Thursday, September 9, 2010

Epiphyseal Fusion versus Growth Plate Cessation

Previously, I've written that growth plates do not fuse.  This conclusion was made due to evidence where the hyaline cartilage remained post ossification during epiphyseal distraction.  It seems that epiphyseal fusion or rather that bone invasion is a separate process from endochondral ossification.

First, let me make it clear that you can always grow taller with absolutely no need for cartilage.  You can grow taller by bone deposition on the longitudinal ends of the bones or by gap fractures.  Just get more stem cells to differentiate into osteoblasts or cause microfractures to the bone while it's in a stretched position.

Estrogen may play a key role in epiphyseal fusion but may not halt growth plate cessation.  Low levels of estrogen may prevent growth plate fusion by preventing your bones from developing properly.  In that case more stem cells may happen into the hyaline cartilage growth plate line and differentiate to chondrocytes.  If you don't have enough estrogen your bones won't develop properly and your bones won't perforate into the cartilage.

In short, estrogen does not help prevent growth plate cessation.  Growth plate cessation is caused by a lack of stem cells in the hyaline cartilage growth plate line.  If you want to take estrogen you should take it when growth has mostly ceased and you are willing to sacrifice some bone health to maintain the hyaline cartilage growth plate line.  Bone growth which requires estrogen into the hyaline cartilage is what results in epiphyseal fusion.

The histology of epiphyseal union in mammals states that the epiphysis does not fuse with the diaphysis during a rat's entire life.  The study was done in the 70s so there may be remnants of the hyaline cartilage that were not visible under examination.  But there are still some scattered parts of cartilage that remain that stems can develop into chondrocytes within.

Stem cells were able to differentiate into chondrocytes without being in a cartiliginous matrix.  Bone cells under LSJL do express TGF-Beta 1 which can get stem cells to differentiate into chondrocytes.  Both osteoblasts and chondrocytes can increase height.  Chondrocytes just have the advantage that they can increase height from anywhere within the bone(whereas osteoblasts have to increase height at the ends) and chondrocytes can hypertrophy giving you more height per stem cell.

Histomorphometric analysis of an adolescent distal tibial physis prior to growth plate closure.

"A human distal tibial growth plate was sampled in three regions (anterior, central, and posterior), with each region further separated medially, in the middle, and laterally. The regions were assessed for the location and extent of bony bar formation as well as for physeal height. Companion sections from optimally fixed tissue in the distal 100 microm of the hypertrophic zone were analyzed for hypertrophic chondrocytic volumes.
Physis closure started in the middle of the central region of the growth plate, with 46% of the volume in this area occupied by trans-physeal bridging bone. The growth plate was also narrowed with the lowest physeal heights evident in the middle of the central and anterior regions of the physis. Disruption of the regular columns of the physis was evident with the cells arranged in clusters with intervening areas of acellularity. The average hypertrophic cell volume was 5,900 microm(3) and did not significantly differ between different areas of the physis."

"The patient had been diagnosed with osteosarcoma in the left distal femur at 11 years of age. The local tumor was treated with wide excision and limb-sparing surgery using a large osteoarticular allograft and plating. The patient received preoperative and postoperative chemotherapy with cisplatin, doxorubicin, and methotrexate. For over 1-year, the patient was fully ambulatory, clinically assessed approximately by normal loading on the distal tibia. By 18 months postoperatively, the patient was diagnosed with a local recurrence and subsequently underwent an above-knee amputation at the age of 12 years and 11 months."
An up close look of the bony bridge in the medial growth plate.

"The physis appears to close in the middle first, then on the medial side, and then the lateral portion."

"Closure was seen, characteristically, to occur in a medial to lateral pattern over a period of 1.5 years."

"Doxorubicin and cisplatin result in decreased growth rate and final height"

Transplantation does not affect growth rate or senescence:

"Ten juvenile to juvenile and five juvenile to adult hind limb transplants were performed in male syngeneic Lewis rats. Upper tibial bone density in isochronograft and heterochronograft limbs was compared with that of the opposite non-operated limbs.
We observed inferior bone quality in heterochronografts compared to isochronografts. After transplantation, isochronografts did not exhibit increases in tibial lengths compared to opposite juvenile non-operated tibias or heterochronograft tibias . However, significant differences were observed between heterochrongraft tibial lengths when and opposite adult non operated tibial lengths.
Age dependent alterations affect bone quality, resulting in post transplantation osteoporosis in heterochronografts, but not isochronografts. However, the growth plates of transplanted limbs retain their properties of longitudinal growth and continue to grow at the same rate."

"The first group consisted of 10 recipient juvenile rats (mean age 23.8 days, range 21-28 days). The second group consisted of 5 recipient adult rats (mean age 72.4 days, range 71-77 days). The hind limbs of these rats were divided into two experimental groups as follows:
Group 1: Microvascular transplants of the right hind limbs of 10 juvenile donors into 10 juvenile recipients served as isochronografts.
Group 2: Microvascular transplants of the right hind limbs of 5 juvenile donors into 5 adult recipients served as heterochronografts."

Physiological closure of the physeal plate of the distal radius: An MRI analysis.

"Twenty-two healthy female volunteers underwent MRI investigations of their left wrist. Absolute width, percentage and localization of the physeal part, closed at the time of investigation were recorded.  In this series T1-weighted sequences were most useful to distinguish open and closed parts of the physis. Total area was 291-469 mm(2) (average, 399 mm(2) ). It did positively correlate with body height , but not with weight or BMI. Physeal closure took place at 15-18 years. There was no significant correlation between menarche and closure. Bony bridging of the growth plate begins centroradial and ends with a small limbus dorsoradial. Sequential scans showed that there are only a few months from beginning to end of physeal closure. Physiological closure of the distal radius growth plate takes place in late adolescence, varying individually. There seems to be no influence of the menarche in female individuals. The process happens within a very short time of less than a year."

"the process of the closure of the physeal plates at the knee joint takes longer and is earlier terminated compared with the distal radius."<-maybe this is why most people have longer arms.

"There was a statistically significant correlation between the total area of the growth plate and the body height."

Rat growth plates do not fuse so what happens?

Calcified Cartilage Islands in Rat Cortical Bone.

"Rats display little to no haversian remodeling of cortical bone. This fact, combined with the endochondral formation of cortical bone, means that rat femoral cortical bone contains highly mineralized cartilage islands in a central band of mid-femoral cross sections. These islands have a significantly higher degree of mineralization than the surrounding bone. The islands are elongated along the femoral long axis. Nanoindentation revealed significantly higher values of both reduced modulus and hardness in the islands compared to the surrounding bone, reflecting a higher degree of mineralization. The calcified cartilage islands were distributed in a central zone of the bone, from the growth plates through the mid-femoral bone. The presence of these cartilage islands and their possible effect on mechanical properties could be an additional reason why haversian remodeling is observed in higher-order species."

Could not get this full study.

The persistence of epiphyseal scars in the adult tibia.

"Following completion of epiphyseal fusion, a transverse radio-opaque line, termed "epiphyseal scar", may be observed in the region of the former growth plate. This line is likely to become obliterated shortly after completion of epiphyseal fusion. Consequently, presence of an epiphyseal scar has been interpreted as an indication of recent epiphyseal fusion; however, this has not been validated by quantitative research. A study was undertaken to determine persistence of the epiphyseal scars in a cross-sectional population of adults between 20 and 50 years of age. This study examined 1,216 radiographs of proximal and distal tibiae from both sexes and sides of the body. This study suggested that 98.05 % of females and 97.74 % of males retained some remnant of the epiphyseal scar at the proximal tibia whilst 92.72 % of females and 92.95 % of males retained some remnant of the epiphyseal scar at the distal tibia. General linear model (GLM) analysis determined that chronological age accounted for 2.7 % and 7.6 % of variation in persistence of the epiphyseal scar at the proximal and distal tibiae, respectively. Obliteration of the epiphyseal scar is not as dependent on chronological age as previously thought."

"The epiphyseal scar is one of the characteristics that may be observed through radiographic imaging. Although remaining visible on cross section and on radiographs, once epiphyseal fusion is complete, it is not possible to observe the epiphyseal scar on the external surface of the bone"

"the persistence of the epiphyseal scar within the tibia was not significantly influenced by the end of the bone. This suggests that the formation and remodelling of epiphyseal scars may be different to other transverse radio-opaque bands"

Letter to the Editor: Misconceptions: Epiphyseal Fusion Causes Cessation of Growth

" This paper brings to light the fact that when the bone reaches its appointed genetically determined length, the following takes place: the longitudinal growth ceases, the epiphysis fuses with the metaphysis, and the growth plate disappears. Pediatric endocrinologists have always believed that growth stops because the epiphysis fuses, and that short adult stature could result from early fusion of the epiphyseal growth plate. The reverse is also true - a sustained linear growth through puberty could be a consequence of failure of epiphyseal fusion.  However, Dr. Parfitt suggests that the epiphysis fuses because growth stops.  In other words, fusion is the marker of growth cessation, not a determinant of it.
Epiphyseal fusion is an active process that might not necessarily be preceded by, nor automatically follow, the cessation of growth.  Endochondral ossification represents the culmination of a sequence of changes in the cartilage cells and their associated matrix. These events must always occur in the same order, requiring a minimum period of time. It has been shown that the growth plate narrows, not because cartilage replacement occurs earlier, but because cartilage addition occurs more slowly as the rate of chondroblast proliferation declines. The growth plate does not begin to disappear until proliferation has stopped altogether.  Collectively, the data demonstrate that epiphyseal fusion does not precede, but rather follows the cessation of growth.  Nevertheless, fusion is not simply the result of continued cartilage replacement with no further cartilage addition; this is an active process with its own hormonal controls, cellular mechanisms and structural features. For example, if there is estrogen deficiency, the epiphyses may remain unfused long after growth has stopped, with resumption of the normal timetable of fusion after replacement of the missing hormone.  However the complexity of estrogen action at the growth plate has contributed to the current confusion.  Estrogen has separate and independent effects on chondroblast proliferation and on active epiphyseal fusion. It has a biphasic effect on proliferation, which is stimulated by low levels and inhibited by high levels.  The latter predominate in late adolescence in both sexes, leading initially to growth cessation and subsequently to active fusion.  Dr. Parfitt concludes that recognizing the correct temporal relationship between growth cessation and fusion is an essential first step to understanding the complexities of growth plate function, but evidently a great deal more work is needed to clarify all the sequences. "

Evidence that estrogen hastens epiphyseal fusion and cessation of longitudinal bone growth by irreversibly depleting the number of resting zone progenitor cells in female rabbits

"With age, growth plate cartilage undergoes programmed senescence, eventually causing cessation of bone elongation and epiphyseal fusion. Estrogen accelerates this developmental process. We hypothesized that senescence occurs because progenitor cells in the resting zone are depleted in number and that estrogen acts by accelerating this depletion. To test this hypothesis, juvenile ovariectomized rabbits received injections of estradiol cypionate or vehicle for 5 weeks, and then were left untreated for an additional 5 weeks. Exposure to estrogen accelerated the normal decline in growth plate height and in the number of proliferative and hypertrophic chondrocytes. Five weeks after discontinuation of estrogen treatment, these structural parameters remained advanced, indicating an irreversible advancement in structural senescence. Similarly, transient estrogen exposure hastened epiphyseal fusion. Estrogen also caused a more rapid decline in functional parameters of growth plate senescence, including growth rate, proliferation rate, and hypertrophic cell size. However, in contrast to the structural parameters, once the estrogen treatment was discontinued, the growth rate, chondrocyte proliferation rate, and hypertrophic cell size, all normalized, suggesting that estrogen has a reversible, suppressive effect on growth plate function. In addition, estrogen accelerated the normal loss of resting zone chondrocytes with age. This decrease in resting zone cell number did not appear to be due to apoptosis. However, it was maintained after the estrogen treatment stopped, suggesting that it represents irreversible depletion. The findings are consistent with the hypothesis that estrogen causes irreversible depletion of progenitor cells in the resting zone, thus irreversibly accelerating structural senescence and hastening epiphyseal fusion. In addition, estrogen reversibly suppresses growth plate function."

"estrogen does not slow functional senescence, which may explain the lack of catch-up growth after
growth inhibition by estrogen."

"Resting zone chondrocytes produce parathyroid hormone-related protein(PTHrP) which, together with Indian hedgehog, forms a feed-back loop that controls the length of the proliferative columns. Loss of resting cell chondrocytes may therefore result in reduced PTHrP production and therefore shorter proliferative columns and possibly other structural changes. Resting zone chondrocytes also secrete other factors including BMP-inhibitors gremlin, chordin, Wnt-inhibitor sfrp5, which may inhibit the differentiation program of growth plate chondrocyte"

"estrogen treatment decreases proliferation of resting zone chondrocytes, which could contribute to depletion. Interestingly, dexamethasone treatment also slows chondrocyte proliferation in the resting zone, but, unlike estrogen, actually conserves the number of resting zone chondrocytes"


  1. Tyler, I have been catching up on all your research. So basically, we have two ways to target leg growth: microfracture and stem cells. You say in this article " Just get more stem cells to differentiate into osteoblasts or cause microfractures to the bone while it's in a stretched position." How can we create microfractures in a stretched position? And, I believe I have grown at least 1/4" in the lower legs, and my epiphysis has definitely gotten bigger. There is much more bone around it. I remember you saying this is due to the stem cells not proliferating into chondrocytes and instead osteoblasts are depositing bone appositionally? Where is the prime area to load? Straight on the epiphysis more towards the growth plate line vs the periostium? It's frustrating seeing the apparent growth on and around the ankle itself while not being able to get gains longitudinally.

  2. I'm going to explain more about this in my newest post. Appositional growth in the epiphysis should not be due to new bone deposition(more in next post). Do you have before and after pictures?

  3. I didn't take before pics, but I may have some pics w/ my leg and/or ankle in it. I will take a pic showing how it is now. It is definitely built up around the original epiphysis of the ankle.