Introduction

 

 The annual IADR conference is a key date in the diaries of dental researchers from all over the world. Juliette Reeves attended the 88 General Session of the International Association of Dental Research in Barcelona, and reports back on some of the latest research presented over the four day program.

 

ONJ has been identified as an area of exposed, non vital bone in the maxilla or mandible that persists over 6-8 weeks following exposure to bisphosphonates and excluding radiation therapy (1). ONJ is a debilitating disease and occurs as a result of reduced local blood supply to the bone. The association of this disease with bisphosphonate use began to emerge in 2003 when case reports, case series and cohort studies began to suggest a link between bisphosphonate treatment and ONJ prevalence rates (2,3). These rates however varied from less than 1% to 28% with neither causality or specific risk factors being established.

 

 

Incidence

 

Prevalence of ONJ in cancer patients receiving intravenous bisphosphonate therapy has always thought to be high (6-10%) (4), and until recently, was thought to be much lower in patients on oral bisphosphonate therapy. In 2009 however, Sedghizadeh et al  reported seeing two to three new patients a week with bisphosphonate-related ONJ, which indicated an ONJ incidence of 4% in patients taking oral bisphosphonates (5) . Research published  by the IADR/AADR conducted by Fellows et al (6)  found that patients taking oral bisphosphonates were 15.5 times more likely to have ONJ than non exposed patients. This study estimated ONJ incidence and odds ratios from bisphosphonate exposure and other risk factors using a manual chart reviews of a 572,606 patient cohort. Among the 23 cases identified 87% had at least one risk factor with 26% receiving bisphosphonates.  Potential risk factors included bisphosphonate treatment, steroid treatment, osteoporosis and head/neck radiation. Absolute risk factors in this study, however were deemed to be low due to the limited number of identified cases in the cohort.  

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ONJ incidence among the cohort was .63/100,00, which was less than that reported by Khosla et al (7) who found 1/100,000. Among oral bisphosphonate users, however, ONJ incidence was 4.1/100,000. They reported that although the number of ONJ cases was limited, patients with any of the risk factors identified were 13.4 times more likely to have ONJ than patients with no risks and 15.5 times times more likely when exposed to bisphosphonates.. 

 

 Risk Factors

 

While the incidence of ONJ in the population is low, in  those exposed to bisphosphonate therapy the incidence is much higher. ONJ was primarily reported in patients with cancer receiving high potency bisphosphonates (8). Several other risk factors have been suggested including  corticosteroid use, dental surgery, radiotherapy, and poor oral hygiene. Other factors include alcohol abuse, smoking, poor nutrition, infection, chemotherapy, hormone treatments and organ transplant.  

 

In the most recent study Barasch et alconducted a case-control study with three dental practice-based research groups  to determine the risk associated with bisphosphonates and identify other risk factors for ONJ, including dental diseases and procedures. Researchers enrolled 191 ONJ cases and 573 controls from 119 dental practices. Bisphosphonate use was strongly associated with ONJ with 71% for intravenous use and 51%  for oral use. In addition there was an inverse relationship between bisphosphonate  use duration and ONJ prevelence with 29% having ONJ with >2-5 years duration. ONJ incidence remained high amongst cancer patients (75%), smoking ((57%), osteoporosis (35%) steroid use(59%) and chemotherapy  60%).  

 

The authors also confirmed pervious observations regarding drug potency (12), noting a significant association between the more potent bisphosphonate drugs and higher prevelence of ONJ. The length of exposure was also significant factor with results confirming that risk begins within 2 years of treatment, showing that even the less potent bisphosphonates were associated with ONJ after only a short period of exposure. Higher risk of ONj occurred within 2 years of bisphosphonate initiation, increasing four fold after 2 years. Amongst non-cancer patients the odds ratio increased substantially after 5 years of treatment.  

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Treatment Protocols  

 

Currently, there are no effective treatments for ONJ. Woo et al (10)  recommend that all patients (including those with osteoporosis) prior to starting aminobisphosphonate treatment (alendronate and risedronate included) should have a dental examination with appropriate preventive dentistry. Oral infections should be actively treated; should have routine restorative care of carious teeth. Prior to beginning bisphosphonate therapy invasive procedures for non salvageable teeth should take place. In addition 6 monthly oral examinations with dental prophylaxis should be performed and oral hygiene monitored closely where indicated.   in the light of Barasch (11) study factors such as poor nutrition, smoking and alcohol use should also be  addressed with attention being paid to smoking cessation advice and nutritional counseling.   It has also been recommend that patients who are already taking oral bisphosphonates should not stop these when they go for dental surgery as the risk of ONJ is very small and the half-life of the bisphosphonates long (13).  

 

Patients may be treated non-invasively with antibiotics such as penicillin or clindamycin, and antimicrobial mouth rinses.  Surgical debridement has also been shown to can make the condition worse and patients should avoid this if at all possible (10). In addition the avoidance of invasive dental procedures is advised once treatment has been commenced particularly in those at risk of ONJ. It appears that most lesions are non-healing or show only slow improvements(9) and that close follow-up and prevention should be the first priority.    

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Vitamin K and Bone Density

 

There is emerging evidence that Vitamin K may have a protective role against age related bone loss. Vitamin K ( as Vitamin K2)  was compared to etidronate (Didronel) in 72 women with osteoporosis (14) This study found no difference in the fracture rates between Vitamin K and the bisphosphonate drug, even though BMD was lower in the Vitamin K group than the Didronel group. The authors concluded that there is evidence to suggest that, despite the lower increase in BMD produced by Vitamin K, this agent, may have the potential to reduce osteoporotic vertebral fractures in postmenopausal women with osteoporosis. This study also demonstrates that avascular denser bone is not necessarily more fracture resistant than  vascular healthy bone with a lower BMD. Further study has also demonstrated that low vitamin K intake is associated with low BMD in women (15).  

 

Vitamin K acts as a co factor in the carboxylation of osteocalcin, a protein believed to be involved in bone mineralization. Osteocalcin (also called bone Gla protein) is a protein synthesized by osteoblasts. Under carboxylation of osteocalcin adversely affects its capacity to bind to bone mineral. The synthesis of osteocalcin by osteoblasts is also regulated by the active form of vitamin D, 1,25(OH)2D3 or calcitriol. There is increasing evidence that Vitamin K may positively affect calcium balance (16). Several studies have reported an association between Vitamin K status, the percentage of osteocalcin that is not carboxylated and the risk of low BMD (17 18) .    

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Vitamin K

 

There are two naturally occurring forms of vitamin K. Vitamin K1 from the plant synthesis of phylloquinone, and Vitamin K2, menaquinone from bacterial synthesis in the large intestine (19).  Vitamin K1 is primarily recognised as a clotting factor in the coagulation cascade, with overt deficiency resulting in impaired clotting.  Vitamin K2 is the form primarily involved in calcium regulation.   Cheung et al (20) reported no protection against age related decline in BMD with daily Vitamin K1 supplementation, however there was some decrease in the incidence of fracture in the treated group.   Vitamin K2 has been shown to be an effective treatment against osteoporosis. A 2-year group comparison study of patients with corticosteroid-associated osteoporosis found that K2 greatly reduced vertebral fractures. Incidence of vertebral fractures was 13.3% in those taking K2 compared to 41% in the control group (21). In a 24-week study, 80 patients with osteoporosis were given either 90 mg/day vitamin K2 or placebo (22). In those taking K2, bone mineral density (BMD) increased in the second metacarpal an average of 2.2%. In those given placebo, BMD decreased an average of 7.31%.  

 

Vitamin K2 has been approved for the treatment of osteoporosis in Japan since 1995. Vitamin K2 treatment in osteoporosis has been shown to inhibit the occurrence of new bone fractures and to maintain BMD. The uniqueness of the prevention of bone fractures by vitamin K2 is that there has been no direct evidence of the relationship between increase of BMD and a decrease in the occurrence of bone fractures.   

 

A recent systematic review of seven Japanese randomized controlled trials by Cockayne (23) has also shown that supplementation with menaquinone (Vitamin K2) , is associated with increased BMD and reduced fracture incidence. meta-analysis of randomized controlled trials in which vitamin K's effectiveness in preventing fractures was evaluated identified 13 trials with data on bone loss, 7 of which reported fracture data. All but one study showed benefit of vitamin K (whether K1 or K2) in reducing bone loss. When data from the 7 trials with fracture analysis were pooled, K2 was significantly more protective than K1with an odds ratio favoring menaquinone (MK-4) of 0.40 for vertebral fractures, 0.23 for hip fractures, and 0.19 for all nonvertebral fractures   The eidence suggest therefore that supplementation with menaquinone-4 (Vitamin K2) reduces bone loss.  

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Green leafy vegetables and some vegetable oils (soybean, cottonseed, canola, and olive) are major contributors of dietary vitamin K (24). Hydrogenation of vegetable oils may decrease the absorption and biological effect of dietary vitamin K (25) and little Vitamin K2 is obtained directly from the diet. Vitamin K1 is the primary form ingested in the Western diet. K1 is converted into K2 in the intestines in the presence of pro-biotic bacteria, however gastrointestinal dysfunction and poor gut flora are often an issue particularly in older adults and those with existing disease and multiple medication use. The research therefore indicates that supplementation may be necessary to ensure adequate therapeutic levels.   

 

Foods rich in vitamin K and supplements may interfere with blood thinning medications such as warfarin. Vitamin K can reverse the therapeutic effects of warfarin, which can increase the risk for blood clots and stroke in patients with certain cardiovascular conditions. Vitamin K supplementation is not advised for those taking anti coagulant medication.

 

In addition to the emerging role of vitamin K in bone density, other nutritional influences are well established. Bone modelling and skeletal consolidation result from a sequence of nutritional and hormonal interactions. Because nutrition is a modifiable pathogenic factor in osteoporosis, which also appears to have important oral health implications, it is a topic that deserves some attention.  

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Conclusion  

 

The association between the use of bisphosphonates and the development of ONJ continues to be studied in further investigations. A 2-year national new patient registration of patients with avascular necrosis of the jaws including bisphosphonate-related osteonecrosis’ (BRONJ) referred to Oral Surgery, Oral Medicine, Oral and Maxillofacial Departments and Dental Hospitals in England, Wales, Scotland and Northern Ireland is being undertaken, with a view to establishing a national incidence, to collect data on risk factors including smoking and periodontal health and to investigate potential risk factors in relation to patient outcome. The project has been supported through The Faculty of the Royal College of General Dental Practice (FGDP(UK). Final reporting is due in October 2012.     

 

It is suggested that patients who undergo bisphosphonate therapy should receive a careful dental check-up and preventive treatment prior to drug application. Patients receiving bisphosphonates should be followed up carefully to avoid the occurrence of extended osteonecrotic lesions. Moreover, established jaw lesions must be diagnosed precisely in order to exclude metastatic disease (26).  

 

For early prevention or inhibition of postmenopausal and age-related bone loss, nutritional interventions and prevention should be the first choice as they are the least toxic, the least invasive and the least expensive option.    

 

References

 

1 Bilezikian JP (2006). Osteonecrosis of the jaw–do bisphosphonates pose a risk? N Engl J Med 355:2278-2281.  

 

2 Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61: 1115-8.  

 

3 Migliorati CA, Schubert MM, Peterson DE, et al.:  Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone : an emerging oral complication of supportive cancer therapy. Cancer. 2005 Jul 1;104(1):83-93  

 

4 Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral MaxillofacSurg 2003; 61: 1104-7.  

 

5 Sedghizadeh PP, Stanley K, Caligiuri M, Hofkes S, Lowry B, Shuler CF. Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: An institutional inquiry. J Am Dent Assoc. 2009;140:61-66.  

 

6 Fellows JL,, Rindal DB, Barasch A et al: ONJ in Two Dental Practice-Based Research Network Regions. J Dent Res:  2011 (published online 11 February 2011).  

 

7 Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 200722:1479-1491.  

 

8 Van Poznak C. The phenomenon of osteonecrosis of the jaw in patients with metastatic breast cancer. Cancer Invest 200624:110-112.  

 

9 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;63:1567–75.  

 

10 Woo SB, Hellstein JW, Kalmar J. Systematic review: bisphosphonates and osteonecrosis of the jaw. Ann Intern Med 2006;144:753–61.  

 

11 Barasch A, Cunha-Cruz Curro FA, Hujoel P, et al: Risk Factors for Osteonecrosis of the Jaws: a Case-Control Study from the CONDOR Dental PBRN.  J DENT RES published online 11 February 2011  

 

12 Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, et al. (2006). Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24:945-952.  

 

13 SHENKER N. G., JAWAD A. S. M:: Bisphosphonates and osteonecrosis of the jaw. Rheumatology 2007;46:1049–1051   

 

14 Iwamoto J, Takeda T, Ichimura S. Effect of menatetrenone on bone mineral density and incidence of vertebral fractures in postmenopausal women with osteoporosis: a comparison with the effect of etidronate. J Orthop Sci. 2001;6(6):487-92.  

 

15 Booth SL, Broe KE, Gagnon DR et al: Vitamin K intake and bone mineral density in women and men. Am J Clin Nutr. 2003 Feb;77(2):512-6.    

 

16 Weber P. : Vitamin K and bone health. Nutrition 2001 Nov-Dec;17(11-12):1024.    

 

17 Kanai T, Takagi T, Masuhiro K, Nakamura M, Iwata M, Saji F. Serum vitamin K level and bone mineral density in post-menopausal women. Int J Gynaecol Obstet 1997;56:25–30.  

 

18 Szulc P, Arlot M, Chapuy MC, Duboeuf F, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res 1994;9:1591–5.  

 

19 Shearer MJ. Vitamin K. Lancet. 1995;345(8944):229-234.  

 

20 Cheung AM, Tile L, Lee Y, et al: Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med. 2008 Oct 14;5(10):e196.  

 

21 Iwamoto J, Takeda T, Ichimura S. Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J Orthop Sci. 2000;5(6):546-51  

 

22 Plaza SM, Lamson DW. Vitamin K2 in bone metabolism and osteoporosis. Altern Med Rev. 005 Mar;10(1):24-35.  

 

23 Cockayne S, Adamson J, Lanham-New S : Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials Arch Intern Med. 2006 Jun 26;166(12):1256-61.  

 

24 Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr 1998;128:785–8.  

 

25 Booth SL, Lichtenstein AH, O'Brien-Morse M, et al. Effects of a hydrogenated form of vitamin K on bone formation and resorption. Am J Clin Nutr. 2001;74(6):783-790.  

 

26 Friedrich RE, Blake FA.: Avascular mandibular osteonecrosis in association with bisphosphonate therapy: a report on four patients. Anticancer Res. 2007 Jul-Aug;27(4A):1841-5.