The number of people with osteoporosis has increased as the population ages. Osteoporosis is often treated with teriparatide (1), which has been demonstrated to promote bone healing and prevent fragility fractures in both rats and humans (2-9). Along with its numerous clinical advantages, teriparatide has some less well-known contraindications, such as a history of radiation therapy (10), the presence of primary malignant and metastatic bone tumors (11), and Paget's disease (12), all conditions under which teriparatide may induce osteosarcoma.

Initial preclinical studies in rats revealed that teriparatide increases the risk of osteosarcoma development. Vahle et al reported that rats given daily injections of recombinant human parathyroid hormone develop proliferative bone lesions, and some rats develop osteosarcoma (13). Watanabe et al reported that teriparatide can induce osteosarcoma in rats, depending on the dose and duration of treatment (14). Vahle et al reported a safe teriparatide dose for rats in 2004(15). Two cases of osteosarcoma following the administration of teriparatide have been reported in the USA. However, in one case, the causality between teriparatide and the osteosarcoma could not be established (10). In addition, in the other case the patient was treated with radiation therapy before teriparatide administration; therefore, it is unclear whether the teriparatide administration or radiation therapy were associated with osteosarcoma onset (11). In the present case, the patient had never received any radiation therapy and there was no history of Paget's disease. To date, there are no reported cases of definite teriparatide-induced osteosarcoma in humans in the USA (12,16) or Japan (17), to the best of our knowledge.

The present study presents the case of an elderly patient with severe osteoporosis in which teriparatide may have accelerated the growth of a pre-existing malignant tumor. This case serves as a caveat against the misdiagnosis of a pathological fracture as a normal fracture in elderly patients, particularly before teriparatide administration. Therefore, care should be taken to diagnose femoral fractures in elderly patients.

A 76-year-old Japanese woman was doing farm work on a ladder and fell 50 cm to the ground. The patient felt pain in her right thigh and was unable to stand. She then visited National Hospital Organization Hirosaki Hospital (Hirosaki, Japan) in September, 2016 and was diagnosed with a right femoral-shaft fracture (Fig. 1). The patient had no history of illness and had never undergone radiotherapy in the past. The laboratory data, including C-reactive protein (CRP), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels, were within normal range, and the fracture was treated immediately by intramedullary nail fixation (Fig. 2). A postoperative bone density test identified severe osteoporosis. The patient was treated with a daily regimen of teriparatide (20 µg/day); however, the drug was discontinued after 2 months due to the onset of nausea. A total of 6 months after the initial surgery, the patient visited Hirosaki University Hospital on April, 2017 with abnormal swelling of the right thigh. At presentation, the right thigh had a circumference approximately twice as large as that of the left thigh, and the right knee had a limited range of motion. Blood tests revealed that the CRP, ALP and LDH levels were slightly elevated, but all tumor markers, including AFP, CA125, CA19-9, CEA and SCC were negative. Plain radiography demonstrated incomplete bone union of the right femoral diaphysis and a periosteal reaction with a sunburst-like appearance around the fracture (Fig. 3). Magnetic resonance imaging (MRI) revealed a soft tissue mass around the femur, with a low-intensity to iso-intense signal on T1-weighted images and a mixed low to high signal intensity on STIR images (Fig. 4). The soft tissue mass also exhibited diffuse and heterogeneous contrast enhancement. Another mass with similar characteristics was identified in the gluteus medius muscle, in a region that would lie along the pathway of the intramedullary nail insertion. No significant accumulation was observed on a whole-body bone scintigraph, except for the right femoral and right gluteus medius muscle regions (Fig. 5). A high-grade malignant mesenchymal bone tumor was diagnosed by needle biopsy. The patient underwent right hip disarticulation with resection of the gluteus medius muscle. The cells were rich in polymorphisms, and strong heteromorphic tumor cells forming osteoids were observed (Fig. 6). The definitive pathological diagnosis was an osteoblastic osteosarcoma of the right femur. Adjuvant chemotherapy was not performed due to the patient's advanced age. The patient provided informed consent.

The present case provides an important reminder that teriparatide may accelerate the growth of a pre-existing malignant tumor in an elderly patient. A previous study demonstrated that teriparatide increases the risk of osteosarcoma in rats, according to the dose and duration of administration (15). In the USA, two patients with osteosarcoma after teriparatide administration have been reported (10,11). In addition, other case reports have described four patients with primary hyperparathyroidism in whom chronically elevated parathyroid hormone levels induced osteosarcoma (18-20). The period of teriparatide administration was only 2 months, which is a limitation of this case as the recommended administration of teriparatide in osteoporosis is up to 24 months (16). The short administration period makes it unlikely that the osteosarcoma arose from a non-pathological fracture. Although the initial radiographs did not reveal any malignant bone lesions in the present case, there may have been a diffuse permeating malignant lesion; it is likely that that would have accelerated the growth of a pre-existing malignant tumor.

The present case study also emphasizes the importance of diagnosing femoral fractures in the elderly, due to the possibility of pathological fractures from malignant disease. Epidemiologically, diaphyseal femoral fractures are not as common as proximal femoral fractures (21,22). In the present case, a pathological fracture should have been considered because the fracture resulted from a fall from a relatively low height, and because the patient mentioned that they had experienced pain in the right thigh 1 week before the injury. These atypical clinical elements suggest that the femoral diaphyseal fracture was a pathological fracture. However, at the initial presentation, the plain radiographs did not reveal any periosteal reaction, osteolytic or osteoblastic change around the fracture site, or other abnormalities that may have made it easier to recognize a pathological fracture. As elderly individuals have a high risk of malignant disease, atypical clinical elements should prompt the clinician to consider the possibility of a pathological fracture. In such cases, clinicians should not hesitate to perform CT scans and/or an MRI.