I don’t usually give trigger warnings, but the journal article that I’m discussing today is likely to be really hard to read, and you may find even the second-hand descriptions of it a little traumatizing. I think it’s still worth reading, but you should make sure you’re in the right frame of mind before tackling it.
The article is “Adolescents’ experience of living with X-linked hypophosphataemia (XLH): a mixed-methods analysis of those who continued and discontinued burosumab treatment after end of skeletal growth” (Note that this is an online pre-print, subject to additional editing before it appears in print.)
It’s traumatizing, not because of any gory details, but because it discusses the experience of real, live patients who were required to go off effective treatment at the end of skeletal growth (EoSG, basically when their growth plates closed or some other occurrence that indicated growth ending), for governmental/financial reasons, not because it was the right thing to do.
Basically, the researchers looked at the pediatric patients’ experiences after EoSG in their teens (not even waiting until their bones really finished growing in their twenties, as recent research suggests is widely true!), and some were forced off treatment while others were able to remain on treatment. Note that this is NOT the fault of the researchers, but of the governmental restrictions. No ethical researcher would ever structure a study whereby some of the pediatric patients got to continue effective treatment while the others were forced to stop the treatment, and if they did propose it, I’d like to believe that the IRB (Institutional Review Board) or equivalent would immediately shoot it down. Experts in XLH understand that taking a patient off treatment like this is harmful to the patient, and doing so (when they didn’t have to according to applicable governmental limitations) would violate their Hippocratic oath.
You can probably guess the conclusion of the study: patients who stop effective treatment at the EoSG have worse health while off treatment than the ones who continue the treatment: “Stopping burosumab treatment at EoSG led to decreased serum phosphate concentrations and in some patients was associated with worsening of functional XLH symptoms and negative impacts on broad aspects of life. … By contrast, adolescents who continued burosumab after EoSG maintained serum phosphate concentrations and symptom control.” I suppose it’s good to have confirmation of that obvious fact, but I can’t help thinking of the needless suffering of the patients who were forced off burosumab.
So, here are the heartbreaking details:
- Twenty-five European patients, more women than men (consistent with the distribution of XLH across genders);
- data collected for six months after stopping burosumab;
- EoSG happened at around 15-17 years old, younger for girls than boys;
- 19 patients were able to continue burosumab, while 6 had to stop (but one of them resumed treatment after three months);
- patients had only been on burosumab for less than ten years (ranging from about two to eight-and-a-half years) by the time of EoSG, so keep in mind that these are not patients who were on it as infants/toddlers, and a lifelong experience with effective treatment might have made the transition off treatment even more startlingly negative;
- “[A]dolescents who discontinued burosumab at EoSG reported worsening or newly emergent pain, fatigue and stiffness, and negative effects on physical and social activities, employment and emotional/mental state.”
- “[Adolescents …who continued burosumab treatment beyond EoSG had stable bone biochemistry markers, stiffness and fatigue scores were low and stable, and pain levels were stable or improved.”
There was one (depressing) conclusion that I hadn’t expected, because it has to do with regional variations in the definition of “End of Skeletal Growth” for purposes of authorizing (or, in this case, NOT authorizing) treatment. The authors note, “Depending on the criterion used for EoSG, girls may stop burosumab treatment earlier than boys, potentially facing increased pain, worse mobility and compromised mental health, both at a younger age and for longer than boys.” Remember, there are more girls/women with XLH, by about a two-to-one ratio, so this conclusion means that the vast majority of the community is even more impacted than average/mean data might suggest.
Another sad realization is that the patients were only off effective treatment for six months when this data was collected. In my experience, and from what I’ve seen of clinical trial data, it takes a year or more before patients get the full benefit of burosumab, so I would expect the full negative effects of stopping burosumab to take a similar amount of time. The authors acknowledge that this short timeframe is a limitation of the study, without explicitly stating that a longer timeframe would likely have even more severe worsening of symptoms.
Personally, I think this short timeframe means the data vastly under-state the likely deterioration that would have shown up in another year or two. Back in the pre-burosumab days, when patients only had phosphorus/calcitriol treatment, there was a well-known pattern (among patients) of treatment ending around age 16-18, and patients not really noticing a big difference right away, just a gradual accretion of symptoms until, by their late twenties or early thirties, the symptoms had become unbearable (and permanent damage had occurred). The first two to five years were frequently a sort of honeymoon period, when the patients’ youthful energy/resilience (and a bit of denial and resistance to seeking treatment for something that had no treatment) could compensate for a lot of the symptoms, but after that, the pain, fatigue, and mobility restrictions quickly became impossible to ignore.
I should note that there is one aspect of the study that I thought was both interesting and useful, not depressing! I’ve long thought that the pain ratings in prior studies were somewhat misleading, because they didn’t take into account activity levels. When collecting only pain levels, without activity levels, the pain can stay the same, seemingly suggesting that treatment hasn’t helped, except that if activity levels have increased while pain remains steady, then the treatment has helped.
This study actually did take a look at activity levels, using a wearable device that measured physical activity levels, plus a diary that tried to get a picture of the patient’s active/sedentary lifestyle. Unfortunately, the article notes that the “data reporting was lower than expected, particularly from the wearable device.” I’ve been in studies, and I know that filling out the diaries is annoying, and add in the rebellion of adolescence, and it’s not really surprising that engagement with this aspect of the study was less than optimal. The “compensation” for doing the annoying bits of the study was also really tiny, which didn’t help. I don’t know how to fix this problem, but some of the solution may come from the interviews the researchers did, where patients could talk about both pain levels and activity levels. It’s harder to extract any correlations between pain/activity from free-form interviews, but I’m glad to see at least an attempt to acknowledge that the pain scores, collected without activity levels, may be misleading.
It’s upsetting to think we need to do this research into the abuse of patients by governmental over-rides of clinical expertise, when it’s absolutely, positively obvious that continuing treatment is the right thing to do (absent patient-specific reasons to stop, as decided by the clinician and patient). We need phosphorus our entire lives, not just for bone growth, but for pretty much every system of the body! I can’t help thinking that if we had a calcium-dependent disorder, it would never even cross anyone’s mind to suggest that a treatment to fix calcium metabolism should stop at EoSG. Everyone knows, both in the medical community and the general public, that we require calcium throughout our lives to stave off osteoporosis by maintaining our calcium metabolism from cradle to grave. In contrast, it feels like the mindset, the “everyone knows,” even in the medical community (except for phosphate-wasting experts), that phosphorus is less important than calcium (probably because it’s so widely available in our diet), so it’s no big deal to starve a person of phosphorus, while starving a person of calcium is unthinkable. We have a long way to go in reeducating the medical community in particular, and once their mindset has changed, we can work on the general population.
Thanks for sticking with me as I went through this article, despite how upsetting it may be. I’ll leave you with an encouraging thought for the future—more and more countries (or subdivisions, as in the case of Canada) are acknowledging that XLH is a life-long disorder that needs treatment during adulthood and are authorizing that treatment with reimbursement from national health care systems, so fewer and fewer patients will be forced off effective treatment due to governmental/financial restrictions.
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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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