After completing the first 3 years of the study, women from the denosumab group had two more years of denosumab treatment (long-term group), and those from the placebo group had 2 years of denosumab exposure (cross-over group). In

the long-term group, lumbar spine and total hip BMD increased further. Yearly fracture incidences for both groups were below rates observed in the placebo group of the 3-year trial and below rates projected for GS-9973 supplier a ‘virtual untreated twin’ cohort [211]. The effects of denosumab on fracture risk are particularly marked in patients at high fracture probability [212]. Adverse events did not increase with long-term administration of denosumab. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw [211]. In a meta-analysis of four clinical trials, the relative risk of serious adverse events for the denosumab group compared with the placebo group was 1.33; of serious adverse events related to infection, 2.10; of neoplasm, 1.11; GF120918 of study discontinuation due to adverse events, 1.10, and of death, 0.78. These risks were all non-significant [213]. The effects of the major pharmacological interventions on vertebral and hip fracture risk are summarised in Table 12. Table 12 Study details and anti-fracture efficacy (relative risk (RR) and 95 % CI) of the major pharmacological treatments used for postmenopausal

osteoporosis many when given with calcium and vitamin D, as derived from randomised controlled trials Intervention Study Entry criteria Mean age (years) Number of patients randomised Fracture incidence (% over 3 years)a RR (95%CI) Placebo Drug a. Vertebral fracture (high-risk population) Alendronate, 5–10 mg [173] Vertebral fractures; BMD, ≤0.68 g/m2 71 2,027 15.0 8.0 0.53 (0.41–0.68) Risedronate, 5 mg [177] 2 vertebral ACP-196 order fractures or 1 vertebral fracture and T-score ≤−2.0 69 2,458 16.3 11.3 0.59 (0.43–0.82) Risedronate, 5 mg [178] 2 or more vertebral fractures—no BMD entry criteria 71 1,226 29.0 18.0 0.51 (0.36–0.73) Raloxifene,

60 mg [161] Vertebral fractures—no BMD entry criteria 66 7,705 21.2 14.7 0.70 (0.60–0.90) Teriparatide, 20 μg c [198] Vertebral fractures and FN or LS T-score ≤−1 if less than 2 moderate fractures 69 1,637 14.0 5.0 0.35 (0.22–0.55) Ibandronate, 2.5 mg [179] Vertebral fractures and LS −5 < T-score ≤ −2.0 69 2,946 9.6 4.7 0.38 (0.25–0.59) Ibandronate, 20 mg [291] Vertebral fractures and LS −5 < T-score ≤ −2.0 70 708 9.6 4.9 0.50 (0.34–0.74) Strontium ranelate, 2 g [201] Vertebral fractures, LS BMD ≤0.840 g/m2 69 1,649 32.8 20.9 0.59 (0.48–0.73) Zoledronic acid, 5 mg [185] FN T-score ≤−2.5, ± vertebral fracture, or T-score ≤−1.5 and 2+ mild or 1 moderate vertebral fracture 73 7,765 10.9 3.3 0.30 (0.24–0.38) b. Vertebral fracture (low-risk population) Alendronate, 5–10 mgd [176] FN T-score ≤−2 68 4,432 3.8 2.1 0.56 (0.39–0.