An in-silico approach to elucidate the pathways leading to primary osteoporosis: age-related vs. postmenopausal

Abstract

Numerical models of bone remodelling have traditionally been used to simulate bone loss in postmenopausal women and the response to drug treatments. These models simulate the menopausal estrogen decline by altering certain signalling pathways. However, they overlook the simultaneous effect that ageing can have on bone cells function and thus on bone loss. Considering ageing and estrogen decline together is important for designing osteoporosis treatments that can counteract one of the two factors.A previously developed bone remodelling model was adapted to consider the effect of ageing through: (1) decreased TGF-beta content within bone matrix; (2) increased sclerostin production by non-skeletal cells. Estrogen deficiency is simulated in three different ways: (a) increased RANKL expression; (b) decreased OPG production; (c) increased responsiveness of osteoclasts to RANKL. The effect of ageing was validated using clinical BMD data of vertebral trabecular bone from males. The joint effect of ageing and estrogen deficiency was validated using the corresponding clinical data in women.In ageing, the effect of increased sclerostin production is more important than the decrease in TGF-beta. The three mechanisms used to simulate the effect of estrogen deficiency yielded almost identical responses. The results show that early menopause leads to lower density in the fifth decade, but after the sixth decade density is almost independent of the age at menopause on average. Osteoporosis treatment with denosumab was also simulated, concluding that the treatment proves more necessary after 10 years since menopause or after age 60.