bisphosphonates and osteonecrosis of the jaw

September 2009 DentalUpdate 415

UpdateonBisphosphonates

Yazdana Arrain

Bisphosphonates and Osteonecrosis of the Jaw - Current ThoughtsAbstract: Bisphosphonates are increasingly being used in a number of bone conditions, including osteoporosis and metastatic cancer. As a consequence, the reported cases of bisphosphonate-related osteonecrosis of the jaw (BONJ) have increased. BONJ remains rare in patients being treated for osteoporosis , but is commoner in cancer patients where the bisphosphonate doses are much higher and mode of delivery is intravenous. Recently, much more is known about classification and mode of action of the bisphosphonates. The potency of the various nitrogen-containing bisphosphonates is dependent on a number of factors including bone binding, zeta potential and inhibition of the enzyme farnesyl pyrophosphate synthase. There is current debate on why BONJ affects the jaw, particularly in relation to whether the jaw has high bone turnover or not. More is being learnt about the micro-organisms involved in the pathogenesis of BONJ and there is increasing evidence on the role of surgical treatment of this disabling condition.Clinical Relevance: Dentists should be aware of the association of bisphosphonates and BONJ. This paper provides recent knowledge on bisphosphonate action, pathogenesis of BONJ and its treatment. Dent Update 2009; 36: 415–419

Bisphosphonates are pyrophosphate analogues which inhibit osteoclastic resorption of bone and are used in the treatment of a variety of bone-related conditions including:

Osteoporosis; Paget’s disease; Hypercalcaemia; Metastatic cancer affecting the bone; and Osteogenesis imperfecta.

The vast majority of bisphosphonate use is for the treatment of osteoporosis, followed by treatment of cancer patients. Bisphosphonates can be given orally (eg etidronate, tiludronate, clodronate, alendronate, risedronate), intravenously (eg pamidronate, zoledronate) or both (ibandronate) and different bisphosphonates have different licensing conditions.

A confirmed case of bisphosphonate-associated osteonecrosis of the jaw (BONJ) is defined as ‘an area of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a healthcare worker, in a patient who was receiving, or had been exposed to, a bisphosphonate and had not received radiation therapy to the craniofacial region.’

BONJ is very rare in those patients receiving a bisphosphonate to treat their osteoporosis. The incidence in this situation is currently thought to be between 1 in 10,000

Yazdana Arrain, BDS, DRDP GDP and part-time Clinical Lecturer in Restorative Dentistry, University of Birmingham School of Dentistry, St Chad’s Queensway, Birmingham B4 6NN and Tahir Masud,MA(Oxon), MBBS(Lond), MSc(Nott), FRCP, Consultant Physician and Professor, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB and Visiting Professor of Musculoskeletal Gerontology, University of Derby, UK.

and 1 in 100,000. In contrast, the incidence for cancer patients receiving bisphosphonates (usually intravenously and in much higher doses) is believed to be much higher, with current estimates suggesting between 1 in 10 and 1 in 100.1 With regards to osteoporosis, it is important to remember that this condition can lead to fragility fractures and is associated with significant morbidity, mortality (due mainly to the complications associated with hip fractures) and cost to the health and social services. Bisphosphonates are generally used as the first line treatment for osteoporosis and have been shown to reduce the risk of fragility fractures significantly.

When it does occur, BONJ can significantly reduce the quality of life. It can affect the ability to eat and, if treatment involves removal of a significant amount of jaw bone, it can result in facial asymmetry, pain, paraesthesia, disfigurement, depression, inability to enjoy food, and possibly affect relationships. From cleft palate studies the

Tahir Masud

pg415-419 Bisphosphonates.indd 1 28/8/09 12:56:53


416 DentalUpdate September 2009

overall effect of dentofacial self perception and social perception depends upon the degree of asymmetry.2 Recently, attention bias to facial deformities has been measured quantitatively using eye movement patterns. This work has suggested that observers tend to focus on deformities, including those around the mouth.3

There is an obvious need for further research into this area. With increasing use of bisphosphonates, the number of reported patients with BONJ is increasing and long-term research into epidemiology, diagnosis and treatment is needed.

Structure, classification and mechanism of action of bisphosphonates

Structurally, all the bisphosphonates consist of two phosphate groups bound to carbon atoms by covalent bonds (Figure 1). The short R1 chain confers pharmacokinetics and the longer R2 chain influences bisphosphonate potency. The resorption ability of the molecule can be increased by adding a chain containing cyclic nitrogen or an aminoterminal group on to the R2 side.

The mode of action of bisphosphonates is now more clearly understood. The newer classification differentiates them into three groups, as in Table 1.4 Groups 2 and 3 contain nitrogen and are more widely used as they are extremely bone selective. For this reason, the first generation non-nitrogen-containing bisphosphonates are now rarely used.

Bisphosphonates have a high affinity for calcium ions and so they are strongly attracted to bone. In the resorptive process, bisphosphonates are released from the bone surface (which is acidified) and are taken up by osteoclasts. In fact, osteoclasts can take up large amounts

of bisphosphonates during natural bone resorption.5

Protein prenylation is important in osteoclastic activities and for the osteoclast to survive. Recent research shows that the nitrogen-containing bisphosphonates target protein prenylation (Figure 2). The effects of nitrogen bisphosphonates on osteoclasts are reversed by the addition of a substrate for protein prenylation in vitro (eg geranylgeraniol).6 The mevalonate pathway (which also produces cholesterol and other sterols) is central to the prenylation process. In this pathway, the action of enzyme farnesyl pyroposphate synthase (FPPS) leads to the production of farnesyl pyrophosphate (FPP), which is necessary for the production of

geranylgeranylpyrophosphate (GGPP) via the actions of enzyme GGPP synthase. FPP and GGPP are both required for prenylation (lipid modification) of GTPases, which are signalling proteins important for osteoclastic function and survival. The nitrogen bisphosphonates are now known to inhibit FPPS, the result of which is the accumulation of unprenylated GTPases, which results in the inhibition of osteoclastic function and reduced bone resorption.4 It is not necessary for cell apoptosis to occur, though this eventually may happen.

Bisphosphonate potencyThere are three factors which

Figure 1. Basic bisphosphonate structure.

GROUP DRUGS IN GROUP EFFECT

1. Non-nitrogen clodronate, etidronate, Incorporation into Adenosine Bisphosphonate tiludronate Triphosphate (ATP),

resulting in osteoclast apoptosis

2. Alkyl-amino pamidronate, alendronate, Inhibits the enzyme FarnesylBisphosphonate ibandronate Pyrophosphate Synthase (FPPS)

3. Heterocyclic risedronate, zoledronate Inhibits the enzyme FarnesylNitrogen Pyrophosphate Synthase (FPPS)Bisphosphonate

Table 1. Contemporary classification of bisphosphonates.

Figure 2. Action of nitrogen containing bisphosphonates on osteoclasts.




contribute to the potency of bisphosphonates: Kinetic binding to bone; Zeta potential; and Enzyme inhibition (Figure 3).

Kinetic binding studies have been important in determining the relative drug binding and excretion of the different bisphosphpnates. The non-nitrogen bisphosphonates (eg clodronate and etidronate) have by far the lowest kinetic binding energy to bone7,8 − these first generation bisphosphonates are less potent and are no longer commonly used for the treatment of conditions such as osteoporosis. The molecular 3D differences between the nitrogen-containing bisphosphonates to form the N-H-O bonds result in a differing bone hydroxyapatite affinity.9 This, in turn, could potentially alter clinical effectiveness and potency of the bisphosphonates.

There are differing electrical charges carried by bisphosphonates on their N atom in the R2 group at a pH of 7.4. Charges are conferred to hydroxyapatite when bisphosphonates bind to it (zeta potential). More positively charged bisphosphonates, such as alendronate, ibandronate and zoledronate, produce a more positive charged bone surface which then attracts more bisphosphonate molecules via their negatively charged phosphate components. This effect probably increases the maximum binding capacity of the

bisphosphonate on the bone.As discussed above, FPPS is

an important enzyme in the mevalonate pathway and the prenylation process, which is vital to osteoclastic functioning. The various nitrogen bisphosphonates differ in their ability to inhibit FPPS, and these differences partly influence their relative potencies.

It is important to recognize that the relative order of the various nitrogen bisphosphonates in terms of kinetic binding, electrical charge (zeta potential) and FPPS inhibition is different according to which of these parameters is considered. Individual properties of each bisphosphonate mean differing potencies and resulting effects on bone. For example, risedronate, which has a lower kinetic binding to bone when compared to alendronate and ibandronate, has a much higher enzyme-binding and inhibiting ability. Risedronate is a relatively strong inhibitor of FPPS (more so than alendronate and ibandronate but not as strong as zoledronate). This is why alendronate and risedronate can be used at fairly similar clinical doses.4 Zoledronate is high up in terms of rank order for kinetic binding to bone, as well as inhibition of FPPS, and is therefore an extremely effective anti-resorptive.

At present, it is not clear which of the three potency parameters, if any, are more relevant in the pathogenesis of BONJ. Also,

it is not entirely clear at present if the risk of BONJ varies between the different nitrogen bisphosphonates. Further work is needed in this area as it may throw light on the pathogenesis of BONJ.

Half life of bisphosphonatesHalf life of bisphosphonates can

be considered in two ways: The half life of the bisphosphonate drug

itself; and The half life of its effects.

When bisphosphonates are ‘entombed’ inside the mineral phase they are not pharmacologically active.10 They are activated when the resorption and remodelling processes release them from the bone.

All bisphosphonates are excreted via the urine. Those with a higher binding affinity, such as zoledronate, pamidronate and alendronate (Figure 3) show less excretion initially but, once treatment is stopped, they can be measured in the urine weeks to years afterwards as they are slowly released from the skeleton.4 On the other hand, risedronate, which has a lower binding affinity and a negative electrical charge, is excreted quicker and is not detected for such a long time in the urine as are the other bisphosphonates.

Pathogenesis of BONJIt is unclear why osteonecrosis

occurs at the jaw site with the use of bisphosphonates. Osteonecrosis in the jaw can occur without bisphosphonate use in the context of patients receiving cancer chemotherapy.11 We know that the various bisphosphonates have different bone affinity, and there may be differential bisphosphonate uptake by trabecular compared to cortical bone, and by endosteal compared to periosteal sites. It is often stated that the jaw has a higher bone turnover than the rest of the skeleton and this is the reason why BONJ occurs. However, this view is now being disputed. Animal studies show that the concentration of injected bisphosphonate (ibandronate) was similar in the bones of the spine, femur and jaw, arguing against any preferential uptake in the latter site.12 More understanding of bone biology is needed to clarify this area.

The route of administration seems to be important in the risk of developing

Figure 3. The nitrogen bisphosphonate potency triangle. (FPPS*=Farnesyl pyrophosphate synthase).



418 DentalUpdate September 2009

BONJ. Although BONJ can occur with oral bisphosphonates, the risk may be higher with the intravenous mode. Using a USA medical claims database of 714,217 people with osteoporosis or cancer, Cartsos et al showed that the intravenous route, but not the oral route, of administering bisphosphponates, was associated with an increased risk of having inflammatory conditions, including BONJ (four-fold increased risk) and also of having undergone major surgical resection of the jaw (six-fold increased risk).13

Some researchers have suggested that BONJ may be initiated in the oral mucosa rather than the underlying bone. Using animal studies, Llandesberg et al have shown that the bisphosphonate pamidronate inhibits oral keratinocyte wound healing. This mechanism may therefore play an important role in the initiation of BONJ.14 This may, theoretically, explain why denture trauma and tori removal can result in BONJ.

The presence of oral disease may be an important issue in relation to BONJ. Ahn and Shin investigated post-extraction bone formation over time in both diseased and healthy sockets in patients not taking bisphosphonates and showed that osseous regeneration in the diseased sockets occurred more slowly, showing that the presence of oral disease means jawbone healing is impaired.15 Delayed wound healing coupled with host responses may mean that extraction of an infected tooth would take longer to heal if the patient was taking a bisphosphonate. Hikita et al found that the healing pattern in extraction sockets of rats was altered with administration of bisphosphonates. Early new bone formation was delayed.16

Another potential mechanism whereby bisphosphonates may adversely affect healing (but also prevent metastases) is by their inhibition of the angiogenesis process which has been described in some models.17

Prevention and treatment of BONJ

Once BONJ has developed, treatment can be problematic and thus it is wise to follow guidelines which aim to prevent the development of BONJ.1,18 This is particularly important in patients with cancer receiving chemotherapy, including relatively higher doses of intravenous bisphosphonates. In this situation, one should consider removing diseased, unrestorable

teeth, restore decayed teeth, address any gum disease and ensure patients are dentally fit prior to bisphosphonate treatment. The dental surgeon should liaise with the medical team as it is important to ensure that life-saving treatment is not delayed.

Treatment of BONJBiofilm formation with

multiorganisms (bacteria and sometimes yeast) are found in sites of BONJ. These sites may contain a host of organisms, including actinomyces, staphylococcus, streptococcus, selenomonas, fusobacterium and treponemes.19 Microbial cultures and liaison with microbiologists can help in patient management, especially in refractory and aggressive cases. Knowing the minimum inhibitory concentrations (MIC − the minimum concentration of antibiotic that results in inhibition of visible growth of colonies on a plate or turbidity in broth culture) and the minimum bacteriocidal concentration (MBC − the lowest concentration of antibiotic that kills 99.9% of the original inoculums in a given time) is important.

Marx et al recommend the use of long-term or continuous penicillin V 500 mg four times a day as actinomyces is a frequent colonizer in the BONJ site. In refractory or very symptomatic cases, metronidazole can be used alongside the penicillin. In severe cellulitis cases, intravenous antibiotics with in-patient monitoring is usually required.20

Surgical treatment of BONJRecent studies show that, in BONJ,

there have been good healing results with aggressive removal of necrotic alveolar bone tissue, which has allowed primary wound closure without extensive mobilization of mucosa. The study by Markose et al chose patients for surgery where pain and infection was associated with a small region of alveolar bone. Of the 15 patients with BONJ, 14 healed completely after 2 weeks. They were all given one pre-operative dose of clindamycin. Resorbable sutures were used, so that the wound was not disturbed again. Toothbrushing and use of 0.2% chlorhexidine mouthwash was advocated.21

Carlson and Basile explored the success of surgical resection. They identified 103 sites of BONJ in 82 patients (30 patients were taking oral and 52 intravenous

bisphosphonates). Resection was performed in 95 sites in 74 patients. In patients taking oral bisphosphonates, 26 out of 27 resected sites (96.3%) healed satisfactorily. With the intravenous bisphosphonate patients, 61 of 68 (89.7%) resected sites healed satisfactorily. Eight patients developed refractory disease which was managed successfully after a more aggressive resection, specifically a segmental resection after a marginal resection of the mandible where refractory disease developed. All 29 patients undergoing resection of the maxilla (oral and intravenous bisphosphonates) healed acceptably.22

Mucke et al recently described two cancer (breast and multiple myeloma, respectively) patient cases where the patients were taking intravenous zoledronate. Both had radical resection and osteocutaneous flaps. Donor sites were screened to exclude metastasis. Radical resection, titanium miniplates and immediate reconstruction with an osteocutaneous iliac crest flap was carried out for the first patient − this was followed by 10 days of intravenous antibiotics. The second patient had undergone five failed attempts at surgical debridement, removal of sequestra and flap closure which, after a thinned mandible, resulted in mandibular fracture. Primary reconstruction was carried out successfully with an osteocutaneous fibula flap. Maximization of blood supply was thought to be important for the healing process.23

Marx suggests that, for mandibular resections, reconstruction using rigid titanium plates can be considered provided there is control of secondary infection. If there is a lot of secondary infection, he recommends delaying plate placement. Pectoralis major myocutaneous flap, trapezius myocutaneous flap or the sternocleidomastoid flap can also be considered. In the maxilla, obturators are constructed following resections. As for cancer resections, the bone defects and missing teeth will need to be dealt with using grafting and, possibly, dental implants.24

Children with bone disease, such as osteogenesis imperfecta, are sometimes given intravenous bisphosphonates, usually pamidronate. There are no records currently of children suffering with BONJ.25−27 The children in this category are advised to visit their dentist regularly. Dentists need to work with such patients to maintain oral health, as prevention is the key. If a child needs surgery




(eg intramedullary rod placement), one should consider stopping the bisphosphonate a few months prior to their operation, although how much this helps in healing is not known. Currently, for both adults and children, there is little evidence that for those patients already taking a bisphosphonate, stopping the latter prior to extraction or invasive jaw surgery improves outcomes, although this is often advocated.

It is essential that, as newer surgical techniques for the treatment for BONJ are tried, the outcomes are carefully assessed and published in the literature.

SummaryIn conclusion, in the last

few years there is newer understanding of the mechanisms of actions of the bisphosphonates, as well as on the pathogenesis and consequences of BONJ. We also have some more literature on the management of BONJ, particularly with regards to surgical management. However, there is still a lot to learn with regards to epidemiology, prevention and management of this disabling condition, and much of the current prevention and management strategies are based on theoretical principles rather than on firm evidence.

References1. Khosla S, Burr D, Cauley J, Dempster D,

Ebeling P, Felsenburg D et al.Bisphosphonate-associated osteonecrosis of the jaw: report of a taskforce of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22:1479−1491.

2. Meyer-Marcotty P, Stellzig-Eisenhauer A. Dentofacial self–perception of adults with unilateral cleft lip and palate. J Orofac Orthop 2009; 70: 224−236.

3. Ishii L, Carey J, Byrne P, Zee DS, Ishii M. Measuring attention bias to peripheral facial deformities. Laryngoscope 2009; 119: 459−465.

4. Russell RGG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficiency. Osteoporosis Int2008; 19: 733−759.

5. Coxon FP, Thompson K, Roelofs AJ, Ebetino FH, Rogers MJ. Visualising mineral

binding and uptake of bisphosphonate by osteoclast and non-resorbing cells. Bone 2008; 42: 848−860.

6. Fisher JE, Rogers MJ, Halasy JM, Luckman SP et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro.Proc Natl Acad Sci USA 1999; 96: 133−138.

7. Nancollas GH, Tang R, Phipps RJ et al. Novel insights into the actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone2006; 38: 617−627.

8. Ebetino FH, Emmerling P, Barnett B et al. Differentiation of hydroxyapatite affinity of bisphosphonate analogs for mechanism of action studies. J Bone Miner Res 2004; 19 (Supp1): S396.

9. Lawson MA, Tifin JT, Ebetino FH et al. Potential bone mineral binding differences among bisphosphonates can be demonstrated by the use of hydroxyapatite column chromatography.J Bone Miner Res 2005; 20(Suppl 1): s396.

10. Sato M, Grasser W, Endo N et al.Bisphosphonate action − Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest1999; 88: 2095−2105.

11. Schwartz HC. Osteonecrosis of the jaws: a complication of cancer therapy. Head Neck Surg 1982; 4: 251.

12. Bauss F, Pfister T, Papapoulos S. Ibandronate uptake in the jaw is similar to long bones and vertebrae in the rat. J Bone Miner Metab 2008; 26: 406−408.

13. Cartsos VM, Zhu S, Zavras AI. Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people. J Am Dent Assoc2008; 139: 23−30.

14. Llandesberg R, Cozin M, Cremers S, Woo V et al. Inhibition of oral mucosal cell healing by bisphosphonates. J Oral Maxillofac Surg 2008; 66: 839−847.

15. Ahn JJ, Shin HI. Bone tissue formation in extraction sockets from sites with advanced periodontal disease: a histomorphometric study in humans. Int J Oral Maxillofac Implants 2008; 23:1133−1138.

16. Hikita H, Miyazawa K, Tabuchi M, Kimura M, Goto S. Bisphosphonate administration prior to tooth extraction delays healing of the extraction socket in rats. J Bone

Miner Metab 2009 [epub ahead of print].17. Fournier P, Bossier S, Filleur S, Guglidmi J,

Carbon F et al. Bisphosphonates inhibit angiogenesis in vitro in the ventral prostate in castrated rats. Cancer Res2002; 62: 6538−6544.

18. Arrain Y, Masud T. Recent recommendations on bisphosphonate-associated osteonecrosis of the jaw. Dent Update 2008; 35: 238−242.

19. Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C et al. Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg 2008; 66:839−847.

20. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate induced exposed bone (osteonecrosis/osteopetrosis) of the jaws − risk factors, recognition, prevention and treatment. J Oral Maxillofac Surg 2005; 63:1567−1575.

21. Markose G, Mackenzie F, Currie WJR, Hislop WS. Bisphosphonate osteonecrosis: a protocol for surgical management. Br J Oral Maxillofac Surg 2009; 47: 294−297.

22. Carlson ER, Basile JD. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2009; 67(5 Suppl): 85−95.

23. Mucke T, Haarmann S, Klaus-Dietrich W, Holzle F. Bisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstruction. J Craniomaxillofac Surg 2009; 37:291−297.

24. Marx RE. Reconstruction of defects caused by bisphosphonate-induced osteonecrosis of the jaws. J Oral Maxillofac Surg 2009; 67(5 Suppl): 107−119.

25. Brown JJ, Ramalingam L, Zacharin MR. Bisphosphonate-associated osteonecrosis of the jaw: does it occur in children. Clin Endocrinol 2008; 68: 863−867.

26. Chahine C, Cheung MS, Head TW, Schwartz S et al. Tooth extraction socket healing in paediatric patients treated with intravenous pamidronate. J Pediatr2008; 153: 719−720.

27. Schwartz S, Joseph C, Iera D, Vu DD. Bisphosphonates, osteonecrosis, osteogenesis imperfecta and dental extractions: a case series. J Can Dent Assoc2008; 74: 537−542.


bisphosphonates and osteonecrosis of the jaw

Documents