The Quest for Osteoporosis Mechanisms and Rational Therapies: How Far We've Come, How Much Further We Need to Go

Abstract

During the last 40 years, understanding of bone biology and the pathogenesis of osteoporosis, the most common and impactful bone disease of old age, has improved dramatically thanks to basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies. Culprits of osteoporosis are no longer a matter of speculation based on in vitro observations. Instead, they can be identified and dissected at the cellular and molecular level using genetic approaches; and their effect on distinct bone envelopes and anatomic regions can be functionally assessed in vivo. The landscape of pharmacotherapies for osteoporosis has also changed profoundly with the emergence of several potent antiresorptive drugs as well as anabolic agents, displacing estrogen replacement as the treatment of choice. In spite of these major positive developments, the optimal duration of the available therapies and their long-term safety remain matters of conjecture and some concern. Moreover, antiresorptive therapies are used indiscriminately for patients of all ages on the assumption that suppressing remodeling is always beneficial for bone, but rebound remodeling upon their discontinuation suggests otherwise. In this invited perspective, I highlight the latest state of knowledge of bone-intrinsic and extrinsic mechanisms responsible for the development of osteoporosis in both sexes; differences between the mechanisms responsible for the effects of aging and estrogen deficiency; and the role of old osteocytes in the development of cortical porosity. In addition, I highlight advances toward the goal of developing drugs for several degenerative diseases of old age at once, including osteoporosis, by targeting shared mechanisms of aging. © 2018 American Society for Bone and Mineral Research.

Elimination of senescent osteoclast progenitors has no effect on the age‐associated loss of bone mass in mice

“…Aging is a critical risk factor for the development of osteoporosis (Almeida et al, ; Manolagas, ), and cellular senescence has emerged as one of the hallmarks of aging and major contributor to age‐associated diseases, including osteoporosis (Childs et al, ; Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, ). In aged mice, several cell types within bone exhibit markers of senescence (Farr et al, ; Kim et al, ; Piemontese et al, ).…”

Bone Health in the Transgender Population

“…Androgen levels may need to be higher to act on trabecular bone and may not have as dominant a role in cortical bone. Additionally, cellular senescence and changes related to aging need to be taken into consideration as they are inexorably linked with bone loss [16, 26].…”

The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging

“…Indeed, a growing body of evidence implicates ROS toxicity with aging as an antagonist to Wnt signaling by diverting the limited pool of β‐catenin from TCF/lymphoid‐enhancer binding factor family of transcription factors to FoxO‐mediated transcription in, eg, osteoblasts thereby reducing bone formation in old age . Thus, similar to other defense mechanisms against aging, FoxO transcriptional activation protects bone against oxidative stress, but as an unintended consequence suppresses Wnt signaling, thus contributing to defective bone formation in old age …”

“…(82,132) Thus, similar to other defense mechanisms against aging, FoxO transcriptional activation protects bone against oxidative stress, but as an unintended consequence suppresses Wnt signaling, thus contributing to defective bone formation in old age. (133) Additional evidence implicating the deleterious effects of excessive oxidative stress on the skeleton comes from studies showing that pharmacological pro-oxidant administration to mice causes bone loss, (129,130) whereas antioxidant treatments at least partially rescues this effect. (128,134) Even further support comes from genetic mouse models of premature aging (135,136) or global deletion of antioxidant genes (eg, Sod1 (137) or Sod2 (138) ), which are characterized by elevated oxidative stress levels yet low bone mass.…”

“…(82,132) Thus, similar to other defense mechanisms against aging, FoxO transcriptional activation protects bone against oxidative stress, but as an unintended consequence suppresses Wnt signaling, thus contributing to defective bone formation in old age. (133)…”