Over the past three years, several reports have been published on the possibility of mandibular osteonecrosis being associated with the administration of bisphosphonates.
Bisphosphonates are highly active inhibitors of osteoclasts, preventing bone breakdown. They are analogs of a naturally occurring compound, pyrophosphate, that regulates calcium activity.
Bisphosphonates have been known to chemists since the middle of the 19th century. The early uses of bisphosphonates were industrial, mainly for corrosion prevention, and largely used in the textile, fertiliser and oil industries, as well as in washing powders.
The first report of the biological characteristics of bisphosphonates as a major class of drugs for the treatment of bone diseases was published in 1968. At that time, scientists discovered that bisphosphonates have a marked ability to inhibit bone
resorption. There are four bisphosphonates currently in clinical use:
• Alendronate (Fosamax)
• Etidronate (Didronel)
• Risedronate (Actonel)
• Pamidronate (Aredia).
These drugs are used for the treatment of multiple myeloma, bone resorption in the case of metastatic malignant diseases, tumourassociated hypercalcaemia, and in the treatment of osteoporosis.
Osteoblasts and osteoclasts are the primary cells involved in the formation of new bone and remodelling of bone in adults. Remodelling begins with bone resorption by
osteoclasts, which is then followed by osteoblasts refilling the resorption sites. It is necessary for bone resorption to occur in order to trigger bone formation. In healthy individuals, the amount of bone formed during bone remodelling is equal to the amount of bone destroyed. Optimal bone density, therefore, is a dynamic balance between
osteoclast activity and the ability of the osteoblasts to deposit new tissue.
Bisphosphonates directly inhibit osteoclast activity, directly and indirectly inhibit osteoblast-mediated recruitment of osteoclasts, and activate osteoclast apoptosis through differing mechanisms.
It has recently been demonstrated that bisphosphonates inhibit endothelial cell functions and that pamidronate inhibits not only bone resorption and bone loss but also bone blood flow (Kapitola J, Zac J, 1998; Fournier P et al, 2002). Therefore bone density increases not through the growth of new bone but from preventing the removal of old bone.
Recently, several authors reported bone necrosis in the jaws associated with bisphosphonate use both in patients that were treated with radiotherapy or chemotherapy and in those that were not (Riggiero SR et al, 2004; Bagan JV et al, 2005; Migliorati CA, 2005a; Migliorati CA, 2003; Wang J et al, 2003; Marx RE, 2003; Migliorati CA et al, 2005b; Marx RE et al, 2005).
It has been suggested, based upon the probable correlation between jaw osteonecrosis and bisphosphonates, that before and during bisphosphonates therapy a careful evaluation of the patients and a strict collaboration between dentists and oncologists are essential for the prevention of this side effect (Merigo E et al, 2006).
Bisphosphonates and BMD
The advantages of prescribing bisphosphonates with reference to osteoporosis lie in the fact that they appear to increase bone mineral density, reduce markers of bone turnover and decrease fracture rates in both men and women (Majima T et al, 2008; Välimäki MJ et al, 2007; Leung JY et al, 2005).
A recent Cochrane review concluded that there is good evidence for the efficacy of risedronate in the reduction of both vertebral and nonvertebral fractures (Cranney A et al, 2008).
Prior to this bisphosphonates had mainly been used to treat Paget’s disease, and for bone-specific treatments in multiple myeloma, breast and prostate cancer, and other metabolic bone disorders.
In addition to a possible link to oral osteonecrosis, the oral bioavailability of bisphosphonates is, however, reported as being extremely limited. Generally less than 1% of an oral dose is absorbed from the gastrointestinal tract and, moreover, intake of any food further diminishes absorption. Patients must take bisphosphonates on an empty stomach with a minimal amount of water.
As a consequence, oral bisphosphonates therapies have surprisingly high noncompliance rates and are reported as being poorly tolerated by some patients (MBC Pharma Inc).
Vitamin K and bone density
There is emerging evidence that vitamin K may have a protective role in age-related bone loss. Vitamin K (as Vitamin K2) was compared to etidronate (Didronel) in 72 women with osteoporosis (Iwamoto J et al, 2001). 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 fractureresistant 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 (Booth SL et al, 2003).
Vitamin K acts as a cofactor in the carboxylation of osteocalcin, a protein believed to be involved in bone mineralisation. Osteocalcin (also called bone Gla protein) is a protein synthesised by osteoblasts. Undercarboxylation 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 (Weber P, 2001). Several studies have reported an association between Vitamin K status, the percentage of osteocalcin that is not carboxylated and the risk of low BMD (Kanai T et al, 1997; Szulc A et al, 1994).
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 (Shearer MJ, 1995).
Vitamin K is primarily recognised as a clotting factor in the coagulation cascade, with overt deficiency resulting in impaired clotting. Green leafy vegetables and some vegetable oils (soybean, cottonseed, canola and olive) are major contributors of dietary vitamin K (Booth SL, Suttie JW, 1998). Hydrogenation of vegetable oils may decrease the absorption and biological effect of dietary vitamin K (Booth SL et al, 2001).
Epidemiological studies have demonstrated a relationship between vitamin K and age-related bone loss. The Nurses’ Health Study followed more than 72,000 women for 10 years. The study reported that women with low vitamin K intakes had a 30% higher risk of hip fracture than women with higher vitamin K intakes (Feskanich D et al, 1999).
The evidence, however, is mixed with a prospective study involving a cohort of 1,869 perimenopausal women, which reported that vitamin K intake was not associated with changes in BMD or fracture risk (Rejnmark L et al, 2006). Half of the participants in this study, however, were using hormone replacement therapy, which could have influenced the outcome.
Further investigation continues to clarify the role of vitamin K in bone health and prevention of osteoporotic fracture.
Nutrition and bone density
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.
The effect of calcium supplementation on systemic bone density is well documented. Adequate calcium intake, however, is only part of the picture. In order for the mineral to be incorporated into bone, it needs to be well absorbed and relies on a number of cofactors, including magnesium. For calcium to be absorbed from the diet it also needs hydrochloric acid (HCl) and vitamin D. Early studies suggest older people tend to lack sufficient HCl, either from a lifetime of nutrient deficiencies or regular use of antacid preparations (Lotz M et al, 1968).
Magnesium acts as an important co-factor in the enzyme-regulated process of Ca+ absorption into bone. Studies have shown that the addition of magnesium supplementation combined with calcium improves BMD (Ericsson Y et al, 1986).
Two recent studies have demonstrated how magnesium deficiency impairs bone growth by decreasing osteoblast numbers, increasing osteoclast numbers and stimulating cytokine activity (Rude RK et al, 2003; Rude RK et al, 1999).
Calcium, magnesium, zinc and vitamin C have been shown to be significantly related to
BMD at several skeletal sites (Ilch JZ et al, 2003).
More research is needed to understand fully the interactions of these nutrients to help identify preventive measures for bone loss and the implications in alveolar bone loss.
There is growing evidence of a positive link between fruit and vegetable intake, acid base homeostasis and bone health. New (2001) has demonstrated a significant positive effect of increased fruit and vegetable consumption on axial and peripheral bone mass and markers of bone metabolism. Meanwhile, Tucker et al (2001) have also suggested that excess protein reduces bone density and is associated with an increased acid base ratio.
The probable association between the use of bisphosphonates and the development of jaw necrosis has to be studied in further investigations.
It is suggested that patients who undergo bisphosphonate therapy should receive a careful dental check-up prior to drug application. These patients should then be followed up vigilantly to avoid the occurrence of extended osteonecrotic lesions. Moreover, established jaw lesions must be diagnosed precisely in order to exclude metastatic disease (Friedrich RE, Blake FA, 2007).
For early prevention or inhibition of postmenopausal and age-related bone loss, nutritional interventions should be the first choice as they are the least toxic, the least invasive and the least expensive option.