Can agromegaly make you taller without growth plates?

Some people have claimed to have grown taller in a non-epiphyseal plate driven method via HGH.  Now it’s important to note that acromegaly is not solely based on HGH and there are some cases in gigantism where HGH levels are lower than people who supplement via HGH so it’s possible there’s another factor driving the length.  This topic was discussed before here.  In that page there are additional acromegalic x-rays and additional discussion of non-growth plate driven height growth.

You don’t just grow interstitially, you also grow appositionally even on the longitudinal ends of the bones.  For most, this is insignificant but for someone with high HGH and thereby higher bone turnover this could be much more significance but the question then becomes if they are gaining height in the feet and hands due to the larger number of bones there then in legs and arms then why aren’t the growing in the torso.

It follows logically that if two people are growing by different methods interstitial growth(traditional growth plate growth) and appostional growth on the longitudinal ends(endochondral ossification of the articular cartilage or some other bone thickening method) then the two bone shapes will look differently on the x-ray.

Here’s a “normal” hand x-ray:

Here’s an acromegalic hand x-ray:

One thing that strikes immediately is the greater whiteness between the acromegalic x-rays and the normal x-rays but the two bone shapes seem largely the same.  However there does seem to be greater articular cartilage spacing which could explain the increased hand size.

I couldn’t find a spine xray of someone with acromegaly but here’s a chest x-ray:

Unfortunately you can’t really tell anything about the spine because the bones are so thick.

Here’s a normal chest x-ray:

So basically the x-rays tell you that acromegaly may or may not cause a form of non-growth plate based longitudinal bone growth.  There’s just not enough x-rays of people with acromegaly to draw conclusions.  Or x-rays of people who supplement with HGH like Richard Piana.

LSJL Update 1-3-2017

Here’s the last LSJL update.

Here’s the latest feet images

20170103_080959

One effect that clamping my right foot has had is that my right quad is a lot bigger than my left quad now.  I left weights as muscle should help with LSJL as muscle can contract to stimulate bone and generate hydrostatic pressure.  Differences in feet size change weight distribution.  So now I’m going to clamp my left foot and not my right foot to try to get it to catch up.  If I can bridge the gap between the two that’ll be strong proof of LSJL.

Here’s a picture from another angle that shows the size difference better:

20170103_081115

The right calcaneus is also bigger so if I get some left foot growth I’ll gain some small but significant amount of height.

I may have gained some arm length but it’s within measurement error.

I don’t think clamping the toes is what’s helping.  I think it’s the clamping of the feet itself.  I am doing hand clamping as well.  I am clamping individual fingers and pretty much the whole hand is growing and not the specific fingers.  I have x-rays showing that my left hand fingers were longer except for the metacarpal.  So if I can’t get my left foot to catch up that’ll be another option to prove LSJL.  If my right hand keeps growing significantly I can get x-rays.

We’ll see how things go with my left foot.  It seemed I was almost ready to go up a shoe size with my right foot but with the muscle imbalance I’ll have to go with my left and get them to equalize.

The Metal Fixator To Hold The Cut Bones In Place Is The Critical Element

Ever since I found out that the company EpiBone was working towards creating lab grown osteochondral tissue, it was obvious that they were working towards making bone tissue that will go through the natural process of chondrocyte formation, chondrocyte condensation, osteocyte differentiation, and eventual total ossification of the previously chondrogenic tissue. This process is called endochondral ossification.

The ultimate goal as claimed by the CEO is that they want to grow bone tissue that can be implanted into bone defects in a living human. Based on the claims made, the obvious corollary to this claim is that they will also be working on bone tissue that can expand and grow on their own.

The idea is like this specific situation.

A young child (8-10 years old) who still has developing and growing limbs develops cancer of the bones aka osteosarcoma. The surgeons realize that they have to remove that bone tissue that has the cancer. That bone part is taken out, which could be a rather large chunk, but the orthopedist realizes that the child has not finished growing. They need to now replace that piece of bone they took out with a new one, which can also grow in length and width along with the bone in the limbs of the kid.

Alsberg’s team as early as the early 2000 showed that it was possible to grow “growth plate like” tissue that grows  volumetrically. Using that research as a stepping stone, the research team at EpiBone would be able to use the same growth factors, scaffolds, and peptides to get a growing bone-cartilage tissue in the lab.

The surgical technique of then implanting that Pseudo-Epiphyseal Cartilage tissue into the area of bone that is missing is not hard. That part where you fuse the bone edge of the implant with the edge of the originally cancerous cut bone does not need to be that difficult, although it can be technically challenging right now.

It appears that the real, true critical part that is limiting the possibility of using just stem cells and tissue engineering techniques to lengthen bone is not in the research.

It comes down to the need to fix the cut bones into alignment with each other, and not move about.

This is the entire reason why the original creator of the limb lengthening method need to ever use the External Fixators. The Fixators were always there to hold the bones in place, so that they don’t become crooked, or bent.

If we now really sat down and thought about it like a Monday Morning Quarterback aka “hindsight is 20/20”, the 2 decades of research on lengthening of bones done by Gavriil Ilisarov in the Kurgan from the 1960s to 1980s to perfect the technique of bone lengthening was bound to be successful, as long at the rate of lengthening of bone was just slow enough to account for osteogenic healing and tissue/callus formation rates. Once you realized that the bones in our body is one of the tissues in our bones with have the highest rate of healing potential in terms of broken bones over time fusing together, on a very theoretical level, there was no doubt that bones that have an external fixator that can pulls bones slowly aka lengthening would eventually heal over, resulting after say 3-6 months of tensile pulling, would result in longer bones.

Ilizarov used the Circular External Fixator to hold the bones into place. The technique for bone lengthening eventually was learned by the Germans ie at Dr. Betz, who developed his own internal fixator technique. Dr. Dror Paley developed his own internal fixator way called PRECISE. You always need some type of really strong, non-biodegradable element to hold the cut bones into place, whether it is to be placed inside the bone or attached to the bone from the outside.

The most minimally invasive method for limb lengthening surgery was developed by Dr. Bai Helong in China as early as the early 2000s, which involved a very thin method rod that is screwed to the top cut bone and the bottom cut bone, which is elongated. The rod would run in parallel to the axis of the long bone. As the metal rod is elongated through a mechanical action, the bones that the metal rod is screwed into, would elongate with the rod.

The callus that is formed in the region where the bones meet is stretched out and then reformed. This is what really happens during distraction osteogenesis. This is, and has always been the way bone lengthening actually works. Tissue that is developed between the interface of two bones, in the form of some pre-chondrogenic tissue aka “callus”, is stretched, ossified slightly, and then stretched again, until the desired lengthening of the bones finally is reached.

Notice how you always need to screw metal rods into the bones. You need the metal rods to go through the bones to give the bones enough structural strength.

This is one of the biggest issues that critics of the current bone lengthening methods have. They don’t like the idea that not only do you break the bones, but you also have to drill into the already cut bones at least in 2 different locations of the long bone, just to hold the overall long bone into position.

If an alternative to the current bone lengthening methods is ever developed, the technique will still need to hold the bones into position, without the chance of the cut bones falling apart and the legs ending up bent, or never fully fused back.

In a previous talk I had with someone over Skype, I had believed that maybe it was possible to implant some really strong bio-degradable material as a replacement to the metal rods or metal fixators.

Another LSJL study shows bone length increase

I actually missed that this LSJL study showed height increase as it was a minor comment that joint loading increased height of the femoral head.  Since the femoral head is a diagonal offshoot of the femur it may not necessarily increase height but it is an increase in bone length all the same.  However, the osteonecrosis induced in the study may be a prerequisite to induce the femoral head growth.  However, it should be noted that the osteonecrosis decreased femoral head height but the degradation of existing bone may have allowed for new bone growth.

This is an LSJL related study published by Yokota and Zhang.  The primary author seems to be more Zhang who seems more into the lengthening effects than Yokota.  This study shows that joint loading increases fibrous differentiation.  And fibrous differentiation would be a potential intermediary step for neo-growth plate formation.  Knee loading increased vessel remodeling and osteoclast formation which would be needed to make room for a new growth plate but these levels were only slightly greater than control group and reduced from the osteonecrosis group so we can not say for sure whether this will happen in LSJL on a normal bone.

Overall this study shows that LSJL does at least one of the steps required for neo-growth plate formation: fibrous type tissue formation.  This fibrous tissue would then have to be further differentiated into more cartilagenous tissue.  The perichondrial ring(or ring of LaCroix) is fibrocartilagenous.

Knee loading protects against osteonecrosis of the femoral head

“Osteonecrosis[loss of blood to the bone] of the femoral head is a serious orthopedic problem. Moderate loads with knee loading promote bone formation.  Using a rat model, we examined a hypothesis that knee loading enhances vessel remodeling and bone healing through the modulation of the fate of bone marrow-derived cells. In this study, osteonecrosis was induced by transecting the ligamentum teres followed by a tight ligature around the femoral neck. For knee loading, 5 N loads were laterally applied to the knee at 15 Hz{this is pretty high frequency} for 5 min/day for 5 weeks. Changes in bone mineral density (BMD) and bone mineral content (BMC) of the femur were measured to evaluate vessel remodeling. Femoral heads were harvested, and bone marrow-derived cells were isolated to examine osteoclast development and osteoblast differentiation.  Osteonecrosis significantly induced bone loss, and knee loading stimulated both vessel remodeling{vessel remodeling shows promise as that would be very helpful for neo growth plate creation} and bone healing. The osteonecrosis group exhibited the lowest trabecular BV/TV in the femoral head, and lowest femoral BMD and BMC. Knee loading increased trabecular BV/TV as well as BMD and BMC. Osteonecrosis decreased the vessel volume, vessel number and VEGF expression, and knee loading increased them. Osteonecrosis activated osteoclast development, and knee loading reduced its formation, migration, adhesion and the level of “pit” formation{pit formation could potentially be beneficial though as that pit could where a neo-growth plate would go}. knee loading significantly increased osteoblast differentiation and CFU-F{An increase in CFU-F means an increase in mesenchymal stem cell proliferation which is a good for neo-growth plate formation but doesn’t guarantee that it will occur}. A significantly positive correlation was observed between vessel remodeling and bone healing. Knee loading could be effective in repair osteonecrosis of the femoral head in a rat model [by] promoting vessel remodeling, suppressing osteoclast development, and increasing osteoblast and fibroblast differentiation. “

“The mechanism of knee loading is considered to change intramedullary pressure of femoral and tibial bone cavities. The load driven pressure may generate fluid flow in a lacuna canalicular network in bone cortex. The pressure activates bone metabolism-related genes in femur and tibia”<-what we are interested in an increase in fluid flow and hydrostatic pressure to induce chondrogenic differentiation.  Hydrostatic pressure by itself isn’t likely to induce chondrogenic differentiation by itself as it is typically three orders of magnitude below the pressure needed to induce chondrogenic differentiation.  But the addition of bone deformation and fluid flow may bridge the gap and induce chondroinduction.

“Male Sprague–Dawley rats (~12weeks of age)”

“knee loading was achieved through dynamic loads applied to the left and right knee joints of rats in the lateral–medial direction, respectively. To position the knee properly, the lower end of the loading rod and the upper end of the stator were designed to form a pair of semispherical cups. The lateral and medial epicondyles of the femur together with the lateral and medial condyles of the tibia were confined in the cups.  The tip of the loader had a contact
area of 15 mm in diameter.”

See Figure 1 of the paper(first link on the page) for an image of the knee loader.

Loading increased vascular remodeling in the osteonecrosis + LSJL group but not versus control.  But there was no normal bone plus loading group.

Joint Loading actually seemed to reduce the number of mesenchymal stem cells but that could be due an increase in differentiation.  Mesenchymal condensation was more visible in the osteonecrosis group and mesenchymal condensation is a prerequisite for neo-growth plate formation.

Bone, Accepted manuscript. doi:10.1016/j.bone.2015.09.012

Knee Loading seemed to restore osteoclast adhesion and migration to slightly above control levels but that slightly above could indicate activity that would remodel the bone enough to allow for mesenchymal condensation.

Bone, Accepted manuscript. doi:10.1016/j.bone.2015.09.012

Knee loading greatly increased CFU-F and Osteoblast differentiation versus both osteonecrosis and control group. “Knee loading enhanced differentiation of osteoblasts and fibroblasts.” Fibroblastic tissue(marked by CFU-F) could potentially become chondrogenic tissue.  Fibrocartilage is a thing.  But to be a true growth plate, additional mechanical stimulation would be needed to turn that fibrocartilage into pure cartilage.

Bone, Accepted manuscript. doi:10.1016/j.bone.2015.09.012

Knee loading increased the height of the femoral head partially

Bone, Accepted manuscript. doi:10.1016/j.bone.2015.09.012

It’s a big breakthrough that LSJL increased height in the femoral head.  The osteonecrotic bone had far more marrow in B, thus under osteonecrosis LSJL may have had more room to induce growth.

The perichondrial ring of the growth plate is fibrocartilagenous in nature and may be the source to provide cells to the growth plate.

“The current histology and bone mineral density data are suggestive of the role of bone marrow-derived stem cells in load-driven bone healing, and they also establish a causal relationship between the observed vessel remodeling and bone healing effects with knee loading”<-This is huge because we want to induce stem cells to form neo-growth plates.

According to this LSJL would increase blood perfusion which would be the most interesting thing.  If the bone has more blood flowing through can create unique biological opportunities remember one of the key steps to distraction osteogenesis is a blood clot.

It was mentioned that LSJL upregulates bone metabolism related genes.  Here’s a study that lists bone metabolism related genes:

Association of osteoporosis susceptibility genes with bone mineral density and bone metabolism related markers in Koreans: the Chungju Metabolic Disease Cohort (CMC) study.

“bone metabolism-related markers, such as serum concentrations of calcium, phosphorus, PTH,
and 25(OH) D”

“genetic variants of MEF2C, ESR1, TNFRSF11B, and SOX6 were associated with bone metabolism-related markers”

Lowering Fbn1 levels may increase bone length

Even though it mainly seems like it’s an active growth plate thing, it’s possible that FBN1 deficiency could stimulate neo-growth plate activation as it does stimulate TGF Beta activation and there’s ectopic tendon calcification.

TENDON-DEPENDENT CONTROL OF LONGITUDINAL BONE GROWTH

“Skeletal abnormalities caused by disproportioned bone overgrowth (LBO), are a common trait in Marfan syndrome (MFS), a connective tissue disease caused by mutations in the extracellular matrix (ECM) protein and TGFβ regulator fibrillin-1 (Fbn1). The cause of LBO in MFS is unknown and therapies are not available. Fibrillin-1 hypomorphic mouse model (Fbn1mgR/mgR) faithfully replicates MFS skeletal manifestations including elongated bones however, its early demise due aortic rupture limit the magnitude of LBO investigation.

To circumvent Fbn1mgR/mgR lethality and investigate the contribution of specific skeletal tissues to LBO, Fbn1 gene expression was targeted in developing limbs by crossing Fbn1Lox/Lox mice with Prx1-Cre, in or bone with Osx-Cre, in cartilage and perichondrium with Col2-Cre, in skeletal muscles with Mef2c-Cre, and ligaments and tendons with Scx-Cre. Bones length of Fbn1 conditional mice KO was measured and relevant histological, cellular and biomechanical parameters were assessed.

Fbn1Prx1−/+ and Fbn1Prx1−/− mice had longer limbs bones compared to WT mice and amount of fibrillin-1 in the limb matrix was inversely proportional to bone length. Interestingly, Fbn1 gene targeting in ligaments/tendons resulted in LBO, altered tissues’ mechanics and TGFβ-induced switch of tendon stem cells to chondrocytes. Gene targeting in other limb’s anatomical locations did not result in LBO thus ruling out the participation of surrounding tissues to this bone phenotype.

Fbn1 gene inactivation in ligament/tendon is associated with increased local TGFβ, altered biomechanical properties and LBO. As previously reported, ligaments/tendons respond to changes in mechanical load by increasing the levels and/or the activity of TGF-β while bones undergo morphological adaptation in response to muscle loads transmitted by tendons. We hypothesize that dysregulation of local TGFβ signaling and altered biomechanical properties of fibrillin-1 deficient ligaments/tendons affect endochondral ossification by improper load transmission to bone. By showing ligament/tendon-dependent regulation of postnatal longitudinal bone growth this study provides a paradigm-shift in tendon biology and it shades a new light on LBO pathophysiology in MFS, thus providing the bases for new pharmacological interventions for this and related skeletal conditions.”

So lower levels of Fbn1 means longer bone length and FBN1 deficient tendons and ligaments alter endochdondral ossification by altering load transmission to bone.  We can alter load transmission without altering FBN1.

Here’s a grant(2016) related to the subject:

TENDON-DEPENDENT CONTROL OF LONGITUDINAL BONE GROWTH

“disproportionate increase of longitudinal bone growth that causes serious malformations of the limbs, anterior chest and Spine is the clinical hallmark of patients afflicted with Marfan syndrome (MFS), a connective tissue disease caused by mutations in the extracellular matrix (ECM) protein and TGFβ regulator fibrillin-1. Our preliminary studies of mice with tissue-specific ablated Fbn1 gene activity have revealed an unsuspected causal relationship between tendon/ligament (T/L) dysfunction and longitudinal bone overgrowth (LBO). Specifically, we found that (1) Fbn1 inactivation in T/L cells was necessary and sufficient to promote linear bone overgrowth associated with dysregulated growth plate (GP) gene expression; (2) fibrillin-1-deficient tendons displayed abnormal tissue architecture and impaired mechanical properties, particularly at bone- insertion sites; (3) the relative amount of fibrillin-1 correlated with discrete changes in tendon mechanics; (4) tendon-derived stem/progenitor cell (TSPC) cultures deficient for fibrillin-1 differentiated improperly as result of increased latent TGFβ activation; and (5) ectopic tendon calcification of fibrillin-1-deficient tendons was commonly observed. We therefore hypothesize that fibrillin-1 assemblies normally restrict GP-driven linear growth of neighboring bones by specifying the mechanical properties of tendons through the control of ECM organization and TGF-regulated TSPC differentiation. Accordingly, the scope of our proposal is two-fold; first, to characterize how fibrillin-1 deficiency translates into tendon dysfunction and tendon-associated LBO, and second, to establish how local TGF hyperactivity in tendons promote tissue degeneration thereby leading to excessive linear growth of the adjacent, structurally normal bones. To this end, we will characterize the expression of molecular and cellular determinants of tendon development and maturation in mice deficient for fibrillin-1 in T/L matrices, in addition to employing computational approaches to identify probable disease-causing molecular abnormalities in the GP of these tendon-defective animals (Aim 1); apply data-driven statistical models to determine how graded fibrillin-1 deficiencies correlate with tendon mechanics and associated LBO (Aim 2); and assess whether systemic TGFβ neutralization modifies tendon pathology and LBO severity in fibrillin-1-deficient mice (Aim 3). The results of these investigations are expected to substantially advance our limited understanding of tendon function in health and disease and implicitly, of the cellular, molecular and tissue factors that coordinate the postnatal growth of musculoskeletal tissues. ”

 

LSJL Update 12-7-2016

Here’s the last LSJL update.

The growth seems pretty solid from last update:

Current

20161206_162420

1 month earlier:

20161108_155418

So increasing the intensity and duration of clamping on the right foot seems to have worked.  I’ll keep trying to see if can get more growth.  I may have some growth in my right hand from clamping there but I’ll wait to see if the growth is more significant as I can always get x-rays there.

I’ll also try to get growth in the longer limbs but once I can prove growth in smaller limbs I can get more resources to use for the longer ones.  It does seem like the foot itself is growing more than the toes so maybe it’s easier to grow those bone shapes even though there’s a lot of the same obstacles for longitudinal bone growth for “short” bones there could be differences we don’t know about.  these bones are also surrounded by different tissues than long bones which could make a difference.

So I’ll try the same intensity/density of clamping on the foot and see if I can grow on the hands and other limbs and increase clamping intensity on those areas.