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For extended space missions, bone loss brought on by microgravity has long been a significant worry. Microgravity’s reduced mechanical loading causes bone loss 12 times faster than on Earth. The risk of fractures during long-duration spaceflight and later in life may increase for astronauts in low Earth orbit due to bone loss that can occur at a rate of up to 1% each month.
For crew members spending up to six months in microgravity, the current mitigation technique for bone loss relies on exercise-induced mechanical loading to encourage bone growth, but it is far from ideal. Exercise can harm some ailments and does not always stop bone loss. It also consumes essential crew time.
The new study led by Chia Soo, MD, vice chair for research in the Division of Plastic and Reconstructive Surgery, professor in the Departments of Surgery and Orthopaedic Surgery at UCLA David Geffen School of Medicine, found an engineered compound given to mice aboard the International Space Station (ISS) largely prevented the bone loss associated with time spent in space. The study highlights a promising therapy to mitigate extreme bone loss from long-duration space travel and musculoskeletal degeneration on Earth.
Scientists began by investigating whether systemic NELL-like molecule-1 (NELL-1) delivery can reduce microgravity-induced bone loss. NELL-1 is crucial for bone development and bone density maintenance.
The team must reduce the quantity of injections to deliver NELL-1 systemically to the ISS. By increasing NELL-1’s half-life from 5.5 to 15.5 hours without losing bioactivity, Ben Wu, DDS, PhD, and Yulong Zhang, PhD, at the Forsyth Institute increased the drug’s therapeutic potential. They also bioconjugated an inert bisphosphonate (BP) to produce a “smart” BP-NELL-PEG molecule that more precisely targets bone tissues without the usual negative effects of BP.
They then assessed the modified molecule to determine the efficacy and safety of BP-NELL-PEG on Earth. They found that BP-NELL-PEG displayed superior specificity for bone tissue without causing observable adverse effects.
The researchers worked closely with the Center for the Advancement of Science in Space (CASIS) and National Aeronautics and Space Administration (NASA) Ames to make extensive preparations for the SpaceX CRS-11 mission to the International Space Station (ISS), where astronauts Peggy Whitson, Ph.D., and Jack D. Fisher, MS, carried out the studies. The remaining mice were flown back to Earth 4.5 weeks after launch for the first live animal return (“LAR Flight”) of mice in US history. In contrast, half of the ISS mice were subjected to microgravity (“TERM Flight”) for a protracted 9-week period to simulate the difficulties of long-duration space travel.
TERM and LAR Flight groups were treated with either BP-NELL-PEG or phosphate-buffered saline (PBS) control. An equivalent cohort of mice remained at the Kennedy Space Center and were treated similarly with BP-NELL-PEG or PBS to serve as normal Earth gravity (“Ground”) controls.
When given BP-NELL-PEG, mice on the ground and in flight showed much more bone growth. In orbit and on Earth, the treated mice showed no apparent adverse health impacts.
Lead corresponding author Chia Soo said, “Our findings hold tremendous promise for the future of space exploration, particularly for missions involving extended stays in microgravity.“
Co-co-principal investigator Kang Ting said, “If human studies bear this out, BP-NELL-PEG could be a promising tool to combat bone loss and musculoskeletal deterioration, especially when conventional resistance training is not feasible due to injuries or other incapacitating factors.”
Co-co-principal investigator Ben Wu said, “This bioengineering strategy can also have important benefits on Earth, offering a potential therapy for patients suffering from extreme osteoporosis and other bone-related conditions.”
Journal Reference:
Ha, P., Kwak, J.H., Zhang, Y. et al. Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice. npj Microgravity 9, 75 (2023). DOI: 10.1038/s41526-023-00319-7
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