Previous studies involving astronauts returning from Russian Space Station Mir showed that extended spaceflight caused a severe loss of bone density and that the time needed to return to preflight bone mass levels was considerably longer than the time spent in space. Dr. Ted A. Bateman is examining countermeasures to prevent loss of bone mass and to quickly replace bone postflight to prevent fractures, kidney stones and susceptibility to osteoporosis. Through an animal study, Bateman is researching whether low doses of osteoprotegerin and zoledronate prevent the inflight loss of mass and allow bone to recover more quickly. The study also will evaluate exercise, ultrasound and parathyroid hormone (PTH) as methods to return bone to pre-flight levels.
Overview
Examination of Anti-Resorptive and Anabolic Treatments/Stimuli on Unloading-Induced Osteoporosis
Principal Investigator:
Ted A. Bateman, Ph.D.
Organization:
Clemson University
Technical Summary
- Both bone resorption and formation are altered to adversely affect bone density; and
- The time required to return bone mass to pre-flight levels may be considerably longer than the period of microgravity exposure.
We developed a treatment regimen that would prevent in-flight bone loss and accelerate the recovery of bone health after flights. Both bone mass and turnover rates are important for evaluating successful recovery. The significance of these factors is illustrated by our demonstrating that low doses of anti-resorptive agents can prevent in-flight loss of bone mass and allow normal bone formation rates. Through a series of iterative studies in mice which were administered either osteoprotegerin (OPG) or zoledronate, doses of 500 μg/kg and 45 μg/kg, respectively, were determined to be the minimum, efficacious comparable doses in that they increased bone mass, while not causing the inhibition of bone formation that generally accompanies anti-resorptive therapies.
These doses of OPG and zoledronate were then tested for their ability to prevent disuse osteoporosis with the hindlimb suspension model in mice. Both anti-resorptive therapies at these lower doses maintained bone mass, strength and structural properties at the level of fully loaded, placebo-treated control mice. This study demonstrates the potential benefits of minimum dosing. A manuscript reporting both aims of this proof of concept approach to developing and testing minimum, efficacious therapies is in revision.
The final year of the grant examined the sequential administration of bisphosphonates and anabolic Parathyroid Hormone (PTH) therapy. A mouse model was used to determine if anabolic treatment after anti-resorptive therapy and hindlimb suspension can reverse the inhibition of bone formation that both unloading and anti-resorptive therapy cause. The primary metric for this examination is an analysis of serum for markers of bone formation and resorption indicating increased bone turnover after treatment with zoledronate, with additional study quantitative histomorphometry for cortical bone formation rates. The duration of suppressed bone turnover was marginally reversed with PTH administration. However, the dose was higher than what has been reported in the literature, possibly because cortical bone has slower turnover rates than trabecular bone. A dose of 50ug/kg/day did increase systemic markers for bone turnover and bone formation rates, accelerating the recovery of these markers after zoledronate treatment by several days.
We have also modified this aim to include a clinical examination of sequential anti-resorptive and anabolic therapies in women receiving treatment for osteoporosis. Preliminary data collected in 105 patients suggest that prior bisphosphonate treatment inhibits the anabolic action of PTH. Our retrospective chart review was expanded to include up to 600 patients, allowing a more definitive determination of the efficacy of sequential therapy and potentially discriminate differences between bisphosphonates.
We also added a study in the final year of this project examining the protein macrophage-colony stimulating factor (M-CSF) for its potential as a novel anabolic therapy for bone. Our studying M-CSF has been an ongoing, but low-priority component of our labs work. Our recent emphasis on radiation-induced bone loss was motivation to perform a simple, but comprehensive, study with M-CSF. The contribution of radiation exposure to increased lifetime cancer risk is of concern in astronauts on long-duration missions as they will be exposed to moderate cumulative doses of proton and heavy ion radiation from solar and cosmic sources. In this context, the administration of PTH, or any anabolic agent to improve bone structure and strength, may not be appropriate as it may synergistically act to further increase cancer risk. Though the contribution of PTH therapy to cancer risk has not been identified in humans and the data are limited in animals, the use of any anabolic agent should be considered carefully.
For this study, a group of mice was administered a relatively high dose of 5 mg/kg/day of huM-CSF for 21 days. In addition to a rapid increase in body mass, M-CSF increased serum bone turnover markers for both bone resorption and bone formation. Microcomputed tomography revealed an anabolic effect on tibial trabecular bone, with higher bone volume fraction (+35 percent), connectivity density (+79 percent), and number (+18 percent), as well as lower trabecular separation (-18 percent). M-CSF had no significant effect on cortical bone mineral content, geometry or strength. There was no change in quantitative histomorphometry parameters of femoral cortical bone. Similar to our observations from radiation-induced bone loss, the anabolic effects of M-CSF appear to be specific to trabecular bone.
In summary, during the four year duration of this study, we demonstrated a proof of concept comparison of two anti-resorptive bone agents for minimum, but efficacious, doses to prevent bone loss from disuse while minimizing the long-term suppression of bone turnover. We also performed a comprehensive examination of human patients receiving PTH after treatment with a bisphosphonate and are finalizing a study of an expanded group of subjects. A similar regimen development in mice was initiated and is still ongoing with the doses of PTH higher than anticipated. Finally, the circulating protein M-CSF was preliminarily identified as a potential therapy to increase bone turnover.
Earth Applications
Research in spaceflight-induced bone loss has implications for the causes of osteoporosis on Earth and for the development of effective therapies to prevent and reverse bone loss. Indeed, studies on the International Space Station reveal that bone loss occurs at a rate much faster than of post-menopausal woman. With over 1.5 million fractures occurring per year due to the proliferation of an aging population and the expansion of space exploration to unprecedented new lengths, the need for the development of a variety of advanced, effective therapies has never been greater.
Both astronauts as a population and spaceflight as a cause are significantly different than the population and pathology current osteoporosis therapies were designed to treat. It should not be presumed that doses and therapies intended for older women are appropriate and efficacious for astronauts on exploratoration missions. Optimizing treatment regimens for populations, like astronauts, may eventually be expanded to modifying regimens to individuals, depending on specific physiological deficits and response.