Bisphosphonates

Bisphosphonates are a group of drugs that are widely used for several bone
disorders and have been approved by the U.S. Food and Drug Administration for
treatment of osteoporosis, metastatic bone cancer, and Paget’s disease.142 A
this time, there are two main types of bisphosphonates: nitrogen containing and
non-nitrogen containing, with subgroups of either oral or intravenous
administration.
History
Bisphosphonates were fi rst used for industrial purposes in the nineteenth
century to prevent corrosion in the textile, fertilizer, and oil industries. In 1968
the first article describing use of bisphosphonates in medicine was published,
discussing the inhibition of bone resorption qualities.143 However, in 2002
reports of serious side effects from these medications after dental surgical
procedures were documented. These complications from bisphosphonates are
bisphosphonate osteonecrosis, bis pho sphonate avascular necrosis,
bisphosphonate osteomyelitis, osteochemonecrosis, and Bis-Phossy jaw.

The complications reported with respect to bisphosphonate use are very similar
to conditions that were reported as early as the nineteenth century. In 1845
numerous cases of jaw necrosis were documented from workers in an industrial
plant that manufactured matches. Symptoms included pain and tissue
inflammation leading to progressive extension with greater areas of bone
involvement and sequestration.144 These lesions resulted in very high rates of
morbidity and mortality until changes in environmental hygiene eradicated the
problem. In the twentieth century, similar cases of jaw necrosis were seen in
workers applying radium to watch instrument dials. These cases also were
eradicated by changes in industrial hygiene.145

Initially, when the first cases of bisphosphonate necrosis were seen, they were
treated and thought to be osteoradionecrosis. However, treatment such as
surgical intervention and hyperbaric oxygen failed to
produce conclusive resolution to the condition.146,147

Marx and Ruggiero reported on bisphosphonateinduced osteonecrosis of the

jaws, particularly from the more potent nitrogen-containing intravenous
bisphosphonates (pamidronate and zoledronic acid). However, a small
percentage of the cases involved the oral bisphosphonates: risedronate (Actonel)
and alendronate (Fosamax).148,149

Chemistry
Bisphosphonates are synthetic compounds that have a chemical structure similar
to inorganic pyrophosphate, which is an endogenous regulator of bone
metabolism. Because bisphophonates comprise two phosphate groups linked
together by phosphoether bonds (P-C-P structure), they are more resistant to
breakdown by pyrophosphatases and hydrolysis.150,151

The general structure of bisphosphonates is rather simple to modify; thus

different generations vary dramatically according to their biological, therapeutic,
and toxicologic characteristics
(Box 20-6).152

Mechanisms of Action
Bisphosphonates work by suppressing and reducing bone resorption by
osteoclasts. Directly, this is accomplished by preventing the recruitment and
function of osteoclasts. Indirectly, they stimulate osteoblasts to produce
inhibitors of osteoclast formation.153

Because of this bone resorption suppression, diseases such as Paget’s

disease of bone, fi brous dysplasia, and metastatic bone cancer are treated very
effectively and relieve pain symptoms.
The blood level half-life of bisphosphonates is very short, ranging from 30
minutes to 2 hours.154
However, after these medications are absorbed into bone tissue, they can persist
for up to 10 years in the skeletal tissues, depending on skeletal turnover
time.130,131
After jaw bone surgery, a radiolucent lesion or bone exposure may develop
rather than a typical healing mechanism.

Osteonecrosis of the Jaws

Although there exist extensive data on the beneficial effects of bisphosphonates
in the treatment of advanced bone diseases, numerous reports have documented
the capability of these medications in causing local lesions of the bone
osteonecrosis of the jaws.148,149
Most cases initially reported were after a jaw bone surgery with the more potent
nitrogen-containing bisphosphonates pamidronate and zoledronic acid.
However, osteonecrosis lesions have been reported in the oral bisphosphonates
risedronate and alendronate.
Osteonecrosis may remain asymptomatic for weeks and possibly months.
Lesions usually develop around sharp bony areas and previous surgical sites,
including extractions, retrograde apicoectomies, periodontal surgery, and dental
implant surgery. Symptoms include pain, soft tissue swelling, infection,
loosening of teeth, and drainage. Radiographically, osteolytic changes are seen
and tissue biopsy has shown the presence of actinomyces, which is possibly
caused by secondary infection.154
Management of Osteonecrosis
Initially, the fi rst cases of biphosphonate osteonecrosis were treated with similar
techniques as for osteo radionecrosis.
These lesions failed to respond to antibiotics, surgical intervention, and
hyperbaric oxygen. The most current recommendation of osteonecrosis is a
nonsurgical approach to the management of these lesions because of impaired
wound healing. Only minimal bony debridement of these lesions should be
performed, such as reduction of sharp edges. Chlorhexidine mouthrinses
(0.12%) and antibiotics should be used supplementally.155

If lesions persist, referral to an oral and maxillofacial surgeon or dental

specialist with experience in the treatment of this condition is recommended.

Laboratory Tests
It has been proposed that assays to monitor markers of bone turnover may help
in the diagnosis and risk of developing bisphosphonate-associated osteonecrosis.
155
A C-telopeptides (CTx) are fragments of collagen that are released during bone
remodeling and turnover. Because bisphosphonates reduce CTx levels, it is
believed that evaluating serum CTx levels can be a reliable indicator of risk
level. The CTx test (also called C-terminal telopeptide and collagen type 1 C
telopeptide) is a serum blood test obtained by laboratories or hospitals
(ICD9 diagnostic code 733.40)

Marx has suggested a preoperative protocol for administering bisphosphonates

to patients who are undergoing oral surgical procedures.155b
His protocol considers the type and duration of bisphosphonate use as well as
radiographic and clinical risk factors.
Depending upon the laboratory values obtained, a“drug holiday” may be
indicated, which includes temporary interruption of bisphosphonate treatment.
However, improvement of bisphosphonate levels may not be observed, because
measurable levels have been to shown to persist in bone for up to 12 years after
cessation of therapy155c (Box 20-7).

Dental Implant Implications

A comprehensive medical history is essential before any elective treatment is
initiated. Potential risk factors should be documented; previous radiotherapy,
chemotherapy, female gender, coagulopathies, exostosis, vascular disorders,
alcohol abuse, and smoking. The most important history of bisphosphonates
is the use of intravenous nitrogen-containing bisphosphonates such as
pamidronate (Aredia) and zoledronic acid (Zometa). The American
Academy of Periodontology stated invasive dental procedures should be avoided
in patients taking IV bisphosphonate therapy unless absolutely necessary.156
In September 2004, Novartis added bisphosphonate osteonecrosis warning to IV
drug guidelines stating to obtain dental exam of the patient prior to drug
administration and to “avoid” invasive dental procedures during dry use.

In the dental setting, the most common bisphosphonates that implant dentists are
exposed to are oral nitrogen-containing bisphosphonates such as risedronate,
ibandronate, and alendronate. The latest studies show that oral bisphosphonate
has a very low probability of causing osteonecrosis.157

For example, the risk of ulcerative colitis is possible with antibiotics, but the
dentist informs the patient of the risk and prescribes the antibiotic when
required.
Likewise, the risk of oral bisphosphonates and bisphosphonate osteonecrosis is
about the same (or less and therefore should be considered a low risk and yet
prudent to inform the patient). However, because of the long half-life and the
studies only being conducted for 3 years, future long-term complications may be
less evident.
With this in mind, the implant dentist should be cautioned on the possibility of
developing osteonecrosis side effects.
The risks versus benefi ts of dental treatment must be discussed with the patient
in detail. A well-documented consent form is recommended with possible
medical consultation if the patient has been on this medication for more than 3
years.
The use of glucocorticosteroids may be contraindicated in patients taking
bisphosphonates, because these drugs have been associated with an increased
occurrence of osteonecrosis.