Evaluation of Osteogenic Phenotype in Postmenopausal Women receiving Anabolic and Antiresorptive Osteoporosis Therapies

Abstract Ageing of the general population has led to a significant increase in the prevalence of osteoporosis over the past decades. While there are effective pharmacological agents that increase bone formation, decrease bone resorption and decrease fracture risk, they do not uniformly cure osteoporosis. This has prompted investigations to examine whether combination therapy with these agents can result in an additive benefit. Since concomitant therapy with denosumab and teriparatide has shown promise in this respect, investigations were undertaken to explore whether the changes in osteogenic phenotype could provide insight into the cellular and molecular mechanism of this effect. Investigations were performed in postmenopausal women receiving denosumab, teriparatide or both for 3 months. Histomorphometric parameters were the primary outcome, while exploratory studies examined RNA expression in bone biopsies as well as in sorted and cultured bone marrow stromal cells. Osteogenic colony forming units of bone marrow stromal cells were also evaluated. The studies demonstrated that combination therapy results in an increase in osteoprogenitors, evidenced by an increase in osteoblastic colony forming units. This was associated with an increased in bone marrow stromal cell expression of LGR6 (Leucine Rich Repeat Containing G Protein-Coupled Receptor 6), a stem cell marker and activator of the canonical Wnt signaling pathway. These data suggest that enhancement of canonical Wnt signaling contributes to the increase in osteoprogenitors and consequently an increase in bone density in postmenopausal women receiving combination therapy for osteoporosis.