Estrogen and bone health form a cornerstone of osteoporosis management. Diagnosis of osteoporosis is performed using bone mineral density (BMD), despite the limitations associated with this. Within the last 25 years, numerous bone turnover markers (BTM) have been developed, and this has led to a marked improvement in drug development for osteoporosis and understanding of fast bone losers. Estrogen research has provided landmark research on understanding the relationship between osteoporosis and BTMs. Clinical studies have illustrated how measurement of BTMs can assist in prediction of rapid bone loss, future fractures and, most importantly, the fracture efficacy of drugs. The BTMs provide information independent of BMD and fracture history. In addition, changes in bone turnover within 1 month predict later changes in BMD, which allows for early efficacy and prognostic measures. The aim is to provide a careful review of the possibilities that implementation of BTMs into clinical practice have provided, while placed in a historical context. The primary focus is on how the BTMs have revolutionized clinical trials on osteoporosis drugs through their ability to supplement bone mass measurements and fracture efficacy endpoints.Estrogen and bone health form a cornerstone of osteoporosis management. Diagnosis of osteoporosis is performed using bone mineral density (BMD), despite the limitations associated with this. Within the last 25 years, numerous bone turnover markers (BTM) have been developed, and this has led to a marked improvement in drug development for osteoporosis and understanding of fast bone losers. Estrogen research has provided landmark research on understanding the relationship between osteoporosis and BTMs. Clinical studies have illustrated how measurement of BTMs can assist in prediction of rapid bone loss, future fractures and, most importantly, the fracture efficacy of drugs. The BTMs provide information independent of BMD and fracture history. In addition, changes in bone turnover within 1 month predict later changes in BMD, which allows for early efficacy and prognostic measures. The aim is to provide a careful review of the possibilities that implementation of BTMs into clinical practice have provided, while placed in a historical context. The primary focus is on how the BTMs have revolutionized clinical trials on osteoporosis drugs through their ability to supplement bone mass measurements and fracture efficacy endpoints.