- Email: [email protected]
Serum N-Telopeptide and Bone-Specific Alkaline Phosphatase Levels in Patients With Osteonecrosis of the Jaw Receiving Bisphosphonates for Bone Metastases
PATHOLOGY J Oral Maxillofac Surg 70:2768-2775, 2012
Serum N-Telopeptide and Bone-Specific Alkaline Phosphatase Levels in Patients With Osteonecrosis of the Jaw Receiving Bisphosphonates for Bone Metastases Patrick G. Morris, MD,* Maurizio Fazio,† Azeez Farooki, MD,‡ Cherry Estilo, DMD,§ Divya Mallam,储 Alison Conlin, MD,¶ Sujata Patil, PhD,# Martin Fleisher, PhD,** Serge Cremers, PhD,†† Joseph Huryn, DDS,‡‡ Clifford A. Hudis, MD,§§ and Monica N. Fornier, MD储 储 Purpose: Oversuppression of bone turnover can be a critical factor in the pathogenesis of osteone-
crosis of the jaw (ONJ). We investigated N-telopeptide of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) as potential predictors of ONJ onset. Patients and Methods: Patients with ONJ and available stored serum were identified retrospectively from the institutional databases. Four approximate points were examined: point of ONJ diagnosis and 12, 6, and 1 month before the diagnosis. NTX and BAP were measured using enzyme-linked immunosorbent assays and examined as possible predictors of ONJ. Results: From March 1998 to September 2009, we identified 122 patients with ONJ. Of these, 56 (46%) had one or more serum samples available. Overall, 55 patients (98%) received bisphosphonates. Using the exact dates, no obvious patterns in either NTX or BAP were noted. Similarly, using the ordinal points, no evidence of suppression of NTX or BAP over time was seen. The consecutive median values were as follows: The median NTX values were 8.0 nmol/L (range 3.8 to 32.9) at 12 months before ONJ; 9.5 nmol/L (range 4.7 to 42.7) at 6 months; 9.5 nmol/L (range 4.5 to 24.6) at 1 month, and 10.4 nmol/L (range 4.4 to 32.5) at the ONJ diagnosis. The median BAP values were BAP 18.0 U/L (range 7.0 to 74) at 12 months before ONJ; 18.0 U/L (range 4.0 to 134) at 6 months; 14.0 U/L (range 4.0 to 132) at 1 month, and 18.0 U/L (range 0.7 to 375) at the ONJ diagnosis. Only 2 patients (4%) had NTX and 17 (30%) had BAP below the normal range at the ONJ diagnosis. Conclusions: In the present large retrospective study, no trends were seen in the NTX and BAP levels before the ONJ diagnosis. © 2012 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 70:2768-2775, 2012 *Special Fellow, Breast Cancer Medicine Service, Memorial SloanKettering Cancer Center, New York, NY. †Breast Cancer Medicine Service, Medical Student, Vita-Salute San Raffaele University, Milan Italy. ‡Assistant Attending, Endocrinology Service, Memorial Sloan-Kettering Cancer Center, New York, NY. §Associate Attending, Dental Service, Memorial Sloan-Kettering Cancer Center, New York, NY. 储Medical Student, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY. ¶Fellow, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY. #Assistant Attending, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. **Chief, Clinical Laboratories, Memorial Sloan-Kettering Cancer Center, New York, NY. ††Assistant Professor, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.
‡‡Chief, Dental Service, Memorial Sloan-Kettering Cancer Center, New York, NY. §§Chief, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY. 储 储Assistant Attending, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, and Assistant Professor, Weill Cornell Medical College, New York, NY. Conflict of Interest Disclosures: Dr. Morris has an honoraria from EISAI and a paid consultantship from Oncologystat.com. None of the other authors reported any disclosures. Address correspondence and reprint requests to Dr Morris: Department of Medicine, Breast Cancer Medicine Service, Evelyn H Lauder Breast and Imaging Center, 300 E 66th Street, New York, NY 10065; e-mail: [email protected] © 2012 American Association of Oral and Maxillofacial Surgeons
0278-2391/12/7012-0$36.00/0 doi:10.1016/j.joms.2011.12.028
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Bone metastases are a common complication of a variety of malignancies, including carcinomas of the breast, prostate, and lung. For example, in advanced breast cancer, it is estimated that up to 85% of patients develop bone metastases during their disease course.1,2 Untreated bone metastases are associated with significant morbidity, captured by a composite endpoint termed “skeletal-related events” (SREs). The incidence of SREs has been decreased by the development of bone targeting agents, including bisphosphonates and, more recently, inhibitors of receptor activator of nuclear factor-B ligand such as denosumab.3-10 However, in approximately 2% of patients, these agents are associated with the development of osteonecrosis of the jaw (ONJ), defined by the American Society of Bone and Mineral Research ONJ Task Force as an area of exposed bone in the maxillofacial region that does not heal within 8 weeks of identification by a health care provider.10-12 The pathogenesis of ONJ is poorly understood, although the suppression of bone turnover, resulting in accumulation of microdamage and impaired bone repair after trauma and infection, has been hypothesized to play a key role.13 To date, the risk assessment tools for ONJ have been limited to clinical factors such as pre-existing dental or periodontal disease, recent dental extractions, comorbid conditions, and tobacco use, as well as administered treatment (eg, anticancer therapy, glucocorticoids, and duration of exposure to bisphosphonate treatment).11,14,15 No biomarkers have been validated to identify patients at greatest risk of developing ONJ. However, several biochemical markers of bone turnover are known, including N-telopeptide of type I collagen (NTX), a degradative product of mature bone collagen, which reflects bone resorption, and bone-specific alkaline phosphatase (BAP), which reflects bone formation.16 In the treatment of osteoporosis, these biomarkers have been extensively investigated. In various oncology settings, these biomarkers correlate with the presence and extent of bone metastases and decrease in response to bisphosphonate therapy.17,18 Given the putative importance of bone turnover in the pathophysiology of ONJ, we hypothesized that patients would have low absolute serum levels of NTX and BAP at the ONJ diagnosis and that “over”suppression of these biomarkers would be seen in the year preceding the diagnosis. We investigated these possible associations in a retrospective study of serum from patients diagnosed with ONJ.
Patients and Methods The institutional review board of Memorial SloanKettering Cancer Center approved the present study. Patients with ONJ were identified from a prospectively maintained database from the Dental Service at
Memorial Sloan-Kettering Cancer Center, according to the American Society of Bone and Mineral Research task force definition.11 In line with these recommendations, where possible, cases were confirmed by repeat examination within 8 weeks. Electronic medical records were reviewed to identify other possible risk factors for ONJ and poor healing, including treatment administered (ie, bisphosphonates, anti-angiogenics, corticosteroids, chemotherapy, and radiotherapy), and patient-related factors (ie, smoking status, obesity, diabetes, and cardiovascular disease). The total bisphosphonate exposure was estimated according to the duration and dose of the individual agents. At Memorial Sloan-Kettering Cancer Center, the patients routinely have serum stored after routine clinical chemistry laboratory testing, including comprehensive metabolic profiles and tumor markers (eg, carcinoembryonic antigen and prostate-specific antigen). Therefore, the medical records were used to identify possible stored serum from up to 4 approximate points: 12 months before ONJ, 6 months before ONJ, 1 month before ONJ, and at the ONJ diagnosis. Using commercially available enzyme-linked immunosorbent assays, the available serum was used to measure both NTX (Osteomark; normal range 5.5 to 19.5 nmol/L BCE) and BAP (Quidel; normal range 14.2 to 42.7 U/L). The absolute values and trends in NTX and BAP over time were examined as possible predictors for ONJ. For the primary analysis, exact dates of serum sampling and ONJ diagnosis were used. In a secondary analysis, we examined the median and range of values using ordinal data, whereby the dates were approximated to 1 of the 4 points. Finally, we examined the proportion of patients with NTX and BAP values below the normal range at the ONJ diagnosis.
Results From March 1998 to September 2009, we identified 122 cases of ONJ. Of these, 56 patients (46%) had at least 1 serum sample available and were included in the present analysis. In 51 cases (91%), the diagnosis of ONJ was confirmed by repeat assessment after 8 weeks (per American Society of Bone and Mineral Research guidelines). The baseline patient characteristics are listed in Table 1. Most patients (65%) had breast cancer, and almost all patients (96%) had documented metastatic disease. In addition, before the ONJ diagnosis, 21 patients (38%) were known to have undergone dental procedures (median interval before ONJ diagnosis 3 months, range 0 to 45), consisting of extractions (20 patients), oral surgery for dentures (1 patient), and implants (1 patient). At the ONJ diagnosis, the body mass index was unknown for 3 patients; for the other 53 patients, the median body mass index was 26.6 kg/m2 (range 19 to 37).
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Table 1. BASELINE PATIENT CHARACTERISTICS (N ⴝ 56)
Characteristic Age (yr) Median Range Gender (n) Male Female Cancer type (n) Breast Prostate Myeloma Ovarian Lung Smoking status (n) Nonsmoker Former smoker Active smoker within 1 yr of diagnosis Comorbidities (n) Hypertension Obesity (BMI ⱖ30 kg/m2) Diabetes Cardiovascular disease Previous treatment (n) Chemotherapy Previous dental procedures Steroid use Antiangiogenic therapy Bevacizumab Thalidomide Bortezomib Anticoagulant therapy Radiation to head and neck
Value 65 41-95 19 (34) 37 (66) 36 (64) 17 (30) 1 (2) 1 (2) 1 (2) 28 (50) 20 (36) 8 (14) 23 (41) 14 (25) 9 (16) 5 (9) 49 (88) 21 (38) 19 (34) 19 (34) 16 (29) 3 (5) 1 (2) 7 (13) 3 (5)
Abbreviation: BMI, body mass index. Data in parentheses are percentages. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
Before the ONJ diagnosis, 55 patients (98%) had received bisphosphonate therapy, and in 1 patient, the diagnosis of ONJ was thought secondary to antiangiogenic therapy (bevacizumab), as previously reported.19 For the 55 patients who had received previous bisphosphonates, the median duration of exposure was 25 months (range 0 to 119; Table 2). NTX AND BAP
Serum was available as follows: from 4 measurement points in 19 patients (34%), from 3 points in 16 patients (29%), from 2 points in 11 patients (20%), and from 1 point in 10 patients (18%). In addition, for technical reasons, NTX and BAP could not be measured in 5 and 1 sample, respectively. Therefore, we had a total of 151 individual results for NTX and 155 individual results for BAP. In the primary analysis (using exact dates), there were no obvious patterns in either NTX (Fig 1A) or BAP (Fig 1B). Similarly, no trends were seen when we
restricted the analyses to patients with 3 or more available blood samples for both NTX (Fig 2A) and BAP (Fig 2B). In the secondary analysis, the data were approximated into 1 of the 4 ordinal points, and we saw no evidence of suppression of NTX levels over time. In fact, an apparently opposite trend for NTX was noted (Fig 3A). At the ONJ diagnosis, only 2 patients (4%) had NTX levels below the normal range (⬍5.5 nmol/ L). For BAP, no evidence was seen of a change over time (Fig 3B). However, at the ONJ diagnosis, 17 patients (30%) had BAP below the normal range (⬍14.2 U/L). Both patients with NTX below normal also had BAP levels below the normal range. Similar findings were seen in subgroup analyses. In patients with breast cancer and 3 or more available blood draws, the median NTX values were as follows: 7.8 nmol/L (range 3.8 to 15.8) at 12 months before ONJ (n ⫽ 17), 8.1 nmol/L (range 4.7 to 42.7) at 6 months (n ⫽ 19), 10.4 nmol/L (range 4.5 to 24.6) at 1 month (n ⫽ 19), and 9.8 nmol/L (range 0.7 to 24.5) at the ONJ diagnosis (n ⫽ 20). For BAP, the median values at the corresponding points were as follows: 19.5 U/L (range 8.0 to 74; n ⫽ 18), 15.0 U/L (range 4.0 to 100; n ⫽ 19), 11.0 U/L (range 4.0 to 132; n ⫽ 20), and 15.0 U/L (range 0.7 to 43; n ⫽ 21). In patients with prostate cancer and 3 or more available blood draws, the median NTX values were as follows: 8.7 nmol/L (range 5.0 to 32.9; n ⫽ 10), 8.9 nmol/L (range 5.5 to 12.6; n ⫽ 10), 8.3 nmol/L (range 7.0 to 14.1; n ⫽ 8), and 8.2 nmol/L (range 4.4 to 21.5; n ⫽ 10) at 12, 6, and 1 month before the ONJ diagnosis and at the ONJ diagnosis, respectively. For BAP, the median values at the corresponding points were as follows:
Table 2. PREVIOUS BISPHOSPHONATE EXPOSURE (N ⴝ 55)
Variable Bisphosphonate administered Zoledronic acid alone Pamidronate and zoledronic acid Pamidronate alone Alendronate and pamidronate Total dose administered (mg) Zoledronic acid (n ⫽ 51*) Median Range Pamidronate (n ⫽ 13) Median Range Alendronate (n ⫽ 1)
Value 41 (73) 10 (18) 3 (5) 1 (2) 70 4-244 2,925 810-8,280 1,680
*Included 2 patients with missing data on total administered dose and 1 patient with missing data for both therapy duration and total administered dose. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
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FIGURE 1. A, Changes in NTX over time relative to diagnosis of ONJ (n ⫽ 55). B, Changes in BAP over time relative to diagnosis of ONJ (n ⫽ 56). Exact dates for blood draws and ONJ diagnosis (red vertical line) used. Results from individual patients represented in different colors and shapes. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
16.0 U/L (range 7.0 to 65; n ⫽ 10), 16.0 U/L (range 8.0 to 49; n ⫽ 10), 9.0 U/L (range 4.0 to 100; n ⫽ 8), and 14.0 U/L (range 5.0 to 74; n ⫽ 11). In the 1 patient who had had no previous bisphosphonate exposure, no obvious pattern of biomarkers was noted. Serum was unavailable from point 1 (12 months before the ONJ diagnosis). For NTX, the available result was 14.7, 5.2, and 7.2 nmol/L 6 months before, 1 month before, and at the ONJ diagnosis. For BAP, the available results were 47.0, 35.0, and 25.0 U/L for the same 3 points.
Discussion In the present large series, NTX and BAP did not predict for the development of ONJ. No meaningful trend for either biomarker was seen. The median NTX level increased from 8.0 nmol/L at baseline to 10.4 nmol/L at the ONJ diagnosis and the median BAP level remained unchanged at 18.0 U/L. Furthermore, we
were unable to identity any subgroup in whom these biomarkers might be useful, including those with 3 or more available results, separation by 2 major disease subtypes (breast vs prostate cancer), and bisphosphonate therapy or not. Finally, despite chronic bisphosphonate exposure, there was limited evidence of suppression of markers of bone turnover (4% and 30% patients had NTX and BAP below the normal range, respectively). Decreased bone turnover in the mandibular region has been proposed as a critical factor in the pathogenesis of ONJ.13 It is thought that after physiologic or iatrogenic trauma (eg, dental extraction) normal healing is prevented by inhibition of osteoclasts by bisphosphonates and other agents, leading to exposure of underlying necrotic bone.11,13 As a biomarker of bone resorption, NTX represents the amino-terminal peptide of type 1 collagen, which is responsible for cross-linking of the bone matrix.16 In contrast, BAP is a highly specific isoenzyme in bone and re-
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FIGURE 2. A, Changes in NTX over time relative to diagnosis of ONJ (restricted to patients with 3 or more blood draws; n ⫽ 33). B, Changes in BAP over time relative to diagnosis of ONJ (restricted to patients with 3 or more blood draws; n ⫽ 35). Exact dates for blood draws and ONJ diagnosis (red vertical line) used. Results from individual patients represented in different colors and shapes. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
flects osteoblastic cellular activity (bone formation).16 We hypothesized that at the time of ONJ diagnosis, the suppression of bone turnover would translate into very low absolute levels of NTX and BAP and that the serum levels would decrease substantially during the year preceding the ONJ diagnosis. Both NTX and BAP have been investigated as biomarkers in osteoporosis and are sometimes used in clinical practice, given that increased bone turnover is a determinant of fracture risk.20 In patients with osseous metastases from a variety of malignancies, elevated biomarker levels, including urinary NTX (uNTX) and serum BAP, have been shown to correlate with increased risk of SREs, extent of bone disease, progression in bone, and inferior overall survival.18,21,22 For example, in 1 study, which included 97 patients with known bone metastases, uNTX was associated with disease progression in bone (average change of 152% from the time of stable disease).18 Furthermore, normalization of uNTX was associated with a reduced risk of SREs and
death in a combined analysis of 3 large, phase III trials of bisphosphonates.23 Despite the strong biologic rationale for the present study, we found no suggestion that these biomarkers might be useful in predicting patients at greatest risk of ONJ. The only notable finding was that 30% of the patients had BAP below the normal range at the ONJ diagnosis, an observation that might deserve additional investigation. Given the rarity of ONJ, relative to the number of patients treated with bisphosphonates, to the best of our knowledge, the present series represents the largest published biomarker study (56 patients), and serum was available from 3 or more measurement points for 63% of these. The ONJ cases were rigorously defined, and the diagnosis was confirmed with repeat examination in almost all patients (91%). In general, patients in the present study had several risk factors known to be associated with an increased risk of ONJ.15 For example, 98% of the patients had received previous bisphosphonate ther-
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FIGURE 3. A, NTX at sequential points (ordinal data). B, BAP at sequential points (ordinal data). Box-and-whisker plots showing range (line), median (crosses), and interquartile range (box). Dates of blood draws approximated to 1 of 4 points. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
apy, with a median previous exposure of 25 months (range 0 to 119), and we were able to document previous dental procedures in 38% of the patients. This highlights awareness of the importance of avoiding invasive dental procedures in patients receiving long-term bisphosphonate therapy, although given the retrospective nature of the present study, it is possible that many more patients had a history of dental extraction. We were able to obtain stored serum from 1 patient without bisphosphonate exposure, who we previously reported as having ONJ secondary to bevacizumab.19 Therefore, our series highlights the possible role of anti-angiogenics in the development of ONJ (34%) and corticosteroid use (34%), as well as patientrelated factors such as smoking (50% of the patients were current or former smokers).14,19 It is likely that the critical reason for a lack of predictive nature for the biomarkers investigated was a lack of specificity for the mandibular region. The
results were confounded by the presence and change in osseous metastases and by the administered bisphosphonates. Costa et al18 showed that both uNTX and serum BAP were reduced by bisphosphonate therapy (average change of 47%, P ⬍ .001, and 69%, P ⫽ .008, respectively), and it appears that similar changes occur with denosumab.24 Because most patients in our series had received long-term bisphosphonates (median duration of exposure 25 months), this would be expected to decrease both NTX and BAP. Therefore NTX and BAP have been proposed as biomarkers to guide the continuation and dosing frequency of bisphosphonates, whereby the frequency of bisphosphonate dosing could be reduced in patients with maximally suppressed bone turnover, resulting in minimally detectable serum levels. However, currently, the American Society of Clinical Oncology advises against using bone turnover markers to guide therapy, and our data support this recommendation.5,25 In contrast, because
2774 bisphosphonates are generally administered for the treatment of osseous metastases, the presence of metastatic disease in bone would have been expected to cause an increase in both biomarkers over time.18,21,22 In our study, despite the relatively high doses of bisphosphonates administered, most patients had no evidence of suppressed NTX and BAP, thereby suggesting that ONJ can occur independently of systemic bone turnover. One possibility is that local bone turnover in the jaw was suppressed, but that systemic bone turnover, as evidenced by the biochemical markers measured, was not suppressed in most patients. There are several important limitations to consider in our study. First, this was a retrospective study, and definitive conclusions are limited by the number and timing of blood draws, which were performed for other (clinical) reasons. However, because 63% of the patients had 3 or more blood draws, we suggest that additional samples would not have changed the results. Second, it is possible that our results could have been confounded by selection bias, because serum was available for 46% of the patients with known ONJ at our institution. However, this was considered unlikely, because the excluded patients were seen by our dental service without institutional medical oncology follow-up and the characteristics of the included patients were similar to those from other published series.14 Third, we did not include a control group of bisphosphonate-treated individuals without ONJ, matched for the burden of skeletal metastases, which would be necessary to definitively know whether a threshold exists for NTX or BAP below which the risk of ONJ increases. The optimal definition of a control group would be challenging vis-à-vis the opposing effects of chronic bisphosphonates, physiologic remodeling, fractures, and progressive osseous metastases on biomarkers over time.18,21,22 Fourth, the premenopausal reference range for “healthy” patients provided by the manufacturer of the assay might not be a valid lower limit in the oncology setting owing to the significant elevations in bone turnover because of metastases. Finally, although the intra- and interassay variability was less than 10%, nonfasting samples at random times of the day could have degraded in storage. We were unable to control for the variation by time of day and diet (bone resorption is reduced by food and follows a circadian rhythm, with peak serum and urinary biomarkers early in the morning).26-29 Notably, although bone alkaline phosphatase does not follow a circadian rhythm, it does have a 15% to 20% cross-reactivity with the liver isoform; therefore, liver metastases could have confounded specificity. Furthermore, our analyses were limited to serum only, rather than uNTX, which requires correction for urinary creatinine.26 It is unknown whether the fasting samples for other bone turnover markers, could be more useful in predicting ONJ.
SERUM NTX AND BAP AS BIOMARKERS FOR ONJ
Other possible biomarkers of ONJ have been examined, including the serum levels of the carboxy-terminal of type I collagen (CTX).30-34 Provocatively, in 1 study, lower CTX levels before dental surgery were seen in 18 patients who developed ONJ compared with those who did not (n ⫽ 60).32 However, other studies have not supported the use of CTX as a biomarker.31,33,34 In more than 5,000 patients treated in 5 clinical trials of zoledronic acid, “low” CTX levels did not predict the development of ONJ, although, notably, only 2 cases of ONJ were seen.31 In the study by Lazarovici et al,32 ONJ was seen in 18 (23%) of 78 patients. In comparison, in a study of preoperative CTX in 163 patients taking oral bisphosphonates and undergoing oral surgery, none developed ONJ;33 and in the large study by Grbic et al,31 the incidence of ONJ was less than 1 in 14,200 patient treatment-years. Hence, it is possible that a lack of adherence to a strict definition of ONJ in some reports might have limited the broader interpretation of the conclusions. Other serum markers of bone formation include osteocalcin, a specific product of osteoblasts, and the propeptide type I procollagen, a specific product of osteoblasts.35 There are multiple biomarkers of bone resorption, including urinary hydroxyproline, which is present in all fibrillar collagens, collagen hydroxylysine-glycosides, bone sialoprotein, a phosphorylated glycoprotein synthesized by osteoblasts and osteoclasts, and specific osteoclast enzymes, such as cathepsin K and tartrate-resistant acid phosphatase.35 The potential role of these biomarkers in predicting ONJ is unknown. Irrespective of the choice of biomarkers, it is likely that the complex interaction between osseous metastases and treatment can only be truly investigated in a prospective study, and this is the subject of several ongoing trials.27 Significant challenges exist in developing a useful biomarker, including the relatively low incidence of “true” ONJ and the confounding effect of underlying disease and administered treatment. Therefore, at present, in the absence of high level prospective evidence: CTX, NTX, and BAP should not be used routinely in clinical practice to identify patients at risk of ONJ.25,36 In conclusion, in this relatively large retrospective study, uncontrolled for fasting status, diurnal variations, and osseous metastases, we were unable to find evidence to support the hypothesis that, in the setting of bisphosphonate use, systemic oversuppression of bone turnover as revealed by biochemical markers, is associated with the development of ONJ.
References 1. Hamaoka T, Madewell JE, Podoloff DA, et al: Bone imaging in metastatic breast cancer. J Clin Oncol 22:2942, 2004 2. Morris PG, McArthur HL, Hudis CA: Therapeutic options for metastatic breast cancer. Expert Opin Pharmacother 10:967, 2009
MORRIS ET AL 3. Aapro M, Abrahamsson PA, Body JJ, et al: Guidance on the use of bisphosphonates in solid tumours: Recommendations of an international expert panel. Ann Oncol 19:420, 2008 4. Body JJ: Effectiveness and cost of bisphosphonate therapy in tumor bone disease. Cancer 97:859, 2003 5. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042, 2003 6. Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 335:1785, 1996 7. Kohno N, Aogi K, Minami H, et al: Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: A randomized, placebo-controlled trial. J Clin Oncol 23:3314, 2005 8. Rosen LS, Gordon D, Kaminski M, et al: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, doubleblind, multicenter, comparative trial. Cancer 98:1735, 2003 9. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17:846, 1999 10. Stopeck AT, Lipton A, Body JJ, et al: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: A randomized, doubleblind study. J Clin Oncol 28:5132, 2010 11. Khosla S, Burr D, Cauley J, et al: Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22:1479, 2007 12. Lipton A, Siena S, Rader M, et al: Comparison of denosumab versus zoledronic acid (ZA) for treatment of bone metastases in advanced cancer patients: An integrated analysis of 3 pivotal trials. Presented at the European Society of Medical Oncology 35th Annual Meeting, Milan, Italy, October 8-12, 2010. Abstract 3826 13. Woo SB, Hellstein JW, Kalmar JR: Narrative [corrected] review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144:753, 2006 14. Estilo CL, Van Poznak CH, Wiliams T, et al: Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. Oncologist 13:911, 2008 15. Vahtsevanos K, Kyrgidis A, Verrou E, et al: Longitudinal cohort study of risk factors in cancer patients of bisphosphonaterelated osteonecrosis of the jaw. J Clin Oncol 27:5356, 2009 16. Lipton A, Costa L, Ali SM, et al: Bone markers in the management of metastatic bone disease. Cancer Treat Rev 27:181, 2001 17. Demers LM, Costa L, Chinchilli VM, et al: Biochemical markers of bone turnover in patients with metastatic bone disease. Clin Chem 41:1489, 1995 18. Costa L, Demers LM, Gouveia-Oliveira A, et al: Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 20:850, 2002 19. Estilo CL, Fornier M, Farooki A, et al: Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol 26:4037, 2008
2775 20. Bonnick SL, Shulman L: Monitoring osteoporosis therapy: Bone mineral density, bone turnover markers, or both? Am J Med 119:S25, 2006 21. Brown JE, Cook RJ, Major P, et al: Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59, 2005 22. Cook RJ, Coleman R, Brown J, et al: Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res 12:3361, 2006 23. Lipton A, Cook R, Saad F, et al: Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 113:193, 2008 24. Eastell R, Christiansen C, Grauer A, et al: Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res 26:530, 2011 25. Van Poznak CH, Temin S, Yee GC, et al: American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 29:1221, 2011 26. Baim S, Miller PD: Assessing the clinical utility of serum CTX in postmenopausal osteoporosis and its use in predicting risk of osteonecrosis of the jaw. J Bone Miner Res 24:561, 2009 27. Cremers S, Farooki A: Biochemical markers of bone turnover in osteonecrosis of the jaw in patients with osteoporosis and advanced cancer involving the bone. Ann N Y Acad Sci 1218:80, 2011 28. Bjarnason NH, Henriksen EE, Alexandersen P, et al: Mechanism of circadian variation in bone resorption. Bone 30:307, 2002 29. Generali D, Dovio A, Tampellini M, et al: Changes of bone turnover markers and serum PTH after night or morning administration of zoledronic acid in breast cancer patients with bone metastases. Br J Cancer 98:1753, 2008 30. Marx RE, Cillo JE Jr, Ulloa JJ: Oral bisphosphonate-induced osteonecrosis: Risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65:2397, 2007 31. Grbic JT, Black DM, Lyles KW, et al: The incidence of osteonecrosis of the jaw in patients receiving 5 milligrams of zoledronic acid: Data from the health outcomes and reduced incidence with zoledronic acid once yearly clinical trials program. J Am Dent Assoc 141:1365, 2010 32. Lazarovici TS, Mesilaty-Gross S, Vered I, et al: Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates. J Oral Maxillofac Surg 68:2241, 2010 33. Lee CY, Suzuki JB: CTX biochemical marker of bone metabolism. Is it a reliable predictor of bisphosphonate-associated osteonecrosis of the jaws after surgery? Part II: A prospective clinical study. Implant Dent 19:29, 2010 34. Bagan JV, Jiménez Y, Gómez D, et al: Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates. Oral Oncol 44:1088, 2008 35. Seibel MJ: Clinical use of markers of bone turnover in metastatic bone disease. Nat Clin Pract Oncol 2:504, 2005 36. Khosla S, Burr D, Cauley J, et al: Oral bisphosphonate-induced osteonecrosis: Risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 66: 1320, 2008
Serum N-Telopeptide and Bone-Specific Alkaline Phosphatase Levels in Patients With Osteonecrosis of the Jaw Receiving Bisphosphonates for Bone Metastases Patrick G. Morris, MD,* Maurizio Fazio,† Azeez Farooki, MD,‡ Cherry Estilo, DMD,§ Divya Mallam,储 Alison Conlin, MD,¶ Sujata Patil, PhD,# Martin Fleisher, PhD,** Serge Cremers, PhD,†† Joseph Huryn, DDS,‡‡ Clifford A. Hudis, MD,§§ and Monica N. Fornier, MD储 储 Purpose: Oversuppression of bone turnover can be a critical factor in the pathogenesis of osteone-
crosis of the jaw (ONJ). We investigated N-telopeptide of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) as potential predictors of ONJ onset. Patients and Methods: Patients with ONJ and available stored serum were identified retrospectively from the institutional databases. Four approximate points were examined: point of ONJ diagnosis and 12, 6, and 1 month before the diagnosis. NTX and BAP were measured using enzyme-linked immunosorbent assays and examined as possible predictors of ONJ. Results: From March 1998 to September 2009, we identified 122 patients with ONJ. Of these, 56 (46%) had one or more serum samples available. Overall, 55 patients (98%) received bisphosphonates. Using the exact dates, no obvious patterns in either NTX or BAP were noted. Similarly, using the ordinal points, no evidence of suppression of NTX or BAP over time was seen. The consecutive median values were as follows: The median NTX values were 8.0 nmol/L (range 3.8 to 32.9) at 12 months before ONJ; 9.5 nmol/L (range 4.7 to 42.7) at 6 months; 9.5 nmol/L (range 4.5 to 24.6) at 1 month, and 10.4 nmol/L (range 4.4 to 32.5) at the ONJ diagnosis. The median BAP values were BAP 18.0 U/L (range 7.0 to 74) at 12 months before ONJ; 18.0 U/L (range 4.0 to 134) at 6 months; 14.0 U/L (range 4.0 to 132) at 1 month, and 18.0 U/L (range 0.7 to 375) at the ONJ diagnosis. Only 2 patients (4%) had NTX and 17 (30%) had BAP below the normal range at the ONJ diagnosis. Conclusions: In the present large retrospective study, no trends were seen in the NTX and BAP levels before the ONJ diagnosis. © 2012 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 70:2768-2775, 2012 *Special Fellow, Breast Cancer Medicine Service, Memorial SloanKettering Cancer Center, New York, NY. †Breast Cancer Medicine Service, Medical Student, Vita-Salute San Raffaele University, Milan Italy. ‡Assistant Attending, Endocrinology Service, Memorial Sloan-Kettering Cancer Center, New York, NY. §Associate Attending, Dental Service, Memorial Sloan-Kettering Cancer Center, New York, NY. 储Medical Student, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY. ¶Fellow, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY. #Assistant Attending, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. **Chief, Clinical Laboratories, Memorial Sloan-Kettering Cancer Center, New York, NY. ††Assistant Professor, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.
‡‡Chief, Dental Service, Memorial Sloan-Kettering Cancer Center, New York, NY. §§Chief, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY. 储 储Assistant Attending, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, and Assistant Professor, Weill Cornell Medical College, New York, NY. Conflict of Interest Disclosures: Dr. Morris has an honoraria from EISAI and a paid consultantship from Oncologystat.com. None of the other authors reported any disclosures. Address correspondence and reprint requests to Dr Morris: Department of Medicine, Breast Cancer Medicine Service, Evelyn H Lauder Breast and Imaging Center, 300 E 66th Street, New York, NY 10065; e-mail: [email protected] © 2012 American Association of Oral and Maxillofacial Surgeons
0278-2391/12/7012-0$36.00/0 doi:10.1016/j.joms.2011.12.028
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Bone metastases are a common complication of a variety of malignancies, including carcinomas of the breast, prostate, and lung. For example, in advanced breast cancer, it is estimated that up to 85% of patients develop bone metastases during their disease course.1,2 Untreated bone metastases are associated with significant morbidity, captured by a composite endpoint termed “skeletal-related events” (SREs). The incidence of SREs has been decreased by the development of bone targeting agents, including bisphosphonates and, more recently, inhibitors of receptor activator of nuclear factor-B ligand such as denosumab.3-10 However, in approximately 2% of patients, these agents are associated with the development of osteonecrosis of the jaw (ONJ), defined by the American Society of Bone and Mineral Research ONJ Task Force as an area of exposed bone in the maxillofacial region that does not heal within 8 weeks of identification by a health care provider.10-12 The pathogenesis of ONJ is poorly understood, although the suppression of bone turnover, resulting in accumulation of microdamage and impaired bone repair after trauma and infection, has been hypothesized to play a key role.13 To date, the risk assessment tools for ONJ have been limited to clinical factors such as pre-existing dental or periodontal disease, recent dental extractions, comorbid conditions, and tobacco use, as well as administered treatment (eg, anticancer therapy, glucocorticoids, and duration of exposure to bisphosphonate treatment).11,14,15 No biomarkers have been validated to identify patients at greatest risk of developing ONJ. However, several biochemical markers of bone turnover are known, including N-telopeptide of type I collagen (NTX), a degradative product of mature bone collagen, which reflects bone resorption, and bone-specific alkaline phosphatase (BAP), which reflects bone formation.16 In the treatment of osteoporosis, these biomarkers have been extensively investigated. In various oncology settings, these biomarkers correlate with the presence and extent of bone metastases and decrease in response to bisphosphonate therapy.17,18 Given the putative importance of bone turnover in the pathophysiology of ONJ, we hypothesized that patients would have low absolute serum levels of NTX and BAP at the ONJ diagnosis and that “over”suppression of these biomarkers would be seen in the year preceding the diagnosis. We investigated these possible associations in a retrospective study of serum from patients diagnosed with ONJ.
Patients and Methods The institutional review board of Memorial SloanKettering Cancer Center approved the present study. Patients with ONJ were identified from a prospectively maintained database from the Dental Service at
Memorial Sloan-Kettering Cancer Center, according to the American Society of Bone and Mineral Research task force definition.11 In line with these recommendations, where possible, cases were confirmed by repeat examination within 8 weeks. Electronic medical records were reviewed to identify other possible risk factors for ONJ and poor healing, including treatment administered (ie, bisphosphonates, anti-angiogenics, corticosteroids, chemotherapy, and radiotherapy), and patient-related factors (ie, smoking status, obesity, diabetes, and cardiovascular disease). The total bisphosphonate exposure was estimated according to the duration and dose of the individual agents. At Memorial Sloan-Kettering Cancer Center, the patients routinely have serum stored after routine clinical chemistry laboratory testing, including comprehensive metabolic profiles and tumor markers (eg, carcinoembryonic antigen and prostate-specific antigen). Therefore, the medical records were used to identify possible stored serum from up to 4 approximate points: 12 months before ONJ, 6 months before ONJ, 1 month before ONJ, and at the ONJ diagnosis. Using commercially available enzyme-linked immunosorbent assays, the available serum was used to measure both NTX (Osteomark; normal range 5.5 to 19.5 nmol/L BCE) and BAP (Quidel; normal range 14.2 to 42.7 U/L). The absolute values and trends in NTX and BAP over time were examined as possible predictors for ONJ. For the primary analysis, exact dates of serum sampling and ONJ diagnosis were used. In a secondary analysis, we examined the median and range of values using ordinal data, whereby the dates were approximated to 1 of the 4 points. Finally, we examined the proportion of patients with NTX and BAP values below the normal range at the ONJ diagnosis.
Results From March 1998 to September 2009, we identified 122 cases of ONJ. Of these, 56 patients (46%) had at least 1 serum sample available and were included in the present analysis. In 51 cases (91%), the diagnosis of ONJ was confirmed by repeat assessment after 8 weeks (per American Society of Bone and Mineral Research guidelines). The baseline patient characteristics are listed in Table 1. Most patients (65%) had breast cancer, and almost all patients (96%) had documented metastatic disease. In addition, before the ONJ diagnosis, 21 patients (38%) were known to have undergone dental procedures (median interval before ONJ diagnosis 3 months, range 0 to 45), consisting of extractions (20 patients), oral surgery for dentures (1 patient), and implants (1 patient). At the ONJ diagnosis, the body mass index was unknown for 3 patients; for the other 53 patients, the median body mass index was 26.6 kg/m2 (range 19 to 37).
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Table 1. BASELINE PATIENT CHARACTERISTICS (N ⴝ 56)
Characteristic Age (yr) Median Range Gender (n) Male Female Cancer type (n) Breast Prostate Myeloma Ovarian Lung Smoking status (n) Nonsmoker Former smoker Active smoker within 1 yr of diagnosis Comorbidities (n) Hypertension Obesity (BMI ⱖ30 kg/m2) Diabetes Cardiovascular disease Previous treatment (n) Chemotherapy Previous dental procedures Steroid use Antiangiogenic therapy Bevacizumab Thalidomide Bortezomib Anticoagulant therapy Radiation to head and neck
Value 65 41-95 19 (34) 37 (66) 36 (64) 17 (30) 1 (2) 1 (2) 1 (2) 28 (50) 20 (36) 8 (14) 23 (41) 14 (25) 9 (16) 5 (9) 49 (88) 21 (38) 19 (34) 19 (34) 16 (29) 3 (5) 1 (2) 7 (13) 3 (5)
Abbreviation: BMI, body mass index. Data in parentheses are percentages. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
Before the ONJ diagnosis, 55 patients (98%) had received bisphosphonate therapy, and in 1 patient, the diagnosis of ONJ was thought secondary to antiangiogenic therapy (bevacizumab), as previously reported.19 For the 55 patients who had received previous bisphosphonates, the median duration of exposure was 25 months (range 0 to 119; Table 2). NTX AND BAP
Serum was available as follows: from 4 measurement points in 19 patients (34%), from 3 points in 16 patients (29%), from 2 points in 11 patients (20%), and from 1 point in 10 patients (18%). In addition, for technical reasons, NTX and BAP could not be measured in 5 and 1 sample, respectively. Therefore, we had a total of 151 individual results for NTX and 155 individual results for BAP. In the primary analysis (using exact dates), there were no obvious patterns in either NTX (Fig 1A) or BAP (Fig 1B). Similarly, no trends were seen when we
restricted the analyses to patients with 3 or more available blood samples for both NTX (Fig 2A) and BAP (Fig 2B). In the secondary analysis, the data were approximated into 1 of the 4 ordinal points, and we saw no evidence of suppression of NTX levels over time. In fact, an apparently opposite trend for NTX was noted (Fig 3A). At the ONJ diagnosis, only 2 patients (4%) had NTX levels below the normal range (⬍5.5 nmol/ L). For BAP, no evidence was seen of a change over time (Fig 3B). However, at the ONJ diagnosis, 17 patients (30%) had BAP below the normal range (⬍14.2 U/L). Both patients with NTX below normal also had BAP levels below the normal range. Similar findings were seen in subgroup analyses. In patients with breast cancer and 3 or more available blood draws, the median NTX values were as follows: 7.8 nmol/L (range 3.8 to 15.8) at 12 months before ONJ (n ⫽ 17), 8.1 nmol/L (range 4.7 to 42.7) at 6 months (n ⫽ 19), 10.4 nmol/L (range 4.5 to 24.6) at 1 month (n ⫽ 19), and 9.8 nmol/L (range 0.7 to 24.5) at the ONJ diagnosis (n ⫽ 20). For BAP, the median values at the corresponding points were as follows: 19.5 U/L (range 8.0 to 74; n ⫽ 18), 15.0 U/L (range 4.0 to 100; n ⫽ 19), 11.0 U/L (range 4.0 to 132; n ⫽ 20), and 15.0 U/L (range 0.7 to 43; n ⫽ 21). In patients with prostate cancer and 3 or more available blood draws, the median NTX values were as follows: 8.7 nmol/L (range 5.0 to 32.9; n ⫽ 10), 8.9 nmol/L (range 5.5 to 12.6; n ⫽ 10), 8.3 nmol/L (range 7.0 to 14.1; n ⫽ 8), and 8.2 nmol/L (range 4.4 to 21.5; n ⫽ 10) at 12, 6, and 1 month before the ONJ diagnosis and at the ONJ diagnosis, respectively. For BAP, the median values at the corresponding points were as follows:
Table 2. PREVIOUS BISPHOSPHONATE EXPOSURE (N ⴝ 55)
Variable Bisphosphonate administered Zoledronic acid alone Pamidronate and zoledronic acid Pamidronate alone Alendronate and pamidronate Total dose administered (mg) Zoledronic acid (n ⫽ 51*) Median Range Pamidronate (n ⫽ 13) Median Range Alendronate (n ⫽ 1)
Value 41 (73) 10 (18) 3 (5) 1 (2) 70 4-244 2,925 810-8,280 1,680
*Included 2 patients with missing data on total administered dose and 1 patient with missing data for both therapy duration and total administered dose. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
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FIGURE 1. A, Changes in NTX over time relative to diagnosis of ONJ (n ⫽ 55). B, Changes in BAP over time relative to diagnosis of ONJ (n ⫽ 56). Exact dates for blood draws and ONJ diagnosis (red vertical line) used. Results from individual patients represented in different colors and shapes. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
16.0 U/L (range 7.0 to 65; n ⫽ 10), 16.0 U/L (range 8.0 to 49; n ⫽ 10), 9.0 U/L (range 4.0 to 100; n ⫽ 8), and 14.0 U/L (range 5.0 to 74; n ⫽ 11). In the 1 patient who had had no previous bisphosphonate exposure, no obvious pattern of biomarkers was noted. Serum was unavailable from point 1 (12 months before the ONJ diagnosis). For NTX, the available result was 14.7, 5.2, and 7.2 nmol/L 6 months before, 1 month before, and at the ONJ diagnosis. For BAP, the available results were 47.0, 35.0, and 25.0 U/L for the same 3 points.
Discussion In the present large series, NTX and BAP did not predict for the development of ONJ. No meaningful trend for either biomarker was seen. The median NTX level increased from 8.0 nmol/L at baseline to 10.4 nmol/L at the ONJ diagnosis and the median BAP level remained unchanged at 18.0 U/L. Furthermore, we
were unable to identity any subgroup in whom these biomarkers might be useful, including those with 3 or more available results, separation by 2 major disease subtypes (breast vs prostate cancer), and bisphosphonate therapy or not. Finally, despite chronic bisphosphonate exposure, there was limited evidence of suppression of markers of bone turnover (4% and 30% patients had NTX and BAP below the normal range, respectively). Decreased bone turnover in the mandibular region has been proposed as a critical factor in the pathogenesis of ONJ.13 It is thought that after physiologic or iatrogenic trauma (eg, dental extraction) normal healing is prevented by inhibition of osteoclasts by bisphosphonates and other agents, leading to exposure of underlying necrotic bone.11,13 As a biomarker of bone resorption, NTX represents the amino-terminal peptide of type 1 collagen, which is responsible for cross-linking of the bone matrix.16 In contrast, BAP is a highly specific isoenzyme in bone and re-
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FIGURE 2. A, Changes in NTX over time relative to diagnosis of ONJ (restricted to patients with 3 or more blood draws; n ⫽ 33). B, Changes in BAP over time relative to diagnosis of ONJ (restricted to patients with 3 or more blood draws; n ⫽ 35). Exact dates for blood draws and ONJ diagnosis (red vertical line) used. Results from individual patients represented in different colors and shapes. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
flects osteoblastic cellular activity (bone formation).16 We hypothesized that at the time of ONJ diagnosis, the suppression of bone turnover would translate into very low absolute levels of NTX and BAP and that the serum levels would decrease substantially during the year preceding the ONJ diagnosis. Both NTX and BAP have been investigated as biomarkers in osteoporosis and are sometimes used in clinical practice, given that increased bone turnover is a determinant of fracture risk.20 In patients with osseous metastases from a variety of malignancies, elevated biomarker levels, including urinary NTX (uNTX) and serum BAP, have been shown to correlate with increased risk of SREs, extent of bone disease, progression in bone, and inferior overall survival.18,21,22 For example, in 1 study, which included 97 patients with known bone metastases, uNTX was associated with disease progression in bone (average change of 152% from the time of stable disease).18 Furthermore, normalization of uNTX was associated with a reduced risk of SREs and
death in a combined analysis of 3 large, phase III trials of bisphosphonates.23 Despite the strong biologic rationale for the present study, we found no suggestion that these biomarkers might be useful in predicting patients at greatest risk of ONJ. The only notable finding was that 30% of the patients had BAP below the normal range at the ONJ diagnosis, an observation that might deserve additional investigation. Given the rarity of ONJ, relative to the number of patients treated with bisphosphonates, to the best of our knowledge, the present series represents the largest published biomarker study (56 patients), and serum was available from 3 or more measurement points for 63% of these. The ONJ cases were rigorously defined, and the diagnosis was confirmed with repeat examination in almost all patients (91%). In general, patients in the present study had several risk factors known to be associated with an increased risk of ONJ.15 For example, 98% of the patients had received previous bisphosphonate ther-
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FIGURE 3. A, NTX at sequential points (ordinal data). B, BAP at sequential points (ordinal data). Box-and-whisker plots showing range (line), median (crosses), and interquartile range (box). Dates of blood draws approximated to 1 of 4 points. Morris et al. Serum NTX and BAP as Biomarkers for ONJ. J Oral Maxillofac Surg 2012.
apy, with a median previous exposure of 25 months (range 0 to 119), and we were able to document previous dental procedures in 38% of the patients. This highlights awareness of the importance of avoiding invasive dental procedures in patients receiving long-term bisphosphonate therapy, although given the retrospective nature of the present study, it is possible that many more patients had a history of dental extraction. We were able to obtain stored serum from 1 patient without bisphosphonate exposure, who we previously reported as having ONJ secondary to bevacizumab.19 Therefore, our series highlights the possible role of anti-angiogenics in the development of ONJ (34%) and corticosteroid use (34%), as well as patientrelated factors such as smoking (50% of the patients were current or former smokers).14,19 It is likely that the critical reason for a lack of predictive nature for the biomarkers investigated was a lack of specificity for the mandibular region. The
results were confounded by the presence and change in osseous metastases and by the administered bisphosphonates. Costa et al18 showed that both uNTX and serum BAP were reduced by bisphosphonate therapy (average change of 47%, P ⬍ .001, and 69%, P ⫽ .008, respectively), and it appears that similar changes occur with denosumab.24 Because most patients in our series had received long-term bisphosphonates (median duration of exposure 25 months), this would be expected to decrease both NTX and BAP. Therefore NTX and BAP have been proposed as biomarkers to guide the continuation and dosing frequency of bisphosphonates, whereby the frequency of bisphosphonate dosing could be reduced in patients with maximally suppressed bone turnover, resulting in minimally detectable serum levels. However, currently, the American Society of Clinical Oncology advises against using bone turnover markers to guide therapy, and our data support this recommendation.5,25 In contrast, because
2774 bisphosphonates are generally administered for the treatment of osseous metastases, the presence of metastatic disease in bone would have been expected to cause an increase in both biomarkers over time.18,21,22 In our study, despite the relatively high doses of bisphosphonates administered, most patients had no evidence of suppressed NTX and BAP, thereby suggesting that ONJ can occur independently of systemic bone turnover. One possibility is that local bone turnover in the jaw was suppressed, but that systemic bone turnover, as evidenced by the biochemical markers measured, was not suppressed in most patients. There are several important limitations to consider in our study. First, this was a retrospective study, and definitive conclusions are limited by the number and timing of blood draws, which were performed for other (clinical) reasons. However, because 63% of the patients had 3 or more blood draws, we suggest that additional samples would not have changed the results. Second, it is possible that our results could have been confounded by selection bias, because serum was available for 46% of the patients with known ONJ at our institution. However, this was considered unlikely, because the excluded patients were seen by our dental service without institutional medical oncology follow-up and the characteristics of the included patients were similar to those from other published series.14 Third, we did not include a control group of bisphosphonate-treated individuals without ONJ, matched for the burden of skeletal metastases, which would be necessary to definitively know whether a threshold exists for NTX or BAP below which the risk of ONJ increases. The optimal definition of a control group would be challenging vis-à-vis the opposing effects of chronic bisphosphonates, physiologic remodeling, fractures, and progressive osseous metastases on biomarkers over time.18,21,22 Fourth, the premenopausal reference range for “healthy” patients provided by the manufacturer of the assay might not be a valid lower limit in the oncology setting owing to the significant elevations in bone turnover because of metastases. Finally, although the intra- and interassay variability was less than 10%, nonfasting samples at random times of the day could have degraded in storage. We were unable to control for the variation by time of day and diet (bone resorption is reduced by food and follows a circadian rhythm, with peak serum and urinary biomarkers early in the morning).26-29 Notably, although bone alkaline phosphatase does not follow a circadian rhythm, it does have a 15% to 20% cross-reactivity with the liver isoform; therefore, liver metastases could have confounded specificity. Furthermore, our analyses were limited to serum only, rather than uNTX, which requires correction for urinary creatinine.26 It is unknown whether the fasting samples for other bone turnover markers, could be more useful in predicting ONJ.
SERUM NTX AND BAP AS BIOMARKERS FOR ONJ
Other possible biomarkers of ONJ have been examined, including the serum levels of the carboxy-terminal of type I collagen (CTX).30-34 Provocatively, in 1 study, lower CTX levels before dental surgery were seen in 18 patients who developed ONJ compared with those who did not (n ⫽ 60).32 However, other studies have not supported the use of CTX as a biomarker.31,33,34 In more than 5,000 patients treated in 5 clinical trials of zoledronic acid, “low” CTX levels did not predict the development of ONJ, although, notably, only 2 cases of ONJ were seen.31 In the study by Lazarovici et al,32 ONJ was seen in 18 (23%) of 78 patients. In comparison, in a study of preoperative CTX in 163 patients taking oral bisphosphonates and undergoing oral surgery, none developed ONJ;33 and in the large study by Grbic et al,31 the incidence of ONJ was less than 1 in 14,200 patient treatment-years. Hence, it is possible that a lack of adherence to a strict definition of ONJ in some reports might have limited the broader interpretation of the conclusions. Other serum markers of bone formation include osteocalcin, a specific product of osteoblasts, and the propeptide type I procollagen, a specific product of osteoblasts.35 There are multiple biomarkers of bone resorption, including urinary hydroxyproline, which is present in all fibrillar collagens, collagen hydroxylysine-glycosides, bone sialoprotein, a phosphorylated glycoprotein synthesized by osteoblasts and osteoclasts, and specific osteoclast enzymes, such as cathepsin K and tartrate-resistant acid phosphatase.35 The potential role of these biomarkers in predicting ONJ is unknown. Irrespective of the choice of biomarkers, it is likely that the complex interaction between osseous metastases and treatment can only be truly investigated in a prospective study, and this is the subject of several ongoing trials.27 Significant challenges exist in developing a useful biomarker, including the relatively low incidence of “true” ONJ and the confounding effect of underlying disease and administered treatment. Therefore, at present, in the absence of high level prospective evidence: CTX, NTX, and BAP should not be used routinely in clinical practice to identify patients at risk of ONJ.25,36 In conclusion, in this relatively large retrospective study, uncontrolled for fasting status, diurnal variations, and osseous metastases, we were unable to find evidence to support the hypothesis that, in the setting of bisphosphonate use, systemic oversuppression of bone turnover as revealed by biochemical markers, is associated with the development of ONJ.
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