Serum Markers of Bone Turnover and Angiogenesis in Patients With Bisphosphonate-Related Osteonecrosis of the Jaw After Discontinuation of Long-Term Intravenous Bisphosphonate Therapy.
OBJECTIVE
To analyze serum markers of bone turnover, angiogenesis, endocrine function, and inflammation in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) who discontinued long-term intravenous bisphosphonate (BP) therapy.


METHODS
Serum samples were obtained from 25 BRONJ patients who had discontinued long-term intravenous BP therapy for an average of 11.4 ± 8.7 months and 48 non-BRONJ controls who continued receiving intravenous BP therapy. Samples were analyzed for total alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, C-telopeptide, vascular endothelial growth factor, triiodothyronine, thyroxine, thyroid-stimulating hormone, 25-hydroxyvitamin D, and C-reactive protein.


RESULTS
The mean number of BP infusions was significantly higher in BRONJ patients compared with controls (38.4 ± 26.3 infusions vs 18.8 ± 7.2 infusions, P < .0001); however, the duration of BP therapy was not significantly different between the groups (P = .23). Overall, there were no significant differences in any of the markers between BRONJ patients and controls (all P values ≥ .16). In a subgroup analysis that matched BRONJ patients and controls according to mean age and number of BP infusions (10 BRONJ patients and 48 controls), log10 vascular endothelial growth factor (2.9 ± 0.4 pg/mL vs 2.4 ± 0.4 pg/mL, P < .001) and C-reactive protein (34 ± 26 mg/L vs 13 ± 8 mg/L, P < .01) levels were significantly higher in BRONJ patients compared with controls. Within BRONJ patients, none of the serum markers were correlated with duration of BP discontinuation.


CONCLUSIONS
Levels of bone turnover and endocrine markers in BRONJ patients who discontinue long-term intravenous BP therapy are similar to those in non-BRONJ controls receiving intravenous BP therapy. However, levels of angiogenesis and inflammation markers are higher in BRONJ patients who discontinue long-term intravenous BP therapy. The prolonged skeletal half-life of BPs may suppress bone turnover markers in BRONJ patients for several years after discontinuation of intravenous BP therapy, suggesting an extended effect on bone homeostasis.
Adjunct Assistant Professor, Division of Periodontology, University of Minnesota School of Dentistry, Minneapolis, MN.
Vivek
V
Thumbigere-Math
Professor, Division of Periodontology, University of Minnesota School of Dentistry, Minneapolis, MN.
Bryan S
BS
Michalowicz
Associate Professor, Division of Oral and Maxillofacial Surgery, University of Minnesota School of Dentistry, Minneapolis, MN.
Pamela J
PJ
Hughes
Adjunct Associate Professor, Boynton Health Service, University of Minnesota, Minneapolis, MN.
David L
DL
Basi
Oncologist, Oncology Research Department, Park Nicollet Institute, Minneapolis, MN.
Michaela L
ML
Tsai
Oncology Research Director, Oncology Research Department, Park Nicollet Institute, Minneapolis, MN.
Karen K
KK
Swenson
Research Nurse Clinician, Oncology Research Department, Park Nicollet Institute, Minneapolis, MN.
Laura
L
Rockwell
Professor, Division of Oral Pathology, University of Minnesota School of Dentistry, Minneapolis, MN. Electronic address: gopal007@umn.edu.
Rajaram
R
Gopalakrishnan
D061605:Administration, Intravenous; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D042501:Angiogenic Proteins / Q000097:blood*; D015415:Biomarkers / Q000097:blood*; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000097:blood*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001842:Bone and Bones / Q000378:metabolism*; D002097:C-Reactive Protein / Q000032:analysis; D016022:Case-Control Studies; D024042:Collagen Type I / Q000097:blood; D004164:Diphosphonates / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D010455:Peptides / Q000097:blood; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood
D042501:Angiogenic Proteins; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D018836:Inflammation Mediators; D010455:Peptides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C052929:collagen type I trimeric cross-linked peptide; D014284:Triiodothyronine; D015675:Osteocalcin; D014807:Vitamin D; D013972:Thyrotropin; D002097:C-Reactive Protein; C104450:25-hydroxyvitamin D; D000469:Alkaline Phosphatase; D013974:Thyroxine