We read with great interest the article entitled ‘Suppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the mechanism of each disease’ published in International Journal of Oral and Maxillofacial Surgery . In this article, the authors suggested different disease mechanisms and treatment options for suppurative osteomyelitis, bisphosphonate-related osteonecrosis (BRONJ) and osteoradionecrosis, and found that BRONJ was characterized by empty marrow space with empty Howship’s lacunae, absence of osteoclasts and extracellular collagen, and viable periosteum. BRONJ was seen as non-inflammatory drug toxicity to bone by osteoclastic death leading to over suppression of bone renewal. It was indicated that microorganisms played only a secondary opportunistic role to a more fundamental pathophysiology in BRONJ.
BRONJ is a rare but severely adverse effect of bisphosphonate treatment due to excessive inhibition of bone resorption. Normal bone formation and resorption is the fundamental concept in bone remodelling, where a certain amount of bone removed will be replaced by a similar amount of new bone. If new bone formation cannot keep pace with bone resorption, osteoporosis may occur; if bone resorption is severely blocked, BRONJ may occur. Both osteoporosis and BRONJ are due to abnormal bone turnover; either too high or too low.
Since excessive inhibition of bone turnover is the main reason for BRONJ, it may be treated by the restoration of normal bone turnover. In other words, promotion of bone turnover may be beneficial for patients with BRONJ. Parathyroid hormone (PTH) is the representative anabolic drug which can stimulate bone formation by promoting bone turnover. In fact, several previous reports have suggested that PTH could be helpful for BRONJ treatment. In one report in 2008, the clinical features of BRONJ occurred after tooth extraction in the mandible of a 74-year-old woman who had received alendronate treatment for 5 years. There was no improvement in lesions despite repeated surgical procedures. The alendronate therapy was stopped and teriparatide (20 μg/day) begun. Two months later, the exposed oral mucosa healed; four months later, the pain subsided completely; six months later, the patient’s eating and drinking habits returned, and the serum concentration of osteocalcin increased 174% compared to baseline. In another report in 2010, an 88-year-old woman, who had taken alendronate for 10 years, had a 12-month history of pain, suppuration and failed healing of a mandibular socket after tooth extraction despite debridement and antibiotic treatment. The patient’s symptoms resolved after 8 weeks of treatment with teriparatide (20 μg/day), and the osteonecrosis lesions healed. Two recent studies also reported healed BRONJ lesions following PTH treatment.
The resolution of BRONJ by PTH treatment should be related to promotion of bone turnover which has been inhibited by bisphosphonate. The absence of extracellular collagen and cellular products was also observed in the study by Marx and Tursun. The authors postulated that impaired osteoclast might fail to release bone regenerative proteins and break the link of differentiating pluri-potential marrow derived stem cells into bone forming cells. Since previous studies suggested that PTH acted primarily on mature osteoblasts to enhance their function and lifespan and might also enhance differentiation of bone marrow mesenchymal stem cells into osteoblastic lineage, promoting osteoblastic bone formation may be another potential benefit of PTH for BRONJ treatment.
The recommendation of the use of PTH for adjunctive treatment of BRONJ is based on a pathophysiological understanding of BRONJ only; reports about the resolution of BRONJ with PTH may be fortuitous, and a rigorous clinical study for evaluation of the effect of PTH on BRONJ would be of interest. In the USA, there is a black box warning on the teriparatide label against using it on patients with metastatic cancer due to concerns that increased bone remodelling by PTH may also promote the development or exacerbation of skeletal metastases. Considering this FDA warning, as well as compliance and the potential adverse effects of daily PTH injection, it may be used in the short term on patients with BRONJ without malignant bone diseases.
This study was supported by a grant from the National Nature Science Foundation of China (No. 81070869 ).