10.59987/ads/2012.1.31-38
Aim: This study investigates the association between cross linked C-terminal telopetide test (CTX) and individual surgical risk of osteonecrosis in patients taking oral bisphosphonates.
Materials and Methods: 32 patients receiving bisphosphonate were treated surgically. Patients were divided into three groups according to type of drug administrated and were subjected to a treatment of oral surgery, such as simple tooth extractions and extraction of all residual teeth of the oral cavity, upon evaluation of CTX values and antibiotic prophylaxis.
Results: Within the sample of 32 patients, 12 patients had been treated with bisphosphonates for several years and none developed osteonecrosis of the jaw upon surgery. As for CTX, patients treated with oral bisphosphonates showed a mean value of serum Ctelopetides of 0.2869 ng/ml. The mean value of CTX did not differ significantly between patients taking oral bisphosphonates and healthy patients not treated with bisphosphonates.
Conclusion: None of the patients subjected to preoperative antibiotic prophylaxis developed osteonecrosis of the jaw after surgery. The pharmacological and surgical protocol tested appeared valid in the prevention of osteonecrosis associated to bisphosphonates.
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M. Baldoni 
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Annali di stomatologia
osteonecrosis of the jaw (ONJ)
Surgical protocol in patients at risk for bisphosphonate osteonecrosis of the jaws: clinical use of serum telopetide CTX in preventive monitoring of surgical risk
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Original Article
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Ann Stomatol (Roma)
M. Baldoni 
2012
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1971-1441
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osteonecrosis of the jaw (ONJ)
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Surgical protocol in patients at risk for bisphosphonate osteonecrosis of the jaws: clinical use of serum telopetide CTX in preventive monitoring of surgical risk
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                                                                                                        Original article


    Surgical protocol in patients at risk for bisphosphonate
    osteonecrosis of the jaws: clinical use of serum telopetide
    CTX in preventive monitoring of surgical risk




                                                                                                       li
                                                                                                    na
    Fabrizio Carini, Md, Dmd                                      Introduction
    Vito Saggese, Mds
    Gianluca Porcaro, Mds                                         Bisphosphonates are drugs used to treat osteoporosis
    Lorena Barbano, Bds                                           when taken orally (1) and in the therapy of bone me-




                                                                                                 io
    Marco Baldoni, Md, Dmd                                        tastases, multiple myeloma and Paget’s disease when
                                                                  taken parenterally. Bisphosphonates exert their phar-
                                                                  macological action accumulating mainly in places with




                                                                            az
    University of Milan-Bicocca, Monza (MB), Italy                elevated bone metabolism; being inorganic pyrophos-
    School of Oral Surgery                                        phate analogues, bisphosphonates have a high affin-
                                                                  ity for calcium and are consequently removed from the
                                                                  circulation and then bind to mineralized bone. After re-
    Corresponding author:




                                                                          rn
                                                                  peated doses they accumulate in the bone matrix. Dur-
    Dott. Gianluca Porcaro                                        ing resorption, the osteoclast acidifies the bone matrix,
    School of Oral Surgery                                        causing the dissolution of hydroxyapatite crystals and
    University of Milan-Bicocca, Monza (MB), Italy                then the release of the bisphosphonate that was linked




                                                                  te
    Phone and Fax: +39 (0) 2333482                                to the crystals themselves. In this way it may come in
    Clinica Odontoiatrica - Villa Serena - Ospedale San Gerardo
                                                                  contact with osteoclasts inhibiting their resorption power.
    Via Pergolesi, 33
                                                                  Bisphosphonates are therefore drugs able to affect bone
    20900 Monza, Italy
    E-mail: porcarogianluca@libero.it
                                                          In      metabolism.
                                                                  Marx in 2002 (2) defined the proportions of the putative
                                                                  causes of osteonecrosis: dental extractions 37.8%, peri-
    Summary                                                       odontal and endodontic surgery 12%, implants interven-
                                                                  tions 3.4%. He also indicated a generic relationship with
                                                 ni

    Aim: This study investigates the association be-              periodontal disease in 28.6% of cases (3). Patients with
    tween cross linked C-terminal telopetide test (CTX)           osteoporosis have an estimated risk of developing os-
    and individual surgical risk of osteonecrosis in pa-          teonecrosis between 0.01% and 0.04%, which rises to
                                           io


    tients taking oral bisphosphonates.                           0.09-0.34% if they have performed dental extractions.
    Materials and Methods: 32 patients receiving                  Patients with multiple myeloma and bone metastases
    bisphosphonate were treated surgically. Patients              pass from 0.88% and 1.15% risk to 6.67% and 9.1% (4).
                                 iz



    were divided into three groups according to type of           The CTX is a serum test proposed by the American So-
    drug administrated and were subjected to a treat-             ciety of Bone Mineral Research Task Force on osteone-
    ment of oral surgery, such as simple tooth extrac-            crosis of the jaws. It is capable of measuring a specific
                 Ed




    tions and extraction of all residual teeth of the oral        marker of bone turnover and for this reason it could be
    cavity, upon evaluation of CTX values and antibiotic          used as a risk indicator in pre-operative assessment. It
    prophylaxis.                                                  is considered a useful test to assess serum and urinary
    Results: Within the sample of 32 patients, 12 patients        metabolites typical of bone resorption. The index serum
    had been treated with bisphosphonates for several             CTX can detect changes in the bone remodeling in a
    years and none developed osteonecrosis of the jaw             range of time comprised between a few days up to two
 IC




    upon surgery. As for CTX, patients treated with oral          weeks, therefore much earlier than with the use bone
    bisphosphonates showed a mean value of serum C-               mineral density (BMD). The assessment of BMD is a
    telopetides of 0.2869 ng/ml. The mean value of CTX            rough procedure, though it remains very useful in the
    did not differ significantly between patients taking          quantitative assessment of skeletal bone mass because
C




    oral bisphosphonates and healthy patients not treat-          it measures the relative bone density. Instead, the value
    ed with bisphosphonates.                                      of CTX test is rather useful for the quantitative assess-
    Conclusion: None of the patients subjected to pre-            ment of bone resorption through the degree of bone re-
    operative antibiotic prophylaxis developed osteone-           newal and such information is of great importance when
©




    crosis of the jaw after surgery. The pharmacological          assessing the risk of ONJ (5).
    and surgical protocol tested appeared valid in the            The dosage of CTX requires the removal of 1 ml of blood
    prevention of osteonecrosis associated to bisphos-            collected in a test tube at room temperature. Sampling
    phonates.                                                     should be collected in the morning, because changes
                                                                  during the day could lead to elevated values in the late
    Key words: serum C-terminal C-telopeptide (CTX),              afternoon or evening. The serum can be analyzed af-
    bisphosphonate, osteonecrosis of the jaw (ONJ).

    Annali di Stomatologia 2012;III (1): 31-36                                                                            31
    F. Carini et al.



    ter 15 minutes needed for blood clotting and provides                      patients in order to obtain information concerning the
    a reliable result up to over 16 hours of storage at room                   remote and recent physiological, pathological and phar-
    temperature for three days if kept refrigerated and three                  macological anamnesis, and preoperative CTX test was
    months if frozen.                                                          performed in order to evaluate the residual bone turn-
    Upon several studies, Marx and co-workers (5) proposed                     over. The patients were scheduled for oral surgery de-




                                                                                                                    li
    guidelines for risk assessment in the laboratory of pa-                    pending on the value of CTX obtained, the clinical evalu-
    tients taking bisphosphonates: CTX values between 0.3                      ation during the oral examination and the radiographic




                                                                                                                 na
    and 0.6 ng/ml are not associated with ONJ, values be-                      analysis (orthopantomography of jaws and Dentascan
    tween 0.150 and 0.299 ng/ml are associated with none                       Tc). For patients taking oral bisphosphonates for less
    or minimal risk of ONJ, values between 0.101 and 0.149                     than three years, in the absence of obvious risk factors
    ng/ml are associated with an intermediate risk of ONJ,                     it is not necessary to change or delay the oral surgical
    and finally CTX values ≤ 0.100ng/ml are associated with                    treatment plan. For patients treated for less than three




                                                                                                              io
    a high risk of ONJ.                                                        years but with at least one systemic risk associated, it
                                                                               is necessary to contact the physician to discontinue the
                                                                               bisphosphonate (drug holiday) at least three months be-




                                                                                          az
    Materials and methods                                                      fore the surgical procedure and the resumption should
                                                                               be delayed until three months after its execution. At the
    Between October 2009 and June 2010 at the Dental                           first examination and three months later it is necessary to
    Clinic of the University Milano-Bicocca 32 patients were                   measure the CTX. Values lower than 0.150 ng/ml would




                                                                                        rn
    recruited of which 12 were treated with oral bisphospho-                   advise against surgical procedures and an interruption
    nates, 11 with intravenous bisphosphonates and 9 not                       prolonged for another three months. In case of detection
    yet treated (Fig. 1). Our study group consisted of patients                of CTX values greater than 0.150 ng/ml, it may be al-




                                                                               te
    who were or are currently treated with oral bisphospho-                    lowed the introduction of elective surgery, informing the
    nates and about to receive invasive dental procedures.                     patients of the risk of developing ONJ, albeit very small.
    Of the 12 patients treated with oral bisphosphonates 3                     Bisphosphonate should not be reintroduced until three
    patients were taking risedronate acid, 8 alendronic acid                   months upon healing. For patients taking oral bisphos-
    and one ibandronic acid (Fig. 2). The control group con-
                                                                     In
                                                                               phonate for more than three years in the absence of
    sisted of patients not receiving bisphosphonates. Pa-                      risk factors it is recommended to contact the physician
    tients showed up at our department and were included                       in order to agree to an interruption of the drug for three
    in the study sample depending on their bisphosphonate                      months before to three months after the surgical ses-
                                                  ni
    assumption. A complete clinical record was made for all                    sion. Moreover, it is recommended to study the level of
                                                                               the cell turnover marker CTX at the first examination
                                                                               and before conducting the planned procedures. A val-
                                       io


                                                                               ue greater than or equal to 0.150 ng/ml is the minimum
                                                                               requirement to perform surgical procedures in patients
                                                                               who belong to this group. If there is an urgent need for
                              iz



                                                                               oral surgery while taking oral bisphosphonates, as in the
                                                                               presence of odontogenic abscesses requiring extraction
                                                  Parenteral bisphosphonates
                                                                               or abscess drainage to decrease pain and to manage
                 Ed




                                                                               infection, the patient should be subjected to the appro-
                                                                               priate procedure rather than maintaining the condition of
                                                                               pain and infection. Usually, the precursors of osteoclasts
                                                                               regain their activity to allow good bone healing following
                                                                               a three-month discontinuation of the bisphosphonate. In
                                                                               any case, it is important to remove all odontogenic foci in
    Figure 1 - Type of bisphosphonate assumption in the sample.
 IC




                                                                               the oral cavity, which are associated to an increased risk
                                                                               of ONJ. It is therefore necessary to inform the patient of
                                                                               possible risks. It has been estimated that for the first 2-3
                                                                               years, the risk of developing ONJ is low for patients tak-
C




                                                                               ing oral bisphosphonates (5-11).
                                                                               All patients in the sample, two weeks before and one
                                                                               week after oral surgery, carried out at the dental clinic of
                                                                               the Milano-Bicocca University according to the criteria
©




                                                                               of minimal invasiveness and high radicality to remove
                                                                               any odontogenic focus, underwent a pharmacological
                                                                               prophylaxis (6,7). Such prophylaxis started two weeks
                                                                               prior to surgery and consisted of amoxicillin and clavu-
                                                                               lanic acid tablets (1 g every 12 hours), metronidazole
                                                                               tablets (250 mg every 8 hours) and omeprazole tablets
    Figure 2 - Typology of oral bisphosphonate.                                (20 mg once daily) for the duration of antibiotic cover-

    32                                                                                                Annali di Stomatologia 2012;III (1): 31-36
    Surgical protocol in patients at risk for bisphosphonate osteonecrosis of the jaws



    age, associated to rinsing with chlorhexidine 0.2% im-                  - the mean value of CTX in patients with oral bisphos-
    mediately before surgery. The 12 patients receiving                     phonates was 0.2869 ng/ml;
    oral bisphosphonates were subjected to 15 surgeries of                  - the mean value of CTX in patients not yet treated with
    which 2 full-mouth tooth extractions and 18 extractions                 bisphosphonates was 0.225 ng/ml, which falls within, the
    of compromised dental elements (Fig. 3). In the group of                range of values reported in literature indicating values
                                                                            between 0.150 and 0.299 ng/ml. In our control sample,




                                                                                                                    li
    patients treated with oral bisphosphonates, due to the
    known complications that these drugs can induce, a total                including patients not treated with bisphosphonates, one




                                                                                                                 na
    of 12 surgeries were performed, of which 26 extractions                 subject showed a CTX value of 0.88 ng/ml. This value
    of hopeless teeth and a full-mouth tooth extraction pro-                does not conform to the rest of the sample. A possible
    cedure (Fig. 4). The antiseptic and antibiotic prophylaxis              explanation may be sought in medical history of this pa-
    was continued for one week after surgery to prevent in-                 tient that revealed she was suffering by bone metasta-
    fection, in order to avoid that it further delays the healing           ses from breast cancer. Marx in his 2005 study claimed




                                                                                                              io
    of the surgical wound. All patients in the sample under-                that the CTX is reliable only in non-cancer patients and
    went a close follow-up 1, 4 and 12 weeks after surgery,                 in cancer patients without bone metastases, because
    then every 3 months until the following year and every                  the latter could alter the real value of bone turnover(4).




                                                                                           az
    6 months thereafter. At each visit the surgical sites were              After having categorized patients belonging to the group
    checked clinically and radiographically to assess epithe-               treated with oral bisphosphonates in ascending order ac-
    lialization, bone sequestra and bone infections.                        cording to the duration of drug exposure we proceeded
                                                                            to observe the change in the CTX value (Fig. 5). Based




                                                                                         rn
                                                                            on the values of CTX belonging to patients in our study
                                                                            treated with oral bisphosphonates, it was performed a
                                                                            statistical test of hypothesis to compare the CTX values
                                                                            in patients taking oral bisphosphonates with those in pa-




                                                                           te
                                                                            tients of the control group. Null hypothesis was that CTX
                                                                            values in the two groups are equivalent. The value of
                                                                            the test statistic (z = 0.4166) was lower than the value
                                                                In          of t-Student (t (n-1) = 2.262). In addition, the confidence
                                                                            interval at 95% indicated, including 0, that it was not pos-
                                                                            sible to exclude the null hypothesis.
                                                                            Thus, in the sample considered for the study, the dif-
                                                   ni
                                                                            ference in CTX values between patients taking oral
    Figure 3 - Typology of oral surgery in patients treated with oral       bisphosphonates and patients of the control group, was
    bisphosphonate in the sample.                                           not statistically significant. In the group of patients tak-
                                           io


                                                                            ing oral bisphosphonates, on a total of 15 surgeries no
                                                                            signs of osteonecrosis in the longitudinal follow-up were
                                                                            found. Nine patients showed an uneventful healing, that
                                 iz



                                                                            is with a full epithelial filling of the surgical site within 30-
                                                                            45 days after surgery, while 6 surgical wound showed
                                                                            a delayed healing within 45-90 days (Figs. 6-7). In the
                 Ed




                                                                            group of patients that at the time of surgery did not take
                                                                            bisphosphonates, 10 surgical sites showed a normal
                                                                            healing within 30-45 days and two a delayed healing
                                                                            within 45-90 days (Figs. 8-9).
 IC




    Figure 4 - Typology of oral surgery in patients not treated with
    bisphosphonate in the sample.
C




    Results

    All patients taking bisphosphonates orally or parenterally
©




    who addressed our department to undergo surgery were
    treated according to the aforementioned surgical proto-
    col. In addition, patients were asked to go to a labora-
    tory for CTX testing to determine the bone turnover. The
    values of CTX obtained from the patients in the sample                  Figure 5 - CTX values in patients treated with oral bisphospho-
    were as follows:                                                        nate versus timing of the therapy.


    Annali di Stomatologia 2012;III (1): 31-36                                                                                            33
    F. Carini et al.




                                                                                                             li
                                                                                                          na
                                                                                                       io
                                                                       Figure 10 - Healing comparison between patients treated with
                                                                       oral bisphosphonate and patients not treated with bisphospho-
    Figure 6 - Timing of wound healing in patients treated with oral
                                                                       nate.




                                                                                  az
    bisphosphonate.
                                                                       Therefore, comparing the two groups, study and control,
                                                                       it can be observed that patients not taking bisphospho-
                                                                       nates had a better post-operative healing than patients




                                                                                rn
                                                                       treated with BF, in which we should consider the pos-
                                                                       sible delayed healing and therefore it becomes neces-
                                                                       sary a rigid follow-up (Fig. 10).




                                                                       te
                                                                       Case report
                                                                       A woman (about 55 years old) addressed our depart-
                                                                       ment for the simultaneous extraction of 3.6 and 4.7
                                                              In       residual roots. Antibiotic prophylaxis was administered
                                                                       in accordance to the protocol, since different operat-
    Figure 7 - Wound healing in patients treated with oral bisphos-    ing sessions would require antibiotic administration at
    phonate.                                                           close times. From the compilation of medical records
                                                 ni
                                                                       the patient resulted treated with oral bisphosphonates
                                                                       for about ten years. After preoperative evaluation by
                                                                       means of orthopantomography (Fig. 11), we performed
                                                                       the intraoral examination (Fig. 12) and CTX test, which
                                       io


                                                                       was found to be 0.3 ng/ml, so with associated low risk
                                                                       of osteonecrosis of the jaw. We then proceeded with the
                                                                       administration of antibiotic prophylaxis, as previously de-
                              iz



                                                                       scribed. The extraction of residual roots was performed
                                                                       following the surgical protocol previously explained (Fig.
                                                                       13). After the surgery a suture 3/0 was performed, which
                 Ed




                                                                       was removed after 8 days (Fig. 14). The patient con-
                                                                       tinued the antibiotic prophylaxis and the antimicrobial
                                                                       therapy with chlorhexidine 0.2% for one week after the
                                                                       surgery. Follow-up checks were scheduled at 2, 4, 6 and
    Figure 8 - Timing of wound healing in patients not treated with    12 months (Fig. 15).
 IC




    bisphosphonate.
C
©




    Figure 9 - Wound healing in patients not treated with bisphos-
    phonate.                                                           Figure 11 - Pre-operative orthopantomography.


    34                                                                                         Annali di Stomatologia 2012;III (1): 31-36
    Surgical protocol in patients at risk for bisphosphonate osteonecrosis of the jaws




                                                                                                                  li
                                                                                                               na
                                                                                                            io
                                                                            Figure 15 - Orthopantomography two months later.




                                                                                           az
                                                                            Discussion

                                                                            According to current knowledge, bisphosphonates are
                                                                            a very useful and effective therapeutic aid in the treat-




                                                                                         rn
    Figure 12 - Pre-operative clinical situation.
                                                                            ment of cancer-induced and metabolic bone diseases,
                                                                            beneficial effect an increasing number of patients makes
                                                                            prolonged use of these drugs; especially in post-menu-




                                                                           te
                                                                            pausal women (8,9), the use of bisphosphonates has
                                                                            become so ordinary that sometimes it is not even speci-
                                                                            fied in anamnesis before performing a dental surgical
                                                                            therapy. However, patients should be informed of possi-
                                                                In
                                                                            ble complications related to the bisphosphonates intake
                                                                            after invasive surgical treatments (10).
                                                                            According to what stated above and based on the results
                                                                            collected by the pharmacological and surgical protocol
                                                    ni
                                                                            adopted in the dental clinic of the University of Milano-
                                                                            Bicocca, inside the Hospital of San Gerardo of Monza, it
                                                                            is essential to consider patients treated with bisphospho-
                                           io


                                                                            nates at risk of ONJ. For this reason, it is necessary to
                                                                            monitor these patients during dental treatment after the
                                                                            surgery, in order to act quickly in case of complications.
                                 iz



                                                                            The observed operative protocol is based on an ade-
                                                                            quate and well-defined system of pre-operative prophy-
                                                                            laxis, a surgery conducted in a sterile environment and
                 Ed




                                                                            aimed to be minimally invasive, the complete debride-
                                                                            ment of all infected and inflammatory tissue, a suture
                                                                            warranting a rapid healing, and finally on a close follow-
                                                                            up program. Given the excellent results obtained by ap-
                                                                            plying the above pharmacological and surgical protocol
                                                                            in terms of reductions in the number of osteonecrosis
 IC




    Figure 13 - Extraction of 3.6 and 4.7 and suture.
                                                                            developed after oral surgery, it should be emphasized
                                                                            the importance of applying this protocol to all patients
                                                                            treated with oral, intramuscular or intravenous bisphos-
                                                                            phonates two weeks before and one week after surgery.
C




                                                                            Finally, as regards the use of serum telopeptide CTX in
                                                                            terms of preventive monitoring of the risk of developing
                                                                            ONJ in patients with oral bisphosphonates in the sample
                                                                            of the study, compared with the values of CTX in healthy
©




                                                                            patients, at present there is no sufficient evidence to
                                                                            affirm that the difference between the CTX values ob-
                                                                            tained in the two patient groups is statistically significant,
                                                                            perhaps because of the limited sample size. Neverthe-
                                                                            less, it is important to highlight that the relevance of CTX
                                                                            as an indicative value to consider patients treated with
    Figure 14 - Clinical situation after 8 days.                            bisphosphonates at potential risk of osteonecrosis.

    Annali di Stomatologia 2012;III (1): 31-36                                                                                         35
    F. Carini et al.



     For this reason, this serum test is an important clinical              2004; 62: 527-534.
    support in the therapeutic planning of the patient treated           7. Rosen HN, Moses AC, Garber J, Iloputaife ID, Ross DS,
    with bisphosphonates.                                                   Lee SL, Greenspan SL. Serum CTX. A new marker of bone
                                                                            resorption that shows treatment effect more often than
                                                                            other markers because of low coefficient of variability ad




                                                                                                              li
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                 Ed
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    36                                                                                          Annali di Stomatologia 2012;III (1): 31-36
