For more than a decade now, my main message has been that XLH and the other chronic hypophosphatemias are far more than a “pediatric bone disorder.” Clinicians are trained in med school to use shorthand labels for conditions, so they can keep track of the overwhelming amount of information they need to remember. It’s necessary, but has drawbacks, like when shorthand is proven to be incorrect, but it remains in use. I mean, seriously, how is it possible that there are still clinicians and websites that refer to Vitamin D Resistant Rickets, when we’ve known for fifty years that the key problem involves phosphorus, not vitamin D? However it happens, we need to convince them to just use hypophosphatemia, not rickets, as the shorthand. Change the shorthand, change the mindset, improve the treatment by non-experts (because the majority of patients do not have access to true experts in chronic hypophosphatamia).
That’s the reason why I’m so adamant about eradicating both “VDRR” and “hypophosphatemic rickets” from the labeling, since those names get translated into the shorthand, “pediatric bone disorder,” for anyone who isn’t already an expert. And since the majority of clinicians, even the majority of endocrinologists, don’t know, and can’t really be expected to know all about every rare disorder, we need to make sure they’re properly prepared to treat us. Which requires them to focus on the hypophosphatemia, not the rickets. They know what hypophosphatemia is, and it’s NOT a pediatric bone disorder, even if it does have some additional consequences for kids whose bones are still growing.
So to counter the “pediatric bone disorder” shorthand, I’ve been mainly focused on the adult issues (the whole-body aspect of the disorder), reminding clinicians that the majority of affected individuals are, in fact, adults. If it’s a whole-life disorder (which it is), then people have it from birth to death, and it’s not terminal, so our life expectancies are pretty much the same as anyone else’s. That means that there are going to be roughly three times as many of us aged twenty to eighty-plus than there are patients who are under twenty. (Slightly less than that due to deaths unrelated to the hypophosphatemia, but at a minimum, there must be at least twice as many adults as kids.)
Then I started reminding clinicians about the muscle issues and fatigue (the whole-body aspect of the disorder), as it became more and more obvious that without fuel (made in large part from phosphorus) for muscle function and energy in general, our muscles don’t work properly, and we’re tired all the time. (There is science about phosphorus as fuel, so this isn’t just me hypothesizing here. It’s mentioned in this video from the International XLH Alliance’s symposium.)
And now there’s evidence of yet another whole-body aspect of the disorder: a unique inflammatory pattern. A recent article in the Journal of Endocrinology entitled “X-Linked Hypophosphatemia, Not Only a Skeletal Disease But Also a Chronic Inflammatory State” concludes just what its title states. Apparently it’s been known for a while that there’s a correlation between elevated FGF23 levels (regardless of cause, so it applies to chronic kidney disease patients too, not just XLHers and TIO, etc.) and inflammation, separate from FGF’s effect on phosphate metabolism. So researchers looked for inflammation markers in the blood of a bunch of XLH patients, and compared them to non-XLHers’ blood. They observed that “Expression of most inflammatory markers was significantly increased … from XLH patients compared to controls [non-XLHers].” (Note: “expression of” something is just science jargon for what we’d call the “quantity of” that thing, so they’re saying XLH blood had more of certain inflammatory markers than non-XLH blood.)
Unfortunately, but perhaps not surprisingly, they also noted, “No differences were observed between the burosumab and [phosphorus/calcitriol] subgroups.” The inflammation seems to be coming, not from the kidneys, where burosumab blocks FGF23, but from the sites in the bones, which produce the FGF23 and are not blocked by the burosumab.
Here’s their conclusion:
We describe for the first time a peculiar inflammatory profile in XLH. Since XLH patients have a propensity to develop arterial hypertension, obesity and enthesopathies, and since inflammation can worsen these clinical outcomes, we hypothesize that inflammation may play a critical role in these extra-skeletal complications of XLH.
My takeaway, in terms of what we need to make sure clinicians (and insurers/payors) know is twofold. They first need to understand that FGF23’s effects on phosphorus metabolism have whole-body, whole-life (and whole-family) effects, since phosphorus is required for multiple body systems throughout our lives. And second, the excessive FGF23, apart from causing phosphate-wasting, may also be causing inflammation that, even if we have enough phosphorus in our blood, is a problem that needs treatment, but there is currently no treatment for it. In other words, while burosumab is a huge step forward in treating XLH and TIO (and possibly some autosomals), it’s not the final answer. If we want to address all of the whole-body, whole-life issues, we need to stop the excessive production of FGF23 at its source, not just block it at the point where it causes phosphate-wasting. We need a cure, not a partial treatment.
The experts, I think, already know this (and that was likely what inspired the research study that found the inflammatory pattern). I’m sure that researchers are looking for that earlier step in the pathway that connects the gene variant to the overproduction of FGF23, so that it can be blocked earlier. You may even notice a reference in the video cited above featuring Signe Beck-Nielsen (high recommended; very comprehensive and insightful overview) to the need to go further down the line of the biochemistry to stop the overproduction of FGF23 in order to have a cure, not just the stopgap measure of dealing with the FGF23 after it’s been overproduced.
We’ve come a long way since XLH was first named Vitamin D Resistant Rickets (and then hypophosphatemic or familial rickets). We now know that the disorder has very little to do with vitamin D, and is far more than rickets. And we have a stopgap treatment in burosumab (and possibly gene therapy that works on essentially the same pathways as burosumab). But we can’t stop now. We need to know what triggers the overproduction of FGF23 and how to block that trigger.
It feels like some in the community have become complacent, since, unlike most rare disorders, we actually have an effective treatment. But it’s just a treatment, not a cure. We deserve a cure, and can’t give up until we have one.
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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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