In the United States, over 10-million people suffer from osteoporosis, while another 40-million persons are diagnosed with osteopenia, a precursor condition to osteoporosis characterized by significantly reduced bone-mineral density. About 2-million people suffer osteoporotic fractures each year, and nearly 20 percent of these patients die within a year because of additional fractures and complications. Now Associate Professor Jungwoo Lee of the UMass Amherst Chemical Engineering (ChE) Department reports a pioneering, in-vitro, humanized-bone-model assay that promises several critical improvements over time-consuming animal models and clinical studies pertaining to osteoporosis.

Lee, Yongkuk Park (post-doctoral research associate in the ChE department at UMass-Amherst), and Tadatoshi Sato (assistant professor at the UMass Chan Medical School) have published their findings in a recent issue of the prestigious journal, Nature Communications

The backstory of Lee’s research concerns cells known as “osteoblasts” and “osteoclasts.” As the website of the Cleveland Clinic explains: “Bone is a dynamic tissue that undergoes repeated turnover by osteoblasts and osteoclasts. Osteoblasts form new bones and add growth to existing bone tissue. Osteoclasts dissolve old and damaged bone tissue so it can be replaced with new, healthier cells created by osteoblasts.” 

According to Lee, “Under normal conditions, there is a delicate equilibrium between osteoblast and osteoclast activities. However, in the context of aging or metabolic bone diseases, this balance is disrupted, resulting in an elevated osteoclast activity compared to osteoblasts. This imbalance leads to a net loss of bone mass and reduced mechanical strength. Consequently, osteoclasts become a primary target for the development of drugs to treat osteoporosis.” 

Park, the lead author of this study, says, “Standard care focuses on the pharmacological prevention of bone loss using antiresorptive and anabolic drugs. However, these drugs are limited for long-term use due to the increased risk of adverse effects. Discontinuing treatment often leads to rapid and substantial bone loss that is difficult to regain.” 

As Park explains, “Moreover, recent studies have revealed that osteoblasts play a pivotal role in regulating the development of osteoclasts, and osteoclasts have a longer lifespan than previously thought. To address this challenge, we have focused on developing in-vitro assays that can accurately reproduce osteoclast function and processes in a quantitative and analytical manner.”

Lee’s team has created functional and analytical in-vitro osteogenic assay platforms in a standard multi-well plate that can faithfully replicate in-vivo-relevant, bone-remodeling processes. These innovative assays offer several key advantages over existing assay platforms, including the preservation of the intrinsic bony collagen structure and semi-transparency for fluorescent imaging. 

Lee says that this breakthrough is based on the novel use of demineralized bone paper – a thin slice of demineralized compact bone matrix that has demonstrated its biological significance in recapitulating the complexity of bone extracellular matrix and cellular processes, as featured in a previous UMass Amherst news article and Science Advances 2021.

As the team explains, “Using our model, researchers can investigate the effects of osteoporosis drugs on osteoclast differentiation, fusion, fission, and apoptosis, as well as their impact on osteoblasts and bone-remodeling cycles. These humanized bone metabolic assays could also provide critical insights into how osteoporosis drugs affect bone remodeling and help identify potential therapeutic targets to prevent bone loss caused by discontinued drug treatments.” 

The team also anticipates that these new bone metabolic assays will expediate the testing timeline for osteoporosis drugs. Conventional drug testing typically takes 6-to-14 weeks in preclinical animal studies and 12-to-24 months in clinical trials. The new in-vitro technique will take much less time. 

Lee adds that traditional preclinical testing also suffers from suboptimal predictive power that can often lead to failures due to unexpected toxicity and lack of efficacy during clinical phases. In-vitro, humanized bone models, capable of accurately forecasting in-vivo drug responses, could offer a new testing dimension between animal models and clinical studies. 

As Lee concludes, “By offering a more accurate representation of bone extracellular matrix and multicellular processes in a scalable and analytical manner, this platform could contribute to osteoclast-targeting drug development and elucidating the mechanism of bone-metabolic regulation. In-vitro bone metabolic assays could become a standard for studying bone-cell biology and osteogenic assays.” (January 2024)

Article posted in Research