… So little time. I can’t keep up! Here are the highlights from a few that seemed particularly interesting.
Height: There’s a new article, “Real-world Impact of Treatment on Growth in Children With X-Linked Hypophosphatemia” that suggests early treatment with burosumab will, in fact, lead to patients being taller as adults. The data on this subject has been less clear until now, so it’s good news. At the same time, it bugs me that too many clinicians (and non-XLH parents) think height is the key issue for patients, and surveys of actual adult patients have shown that it’s not. (See, e.g., the Voice of the Patient report, Appendix 4.) It leads to health care providers and insurers (and some patients) thinking adult treatment doesn’t matter, because, after all, we’ve already stopped growing (vertically).
Height, another perspective: First, let me say up front that I don’t fully understand the concept of “bone age,” as discussed in “Bone Age Delay in X-linked Hypophosphatemia.” Next time I’m at Yale, I need to remember to have someone there explain it to me, since they did this research!
As best I understand the article, the parents of XLHers (presumably especially when the kids are spontaneous cases) are particularly anxious about their kids’ height (although, see above, that height is really, truly not our biggest challenge), and there are some standard methods for determining a patient’s adult height, based on their “bone age” as a child. These methods are used for all kinds of pediatric patients, not just those of us with bone disorders, so the researchers wanted to be sure that the methodology, presumably established by studying “normal” kids, actually worked for XLHers. If I understood it correctly (and, warning, I’m not entirely sure I did), they concluded that yes, for the most part, the standard methodologies apply to XLHers, although the calciulations might be slightly overly optimistic, more so for males than females. Note that this study was done using data from patients who were NOT consistently on burosumab for the entire period of bone growth (data goes back to before the new treatment was widely available), so there is no comparison of whether the methodology is more accurate for burosumab-treated patients than for supplements-treated patients. The article concludes with an acknowledgment that further studies are needed, especially with respect to the impact of burosumab.
Autosomals: There’s a new case report (and for once, it’s a valuable case report, since so little is known about autosomal hypophosphatemias) on a patient with autosomal recessive hypophosphatemia who was on burosumab treatment, presumably via a compassionate-use type exception: “Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.” Unfortunately, I only have access to the abstract, so I can’t see if there’s any discussion of the effectiveness of burosumab for the autosomal patient, and the main focus, as described in the abstract, is on genetic information that’s too advanced for me to understand.
This report is important, because patients with chronic hypophosphatemia caused by an autosomal genetic variant are generally left out of research and access to treatment that might help them, since burosumab research has excluded patients with non-PHEX variants, and the FDA/EMA have approved its use only for XLH and TIO, not a more general community of “FGF23-mediated hypophosphatemia.” I’ve long wished that the burosumab clinical trials had included all the forms of FGF23-mediated phosphate wasting by using “genetic, FGF23-mediated phosphate wasting” to define the subjects, rather than just XLH. I understand that it would have complicated the research, but surely there were ways to do it, short of completely excluding these patients. Because now the autosomals are stuck in a no-man’s-land, where in theory some could benefit from burosumab, but they can’t access it without FDA/EMA approval (or special permission), and it costs too much to do a clinical trial to get that approval for just a handful of patients with an ultra-rare condition.
I should note that not all of the autosomal variants of chronic hypophosphatamia would necessarily benefit from burosumab treatment. It appears that Autosomal Dominant Hypophosphatemia can be treated successfully with iron supplementation. “Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron-Deficient Patients With Autosomal Dominant Hypophosphatemic Rickets” (Yeah, I hate that they still haven’t changed the name to remove the “rickets,” since these patients still have phosphate-wasting in adulthood, just like XLHers. Sigh. Get your act together, medical community, and #ListenToPatients.)
Phosphorus cycle: One of the big problems with phosphate supplements to treat XLH is that the body processes phosphorus so quickly that it’s difficult to maintain a constant level in the bloodstream. And that’s true even before you factor in our counterintuitive, vicious cycle whereby raising our phosphorus levels to a normal level triggers the parathyroids to send out a message to the kidneys to dump all the phosphorus until we get back down to below a normal level, and the higher our phosphorus levels get, the more desperate the parathyroids are to dump the phosphorus. So, one of the benefits that researchers hoped to get from burosumab was the ability to keep our phosphorus levels normal for prolonged periods instead of constantly being in flux, a sort of never-ending panic-attack situation for the parathyroids. To learn more about the ups and downs of our phos levels on burosumab, some of the patients in the clinical trials (including me!) participated in a sub-study that tracked our phosphorus intake (we ate meals with a specific phosphorus content) and then checked the rise and fall of our phosphorus levels before/between/after the meals. The results have just been published in “Postprandial serum phosphorus and calcium concentrations in adults and children with X-linked hypophosphatemia during burosumab treatment.” (Isn’t “postprandial,” meaning “after meals,” a great word?)
While the conclusion of the article relates to whether phosphorus (and calcium) bloodwork really needs to be done fasting for patients on burosumab (spoiler: it’s better but not absolutely necessary, the way it is for patients not on burosumab), what’s of more interest to me is just the confirmation that burosumab does indeed keep our phosphorus levels steady over much longer periods of time than supplements. On supplements (or regular dietary intake), the entire cycle, from too-low to normal and back to too-low, takes place over the course of something less than four hours (which is why supplements have to be taken so often, to minimize the time spent below normal). A graph of phosphorus levels while on supplements looks like a series of bell curves, while the graph of phosphorus levels while on burosumab is pretty much a straight horizontal line.
Pregnancy: “Management of X-Linked Hypophosphatemia During Pregnancy” Nothing new here, but I mention it for the state of our understanding of XLH during pregnancy. I was hoping for something more advanced than “patient who was briefly on burosumab only as an adult, went off it and received supplement treatment during pregnancy, and both patient/child did okay.” I don’t know how research can happen ethically to see if an XLH mother and child (especially with an XLH child, genetically tested in utero) will do better on burosumab versus on supplements, but that’s what we really need to know. In this case, the mother had a total of only eight months on burosumab before she conceived and stopped getting it, so she hadn’t even reached the full benefit of the treatment! And the child in this case was known to NOT have XLH, although I’m not sure that even matters, since as I understand it, an XLH child’s phosphorus is normal at birth and is not regulated by FGF23 in the child’s kidneys. Theoretically then, the mother would have more phosphorus available for the child if on burosumab, and more left over for herself after the necessary amounts go to the child first.
Believe it or not, there are actually more journal articles that I don’t have time or space for here, all published over the last few days of March. I’ll share the best ones in the future!
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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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