Bisphosphonate-induced osteonecrosis of the jaws, bone markers, and a hypothesized candidate gene

J Oral Maxillofac Surg. 2009 Jan;67(1):159-61. doi: 10.1016/j.joms.2008.09.015.


Purpose: To determine whether any abnormality in serum bone markers is related to bisphosphonate-induced osteonecrosis of the jaw.

Materials and methods: We obtained serum bone markers and other relevant endocrine assays on 7 patients with osteonecrosis of the jaws (ONJ). The assays were C-telopeptide, N-telopeptide, bone specific alkaline phosphatase, osteocalcin, intact parathyroid hormone, T3, T4, TSH, and vitamin D 25 hydroxy. Diagnostic criteria for ONJ were those formulated by the American Association of Oral and Maxillofacial Surgeons.

Results: Five of our patients were women. Two had metastatic breast cancer and had been treated with zoledronic acid; 1 had also received pamidronate. Three others had osteoporosis and had been treated with daily alendronate. One man had metastatic prostate cancer treated with zoledronic acid. Another man had Gaucher's disease treated with zoledronic acid. All patients had been withdrawn from bisphosphonate for at least 6 months. None was taking or had taken corticosteroids. None of the lesions had shown any significant healing and all were still causing the patients considerable distress, yet the bone markers were within the normal range as measured in our laboratory, except for intact parathyroid hormone, which was slightly elevated in 1 case of metastatic breast cancer (177 pg/mL).

Conclusions: We hypothesize that matrix metalloproteinase 2 (MMP2) is a candidate gene for bisphosphonate-induced ONJ for 3 reasons: 1) MMP2 is associated with bone abnormalities which could be related to ONJ. 2) Bisphosphonates are associated with atrial fibrillation, and MMP2 is the only gene known to be associated with both bone abnormalities and atrial fibrillation. 3) A network of disorders and disease genes linked by known disorder-gene associations indicates that cardiovascular disease and bone disease are closely related, suggesting that a single drug such as bisphosphonate, acting on a single gene, MMP2, could have both bone and cardiovascular side effects different from the osteoclast inhibition that is characteristic of bisphosphonate.

MeSH terms

  • Alendronate / adverse effects
  • Biomarkers / blood
  • Bone Density Conservation Agents / adverse effects*
  • Bone and Bones / metabolism
  • Collagen Type I / blood
  • Cysteine Endopeptidases / blood
  • Diphosphonates / adverse effects*
  • Female
  • Humans
  • Imidazoles / adverse effects
  • Male
  • Mandibular Diseases / blood*
  • Mandibular Diseases / chemically induced
  • Mandibular Diseases / genetics
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Maxillary Diseases / blood*
  • Maxillary Diseases / chemically induced
  • Maxillary Diseases / genetics
  • Osteocalcin / blood
  • Osteonecrosis / blood*
  • Osteonecrosis / chemically induced
  • Osteonecrosis / genetics
  • Parathyroid Hormone / blood
  • Peptides / blood
  • Vitamin D / analogs & derivatives
  • Vitamin D / blood
  • Zoledronic Acid


  • Biomarkers
  • Bone Density Conservation Agents
  • Collagen Type I
  • Diphosphonates
  • Imidazoles
  • Parathyroid Hormone
  • Peptides
  • collagen type I trimeric cross-linked peptide
  • Osteocalcin
  • Vitamin D
  • Zoledronic Acid
  • 25-hydroxyvitamin D
  • Cysteine Endopeptidases
  • alkaline peptidase
  • Matrix Metalloproteinase 2
  • Alendronate