Bisphosphonates and Orthodontics: Clinical Implications
VOLUME 40 : NUMBER 07 : PAGES (425-428) 2006
JOHN W. GRAHAM, DDS, MD
While adult patients have been
welcome in most orthodontic practices, they present a number
of challenges, not all of which are related to malocclusions.
For example, the oral administration of bisphosphonates is
rising dramatically in the form of anti-osteoporosis medications,
especially in women. Osteonecrosis of the jaws has been associated
with intravenous administration of bisphosphonates, and there
are also reports of oral lesions from "chronic" oral
bisphosphonate use.1 Although many of these cases were associated
with dental extractions or mucosal trauma, some of the lesions
seem to have appeared spontaneously.2
This article is a brief review of the pharmacology of bisphosphonates
and their potential impact on orthodontic patients.
Bisphosphonates
Bisphosphonates are a synthetic class of pyrophosphate analogues
that are powerful inhibitors of bone resorption. They have
a high affinity for calcium, and are either maintained in the
bone, recirculated, or excreted in the urine.3 Because bisphosphonates
are not metabolized, high concentrations will persist in the
bone for long periods.
All bisphosphonates share a common chemical structure, in which
two PO3 (phosphate) groups are covalently bound to carbon atoms
(Fig. 1). The long (R2) side chain determines the potency of
the drug, while the short (R1) side chain influences the pharmacokinetics.4
Either an aminoterminal group or a cyclic-nitrogen-containing
chain on the R2 side will increase the resorptive potential
logarithmically (Table 1).
The mechanism of action of bisphosphonate drugs is still under
investigation, but some basic pathophysiology is understood.
Bisphosphonates attach to bone because of their parachlorophenol
moiety's affinity for hydroxyapatite, and are then phagocytized
by osteoclasts.4 The ingestion of bisphosphonates by osteoclasts
triggers apoptosis (programmed cell death) by competing with
adenosine triphosphate or interfering with the HMG-CoA reductase
pathway.6 Osteoblast-mediated osteoclastic resorption is also
inhibited.3 Recent evidence points to an anti-angiogenic mechanism
that may reduce the healing potential of already compromised
bone by inhibiting vascularization.7
The efficacy of bisphosphonates cannot be denied.8,9 They are
commonly used intravenously for treatment of hypercalcemia
of malignancy, osteitis deformans ("Paget's disease of
bone"), bone metastasis (with or without hypercalcemia),
and multiple myeloma, and orally for osteoporosis.10-12 Television
ads targeting the demographic group prone to osteoporosis are
increasingly common.
Osteonecrosis of the Jaws
In a recent study by Marx and colleagues, 119 well-documented
cases of bisphosphonate-induced osteonecrosis of the jaws were
reviewed for potential risk factors and etiologies.13 Of course,
the underlying malignancies and all their negative sequelae
were the greatest risks among these patients. Aggravating factors
such as smoking, alcohol use, and ongoing chemotherapy have
also been recognized.
Of the 119 cases of osteonecrosis reviewed by Marx and colleagues,
45 cases (37.8%) were related to the removal of a tooth or
teeth, 34 (28.6%) to obvious existing periodontal disease,
five (11.2%) to periodontal surgery, four (3.4%) to dental
implant placement, and one (.8%) to an apicoectomy. On the
other hand, 30 cases (25.2%) occurred spontaneously without
any apparent dental disease, treatment, or trauma.13
Both Novartis Pharmaceuticals Corporation and the Food and
Drug Administration have issued drug precautions for health
professionals regarding osteonecrosis of the jaws. In 2004,
Novartis made corresponding changes to the Precautions sections
of its Zometa and Aredia labels.
The initial oral lesion seen in a case of bisphosphonate-associated
necrosis of the jaws is a mucosal dehiscence, with exposure
of the underlying mandible or maxilla (Fig. 2). Although the
lesion itself is reportedly quite painful, some patients have
first noted irritation of adjacent structures, such as the
lateral border of the tongue, due to constant abrasion from
the exposed bone. What is most disturbing about this type of
lesion is that it does not respond well to any known treatment
regimen. Surgical debridement results in more necrotic bone
and further deterioration. Cessation of the bisphosphonate
therapy will not improve the situation, probably due to the
persistence of the compound in bone. Even treatment with hyperbaric
oxygen, which is beneficial in treating osteoradionecrosis,
is of no benefit with bisphosphonate-induced bone exposure.13
Orthodontic Implications
Millions of peri- and postmenopausal women are currently taking
oral bisphosphonates at the recommendation of their physicians
for the prevention of skeletal events related to osteoporosis.
Tens of thousands of patients are also receiving bisphosphonate
therapy as part of their chemotherapeutic regimens for the
treatment of malignant diseases. As we continue to treat an
aging population, it is incumbent upon orthodontists to be
acutely aware of the potential impact of this class of drugs
on our patients.
In my own practice, I have changed my health history form to
identify patients who are taking bisphosphonates, whether for
cancer therapy or prevention of osteoporosis. I certainly do
not include invasive laser therapy or miniscrew anchorage in
the treatment plans for those who are currently receiving intravenous
administration of bisphosphonates, nor will I recommend extractions.
In fact, orthodontic treatment itself must come into question
with these patients. Kim and colleagues14 and Igarashi and
colleagues15 have found that experimental animals challenged
with bisphosphonates, either in systemic or topical form, demonstrated
enhanced resistance to orthodontic relapse. This evidence suggests
that tooth movement in patients receiving parenteral bisphosphonate
therapy may be retarded. If prolonged orthodontic treatment
is undertaken, are we increasing the potential for osteonecrosis
of the jaws? Additionally, does our treatment plan change if
a patient is diagnosed with cancer during treatment, as has
happened in my practice? Do we discontinue treatment with less-than-ideal
results, or do we carry on with heightened vigilance?
The ADA Council on Scientific Affairs recently published on
its website an expert panel's recommendations for dental management
of patients on oral bisphosphonate therapy16 (see the Editor's
Corner, p. 403). Every orthodontist should consider this report
required reading.
Conclusion
The increasing popularity of bisphosphonate drugs requires
all of us to be cautious. The evidence is inconclusive at this
point as to how long a patient must take oral bisphosphonates
before the risk of osteonecrosis becomes high. It becomes a
matter of clinical judgment on our part as to the treatment
and level of invasiveness that we are willing to tolerate with
this group of patients.