Randomized, double-blind, placebo-controlled, multicenter study to evaluate efficacy and safety of the denosumab biosimilar MW031 in Chinese postmenopausal women with osteoporosis.

BACKGROUND: This study aimed to assess the efficacy and safety of MW031 in Chinese postmenopausal women with osteoporosis. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled, multicenter clinical trial, 448 postmenopausal women with osteoporosis were randomized 3:1 to receive MW031 and placebo for 12 months. The primary efficacy endpoint was the percentage change from baseline in BMD at lumbar spine in month 12. The safety and immunogenicity profiles were also included. RESULTS: Of 448 randomized patients, 421 completed the study (MW031, n = 322; placebo, n = 99).After 12 months of MW031 treatment, BMD increased by 5.80% at lumbar spine,3.65% at total hip, and 2.93% at femoral neck. The model-adjusted difference was 3.86% (P<0.0001), 2.34% (P<0.0001), and 1.05% (p = 0.08) compared with placebo group, respectively. For the bone turnover markers, serum CTX level in MW031 group decreased to the maximum difference in month 1 (-71.71%, 95% CI: -77.83%, -65.60%, P<0.0001) compared with the placebo group. The safety analysis showed no significant differences in the proportion of patients reporting any adverse events between the two groups. CONCLUSION: This study demonstrated that MW031 safely and effectively increased BMD and rapidly decreased the level of bone resorption marker in Chinese postmenopausal women with osteoporosis. TRIAL REGISTRATION: NCT05215977 (ClinicalTrials.gov.).

Jintiange combined with alfacalcidol improves muscle strength and balance in primary osteoporosis: A randomized, double-blind, double-dummy, positive-controlled, multicenter clinical trial.

Objective: To investigate the effectiveness of a Chinese patent medicine, Jintiange capsules with the main component of artificial tiger bone powder, combined with alfacalcidol on muscle strength and balance of the lower extremities in patients with primary osteoporosis. Design: A randomized, double-blind, double-dummy, positive-controlled, multicenter clinical trial. Subjects and methods: A total of 400 patients diagnosed with primary osteoporosis or osteopenia were recruited and randomized into the Jintiange or control groups. During the 52-week treatment, the participants in the Jintiange group were treated with Jintiange capsules (1.2 â€‹g each time, 3 times per day) and calcium carbonate simulant, while those in the control group were treated with calcium carbonate (element calcium 0.3 â€‹g, twice a day) and a Jintiange capsule simulant. Alfacalcidol (0.25 â€‹µg/d) was applied in both groups. The timed up and go test (TUG), chair rising test (CRT), and tandem gait test (TGT) were performed to evaluate balance, muscle strength and fall risk of the participants. Results: There were 154 participants in the Jintiange group, and 157 participants in the control group were included in the per-protocol set. Comparing the data at week 52 from those at baseline, the TUG time decreased from 9.60 â€‹± â€‹2.25 â€‹s to 8.53 â€‹± â€‹2.06 â€‹s (p â€‹< â€‹0.001) in the Jintiange group and decreased from 9.50 â€‹± â€‹1.91 â€‹s to 9.11 â€‹± â€‹1.95 â€‹s (p â€‹< â€‹0.001) in the control group; the CRT time decreased from 11.49 â€‹± â€‹4.05 â€‹s to 8.57 â€‹± â€‹2.13 â€‹s (p â€‹< â€‹0.001) and 11.17 â€‹± â€‹3.21 â€‹s to 9.74 â€‹± â€‹1.98 â€‹s (p â€‹< â€‹0.001) in the Jintiange and control groups, respectively; the number of correct steps in the TGT increased significantly in both the control (7.40 â€‹± â€‹1.27 vs. 7.69 â€‹± â€‹0.87, p â€‹< â€‹0.01) and Jintiange groups (7.21 â€‹± â€‹1.58 vs. 7.60 â€‹± â€‹1.12, p â€‹< â€‹0.001). At the end of the study, the TUG and CRT results in the Jintiange group were superior to those in the control group (all p value â€‹< â€‹0.05), while no obvious difference was found in the TGT between the two groups. At week 52, the high fall risk proportions in the Jintiange group were significantly lower than those in the control group according to TUG (3.25% vs. 9.55%, p â€‹= â€‹0.023) and CRT (20.78% vs. 33.76%, p â€‹= â€‹0.01). Conclusion: Jintiange capsules combined with alfacalcidol can effectively improve muscle strength and the balance of the lower extremities and reduce fall risk in patients with primary osteoporosis/osteopenia. The translational potential of this article: Artificial tiger bone powder, a traditional Chinese patent medicine, can improve muscle strength and balance and reduce fall risks effectively among patients with primary osteoporosis. It might be a therapeutic option for osteoporosis individuals combined with sarcopenia to improve their muscle function.

The higher osteoprotective activity of psoralidin in vivo than coumestrol is attributed by its presence of an isopentenyl group and through activated PI3K/Akt axis.

Prenylation of bioactive natural compounds has been postulated to be able to enhance the utilization rate and affinity of the compounds with cell membranes, thus promote their bioactivities. Coumestrol, isolated from Medicago sativa, has been known as a phytoestrogen which has bone health benefits. In our previous work, psoralidin, a prenylated coumestrol, was proved to have a higher ability than coumestrol to promote bone formation and to attenuate resorption in vitro. However, it remains to be investigated whether psoralidin will have stronger bone health benefits than coumestrol. In the current study, psoralidin was isolated from Psoralea corylifolia L. and the osteotropic activities of coumestrol and psoralidin were compared in ovariectomized (OVX) rats. Both coumestrol and psoralidin were found to suppress OVX-induced bone loss in vivo, as shown by improved total bone mineral content (t-BMC) or density (t-BMD) and mineral apposition rate, bone biomechanical properties, microstructure and trabecular bone formation, enhanced osteogenic differentiation but suppressed adipogenic differentiation of bone marrow stromal cells (BMSCs), and activation of PI3K/Akt axis and downstream factors such as GSK3ß/ß-catenin and Nrf-2/HO-1. However, psoralidin was shown to have higher activities than coumestrol in the above measurements/indices. Our findings demonstrate that psoralidin, as a novel anti-osteoporosis candidate, could suppress bone loss in OVX rats and have better osteoprotective effects than coumestrol, which may be related to the presence of the isopentenyl group in psoralidin.

Psoralidin, a prenylated coumestan, as a novel anti-osteoporosis candidate to enhance bone formation of osteoblasts and decrease bone resorption of osteoclasts.

Traditional Chinese medicines (TCM) have been proven to prevent osteoporosis, but their clinical applications are not widely recognized due to their complicated ingredients. Psoralidin, a prenylated coumestan, has been reported to prevent bone loss of ovariectomized rats, but detailed mechanisms are still not clear. In current study, we found that both psoralidin and coumestrol promoted osteoblast proliferation and differentiation, as evidenced by improvements in cell proliferation and alkaline phosphatase activity; increased formation of ALP colonies and calcified nodules; enhanced secretion of collagen-I, BMP-2, osteocalcin and osteopontin; and stimulation of the expression of IGF-1, ß-catenin, Runx-2, Osterix, and OPG, as well as the mRNA ratio of OPG/RANKL, while significantly decreasing the expression of RANKL. In addition, both psoralidin and coumestrol inhibited osteoclast formation and osteoclastic bone resorption, as demonstrated by the lower tartrate-resistant acid phosphatase activity and smaller area, with fewer resorption pits formed. Interestingly, psoralidin showed much stronger effects than coumestrol at enhancing osteoblast proliferation/differentiation or inhibiting osteoclast differentiation and bone resorption. Moreover, we found that both psoralidin and coumestrol suppressed COX-2 and ROS production in rat osteoblastic calvarias cells, and psoralidin showed stronger effects than coumestrol. Furthermore, we detected that by blocking estrogen receptors with ICI 182.780 (an estrogen receptor antagonist), the osteoprotective effects of psoralidin and coumestrol were also blocked. Our findings demonstrated that psoralidin and coumestrol exert their bone-protective effects by enhancing bone formation of osteoblasts and inhibiting bone resorption of osteoclasts. These roles might be mediated by their antioxidant activity and transduced through estrogen receptor signaling.