The bisphophonate Aldronate reduces height.  Other bisphophantes such as zoledronate have an impact on the growth plate and may have an impact on height.  I don’t know for sure what affect bisphophonates have on height but if I had to guess I would say that they result in decreased height.

Effect of Bisphosphonates on the Rapidly Growing Male Murine Skeleton

“C57Bl6/J male mice were treated from 18 to 38 days of age with vehicle, alendronate, pamidronate, zoledronate or clodronate at doses selected to replicate those used in humans. Treatment with alendronate, pamidronate and zoledronate, but not clodronate led to a decrease in the number of chondrocytes per column in the hypertrophic chondrocyte layer. This was not associated with altered hypertrophic chondrocyte apoptosis or vascular invasion at the growth plate.

The effects of pamidronate on trabecular microarchitecture were less beneficial than those of alendronate and zoledronate. Pamidronate did not increase cortical thickness or cortical area/total area relative to control mice. These studies suggest that bisphosphonate administration does not adversely affect skeletal growth.”

“Technicium, 99mTc-labeled 1-hydroxy-methyledene bisphosphonate, a compound closely related to clodronate, is used for bone scans. In children and growing animals, this agent is avidly taken up in the region of the growth plate where cartilage is being replaced by bone”

“first generation bisphosphonates (ethane-1-hydroxy-1,1-diphosphonate and dichloromethylene diphsophonate), performed in growing rats more than four decades ago, demonstrated expansion of the growth plate and persistence of columns of calcified cartilage”<-note that expansion of the growth plate does not always lead to increased height.

“Pamidronate decreases basal ERK1/2 phosphorylation in hypertrophic chondrocytes”<-other bisphosphonates did not alter ERK1/2 phosphorylation.

“Treatment of hypertrophic chondrocytes with phosphate leads to rapid phosphorylation of Erk1/2 which is required for phosphate-mediated hypertrophic chondrocyte apoptosis”

“Bisphosphonates do not impair hypertrophic chondrocyte apoptosis in vivo”<-although the pamidronate group had a slight increase in hypertrophic chondrocyte apoptosis.

“zoledronate suppresses MMP-9 expression, whereas pamidronate increases MMP-9 mRNA
levels in cells of the monocyte/macrophage lineage, and clodronate has no effect”

“The number of osteoclasts in this region [metaphysis] (350 microns) was significantly decreased in the mice treated with alendronate and zoledronate relative to control mice (2.3  and 3.3 respectively vs 7.5 in control mice). Pamidronate and clodronate treatment resulted in a small and insignificant decrease in cortical osteoclasts in this region relative to control animals (6.0 and 7.0 respectively).”

“Femoral length did not differ between control and treated mice, nor among treatment groups(data not shown).”<-This is unfortunate as any non-signficiant difference in femur length could be notable.

“the non-nitrogen containing bisphosphonate, clodronate, did not alter the number of hypertrophic chondrocytes per column and led to fewer growth plate changes than the nitrogen-containing bisphosphonates.”

This study has to do with the brain but it has to do with loading effects and is done by Hiroki Yokota one of the LSJL scientists.  The study shows that in some cases LSJL may upregulate Sim1 which does have an effect on height.  However, it’s usually Sim1 deficiency that increases height(but also obesity).

The intent of the study seems to be establishing that Lateral Synovial Joint Loading can be used on sedentary individuals who can’t do other forms of exercise can do this exercise to help prevent various mental problems.  Since LSJL decreases Nerve Growth Factor-Beta(which is involved in pain perception) and increases Serotonin it could induce a feeling of euphoria or well-being.  I have noted this myself when performing LSJL.  Treadmill exercise was compared as well which has bounds of anecdotal evidence of not being able to increase height so tph2 is not likely able to increase height as an adult.

If LSJL upregulates genes that are negative for growth such as Sim1 and NGF-Beta(even if these genes are not very directly related to the processes key to growth plate chondrogenesis), maybe this could indicate that other genes related to growth are regulated in the wrong direction at this load level too.  Although the LSJL lengthening study did take place at similar loads.  It could indicate that the loads used were not sufficient enough.  And the loads need to be such that NGF-Beta is upregulated and Sim1 is downregulated however these two genes could just be tangentially related to longitudinal bone growth and their regulation is independent of LSJL’s lengthening effects.

Physical weight loading induces expression of tryptophan hydroxylase 2 in the brain stem.

“Knee loading, a form of physical activity, has been found to mimic effects of voluntary exercise. Focusing on serotonergic signaling, we addressed a question: Does local mechanical loading to the skeleton elevate expression of tryptophan hydroxylase 2 (tph2) that is a rate-limiting enzyme for brain serotonin? A 5 min knee loading{applied laterally so this is an LSJL study} was applied to mice using 1 N force at 5 Hz for 1,500 cycles. A 5-min treadmill running was used as an exercise (positive) control, and a 90-min tail suspension was used as a stress (negative) control. Expression of tph2 was determined 30 min – 2 h in three brain regions –frontal cortex (FC), ventromedial hypothalamus (VMH), and brain stem (BS). We demonstrated for the first time that knee loading and treadmill exercise upregulated the mRNA level of tph2 in the BS, while tail suspension downregulated it. The protein level of tph2 in the BS was also upregulated by knee loading and downregulated by tail suspension. Furthermore, the downregulation of tph2 mRNA by tail suspension can be partially suppressed by pre-application of knee loading. The expression of tph2 in the FC and VMH was not significantly altered with knee loading. In this study we provided evidence that peripheral mechanical loading can activate central tph2 expression, suggesting that physical cues may mediate tph2-cathalyzed serotonergic signaling in the brain.”

“C57/BL/6 male and female mice, 6 to 8 weeks of age”

“The loaded tissue [under LSJL] is significantly softer and more energy dissipative than bone matrix in the femur and tibia.”

“In response to a 1 N force applied at 5 Hz to the mouse knee, the phase shift angle between the force and resulting displacement was found to be 18.1°. The energy loss per cycle was calculated to be 0.201 mJ, and the Young’s modulus of the knee joint was determined as 166 MPa”

“Cyclic compression was applied to the mouse left knee using an electro-mechanical loading device (ElectroForce® 3100, Bose Corporation, Eden Prairie, MN).”<-Electroforce is available for sale here.  The other versions ie. 3200 are even more expensive but can apply heavier loads.  I’m not sure how viable it is to apply this to the knee and there’s no price so it’s probably incredibly expensive.

“Knee loading and treadmill exercise induced significant upregulation of type I collagen mRNA in the femur and tibia, as well as type II collagen mRNA in cartilage. Furthermore, unloading through tail suspension for 90 min led to significant reduction of type II collagen in cartilage. However, unloading did not present significant change in type I collagen mRNA as compared to the untreated controls. Although not significant, knee loading at 1 N showed a decreasing trend of NGFß in the femur and cartilage as compared to the control”

Knee loading not increasing Type II collagen expression in the femur and tibia bone is inconsistent with the LSJL gene expression study.

In fact Treadmill exercise had a stronger impact on type II collagen than LSJL did.  I emailed Hiroki Yokota and he says he believed the removed all the cartilage from the bone in this study including growth plate cartilage.  It’s possible that this removal of cartilage also removed other regions of the bone that would normally express type II collagen.    Ideally we would want to see expression of type II collagen in other regions of bone other than the growth plate cartilage as that would be a clear sign of ectopic chondrocyte differentiation.

In this study, the mRNA at an unclear timepoint post loading in contrast to 1 hour following loading as done in the LSJL gene expression study.  It’s possible that Col2a1 was upregulated 1 hour following loading but returned to normal at some period post loading.  There are some pathways that are upregulated 1 hour post loading.  For example, plasma discharge treatment only elevates some factors one hour post treatment.  And enhanced phosphorylation of JNK can return to baseline at one hour in some cases.  Also, the LSJL gene expression study involved microarray data and this involve RT-PCR.

” Among two known upstream transcription factors, mRNA expression of Sim1 in the BS of mice treated with knee loading was significantly increased as compared to that of the sham loaded controls.”<-Does Sim1 have any effect on height?

According to Rare variants in single-minded 1 (SIM1) are associated with severe obesity., Sim1 mainly relates to energy homeostasis.

“Final height in SIM1-deficient adults was not increased. The lack of accelerated linear growth in patients with SIM1 mutations contrasts with the phenotype of [one] patient and the phenotype of Sim1 heterozygous mice. This difference may be explained by partial versus complete loss of SIM1 activity. ”  Height was less than versus control obese subjects.  Height was increased in MC4R deficient subjects.

“accelerated linear growth and increased final height seen in MC4R deficiency”

Here’s the study dealing with the patient mentioned:

Profound obesity associated with a balanced translocation that disrupts the SIM1 gene.

“We have studied a unique girl with early-onset obesity and a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2. Her weight gain is most likely due to excessive food intake, since measured energy expenditure was normal. We cloned and sequenced both translocation breakpoints. The translocation does not appear to affect any transcription unit on 1p, but it disrupts the SIM1 gene on 6q. SIM1 encodes a human homolog of Drosophila Sim (Single-minded), a transcription factor involved in midline neurogenesis, and is a prototypical member of the bHLH-PAS (basic helix-loop-helix + period, aryl hydrocarbon receptor, Single-minded) gene family. Our subject’s trans- location separates the 5′ promoter region and bHLH domain from the 3′ PAS and putative transcriptional regulation domains. The transcriptional targets of SIM1 are not known. Mouse Sim1 is expressed in the developing kidney and central nervous system, and is essential for formation of the supraoptic and paraventricular (PVN) nuclei of the hypothalamus. Previous neuroanatomical and pharmacological studies have implicated the PVN in the regulation of body weight: PVN neurons express the melanocortin 4 receptor and appear to be physiological targets of alpha-melanocyte-stimulating hormone, which inhibits food intake. We hypothesize that haploinsufficiency of SIM1, possibly acting upstream or downstream of the melanocortin 4 receptor in the PVN, is responsible for severe obesity in our subject.”

“The proband (SW116) was referred to a pediatric geneticist at age 18 months because of excessive growth.”

“We identified a mutation in the SIM1 gene in a girl with profound obesity and increased linear growth.”<-they suspect the mutation was SIM1 haploinsufficiency.

Back to the LSJL study:

“Knee loading led to increases of transcription factor, Sim 1 and Pet 1 mRNA but not REST/NRSF in the BS”

” Other target genes of Sim1, lhx8 and RGS4 did not show significant alteration with knee loading applied in the present study. However, we did find the upregulation of lhx8 and RGS4 mRNA in the BS (hindbrain) as compared to the VMH (midbrain)”

“load-driven upregulation of tph2 mRNA persisted at least 2 h”

“In this study, we showed the effect of peripheral mechanical loading on the brain. The observed remote effect can potentially be mediated through central projecting stimulation and neuronal signaling with neurotrophins. For instance, NGFß is a member of the neurotrophins that is involved in pain sensation and survival of neuron in the brain. Alternatively, loading can be sensed through alterations in the level of hormones and growth factors in the serum. Through signaling molecules in blood circulation, gene expression in the BS might be regulated. Knee loading induces direct loading effects, including formation of new bone, stimulation of fracture healing, prevention of cartilage degeneration, and suppression of pain in the knee.  Knee loading can modulate brain serotonin level through tph2 in the BS.”<-Here’s the study that shows that LSJL decreases NGF-Beta.  Serotonin may have an effect on height via LRP5.  Although the exact effect of LRP5 on height is unclear.

Fzd9 is upregulated in cartilage formation.

Since fracture healing often involves endochondral ossification, similar processes as those involved in fracture healing could induce height growth in intact bone.  As for whether a gap is needed for longitudinal bone growth remember that bony bridging can be overcome.  And it may be the limited pool of progenitor cells that limit growth and not the prescence or absence of the gap.  S1p-ko mice are capable of forming new growth plates from this progenitor cell pool.

Fzd9’s role in height increase seems to be later and relates to the conversion of the cartilage to bone.  So Fzd9 will affect height increase per chondrocyte but will not create chondrocytes in the first place.

The below study does provide us with the insight that the periosteum is the location of the key region of progenitor cells that can undergo growth plate chondrogenesis and increase height.  How do we get these stem cells past the cortical bone and into the bone itself where they have potential to increase height?

The wnt serpentine receptor frizzled-9 regulates new bone formation in fracture healing.

“The serpentine receptor Fzd9, a Wnt receptor of the Frizzled family, is essential for osteoblast function and positively regulates bone remodeling via the non-canonical Wnt pathway without involving β-catenin-dependent signaling. Here we investigated whether the Fzd9 receptor is essential for fracture healing using a femur osteotomy model in Fzd9 (-/-) mice. After 10, 24 and 32 days the fracture calli were analyzed. Our results demonstrated significantly reduced amounts of newly formed bone at all investigated healing time points in the absence of Fzd9 and, accordingly, a decreased mechanical competence of the callus tissue in the late phase of fracture healing. In contrast, cartilage formation and numbers of osteoclasts degrading mineralized matrix were unaltered{So could Fzd9 not be linked to growth plate formation?}. Canonical Wnt-signaling was not affected in the absence of Fzd9 in osteoblasts as well as in proliferating and mature chondrocytes within the fracture callus. The expression of established differentiation markers was not altered in the absence of Fzd9, whereas chemokines Ccl2 and Cxcl5 seemed to be reduced. Collectively, our results suggest that non-canonical signaling via the Fzd9 receptor positively regulates intramembranous and endochondral bone formation during fracture healing, whereas it does not participate in the formation of cartilage or in the osteoclastic degradation of mineralized matrix.”

“Wnt4, Wnt5a, Wnt10b, Wnt11 and Wnt13, Wnt receptors, including Fzd1, 2, 4 and 5, the co-receptors Lrp5 and Lrp6, β-catenin and Wnt target genes, including Runx2, a transcription factor associated with osteoblast differentiation, were up-regulated in the facture callus during bone regeneration”

“FZD9 is one of the genes, whose homozygous deletion in humans induces Williams-Beuren syndrome, a disorder associated with multiple manifestations, including low bone mass”

According to Statural growth in Williams-Beuren syndrome, Williams-Beuren syndrome does reduce height.

“After 10 days, most of the callus was composed of cartilage and fibrous tissue. New bone formation, which started at some distance from the fracture gap near the periosteum, was significantly reduced by 45% in the absence of Fzd9, whereas the amount of cartilage was not significantly affected”<-So the periosteum is where the pool of chondrogenic progenitor cells resides and Fzd9 does not appear to affect to conversion of these progenitor cells to chondrocytes.

You can almost see the stem cells flooding into the fracture gap of the bone.  Note that this region of stem cells seems to extend slightly beyond the region of the fracture gap in d24 and d32.

“bone marrow stromal cells derived from Fzd9-knockout mice exhibited a diminished capacity to proliferate and form mineralized matrix”

Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo.

“Bone metastasis remains incurable with treatment restricted to palliative care. Cabozantinib (CBZ) is targeted against multiple receptor tyrosine kinases involved in tumour pathobiology, including hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR-2). CBZ has demonstrated clinical activity in advanced prostate cancer with resolution of lesions visible on bone scans, implicating a potential role of the bone microenvironment as a mediator of CBZ effects. We characterised the effects of short-term administration of CBZ on bone in a range of in vivo models to determine how CBZ affects bone in the absence of tumour.
Studies were performed in a variety of in vivo models including male and female BALB/c nude [mice without strong immmune systems] mice (age 6-17-weeks). Animals received CBZ (30mg/kg, 5× weekly) or sterile H2O control for 5 or 10days. Effects on bone integrity (μCT), bone cell activity (PINP, TRAP ELISA), osteoblast and osteoclast number/mm trabecular bone surface, area of epiphyseal growth plate cartilage, megakaryocyte numbers and bone marrow composition were assessed. Effects of longer-term treatment (15-day & 6-week administration) were assessed in male NOD/SCID and beige SCID mice.
CBZ treatment had significant effects on the bone microenvironment, including reduced osteoclast and increased osteoblast numbers compared to control. Trabecular bone structure was altered after 8 administrations. A significant elongation of the epiphyseal growth plate, in particular the hypertrophic chondrocyte zone, was observed in all CBZ treated animals irrespective of administration schedule{although epiphyseal growth plate elongation does not always lead to increased height}. Both male and female BALB/c nude mice had increased megakaryocyte numbers/mm(2) tissue after 10-day CBZ treatment, in addition to vascular ectasia, reduced bone marrow cellularity and extravasation{leakage} of red blood cells into the extra-vascular bone marrow. All CBZ-induced effects were transient and rapidly lost following cessation of treatment.
Short-term administration of CBZ induces rapid, reversible effects on the bone microenvironment in vivo highlighting a potential role in mediating treatment responses.”

The elongation of epiphyseal growth plate may or not be promising based on what’s causing it.  It could be a result of inhibition of endochondral ossification.  The leakage of red blood cells could also be promising.

Cbz results in bone loss but perhaps it can do so in such a way to permit neo-growth plate formation.  In the Cbz group there was much more bone marrow than control.

“CBZ induces reversible alterations to the epiphyseal growth plate by disrupting chondrocyte differentiation.”

PEMFs(Pulsed Electric Magnetic Fields) have been implicated as having height growth potential before.

Physical Stimuli-Induced Chondrogenic Differentiation of Mesenchymal Stem Cells Using Magnetic Nanoparticles.

“Chondrogenic commitments of mesenchymal stem cells (MSCs) require 3D cellular organization. An approach is reported to drive 3D cellular organization and enhance chondrogenic commitment of bone-marrow-derived human mesenchymal stem cells (BM-hMSCs) via magnetic nanoparticle (MNP)-mediated physical stimuli. MNPs isolated from Magnetospirillum sp. AMB-1 are endocytosed by the BM-hMSCs in a highly efficient manner. MNPs-incorporated BM-hMSCs are pelleted and then subjected to static magnetic field and/or magnet-derived shear stress. Magnetic-based stimuli enhance level of sulfated glycosaminoglycan (sGAG) and collagen synthesis, and facilitate the chondrogenic differentiation of BM-hMSCs. In addition, both static magnetic field and magnet-derived shear stress applied for the chondrogenic differentiation of BM-hMSCs do not show increament of hypertrophic differentiation.”

Although stimuli applied to pellet culture is a lot different than applying it to scattered stem cells throughout the human bone.

“cellular condensation is prerequisite for chondrogenic differentiation”

“Magnetic nanoparticles (MNPs) have shown to offer a promising strategy to induce multicellular organizations. Forcing the cellular condensation via magnetic forces mimics the cellular condensation that takes places in vivo during limb development”<-maybe magnets can force the condensation in the limb.

“Physical stimuli were applied to MNP-incorporated cell pellets for 1 h for five consecutive days up to 3 weeks in chondrogenic differentiation medium.”

“MNPs themselves did not have any direct effect on chondrogenic differentiation, exogenously applied static magnetic field, and magnet-derived shear stress have probably induced closer cell–cell interactions and increased the nutrient perfusion within the pellets, respectively.”<-We couldn’t do anything with these MNPs anyways but the shear stress and magnet forces absolutely.

“The results of gross images demonstrated that the diameter of cell pellets increased when more than one of static magnetic field and magnet-derived shear stress was applied. However, there was no cellular proliferation regardless of MNPs and physical stimuli following the DNA content analysis.  The ECM is osmotically swollen following the chondrogenesis progression, due to cross-linked GAG, one of the major components in chondrogenic ECM. Increment in volume of cell pellets with physical stimuli would signify their sufficient chondrogenic differentiation”

“single magnet-derived shear stress had more chondrogenic differentiation effect than single static magnetic field, and static magnetic field synergized with magnet-derived shear stress was more effective than single magnet-derived shear stress in chondrogenesis. Although the physical stimuli referred to as static magnetic field and magnet-derived shear stress needed more precise optimization, it was obvious that static magnetic field synergized with magnet-derived shear stress would be the most effective biophysical stimuli on chondrogenesis”

Earlier I wrote that Meclizine was a very promising height growth supplement for people with open growth plates.

Here’s information on the dosages of Meclizine.  Information on the bottle should be followed.  25 to 50mg daily is what seems to be recommended.  Resistance to Meclizine may develop over time if the body begins to produce more CYP2D6.  At that point cycling would be necessary.  I can’t do research on all the possible side effects on Meclizine.  Since Meclizine is a common medication given for nausea, a doctor or pharmacist would be helpful for insight.  Especially, since it is something I just recently discovered and do not have a great deal of experience with.

Theoretically, Meclizine will only increase height in people with actively proliferating growth plate chondrocytes.  And it will only increase height in proportion to how much proliferation growth plate chondrocytes have.  So if you don’t have much natural growth left, meclizine won’t give you much growth.

Meclizine has similar effects to CNP in that both inhibit FGFR3.  However, CNP has additional effects.  For one, CNP increases levels of Guanyl Cyclase.  Since studies on Meclizine are limited, it is possible there are also as of yet unknown side effects.

Can Meclizine be absorbed and get to the growth plate chondrocytes where it exerts it’s height increasing effects by inhibiting FGFR3?

Given the below results of Meclizine being present in the serum, which would likely be delivered to growth plate chondrocytes, it is likely that yes Meclizine could indeed get to the growth plate chondrocytes.

Meclizine metabolism and pharmacokinetics: formulation on its absorption.

“the onset of action of meclizine was about 1 hour for the treatment of motion sickness and vertigo. A new suspension formulation of meclizine (MOS) was developed with the intention to achieve a rapid effect. To investigate the pharmacokinetics of the new MOS formulation versus the marketed meclizine oral tablet (MOT), a phase 1 pharmacokinetic study was performed in 20 healthy volunteers. In addition, an in vitro metabolic study using human hepatic microsome and recombinant CYP enzyme was also performed to determine the metabolic pathway in the human body. The plasma concentration of MOS appeared more rapidly in comparison to the MOT. The geometric mean ratios (90% confidence interval) of AUC(0-24) and AUC(0-∞) indicated no significant difference in bioavailability between the 2 formulations. CYP2D6 was found to be the dominant enzyme for metabolism of meclizine, and its genetic polymorphism could contribute to the large interindividual variability{So individual variations in CYP2D6 enzyme could affect the ability of meclizine to increase height in individuals with active growth plates?}.”

” In one anecdotal report, a serum level of 10 ng/mL was reported at 12 hours following an oral dose of 75 mg, and the elimination half-life of the parent compound was 6 hours. In another report, the plasma concentration-time profile of 1 subject was described, and the AUC0–24 and half-life were found to be 66.6 ng/ml·h and 7 hours, respectively. In rats, meclizine was distributed throughout most body tissues, found to cross the placenta, and metabolized in the liver to an inactive form, norchlorcyclizine. When give extravascularly, the drug is excreted in feces and urine unchanged or as metabolites such as norchlorcyclizine”<-If Meclizine is excreted or converted to the inactive form it’s not going to increase height.  However, Meclizine does seem to be present in serum and in rats was present in most body tissues

Meclizine Inhibits Mitochondrial Respiration through Direct Targeting of Cytosolic Phosphoethanolamine Metabolism.

“meclizine, an over-the-counter drug, as an inhibitor of mitochondrial respiration{Could this inhibition of mitochondrial respiration be linked to the height increase effects?}. Curiously, meclizine blunted respiration in intact cells but not in isolated mitochondria, suggesting an unorthodox mechanism. Using a metabolic profiling approach, we now show that treatment with meclizine leads to a sharp elevation of cellular phosphoethanolamine, an intermediate in the ethanolamine branch of the Kennedy pathway of phosphatidylethanolamine biosynthesis. Metabolic labeling and in vitro enzyme assays confirmed direct inhibition of the cytosolic enzyme CTP:phosphoethanolamine cytidylyltransferase (PCYT2). Inhibition of PCYT2 by meclizine led to rapid accumulation of its substrate, phosphoethanolamine, which is itself an inhibitor of mitochondrial respiration. Our work identifies the first pharmacologic inhibitor of the Kennedy pathway, demonstrates that its biosynthetic intermediate is an endogenous inhibitor of respiration. ”

They tested on fibroblasts but not on chondrocytes and stem cells.