Can anyone please provide what the current status is for shifting multiple myeloma bone anabolism with the parathyroid hormone to catabolism vs. bisphosphonates, as well as supplementing with Vit D when there is deficiency?
What is the current therapeutic status of PTH hormone vs bisphosphonates?
I ran across this Beacon article from 2009 and was wondering if there were any updates:
https://myelomabeacon.org/news/2009/07/25/vitamin-d-may-cause-skeletal-complications/
It seems they are using parathyroid hormone with success in breast cancer bone metastases but not in multiple myeloma.
It would be particularly interesting to learn about the parathyroid hormone vs bisphosphonates given that we are now finding that the proteasome inhibitors increase bone anabolism and there has been synergism shown with protesasome inhibitors and parathyroid injections.
http://www.ncbi.nlm.nih.gov/pubmed/16173965
http://ash.confex.com/ash/2008/webprogram/Paper8718.html
http://www.haematologica.org/content/96/2/333.full
I am just wondering what the doctors are finding in their clinical practices, along with what is being recommended by IMF etc, or has been seen at ASCO/ASH since 2009.
What would be the recommend dosing for Vit D deficiency?
The primary question I am pondering is whether parathyroid hormone therapy is a good alternative to biphosphonates particularly when we look at upregulating osteoblast activity and inhibiting RANKL along with not incurring ONJ vs. only suppressing osteoclasts (bisphosphonates)
Thanks to anyone willing to weigh in on this one...
Forums
3 posts
• Page 1 of 1
Re: Parathyroid Hormone vs. Vit D vs. Bisphosphonates
Suzie Rose brings up a several important points in the context of myeloma bone disease- something that we struggle with as a terrible complication of bone marrow resident myeloma cells. I think it is important to frame some of the issues that are brought up in this post.
First, what causes the lytic bone disease associated with myeloma?
In general terms, normal bone strength is the result of a balance between two major populations of cells within the bone: Osteoblasts (bone builders or anabolic effectors) and Osteoclasts (bone destroyers or catabolic effectors). In myeloma, factors made by the myeloma cells turn off the bone builders and promote the activity of bone destroyers (osteoclasts). So, the balance favors bone destruction and lytic bone disease.
Second, how do we manage bone disease in myeloma?
Currently, standard of care in myeloma is to treat patients with monthly bisphosphonates for two years (except while receiving transplant) and then to discuss further frequency of dosing thereafter. The two drugs that are utilized in the US are Zometa (zolendronic acid) and Aredia (pamidronate). Zometa is preferred, but there are times in which Aredia may be safer or better tolerated. These drugs act by targeting and decreasing osteoclast activity (decreasing bone destruction / decreasing bone catabolism). These drugs are very effective and are able to decrease skeletal related events in myeloma (and other cancers with bone involvement). Further, in the case of Zometa, a statistically significant overall survival advantage has been observed in patients receiving Zometa relative to another bisphosphonate Bonefos (clodronate) (not sold in the U.S.) in a randomized phase III study. These issues make bisphosphonates important components of meyloma therapy.
Third, more recently Xgeva (denosumab) has become a treatment option. It is a neutralizing antibody recognizing RANKL, a factor within the bone marrow that activates osteoclasts (bone destroyers. So, Xgeva inhibits catabolic events (bone destruction). Xgeva has been compared in clinical trials to Zometa and demonstrated non-inferiority when comparing rate of skeletal events, overall survival, and osteonecrosis of the jaw in a study of myeloma and metastatic solid tumor patients. Hypocalcemia was noted at a higher degree in the Xgeva arm.
-> Nearly there, but not standard of care
Fourth, how do we address osteonecrosis of the jaw (ONJ)? ONJ is a non-healing bone lesion that occurs while patients are on bisphosphonates and undergo a bone affecting surgery- e.g. dental extraction. This is an issues that has been minimized due to patient education and prudent discontinuation and initiation of bisphosphonates (and Xgeva). But it remains an important issue that requires a dental consultation and discussion of potential dental/orthodontic issues prior to initiation of treatment.
Fifth, what about the anabolic bone metabolism (bone building)? We have thus far only spoken about catabolic (bone destroying) effectors of bone metabolism. Can we also increase the number of bone building cells?
Currently, an antibody to DKK1 is in clinical trials, code-named BHQ880. DKK1 is a factor produced by osteoclasts and myeloma cells that decrease the number of bone building cells (anabolic cells). More recently, another factor that inhibits bone anabolism has been identified, sclerostin (a recent Beacon news article discussed a study re: sclerostin). Antibodies to this protein are also in development but are behind that of DKK1 (only tested in non-human primates to date; by Amgen). Activin Receptor Type IIA, and GSK3beta, may also be important targets.
However, none of these factors have been shown to have the same clinical benefit as the more well studied bisphosphonates or even Xgeva, and therefore are not used outside of clinical trials. So more work is necessary before we can truly comment about the pros and cons of anabolic and catabolic bone metabolism inhibitors.
Sixth, what about Velcade (bortezomib)? Regarding the observation of decrease skeletal events in Velcade-treated individuals, this may result from Velcade inhibiting the production of factors like DKK1 or sclerostin that inhibit osteoblast differentiation and activity. Another or additional possibility is that Velcade may affect parathyroid hormone production, as one of the articles provided by suzie rose suggests, thereby favoring bone building. But, in regard to Velcade, continuing and future studies are necessary.
Lastly, as with most of the treatments for myeloma bone disease, options come from studies of osteoporosis. Parathyroid hormone has been examined and used in that setting. However, I am not aware of positive studies in myeloma to date. Vitamin D in patients with vitamin D deficiency is warranted, but remains unnecessary otherwise (at least as I practice).
I hope this sheds a little light on the subject.
First, what causes the lytic bone disease associated with myeloma?
In general terms, normal bone strength is the result of a balance between two major populations of cells within the bone: Osteoblasts (bone builders or anabolic effectors) and Osteoclasts (bone destroyers or catabolic effectors). In myeloma, factors made by the myeloma cells turn off the bone builders and promote the activity of bone destroyers (osteoclasts). So, the balance favors bone destruction and lytic bone disease.
Second, how do we manage bone disease in myeloma?
Currently, standard of care in myeloma is to treat patients with monthly bisphosphonates for two years (except while receiving transplant) and then to discuss further frequency of dosing thereafter. The two drugs that are utilized in the US are Zometa (zolendronic acid) and Aredia (pamidronate). Zometa is preferred, but there are times in which Aredia may be safer or better tolerated. These drugs act by targeting and decreasing osteoclast activity (decreasing bone destruction / decreasing bone catabolism). These drugs are very effective and are able to decrease skeletal related events in myeloma (and other cancers with bone involvement). Further, in the case of Zometa, a statistically significant overall survival advantage has been observed in patients receiving Zometa relative to another bisphosphonate Bonefos (clodronate) (not sold in the U.S.) in a randomized phase III study. These issues make bisphosphonates important components of meyloma therapy.
Third, more recently Xgeva (denosumab) has become a treatment option. It is a neutralizing antibody recognizing RANKL, a factor within the bone marrow that activates osteoclasts (bone destroyers. So, Xgeva inhibits catabolic events (bone destruction). Xgeva has been compared in clinical trials to Zometa and demonstrated non-inferiority when comparing rate of skeletal events, overall survival, and osteonecrosis of the jaw in a study of myeloma and metastatic solid tumor patients. Hypocalcemia was noted at a higher degree in the Xgeva arm.
-> Nearly there, but not standard of care
Fourth, how do we address osteonecrosis of the jaw (ONJ)? ONJ is a non-healing bone lesion that occurs while patients are on bisphosphonates and undergo a bone affecting surgery- e.g. dental extraction. This is an issues that has been minimized due to patient education and prudent discontinuation and initiation of bisphosphonates (and Xgeva). But it remains an important issue that requires a dental consultation and discussion of potential dental/orthodontic issues prior to initiation of treatment.
Fifth, what about the anabolic bone metabolism (bone building)? We have thus far only spoken about catabolic (bone destroying) effectors of bone metabolism. Can we also increase the number of bone building cells?
Currently, an antibody to DKK1 is in clinical trials, code-named BHQ880. DKK1 is a factor produced by osteoclasts and myeloma cells that decrease the number of bone building cells (anabolic cells). More recently, another factor that inhibits bone anabolism has been identified, sclerostin (a recent Beacon news article discussed a study re: sclerostin). Antibodies to this protein are also in development but are behind that of DKK1 (only tested in non-human primates to date; by Amgen). Activin Receptor Type IIA, and GSK3beta, may also be important targets.
However, none of these factors have been shown to have the same clinical benefit as the more well studied bisphosphonates or even Xgeva, and therefore are not used outside of clinical trials. So more work is necessary before we can truly comment about the pros and cons of anabolic and catabolic bone metabolism inhibitors.
Sixth, what about Velcade (bortezomib)? Regarding the observation of decrease skeletal events in Velcade-treated individuals, this may result from Velcade inhibiting the production of factors like DKK1 or sclerostin that inhibit osteoblast differentiation and activity. Another or additional possibility is that Velcade may affect parathyroid hormone production, as one of the articles provided by suzie rose suggests, thereby favoring bone building. But, in regard to Velcade, continuing and future studies are necessary.
Lastly, as with most of the treatments for myeloma bone disease, options come from studies of osteoporosis. Parathyroid hormone has been examined and used in that setting. However, I am not aware of positive studies in myeloma to date. Vitamin D in patients with vitamin D deficiency is warranted, but remains unnecessary otherwise (at least as I practice).
I hope this sheds a little light on the subject.
-
Dr. Ken Shain - Name: Ken Shain, M.D., Ph.D.
Beacon Medical Advisor
Re: Parathyroid Hormone vs. Vit D vs. Bisphosphonates
Thanks so much for that exceptional overview Dr Shain!!
I really appreciate how you put all the options in perspective.
Happy Thanksgiving!!
I really appreciate how you put all the options in perspective.
Happy Thanksgiving!!
-
suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
3 posts
• Page 1 of 1
Return to Treatments & Side Effects