health Products (AFSSAPS), in 2007, in collaboration with a group of experts including clinicians, stomatologists, maxillofacial surgeons and dental surgeons, developed recommendations concerning the oral care of patients treated with BP. -These recommendations concern three situations: *Patients who are candidates for treatment with bisphosphonates.
*Patients treated with bisphosphonates without evidence of osteonecrosis.
*Patients with proven osteonecrosis.
ONJ continues to progress even with treatment.
Prevention
Preventive measures before treatment: clinical and radiological oral health assessment.
Elimination of proven or potential infectious foci by extraction or conservative treatment.
Periodontal sanitation (scaling and rigorous oral hygiene).
Elimination of all possible causes of mucosal trauma.
Inform the patient of the risks involved and their role in preventing ONJ.
After treatment: clinical follow-up to intercept any problem and manage it in the least invasive way.
1. Patients who are candidates for bisphosphonate treatment:
a. In patients who are to receive a BP for malignant pathologies :
*it is essential to carry out an oral health assessment: this will be carried out by a dental surgeon or a stomatologist.
*To perform a radiological assessment: the dental panoramic should be supplemented by retro-alveolar images or even a dental scanner or CT scan in case of doubt concerning an infectious focus.
*It is preferable to start treatment with BP, if the patient’s clinical condition allows it, only once the dental situation has cleared up: the necessary dental care must be carried out, all infectious foci must be eliminated, the mucous membranes must be healed and, if possible, the bone must heal completely (120 days).
b. In patients who need to receive BP in the context of osteoporosis/Paget’s disease
*it is recommended to perform an oral-dental assessment, follow-up of the necessary dental care. This care must not delay the start of treatment with BP in patients at high risk of fractures.
2. Patients treated with bisphosphonate without evidence of osteonecrosis:
a. In patients receiving bisphosphonate for malignant diseases ,
*it is essential to carry out oral-dental monitoring. This will be carried out by a specialist every 4 months and at the slightest oral-dental symptom, in collaboration with the oncologist.
– Detect and treat infectious foci using procedures that are as non-invasive as possible for the bone, periodontium and mucosa. Extractions should be limited to teeth that cannot be preserved (stage 3 mobility or presence of an active infectious focus) without stopping BP treatment, under local or locoregional anesthesia, without vasoconstrictor, under antibiotic treatment the day before extraction and then until complete healing (assessed clinically and radiologically),
– Regularize the alveolar ridge and suture the edges hermetically, consider making a periodontal splint to stabilize teeth with stage 1 to 2 mobility, rather than extraction;
– To avoid extraction in the presence of a tooth with decaying caries but without pathological mobility, by performing root canal treatment (cutting the crown of the tooth flush with the gum), and by reconstructing the tooth with conventional techniques, taking precautions not to alter the surrounding tissues;
– To contraindicate surgical periodontal treatments;
– To contraindicate implantology. On the other hand, the presence of implants already integrated into the bone structure does not increase the risk of ONJ; they must be preserved.
b. In patients receiving a bisphosphonate for osteoporosis/disease Page
*it is recommended:
-To carry out oral-dental monitoring, at least once a year.
-To perform dental extractions, when necessary, under antibiotic treatment and in the least traumatic way possible.
-The necessary surgery will be performed while avoiding lifting one or more full-thickness flaps; If there are problems with wound closure, a partial thickness flap will be preferred to best preserve the vascularization of the underlying bone.
*The data currently available do not allow us to consider that taking BPs for osteoporosis is a contraindication to the placement of a dental implant.
Dental extraction protocols:
Stop or not treatment with BPs by discussing with the prescribing physician.
Radiological assessment to assess the severity of the necrosis and the presence of sequestra
Strict oral hygiene
Local analgesic and antiseptic treatment (chlorhexidine mouthwash 0.1%) at stage 1
Under antibiotic treatment for 24 hours (AFSSAPS; Amoxicillin
02g/day) or 48 hours (DOESAK: German-Austrian-Swiss scientific working group on tumors of the mandible and the cervicofacial region; recommends the use of: Augmentin ®/in case of allergy it recommends clindamycin) of the extraction and then until complete healing.
Under local or locoregional anesthesia, without vasoconstrictor.
Avoid intraligamentous, intraseptal and intraosseous anesthesia.
Tooth extraction followed by regularization of ridges and hermetic sutures
Soft
ATB splint post-op: 7 to 14 days.
-Liquid to soft
diet Daily rinse with 0.2% chlorhexidine post-surgery.
Removal of sutures after 10 to 14 days
Removal of prostheses for at least 3 weeks.
Patients with proven osteonecrosis:
– Management in a hospital department of maxillofacial surgery, ENT or dentistry.
– Radiological assessment (OPT) to assess the extent of the necrosis and the possible presence of a sequestrum.
– Avoid any surgical procedure
– Treat the pain medically
– Strict oral hygiene: daily rinses with an antiseptic solution – 0.1% aqueous chlorhexidine – in the presence of ulcers with a visible area of necrotic bone in the mouth. – Minimal
surgical treatment (clean surgery with regularization of the traumatic edges, removal of mobile sequestrum). – In the event of fracture and significant bone necrosis of the mandible, reconstructions with free or pedicled bone grafts should be avoided. -Resection of the necrotic bone near the fracture and external fixator or better reconstruction plate with screw anchors as far as possible from the area of necrosis. 1-Management of proven maxillary osteonecrosis: a-Conservative treatment: *Limited ONJ : long-term broad-spectrum antibiotic therapy (penicillins-macrolides or tetracycline) + antiseptic rinses several times a day + analgesics lead to healing in the majority of cases. *Otherwise minimal surgery : regularization of the bone edges traumatizing the soft tissues or if painful symptoms. b-Invasive treatment: -Medical treatment +
surgery allows a lasting mucosal closure to isolate the bone from the oral cavity to avoid secondary superinfections (good results if surgery is performed quickly after the onset of ONJ).
-Conservative laser treatment + early excision surgery
Therapeutic window: suspend or not treatment with BPs???
* Procedure for treating proven ONJ:
-Start preoperative antibiotic therapy with Augmentin® or failing that with clindamycin 48 hours before surgery per os or 24 before by intravenous injection.
-Postoperative antibiotic therapy for 10 to 14 days by IV route if the patient is hospitalized and per os if the patient is an outpatient.
-Subperiosteal section with wide exposure of the surgical site in the event of endotracheal anesthesia.
-Complete manual or electrical excision of the osteonecrosis until macroscopic detection of bleeding points.
-Regularization of bone ridges with diamond burrs.
-Osteosynthesis according to the surgeon’s decision.
-Possibility of closing the wound with mucosal flaps “in several layers”.
-(a) With the soft tissues of the floor of the mouth for cases of loss of substance “in box” of the mandible.
-(b) With the Bichat fat ball in case of opening of the maxillary sinus.
-Hermetic sutures by separated stitches and protective gutter in soft non-compressive silicone.
-Feeding by nasogastric tube for 3 to 5 days for extensive surgeries; then liquid and soft diet for 10 to 14 days.
-Daily rinses with antiseptics (Chlorhexidine 0.2%) after surgery.
-Hospitalization for at least 7 days.
-Removal of the sutures after 10 to 14 days.
-Remove the prosthesis for at least 3 weeks.
BPs and dental implantology
The risk of osteonecrosis associated with implant placement is low, but cannot be completely ruled out, in patients treated for a benign condition with oral BPs.
Implantology is therefore possible, however it is necessary to rigorously assess the risk; it is also authorized in patients with osteoporosis and treated with intravenous BPS, however the patient must be informed that at present there is no data to assess the risk.
The risk associated with implant placement is higher, and the occurrence of osteonecrosis is faster in patients treated with intravenous BPs for a malignant disease. The AFFSAPS considers that dental implants are formally contraindicated in patients treated with intravenous BPs.
Management of patients with implants or candidates for dental implants
Patients with dental implants and candidates for treatment with BPs:
The recommendations are identical to those for patients not wearing dental implants.
The presence of implants already integrated into the bone does not increase the risk of osteonecrosis, so their removal is not necessary.
a)- Patients on oral BPs and candidates for implant placement:
The risk of osteonecrosis is low but should not be neglected. It increases even more when the duration of treatment is greater than 2 years.
The patient must be informed of alternative solutions to implantology and the associated risks; Some recommendations suggest that an informed consent form must be signed by the patient.
The prescribing physician should be contacted to discuss the benefit/risk ratio of surgery, to adapt or temporarily stop treatment if necessary.
No data in the literature has established surgical protocols for implant placement in a patient on oral BPs. However, professional organizations recommend:
– Carry out hygiene measures before the procedure.
– Prescribe antiseptic mouthwashes (chlorhexidine) before and during the days following the procedure.
– Prescribe antibiotics the day before the procedure and until complete healing (Amoxicillin 2g/day or Clindamycin 600mg/day).
– Start with a localized area and wait 2 months before the next procedure when there are multiple surgical sites, so as not to immediately expose the patient to extensive osteonecrosis.
– Avoid intra-ligamentous, intra-septal and intra-osseous anesthesia. Although debated, no validated data contraindicates the use of vasoconstrictors.
– Avoid raising full-thickness flaps.
– Regularize sharp bone edges.
– Suture the edges without tension and hermetically.
– Perform a surgical procedure that is as non-traumatic as possible.
– Monitor healing and continue hygiene measures.
– Follow the patient regularly (2 times a year minimum).
b)- Patients on BPs and with dental implants
Several complications can occur:
1- Peri-implantitis: peri-implantitis is likely to increase the risk of ONJ, it must therefore be treated as quickly as possible. Non-surgical measures based on a mechanical approach that is as non-traumatic as possible (curettage, surface disinfection) and pharmacological (antibiotic therapy) with follow-up every 4 to 6 weeks are to be preferred.
Implant failure : If these surgical revision measures fail, the implant will have to be removed.
The recommendations related to implant removal are similar to the protocol recommended for tooth extraction.
Peri-implant osteonecrosis: In the event of peri-implant osteonecrosis, treatment must be carried out in a hospital setting and is inspired by the classic management of osteonecrosis. The goal is to reduce pain, soft tissue infection, and to reduce the progression of bone necrosis.
Conclusion:
Osteonecrosis of the jaws is a serious side effect of bisphosphonate treatment. While waiting for the development of a specific treatment for this complication; prevention remains the best initiative, it involves informing patients about the risks of treatment and educating them on good oral hygiene.
should be carried out in a hospital setting and is inspired by the classic management of osteonecrosis. The goal is to reduce pain, soft tissue infection, and to reduce the progression of bone necrosis.
- Conclusion :
Osteonecrosis of the jaws is a serious side effect of bisphosphonate treatment. While waiting for the development of a specific treatment for this complication, prevention remains the best initiative, which involves informing patients about the risks of treatment and educating them on good oral hygiene.
OSTEITIS DUE TO BIPHOSPHONATES AND ANTIRESORBERS
Cracked teeth can be healed with modern techniques.
Gum disease can be prevented with proper brushing.
Dental implants integrate with the bone for a long-lasting solution.
Yellowed teeth can be brightened with professional whitening.
Dental X-rays reveal problems that are invisible to the naked eye.
Sensitive teeth benefit from specific toothpastes.
A diet low in sugar protects against cavities.