LAUSR

Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor kappaB ligand (RANKL), is considered an efficient and safe treatment of postmenopausal osteoporosis [1]. Its main adverse effects, including osteonecrosis of the jaw, atypical femoral fractures, and vertebral fractures occurring upon its discontinuation, are rare, thus the benefit from the reduction of osteoporotic fractures overcomes the risks [2]. We describe a 52-year Caucasian woman who developed leukopenia following denosumab treatment. The patient provided a written informed consent. The diagnosis of postmenopausal osteoporosis was established 5 years after the menopause, based on low bone mineral density (BMD) in the absence of secondary osteoporosis. The course of the patient treatment and laboratory findings of interest are summarized in Table 1. Oral bisphosphonates were not administered, because of concomitant gastrointestinal reflux disease. The patient received initially one infusion of zoledronic acid (5 mg). Because BMD was not improved 1 year after zoledronic acid, the patient started denosumab subcutaneously, 60 mg twice/year. She has been receiving calcium carbonate (1000 mg/day) and cholecalciferol (800 IU/day) since the diagnosis of osteoporosis. On physical examination before the first denosumab injection, her weight was 82 kg, height 1.62 m (BMI 31.2 kg/m) and remained essentially unchanged thereafter. No fracture was reported before treatment or observed during treatment. Concomitant medications were l-thyroxine per os (75 μg/ day) for the treatment of hypothyroidism due to Hashimoto thyroiditis, and hydroxycobalamin intramuscularly (5 mg/ 4 months) due to atrophic gastritis (started four and 25 years, respectively, before the diagnosis of osteoporosis). Four injections of denosumab were initially administered. BMD was improved as expected (Table 1). However, a gradual decline in leukocytes was observed, reaching 34% after the fourth injection compared with the last available data pre-denosumab. Both neutrophils and lymphocytes were similarly declined (Table 1). Despite leukocyte decrease, the patient remained asymptomatic. Due to this decline, denosumab was discontinued and the patient was subjected to laboratory examinations, including serologic tests for infections (toxoplasmosis, hepatitis B and C viruses, Epstein–Barr virus, cytomegalovirus, and human immunodeficiency virus), immunodeficiency (immunoglobulins and complement) and markers of autoimmune diseases (antinuclear, anti-double-stranded DNA, anti-smooth muscle, antimitochondrial, anticardiolipin, and antineutrophil cytoplasmic antibodies), which were all normal. Leukocytes were restored a year after the fourth denosumab injection. The patient did not consent to receive another infusion of zoledronic acid and remained off treatment for 14 months, when BMD was declined again, and she was decided to restart denosumab. Again, leukocytes declined after retreatment; however, they did not decrease below 3000/μl and the patient remained asymptomatic. To our knowledge, this is the first case of leukopenia following denosumab treatment. The mechanism through which denosumab may have caused leukopenia is elusive and cannot be shown by this observational report, but warrants further mechanistic studies. Although denosumab may interfere with the effects of granulocyte-macrophage colony-stimulating factor on leukocytes, it remains to be shown. Leukopenia might also represent a rare idiosyncratic * Stergios A. Polyzos [email protected]