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Dr. John Jurist, Tuesday, 3-27-12 March 27, 2012

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Dr. John Jurist, Tuesday, 3-27-12

http://archived.thespaceshow.com/shows/1744-BWB-2012-03-27.mp3

Part 1, Bisphosphonate Usage in Microgravity

Guest:  Dr. John Jurist.  Topics:  This is the first in a series of programs focused on the use of bisphosphonates to mitigate bone loss in long duration spaceflight.  You are invited to comment, ask questions, & discuss the Space Show program/guest(s) on the Space Show blog, https://thespaceshow.wordpress.com. Comments, questions, & any discussion must be relevant & applicable to Space Show programming. Transcripts of Space Show programs are not permitted without prior written consent from The Space Show (even if for personal use) & are a violation of the Space Show copyright.  We welcomed back Dr. John Jurist for the first of several programs devoted to understanding bone loss in microgravity & the use of prescription the bisphosphonate family of drugs to mitigate the problem.  Dr. Jurist provided talking points which you can find below this summary on The Space Show blog.  A significant portion of the second segment is devoted to understanding these talking points so follow along.  We started our discussion with an explanation of the bone loss problem facing those in microgravity.  Following this brief overview, Dr. Jurist told us about bisphosphonates, the origins of this drug, how it was developed, how its usage, what some of the side effects are, some of the trials that have been associated with the drug, & space/NASA studies.  Later in this nearly hour long segment, we talked about the human population & what happens to our bone mass at various stages in our life. We talked about gender, racial, & ethnic differences in human bone mass issues.  As you will hear, there are gender & other differences among our diverse population.  This led us to asking about using targeted genetics in selecting crews for longer spaceflight missions.  Genetic modification was mentioned, especially for the long term, but for the near term, looking for better exercise routines & pharmaceutical modification/treatment seem to hold the most promise.  Dr. Jurist then talked about bisphosphonate side effects.  Fast transit time to Mars or a long duration mission destination came up. As you will hear, even if you get to Mars faster, you still have the problem on the surface of Mars.  The big problem is we have no credible information on what the gravity prescription for humans needs to be so we do not know if Martian gravity is sufficient to mitigate the problem.  Next, we focused on the need for an orbiting centrifuge, we talked about the size & spin rate of the centrifuge, & what to actually test for in experiments.  Dr. Jurist suggested that starting with 1/6th lunar gravity made sense because if it was sufficient, we would know that anything stronger than 1/6th would work.  If not, we should probably next experiment with Martian gravity which is about 1/3rd Earth gravity.

In our second segment, Dr. Jurist referred to his talking points which you will find on The Space Show blog. We went line by line so follow along with us.  Despite interruptions, John stayed on topic with the talking points.  Listener questions asked about how gravity & having a load on bones works & what happens in space when that load is no longer present.  We talked about the time prescription as well as the load factor (G force).  Toward the end, John told us about a reviewed radiation article from 2010 showing that radiation impacted bone loss so the issue in space is more complex than just microgravity.  Near the end, John got a question asking about ETs & their thin, pencil like shape making them perfectly designed for microgravity.  This was both an interesting & fun discussion, bordering on science fiction.  Another question asked about fish, reptilian, sea mammal, & bird bones.  Our final topic dealt with the release of personal astronaut medical information & others & the ways for private information to be legally released to the public.

Please post your comments/questions on The Space Show blog URL above.  Email for Dr. Jurist can be sent to me for forwarding.

________________________________________________________

Dr. John Jurist Bisphosphonate Talking Points:

Bisphosphonate show Tues 8:00-9:30 MDT Talking Points

Introduction:             Bone is incredibly complex with many inter-related factorsGoal:                          Brief outline of cellular, structural, and functional aspects of bone metabolism in order to help listeners better understand and appreciate the potential role of bisphosphonates (which is the subject of a future show)

Bone Function:          Two types of bone – compact and trabecular: Compact is outer shell, very dense, and fairly strong

Trabecular – also called spongy, contains spicules, plates, and struts of bone tissue with lots of vascular and fatty marrow, called trabecular

Remodeling:             Bone is constantly being turned over or remodeled with portions being torn down and constituents dumped into bloodstream and other portions being built up from nutrients supplied by blood

Very rapid bone loss can lead to kidney stone formation from calcium dumped into blood

Turnover rate and the volume of total skeleton undergoing remodeling at any given time tends to go down with increasing age (remember this – important)

Balance between formation and resorption (tearing down) also tends to be lost after about age 30, lack of activity, certain hormonal imbalances, diseases, etc. with resorption predominating – one rationale for estrogen replacement therapy after menopause

Coordination between formation and resorption partly controlled by mechanical strains on bone tissue (called Wolff’s Law and issue in microgravity) – some evidence that mechanism is electrical in nature – rationale for electric and electromagnetic bone growth stimulators used to treat problematic fractures and improve incorporation of bone grafts

Cells:                          Stem cells differentiate (or specialize) into osteoprogenitor cells which differentiate into osteoblasts which are the bone formers

Osteoblasts create and secrete a protein and polysaccharide matrix called osteoid which is then calcified later to form the stuff we call bone

Interference in that calcification leads to rickets in children and osteomalacia (Greek for soft bones) in adults

Osteomalacia is often a result of interference in Vitamin D metabolism or dietary deficiencies

During bone formation, some osteoblasts “paint” themselves into a corner and get surrounded by bone – they are then called osteocytes and somehow maintain bone tissue

If osteocytes die in a volume of bone, that devitalized bone no longer undergoes remodeling but can eventually be replaced by a process called creeping substitution (remember comment about remodeling volume going down with age)

Devitalized bone can accumulate fatigue defects and eventually suffer fatigue fractures (called stress fractures – common in military recruits and deconditioned people who recondition too rapidly) if the defects are not replaced by new bone during creeping substitution

Other cells, with multiple nuclei and called osteoclasts, differentiate from marrow cells (monocytes and macrophages) which in turn differentiate from stem cells

Osteoclasts are the bone resorbers and destroyers

Autoradiographic studies show that their nuclei also came from osteocytes as well – presumably as they are resorbed during bone destruction process

Osteoclasts are related to multinucleated “giant cells” which are associated with inflammation in ways I do not understand

Bisphosphonates:      Used over past 20-30 years in clinical medicine – brands include Actonel, Boniva, Fosamax, Aredia, etc.

Multiple mechanisms with different dose-response properties results in clinicians juggling doses and brands to get effects they want without effects they do not want

Bind to hydroxyapatite – the mineralized  portion of bone tissue (calcified osteoid)

Inhibit bone resorption by inhibiting osteoclastic activity

Inhibition of resorption signals osteoblasts to slow down formation rates after a delay (but increases their lifetimes (anti-apotosis)

Bisphosphonates also inhibit mineralization of osteoid – especially at higher doses

That eventually reduces turnover rate and can lead to fatigue fractures with prolonged treatment (remember to call 1-800-BAD-DRUG)

Orthopedic surgeon (Frost atHenryFordHospital) figured out that cyclic therapy exploits delay in osteoblast inhibition relative to osteoclast activity and results in better bone mass gains

Bisphosphonates used in oncology to preserve bone and reduce pathological fractures with osteolytic tumors such as breast and prostate cancers.  Also to counter hormonal blocking therapy used for prostate and breast cancers, but side effects increase with duration of treatment

Interesting sidelight with oncology is some evidence that bisphosphonates reduce risk of tumor metastasis to bone and other sites (somehow involving same signaling pathway as giant cells?)

Oral bisphosphonates cause stomach upset – advise staying upright for an hour or two after taking pill – how does this affect microgravity exposure?

Intravenous bisphosphonates get around oral gastric upset, but placing line or port has risks too (most oncology patients have ports during active treatment)

Also cause osteonecrosis – especially jaw which I believe is septic or infective – and atrial fibrillation (talk to Bill Rowe on this one since he is interested in heart physiology in space)

Bone quality:             Turnover rates and percent of skeleton not devitalized important factors in determining bone strength – measuring bone mass by DEXA or other means is not the be all and end all in evaluating bone strength and risk of fracture.

My Goal:                   General background on bone physiology and function to aid in appreciating upcoming show(s) on bisphosphonates in space medicine

Comments»

1. Joe - March 28, 2012

Based on Dr Jurist’s answers to my on-air questions, I believe there are a rare few astronauts that indeed had no bone loss even though they keep this fact hidden from the public for some privacy protective (dumb) reason.

These fortunate individuals may have had an exercise regiment and bisphonsphonate-free diet that may or may not have contributed to the desired effect. The only way to tell if it was just in their genes or their exercise regiment is to send them up for another 6 month jaunt and significantly decrease their previous exercise regiment. If they lost bone, then one could easily conclude that their previous exercise regiment was the effective countermeasure to bone loss. If they did not lose bone, then one can easily conclude that it was their genes that prevented their bone loss.

I know it can’t be as simple as that, but bare with me.

Nothing works better than a good experiment.

Either way, we will not likely do this because astronauts do not want to be guinea pigs in a space experiment.

If they do wake up someday and do this type of experiment and it turned out to be related to good genes, it would naturally lead to gene comparisons of those who had no bone loss to isolate the bone stabilization gene that would be used to screen out future long duration astronauts that do not exhibit the bone stabilization gene. NASA screens astronauts in all types of categories, so, one more screening criteria is not going to stop all candidates from going to space. It will have the opposite effect.

In other words, if you wanted to be an astronaut and you possessed the bone stablization gene, you would have a good chance of becoming an astronaut if you were in relatively good shape, liked camping, and were not scared of heights or closed in spaces. Never mind if you can fly an airplane or hold your breath for 6 minutes.

If it turned out to be an exercise and bisphonsphonate-free diet regiment, they would prescribe that regiment for future astronauts living long term in space.

Either way, just trying that experiment would advance the cause for human exploration of space. Not doing such an experiment puts all of your eggs in one basket which is by far always riskier to the speedy advancement of space medical research.

Are we going to explore space by buying just one lottery ticket at a time? I think Christopher Columbus would have answered “No, we need the Nina, the Pinta, and the Santa Margarita”!

2. Joe - March 27, 2012

I found this interesting paper published on the web. It is entitled “Preliminary Results of Bisphonsphonate ISS Flight Experiment”.

http://www.dsls.usra.edu/meetings/IAA/pdf/2055.pdf

Do the final results of bisphonsphonate ISS flight experiment differ much from the preliminary one or is this it?

Interested people want to know. We are anxiously waiting for your response.

3. Joe - March 27, 2012

I am ready to hear what difference appeared in astronauts taking bisphonsphonates in space compared to people taking bisphonsphonates on the ground. Based on your interview, the bisphonsphonates taken in space delayed the destruction cycle.

Did they delay the destruction cycle longer or shorter than what has been observed in people taking the same drug on the ground?

4. Joe - March 27, 2012

What is the main barrier to establishing the use of intermittent artificial gravity exposure as a potential countermeasure to bone loss?

J M Jurist - March 28, 2012

Re: the abstract and 3 questions — I believe that Dr Lang is scheduled for upcoming The Space Show panel on bisphosphonates. That discussion would provide more details. Basically, there is nothing in the abstract that is a surprise. Bisphosphonates inhibit osteoclastic activity, so reduction in bone loss (or even a gain provided the inhibition is sufficient) is not a surprise. Note the variability in response cited in the abstract. The interesting aspect will be whether the effect is prolonged in microgravity or whether it is shortened compared to the 1G environment. Re: intermittent centrifugation, duration and level are both factors as is the centrifuge configuration. Main barrier in my opinion is getting the experiments done given the current funding, management, and prioritization situations related to human spaceflight.

Joe - March 28, 2012

Thanks Dr Jurist. I believe your answer to the main barrier question is correct. It is the lack of funding or rather, the difficult act of triggering the buy-in in those who could fund it.

Go figure.

If we can find a way to effectively establish the buy-in in those who fund such things, we can ignore the other less significant barriers to such research and let them play out after the funding is established.

I highly recommend reading this book about how successful people save their good idea from getting shot down. It is called “Buy-In: Saving Your Good Idea from Getting Shot Down”. It consistently works for me!

http://www.amazon.com/Buy-In-Saving-Your-Good-Getting/dp/1422157296

What if we miraculously find out someday that intermittent artificial gravity works better than bisphonsphonates in terms of efficacy and side-effects?

Which bone loss countermeasure method do you suppose we would choose that would be better, cheaper, and safer?

1) Using the recommended bisphonsphonate intake in a tethered spinning spacecraft with a complicated and unproven control system.

2) Using a non-spinning and non-tethered spacecraft with an enclosed intermittent artificial gravity system and a proven and reliable spacecraft control system.


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