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Introduction: Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL), an essential mediator of osteoclast formation, function, and survival that has been shown to decrease bone turnover and increase bone mineral density (BMD) in treated patients. We assessed the long-term efficacy and safety of denosumab, and the effects of discontinuing and restarting denosumab treatment in postmenopausal women with low bone mass., Methods: Postmenopausal women with a lumbar spine T-score of -1.8 to -4.0 or proximal femur T-score of -1.8 to -3.5 were randomized to denosumab every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral alendronate weekly. After 24 months, patients receiving denosumab either continued treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued treatment for 12 months then re-initiated denosumab (60 mg Q6M) for 12 months. The placebo cohort was maintained. Alendronate-treated patients discontinued alendronate and were followed. Changes in BMD and bone turnover markers (BTM) as well as safety outcomes were evaluated., Results: Overall, 262/412 (64%) patients completed 48 months of study. Continuous, long-term denosumab treatment increased BMD at the lumbar spine (9.4% to 11.8%) and total hip (4.0% to 6.1%). BTM were consistently suppressed over 48 months. Discontinuation of denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months of treatment discontinuation. Retreatment with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Levels of BTM increased upon discontinuation and decreased with retreatment. Adverse event rates were similar among treatment groups., Conclusions: In postmenopausal women with low BMD, long-term denosumab treatment led to gains in BMD and reduction of BTM throughout the course of the study. The effects on bone turnover were fully reversible with discontinuation and restored with subsequent retreatment.

Abstract: This randomized, double-blind, double-dummy, multicenter trial assessed safety and efficacy of a single dose of IV zoledronic acid (ZOL) 5 mg vs. oral alendronate (ALN) 70 mg weekly in postmenopausal women with low bone mineral density (BMD) who had previously been treated with ALN. Postmenopausal women who were receiving oral ALN for at least 1 year immediately prior to randomization and with lumbar spine or femoral neck BMD T-score values ≤ −2.0 prior to initiation of ALN were randomized to one 15-min IV infusion of ZOL 5 mg plus 52 weeks of oral placebo (n =113) or one IV infusion of placebo plus 52 weeks of oral ALN 70 mg (n =112). End points included percent change in lumbar spine BMD from baseline to month 12 and relative change from baseline in urine N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen (CTX), amino terminal propeptides of type I collagen (PINP), and bone-specific alkaline phosphatase (bone ALP) over 12 months. Adverse events, bone histomorphometry and microscopic appearance, and patient preference for the 2 treatment regimens were also assessed. In this study, a single infusion of ZOL 5 mg maintained BMD 12 months following the switch from oral ALN in women with osteoporosis. The mean duration of prior ALN therapy at baseline was 4 years. Mean biomarker levels in the ALN 70-mg group remained at or close to baseline levels for the duration of the study. In the ZOL 5-mg group, mean biomarker levels were reduced from baseline after 3 months, returned to baseline after 6 months, and increased thereafter but remained within the premenopausal range. The overall rates of adverse events were comparable in the 2 groups (ZOL 5 mg, 86.7%; ALN 70 mg, 80.4%). Headache occurred more commonly within the first 3 days after infusion with ZOL 5 mg (12.4%) than with ALN 70 mg (6.3%). Bone biopsies indicate that both treatments decrease excessive remodeling seen in osteoporosis. The majority (78.7%) of patients expressed preference for once yearly infusion over weekly oral therapy. We conclude that patients can be switched from oral ALN to ZOL 5 mg infusion with maintenance of therapeutic effect for at least 12 months and that patients prefer a once yearly infusion to weekly oral therapy. [Copyright &y& Elsevier]

Abstract: Introduction: Monthly oral ibandronate has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with osteoporosis, but its efficacy has not been investigated in women with low bone mass. The objective of this study was to examine the efficacy and safety of monthly oral ibandronate (150 mg) treatment in postmenopausal women with low bone mass. Methods: This 1-year, double-blind, placebo-controlled, randomized study enrolled ambulatory postmenopausal women aged 45–60 years with baseline lumbar spine (LS) BMD T-score<−1.0 and >−2.5 and baseline T-score>−2.5 at the total hip, trochanter, and femoral neck (collectively defined as the proximal femur) and no prior vertebral or low-trauma osteoporotic fractures at baseline. Subjects received either 150 mg monthly oral ibandronate or placebo. All subjects received calcium and vitamin D supplements. The primary endpoint was the relative change from baseline (%) in mean LS BMD at 1 year (intent-to-treat population). Treatment groups were compared by means of a two-way ANOVA model which adjusted for independent factors including treatment group, baseline LS BMD T-score, and time since menopause. Responder analyses examined the percentage of participants with changes from baseline in LS BMD and proximal femur BMD≥0%. Adverse events and safety laboratory parameters were monitored continuously. Results: A total of 77 women received monthly ibandronate and 83 women received placebo. Subjects treated with ibandronate achieved larger increases in LS BMD after 1 year compared with subjects receiving placebo (3.7% vs −0.4% [difference of 4.1%, p <0.0001]). After 3 months, median serum C-terminal telopeptide of type I collagen levels were reduced by >55% in the ibandronate group compared with ∼4% in the placebo group. At 1 year, 88.2% of the participants treated with ibandronate achieved increases in LS BMD≥0% compared with 38.6% of subjects receiving placebo. Treatment regimens were well tolerated in both the ibandronate-treated and placebo groups. Conclusion: Monthly ibandronate therapy prevents bone loss in postmenopausal women with low bone mass. [Copyright &y& Elsevier]