I’m not a big fan of most case reports, which in the #XLH setting, too often add nothing to our understanding, but there’s a new one that actually taught me something new! It’s “Recurrent Tumor-Induced Osteomalacia After Surgical Resection.”
It’s not a new insight for expert clinicians, but it’s something I didn’t realize, since it’s about #TIO, which is ultra-rare and isn’t studied as much as XLH is. Most of the article offers nothing surprising, but what I found interesting is how tiny the effective dose of burosumab was for the TIO patient that inspired the case report.
The patient was started on what I assume is the standard recommended initial dosage for a TIO patient whose tumor could not be completely removed, which was 40 mg every 4 weeks. She developed hyperphosphatemia (high levels instead of low), and the dose was eventually dropped to just 10 mg, still every 4 weeks. Compare that to the 90 mg maximum dose for XLH (nine times the TIO dose!), which is what a lot of adults receive!
The low dose for TIO actually makes sense, if you follow the FGF23 to its source. I was surprised, because I knew that the blood levels of FGF23 can be higher in TIO patients than in XLH patients, so I would have expected them to need, if anything, a higher dose of burosumab. What I hadn’t realized is that apparently burosumab can target the source of the FGF23, acting there instead of in the blood. With TIO, there’s only one tiny tumor pumping out all of that excess hormone, making it relatively easy for the burosumab to focus on that one source. With XLH, however, the excess FGF23 is produced in our bones, so our entire skeleton is pushing out the excess hormone, and therefore burosumab has to essentially blanket our entire skeleton instead of focusing on one tiny tumor.
Still, the fact that the dosing started out closer to XLH dosages for the TIO patient is a reminder that dosing is not as one-size-fits-all as we’d like, and there’s still a fair amount of trial-and-error in getting the dose correct. I’ve been thinking about that issue a lot lately, since after ten years on the same dose (70 mg), I recently reduced it by 10 mg and was really surprised to find that my phosphorus and calcium levels didn’t change—if anything, they’re higher than they were in the clinical trial when I was on 70 mg! Which makes me wonder just how much smaller a dose I could take before those levels start to drop. And whether the levels staying stable is a factor of how long I’ve been on burosumab, with my body getting used to retaining phosphorus, and in that case, is it possible that at some point in the life-long treatment, we might only need a relatively small dose compared to the initial dose. In other words, perhaps “maintenance” doses can be lower than the initial doses. Perhaps once the bones/muscles that were starved of phosphorus have been brought up to “normal,” then we can maintain them with a lower dose.
There aren’t many significant side effects of burosumab, so in most cases, it may not matter that we’re getting a higher dose than necessary (if indeed we are), but we do need some FGF23 for purposes other than regulating phosphorus, so it’s possible that there are long-term consequences to suppressing more than we need to. I also wonder (although I’m told it’s unlikely) if a lower dose would stave off resistance to the antibody in the relatively small number of patients who develop an antibody to burosumab.
Just thinking out loud here, and I could well be wrong in my hypotheses! Remember, I’m not a doctor, just a well-read patient. But it bugs me that we don’t know for sure about ideal dosing.
There is some research ongoing with respect to dosing, investigating a version of burosumab that would last for two months instead of one (or less). You can read about it here. (Note that if you’re interested in participating in this study, it excludes anyone who has been on burosumab during the seven months prior to enrolling in the study.) Personally, I don’t see that as a particularly useful upgrade, but it might be good for patients in college (or who are away from home for long periods for other reasons), far from where they usually get their injections. Of course, getting approval for self-injection would also make it simpler for college students (and everyone else)!
What I’d really like to see, though, is more basic research on dosing adjustments for individual patients, and possibly whether long-term dosing in adulthood needs to be as high as it currently is. There’s a brand new and extremely interesting study in the UK looking into whether kids are being started on a too-high dose. From the introduction: “NICE [UK’s National Institute for Health Care and Excellence] recommends a starting dose of 0.4mg/kg, a normal maintenance dose of 0.8mg/kg …. The British National Formulary for Children (BNFC) gives the same advice. However, the European Medicines Agency recommends a starting dose of 0.8mg/kg per dose which is, therefore, the standard starting dose now. Some patients achieve symptom and biochemical control on less than 0.8 mg/kg per dose. They may be exposed to higher doses than necessary.”
Looking into this dosing issue for kids sounds like a good start, but we also need to do something similar for adults. A lot of the resistance to treating adults with burosumab has been concern about the long-term effects of something that, at least in theory, the patient who began treatment in childhood might end up receiving for eighty years! Or more! I’ve generally been impatient with that concern, given how much we know about how burosumab works and how minimal the side effects are, but if it turns out that the dose is unnecessarily high, then I’d be more understanding of the concern about long-term treatment.
As with so many things related to XLH (and most rare disorders), we need more research! Unfortunately, I’m not seeing much in the pipeline at clinicaltrials.gov, which is why most of what we’re seeing in the journals now is either 1) case reports, or 2) analysis of research that’s already been undertaken, mostly the data from natural history studies in Europe. Even more unfortunately, with the state of science in the United States, I don’t see any real chance of more pure-science (non-pharma-sponsored) XLH research happening in the foreseeable future. I hope I’m wrong, or that Europe and Asia take the lead in rare-disease research!
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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