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Bisphosphonates and orthodontics: Clinical implications

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Bisphosphonates and orthodontics: Clinical implications

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 adminis-
tration of bisphosphonates is rising dramatically in
the form of anti-osteoporosis medications, espe-
cially in women. Osteonecrosis of the jaws has been
associated with intravenous administration of bis-
phosphonates, 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 pharma-
cology 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 chem-
ical 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 influ-
ences the pharmacokinetics.4Either an amino-
terminal 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.4The ingestion of bis-
phosphonates by osteoclasts triggers apoptosis
(programmed cell death) by competing with adeno-
sine triphosphate or interfering with the HMG-CoA
reductase pathway.6Osteoblast-mediated osteo-
clastic resorption is also inhibited.3Recent evidence
points to an anti-angiogenic mechanism that may
reduce the healing potential of already compro-
mised 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 metas-
tasis (with or without hypercalcemia), and multi-
ple myeloma, and orally for osteoporosis.10-12
Television ads targeting the demographic group
prone to osteoporosis are increasingly common.
VOLUME XL NUMBER 7 © 2006 JCO, Inc. 425
Bisphosphonates and Orthodontics:
Clinical Implications
JOHN W. GRAHAM, DDS, MD
Dr. Graham is in the private practice of
orthodontics at 13575 W. Indian School
Road #400, Litchfield Park, AZ 85340;
johnwgraham@cox.net. Fig. 1 Basic chemical structure of bisphosphonate.
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 poten-
tial 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 relat-
ed 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 den-
tal 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 bis-
phosphonate-associated necrosis of the jaws is a
mucosal dehiscence, with exposure of the under-
lying mandible or maxilla (Fig. 2). Although the
lesion itself is reportedly quite painful, some
patients have first noted irritation of adjacent struc-
tures, 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 osteo-
426 JCO/JULY 2006
Bisphosphonates and Orthodontics: Clinical Implications
TABLE 1
RELATIVE POTENCY OF BISPHOSPHONATES
OBSERVED IN HUMAN CLINICAL TRIALS*
Compound (Brand Name) Relative Antiresorptive Potency Route of Administration
Short Alkyl or Halide Side Chain
Etidronate (Didronel**) 1 Oral/intravenous
Cyclic Chloro Side Chain
Tiludronate (Skelid***) 10 Oral
Aminoterminal Group
Pamidronate (Aredia†) 100 Intravenous
Alendronate (Fosamax‡) 100-1,000 Oral
Cyclic-Nitrogen-Containing Side Chain
Risedronate (Actonel**) 1,000-10,000 Oral
Ibandronate (Boniva††) 1,000-10,000 Oral
Zoledronic acid (Zometa†) >10,000 Intravenous
*Adapted from Watts.5
**Registered trademark of Procter & Gamble Company, Box 599,
Cincinnati, OH 45201.
***Registered trademark of Sanofi-aventis, 300 Somerset Corpor-
ate Building, Bridgewater, NJ 08807.
†Registered trademark of Novartis Pharmaceuticals Corp., 1 Health
Plaza, East Hanover, NJ 07936.
‡Registered trademark of Merck & Co., Inc., 1 Merck Drive, White-
house Station, NJ 08889.
††Registered trademark of Roche Pharmaceuticals, 340 Kingland
St., Nutley, NJ 07110.
radionecrosis, 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 rec-
ommendation of their physicians for the preven-
tion of skeletal events related to osteoporosis.
Tens of thousands of patients are also receiving bis-
phosphonate therapy as part of their chemothera-
peutic regimens for the treatment of malignant
diseases. As we continue to treat an aging popu-
lation, 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 bis-
phosphonates, whether for cancer therapy or pre-
vention 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 bis-
phosphonates, 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
VOLUME XL NUMBER 7 427
Graham
Fig. 2 Spontaneous osteonecrosis at mylohyoid plate, present for months in patient with metastatic breast
carcinoma who was taking zoledronic acid. A. Initial presentation on left mandible. B. Initial presentation on
right mandible. C. Progress of bone exposure one year later, showing bone necrosis and secondary infection
on left mandible after extraction of upper right third molar and part of fixed bridge. D. Left mandible one
month before patient’s death. (Reprinted with permission.2)
A
C
B
D
bisphosphonates, either in systemic or topical
form, demonstrated enhanced resistance to ortho-
dontic relapse. This evidence suggests that tooth
movement in patients receiving parenteral bis-
phosphonate therapy may be retarded. If prolonged
orthodontic treatment is undertaken, are we increas-
ing 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 recent-
ly published on its website an expert panel's rec-
ommendations 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 tol-
erate with this group of patients.
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Bisphosphonates and Orthodontics: Clinical Implications
428 JCO/JULY 2006
... Do podobnych wniosków doszli Dewachi i wsp., wykazując istotnie większą stabilizację wtórną mikroimplantów oraz niższy poziom prozapalnej IL-1β w płynie dziąsłowym po miejscowej aplikacji zoledronianu u psów z wywołaną farmakologicznie cukrzycą (49). Należy nadmienić, że liczba badań na temat wpływu lokalnej podaży BP na lepsze utrzymanie mikrośrub nie jest wystarczająca, a poszczególni autorzy różnie podchodzą do stosowania mikroimplantów ortodontycznych u pacjentów przyjmujących bisfosfoniany w terapii choroby podstawowej (50,51). Różnica poglądów badaczy i brak bezpośrednich wytycznych ukazuje złożoność problemu oraz konieczność indywidualnego rozpatrywania każdego przypadku z uwzględnieniem ryzyka wystąpienia martwicy kości. ...
... Similar conclusions were reached by Dewachi et al. who showed significantly higher secondary stability of microimplants and lower levels of proinflammatory IL-1β in gingival fluid after local application of zoledronate in dogs with pharmacologically induced diabetes (49). It should be mentioned that the number of studies on the effects of local BP supply on better maintenance of microscrews is not sufficient, and individual authors have different approaches to the use of orthodontic microimplants in patients taking bisphosphonates for the treatment of their underlying diseases (50,51). As the opinions of researchers vary, and there is a lack of direct guidelines, this problem is complex, and it is necessary to consider each case individually, taking into account the risk of bone necrosis. ...
... BP has been used to treat various bone diseases associated with bone resorption such as osteoporosis, Paget's disease, multiple myeloma, and metastatic bone cancer because it can selectively inhibit osteoclast activities [7,8]. However, the side chain structure of the carbon atom of BP (phosphorus-carbon-phosphorus) is the key to its potency because it has a high affinity toward hydroxyapatite [9,10]. Recent studies show that BPs containing nitrogen (BP-N) are more potent than those without nitrogen [1]. ...
... Recent studies show that BPs containing nitrogen (BP-N) are more potent than those without nitrogen [1]. Zoledronate (ZOL) is the newest class of BP-N that has a heterocyclic ring and is considered 10.000 times more potent than BP non-nitrogen; in addition, it has the highest bone affinity [1,9,10]. ...
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Objective: This study aimed to analyze the physical stability and drug content of zoledronate (ZOL) gel emulsion in virgin coconut oil (VCO) as a new pharmaceutical product at 25°C as room temperature and 40°C as an accelerated temperature for a stability physics test. Methods: The ZOL gel emulsion comprises the following ingredients: 0.16% ZOL powder, 2% carboxymethyl cellulose, 5% VCO, 0.44% sodium benzoate, and 0.009% antioxidant butylated hydroxytoluene, and distilled water. Samples of this gel emulsion were stored for 1 month at 25°C and 40°C, and the parameters used for stability tests were pH, viscosity, spreadability, and adhesive strength. The drug content was also evaluated with a spectrophotometer. The ZOL gel emulsion was evaluated against these metrics on days 1, 7, 14, and 28. Results: The results showed that ZOL pH, viscosity, spreadability, adhesive strength, and drug content gel emulsion were clinically stable over 28 days of storage at 25°C, whereas it was not stable when stored at 40°C for the same duration. pH value of ZOL gel emulsion significantly decreased at 28 days (p<0.05). Also for viscosity, adhesive strength, and drug content of ZOL gel emulsion showed statistically significant (p<0.05), except for spreadability value (p>0.05). The spreadability value between ZOL gel emulsion that stored at 25°C and at 40°C showed no significant result at 7 and 14 days (p>0.05). Conclusion: ZOL gel emulsion was stable at 25°C when stored for 28 days, suggesting that this is a suitable storage temperature at which its physical stability and drug content can be maintained.
... 8,9 The aging of the population, exposes the surgeon dentist each day more to care for this group with osteoporosis, therefore, it is up to the orthodontist to be informed of the potential impact of this class of drugs in our patients. 10,11 The use in long-term of bisphosphonates to treat osteoporosis can lead to the accumulation of the drug in the bone. Once incorporated, the drug is released slowly during physiologic bone remodeling and in a greater degree during bone remodeling, i.e., in the processes associated with the orthodontic movement, increasing its absorption in locali-zed areas of the maxilla and the mandible. ...
... Depending on the category of patient's risk (dose, route and duration of treatment with bisphosphonates), elective surgeries, dental extractions, surgery involving bone such as placing minis crews should be avoided, in addition to infections of dental and periodontal origin. 10,[15][16][17][18] If necessary the performance of invasive procedures, the physician should be consulted and the patient should be referred to a dental surgeon with experience in the area. 9 The use of bisphosphonates is not an absolute contraindication for the orthodontic treatment, especially for low-risk patients. ...
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The use of bisphosphonates is not an absolute contraindication for the orthodontic treatment, especially for low-risk patients. However, the outcome of the treatment is still not predictable in high risk patients.
... Ortodontisk bevegelse av tenner avhenger av osteoklastmediert omdannelse av benvev. Det påpekes i kjeveortopedisk litteratur at bisfosfonatbehandling både kan hemme bevegelse av tenner og innebaere risiko for osteonekrose (26,27). Tatt i betraktning den utbredte bruk av bisfosfonater, er det sannsynlig at de fleste klinikere vil møte pasienter med bisfosfonatrelatert kjeveosteonekrose (15). ...
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I en lederartikkel i Journal of Bone and Mineral Research gis følgende punktvise anbefalinger for å forebygge kjeveosteonekrose ved bisfosfonatbehandling av osteoporose eller Pagets sykdom (11)*: Pasienter som skal behandles med perorale bisfosfonater bør om mulig undersøkes av tannlege, helst før eller så snart som mulig etter påbegynt behandling. Det samme gjelder utførelse av nødvendige oralkirurgiske eller andre invasive dentale prosedyrer, dersom tilstanden til pasientens skjelett tillater utsettelse. Pasientene bør informeres om den lave risikoen for kjeveosteonekrose ved oralkirurgiske eller andre invasive dentale prosedyrer. Pasientene bør få den samme tannbehandling som anbefales for befolkningen generelt så som godt tannrenhold og nødvendig konserverende tannbehandling. Det er ikke nødvendig å avbryte behandlingen med bisfosfonat eller ta spesielle forholdsregler. Pasienter som tar perorale bisfosfonater bør informere sin tannlege om denne medisineringen og, om mulig, sin lege dersom oralkirurgiske eller andre invasive dentale prosedyrer er nødvendig. Oralkirurgiske inngrep bør begrenses til slike som er nødvendige for god tannhelse, og kun utføres når mer konservative ikke-kirurgiske behandlinger er uhensiktsmessige eller ineffektive. Pasienter med lesjoner som gir mistanke om kjeveosteonekrose bør henvises til en tannlege eller oralkirurg for utredning og behandling. Enkelte anbefaler å seponere behandlingen med bisfosfonater noen uker før og etter dentoalveolær kirurgi. Tatt i betraktning den meget lange halveringstiden for bisfosfonater i ben, er det ikke sannsynlig at dette vil ha noen skadelig effekt på behandlingen av osteoporose eller Pagets sykdom. På den annen side er det også usikkert om slik seponering kan redusere den lave risikoen for å utvikle kjevebennekrose. * Følgende organisasjoner har gitt sin tilslutning til denne artikkelen: The American Association of Clinical Endocrinologists, The American College of Rheumatology, Bone, The Canadian Society of Endocrinology and Metabolism, The Endocrine Society, The European Calcified Tissue Society, The International Bone and Mineral Society, The International Society of Clinical Densitometry, The National Osteoporosis Foundation, Osteoporosis Canada, Osteoporosis International, and The Paget Foundation. Disse anbefalingene overensstemmer ikke helt med anbefalinger som nylig er gitt av The American Association of Oral and Maxillofacial Surgeons (15) og Marx (14) For pasienter som skal få bisfosfonater mot osteoporose, bør nødvendige oralkirurgiske eller andre invasive dentale prosedyrer utføres før, eller snart etter påbegynt behandling, helst i løpet av de første tre årene (14, 15). Dess lenger slik behandling utsettes, dess større blir risikoen for kjevebennekrose på grunn av akkumuleringen i benvev. Dersom ekstraksjoner eller benkirurgi er nødvendig under bisfosfonatbehandling, bør det om mulig satses på primær vevslukning (21). Før slike inngrep anbefales munnskyllig med 0,1 % klorheksidinoppløsning. Det er også anbefalt å fortsette med to daglige skyllinger i noen uker (21). Periodontal sykdom bør fortrinnsvis behandles ikke-kirurgisk (21), og det bør etableres så gode periodontale forhold som mulig. Tannrens og scaling bør utføres på en skånsom måte, slik at bløtvevsskader om mulig unngås. Det er rapportert kjeveosteonekrose etter mekanisk periodontalbehandling (28). Pasienten bør utføre god plakk-kontroll hjemme og kontrolleres regelmessig hos tannlegen. Det bør satses på endodontisk behandling fremfor kirurgi dersom en tann kan reddes, og det bør ikke manipuleres utenfor apex (21). For endodontiske kirurgiske prosedyrer gjelder de samme restriksjoner som ved andre oral- eller kjevekirurgiske inngrep. All rutinemessig konserverende og gjenopprettende tannbehandling kan og bør utføres for å sikre funksjonelt gode tenner (12, 21). Pasienter med hele eller partielle proteser bør undersøkes grundig for eventuelle protesebetingede slimhinnetraumer. Om nødvendig må protesene justeres og tilpasse nøye (12, 21). Fordi bisfosfonaterbehandling kan ha en gunstig innvirkning på bentilhelning, kan slik behandling antagelig være en fordel for noen implantatpasienter, mens andre kan få kjeveosteonekrose. De fleste autoriteter angir at pasienter som får intravenøs behandling med bisfosfonater, ikke bør få dentale implantater. Mer kontroversielt er spørsmålet når det gjelder osteoporosepasienter som behandles med bisfosfonat. Noen anbefaler å avvente resultatene av langtidsstudier av bisfosfonatbehandlede pasienter som har fått implantater, og at det bør utvises stor tilbakeholdenhet innsetting av nye implantater (21, 29). Marx angir at implantakirurgi vanligvis kan utføres de første tre behandlingsårene, men at informert samtykke fra pasienten er en forutsetning (14). Eventuelle alternative behandlingsplaner bør diskuteres med pasienten, f. eks. rotfylling i stedet for ekstraksjon og broer eller proteser som alternativ til implantater (21)
... Four of the five studies that evaluated the effect of the drug on decreasing OTM obtained positive results. In the study by Utari et al., it was observed that osteoclasts were abundant in the alveolar bone of the control group, but decreased in the Bis-CR250 and Bis-CR500 groups, which demonstrates the inhibition of the osteoclastic activity of bisphosphonates [27]; these are drugs with high affinity for calcium and are directed to areas of bone remodeling, which inhibit osteoclastic metabolism and reduce the number of these cells [40,41]. Consequently, post-treatment physiological retention is promoted. ...
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The objective of this article is to conduct a systematic review of the literature to contrast the existing evidence regarding the use of hydrogels during and after experimental orthodontic treatment in animals. An extensive search was performed through the electronic databases, Medline, Web of Science and Scopus, from December 2020 to April 2021 for in vivo animal studies. A total of 282 studies were reviewed. Eight studies were included for final revision; four studies were conducted in rats, two in rabbits, one study in mice and one study in guinea pigs. The quality assessment of the eight included studies was performed according to the ARRIVE guidelines and the risk of bias was assessed using the Center for Systematic Review of Laboratory Animal Experimentation tool; in four of the eight articles evaluated, a high risk-of-bias rating was obtained in 40% of the criteria evaluated. In the studies reviewed, the hydrogel acted as a carrier, and inhibition (post-treatment retention) or acceleration of orthodontic tooth movement was assessed according to the active substance used in each of the articles. The uses of hydrogels for transporting active substances to regulate the rate of orthodontic tooth movement remains debatable. Future studies are suggested to evaluate the feasibility of hydrogel as a transport method in humans.
... BPs are pyrophosphate analogs distinguished by two C-P bonds. 5,9 Like pyrophosphates, BPs promote the precipitation of calcium phosphate, which crystallizes in the form of hydroxyapatite; the BPs then bind to the latter with a high affinity. 10,11 BPs are classified in two main groups: nitrogen-containing and non-nitrogen-containing, which differ in terms of chemical structure and mechanism of action. ...
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Older women on bisphosphonate therapy are increasingly seeking orthodontic treatment. The authors review current evidence regarding the biological characteristics of postmenopausal women and the potential effects of BPs on tooth movement. Recommendations are provided for managing such patients.
... It has been demonstrated that a combination of systemic hormones and local factors can affect tooth movement 32,33 . With the increasing number of elderly orthodontic patients, the influence of osteoporosis on OTM has attracted great attention in both clinical and basic studies 3,4,34 . The previous studies mostly focused on the influences of osteoporosis on the rate of tooth movement, but the safety of OTM in patients with osteoporosis remains obscure and the underlying mechanism is also unclear. ...
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As the number of elderly orthodontic patients increases, the impact of postmenopausal osteoporosis on orthodontic tooth movement (OTM) has attracted a great deal of attention because OTM relies on alveolar bone remodeling. The question of whether OTM causes subsequent alveolar bone loss and is harmful to alveolar bone health under osteoporotic conditions remains to be answered. The present study aimed to clarify the influences of OTM on alveolar bone in osteoporotic rats. OTM was accelerated in ovariectomized (OVX) rats as a result of increased bone resorption in the pressure area. At the same time, anabolic bone formation was promoted in the tension area during OTM in OVX rats. Micro-CT analysis of alveolar bone revealed a decrease in BMD, BV/TV and Tb.Th. in the OTM group compared with that in non-OTM rats on day 21 of OTM, suggesting that OTM caused alveolar bone loss in OVX rats during OTM. However, the OTM-induced bone loss could be recovered 3 months after OTM in OVX rats. Thus, our findings suggest that increased osteogenesis may compensate for the increased bone resorption during and after OTM and enable effective accelerated OTM in OVX rats.
... Bisfosfonat (BP) adalah kelompok obat yang memiliki kemampuan mencegah hilangnya massa tulang dengan mekanisme penghambatan osteoklas sehingga menekan turnover tulang. 1 BP paling sering digunakan untuk pengobatan osteoporosis, penyakit Paget's, metastasis keganasan pada tulang dan kondisi-kondisi lain yang menyebabkan kerapuhan tulang. 2,3 Walaupun sudah banyak laporan adanya efek samping penggunaan BP yang terkait dengan bidang kedokteran gigi, namun penggunaan obat ini untuk kepentingan perawatan di dalam rongga mulut juga sedang diteliti. Dalam dunia kedokteran gigi, penggunaan BP kemungkinan dapat memberikan harapan dalam upaya menstabilkan gigi dalam tulang alveolar. ...
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Bisphosphonate (BP) is a class of drug that prevent the loss of bone mass. It inhibits the resorption of bone by encouraging osteoclast to undergo apoptosis. Considering that oral diseases and dental procedures may lead to teeth instability whereas alveolar bone is the main tooth supporting tissue, forceful indication of this drug is for preventing and minimizing bone resorption following oral surgery and relapse movement in orthodontic treatment. Clinical use of BP in dentistry is limited by risk of osteonecrosis of the jaw (ONJ) and of its systemic effects such as an increase of the bone mineral density in another bone area. Topical application with local effect would seem the choice of administration route for usage in dentistry. Until recently, no clinical usage of topical BP has been studied, however some experimental laboratory studies proved that this drug would be beneficial in a wide scope of dental treatments.DOI: 10.14693/jdi.v18i1.154
... Les auteurs admettent que la dose reçue et la durée des BP pourraient diminuer le mouvement dentaire mais ceci n'a pas été quantifié chez l'Homme [21]. Alors que certains auteurs s'accordent à dire qu'un traitement orthodontique devrait être évité chez les adultes sous BP [22,23], Krieger et al. exposent, dans une récente revue de littérature, le cas d'une adolescente de 15 ans atteinte de DF de forme polyostotique, considérée à haut risque, sous 135 mg de pamidronate IV par cure depuis deux ans, ayant bénéficié avec succès d'une greffe alvéolaire pour une fente labiopalatine avec supraclusie antérieure. Un traitement ODF prolongé de 42 mois a été nécessaire pour obtenir une occlusion satisfaisante [24]. ...
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Introduction: The prolonged use of intravenous bisphosphonates (BP) leads to a risk of bisphosphonate-related osteonecrosis of the jaws (BRONJ), that increases after oral surgical procedures. To date, no cases of BRONJ have been described in children after receiving BP therapy. Observation: We describe a situation where a young female adult who had received intravenous BP therapy for prolonged periods in childhood to treat fibrous dysplasia required extraction of her third molars. Discussion: The BP pharmacokinetics after a long period of BP treatment is still difficult to assess, leading to questioning the safety of their use many years after the end of a treatment initiated in childhood. Childhood is a specific period of high cellular turnover and growth activity; therefore, the impact of such an intensive treatment on dental eruption and craniofacial skeleton growth should be taken into consideration during this time. Conclusion: BRONJ risk factors in a paediatric population are different from those of an adult population, as underlined by the lack of guidelines, and critical to assess.
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Endocrinopathies have a variety of orofacial presentations which span from dental malocclusion to facial disfigurement. These characteristics depend on the nature and severity of the condition. An orthodontist should understand the body’s physiological processes to be able to timely determine the optimum intervention and plan treatment stages accordingly in compromised individuals. Communication between the two specialties should be well coordinated and should help facilitate quality health care to the patient. This review was aimed to impart the basic knowledge and the pivotal guidelines for orthodontic management in these conditions. Systemic conditions require multidisciplinary management and the dental team should aim to provide quality oral health care to enhance the overall quality of life and the orthodontist plays a vital role in helping patients achieve physical and psychological health.
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To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly. The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P = .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy. Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.
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Background: In light of the uncertainty surrounding the incidence of bisphosphonate-associated osteonecrosis of the jaw (BON) and concomitant risk factors, dentists have questioned how to manage the care of patients receiving oral bisphosphonate therapy. Expert panelists were selected by the American Dental Association Council on Scientific Affairs on the basis of their expertise in the relevant subject matter and on their respective dental or medical specialties, and the panel was tasked with developing guidance for dentists treating these patients. Methods: There are no data from clinical trials evaluating dental management of the care of patients receiving oral bisphosphonate therapy and, therefore, these recommendations are based on a thorough review of the available literature relating to bisphosphonate use and osteonecrosis of the jaw. After reviewing the literature, the panel developed these recommendations based on their expert opinion. Results: These panel recommendations focus on conservative surgical procedures, proper sterile technique, appropriate use of oral disinfectants and the principles of effective antibiotic therapy. Conclusions: The recommendations are a resource for dentists to use in their practice, in addition to the dentist's own professional judgment, the information available in the dental and medical literature, and information from the patient's treating physician. The recommendations must be balanced with the practitioner's professional judgment and the individual patient's preferences and needs.
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A total of 295 patients with lytic bone metastases from breast cancer were randomized to receive chemotherapy or chemotherapy plus pamidronate (Aredia) 45 mg intravenously every 3 weeks. Primary endpoints were time to progressive bone disease (evaluated by blind extramural review), and improvement in pain (according to a 6-point self-assessment scale). Secondary endpoints included incidence of bone-related complications (pathological fractures, tumor-induced hypercalcemia, need for radiotherapy), sclerotic response of lytic lesions, WHO performance status, and analgesic score. Median time to bone progression was 249 days and 168 days in the pamidronate and control groups respectively (p = 0.02). Marked improvement in bone pain was observed in 44% of patients receiving pamidronate compared to 30% in controls (p = 0.025). With respect to secondary endpoints, pamidronate reduced the need for radiotherapy (66 times vs. 82 times in controls), and median time to radiotherapy was 697 days with pamidronate, 571 in the control arm. No severe adverse reactions or worsening of chemotherapy-induced toxicities were observed during 1598 pamidronate infusions. We conclude that intravenous pamidronate is well tolerated, significantly prolongs time to progressive bone disease, and significantly improves bone pain in patients with osteolytic metastases from breast cancer.
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The purpose of this study was to examine the effect of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP), a potent blocker of bone resorption, on orthodontic tooth movements in rats. In the first experiment, the right and left upper first molars were moved buccally for 3 weeks with a uniform standardized expansion spring under systemic administration of AHBuBP every other day. The total tooth movement during the 3-week experimental period was 40% of that in the control at a dose of 0.5 mg P/kg. In the second experiment, the right and left upper first molars were first moved buccally for 3 weeks without AHBuBP. The spring was then removed and administration of AHBuBP was initiated. The total relapse movement during the 3-week experimental period was 50% of that in the control at a dose of 0.5 mg P/kg. Results of the first and second experiments were both dose dependent. Histologic examination showed that in the experimental animals fewer osteoclasts appeared on the alveolar bone surface, and both bone resorption and root resorption were inhibited. Inhibition of tooth movement was also observed when AHBuBP was applied topically. These results suggest that AHBuBP could be useful in enhancing anchorage or retaining teeth in orthodontic treatment.
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Osteoporosis in children and adolescents is relatively uncommon and usually secondary to identifiable causal factors. There are no generally accepted therapies for patients with no treatable underlying cause of disease. Any treatment of young patients with bone-acting compounds should be not only effective but also devoid of adverse effects on bone growth and remodeling. For many years we have been studying the effects of bisphosphonates-an effective treatment of postmenopausal osteoporosis-on the growing skeleton. We review here our experience in the treatment of young patients with osteoporosis with special emphasis on issues of skeletal safety and effectiveness, and we discuss the available literature data. We studied 12 patients aged between 10.7 and 17.2 years with symptomatic osteoporosis and multiple fractures treated with the bisphosphonates pamidronate or olpadronate for periods between 2 and 8 years continuously. Linear growth continued normally on treatment; there was even a catch-up growth in prepubertal patients, and there was no excessive suppression of bone remodeling, assessed biochemically. Bone biopsies obtained at various stages during treatment showed bone of normal lamellar structure without mineralization defects. There was an increase in calcium balance, already evident within 10 days, the level of which was maintained for at least 3 years of treatment. This was associated with progressive increases in bone mineral density along a different slope from that of healthy peers as well as correction of vertebral deformities on X-rays in patients given bisphosphonates before puberty. Treatment was well tolerated and clinical improvement was remarkable. Our studies, supported by literature data, strongly suggest that bisphosphonate therapy can be beneficial to young patients with osteoporosis for whom no other options are currently available, and justify planning controlled studies in more common conditions for which no treatment is currently available, such as osteogenesis imperfecta.
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Pamidronate, an aminobisphosphonate, has been shown to lower the risk of skeletal complications associated with lytic bone lesions for up to 1 year in women with stage IV breast cancer who received chemotherapy. We studied the long-term effectiveness and safety of continued treatment with intravenous pamidronate infusions for up to 2 years. Three hundred eighty-two women with metastatic breast cancer and lytic bone lesions who received chemotherapy were randomly assigned to receive either 90 mg of pamidronate or placebo intravenously every 3 to 4 weeks in this double-blind, multicenter, parallel-group trial. Patients were evaluated monthly for 2 years for skeletal complications, which included pathologic fractures, need for radiation or surgery to treat bone complications, spinal cord compression, and hypercalcemia. Bone pain, analgesic use, bone biochemical markers, performance status, quality of life, radiologic response in bone, and survival were also evaluated. As in the first year of treatment, the proportion of patients with any skeletal complication was significantly less for the pamidronate than the placebo group at 15, 18, 21, and 24 months (P < .001). The proportions of patients with any pathologic fracture (i.e., vertebral and nonvertebral fractures), need for radiation or surgery to treat bone complications, and hypercalcemia were also statistically less for the pamidronate than the placebo group. The median time to the first skeletal complication was 13.9 months in the pamidronate-treated women and 7.0 months in the placebo group (P < .001). Long-term treatment did not result in any unexpected adverse events. Survival did not differ between the two groups. The risk for osteolytic bone lesion complications in metastatic breast cancer was significantly decreased with monthly infusions of 90 mg of pamidronate, and this effect was maintained for at least 2 years. Pamidronate is a useful adjunct to standard chemotherapy in the palliative treatment of metastatic breast cancer.
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To assess whether pamidronate can reduce the frequency of skeletal morbidity in women with lytic bone metastases from breast cancer treated with hormone therapy. Three hundred seventy-two women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy were randomized to receive 90 mg of pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 weeks for 24 cycles. Patients were evaluated for skeletal complications: pathologic fractures, spinal cord compression, irradiation of or surgery on bone, or hypercalcemia. The skeletal morbidity rate (the ratio of the number of skeletal complications to the time on trial) was the primary efficacy variable. Bone pain, use of analgesics, quality of life, performance status, bone tumor response, and biochemical parameters were also evaluated. One hundred eighty-two patients who received pamidronate and 189 who received placebo were assessable. The skeletal morbidity rate was significantly reduced at 12, 18, and 24 cycles in patients treated with 90 mg of pamidronate (P = .028, .023, and .008, respectively). At 24 cycles, the proportion of patients having had any skeletal complication was 56% in the pamidronate group and 67% in the placebo group (P = .027). The time to the first skeletal complication was longer for patients receiving pamidronate than for those given placebo (P = .049). There was no statistical difference in survival or in objective bone response rate. Pamidronate was well tolerated. Treatment with 90 mg of pamidronate as a 2-hour intravenous infusion every 4 weeks in addition to hormonal therapy significantly reduces skeletal morbidity from osteolytic metastases.
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This study was designed to clarify the effects of systemic administration of bisphosphonate, pamidronate, on the bone resorbing activity of osteoclasts during relapse of rat molars, after experimental movement. An elastic band was inserted between the upper first and second molars of 7-week-old rats and removed 21 days later. At 1 day before elastic band removal, bisphosphonate was administered via a tail vein. After elastic band removal, the rats were further maintained for 0, 5, or 10 days. The relapse of the first molars was studied by means of light and scanning-electron and transmission-electron microscopy. When an elastic band was removed, the mean interdental distance between the first and second molars in all rats was approximately 435 micrometer. In the control rats, it had decreased to 108 micrometer by day 5 and 57 micrometer by day 10. In these control rats, numerous osteoclasts appeared along the alveolar bone surface in the compressed side of the periodontal ligament of first molars. Administration of bisphosphonate significantly inhibited the prominent decrease in interdental distance. In these rats, it averaged 313 micrometer at day 5 and 115 micrometer at day 10. In bisphosphonate-treated rats, osteoclasts aggregated mainly in vascular canals of alveolar bone but were occasionally observed along the alveolar bone surfaces facing the periodontal ligament. Administration of bisphosphonate also induced structural changes, such as disappearance of ruffled borders and cytoplasmic polarity, in osteoclasts. A degenerated osteoclast was also observed in a bisphosphonate-treated rat. However, bisphosphonate induced no structural changes in osteoblasts, osteocytes, or periodontal ligament fibroblasts. These results suggest that a single systemic administration of bisphosphonate decreases the extent of initial relapse in experimentally moved rat molars via a mechanism involving impairment of the structure and resorptive functions of osteoclasts.
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Bisphosphonates are chemically stable analogs of inorganic pyrophosphate, which are resistant to breakdown by enzymatic hydrolysis. The biological effects of bisphosphonates on calcium metabolism were originally ascribed to their physico-chemical effects on hydroxyapatite crystals. Although such effects may contribute to their overall action, their effects on cells are probably of greater importance, particularly for the more potent compounds. Remarkable progress has been made in increasing the potency of bisphosphonates as inhibitors of bone resorption, and the most potent compounds in current use are characterized by the presence of a nitrogen atom at critical positions in the side chain which, together with the bisphosphonate moiety itself, seems to be essential for maximal activity. As a class the bisphosphonates offer a very effective means of treating Paget's disease.