Exploring Novel Treatments for Osteoporosis: Lessons for Future Treatment Development

This study was conducted by Yong Wan, PhD, research assistant professor in the Department of Medicine in the Division of Endocrinology and Metabolism at the University of Pittsburgh School of Medicine.

Overview of Osteoporosis

Osteoporosis is the most common form of bone disease, affecting approximately 54 million Americans. According to data from the Centers for Disease Control and Prevention (CDC), osteoporosis-related morbidity for men above the age of 50 is 4.2%, while for women above the age of 50 the rate is much higher at 18.8%. Osteoporosis is an age-related disease caused by imbalanced bone remodeling with coupling of osteoblastic bone formation and osteoclastic bone resorption, causing “porous bone” with decreased bone mineral density. When the balance favors osteoclastic bone resorption, it leads to fragile bones with a high risk of bone fracture.^1-3 Osteoporosis is not a painful disease and, as a result, many patients do not seek treatment until a bone fracture occurs. There has, however, been increased interest in seeking new osteoporosis therapies. In the past three decades, the United States Food and Drug Administration (FDA) has approved 11 drugs for osteoporosis treatment. These drugs target either osteoblasts or osteoclasts, if not both. Three major limitations of these medications include: (1) poor efficacy in preventing nonvertebral fractures; (2) long-term side effects; and (3) tight activity coupling of osteoblasts and osteoclasts.⁴ As such, it is of great interest to explore novel targets to inhibit bone resorption and/or promote bone formation within bone context. These novel targets might serve as potential therapeutic targets to prevent age-related bone loss, and thus be relevant in the treatment of osteoporosis.

Cross-talk between Osteoblasts and Osteoclasts

Bone is a complex endocrine organ that secretes several hormones, including Osteocalcin (OCN),^5,6 Lipocalin 2 (LCN2),7 Fibroblast Growth Factor 23 (FGF23),^8,9 and Sclerostin (SOST),¹⁰ which have various endocrine effects on energy metabolism.¹⁰ Osteoblastic bone formation starts during the embryonic stage and continuously regulates bone dynamics throughout life,¹¹ while osteoclasts activity is evident in embryonic bones, but also increases throughout the aging process.^12,13 In addition to the endocrine function of bone, both osteoblasts (osteocytes) and osteoclasts can secrete several cytokines and growth factors exerting an autocrine and paracrine effect on each other.¹⁴ There are several proteins, Wnt, Notch, and Bone Morphogenetic Protein (BMP), secreted by osteoblasts that regulate osteoblast proliferation and/or differentiation in autocrine and paracrine manner.^14-17In addition, osteoclasts secrete several cytokines, including BMP6, collagen triple helix repeat containing 1 (CTHRC1), EphrinB2 (EFNB2), Sphingosine 1-phosphate (S1P), Wnt10b, Semaphorin 4D (SEMA4D), and Cardiotrophin-1(CT-1) to regulate osteoblastogenesis.^14,18-22 A bone remodeling unit (BMU) mainly consists of osteoblasts, osteoclasts, bone-lining cells, and osteocytes.³ In healthy human adults, there are about 1 million active BMUs at any given moment.²³ As major components of a BMU, the cross-talk between osteoblasts and osteoclasts is critical to regulating bone remodeling. The functional coupling of osteoblasts and osteoclasts causes most osteoporosis medications to become less effective. Antiresorptive medications, which inhibit bone resorption, leads to decreased bone turnover, while anabolic medications improve bone turnover with increased bone formation, as well as bone resorption.⁴ It would be ideal to target the functional activity of osteoblasts or osteoclasts instead of its differentiation ability.

Wnt Signal in Osteoporosis

The most recently FDA approved medication is romosozumab, an anti-Sclerostin (SOST) antibody. SOST, mainly secreted by osteocytes, can bind with the LRP5/6 receptor, thus inhibiting the Wnt/ beta-catenin signal. The primary biological function of SOST is to inhibit osteoblast differentiation.^24,25 Even though SOST is not expressed in osteoclasts, SOST is capable of regulating osteoclastogenesis in a direct and indirect manner. As the only medication that promotes bone formation and inhibits bone resorption, the molecular and cellular mechanism of SOST sets a good example for the development of anabolic medications with antiresorptive activity. Wnt/beta-catenin signal is a conserved signal that regulates adult tissue homeostasis. Wnt/beta-catenin signal might positively regulate osteoblastogenesis, while negatively regulating osteoclastogenesis. As such, it is still of interest to target Wnt signal specifically in the bone context to treat osteoporosis.

Beyond Osteoporosis, Treating Osteoporosis as an Aging Disease

Aging leads to the time-dependent functional decline of all tissues, including bone. At least nine separate hallmarks are reported to contribute to aging, such as telomere shortening and cellular senescence.²⁹ Recent publications have shown links to mitochondrial dysfunction^30-32 and cellular senescence³³ with aging-related bone loss. Findings like these have piqued investigators’ interest in seeking new osteoporosis treatment options as part of the aging process. For example, Sirtuins 6 (SIRT6), one member of the Sirtuins (1-7) family, has been reported to extend the lifespan of mice by approximately 15%^34,35 while deletion of SIRT6 in mice leads to osteoporosis phenotype with decreased bone formation and enhanced bone resorption.^36-38 As bone closely interacts with other tissues, such as muscle and adipose tissue, the potential anti-aging medication will not merely improve bone quality, but also improve the function of bone related tissues, which in turn is beneficial to bone functions.

Exploring Novel Targets through Secretome Analysis for the Treatment of Osteoporosis

Investigators in the Wan Lab have established that osteoblasts/osteocytes secrete Wnt proteins that regulate osteoblasts and osteoclasts.^16,17 In order to explore novel secreted proteins from osteoblasts/osteocytes that exert paracrine and/or endocrine effect on bone metabolism, the Wan Lab research team is currently conducting secretome analysis of osteoblasts/osteocytes both in vitro and in vivo. For that purpose, they have been capable of overexpressing biotin ligase in endoplasmic reticulum of bone cells, which will biotinylate proteins through conventional secretion. These secreted biotinylated proteins allow for rapid purification and mass spectrometry analysis. The Wan Lab researchers will further screen the top hits from mass spectrometry analysis through the functional study of bone cells and neonatal bone cultures. The candidate targets will be further validated by their ability to prevent osteoporosis in aged mice. This hypothesis, if validated, will help to find novel target(s) to prevent age related bone loss, thus serving as potential targets for the treatment of osteoporosis.

Conclusion

The United Nations describes the Decade of Healthy Ageing (2021-2030) as a way to bring together governments, society, agencies, professionals, and academia to improve the lives of older people, their families, and the communities in which they live.³⁹ Osteoporosis adds to the societal burden of those entering the “Decade of Healthy Aging” and requires attention. The cross-talk between osteoblasts and osteoclasts, as well as other cells involved in bone remodeling, continue to be the remaining primary targets for the treatment of osteoporosis.

Romosozumab is the only anabolic medication with antiresorptive activity, which raises special interest on the Wnt signal in regulating bone remodeling. This is encouraging for attempts to develop new medications that benefit the balance between bone formation and bone resorption. As new anti-aging medications emerge, it will be of general benefit to approach osteoporosis as part of the aging process. Given the aging population, it is more critical than ever to ensure that people not only live longer, but that they remain healthy, mobile, and functional longer. Having healthy bones is an essential component of healthy aging, and Dr. Wan’s research will help achieve this goal.

References

Please refer to the Update in Endocrinology Fall 2021 CME course on UPMCPhysicianResources.com for a full list of references featured in this article.