We’re a few months past the fifth anniversary of the FDA approval of burosumab for treatment of XLH, which got me to wondering about when the medical community will catch up to the fact that the pre-burosumab treatment regimen does not work. (Slight exaggeration, but necessary to move the needle, I think.) It’s beyond time to 1) stop calling burosumab “new,” and, even more importantly, 2) stop calling the old treatment “effective.”
Even before burosumab, the XLH community was considered lucky to have a known (even if not FDA-approved) treatment protocol (e.g., phosphate supplements and calcitriol, abbreviated here as phos/calcitriol), when most rare disorders don’t have any treatment whatsoever. Some treatment is better than no treatment, but that doesn’t necessarily mean the treatment is either good or particularly effective.
The problem, of course, is the definition of “effective.” Were XLH patients better off with phos/calcitriol than with no treatment whatsoever? For most patients, sure. At least marginally. But everyone in the patient community knows that the old treatment was hit or miss, and nowhere near a cure. Some patients didn’t respond at all, while most responded at least partially and temporarily (rickets healed eventually and bones may or may not have straightened somewhat), but that was also true of patients (like me) who did not get any phos/calcitriol treatment. Of those getting phos/calcitriol, many (most?) patients still required orthopedic surgery, many/most went on to have increasingly disabling symptoms at a relatively young age (early-middle years, rather than old age), and many/most also experienced significant side effects from the phos/calcitriol treatment (gastrointestinal issues, kidney calcification, hyperparathyroidism, and hypertension). And that’s assuming the best-case scenario of a patient/family with the resources to maintain a complicated dosing routine, and access to a clinician who actually knew what they were doing and didn’t prescribe harmful amounts/ratios of phosphorus and calcitriol. It also assumes that only pediatric effectiveness matters, conveniently forgetting that most adults with XLH go on to have progressively debilitating symptoms starting in their early thirties, even after the supposedly effective pediatric treatment (and with or without ongoing treatment with phos/calcitriol as adults).
So, when the options were phos/calcitriol or nothing, sure, you could say that the treatment was effective to some degree. What you could NOT say, however, was that the treatment did much more than the equivalent of temporarily placing a bandage and pressure on an arterial wound. Would a bandage on that kind of wound be better than doing nothing? I would assume so, at least in the moment (I’m not a doc though). But is it a truly effective treatment? Absolutely not. Or you could say the situation is like the use of the pre-phos/calcitriol treatment (megadoses of vitamin D) when the phos/calcitriol regimen debuted — did the megadoses of vitamin D help? Maybe. I was on that regimen and had mild symptoms as a kid. But did clinicians insist on continuing with that regimen once the phos/calcitriol treatment became available? There probably was some resistance (change is hard for everyone, including clinicians), but eventually it became widely accepted that, no, the previously-considered “effective” treatment was not, in fact, effective, and it was time to move on to what actually worked significantly better (and didn’t run the risk of killing patients by way of vitamin D overdose).
Most patients/parents who have experienced burosumab know that burosumab is a truly effective treatment for most patients (and all the data I’ve seen agrees). It addresses the currently-known root cause of the phosphate wasting by blocking the excess FGF23 in the kidneys. (Even better would be to block the initial overproduction of FGF23, which would, presumably, be even more effective, but we don’t have the necessary scientific understanding to do that yet. And that will be another battle for another day.) It’s absolutely clear that burosumab, unlike phos/calcitriol, fully mineralizes bones, heals/reduces fractures, straightens bones without surgery (in most cases), and even addresses the pain/fatigue issuesl without significant adverse events.
So now we’ve got a treatment that is as revolutionary in relation to phos/calcitriol as phos/calcitriol was to vitamin D megadoses. Burosumab is a treatment that, if started early and continued throughout life, is just short of a cure (since there appear to be some ongoing symptoms that are not fully resolved, even with burosumab). And yet, too many in the medical community, and especially among payers (the insurers and, in national health care systems, the governmental agencies who decide whether to pay for treatment), insist on clinging to the equivalent of using bandaids to stop arterial bleeding. There are already several examples of governmental agencies considering both burosumab and phos/calcitriol to be “safe and effective,” as if there’s no significant difference between them, and therefore denying access to burosumab solely based on the (admittedly high) cost of the newer treatment option. I believe a similar calculation is taking place among insurers in the U.S., who may insist on what is essentially “step therapy,” forcing patients to start with the ineffective treatment until, as expected, the treatment is shown to be ineffective, before paying for the more expensive but effective treatment. Adults might be able to wait out the step therapy without lasting damage, but time is of the essence for kids, and they will be permanently adversely affected by any delay in starting truly effective treatment.
It makes me think of what life must have been like in the early days of antibiotics. When they were first developed, they would have been competing with a number of folk remedies offered for infections, and those remedies might have helped some patients to some small degree (or, more likely, just made the patient a little more comfortable for weeks and weeks until time and their own body’s defenses could finally eradicate the infection). And then along came antibiotics, which would eradicate the infection in most patients within a week or two. I’m sure there were medical professionals back then who were debating whether to start with the folk remedies or just go ahead and automatically prescribe the antibiotics. (Yes, I know that antibiotics are overly prescribed now, but assume I’m talking about a situation where they’re being properly prescribed.) Eventually, of course, antibiotics became the standard for certain infections, and today we can’t imagine a doctor suggesting that we should try a folk remedy for a month or two before going on the appropriate antibiotics. But consider all the suffering that happened while doctors were debating whether to prescribe these newfangled antibiotics.
I think someday the medical community involved with XLH will look back and wonder what on earth the “phos/calcitriol is highly effective” doctors were thinking to insist on starting with a treatment that is “effective” only when compared to placebo, and only for some patients, to a small degree and only in the short term, after there was an available treatment that is, in fact, much more effective for most patients, with no significant side effects, and is likely to remedy most symptoms if started early and taken for a lifetime.
History may well judge the foot-draggers, but patients are the ones who will pay the price. We can’t simply tell our symptoms to stop until the day when phos/calcitriol treatment is viewed as obviously, insanely inadequate when contrasted with burosumab. We need to be speaking up now, pointing out that the so-called “standard” or “conventional” treatment is not, in fact, what anyone would consider effective at all. We need to keep shouting that phos/calcitriol treatment is (to steal a phrase) a terrible, horrible, no good, very bad treatment. It doesn’t work, and it has potentially serious and permanent side effects.
There is ample evidence that phos/calcitriol is not, in fact, effective, except when compared to placebo, and even then it’s not hugely more effective than no treatment at all. A journal article (on an unrelated subject that I’ll cover on another day) caught my eye recently with this statement about a child who started phos/calcitriol at about age two: “Poor biochemical and radiographic control persisted, despite good therapeutic compliance, requiring hemi-epiphysiodesis at 4 years old due to the significant deformity in the lower limbs. This led to walking disturbance and there was no improvement whatsoever.” (If the jargon is too much, the simplified translation is: kid who was on phos/calcitriol and whose parents actually made sure the kid got the doses on the prescribed schedule still didn’t have normal blood tests or leg straightening.) The second patient was a little better off, in that she also started phos/calctriol young, had “persisting hypophosphataemia and worsening of the lower limb deformities” which required surgery, but the surgery was more successful. So, treatment ranged from totally ineffective to somewhat effective, but only when the phos/calcitriol was combined with surgery, which doesn’t seem particularly effective to me!
In my experience, when clinicians/paers defend the use of phos/calcitriol instead of burosumab, it’s based on the claim that phos/calcitriol can in fact work miracles if prescribed and taken correctly. I don’t believe that’s true, and the quotes above would seem to support my position, but beyond that, even if there is an element of truth to it, it’s an outrageous statement from a patient-focused point of view. Those clinicians are blaming the patients for their poor outcome, as if the patient is an obstreperous child who doesn’t want to get better. It’s a much more complicated issue than that, not a simple matter of a patient refusing to take simple steps to improve their health. For one thing, not all patients respond to the treatment, even if extraordinary efforts are taken with following the treatment regiment. For another, the recommended regimen for phos/calcitriol treatment is an extremely burdensome regimen (multiple doses spaced at strict times throughout the day, with restrictions on what foods can be ingested at the same time, and some clinicians even require the parents to get the kid up in the middle of the night to take a dose). Not all families have the resources to maintain that kind of vigilance, or school systems that will cooperate with the regimen. It makes no sense to call a treatment “effective” if the prescription is for a regimen that’s so complicated that it’s not feasible for patients to follow it for a lifetime.
The evidence, however, is piling up that phos/calcitriol is barely effective, regardless of how well a patient follows the complicated schedule, while burosumab is extremely effective for most patients (and doesn’t require a complicated dosing regimen). It’s even more true for adults, given that the risks of phos/calcitriol treatment in adults (i.e., nephrocalcinosis, hyperparathyroidism, and gastrointestinal distress) are generally so much greater than any minor benefits, that the consensus has long been that phos/calcitriol treatment of adults should be limited to periods of bone healing or persistent bone pain.
It’s beyond time to stop calling phos/calcitriol the “standard” or “conventional” treatment. The use of those terms carries with it the connotation that the old treatment is effective, and we know now that phos/calcitriol is simply not effective by any reasonable standard. The adjectives’ implicit endorsement of phos/calcitriol as a better choice than burosumab is exacerbated by continuing to call one standard/conventional and the other “new” or “novel.” The comparison makes one sound safe and the other sound risky, when in fact, the truth is the opposite: phos/calcitriol is far riskier for the patient (and the clinician who could commit malpractice more easily with the old, complicated regimen) than burosumab is.
Burosumab has been commercially available for over five years now (and some patients have been on it for seven or more years with no serious adverse events). We know it’s safe. We know it’s effective, not just in comparison to nothing (placebo), but in comparison to phos/calcitriol. And not by just a little, but by leaps and bounds!
So why is it even a debate? It’s just habit, I think, repeating what others in the medical community have said before without stopping to think about the language’s connotations. But at some point, new things become standard, and for burosumab, that time is now, before too many more patients suffer needlessly. We need to refer to the two options for treatment with value-neutral language. I’ve chosen to call one burosumab and the other phos/calcitriol for lack of anything better (and knowing it’s not ideal, since some places use a different vitamin D analogue in place of the calcitriol, but phos/vitDanalogue gets too unwieldy!).
Imagine if you were a clinician, unaware of the history of the two treatment options, and learned that there was, on the one hand, a treatment that was cheap, marginally effective, but difficult to prescribe, and with some serious side-effects; and on the other hand, there was an expensive treatment that was significantly better than the cheap treatment, relatively easy to prescribe, and with no serious side effects. Would there be any question which one the clinician should recommend in the patient’s (and their own!) best interest?
Now imagine that you’re that same inexperienced clinician, and are told only that there’s a “standard” or “conventional” treatment, plus a “new” or “novel” treatment. Which one are you likely to choose (given that clinicians are by nature risk-averse, with an oath to first do no harm)– the safe, “standard” one or something that’s new?
Sure, experts understand the nuances, and we’d like to think that all patients are being treated by experts, but the reality is that many of us are being seen by clinicians who have treated few (if any) other XLHers before, and are therefore particularly susceptible to the implicit judgments included in the language used to describe the treatment options. The experts need to help their colleagues by using more accurate, value-neutral language to describe phos/calcitriol v. burosumab, so the less expert clinicians (and payers) won’t be misled into believing that the older, largely ineffective treatment actually works.
I hope you’ll join with me in politely reminding the medical community, whenever the issue comes up, that phos/calcitriol does not deserve the label of “standard” or “conventional,” because it is a terrible, horrible, no good, very bad treatment.
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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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