Zoledronic Acid Is an Effective Treatment for Osteoporosis in Patients with Thalassemia Major: Results of a Randomized, Placebo-Controlled, Trial.
Authors: Voskaridou Ersi , Loukopoulos Dimitris , Stoupa Eleni , Spyropoulou Eugenia , Meletis John , Terpos Evangelos 
Published: April 2020

Osteoporosis in thalassemia major (TM) is due to several factors, including bone marrow expansion, iron overload, hormonal deficiency, and increased osteoclast activity. Potent inhibitors of osteoclast function, such as bisphosphonates, have been recently used in the management of TM-induced osteoporosis. The aim of this trial was to determine the efficacy and safety of a third-generation aminobisphosphonate, zoledronic acid, on osteoporosis and bone remodeling in patients with TM. Sixty-six patients with TM-induced osteoporosis (21M/45F; median age 35.5 years) have been enrolled in this study. The majority of patients had pathological fractures and/or bone pain due to osteoporosis at baseline. Patients were randomized to receive zoledronic acid at a dose of 4 mg, iv, in 15 min infusion, every 6 months (23 patients; group A) or every 3 months (21 patients; group B), or to receive placebo every 3 months (22 patients; group C), for a period of one year. All patients were under oral calcium (500 mg) administration during the treatment period. Effects were monitored by measuring bone mineral density (BMD) in comparison with a series of serum bone remodeling indices: i) bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], ii) bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)], and iii) osteoclast stimulating factors [receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG)]. BMD of the lumbar spine, femoral neck and forearm was determined using DEXA, before and 12 months after treatment. The above biochemical parameters were measured at baseline and before the administration of zoledronic acid or placebo in each cycle. We also evaluated these markers in 30 healthy, age and gender-matched, controls. All patients had increased values of CTX, TRACP-5b, bALP, CICP, sRANKL, OPG, and sRANKL/OPG ratio, compared with controls (p&lt;0.02). Patients of group A showed no differences in terms of BMD of all three evaluated sites after 12 months of treatment, while they showed a reduction in serum levels of CTX (p=0.02), bALP (p=0.02) and OC (p=0.01). Conversely patients of group B achieved a significant increase in their lumbar spine BMD after 12 months of therapy (p=0.007), which was accompanied by a dramatic decrease in serum CTX (p=0.004), bALP (p&lt;0.0001), CICP (p&lt;0.0001), and OC (p=0.005). Patients of group C showed an aggravation of BMD of the lumbar spine (p=0.041) at 12 months, while there was no alteration in BMD of other sites as well as in markers of bone remodeling. There was no effect of zoledronic acid on sRANKL and OPG in all patients. Zoledronic acid reduced bone pain in patients of groups A and B, while there was no bone pain relief in placebo group. No severe side-effects were observed in this study. We conclude that zoledronic acid, at a dose of 4 mg, iv, every 3 months is an effective treatment in increasing BMD and reducing osteoclast activity and bone resorption in TM-induced osteoporosis. Longer follow-up studies are required to clarify the exact role of zoledronic acid in the management of these patients.