Sunday, June 6, 2010

Can Your Height Increase with Teriparatide?

Teriparatide is a drug used for treatment of osteoperosis.  Osteoperosis research is one of the areas of research that helps answer the question of can your height increase along with cancer research(cellular proliferation and differentiation), exercise research(IGF-1, Insulin sensitivity, mechanical stimulus effect on bones), and endocrinology.  Osteoperosis deals with osteoblasts versus osteoclasts and long bones grow primarily via chondrocytes.  However, short/irregular type bones do grow by osteoblast depositing new bone beneath the periosteum and there are a myriad of these types of bones that can increase height(plus wingspan and foot length) such as the spinal bones, calcaneus, pelvic bone, patella, etc.  But of course, there may be a method in which teriparatide can influence chondrocytes(like via stem cells which can differentiate into chondrocytes).  Teriparatide is a parathyroid hormone peptide. 

Orthopedic uses of teriparatide. 

"Teriparatide is a drug currently approved for treating patients with osteoporosis who are at high risk for future fracture. In the treatment of osteoporosis, teriparatide works as an anabolic agent stimulating bone formation throughout the skeleton by principally enhancing osteoblast-derived bone formation relative to osteoclast-derived bone resorption. The net effect is increased bone mass. For patients with a fracture, a similar process of increased bone formation is required transiently at the fracture site for repair. Teriparatide has been investigated in animal models and in patients as a potential agent to enhance fracture repair. Teriparatide enhances chondrogenesis. Teriparatide may have [effects] on mesenchymal stem cells." 

Basically, teriparatide stimulates osteoblastistic activity and the risk with that is that osteoblast activity leads to increased RANKL expression which leads to increased osteoclast activity which leads to calcium deposits.  That however, does not happen in all cases.  What effect does teriparatide have on Mesenchymal Stem Cells? 

"treated animals with 10 μg/kg per day of teriparatide showed a 1.4-fold increase in cartilage[40% is huge] in the fracture callus of treated animals compared with controls. This difference disappeared by day 21[so it's possible PTH only affects growth rate], and the callus in all animals differentiated into healed bone. Gene expression of the cartilage differentiation gene SOX-9 also was elevated by 1.4-fold on day 4 in the teriparatide-treated group[SOX9 is crucial for chondrogenesis so PTH may be a very promising chondroinductive compound], suggesting a stimulation of chondroprogenitor cells with intermittent teriparatide exposure"

"[In] a mouse fracture model , 30 μg/kg per day of teriparatide [was used] to demonstrate that PTH primarily influenced the early phases of fracture healing through chondrocyte recruitment increases and accelerated chondrocyte differentiation in the fracture callus. Callus in these animals was larger in length, cross-sectional area, and total volume. Expression of the signaling genes Wnt 4, 5a, 5b, and 10b were all increased in the teriparatide-treated animals "<-If PTH can increase callus length, why not bone length?

"Animal models of fracture healing and spine fusion have demonstrated an increase in cartilage formation at the fracture or fusion site when teriparatide-treated animals are compared with placebo-treated animals, an increase even greater than the increase in bone formation that is observed. "<-So the increase in cartilage size is greater than the final bone size.  Maybe some extra stimulus is needed to keep the extra cartilage?

Intermittent treatment with parathyroid hormone (PTH) as well as a non-peptide small molecule agonist of the PTH1 receptor inhibits adipocyte differentiation in human bone marrow stromal cells. 

"Whereas continuous PTH infusion increases bone resorption and bone loss, intermittent PTH treatment stimulates bone formation, in part, via reactivation of quiescent bone surfaces and reducing osteoblast apoptosis. We investigated the possibility that intermittent and continuous PTH treatment also differentially regulates osteogenic and adipocytic lineage commitment of bone marrow stromal progenitor/mesenchymal stem cells (MSC). The MSC were cultured under mildly adipogenic conditions in medium supplemented with dexamethasone, insulin, isobutyl-methylxanthine and troglitazone (DIIT), and treated with 50 nM human PTH(1-34) for either 1 h/day or continuously (PTH replenished every 48 h). After 6 days, cells treated with PTH for 1 h/day retained their normal fibroblastic appearance whereas those treated continuously adopted a polygonal, irregular morphology. After 12-18 days numerous lipid vacuole and oil red O-positive adipocytes had developed in cultures treated with DIIT alone, or with DIIT and continuous PTH. In contrast, adipocyte number was reduced and alkaline phosphatase staining increased in the cultures treated with DIIT and 1 h/day PTH, indicating suppression of adipogenesis and possible promotion of early osteoblastic differentiation. Furthermore, intermittent but not continuous PTH treatment suppressed markers of differentiated adipocytes such as mRNA expression of lipoprotein lipase and PPARgamma as well as glycerol 3-phosphate dehydrogenase activity. All of these effects of intermittent PTH were also produced by a 1 h/day treatment with AH3960 (30 microM), a small molecule, non-peptide agonist of the PTH1 receptor. AH3960, like PTH, activates both the cAMP and calcium signaling pathways. Treatment with the adenylyl cyclase activator forskolin for 1 h/day, mimicked the anti-adipogenic effect of intermittent PTH, whereas pretreatment with the protein kinase-A inhibitor H89 prior to intermittent PTH resulted in almost complete conversion to adipocytes. In contrast, the MAP kinase inhibitor PD 98059 failed to prevent the anti-adipocytic effect of intermittent PTH, suggesting that the inhibitory effect of PTH on adipocyte differentiation is predominantly cAMP-dependent. These results demonstrate a differential effect of PTH1 receptor agonists on the adipocytic commitment and differentiation of adult human bone marrow mesenchymal stem cells." 

So "cycling" Parathyroid Hormone increases bone formation.  Bodybuilders have long known the power of cycling with steroid cycles and some weightlifting regimes.  Cycling disrupts the bodies homeostatic defenses.  Does teriparatide have an effect on stem cell differentiation(it doesn't seem to effect proliferation) that the entire Parathyroid Hormone doesn't have?  Bone Morphogenic Protein -2 seems to be more anabolic in getting stem cells to differentiate into osteoblasts or chondrocytes. 

Then there's the whole problem of getting teriparatide if you don't have osteoperosis but we can see if teriparatide responds to mechanical loading(LSJL), hypoxia(sprinting or intense cardiovascular exercise), or changes in body composition(changing bodyfat percentage or building more body mass).  I think BMP-2 has more potential for stimulating bone growth however.  Teraparatide still has an anabolic effect on bone though. 

Effects of osteoporosis medications on bone quality.

"Bone quality encompasses a number of bone tissue properties that govern mechanical resistance, such as bone geometry, cortical properties, trabecular microarchitecture, bone tissue mineralization, quality of collagen and bone apatite crystal, and presence of microcracks. All these properties are dependent on bone turnover and its variations. In populations, the decreases in bone resorption markers achieved with resorption inhibitors may predict in part the decrease in fracture risk. At the spine, however, this correlation exists down to a 40% fall in bone resorption markers; larger drops did not provide further protection against fractures in patients taking risedronate in one evaluation of this relationship. Osteoporosis medications can exert favorable effects on bone size and cortical thickness[Increase in bone size is an increase in height in some bones]. Such effects have been documented with teriparatide (PTH 1-34), which is the unique purely anabolic treatment for osteoporosis available to date. More surprising are the favorable effects on bone size seen with some of the bone resorption inhibitors such as neridronate in adults with osteogenesis imperfecta. Similarly, estrogens and alendronate can increase femoral neck size in postmenopausal women. Preservation of the trabecular microarchitecture was demonstrated first with risedronate and subsequently with alendronate. In placebo-controlled studies, a deterioration in trabecular microarchitecture occurred within 1 to 3 years in the placebo groups but not in the bisphosphonate groups. Teriparatide, in contrast, improves trabecular microarchitecture, in particular by increasing connectivity and improving the plate-rod distribution. The minerals within trabecular or cortical bone can be evaluated using microradiography or synchrotron micro-computed tomography. Marked or prolonged secondary mineralization may result in poor bone quality. Increased bone mineralization is among the key effects of bone resorption inhibitors, most notably bisphosphonates. Prolonged use of the most potent bisphosphonates may lead to unwanted effects related to excessive mineralization. Microcracks may play a physiological role; however, a large number of microcracks may be deleterious via an effect on osteocytes. Excessive mineralization may promote the development of multiple microcracks. Studies of bone crystal and collagen properties with several bone resorption inhibitors, including risedronate and raloxifene, showed no harmful effects. An increasing number (several hundreds) of mandibular osteonecrosis associated with bisphosphonate therapy has been reported. The typical patient was receiving injectable bisphosphonate therapy for bone cancer and had undergone dental work shortly before bisphosphonate administration."

Here's a study that reveals a possible mechanism of how PTH stimulates chondrogenesis:

In vitro studies on Itm2a reveal its involvement in early stages of the chondrogenic differentiation pathway.

"The Integral membrane protein 2A (Itm2A) is a transmembrane protein belonging to a family composed of at least two other members, Itm2B and Itm2C, all of them having a different expression pattern. The Itm2a gene serves as a marker for early stages in endochondral ossification[so we could use Itm2a antibodies to test if LSJL induces chondrogenesis]. In order to understand the role of Itm2A in this process, expression of the gene was investigated in different cell systems. In C3H10T1/2 cells, the gene was upregulated early on when the cells were induced to the chondrogenic lineage but less to the osteogenic lineage. In MCT cells, expression was upregulated at permissive temperatures but not at non-permissive temperatures. When induced with insulin, ATDC5 cells expressed Itm2a in early stages but not at late stages. Furthermore, PTH treatment seems to upregulate Itm2a transcription. In order to understand the role of Itm2a in the chondrogenic differentiation process in more detail, we constitutively overexpressed exogenous Itm2A in mouse ATDC5 cells. Two clones expressing high levels of Itm2a were isolated and characterized. Gene expression analysis of the overexpresser clones demonstrated that expression of collagen type X was delayed. Overexpression of Itm2a in mouse ATDC5 cells impede the transition to hypertrophic cells. Itm2a [is involved] in the early stages of chondrogenesis in vitro."

LSJL upregulates ITM2A as "Mus musculus 3 days neonate thymus cDNA, RIKEN full-length enriched library, clone:A630088B15 product:integral membrane protein 2A, full insert sequence [AK042395]"
PTH upregulates Itm2a which plays a role in chondrogenesis.

PTHrP isoforms have differing effect on chondrogenic differentiation and hypertrophy of mesenchymal stem cells

"MSCs isolated from fresh bone marrow were cultured in pellet in chondrogenic medium containing 5 ng/ml of transforming growth factor (TGF)-β3. From day 14 of culture, subsets of pellets were additionally treated with one of the four PTHrP isoforms (1-34[teriparatide], 1-86, 7-34, and 107-139) at 100 nM. After a further 2 weeks of in vitro culture, pellets were harvested for analysis. PTHrPs 1-34 and 1-86 significantly decreased the DNA level while PTHrPs 7-34 and 107-139 significantly increased DNA level compared with the control treated with TGF-β3 only. Glycosaminoglycan per DNA significantly increased when treated with PTHrPs 1-34 and 1-86 while it significantly decreased with PTHrPs 7-34 and 107-139. PTHrP 1-34 significantly increased the gene and protein expression of the chondrogenic marker COL2A1, and decreased those of hypertrophic markers COL10A1 and alkaline phosphatase while other isoforms showed inconsistent effects. All of PTHrP isoforms significantly suppressed the gene and protein expression of indian hedgehog while all isoforms except PTHrP 107-139 significantly reduced the gene and protein expression of patched 1. PTHrP 1-34 most significantly enhanced chondrogenesis and suppressed hypertrophy in MSCs, supporting its use for cartilage tissue engineering."

This does not mean that Teriparatide increases height under many circumstances an increase in growth plate height results in a reduction of height growth.

"[In one study there was] suppression of types I and X collagen without a change in type II collagen after treating chondrogenic cultures of human MSCs with PTHrP"

1 comment:

  1. Opportunity to increase heigth with low intensity pulsed ultrasound!!!

    Low intensity pulsed ultrasound (LIPUS) is a medical technology.

    Researchers at the University of Alberta have used LIPUS to gently massage teeth roots and jawbones to cause growth or regrowth, and have grown new teeth. As of June 2006, a large device has been licensed by the Food and Drug Administration (FDA) and Health Canada for use by dentists. A smaller device that fits on braces has also been developed. In order to regrow teeth, the tooth root must be massaged by the LIPUS device for 20 minutes each day for 4 months. It has been approved by both Canadian and American regulatory bodies and a market-ready model is currently being prepared. LIPUS was expected to be commercially available before the end of 2009.

    According to Dr. Chen from the University of Alberta, LIPUS may also have medical/cosmetic benefits in allowing people to grow taller by stimulating bone growth.