Denosumab versus Bisphosphonates for the Treatment of Osteoporosis in Post-menopausal Women

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; ALCARAZ, A.; GLUJOVSKY, D.; LOPEZ, A.; REY-ARES, L.; BARDACH, A.; CIAPPONI, A; SECCO, A

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Osteoporosis (OP) is a disease characterized by a decrease in bone mass and impairment of the bone micro-architecture resulting in an increased fracture risk. It is estimated that there are approximately 200 million people affected by this disease worldwide and there are approximately 1.5 million fractures due to this cause.As regards treatment, it is recommended to indicate calcium and vitamin D supplements as well as anti-resorptive drugs such as bisphosphonates, hormone replacement therapy and selective estrogen-receptor modulators. Other available drugs include the parathyroid hormone analogs and the strontium ranelate; denosumab becomes a new therapeutic choice.TechnologyDenosumab is a human monoclonal antibody that binds with good affinity and specificity to the RANK ligand (RANKL), which is essential for osteoclast formation, activation and survival. It has been approved by the FDA, EMA and ANMAT for the treatment of osteoporosis in post-menopausal women at high risk of fractures.It is administered subcutaneously at 60 mg doses every 6 months.PurposeTo assess the available evidence on the efficacy, safety and coverage policy related aspect for denosumab versus bisphosphonates in decreasing the risk of fractures due to post-menopausal osteoporosis.MethodsA bibliographic search was carried out on the main literature databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews, meta-analyses, controlled randomized clinical trials (RCTs), health technology assessments and economic evaluations, clinical practice guidelines (CPG) and coverage policies from other health systems.ResultsNo studies comparing denosumab and bisphosphonates which assessed the decrease in fracture risk as primary outcome have been found. Five meta-analyses, one RCT comparing denosumab versus placebo, two CPG and four Health Technology Assessments were found.The only direct meta-analysis found was published in 2012 and compared denosumab with alendronate; it included four RCTs with 1,942 post-menopausal women. Three out of these four RCTs assessed the decrease in fracture risks as secondary objective; no significant differences have been found between both drugs (OR: 1.42; 95% CI 0.84 ? -2.40).Four indirect meta-analyses analyzed different drugs for the treatment of post-menopausal osteoporosis. One of them, published in 2013, included 34 studies and showed superiority of denosumab compared with alendronate and with risedronate in decreasing the risk of new vertebral fractures with a RR: 0.58 (95% CI, 0.42- 0.79) and RR: 0.53 (95% CI, 0.38- 0.73) respectively; no significant differences were found versus zoledronic acid or etidronate. As regards non-vertebral and hip fractures, no significant differences have been found between denosumab and each of the above mentioned bisphosphonates. Another study published in the same year included 31,393 post-menopausal women and assessed the appearance of new vertebral fractures. A higher risk was observed in patients treated with alendronate versus denosumab (OR: 1.6 95% CI: 1.17- 2.27), as well as in those treated with risedronate versus denosumab (OR: 1.84 95% CI: 1.29- 2.63).In 2012, one meta-analysis that included 139,647 patients (86% women) did not find differences between denosumab and bisphosphonates in decreasing the fracture risk of any kind, due to post-menopausal osteoporosis. In 2011, one meta-analysis including 59,209 post-menopausal women, showed the superiority of denosumab over alendronate and risedronate in preventing vertebral fractures with an OR: (0.63, 95% CI, 0.38- 0.97) and OR: 0.53(95% CI, 0.32- 0.82), respectively; no differences have been found when comparing it with etidronate, ibandronate and zoledronic acid. There were not differences in reducing the risk of non vertebral and hip fractures when compared with the analyzed bisphosphonates either. One RCT including 7,868 patients who were followed up for three years, compared denosumab with placebo and showed a significant decrease in the risk of vertebral (OR: 0.32; 95% CI, 0.26-0.41), hip (OR: 0.60; 95% CI, 0.37-0.97), and non-vertebral fractures (OR: 0,80 95% CI: 0.67-0.95) in the denosumab-treated group.The 2011 Columbia Medical Association?s CPG considered there is not enough information to assess its superiority over alendronate. A 2010 American Endocrinology Society´s CPG recommends denosumab as one of the first-line treatment drugs.Different health technology assessment agencies recommend the use of denosumab in post-menopausal women at increased risk of fractures who cannot follow oral bisphosphonate treatment; they have contraindications or intolerance to them.As regards coverage policies, three U.S. health sponsors cover denosumab in patients with post-menopausal osteoporosis with failure, contraindication or intolerance to bisphosphonates. No Economic Evaluation has been found in Argentina. The current cost of a pre-filled syringe is $2,163.10. (Argentine pesos, May 2013)ConclusionsThere is not enough comparative evidence to indicate the superiority of denosumab over bisphosphonates in the treatment of post-menopausal osteoporosis. Its indication would be limited to those cases at high risk of fracture (according to specific criteria) and intolerance, contraindication or failure to bisphosphonate treatment.