LSJL studies 5: LSJL device design

This paper discusses a lateral bone loading device. It mentions a capacity of 40N which I think won’t be enough for lengthening purposes as since lengthening post growth plate senesence is an abnormal task it probably requires very abnormal stimuli. It’s interesting to look at the device though.

The study mainly mentioned the technical design of the device and no analysis of the applications.

A Mechatronic Loading Device to Stimulate Bone Growth via a Human Knee

“This paper presents the design of an innovative device that applies dynamic mechanical load to human knee joints. Dynamic loading is employed by applying cyclic and periodic force on a target area. The repeated force loading was considered to be an effective modality for repair and rehabilitation of long bones that are subject to ailments like fractures, osteoporosis, osteoarthritis, etc. The proposed device design builds on the knowledge gained in previous animal and mechanical studies. It employs a modified slider-crank linkage mechanism actuated by a brushless Direct Current (DC) motor and provides uniform and cyclic force.”

Here’s an example of what slider crank linkage looks like:

“The functionality of the device was simulated in a software environment and the structural integrity was analyzed using a finite element method for the prototype construction. The device is controlled by a microcontroller that is programmed to provide the desired loading force at a predetermined frequency and for a specific duration. The device was successfully tested in various experiments for its usability and full functionality. The device works according to the requirements of force magnitude and operational frequency. This device is considered ready to be used for a clinical study to examine whether controlled knee-loading could be an effective regimen for treating the stated bone-related ailments{Hopefully bone length is one of those bone-related ailments unfortunately Ping Zhang’s name is not on this paper and he was always the one more interested in bone length}.”

“When a specific loading force is applied to the epiphyses of the femur and tibia, the trabecular bone tissue, which is characterized by axial stress resistance, resists this force from the opposite direction. This results in deformations in that area. These deformations create a variation of the fluid pressure in the intramedullary cavity. This pressure gradient allows the flow of fluids that carry essential nutrients to the bone cortex initiating osteoblast differentiation and osteogenesis, thus helping in repair and regeneration of the bone tissue. This unique reaction makes this procedure an effective treatment for bone rehabilitation. It helps in reduction of healing time of bone fractures and hastens recovery from bone-related injuries and diseases. The lateral stress application is also less strenuous to the knee bone and reduces the amount of force that needs to be applied to get this result.”

B is the force we’re looking for. The pressure generated by fluid flow not just on the bone but on the stem cells to initiate chondrogenic differentiation. The pressure on the intact bone may also allow the creation of cartilage canals to enable that requirement for a neo growth plate.

It’s also interesting to note that in the proposed knee loading device the load the entire lateral area of the epiphysis this may be a way to reduce slippage.

” it was decided that the proposed device should be robust enough to produce different magnitudes of linear force up to a maximum of 40 N”<-Since lengthening is not being considered in this study forces required for lengthening may be higher.

The device doesn’t look wide enough for the knee really. The dimensions of the device listed are:

Length: 0.3	m
Width: 0.1
Height: 0.2

There are about 39 inches in a meter so about 3.9 inches in width. I don’t know if that’s enough.

Also the device looks more like this kind of clamp:

Then the other clamps we’ve been using. Although you’d have to make new pads to actually adjust to knee. Well actually more like:

But the pipe gets in the way of getting around the knee. Although I’m not really sure that a pipe clamp is superior to the other clamps. I’m just pointing out that it’s the clamp that looks most like the design mentioned in the study.

Here’s some more details on the device:

Here’s an actual physical prototype:

Here’s an update on that device:

Analysis of Force Transmission by a Knee Loading Device from Skin and Soft Tissue to Knee Joint Elements

“Dynamic loading to a knee joint is considered to be an effective modality for enhancing the healing of long bones and cartilage that are subject to ailments like fractures, osteoarthritis, etc. We developed a knee loading device and tested it for force application. The device applies forces on the skin, whereas force transmitted to the knee joint elements is directly responsible for promoting the healing of bone and cartilage. However, it is not well understood how loads on the skin are transmitted to the cartilage, ligaments, and bone. Based on a CAD model of a human knee joint, we conducted a finite element analysis (FEA) for force transmission from the skin and soft tissue to a knee joint. In this study, 3D models of human knee joint elements were assembled in an FEA software package (SIMSOLID). A wide range of forces was applied to the skin with different thickness in order to obtain approximate force values transmitted from the skin to the joint elements. The maximum Von Mises stress and displacement distributions were estimated for different components of the knee joint. The results demonstrate that the high load bearing areas were located on the posterior portion of the cartilage. This prediction can be used to improve the design of the knee loading device.”

Step 1 for improving effectiveness of the device is to prove that it loads where it’s expected to be loading.

“A lateral application of force on the knee joint was found effective in protecting bone tissue in the areas of distal femur and proximal tibia of the knee bone. The effects of the stimulation of bone regeneration are not limited to the applied areas but are seen along the length of the long bone. When a specific loading force is applied to the epiphyses of the femur and tibia, the trabecular bone tissue, which is characterized by axial stress resistance, resists this force from the opposite direction.”

“This results in reversable deformations in that area. These deformations create a variation of the fluid pressure in the intramedullary cavity. This pressure gradient allows the flow of fluids that carry essential nutrients to the bone cortex initiating osteoblast differentiation and osteogenesis thus helping in repair and regeneration of the bone tissue“<-this pressure gradient at minimum should help carry nutrients to the growth plate at a minimum.

There’s a lot more information within the paper itself about potential joint loading device design.

Lowering Fbn1 levels may increase bone length(Marfan’s Syndrome)

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. This Franscesco Ramirez scientist seems one to watch in understanding why Marfan’s Syndrome causes longitudinal bone overgrowth. If we understand why Marfan’s Syndrome causes overgrowth then maybe we can use that to our advantage especially if it is connected to tendons which are connected to muscles and are therefore easier to manipulate. Interesting that in the grant FBN1 inactivation is associated with greater TGF-Beta in the tendon/ligament but decreases TGF-Beta in the perichondrium.

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{could we make tendon cells turn into chondrocytes as adults via TGF Beta?}. 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[longitudinal bone overgrowth]. 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 via mechanical stimulation 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, (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. 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 TGFB-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 TGFB 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. ”

Here’s the updated 2020 grant.

It seems exactly the same as the 2016 grant.

Fibrillin-1 deficiency in the outer perichondrium causes longitudinal bone overgrowth in mice with Marfan syndrome

“A disproportionate tall stature is the most evident manifestation in Marfan syndrome (MFS), a multisystem condition caused by mutations in the extracellular protein and TGFβ modulator, fibrillin-1. Unlike cardiovascular manifestations, there has been little effort devoted to unravel the molecular mechanism responsible for long bone overgrowth in MFS. By combining the Cre-LoxP recombination system with metatarsal bone cultures, here we identify the outer layer of the perichondrium as the tissue responsible for long bone overgrowth in MFS mice{the perichondrium is less mature than the periosteum so it is unclear whether manipulating the periosteum would have any impact on longitudinal bone overgrowth}. Analyses of differentially expressed genes in the fibrillin-1-deficient perichondrium predicted that loss of TGFβ signaling may influence chondrogenesis in the neighboring epiphyseal growth plate (GP). Immunohistochemistry revealed that fibrillin-1 deficiency in the outer perichondrium is associated with decreased accumulation of latent TGFβ-binding proteins (LTBPs)-3 and -4, and reduced levels of phosphorylated (activated) Smad2. Consistent with these findings, mutant metatarsal bones grown in vitro were longer and released less TGFβ than the wild-type counterparts. Moreover, addition of recombinant TGFβ1 normalized linear growth of mutant metatarsal bones. We conclude that longitudinal bone overgrowth in MFS is accounted for by diminished sequestration of LTBP-3 and LTBP-4 into the fibrillin-1-deficient matrix of the outer perichondrium, which results in less TGFβ signaling locally and improper GP differentiation distally.”

<-I could not get this full paper. But also note that it’s the long bones that grow more with marfan’s syndrome so it’s possible that in different bones FBN1 has a different effect on TGFBeta

Interesting that less TGF Beta resulted in more longitudinal bone growth. I’ve always thought that TGF Beta is good for height. It could be that Smad 1/5/8 phosphorylation results in terminal differentiation. According to Inhibition of TGF-β Increases Bone Volume and Strength in a Mouse Model of Osteogenesis Imperfecta, inhibition of TGF Beta increases bone strength(no mention of bone length however).

According to this study by Ramirez:

Fibrillin-1 Regulates Skeletal Stem Cell Differentiation by Modulating TGFβ Activity Within the Marrow Niche

“limbs deficient for fibrillin-1 (Fbn1^Prx1–/– mice) is accounted for by premature depletion of MSCs and osteoprogenitor cells combined with constitutively enhanced bone resorption. “

Tiffanie Didonato grew 14 inches with distraction osteogenesis

Tiffanie Didonato grew 14 inches with distraction osteogenesis but the limit for a normal person is about six inches. Why?

Looking at her instagram she seems to be doing fine.

According to Paley’s FAQ on limb lengthening surgery, “The total height gain with two lengthenings is up to 13cm (8cm in the femurs and 5 cm in the tibias. (8cm is not well tolerated in the lower leg (tibia) and
exceeding 5cm can lead to more serious complications such as equinus contracture [ballerina foot]). Most
patients will not tolerate more than 5cm in the tibias. Of course the cost of two lengthenings is nearly twice that of one lengthening. Although the Precice can lengthen up to 8cm, not every patient can safely achieve this much even in the femurs. We will only allow lengthening to the tolerance of the patient’s bone and soft tissues. SAFETY first. We will not risk a loss of function to gain one more cm. To get the full 8cm from both femurs and both tibias requires three lengthening surgeries (see option 5 below).”

Option five as mentioned is “Combined tibia (up to 4cm) and femur (up to 4cm) lengthening three
weeks apart: total 8cm followed by re-breaking femur and tibia with same nail in place and repeating up to 4cm femur and up to 4cm tibia lengthening one year or more later (up to total 16cm; 6.3 in.)”

So normal person can gain 6.3 inches but someone with achondroplasia can gain 14 inches. The answer may involve the ligaments.

According to the chandler project, “When we stretch the bones were also stretching the muscles, and the ligaments and the nerves in the blood vessels around it and some of those get tight, and when they get tight there can be other problems that come up” But for dwarfism, “[dwarves have] all the skin in the ligaments and everything like that to be average height, but her bones are shorter, and they just don’t get the signals to grow,” Lisa explained.”

So the reason that people with achondroplasia can grow taller with Limb Lengthening Surgery than people without it is because they have the ligaments etc of an average height person thus their muscles etc don’t stretch.

But why is the soft tissue such as problem in the first place with limb lengthening surgery?

Well the ligaments normally attach at the enthesis, and the enthesis is attached near the growth plate. It’s very likely that ligament and bone growth are connected in this way so that the ligaments can grow as needed to support longitudinal bone growth. ““Entheses are fibrocartilaginous organs that bridge ligament with bone at their interface” More info about the enthesis here.

So it’s likely that a superior option to limb lengthening surgery will develop that involves stimulating enthesis development as well.

A website has an interesting interpretation of what Lateral Synovial Joint Loading in

I have not been experimenting with Lateral Synovial Joint Loading as I’m focusing more on lateral impact because slippage was too much of an issue. I think joint loading may work more easily on wingspan then on height just because the joints are less cumbersome and the wrist is more moveable. The ankle is just a pain. In 2015 I report getting an increase of 1/2″ inch of wingspan from 74.5″ to 75″. My wingspan is still 75″ but it may be a more solid 75″. It is not measurement error for wingspan as easy to self measure lying down.

Anyways, here’s the site:

What is lateral synovial joint loading?

“

Question:

What is lateral synovial joint loading?

Synovial Joints:

Synovial joints are the types of joints in the body that allow movement. They are places where two or more bones meet yet are able to move at their connection point. Lateral is a term that means from or related to the side rather than above or below.

Answer and Explanation:

Lateral synovial joint loading is a process where lateral pressure applied to a joint increases the fluid pressure in the joint cavity. The pressure on the synovial fluid in the joint cavity causes it to become more viscous as a means of resisting the pressure. However, the increased hydrostatic pressure can cause stretching of the membranes containing the fluid and cause inflammation of the joint.”

Here’s more on hydrostatic pressure. More on the power of hydrostatic pressure. Hydrostatic pressure may be be linked to bone via the periosteum. So load on the joints can have an effect on bone whether that can increase height is TBD.

Paper with interesting supplements that impact longitudinal bone growth

Novel Treatment Options in Childhood Bone Diseases

“Several novel treatment options have recently become available in childhood bone diseases. The purpose of this article is to provide an update on some of the therapeutic agents used in the treatment of pediatric osteoporosis, X-linked hypophosphatemic rickets, and achondroplasia (ACH){this is what we’re interested in as it’s related to height}. Summary: Vitamin D3 and Ca supplementation remains the basis of childhood osteoporosis treatment. Bisphosphonate (BP) therapy is the main antiresorptive therapeutic option, while denosumab, a human monoclonal IgG2 antibody with high affinity and specificity for a primary regulator of bone resorption – RANKL, represents a possible alternative. Its potent inhibition of bone resorption and turnover process leads to continuous increase of bone mineral density throughout the treatment also in the pediatric population. With a half-life much shorter than BPs, its effects are rapidly reversible upon discontinuation. Safety and dosing concerns in children remain. Novel treatment options have recently become available in two rare bone diseases. Burosumab, a monoclonal antibody against FGF-23{FGF23 has an impact on height but there’s mixed evidence on whether it’s good or bad therefore Burosumab may have an impact on height too}, has been approved for the treatment of children with X-linked hypophosphatemic rickets older than 1 year. It presents an effective, more etiology-based treatment for rickets compared to conventional therapy, without the need for multiple daily oral phosphate supplementation. Its long-term efficacy and safety are currently being investigated. After years of anticipation, a novel treatment option for ACH has become available. C-type natriuretic peptide analog vosoritide effectively increases proportional growth and has a reasonable safety profile in children >2 years. Its effect on other features of the disease and the final height is yet to be determined.{studies show that vosoritide definitely increases growth rate but there’s yet a study that shows it’s impact on adult height; Micheal’s thoughts on vosoritide; I also speculate that CNP could help with longitudinal bone growth in adults if one as an adjunct to other methods or maybe to help grow via the cartilage in the spine or knee etc; CNP increases the proliferation of chondrocytes in general} Several other treatment options for ACH exploring different therapeutic approaches are currently being investigated. Key Messages: Denosumab is effective in the treatment of childhood-onset osteoporosis; however, further studies are necessary to determine the optimal treatment protocol. Burosumab is more etiology-based and convenient in comparison to conventional treatment of X-linked hypophospha-temic rickets in children and adults. Vosoritide importantly changes the natural course of achondroplasia, at least in the short term.”

“Burosumab is the first etiologic treatment option that actively increases phosphate levels while also decreasing FGF-23 actions in XLH. It is a monoclonal IgG1 antibody that suppresses the actions of FGF-23. FGF-23 is the key phosphaturic hormone and acts as a regulator of phosphate homeostasis. It mediates its actions by binding to its cofactor alpha-Klotho and FGF-receptor 1 (FGFR1), through which it inhibits phosphate reabsorption in the kidney via downregulation of the sodium-dependent phosphate transporters (NaPi-2a and NaPi-2c) in proximal renal tubules. Additionally, it suppresses renal 1α-hydroxylase (CYP27B1) and activates 24-hydroxylase (CYP24A1), both of which contribute to lowering serum concentrations of 1,25-dihydroxy cholecalciferol and thus reduce intestinal uptake of phosphate. The elimination of burosumab follows the endogenous immunoglobulin degradation pathway”

“In another phase 3 study (study identifier NCT02915705) burosumab treatment was superior to conventional therapy regarding growth velocity and disease progression determined by RSS”<-burosumab’s impact on growth velocity suggests that it may impact height. IF you look at the study menionted figure 4,Height was increased by about 0.2cm.

“Excessive FGFR3 activation results in downstream activation of multiple intracellular signaling pathways, leading to intensified inhibition of cartilage tissue formation at the level of chondrocyte proliferation (via STAT1), hypertrophy, differentiation, and synthesis of the extracellular matrix (via Erk-MAPK signaling pathway) “

“Growth hormone supplementation has not shown promising results and is not viewed as a standard treatment for ACH. The progress in the understanding of ACH pathogenesis has led to the development of many potential therapeutic strategies for modulating excessive FGFR3 activation. Approaches are varied and include inhibiting the tyrosine kinase activity of FGFR3 (infigratinib), producing artificial FGFR3 as a decoy for FGF ligand (recifercept), inhibition of FGFR3 downstream signaling pathways (meclizine, C-type natriuretic peptide [CNP] analogs), modulation of growth via natriuretic peptide receptor 2 (NPR2) receptor (CNP analogs) and use of aptamers or monoclonal antibodies to prevent binding of FGF to its receptor (aptamer RBM-007, vofatamab). The investigations into analogs of CNP, especially vosoritide, are currently the most advanced”

“Vosoritide is a recombinant CNP analog. Endogenous CNP and its action on the growth plate through NPR-B are recognized as one of the important regulating mechanisms of longitudinal bone growth. Coupled with NPR-B, CNP antagonizes downstream FGFR3 signaling by inhibiting the Erk-MAPK signaling pathway at the level of Raf. This leads to chondrocyte proliferation, differentiation and increases the extracellular matrix synthesis. CNP-targeted overexpression in the cartilage or its continuous delivery by intravenous infusion has shown normalization of the impaired bone growth in mouse models with ACH”

” In August 2021, results of the extension phase 3 clinical trial in children with ACH aged between 5 and 18, receiving vosoritide 15 μg/kg once daily in subcutaneous injection, were published. An increase in annualized growth velocity was observed, with 3.52 cm of height gain over a 2-year treatment period in comparison to untreated patients. In addition, improvement in the proportionality of body segments and no acceleration of the bone maturation process (determined by bone age assessment) was observed{this is a positive indicator that the treatment will increase adult height}“

“Recent preclinical data in healthy cynomolgus monkeys showed that treatment with TransCon CNP subcutaneously once per week resulted in significant growth increases in body, tail, and long bones compared to controls. An increase in height was also more pronounced in comparison to the animals receiving a daily dose of CNP analog with the same amino acid sequence as vosoritide (5% vs. 3%, respectively), and no significant changes in bone quality were observed with both treatments. Moreover, sustained CNP release resulted in lower systemic CNP peak levels and has not been associated with adverse cardiovascular effects in monkeys treated with repeated weekly doses up to 100 μg/kg”

According to A long-acting C-natriuretic peptide for achondroplasia, “CNP-38 was slowly released into the systemic circulation and showed biphasic elimination pharmacokinetics with terminal half-lives of ∼200 and ∼600 h. Both preparations increased growth of mice comparable to or exceeding that produced by daily vosoritide.”

So both vosoritide and Transcon CNP increase height during development and I suspect may have some applications for adults as well. Burosomab and the other FGFR3 inhibitors likely have impact on height as well.

{Note I accidentally made this post in Michael’s account}

Big Breakthrough: Vosoritide to grow taller

Update on Vosoritide: New studies have come in about it that show very promising results and I am like 99% confident that it would work on children that do not have dwarfism because they also are impacted by CNP and have FGFR3 receptors. Vosoritide is very promising and I think will eventually be used for children of normal growth velocity.

Vosoritide is basically a daily CNP injection. It’s targeted for dwarfism but as everyone has FGFR3 receptors it can work normal children but testing would be needed.

<-From the video it seems that it’s progressing very slowly. Which is unfortunate as it has potential to happen normal children and possibly even adults. Unfortunately it doesn’t seem like they’r keen on testing Growth Hormone and CNP at the same time because Growth Hormone may only increase growth velocity but not final height but perhaps together. They address other potential uses kindof at around the 25 minute mark.

Here’s more on CNP.<-“we developed transgenic mice with an elevated plasma concentration of CNP under the control of human serum amyloid P component promoter and exhibited that these mice showed prominent skeletal overgrowth phenotype”

CNP delays mineralization.->”The femur, skull, and spine (L2-4) measurements were longer than that of the wild-type littermates” It could potentially affect adults via spinal height even if limbs do not increase.

“CNP activates bone turnover and remodeling in vivo”

More on CNP.<-also there’s a snippet from free patents online for CNP being used to increase height in people free of FGFR3 abnormalities meaning normal children.

Who knows if CNP could potentially increase height in adults until it is tested….

Apparently Biomarin did test this on adults but did the adults get taller? Although the study was only for a short period of time approx two weeks which is not a lot of time to evaluate if the adults grew taller.

Note Meclozine has been associated with height growth too.

Note based on this image, barring other effects the benefit of CNP is limited based on how much growth inhibiting effects FGFR3 induces. Though according to Dose dependent effect of C-type natriuretic peptide signaling in glycosaminoglycan synthesis during TGF-β1 induced chondrogenic differentiation of mesenchymal stem cells., CNP may induce differentiation of MSCs to chondrogenic lineage so it’s effects may not solely be limited based on how much FGFR3 there is to inhibit.

“A multinational study of 35 children (5–14 years of age) receiving daily subcutaneous vosoritide at a dose of 15 µg/kg demonstrated a sustained increase in the annualized growth velocity of approximately 1.5–2.0 cm/year over 42 months of treatment.” Let’s say that’s 1.5 inches over 3 years. That’s pretty significant. How long that can be sustained will be revealed with further testing.

Here’s another study on Vosorotide:

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial

“Methods: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 μg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11.

Findings: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred.”

1.57cm is small but significant. And major if it can be maintained throughout development.

Here’s another study on Vosorotide:

Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study

“Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported.

Methods

After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day.

Results

In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected.”

Now growth velocity does not always coincide with final height.

“Due to the inherent variability of growth and the lesser magnitude of the pubertal growth spurt in children with achondroplaisa, these long-term effects will only be known once these children reach final adult height”

Efficacy of vosoritide in the treatment of achondroplasia

“Achondroplasia is the commonest form of dwarfism and results from a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4p16.3. The mutation is at nucleotide 1138 resulting in a G-to-A transition (134934.0001). This condition is characterized by full penetration meaning that everyone with this genetic mutation will exhibit the phenotypic characteristics of achondroplasia. It is a gain-of-function mutation that causes increased inhibition of cartilage formation. C-type natriuretic peptide (CNP) acts on the growth plate through the natriuretic peptide receptor-B (NPR-B) causing the transformation of guanosine 5′-triphosphate into cyclic guanosine monophosphate. However, CNP cannot be used in the treatment of achondroplasia because it is rapidly degraded by neutral endopeptidase. Vosoritide is a modified recombinant human CNP and has a half-life 10 times that of CNP. Clinical trials have demonstrated that vosoritide is effective in significantly increasing the annualized growth velocity in children with achondroplasia before the fusion of the epiphyses.”

<-couldn’t get this full study.

Natural Height Growth

Cancer, Stem Cells, Regenerative Tissue Engineering, Transdifferentiation