Monday, September 25, 2017

DX Severe Osteoporosis: Part V -- A Race of a New Kind




This is Part V of a multi-part essay about my own personal experience with osteoporosis. I will be taking you through the diagnostic and treatment phases of my care in hopes that it provides you a better understanding of osteoporosis in general, and pearls that you can use to better your own bone health. 


"Without struggle, without enduring pain, there can be no full awareness of one's being."
           Crucibles of Will



I had never lost my self-image as an athlete, even as I approached middle age. It's natural for most men in the prime of their life to think they are fairly invincible. I certainly did. My time as an Olympian and decades of competing in triathlons and road races erased any sense of mortality that I may have had. Osteoporosis--my bones dissolving from the core--just didn't fit.

The best thing that could ever happen to me was someone doubting my ability to do something. Ben (not his real name) a close relative of mine once said, "You won't ever make the Olympic Team." And there was another time when I wanted to get into horse racing and he said, "You won't even get a horse to the track, let alone win a race." His words would cut deep; they would linger in the pit of my gut, in the deep recesses of my bones. From that point on, you could try, but you couldn't stop me. I might not be the best in the Olympics and my horse might not have the legs of Secretariat, but I wasn't about to fail and I would just about die trying to succeed.

When I started searching for the causes of my osteoporosis I began to wonder if this trait of mine, my intensity, could have somehow contributed to the severity of the bone loss. Many serious health disorders are caused by multiple factors; life style and stress are certainly major contributors to disease. Whether from emotional or physical causes, stress stimulates a huge release of cortisol from the adrenal glands and it weighs heavy on the immune system. Just a cursory internet search into the causes of bone loss brings up the damaging effects of excess cortisol, the stress hormone, and the involvement of the immune system in bone remodeling.

Many different aspects of who you are and how you live either contribute to health, or lessen its hold. The daily patterns of ones life as it is seen over the span of years can often shed light on who we are...who we have become. Since childhood the dominant pattern for me--and, coincidentally, the cause of why I had to go seek the help of an orthopedist for my hip pain when this whole mess started--was that of my athleticism. I was a hard grinding athlete who believed that it wasn't just the quality of the effort that mattered but it was the quantity of miles that would make me the best. With this erroneous training method, I racked up way to many miles and was constantly in a state of over-training. A ten-mile run usually wasn't good enough...it had to be twenty. And a 75 mile training session on my bike probably wouldn't do when thoughts of my competitors somehow getting an advantage over me during the night as I wasted valuable time sleeping. No, that just wouldn't be enough. I HAD to go 110 miles instead. Usually, this was with no food and minimal fluid and electrolyte replacement. That is how I trained and lived, for decades. It wasn't that I was trying to be foolish or irresponsible; it was just that back then (forty years ago) there weren't a lot of athletes putting in the miles I was and there had been minimal research and awareness into the detrimental effects of over-training and the need to refuel and allow the body to rest. Rest was just a dirty word to me. I was simply totally focused on training hard...not on taking note of the needs of my body. Recovery wasn't in my vocabulary. If I wasn't totally flogged by the end of a training day (and days off were non-existent) then my competitors might be getting a jump on me...or at least that is what I thought.

Throughout high school I ran on the cross-country and track teams, swam on two different swim teams, and rode hunters and jumpers at our farm and in horse shows. Three run workouts a day, even during the "off" season, were more the norm than the exception. A two- or three-hour run, making a bee-line to a distant hill on the horizon, was my fun for an afternoon. Eating, replenishing my bones, was not on my radar. 

Each mile I ran felt like it fueled some magical fire that was deep within me. It was as if my body was a furnace built to carry this fire and that my earthly life was a burning. I didn't really see my body as a furnace that sometimes needed repairs and maintenance, I only looked forward to the burning. I only knew that the harder and longer I ran the hotter that fire seemed to get until an alchemy of sorts would take place. With the intensity of each run I became a crucible that got hotter and hotter until an amalgamation of all the forces within me and all the natural forces that surrounded me, came together, as one. I knew only one thing as I ran, that the intensity by which I ran nurtured that small burning coal that was in me. A coal that we all have within us, that we are all born with, and which will take us where ever we want to go. When I ran, ran hard, I would blow those coals into flame...into what I thought would be an inextinguishable fire.

Now, it looked like I might have been wrong about the inextinguishableness of that fire. Now I was at the starting line of a new race, one to figure out why I had osteoporosis, and it was a race against time. Sooner or later things were going to start crumbling, and I needed to find a way not only to stop the disintegration but to reverse the damage before the infrastructure started breaking down. And there were bigger threats. Early osteoporosis has a high correlation with other diseases such as diabetes, cancer, heart disease, and Alzheimer's. Once you're caught in an avalanche, once cramps seize up your muscles during a race, once a fire starts dwindling...it's usually all over. The stage was being set in my body; it was easy to see what would happen if I couldn't change the course it was on. With a T score of -4.3 my spine looked worse than a 100-year old's, but I was determined to put out this metabolic fire that was consuming my bones, and find a way to help them heal, if I could.

Bone densitometry is the gold standard for defining bone loss and determining fracture risk. If your density is low, you are at a greater risk for breaking a bone. When really low, like -4.3, it doesn't take much trauma to break something. A T score of -1.0 or better is normal. Between -1.1 and -2.4 is osteopenia and -2.5 or worse is considered osteoporosis. Anything below -3.5 is considered severe osteoporosis. At -4.3 and as a 46-year-old, I knew I was in for a rough ride.

The next few months were, indeed, bumpy. I had difficulty finding ways to educate myself in depth about the disease, and about all the bodily processes skeletal health, or lack there of, seemed to be involved in. I also had to identify the lab tests that would help lead me to the cause of my bone loss and to monitor progress. Then there was the treatment plan, one I felt would have a good chance of success because it would be tailored, individualized. A plan based on healing my whole body, not one relying only on drugs that built up bone density while ignoring or compromising overall health. My plan would be comprehensive, fine-tuned, based on how my particular body works, paying attention to its underlying functional patterns. I wanted to get this ALL figured out before I really started breaking things...but that didn't happen.

The Medical Scene:

After the two rib fractures while cross-country skiing, I sustained a mild compression fracture of a mid thoracic vertebra. In retrospect (isn't that always the way it is) I guess I shouldn't have been lifting that couch. In a medically inquisitive way of thinking, it was an "interesting" experience. It "felt" like a "pfffst"...like air rushing out of a blown tire when the vertebra broke. From a personal way of thinking--it wasn't actually interesting at all--just painful and distressing. When I told the endocrinologist about the fracture he wanted to see me right away. I didn't know why. As a chiropractic physician who has seen lots of compression fractures in patients over the years, I knew there wasn't much a medical doctor could do to help. But I went in to see him anyhow.

Health care should be a little less like processing cattle and more of an investigation of what is happening to real people with real hearts and real feelings. You have probably sensed the same, especially at the beginning of each doctor's visit. Each appointment always begins with allegorical weigh-in and measure. As if they are saying, "Yes, you are NOW at the doctor's office."

Being a doctor, the medical scene was completely familiar to me. (Although I don't weigh and measure patients at every visit unless it is warranted.) At the same time, the assumption was that now I was the patient and I would go along passively with whatever my doctor recommended. In general, this is the expectation of what patients should do, and it works out well much of the time. Most patients either don't actively engage in their own health are, or they just ask a few questions and look up some articles on the Internet. The medical jungle is daunting to the lay person. The amount of information available and the technical language it's encoded in shuts down just about any attempt to engage with it. For most people, it is hard to explore this territory and stay oriented. Amidst the confusion and complexity, it is easier to get lost than to stay on the trail. But I had a major jump on the game. I didn't know much about osteoporosis, but I could speak the language.

The endocrinologist that I had found at UConn seemed more like a coach than a guarded, emotionless physician. Of course he still had his nurses weigh and measure me at each visit--we couldn't do without that--but from the beginning he let me know he was on my bench. He was direct and told me he had never seen anyone with the extreme low bone density that I had who did not have multiple fractures. He never seemed to be rushed and would always take time to listen to my thoughts and concerns. Best of all, he didn't have those invisible blinkers strapped to the side of his head. He was willing to consider things from all angles, and to help me take this to any level of investigation that I wanted. Now with this compression fracture, I realized that he wanted to see me because he wanted to reassure me that we would find the underlying cause of this mystery and that I wasn't alone in this mess. He also explained the surgical procedures, vertebroplasty and kyphoplasty.

Once a person has sustained one compression fracture, the chances of them sustaining another within a year increases 4- to 6-fold! This phenomena is referred to as "vertebral fracture cascade" and he wanted to avoid this at all costs. Once several vertebra collapse a person's posture becomes kyphotic, bent forward, and this can eventually compromise heart and lung function when the kyphosis becomes severe.

Compression fractures of the spine can result from major trauma such as falling backwards onto the buttocks, or from minor traumas such as bending, lifting, coughing, or twisting. When bone is EXTREMELY fragile, fractures can result from simply walking around or, as with the second compression fracture I sustained, bending forward to pick up a stick when running. When the spine structure is severely weakened, it doesn't take much strain at all for the vertebrae to simply collapse.

Both of my compression fractures gave me a fair amount of pain for about a year. But it is not unusual (nearly 50%) for vertebral compression fractures to cause minimal or no pain and may go undetected. In fact, many of these fractures are discovered as "secondary findings" when radiological procedures are being performed for other medical reasons. (Tip: if you have had radiographs taken and read at a medical facility, it is a VERY good idea to have your chiropractor double check them.)

So how do you know if you have sustained a vertebral compression fracture? Typically your chiropractor or medical physician will be able to find a localized area of tenderness when they are examining your spine. He or she may also notice an increased kyphotic or forward angulation in your spine if there is a fracture in the thoracic area. Thoracic and lumbar spine fractures are the most common areas of the spine to sustain compression fractures although they can occur in the cervical region also. If your doctor suspects a fracture, x-rays will be ordered. A bone scan, CT (computed tomography), and/or MRI (magnetic resonance imaging) may also be indicated to determine if the fracture has occurred recently or if it is old and occurred months or years ago. These tests can also help your doctor evaluate any neurological involvement and also to rule out any suspicion of cancer.

The endocrinologist explained to me that if the compression fracture was severe enough they could inject cement directly into the vertebral body to reduce the pain and stabilize the fracture, a procedure called a vertebroplasty, or use a balloon to expand the fracture prior to injecting the cement. This second procedure, a kyphoplasty, attempts to bring the collapsed vertebra back to its original size. After assessing the fracture, he determined that it was not in need of either procedure. (Whew!)

At that time, 18 years ago, these surgical procedures were becoming a common treatment for compression fractures. But more recently, they have come under considerable scrutiny, not only due to the significant risk of adverse effects such as bleeding, infection, allergic reactions, and leakage of bone cement into the surrounding tissues, but also regarding questions concerning their long-term benefit. In fact, many believe that these procedures may increase the risk of the fracture cascade by placing undue mechanical stress on adjacent vertebrae.

In 2010, the American Academy of Orthopaedic Surgeons actually recommended against using vertebroplasty and only gave a weak recommendation for kyphoplasty.(1) In 2013, a study by Martinez-Ferrer et al.(2) published in the Journal of Bone and Mineral Research showed that there was a 30% chance of sustaining another compression fracture after a vertebroplasty. They also found that leakage of cement into the disk beneath the vertebra being repaired contributed up to a six-fold increased risk for developing a new vertebral fracture. When hard cement leaks into the disk this places increased mechanical pressure on the vertebra below. The authors state that other comparative studies indicate a similar problem with kyphoplasty.

As a chiropractor, I wasn't too keen on surgical procedures or drugs. Certainly in the case of the vertebroplasty or kyphoplasty, these would not have been my first choice even if they had been recommended by the endocrinologist. Chiropractors as a general rule are dedicated to the goal of genuine healing. We are not satisfied with eliminating symptoms by suppressing them or by short-circuiting the body's patterns of functioning. Chiropractors support the body's innate ability to heal, and feel that drugs and surgery should be used only as a last resort. Sometimes these interventions are a necessary part of treatment, but even then, there is a lot that can be done to strengthen the body through conservative means. In my case, I wanted to try to find the underlying causes of my disease and to address them. I wanted to give my body the best possible chance to heal itself. Most of the other doctors I saw had different ideas so I always had to reel them back in and get them headed in the right direction...the direction I CHOSE for treatment.

Genetically speaking we humans were only designed to live for thirty-five years or so. After that, after we have procreated, we really didn't have much reason to live...genetically speaking that is. Bone density follows this script and only actively increases up to about age 35; after that bone is still actively replaced, but only maintains the density it achieved earlier. Eventually this density starts to decline, and my density had been declining for years--possibly decades. In terms of nature's plan for my bones, there was nowhere to go but down. I, on the other hand, had other plans in mind.

               "This is why I run: for the sake of the fire; for the burning."


1) The Treatment of Symptomatic Osteoporotic Spinal Compression Fractures ̴ Guideline and Evidence Report. Adopted by the American Academy of Orthopaedic Surgeons Board of Directors, September 24, 2010. http://www.aaos.org/research/guideline.pdf and http://www.aaos.org/news/aaosnow/oct10/cover1.asp

2) Martinez-Ferrer, A. et al. 2013. Risk factors for the development of vertebral fractures after percutaneous vertebroplasty. Journal of Bone and Mineral Research 28(8):1821-1829.

Tuesday, September 5, 2017

DX Severe Osteoporosis: Part IV -- Zebras



The Will

"Sometimes you don't know how deep inside you can go until you put yourself in a place where there is nothing between you and the mirror in front of you to blur the image; a mirror that shows not just your form, but your capacity--what you are made of. To give off light, along with passion you also need will. Will carries you through hard times and loneliness when no one else believes you can accomplish what you have set out to do. The will focuses the flare of passion, it is your navigator, the director of our life force, the hands that tend your flowering. Like the skeleton, will gives you form. It doesn't just support your movements, nor is it just a reflection of your musclular capabilities, but your will defines the absolute raw intensity of your nature, and by this you can bring into being all that lies within you as potential."
Crucibles of Will


This is Part IV of a multi-part essay telling you about my own personal experience with osteoporosis.


Zebras

After receiving "the diagnosis" I realized I had been getting signals for some time that something was wrong. My hands and lower back ached constantly; I had about as much energy as a dog in August; and felt cold all the time, as if it were perpetually January. My skin, especially on my chest and arms was incredibly sensitive and I hated being touched in these places. I was irritable and I guess I was depressed, although I would have denied it completely. Sharp noises or gentle pokes from my children during play caused a sickening wave of adrenaline response to course through me. The two fractured ribs I sustained while training for the American Berkebeiner, a 50-kilometer cross-country ski race in Wisconsin, now made more sense. I had just been pulling hard on the ski poles going up the hills...no falls, no direct trauma; just intense muscular shear forces on the now obviously structurally unsound bone.

The newly discovered frailty also began to take its toll on my professional life as a chiropractor. Every time I entered a treatment room I felt as if I were taking on a sumo wrestler...heaven forbid if the patient was 6 feet plus and weighed over 200 pounds. Chiropractic treatment in general is very precise and gentle, but it does require some motions that impart more physical stress to the doctor than they do to the patient. Even when treating normal-sized adults, adjusting them would send shock vibrations rattling through me. It was as if my resilience and strength had faded away, and it wasn't the running shoe that was broken down in the morning, it was me.

Lab tests are an important source of information, not only about what is going on inside a body, but also about what isn't going on. Over the next five years laboratory testing would play a huge part in my life as I tried desperately to find out not only why I had osteoporosis but how to fix it.  Severe osteoporosis (-4.3 T score on bone density examination) in a relatively young male is rare. For several weeks after the initial diagnosis the endocrinologist thought there may be a more serious disease process lurking and that it was the source of the unusually severe bone theft from my body. The list of diseases that can cause extensive bone loss is very long. From the common condition where one of the parathyroid glands becomes overactive (hyperparathyroidism), to the deadly bone-destroying multiple myeloma. We had to rule each of them out. Initial lab work helped eliminate most of the dreaded disorders. The only real clues we came up with were that my urine was rich in calcium and had large amounts of bone collagen in it, the result of active bone destruction--way too much of it.

There is an old saying, "When you hear hoof-beats, don't think zebras." In other words, if you hear hooves behind you, don't expect to see a zebra when you turn around...it will probably just be a horse. Dr. Theodore Woodward, a medical doctor in the 1940s, coined this phrase as a way of encouraging fellow doctors not to delay treatment by looking for rare, complex diseases at the beginning of the differential diagnostic process, because in all likelihood, the patient's symptoms are probably being caused by something simple and easy to treat. There is a lot of truth to this...although sometimes, there are zebras.

To rule out the systemic mastocytosis the doctors had to drill a hole through my bone and take out a core sample to look at under a microscope. As an added benefit to this procedure, it was also a good way to see how my bones were really holding together and to assess the quality of my bones. 

Normal bone on the left. My biopsy on the right.
During the two weeks before the biopsy, I took two short courses of oral tetracycline. This would be absorbed into my bones and used as markers for the lab to determine the pace at which my bone was being made. The bone tissue was taken from the right side of my pelvis. The surgeon from UConn Health Center first injected a local anesthesia into the area, made a small incision and then, with a hollow hand-drill called a trephine, began drilling through the bone. The trephine was shiny but still medieval-looking, and had a rudimentary handle on one end with large jagged teeth on the other. The doctor took her time twisting the trephine; I could feel the teeth as they passed through each layer of bone. She explained that it was easy to damage the sample; osteoporotic bone is fragile, especially the trabeculae--the lattice of three-dimensional structural beams sandwiched between the inner and outer cortex that give bone its ability to be light yet strong. Trabeculae are designed to withstand the forces of normal activity, like running, but not drilling. If she used too much force, the trabeculae would snap and the pathologist would not get a good picture of their integrity, their "connectivity."

I must admit, having a hole drilled through my pelvis was unnerving. I know it really wasn't a major procedure, patients have a lot worse things done to them. It didn't even hurt that much except for the injections of anesthesia through my abdomen to help numb the inner part of my pelvic bone. But the whole procedure just seemed crude. My response had nothing to do with the doctor; she was extremely sensitive, caring and competent. Maybe it was the sedative she gave me, but during the surgery I kept thinking about the ancient Indians of South and Central American, and how archeologists have discovered skulls with holes drilled into them. Holes that had healed around their edges, indicating that the people/patients had been alive when the procedures were performed. Although they were performed with the intention to heal, it had to have been excruciatingly painful--such an invasion, an assault upon those individuals. What was being done to me had been done to them long before--the drilling-- the same procedure of a person twisting a tool into the inner physical being of another.

The doctor finally broke through the inner bone cortex to the softer tissues underneath, and pulled out a 3/4 inch, pencil-thick, piece of bone. She placed it carefully into a small bottle of chemical solution and handed it to me. I had never seen a piece of my body like that before. It was all so odd to me.

I had been told that the aftereffects would not be any worse than if I had bumped my hip into a kitchen counter. That description might have been accurate, but only if I had been running twenty m.p.h. through my kitchen when I hit it. For the next three days I dragged my leg around like a lead weight; I couldn't even think about running for two weeks.

Trabeculae in bone should be plentiful, robust, and intact. What we found when we looked at the biopsy slides was that mine were few in number, thin, and disconnected. In a crime lab with just bone to look at, a technician would have pinned me as a 100-year-old malnourished female. Rapid loss of bone does that to trabeculae. When osteoclasts become aggressive, devouring excess bone and leaving large deep gouges in the bone surface, even normal functioning osteoblasts are incapable of fully filling in the holes with new bone. The result is pitting in the cortex of the bone and trabeculae that get thinner and thinner until they separate from adjacent bone.

Looking at my bone biopsy under the microscope, we could see a lot of the trabeculae just hanging there like stalactites and stalagmites giving no strength at all to the bone. It was similar to the beech trees in New England that become weakened by a fungal pathogen. Hidden from view just under the bark, the beech's inner structural core is silently being eaten away. To the untrained eye, the trees appear healthy enough, beautiful majestic giants in the forest, until a small wind topples them over...the result of "beech snap." Osteoporosis is similar. Often silent, often afflicting healthy appearing individuals, but underneath hidden from view are overzealous osteoclasts eating away, like a fungus, at the structural core.

As with the wood in "beech snap," trabeculae, in osteoporotic bone, become incapable of resisting the stresses of everyday life. Hips snap and the spine crumbles, and like the broken beech that can't regenerate, the trabeculae can never re-attach. The manner by which bone forms does not allow for it to develop where there is nothing but empty space. This is where all those articles I had read about severe bone loss being "irreversible," began to make sense. But I did not want to accept that. I wanted to find a way around this seemingly impossible physiological impasse. There had to be a way, not just to gain back density by using a drug, but to gain back both the bone density and the structural integrity of newly remodeled bone.

The biopsy ruled out mastocytosis but actually brought up more questions than it did answers.
Zebra striping. Intermittent bone formation.
Besides having disconnected trabeculae, my bone had an odd appearance. The biopsy report called it "zebra striping," or intermittent bone deposition. There would be up to four layers in some areas, with new bone and then no mineralized bone, then bone, then no mineralized bone. It looked like the layers of different soils at an archeological dig. The endocrinologist estimated that the time-lapse between each stripe was days or weeks, not months. Neither the pathologist who read the biopsy nor my endocrinologist knew what to make of the queer stratification. They had seen this striping before on rare occasions with metal toxicity, but the biopsy had been stained for aluminum and iron and it came out negative. Lab testing of blood, urine, and hair for other heavy metals came up negative as well.

It was becoming clear to me that the only way to track down and destroy the beast that stole my structural strength was to immerse myself deep in the study of osteoporosis. I wasn't about to leave this solely in the hands of doctors who would drop me into a file drawer and leave me there for weeks and months at a time. I began to read everything I could about bone biology, and specifically, osteoporosis. I went to osteoporosis seminars and week-long conventions. I took courses on how to read bone density exams. I joined the American Society for Bone and Mineral Research, the International Bone and Mineral Society, and the International Society for Clinical Densitometry. I had dissected a lot of human cadavers in anatomy class at chiropractic school so I knew what it was like not only to study something intensely, but to pick through each and every part of a very complex puzzle. I wasn't just going to study this disease, I was going to rip it apart, piece by piece, clue by clue. Like a dog kicked into a corner, (s)he will come out fighting. I may have skipped a few beats when I first heard the words "severe osteoporosis" as my diagnosis, but my heart quickly rebounded, pounding like a competition-starved athlete ready to do battle. I was sure this beast wasn't much tougher than some of the big ugly guys I had competed against when I was vying for a spot on the USA Olympic Team. I might not win but I sure as hell would attack with everything I had, even down to the center of my physical being, down to my bones. Or at least what was left of them.

"When you go to the core of anything, you go to the heart of its reality, its truth, its real substance."



Saturday, September 2, 2017

Is Prolia the right choice to help reduce fracture risk ???

When faced with fractures from severe osteoporosis, taking a bone specific medication to gain bone density (and hopefully bone strength) can be warranted, at least in the short-term. Prolia (denosumab), or one of the four available bisphosphonate medications on the market, are typically the options given by medical doctors for treatment of osteoporosis. None of these drugs are great--they can all cause mild to severe adverse side effects and long-term use can lead to atypical femur fractures and osteonecrosis of the jaw (ONJ)--but in some severe cases, when fracture risk is extremely high, we just have no choice but to use a medication. More and more doctors are beginning to prescribe Prolia, and less so the bisphosphonates. The reason for this is that studies show Prolia to increase bone density more so than the bisphosphonates. But...there is a hitch. (There usually is when it comes to drugs.)

Prolia is a human monoclonal antibody that inhibits an immune protein called RANKL. (Dr. McCormick talks about RANKL in his book, The Whole-Body Approach to Osteoporosis.) RANKL stimulates osteoclast cells to
resorb (break down) bone. By limiting the body's ability to produce RANKL, Prolia is able to effectively reduce osteoclastic bone resorption and increase bone density. The problem is that RANKL is also needed for the immune system to work properly. So by limiting RANKL production we see immune related side-effects such as muscle and joint pain (inflammation), nausea, diarrhea, headache, skin irritation, skin blistering, fever/chills, dizziness, numbness, urinary tract infections, abdominal pain, elevated heart rate...etc....etc....

But side-effects may not be the worst thing about USING this drug...it may be from STOPPING this drug. In a review of the literature, the European Calcified Tissue Society (ECTS) found that when Prolia is discontinued there is "a rapid decrease of bone mineral density (BMD) and a steep increase in bone turnover markers (BTMs)". Case studies show "multiple vertebral fractures, after discontinuation of denosumab."

Analysis of the FREEDOM and FREEDOM Extension Trial suggests "the risk of multiple vertebral fractures may be increased when denosumab is stopped due to a rebound increase in bone resorption." "Clinicians and patients should be aware of this potential risk."

This rebound effect makes taking Prolia short-term not an option unless it is backed up by a minimum of 6 to 12 months of a bisphosphonate.

Tsondi, E. et al. 2017. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS,
Bone Aug 5;106:11-17.
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