Bone-Forming and Antiresorptive Effects of Romosozumab in Postmenopausal Women With Osteoporosis: Bone Histomorphometry and Microcomputed Tomography Analysis After 2 and 12 Months of Treatment

Abstract

Sclerostin, a protein produced by osteocytes, inhibits bone formation. Administration of sclerostin antibody results in increased bone formation in multiple animal models. Romosozumab, a humanized sclerostin antibody, has a dual effect on bone, transiently increasing serum biochemical markers of bone formation and decreasing serum markers of bone resorption, leading to increased BMD and reduction in fracture risk in humans. We aimed to evaluate the effects of romosozumab on bone tissue. In a subset of 107 postmenopausal women with osteoporosis in the multicenter, international, randomized, double‐blind, placebo‐controlled Fracture Study in Postmenopausal Women with Osteoporosis (FRAME), transiliac bone biopsies were performed either after 2 (n = 34) or 12 (n = 73) months of treatment with 210 mg once monthly of romosozumab or placebo to evaluate histomorphometry and microcomputed tomography‐based microarchitectural endpoints. After 2 months, compared with either baseline values assessed after a quadruple fluorochrome labeling or placebo, significant increases (P < 0.05 to P < 0.001) in dynamic parameters of formation (median MS/BS: romosozumab 1.51% and 5.64%; placebo 1.60% and 2.31% at baseline and month 2, respectively) were associated with a significant decrease compared with placebo in parameters of resorption in cancellous (median ES/BS: placebo 3.4%, romosozumab 1.8%; P = 0.022) and endocortical (median ES/BS: placebo 6.3%, romosozumab 1.6%; P = 0.003) bone. At 12 months, cancellous bone formation was significantly lower (P < 0.05 to P < 0.001) in romosozumab versus placebo and the lower values for resorption endpoints seen at month 2 persisted (P < 0.001), signaling a decrease in bone turnover (P = 0.006). No significant change was observed in periosteal and endocortical bone. This resulted in an increase in bone mass and trabecular thickness with improved trabecular connectivity, without significant modification of cortical porosity at month 12. In conclusion, romosozumab produced an early and transient increase in bone formation, but a persistent decrease in bone resorption. Antiresorptive action eventually resulted in decreased bone turnover. This effect resulted in significant increases in bone mass and improved microarchitecture.© 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains

“…A need for a drug with high specificity and minimal side effects exists. Previously, a humanized monoclonal antibody targeting SOST was developed for treating osteoporosis in postmenopausal women 23 , 24 , but critical cardiovascular side effects (such as cardiac ischemia) were reported 25 . An antibody targeting both the loop 2 and C-terminal peptides may be another option for new osteoporosis drugs with better therapeutic effects and fewer side effects.…”

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

“…However, because of the coupling and synchronization of bone resorption and new bone formation, anti‐bone resorption drugs can inhibit both bone resorption and bone formation, while anabolic drugs, such as parathyroid hormone (PTH) or parathyroid hormone–related protein (PTHrP), mainly enhance bone formation and meanwhile stimulate bone resorption . Researchers are constantly striving to explore dual‐action agents that modulate bone remodeling for the treatment of osteoporosis, such as an anti‐sclerostin antibody that is now available on the market and several others that are under investigation …”

Sklerostin des Osteozyten – von der Expression zur klinischen Anwendung

“…Hierbei zeigte sich bei postmenopausalen Frauen nach vorheriger Bisphosphonat-Behandlung auch ein substanzieller Effekt auf die Hüftregions-BMDmit 2,6%iger Erhöhung nach zwölf Monaten Romosozumab-Behandlung im Vergleich zu -0,6% nach Teriparatid-Behandlung [92]. Dynamische Histomorphometrie in transiliakalen Knochenbiopsien postmenopausaler Frauen mit Osteoporose wies sowohl trabekulär als auch endokortikal eine deutlich erhöhte Knochenformation nach zwei Monaten Romosozumab-Behandlung auf, wobei der anti-resorptive Effekt von Romosozumab, gemessen an Osteoklastenanzahl und -aktivität, auch nach zwölf Monaten Behandlung bestehen blieb [93].…”