Could teriparatide be the treatment for osteonecrosis of the jaws?

To the Editor: We read with great interest the case reported by Lee et al in the Early View section of the journal, presenting a case of aledronate-induced osteonecrosis of the jaws (ONJ), which healed following teriparatide administration. The authors conclude that teriparatide can be an important adjuvant to other measures in the management of ONJ that should be considered prior to major resection with reconstruction and aspire for future studies. Overall, these are true and teriparatide might be the best news for pharmaceutical treatment of ONJ since its recognition. Lee et al discuss that teriparatide is not recommended for patients with hypercalcemic disorder, osteosarcoma, metastatic bone disease, Paget’s disease of bone, pregnancy, and radiation therapy to the skeleton or to soft tissue in which a skeletal port is exposed. This might be correct, although it is based on insufficient or nonexisting evidence. To date, there are no clinical trials examining the efficacy of teriparatide in patients with cancer-related skeletal events. Of note, ONJ has mainly been described in the latter population that—for the most part—comprises patients with multiple myeloma, breast cancer, and prostate cancer. The breast functions as an accessory parathyroid gland during lactation, producing parathyroid hormone–related peptide (PTHrP). Thus the administration of parathyroid hormone (PTH) or teriparatide in patients with breast cancer could be expected to interfere with the disease. However, contradictory evidence exists with regard to the association between PTH and breast cancer. No evidence exists with regard to teriparatide administration in patients with prostate cancer or multiple myeloma. The single malignancy that has been reported to be associated with teriparatide administration is osteosarcoma. This association has been reported in Fisher rats in a single study, but not in primates in a number of experimental studies. Large power epidemiological studies were also not able to detect any association that would change the risk–benefit profile for teriparatide. Teriparatide is metabolized in the liver and kidneys. Thus, future clinical trials for the use of teriparatide in cancer patients would need to designate these toxicities as safety issues. In primate experimental models, teriparatide was reported to increase bone mass and strength, an effect that was lost during the withdrawal phase, for the vertebrae but not for the proximal femur. This effect of withdrawal would probably be insignificant for its utility for the treatment of ONJ. Importantly, both published case reports indicate that healing of ONJ occurs well before the 18-month FDA-approved administration period. PTH is an 84–amino acid peptide, produced by the parathyroid glands, that plays a major role in the regulation of calcium and phosphate metabolism. Teriparatide is the N-terminal (1–34) fragment of the human PTH peptide biosynthesized using Escherichia coli as a host. It has been proposed that the complete PTH peptide has additional biological actions to teriparatide—attributed to a putative C-terminal PTH receptor—that are often in opposition to those that occur following PTH-1 receptor activation. For example, C-terminal PTH fragments may blunt the increase in serum calcium levels induced by teriparatide, inhibit bone resorption, and stimulate apoptosis in bone cells. The lack of these additional biological responses in teriparatide, along with others, unknown to date, may lie beneath the ability of teriparatide to cure ONJ. Lee et al comment that teriparatide has been reported to reduce microdamage accumulation. Microdamage accumulation, or ‘‘fatigue,’’ was reported to have a role in the aetiopathogenesis of osteonecrosis of the jaws based on experimental and clinical data. Importantly, teriparatide could be able to revert the ‘‘fatigue’’ process induced by bisphosphonates through the above-mentioned biological actions. Lee et al appositely report that treatment options for osteonecrosis of the jaws are controversial and management of these patients is an important problem for head and neck surgeons, endocrinologists, and oncologists. Nowadays, it could be justified to prescribe teriparatide to patients with bisphosphonatetreated osteoporosis who already have ONJ. Given that (1) teriparatide is licensed for the treatment of osteoporosis and is considered a second-line treatment, (2) the limited evidence of a potential protective effect for ONJ, and (3) the lack of appropriate treatment modalities for ONJ, its prophylactic use also in patients who need to undergo oral cavity surgery might be recommended instead of bisphosphonates. Head & Neck 33: 1382–1383, 2010 Published online 4 August 2010 Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/hed.21512