Osteoporosis AND Bone Marrow Disorders

I've been putting this off, yet I think the only straight answers I'll get are from Dr McCormick. He has a compassion to pass on his well reasearched understanding of this field. The fact he's a DC and not MD has no bearing since he is lightyears ahead of the medical profession. I hope moffit & McCormick can agree on some path to treat.

My oncologist keeps reminding me to keep my immunity up. However, I have low gamma globulin, low IgG, and low kappa and lambda light chains. I don't think I can afford any further decrease in immunity from Evenity.

windyshores | @windyshores | 33 minutes ago
@hopefullibrarian
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362945/
" More importantly, the robust anabolic effect of treatment is limited to the first few months of therapy, curtailing the progressive, large increases in bone mass. Perhaps a strategy can be identified whereby patients can experience the anabolic effects of romosozumab on multiple occasions with a limited interval or the use of alternate drugs between courses."

Other studies I emailed to myself! There are probably more on my email....
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567484/
https://pubmed.ncbi.nlm.nih.gov/32777516/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085670/
others w/out links

In summary, our studies extend previous studies and reveal novel information on the effects of sclerostin deficiency in bone and sclerostin-depleting treatments on hematopoietic stem cells. Our data indicate that SOST depletion and Sost deficiency not only affects B cell development in the BM relatively early, but also creates an inflammatory bone marrow microenvironment that may become more severe over time. Investigation of the changes in the bone marrow architecture, including alterations in vasculature function and quality, proportions of arterioles and sinusoidal vessels, and local oxygen tension [67,101,102,103], may provide evidence for the specific cell-extrinsic mechanisms that drive the promotion of myelopoiesis in the Sost−/− mice and Scl-Ab-treated mice. In future studies, it would be interesting to investigate the localization of HSC in the Sost−/− bone marrow endosteal and sinusoidal niches, and quantify if specialized niches that promote myeloid differentiation or recruitment are increased [104]. Studies to test possible combinational therapy of Scl-Ab with IL-1 antagonists or TNFα blockade to control myeloid skewing are another potential area of further investigation. The information provided by our studies may be useful in monitoring humans treated with romosozumab for changes in immune cell frequencies, chronic inflammation, and signs of anemia, such that treatments for osteoporosis can be modified to address these hematopoietic changes.

and

Recent findings: Changes in sclerostin levels affect distinct niches within the bone marrow that support hematopoietic stem cells and B cell development. Sclerostin's regulation of adipogenesis could also be important for immune cell maintenance with age. Surprisingly, B cell development in the bone marrow is influenced by Sost produced by mesenchymal stem cells and osteoblasts, but not by osteocytes. Additionally, extramedullary hematopoiesis in the spleen and increased pro-inflammatory cytokine levels in the bone marrow are observed in global Sost-/- mice. In addition to changes in bone marrow density, sclerostin depletion affects B lymphopoiesis and myelopoiesis, as well as other changes within the bone marrow cavity that could affect hematopoiesis. It is therefore important to monitor for hematopoietic changes in patients receiving sclerostin-depleting therapies.

Finally

"The study will investigate if it is possible to maximize the effect of romosozumab by giving it in 2 periods of 6 months interrupted by zoledronate for 12 months compared to romosozumab for 12 months uninterrupted followed by zoledronate for 12 months. The investigators will also evaluate if 6 months of romosozumab followed by 18 months of zoledronate is non-inferior to the standard regimen of romosozumab for 12 months followed by zoledronate for 12 months."
Links (both are about the same study):
https://ctv.veeva.com/study/the-optimised-use-of-romozosumab-study
https://classic.clinicaltrials.gov/ct2/show/NCT06059222

rola,
there is very little research on CLL and osteoporosis. Both are thought to be conditions of ageing and not interactive or causative either way.
'A recently published study places suspicion on the bisphosphonates as unsafe in low dose and unsafe in higher dose with Cll as it advances the disease. It is a carefully arranged Italian study using human cll cells in petri dishes.
Of the remaining drugs Prolia, Evenity, Tymlos and Forteo, Prolia and Evenity has enough risk factors for everyone, though nothing siginificant is evidenced for CLL.
Of the final two medication Tymlos and Forteo I've found no studies regarding CLL. The nice aspect of both of these drugs is that they leave the body within 24 hours. So if you noticed anything untoward you can simply stop the drug. I'd choose Forteo because of its lower dosage.
You want to be careful that there are no interactions with other medications you are taking.
You may encounter medical providers who are not aware that there is not longer a warning on Forteo for bone cancer. This supposition has been determined incorrect.
You might copy this report for physicians who may not have seen it. The direct relationship between bisphosphonates and CLL is compelling. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10821833/#:~:text=Chronic%20lymphocytic%20leukemia%20(CLL)%20is,treatment%20with%20bisphosphonates%20(BPs). " Unexpected Chronic Lymphocytic Leukemia B cell Activation by Bisphosphonates. . ."
You shouldn't have to struggle for this information on your own. I hope your appointment at Moffit will advantage you.

I am not talking about being causative but are treatments contraindicated because of a bone marrow issue. I really like being in stage 0 and do not want anything that might kick me to stage 1 or higher. Or make me more prone to infections.

Forteo is lower dosage but Tymlos has adjustable doses on the pen with "clicks." Half life of Tymlos and Forteo is 1 hour. Peak action is .25-.52 hours. Forteo peaks in 30 minutes and is gone in 3 hours, pretty much the same as Tymlos. Problem is, these meds need follow up with a bisphosphonate.

Some literature says follow-up with hrt may work, if tolerable.

@gently Thank you so much for taking the time and trying to help me sort this out. I so respect your understanding and opinion of these complicated issues. The mention of leaving my system in 24hrs makes me more at ease and hopefully with careful monitoring the Dr at Moffit will give me some hope in managing this too. I will definately bring this information with me.

Thank you so very much Gently💓, I appreciate you all so much!

@windyshores Yes, exactly, the follow up of a bisphosphonate or if possible @sallyj2 "hrt" you're all so very helpful! I have a lot to go on now at Moffit when I speak to the Dr.

I'm still trying to absorb this article and it's mention of
infliximab?
It's just so complicated... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485691/

Open Evidence:

"The medical literature does not provide direct evidence on the use of infliximab, a TNF-alpha inhibitor, for chronic lymphocytic leukemia (CLL) patients on bisphosphonates. However, there is evidence that proinflammatory cytokines, including TNF-alpha, may be involved in the pathogenesis of osteopenia or osteoporosis in inflammatory diseases, and that infliximab has been studied for its skeletal impact in patients with Crohn's disease.[1] In this context, infliximab, when used concurrently with bisphosphonates, was associated with a greater increase in spinal bone mineral density compared to bisphosphonates alone, suggesting a potential benefit in bone health.[1]
In CLL, bisphosphonates have been shown to have hormetic effects on leukemic cells in vitro, with higher doses inducing cytotoxicity and lower doses potentially augmenting CLL B cell activation/proliferation.[2] This indicates that while bisphosphonates are used to manage osteoporosis in CLL patients, their impact on CLL itself may be complex and requires further investigation.
There is no evidence in the medical literature provided that directly addresses the use of infliximab in CLL patients on bisphosphonates for the management of CLL or its skeletal complications. Therefore, any potential use of infliximab in this patient population would be off-label and not based on established clinical guidelines for CLL management. When considering the use of infliximab, it is also important to be aware of the potential increased risk of lymphoma with TNF blocker therapy, as noted in the labeling information for infliximab.[3-4]
In summary, while infliximab may have a role in improving bone mineral density in inflammatory conditions when used with bisphosphonates, its effects on CLL patients on bisphosphonates are not established, and its use would not be based on current evidence or guidelines for CLL management.[1] Any decision to use infliximab in this context should be made with caution and based on a thorough evaluation of the potential risks and benefits."

hi njhornung,
" Higher doses [of bisphosphonate] induced cytotoxicity. . ."
. . . [L]ower concentrations, generated a protective effect from spontaneous and chemotherapy-induced apoptosis, and augmented CLL B cell activation/proliferation. This CLL-activation effect promoted by the BPs was associated with markers of poor CLL prognosis and required the presence of bystander stromal cells.
While the authors aren't positing contraindication, the findings in vitro would be contraindicative of bisphosphonate use for any stage of CLL.