Slapdash thoughts on osteoporosis.

I finally put a pitch deck together for the VR device and did a mock presentation with a friendly VC. As I wait for their no nonsense critique and the path forward to the Mk III development I've been reminiscing about my time as a bench scientist, all those six months ago. I do miss it. It's straight forward. You control every aspect of the experimental design. You run the experiment, interpret the data for a clear yes/no (fml when it's fuzzy) and accept or reject the hypothesis. It isn't video game instant gratification. However, the time invested makes it feel well earned, enriching, or straight crushing when it fails. Simpler times. So let's ramble about the limitations of molecular interventions for osteoporosis!

Disclaimer: I've never researched osteoporosis professionally, which is why I can talk about it. I can't be sued, but also won't be competent on the subject either. Think of this as a thought experiment in cross disciplinary problem solving and please correct in the comments. For anyone that doesn't know, osteoporosis is a disease where aging adults lose bone density and are more prone to fractures. It is more prevalent in women than men and most likely to occur after menopause. I'm not a medical professional and am not giving medical advice.

In the book, "Overdiagnosed: Making People Sick in the Pursuit of Health" the authors (Dr. H. Gilbert Welch, Dr. Lisa Scwartzl, and Dr. Steve Woloshin) describe an interaction with a doctor and a pharma sales rep. I'm going to paraphrase.

Pharma Sales asks, "Doc, you have a lot of osteoporosis patients?"

Doc replies, "Sure do."

Pharma Sales excitedly responds, "That's great! We've got this new drug in the clinic. It's one of a kind. Nothing works like it! The bone density! Wow! Good stuff"

Doc asks, "Does it prevent falling?"

Pharma Sales confusedly, "What? Falling?"

Doc asks, "Does your wonder drug prevent people from falling over?"

Pharma Sales, "Ugh, no."

Doc sighs, "It isn't going to work then."

Pharma Sales, "Oh yea, no, it does. It prevents it. Totally. What else do you need it to do?"

Doc sighs.

The doctor explains that losing bone density is only a problem when someone with low bone density falls over. That's when they become clinically morbid. Morbidity simply means being in a state of disease, but there are two states of any disease. I don't know if these are the proper terms, but there are sub-clinical and clinical morbidity. Meaning you may have the progression of disease (loss of bone density) without feeling the effects and having a lowered quality of life because of a fracture (clinical manifestation). The clinical manifestation occurs when the patient falls. They won't always fracture their bones, but they're at a greater risk of fracture compared to non diseased people of the same age.

The mechanism of osteoporosis disease is bone demineralization, but the clinical manifestation is a greater chance of fracture, not a guaranteed fracture. Someone can have the disease, but not feel it until a tipping point. Pun intended. As a molecular engineer, that exchange was eye opening. I viewed medicine through a simple lens. When I was a child there was a poster in the garage that said, "If it moves and it shouldn't: Duct tape. If doesn't move and it should: WD-40. Measure twice, cut once. Have fun." That was the basic principle of molecular intervention in cellular pathology. "If it's not supposed to be there: block it (secreted with protrusion = antibody, inside cell with pocket = small molecule, inside cell without pocket = protac [shout out to my former boss Taavi]). If it's supposed to be there, replace it (enzyme replacement, substrate supplementation). That's the basics.However simple the concept, it just doesn't work that way in the real world because of the recursive nature of biological signaling. Loopy feedbacks. The bane of pharma research.

The basic players of the mechanism of osteoporosis are osteoclasts (catabolize bone) and osteoblasts (build bone). We can consider these cells as huge, multi functional enzymes or giant enzyme factories for simplicity. The substrates would be calcium and phosphate to be converted into the raw building blocks of bone; hydroxyapatite (HA). HA gets layered on top of collagen. [At this point of the ramble I started looking up more details of bone and was immediately drowning in the complexity]. Staring at a bone with the naked eye is boring, but it is a bustling metropolis at the molecular level and fascinating organ.

Simple approach, if osteoclasts break down bone lets shut 'em down. If we could specifically target osteoclasts over osteoblasts and kill them or stop their function, which we can't, but if we could would that work? Not necessarily if the cause of the diseases is lack of osteoblast actvity. Should we boost osteoblast activity? Well, we can't directly target and cause osteoblast proliferation specifically, but if we could, would that work? Not necessarily if the cause of the disease is lack of substrate (not enough raw building materials). If we could supplement raw materials and boost ostoeblast activity and shut down osteoclast activity wouldn't that work? Yes, because you would be dead and dead people don't have diseases. That hypothetical approach would result in the near full (beyond the 99% to 1% calcium sequestration in bone vs circulation) would convert too much calcium into hydroxyapatite. How would that kill you? Calcium is critical for muscle contraction and the heart is a muscle. Also, breathing requires muscle contractions, and blood vessels work via peristalsis of smooth muscle contractions. I know, it's a straw man.

If we could preferentially supplement with calcium and phosphate and upregulate osteoblast activity that might increase bone density at a terrible cost. What if that depletes chondrocyctes and results in loss of cartilage? What if the excess HA formation creates crystals deposits in the joints? In either case, you have replaced sub clinical osteoporosis with clinically morbid cases of arthritis or pseudo gout. Osteoporosis is bad when it results in a fracture. If the preventative treatment makes it painful to move then the patient will be sedentary, resulting in muscle atrophy, decreased bone density, and decreased coordination skills. This would increase their risk of falling. The whole point of this is to stop them from falling.

What if we go deeper? What if we were to selectively target enzymes! Nope. Cellular signaling is annoyingly redundant. We found this out when trying to target kinases and proteases. It's possible to target parasitic kinases and proteases when they're evolutionarily different (in the active domain) than the host organism. This was the breakthrough for HIV treatment. We found a small molecule that preferentially shut down HIV protease and didn't do that too much to the normal human ones. We also succeeded in developing a one size fits all protease inhibitor. That killed everything. Some viruses produce human enzymes and can't be preferentially targeted without also targeting the normal enzyme. This can still be a viable approach so long as you get the dose right. It's can be a tough balancing act and most medications are medicinal in certain doses and ineffective or toxic at others.

Even if there was a single cell pathway to shutdown it wouldn't be specific to osteoclasts/blasts whatever. It would probably be active and functionally different in other cell types. This is a result of pleoitropic antagonism and I'll get into that more later (spoilers, I don't). Anatomy doesn't always have redundancy, but cell signaling almost always does. Why am I stating almost always? Because I can't say anything with certainty due to the unknown unknowns. In principle, there are cell signaling cascades that don't have redundancy. These are the monogenic, rare disorders that are so severe they're self limiting. They're limiting because they kill the host before they can reproduce. Those rare, severe diseases can be solved with the garage poster approach.

Directly targeting the actors in osteoporosis is logistically impossible at the moment. So we have to look at other influences at the molecular level. Osteoblasts are produced from mesenchymal stem cells. What if you banked some bone marrow at age 5, 10, 15, and 20 years old. What if those banked cells were thawed, revived, proliferated and injected into your adult body to combat the demineralization of osteoporosis? That could potentially work. See, the osteoblasts in your older body resulting in disease may not be able to proliferate anymore because they may have exhausted their stem cell population.

A bit of a tangent, a scandanavian PhD gave a talk. I don't remember his name. It was about cell aging. He looked about 20, but was probably closer to 50. He was charming, possibly a vampire, or he kept the true secrets of his research to himself. What he did, if memory holds, is transplanted old mitochondria into young stem cells, forced the young stem cells with old mitochondria to divide and found they were more likely to divide symmetrically! What that means is one stem cell turned into two differentiated cells and the stem cell was lost forever. It's best for regeneration if the stem cell divides asymmetrically. For instance, a satellite cell (striated muscle stem cell) would divide into a new muscle cell and a perfect copy of the original stem cell. If that happens, that stem cell still exists and can make another muscle cell when needed. Symmetric stem division is a loss of regenerative function. No bueno. I might be getting some papers mixed up, but the crux of each was similar, orthogonal observations that older stem cells are more likely to divide symmetrically. The mitochondria seemed to be a contributing factor to this.

This is why I would prefer banked, self stem cells for reinjection into the trouble spots. However, this doesn't systemically solve the problem. Where do you inject? This is preventative so it would have to be areas that cause the most morbidity when fractured. Hips, skull, I don't know. Let's say this works. You have dozens of bone marrow injections all over your body. It hurts for months, but your bone density is restored to normal levels, maybe even thicker. Congratulations you're bone density is normal. The fix wasn't a molecular intervention. It was a surgical tissue transplant. Does this prevent you from falling?

Let's zoom out to the macroscopic. What causes falling? Poor coordination, environment (ice, water, loose gravel), unexpected pain (stepped on a nail), bad luck, weak muscle tone, etc. What could cause those? Depression, previous injury, chronic pain from constant inflammation that is unrelated to osteoporosis, etc. The NIH website suggests not to drink alcohol if you have osteoporosis because it will exacerbate the disease. Alcoholics self medicate for depression and the suggestion is, "you shouldn't do that". Meh.

What approaches exist that would bolster physical strength, mental health, and coordination that would prevent falling and also increase bone density. I'm sorry you've read this far for the obvious answer. Be active. Do sports. Have fun. This is suggested for people with osteoporosis. Psychologically, if I wasn't active before and a doctor is telling me I have to be so I don't get a hip fracture, but I feel normal, why would I drastically change my life? That requires effort and I don't have a broken bone yet. What if I'm not active because I don't have anyone to play with? That's not the doctors' problem, but that could be the root cause of the disease and road block to addressing it.

What interventions would enable someone to be more active? Anti-depressants, stimulants, strong social support, sense of purpose. This disease effects post menopausal women. Menopause is characterized by loss of estrogen production. Estrogen seems to have a protective effect on bone density. Estrogen replacement therapy has been prescribed in the past to ease the transition of menopause. Unfortunately, statistical analysis of that treatment plan showed a higher cancer risk and it's not done that often anymore. I don't know what dose it was prescribed, but it may be less risky and slightly beneficial to either decrease the dose or create an estrogen analogue with worse target binding than estrogen for a slight boost in signaling. I'm not sure it has a direct effect or was associated with an indirect protective effect.

In the book, "The Female Brain" written by Dr. Louann Brizendine, a pioneer of studying the different physiology of men and women to psychiatric interventions, she mentions prescribing testosterone for psychological and physical relief from menopause symptoms. An unexpected side effect was if a dose of testosterone was too high it could result in a near uncontrollable sex drive. However, testosterone was effective in alleviating malaise, lack of energy, lack of focus, lack of sex drive for post menopausal women. Testosterone could also increase bone density and gets converted into estrogen (so long as those enzymes are still active post menopause, I don't know). From what I understand, there are many long lasting formulations of testosterone to increase the half life and I don't think it can be ingested orally like estrogen.

Could osteoporosis patients benefit from a daily low dose of quick clearing testosterone? That approach could increase bone density, energy, mood, and physical activity. Those combined effects would help prevent falling.

End of blather.

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