Pain Comments to FDA

The FDA recently hosted a Patient Focused Drug Development meeting on Chronic Pain, and the public is invited to provide comments about the information presented, as well as their own experiences with pain. The XLH Network, Inc., provided a full statement on behalf of our community, and a small portion of that statement is included below. We want to encourage our members to review the PFDD information at https://www.fda.gov/Drugs/NewsEvents/ucm603093.htm and to write their own responses and comments if they believe the information will help the XLH community. You can submit your comments here: https://www.regulations.gov/document?D=FDA-2018-N-1621-0001. Comments are due by September 10th.

Pain is a life-long part of the XLH experience that includes chronic bone pain (either due to fractures or due to mineralization defects without fractures), osteoarthritis at an earlier age than the general population due to cartilage thinning, dental pain from spontaneous abscesses, neurological pain from calcifications that impinge on the spinal canal, and pervasive, early-onset bone spurs (enthesophytes) that affect many of the tendon and ligament insertion sites throughout the skeleton and spine.

The most significant downsides to the available current treatments for the pain of individuals with XLH are as follows: 1) they not effective in some patients; 2) they work somewhat but cause significant adverse effects from the drug; 3) they work but at the risk of addiction or stomach, kidney, or liver damage; 4) generally they don't completely resolve the pain, just dull it a bit; and 5) they are a treatment and not a cure, because they don't get to the root cause of the pain.

Some individuals with XLH report having difficulty getting effective dosages or sufficient quantities of pharmacological treatments to handle the extreme severity of pain they experience. Other patients report being viewed as drug-seeking or having a psychosomatic complaint because their pain is both diffuse and severe. In addition, the origin of pain often evolves from time to time without an obvious clinical cause to explain the source of the pain. Finally, many health care providers are unaware that XLH is associated with pain and/or are unaware that there is such a thing as bone pain in the absence of trauma, and this may result, too often, in accusations of drug-seeking behavior or as having psychological issues.

Survey on adults living with familial hypophosphatemia

The Pre-Event survey for the Symposium will help us to have even a bigger impact on our audience members, which include the medical community, researchers and insurers. Make sure your voice is heard! It will only take a few minutes. Click here to start:

https://docs.google.com/forms/d/e/1FAIpQLSe-dwpdUVrZ7-GauuFK3xDBjIRYUPiYr1s4QJe1v-cyCOMzMQ/viewform

Bone biopsy data

First, a quick note -- if you've registered for XLH Day (or plan to) and don't have your hotel reservations yet, make them now. The discounted rate is only good through September 5. Also, if you'd like to apply for financial assistance with the hotel cost, apply before September 5. Instructions for both hotel reservations and hotel stipend here: http://xlhday.com/?page_id=220

Now for the news: Ultragenyx Pharmaceutical has released some very encouraging results from the clinical trial involving bone biopsies of patients before and after treatment with KRN23/burosumab. Note that the results from after treatment are only for two patients, an obviously tiny sample size!

Here's the summary from a recent press release: 

Bone biopsy results from the first two adults in the bone quality study will be included in the burosumab BLA. In this study, baseline biopsies obtained from 11 patients confirmed that a majority of the patients had severe osteomalacia with a mean osteoid volume/bone volume of 26% vs. normal range of 0.3%-3.1%. These data verify that adult XLH patients have severe underlying bone disease even many years past puberty. Follow-up biopsies after 48 weeks of burosumab treatment are available from the first two patients. For these two patients, osteoid volume/bone volume was decreased from 24% and 29% to 9% and 7%, respectively. Osteomalacia was characterized by the pathologist as improving from severe to mild disease. Additionally, a post-hoc statistical analysis of bone fracture healing in the recently announced adult Phase 3 placebo-controlled study showed an odds ratio of 7.76 for complete healing of fractures and pseudofractures in the burosumab group compared to the placebo group (p=0.0004) at 24 weeks.

You can read the entire press release here:
http://ir.ultragenyx.com/releasedetail.cfm?ReleaseID=1034806

XLH: it's not just for kids any more!

Last year, when Network board members had a booth at the Endocrine Society's annual conference, the most frequent statement they heard from passing doctors was "Oh, I don't need to know about XLH because I only treat kids."

The board members jumped up and down, pulled their hair out and dragged the doctors back to the booth (slight exaggeration there; professional demeanors were maintained, despite all temptation to the contrary) to say, "It's not just for kids any more!"

Of course, we know it's never been a kids-only disorder. It's just that the adult symptoms weren't well known before the Network connected patients who could share their experiences and get confirmation that there was a pattern to the symptoms, that they weren't alone in developing calcifications and arthritis much earlier than the general population, or in needing joint replacement well ahead of the usual timeframe. At the same time, a few doctors like Karl Insogna at Yale University, Michael Econs at Indianopolis University and Suzanne Jan deBeur at Johns Hopkins University began treating larger numbers of adult XLH patients and noticing the pattern of adult symptoms.

The problem now is that the facts about adult issues, well known to patients and the few experts, haven't been absorbed by the broader medical community. There's an often-quoted statistic that it takes seventeen years from the time medical research establishes something definitively until the findings from that research are used by the clinicians treating patients, and it wouldn't be surprising to find that it can take even longer for rare diseases.

Even pediatric endocrinologists who treat a lot of XLH kids may know a lot about the childhood issues, but since they don't see the later progression of the condition after the patients leave the practice, they may be unaware of the adult issues. It's often assumed that the successful straightening of legs with childhood treatment will take care of all the problems, but we're seeing now that that is not the case. Patients who were treated after Phos/calcitriol first became available shortly before 1980 are now in their twenties and thirties and are still reporting a recurrence of bone pain and a variety of more significant joint issues than others their age.

Destroying the myth that adults have no symptoms is a major undertaking, but one that the Network will pursue with our community's support. We're confident that someday, board members will go to a medical conference and no longer have to explain, "It's not just for kids any more!"

Calcified tissue issues

XLHers frequently experience calcified soft tissue, either in the kidneys (generally believed to be a side-effect of treatment) or in tendons and ligaments (the exact cause of which is unclear at present).

One such condition is OPLL or Ossification of the Posterior Longitudinal Ligament (the ligament that runs down the outside of the spine). These calcifications can occur in a variety of other places too, generally wherever tendons or ligaments attach to the bone. These calcifications are known as entheses and the condition is known as enthesopathy.

A recent journal article discusses whether the current treatment regimen (phosphorus and calcitriol supplements) reduces these calcifications, and unfortunately concluded that it does not. You can read it here:
https://www.ncbi.nlm.nih.gov/pubmed/26176801
And there's a related commentary here:
https://www.ncbi.nlm.nih.gov/pubmed/26439151

XLHers aren't the only ones who experience calcified tissues. There's a whole medical journal dedicated to them: Calcified Tissue, International (http://link.springer.com/journal/223).

You might think "calcified tissue" is a micro-specialty, but there's actually a European Calcified Tissue Society, which meets with the International Bone and Mineral Society every year in Europe (http://ects2017.org/), and there's also an Israel Society on Calcified Tissue Research (http://www.iofbonehealth.org/iof-national-societies/1140).

More patients with joint replacement surgery

We previously shared information about a research survey for XLH patients who have had joint replacement surgery.

Here's the gist of the project: "We [the researchers] are seeking men and women aged 18 or older with X-linked hypophosphatemia (XLH) who have had a hip or knee replacement to participate in an online questionnaire in exchange for a Starbucks gift card. The purpose of this questionnaire is to learn more about joint replacements in patients with XLH. With the information gathered, we will be able to educate clinicians about joint replacements in patients with XLH."

The researchers have had some response, but could use some more, and have expanded the criteria for eligibility, so that patients previously ineligible may now be eligible. In particular, those who are in clinical trials now are eligible. Accordingly, if you didn't do the survey before and you're interested in sharing your joint-replacement experiences with researchers now, here's the official announcement (and make sure to read the full announcement in the link below):

We are currently accepting new submissions from patients who are either enrolled, or not, in a clinical trial! If you were previously excluded because of your involvement in a clinical trial and you are interested in participating in this very important assessment of pain and joint health, please complete the survey using the updated link below.

Additionally, if you have attempted the survey previously but have not completed it, you can restart the survey using the same link below.

If you could not take the survey because you had a joint replacement within 6 months, please take the survey as soon as you pass the 6-month mark.

Thank you for your participation!

http://quinnipiacmed.qualtrics.com/SE/?SID=SV_6n9bQ8DOWPiITvT

Questions?

Contact: XLHPainStudy@Quinnipiac.edu or (203) 582-4053

*If you have already successfully completed the survey, there is no need to resubmit your response.

NOTE: As always, the XLH Network, Inc. does not endorse or critique specific research, and does not counsel individual patients either for or against participation in any specific research study. Prospective volunteers should always carefully review the research study's documentation, and discuss the pros and cons of their participation with trusted advisers, including their health care providers and family members.

Representing the XLH community

Even as we're recovering from an amazing XLH Day in Houston, Texas (more on that next week), we're gearing up to represent the XLH community at other events this fall.

First up is the American Society for Bone and Mineral Research (ASBMR) annual conference in September, to be held this year in Atlanta. You can read about it here: http://www.asbmr.org/annual-meeting

We are part of the Rare Bone Disease Patient Network, which will have a booth at the conference, and is involved in a workshop that will include brief talks on a number of rare bone diseases. The section on XLH will be presented by the Network's Scientific Advisory Board member, Suzanne Jan deBeur.

Karl Insogna, MD, will be one of several doctors talking about "How Discoveries Lead to Treatment of Rare Bone Disease Treatment." His presentation will be focused specifically on XLH in adults.

In addition, several members of our Scientific Advisory Board will also be there for posters and/or presentations, and we'll report back on the details after the event.

What can XLHers do?

XLH patients probably won't be playing professional basketball (until we find a cure or at least an effective treatment), but for anything that doesn't require height, XLHers can and do participate in a wide variety of careers and activities.

We recently asked a number of XLHers about their  careers and activities, and got some great responses.

It shouldn't surprise anyone to hear that XLHers engage in a number of professional careers, including doctors, lawyers, teachers, nurses, writers, researchers, engineers and assorted computer/tech-related jobs. We also heard from a professional chef, a loan officer, a real estate agent, a mental health therapist and a master florist!

It's a little more surprising, given the physical limitations experienced by many adults with XLH, that some of them engage in strenuous activities like building rock walls, logging, shooting targets, biking, horseback riding ("even if I can't do all the things on horseback I wish I could, any riding is better than no riding"), drumming ("I've fractured my arms a lot since I started drumming, but it's too much fun to avoid doing"), and even triathlon competitition (jointly with her husband; he does the running, and she does the biking and swimming).

Bottom line: XLHers can do just about anything they want to do!

Changing mindsets

Today's guest post is by Network member, Andrew Shortall. He was diagnosed with XLH at age two, and has become a self-taught chef, wine business person and a writer, with aspirations to become a novelist. 

“Wait, I’m not disabled!”

How familiar is that statement among XLH patients? Very! Or at least it is in my life. While I understand and accept that I have a life altering condition, I’ve always been stubbornly proud and hesitant to admit that I do indeed have a disability or handicap. The same stubborn pride that I’ve seen in other XLH patients; the thing that drives us all forward and never allows us to give up on ourselves or each other.

However, as I grow older and my condition progresses, I’m finding it increasingly difficult to continue saying I don’t have anything more than physical limitations. The truth of the matter is, while my condition isn’t as serious as others, I do in fact, have a physical disability.  

But, accepting that truth doesn’t mean I have to give up my stubborn pride!

It is a streak that makes me always want to do things for myself. I carry my own laundry basket. I drive a car with a manual shifter and no control modifications. I can cook, clean house, maintain the car and do a multitude of other things that a more severely disabled person might not be able to do. For that, I’m hugely grateful. Yet, I must still accept that there are a great many things that I am simply physically incapable of doing.

I cannot walk for long distances, let alone run. When I’m working in the kitchen, I have to sit down every so often. These, and others, are things I cannot do. I do not have the physical ability for them. That’s basically what a disability is, and exactly what I’ve been trying to get my head around these past months and years.

It truly bothers me that handicap and disability is so heavily stigmatized. In a world where equality is at the forefront of daily life, we still have inequality and discrimination towards those who aren’t “normal.” Perhaps that’s why it has been so difficult for me to accept that I have a disability. Because of the perceived stigma attached.

What I do know is that we must strive to show people that while we may have a physical disability or handicap, they don’t change who we are as humans. They don’t make us less useful or relevant in modern society.

This change in mindset came about for me because a friend asked what government benefits I receive for my disability. Which is when I exclaimed, “wait, I’m not disabled!” Their acceptance of me and the things I can do made me realize that while I am disabled, I am still relevant and useful. And that will make it easier for me to accept the help I will most certainly need in the future.

I have to accept that my physical limitations are now disabilities. Yes, I am disabled. And I’m okay with that!

Travel jitters

With summer vacation time rapidly approaching, you may be feeling anxious about the physical challenges of air travel. Guest blogger Andrew Shortall is here with some tips and anecdotes.

*bing* 

“I’m sorry sir, would you step over here, please?”

These are probably some of the most dreaded sounds and words for an XLH’er but I’m here to tell you they don’t have to strike fear into your being! I've been travelling internationally for many years. Being Irish, my osteotomy implants have almost always set off the metal detectors in Dublin airport. And when questioned, I explain that I have surgical implants in both my legs. A mere wave of their detector wands and seconds later, I'm free.

The most personally invasive experience was in Chicago O'Hare in 2009 when I was returning to Ireland. Naturally, my appliances set off the detectors and I was called aside by a very kind and respectful gentleman of what is now the TSA. I mentioned the metal, and he asked me to follow him a few paces to a small, private room. He asked me if I minded showing my surgical scars, which I didn’t. But really, how in the world can I hide them? I rolled up my pants legs and showed them to him. And to be quite honest, it was HE who was more embarrassed at having to ask.

And that’s why you don’t need to be afraid. The TSA and their counterparts around the world understand that millions of people have surgical implants, be they joint replacements, skull plates, or in our cases, plates and pins. Personally, I view my scars and metal as trophies. I won them on the hard road through my treatments. I don’t feel self-conscious about them now, as they have been a part of me for a long time. And I’m proud of them!

Finally, as summer rapidly approaches, many of us will choose to take a vacation and fly to our destinations. I’ve looked through the TSA website, and I’m impressed with how accommodating they are, even with today’s need for such increased security measures. While their primary concern is safety and security of air passengers, they also focus on passenger comfort, respect and dignity. Here are some helpful links:

This page is the launching pad for medical and disabilities information:

http://www.tsa.gov/traveler-information/travelers-disabilities-and-medical-conditions

Here you’ll find information most suited to XLHers:

http://www.tsa.gov/traveler-information/metal-implants

This page provides advice for anyone with limited mobility:

http://www.tsa.gov/traveler-information/mobility-impairments

In all cases, you need to speak to the TSA at least 72 hours before your flight. This will make their job easier, and will help reduce your stress and worry about the checkpoints. It’s also highly recommended to speak to your airline, as they will provide mobility assistance upon your arrival at the airport, and throughout your flight, should you need it.

And while this post is written primarily about the USA, I know from personal experience that similar procedures are in place around the world. Speak to your airline, and the airport authority well in advance of travelling. They’re all there to help!

If the shoe fits

Today's guest post is by Network member, Andrew Shortall. He was diagnosed with XLH at age two, and has become a self-taught chef, wine business person and a writer, with aspirations to become a novelist. 

I was always a difficult person to buy shoes for. My feet are wide, so I generally had to get the next size up. I never truly understood the importance of having comfortable shoes as an XLHer. And now that I have you hooked, allow me to explain.

Many years ago, I slipped in the shower and broke the fifth metatarsal of my right foot. The so-called “soccer player’s injury,” or at least it was, according to the orthopaedic specialist looking after me.

Over the course of my recovery, I had a fiberglass cast and cast shoe. Both combined to have the effect of giving my right leg an extra inch in length, which leveled out my hips. Rather miraculously, this lead to a significant reduction in my back pain. So, I asked the specialist and he referred me to an orthotics clinic who outfitted my shoes with a raise designed to do the same job as the cast and shoe.

While my walking and back pain improved, it wasn’t perfect. And I didn’t understand why until I moved to France and my now well-worn shoes finally started falling apart. I got them re-soled but that made them increasingly uncomfortable. So, when a lace snapped, I put on some old trainers or running style shoes. Within a day or two, I felt more at ease on my feet and started walking better. So, I bought new trainer style walking shoes. They were cheap, but they were also a stop gap.

Again, my walking improved, as did my stamina for standing in the kitchen. However, as is inevitable with cheap shoes, they quickly became uncomfortable so on the recommendation of my Dad I researched some specific walking boots and went to try them on early in January. Again, I ended up buying a couple of sizes bigger than normal, but apparently French feet are smaller than Irish ones!

Happily, my new walking boots are far more comfortable than the old ones. And once again, I’m walking easier and have more stamina while standing in the kitchen. But the best part of this story is that I’ve drastically reduced my reliance on NSAID pills to manage my back and joint pain. I’ve gone from two to four pills a day to two pills a week. Although I do take one or two when I’m working.

I never realized that footwear could have such a profound effect on mobility and stamina. While I won’t be walking a 10K any time soon, I’m very grateful for the improvements. So, if you have similar issues, please consider trying some different shoes. You might be surprised!

Notes from a guinea pig

Ever wonder what it's like to be a guinea pig? A few XLHers had the chance to find out a few weeks ago, when I volunteered for the Gait, Mobility and Range of Motion study led by SAB chair, Carolyn M. Macica, PhD at Quinnipiac University's Frank H. Netter MD School of Medicine.

The results of the study won't be available for a while, since the researchers need to crunch all the data and study the information. But the results should offer some basic information for understanding adult issues related to XLH and the various services (physical therapy or occupational therapy) that might be of use for professionals who can help improve our quality of life.

As described in the call for volunteers, the study had five pieces: diagnostic imaging, biomechanical data, a physical therapy work-up and an occupational therapy work-up. There were four volunteers the day I went, and we all agreed that the diagnostic imaging (x-rays, in particular) was the most challenging for us. X-ray beds are NOT designed to lie on for more than a couple minutes, and we were getting full-body x-rays, not just one or two quick images. All of us also agreed that it was worth the discomfort to make this information available to scientists who were genuinely interested in our issues.

The biomechanical lab was the most interesting, simply because it was something I'd never experienced before. It was similar to what is done to create video game characters, where an actor has sensors attached to his joints, and then he goes through a range of motions while cameras pick up the movement of those sensors. The computer can then create a figure on the screen, using the data from the sensors. They did essentially the same thing with the XLH adults in the place of the actors. Sensors were attached to our wrists, elbows, shoulders, spine, hips, knees and feet. Then we went through a series of normal, everyday movements (walking, standing after sitting, moving the knee, moving hands, etc.) while they were recorded.

We also spent an hour each with a social worker, answering questions about our experiences with XLH and how the condition affected us emotionally. And finally, there was a session with an occupational therapist, which involves more than just job-related issues, but also hobbies and basic things like being able to get dressed and take care of daily hygiene. I found it interesting that there's a trend toward asking the patients what WE care about getting done, instead of assuming that everyone wants the same help. For example, one person might care a lot about keeping her house clean (not me!) while another may not care if she can sweep and mop, as long as she can pursue a hobby she's passionate about, so the focus would be on what assistance might enable the pursuit of that hobby, rather than the assistance that would help with sweeping and mopping.

All in all, it was a fascinating experience, and so heartwarming. Patients with a rare condition can get a little cynical after dealing with doctors who, not entirely surprisingly, have never heard of XLH, don't quite know what to do with us and are too busy to really find out. The scientists we worked with -- and I heard this from the other volunteers too, so it wasn't just my impression -- were obviously interested in what we had to say, very grateful for our willingness to share our experiences and our physical data with them despite the discomfort it caused us, and incredibly understanding about our physical (and emotional) limits when we were simply unable to do some portion of the study.

The data-collection part of this study is over, but I encourage everyone to watch for future studies and consider participating in one. It's important work, and it can help the participants too, giving some relief, at least briefly, from the feeling that we're helpless in dealing with this disease.

Alternatively, if you haven't done it already, the Burden of Illness study sponsored by Ultragenyx Pharmaceutical, and which doesn't require you to do anything more than sit at your computer and answer a bunch of questions (in English or French), is still collecting data. You can find it here:  https://www.amihealthy.com/custom/ultragenyx/burdenofillness/burdenofillnesshome.aspx?SITE=XLHNETWORK

Describing pain

Today's guest post is by Network member, Andrew Shortall. He was diagnosed with XLH at age two, and has become a self-taught chef, wine business person and a writer, with aspirations to become a novelist. 

“Can you describe the pain for me?”

This is a familiar, and often frustrating question for both patients and doctors. Especially for many XLH sufferers who invariably deal with chronic pain during their lives. How do you describe something to a medical professional that simply defies explanation? And how does a doctor interpret the varied phrases and descriptions provided by the patient?

I’ve read stories of patients becoming upset by the inability to accurately give details to their doctor. The doctor’s understandable frustration never helps, either. Nobody is at fault, of course. Pain is different for everyone. My daily pain varies in location, intensity and type. And my mother describes her XLH-related pains differently.

For example, I have osteoarthritic pain in my hips. Because the joint can stick and click sometimes, that can be very painful. But, what kind of pain? I’d say a burning ache that builds to a sudden stabbing crescendo, followed by blissful relief once the joint clicks and frees itself. As for my back pain, that’s different again. At rest, I have a mild to dull ache in the lumbar muscles. If I’m working in the kitchen, it builds in intensity and spreads across my mid back and then becomes pinching with every movement. And at that point, I know to sit down and rest if possible.

I’d almost liken the effort of describing pain to a beloved pet dog trying to tell us they’re not well. We know the signs, such as a limp when the dog is walking, or raising a paw to have it checked, or even not eating. But how do they explain it?

I think both patients and doctors need to find common ground. And one brilliant article I read recently by Christine Miserandino describes “spoon theory.” It is something a lupus sufferer created to describe her condition to friends and family. Spoons represent her energy on a given day, and every task takes one spoon away. By having common terminology, we can make it easier for all. After all, understanding our bodies and pains more won’t hurt, will it?

Attitude

Today's guest post is by member Nancy J. Alauzen. She is an adult with XLH and a positive attitude. In her spare time, she loves to read and recycle.

I have had XLH since I was born over five and a half decades ago. My mom skillfully managed my XLH until my college graduation. The main thing that has helped me successfully manage my XLH has been my positive attitude, inspired by my last name, Alauzen, which is pronounced "All Is In."

Over 20 years ago I started a business and planned to be a professional speaker giving presentations on overcoming obstacles. A mentor suggested “All Is In Attitude” to capture the correct pronunciation of my last name and the way I approach life. I’ve known from an early age that the glass can be seen as 'half full' or "half empty." I have chosen to approach life with the glass "half full." This has helped tremendously with living with XLH.

Those of us who live with XLH can fill a sheet of paper (or more!) with the many challenges we have faced along  the way. Early in my XLH journey, I naively believed that having tibial osteotomies to correct the deformity of the legs was the only hurdle to overcome! 

My checklist has grown over the last 40 years to include some of the following: Tibial osteotomies and subsequent removal of the hardware; Baker Cysts; two knee replacements; modification to a knee replacement; hearing loss, DVT, parathyroidectomy, chiropractic and podiatric issues; and classic dental abnormalities for XLHers, including almost a dozen root canals, half a dozen extractions, two fixed bridges and five implants.

Your checklist may be shorter or longer but the questions remain the same. Is it easy to live with XLH? No. Is it manageable to live with XLH? Yes. How? I believe the one secret and key to successful XLH management is “All Is In Attitude.” If we see our glasses as half full, we can manage our XLH more successfully.

Burden of Illness Study data

The first official presentation of the XLH Burden of Illness Study's data happened this week at the 2015 ENDO Meeting of the Endocrine Society in San Diego, CA.

It comes as no surprise to XLH patients that the study confirmed that "XLH can lead to significant long-term morbidity in the form of pain, stiffness, functional limitations, and fractures," but it has long been a widespread belief among the medical community (outside the few specialists in XLH) that the condition was primarily one of childhood, without long-term consequences.

For anyone who hasn't already completed the study, it has been extended, and you can contribute your information here: https://www.amihealthy.com/custom/ultragenyx/burdenofillness/burdenofillnesshome.aspx?SITE=XLHNETWORK

For more on the Study's data, see the full press release here: http://globenewswire.com/news-release/2015/03/09/713519/10123739/en/Ultragenyx-Announces-Presentation-of-Disease-Burden-Data-in-Adult-Patients-With-X-Linked-Hypophosphatemia.html