Sequential Treatment for Osteoporosis After Teriparatide: A Real-Life Long-Term Comparison Between Zoledronic Acid and Denosumab

<b>Background/Objectives:</b> The efficacy of zoledronic acid (ZOL) compared to denosumab (DMAB) after teriparatide (TPTD) is largely unknown. We compared the effect of ZOL or DMAB treatment after TPTD on BMD changes and fracture (FX) occurrence. <b>Methods:</b> We retrospectively revised data from 77 patients treated at Fondazione IRCCS Ca'Granda Milan, Italy, with TPTD (≥18 months), given at withdrawal (T0), single ZOL 5 mg (Group A, N = 56) or DMAB 60 mg/6 months (Group B, N = 21). BMD changes and incident FX were assessed after 24 months (T1) in all patients and after 48 months (T2) in 46 patients (Group A1, N = 15, treated with a single ZOL at T0; Group A2, N = 17, treated with ZOL at T0 and T1; Group B, N = 14, treated with DMAB since T0 to T2). <b>Results:</b> During the T0-T1 period, in all groups, both spine (LS) and total hip (TH) T-scores improved (mean ± SD, T0 vs. T1): Group A (LS -2.5 ± 1.2 vs. -2.3 ± 1.3, <i>p</i> = 0.006; TH -2.2 ± 1.0 vs. -2.0 ± 1.1, <i>p</i> = 0.002) and Group B (LS -2.4 ± 1.4 vs. -1.8 ± 1.4, <i>p</i> < 0.001; TH -2.4 ± 1.0 vs. -2.2 ± 1.0, <i>p</i> = 0.003). At T2 vs. T0, all groups showed an increase in TH-BMD (A1 -1.8 ± 0.9 vs. -1.4 ± 1.0, <i>p</i> = 0.008; A2: -1.8 ± 0.8 vs. -1.6 ± 0.9, <i>p</i> = 0.032; B: -2.6 ± 0.7 vs. -2.2 ± 0.7, <i>p</i> < 0.001), while LS-BMD increased only in Group B (-2.7 ± 1.4 vs. -2.0 ± 1.2, <i>p</i> = 0.002), with stability in A1 and A2. No significant differences in incident FX between groups were observed. <b>Conclusions:</b> At 24 months after TPTD withdrawal, both ZOL and DMAB improved BMD at all sites; after 48 months, both ZOL (1 or 2 infusions) and DMAB led to BMD improvement at TH, whereas only DMAB led to an increase in LS-BMD.