Long-term use of bisphosphonates in the treatment of HIV-related bone pain in perinatally infected pediatric patients

Decreased bone mineral density (BMD) is being increasingly reported as part of the metabolic syndrome related to HIV infection and to the use of antiretrovirals (ARVs) in pediatric age [1–3]. The amount of bone gained during childhood and adolescence is the main contributor to peak bone mass, which, in turn, is a major determinant of osteoporosis and fracture risk during adulthood. In children, osteoporosis may cause microfractures that lead to bone pain and disability. No specific treatment for osteoporosis is available in pediatric age. Currently, recommendations for the prevention of osteoporosis in HIV-infected children [4] suggest an adequate intake of calcium and vitamin D, appropriate weight-bearing exercise and, in HIV-infected adolescents, avoidance of alcohol and smoking. Bisphosphonates (BPP) are synthetic analogues of pyrophosphate that inhibit osteoclast-mediated bone resorption. In adult patients, BPP have been successfully used to treat a variety of conditions, including HIV-related osteoporosis [5,6]. Because of fears about its side effects on the growing bone, the use of BPP in pediatric age has not been yet approved. In the investigational setting, BPP have shown great benefits in the treatment of severe osteogenesis imperfecta and other pediatric diseases leading to osteoporosis, without significant short or mid-term toxicity [7]. We report a series of three Caucasian HIV perinatally infected pediatric patients with decreased BMD and lumbar bone pain that received BPP in a compassionate use program. These children belong to a cohort of 90 HIV-infected children followed up in Hospital Sant Joan de Déu (Barcelona, Spain). BMD was assessed by dual-energy X-ray absorptiometry (DXA) scan, and expressed in terms of Z-score [8]. Osteoporosis was defined as a Z-score value below −2.5 SD. Parents provided their written informed consent and the Spanish Ministry of Health (RD 561/1993) approved each individual treatment for compassionate use. Main characteristics of the patients are summarized in Table 1. Daily calcium and vitamin D supplements were used in all cases. Patients 1 and 2 received, respectively, two and five annual infusion cycles of intravenous disodium pamidronate (Aredia, Novartis, East Hanover, New Jersey, USA; 2–3 mg/kg body weight and infusion cycle) during a 1-day admission. Pamidronate was diluted in 1000 ml of isotonic saline and administered intravenously over an 8-h period. Mild hyperthermia during the infusion cycle occurred twice in patient 2 and was controlled with usual doses of intravenous acetaminophen. Common gastrointestinal pamidronate-related side effects were prevented with intravenous ondansetron. No other side effects were observed. ARVs were normally administered during admission. For patient 3, weekly doses of 70 mg oral alendronate (Fosamax, Merck Sharp & Dohme, Pavia, Italy) were initiated, with optimal adherence and tolerance.Table 1: Main clinical and biological characteristics at BPP implementation and their evolution.No vertebral fractures were observed on lumbar radiography, neither at baseline, nor during follow-up. An increase in BMD Z-score was observed in all patients (Fig. 1). All patients reported a rapid improvement in bone pain, within weeks after the first pamidronate infusion cycle, and 2 months after the implementation of alendronate.Fig. 1: Evolution in BMD Z -scores along treatment with BPP (normal values lie between +1 and −1).The pathogenesis of bone loss in HIV-infected pediatric patients is not only likely multifactorial, involving HIV- and ARV-related factors, but also other comorbidities, such as low body mass index or lack of mobility, as in the patients we present. Increase in bone turnover is considered to be the most important pathogenic pathway leading to decreased BMD in ARV-treated HIV-infected children, with several studies having reported changes in bone resorption and formation markers in these patients [10,11]. The good clinical and radiological response to BPP in our series supports this pathogenic hypothesis, as BPP inhibit bone resorption. The correlation between BMD and fracture risk in children has not been established. BMD in growing subjects is strongly influenced by gender, body size, pubertal stage, skeletal maturation and ethnicity, factors that need to be taken into account when interpreting DXA scan values in pediatric patients. Beyond the clinical significance of Z-score results, it should be emphasized that all patients in our series presented with lumbar pain and disability in daily life, two common symptoms in children affected with primary or secondary osteoporosis [12]. Recently, the successful use of alendronate was reported in an HIV perinatally infected ARV-naïve 6-year-old girl affected with severe osteoporosis and multiple pathological fractures [13]. No experience with BPP in ARV-treated HIV-infected children has been reported to date. Patients 1 and 2 were treated according to our protocol for the treatment of osteoporosis in the pediatric population [14,15]; patient 3 received oral alendronate because of her age and previous optimal adherence to treatment. Despite the fact that further studies are required, the compassionate use of BPP should be considered in HIV-infected pediatric patients affected with osteoporosis when bone-related pain or atraumatic fractures appear. Acknowledgement This work was presented in the 11th European AIDS Conference, Madrid, Spain, October 2007. Abstract number P15.4/01.

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