Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model

Abstract

Objectives: The objectives of this study were to establish a bisphosphonate-related osteonecrosis of the jaw (BRONJ) rat model and to analyse the effects of teriparatide (TP) on this model.

Methods: Sprague-Dawley rats were divided into three groups: I-zoledronic acid (ZA, n = 10); II-ZA and teriparatide (ZA + TP, n = 10); III-control (n = 10). Osteonecrosis was induced by administering zoledronic acid to groups ZA and ZA + TP. A week after the injections, rats underwent extraction of the first left mandibular molar. Following a four week period, TP was administered to the ZA + TP group for 28 days. Upon killing, extraction sockets were examined clinically, radiologically and histopathologically.

Results: Clinical examination revealed necrotic bone exposure in none of the animals. MicroCT (µCT) examination showed that bone mineral density of the newly formed bone in the extraction socket was lower in the ZA group than in the ZA + TP group (p < 0.05). Histopathological examination revealed that only the ZA and ZA + TP groups developed osteonecrosis, and the osteonecrotic bone area in the ZA group was larger than that in the ZA + TP group (p < 0.05). Tartrate-resistant acid phosphatase (TRAcP) enzyme histochemistry revealed that the number of detached and large osteoclasts were higher in the ZA group than in other groups, whereas the number of apoptotic osteoclasts in both ZA and ZA + TP groups were higher than in the control group (p < 0.05).

Conclusions: Our data indicate that bisphosphonate-related osteonecrosis of the jaw model used in the present study is an attractive model to investigate treatment modalities and that TP might be an effective treatment in BRONJ.

Keywords: Microcomputed tomography; bisphosphonate-associated osteonecrosis of the jaw; tartrate-resistant acid phosphatase; teriparatide; zoledronic acid.

Figures

Figure 1

Micrographs of (a) an osteoclast attached to the bone surface (arrow), (b) a detached osteoclast (arrow), (c) a giant osteoclast (arrow), (d) an apoptotic osteoclast (arrow), taken from the extraction socket (tartrate-resistant acid phosphatase staining, ×1000)

Figure 2

MicroCT image of a rat mandible of the (a) zoledronic acid group, which indicates the impaired wound healing in the extraction socket (arrow, axial view) and (b) control group, which indicates the bone formation in the extraction socket (arrow, axial view)

Figure 3

Micrograph of the haematoxylin and eosin stained section showing (a) failure in healing of the bone in the extraction socket of a rat of the zoledronic acid (ZA) group (×100), (b) a small necrotic portion of the alveolar bone surrounding the extraction socket of a rat of the ZA + teriparatide group (×200). es, extraction socket; nb, necrotic bone; vb, vital bone

Figure 4

Quantification of the ratio of necrotic bone area to the total bone area in the zoledronic acid (ZA) and ZA + teriparatide (TP) groups

Figure 5

Number of tartrate-resistant acid phosphatase positive (TRAcP+) osteoclasts (OCs) attached to the bone of the rats of the zoledronic acid (ZA), ZA + teriparatide (TP) and control groups (*p < 0.05)

Figure 6

Bone surface area occupied by tartrate-resistant acid phosphatase positive attached osteoclasts of the rats of the zoledronic acid (ZA), ZA + teriparatide (TP) and control groups (*p < 0.05)