KEY POINTS■ Normal bone remolding is balanced by osteoblast and osteoclast activity. Osteoblasts cause bone formation and osteoclasts cause bone resorption. A fine balance between osteoblast and osteoclast activity allows for normal bone metabolism and necessary maintenance of optimal bone mineral density.
■ In patients taking bisphosphonates, osteoclast activity is inhibited for many years because bisphosphonate metabolites accumulate in the bone matrix and prolong bioactivity. Thus, even when the drugs are discontinued, the influence on osteoclastic activity can remain in effect for more than 10 years.
■ The risk of BRONJ is significantly greater for patients receiving IV bisphosphonate therapy compared with the risk for patients receiving oral bisphosphonate therapy. The estimated cumulative incidence of IV therapy-associated BRONJ is 0.8% to 12%. The prevalence of BRONJ in patients on oral bisphosphonate therapy appears to be very small (0%-0.04%).
■ Patient should undergo a comprehensive oral examination; and any treatment needed, including extraction of any unsalvageable teeth, should be provided before initiation of IV or oral bisphosphonate therapy. In patients already on bisphosphonate therapy, invasive dental procedures should not be delayed until optimal periodontal health is achieved but should proceed conservatively with concurrent antibiotic coverage.
More than 100 years ago, unexplainable, nonhealing bone exposures were seen on the jaws of phosphate miners and match workers in the United States and Great Britain. At that time, the condition was diagnosed as an occupational industrial disease called phossy jaw. The daily exposure to phosphate was postulated to cause an accumulation of the compound in the jaw, eventually leading to bone necrosis.
1Today, a similar pattern of exposed, nonhealing bone is being seen in patients taking bisphosphonates (Figure 1). This phenomenon is referred to as bisphosphonate-related osteonecrosis of the jaws (BRONJ). Osteonecrosis is bone death resulting from poor blood supply to an area of bone. However, no universal definition of BRONJ has been established to date, making the diagnosis and determining the actual prevalence of the disease difficult.2
ETIOLOGY AND PATHOPHYSIOLOGY
Bisphosphonates, which are related to pyrophosphate compounds, have an affinity for sites with high bone turnover. They were first introduced in the 1980s as treatment for Paget's disease of bone. Currently, IV bisphosphonates are used to treat hypercalcemia of malignancy and skeletal-related events associated with bone metastases of solid tumors, such as breast cancer, prostate cancer, and lung cancer, and to manage lytic lesions in patients with multiple myeloma.3 Additionally, oral bisphosphonates are prescribed as treatment for osteoporosis and osteopenia.
Normal bone remolding is balanced by osteoblast and osteoclast activity. Osteoblasts cause bone formation and osteoclasts cause bone resorption. A fine balance between osteoblast and osteoclast activity allows for normal bone formation and necessary maintenance of optimal bone mineral density (BMD). Bisphosphonates bind to osteoclasts, causing a reduction in their recruitment, life span, and activity. When osteoclast activity is reduced, less bone is resorbed and subsequently less bone is remodeled. In patients taking bisphosphonates, osteoclast activity is inhibited for many years because bisphosphonate metabolites accumulate in the bone matrix and prolong bioactivity. Thus, even when the drugs (such as alendronate sodium) are discontinued, the influence on osteoclastic activity can remain in effect for 10 years or longer.
The upper and lower jaws are comprised of two types of bone: alveolar and basal bone. These bones are more susceptible to BRONJ because they have unique characteristics. For instance, alveolar bone resides in the tooth-bearing segments of the upper and lower jaws. Its functions are to support and to maintain dentition. Alveolar bone is the only bone exposed to the outside environment. Its remolding rate is 10 times faster than the remolding rate of the tibial bone; as a result the jaw bones have a greater uptake of bisphosphonates, which causes the metabolite to readily accumulate at higher concentrations.1,4 In patients with osteoporosis, the accumulation of bisphosphonates in the bone eventually causes hypermineralization, thus increasing BMD. This process helps to increase BMD in the lumbar spine and axial skeleton, areas often affected by osteoporosis and osteopenia; however, it can go awry in the maxilla and mandible.
For example, a tooth extraction leaves a large residual void that is exposed to the outside environment. Healing involves the formation and stabilization of a blood clot and progression through the natural phases of bone healing that include osteoid deposition, mineralization, and remodeling. The bone of the jaw must progress through the natural healing phases, including remolding through balanced osteoblast and osteoclast activity. Bisphosphonate-induced suppression of osteoclast activity disrupts that balance and leaves nonhealing bone exposed, which leads to osteonecrosis.
Bioavailability of the oral form of bisphosphonates differs from that of the the IV form. Oral bisphosphonates are poorly absorbed into the blood stream from the GI tract compared with direct serum induction. IV administration bypasses gastric absorption; therefore, uptake is up to 10 times faster. The difference in the absorption rates could make 6 to 12 months of IV therapy equivalent to 3 to 5 years of oral therapy.1 Therefore, the incidence of BRONJ is higher in patients on IV therapy than it is in patients on oral therapy.