Pseudo-Reactivation of growth plates with Osteomalacia

Tumor-induced osteomalacia

"Tumor-induced osteomalacia (TIO) is a rare paraneoplastic[a disease or symptom that is the consequence of the presence of cancer in the body, but is not due to the local presence of cancer cells] syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D."

"99Tc-MDP bone scans often show uptake at the costochondral junctions (a sort of adult rachitic rosary) and areas of the bone in skeletally mature adults where the growth plates were previously located. This finding may represent a sort of ‘pseudo-reactivation’ of growth plates in the adult skeleton."

"(B)patient with TIO showing areas of intense tracer uptake and evidence of ‘growth plates’ in a 54-year-old man who had senesced his growth plates decades before."

The compounds involved in osteomalacia are FGF23, Vitamin D, and Phosphate.  FGF23 may be a compound that can "reactivate" growth plates.

FGF23 may be involved in chondrogenesis:

Genetic evidence of serum phosphate-independent functions of FGF-23 on bone.

"Maintenance of physiologic phosphate is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis[perhaps phosphate levels regulate osteogenic versus chondrogenic differentiation]. Targeted disruption of the Fgf-23 gene in mice (Fgf-23-/-) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23-/- mice and to examine serum phosphate-independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23-/- mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23[FGF-23 is involved in chondrocyte differentiation] that are independent of phosphate homeostasis."

"skeletal abnormalities observed in Fgf-23−/− mice including the decrease in hypertrophic chondrocytes in the growth plate, the increased mineral deposition adjacent to the growth plate, and the osteomalacic phenotype"<-if FGF-23 drives chondrocytes to hypertrophy then perhaps it drives stem cells to differentiate into chondrocytes in the first place.

Calcitrol can enhance FGF-23 levels.

Bone growth during daily or intermittent calcitriol treatment during renal failure with advanced secondary hyperparathyroidism.

"Calcitriol is a standard therapy for secondary hyperparathyroidism in chronic renal failure. We evaluated whether the effect of daily or intermittent calcitriol administration is more efficient in enhancing bone growth in renal failure with advanced secondary hyperparathyroidism in weanling 5/6 nephrectomized rats loaded with phosphorus to induce severe secondary hyperparathyroidism. The animals were treated daily or three times weekly with calcitriol for 4 weeks but the total weekly dose of calcitriol was the same. Although calcitriol increased the serum calcium, it did not lower parathyroid hormone (PTH) or improve tibia and body length. Animals with renal failure and advanced secondary hyperparathyroidism had decreased PTH/PTHrP, which was accompanied by an increase in the cyclin kinase inhibitor p57(Kip2). Calcitriol treatment upregulated the PTH/PTHrP receptor but also increased inhibitors of cell proliferation such as p21(Waf1/Cip1), IGFBP3, and FGFR3[FGFR3 is one of the most anti-height proteins there is]. Calcitriol also enhanced markers of chondrocyte differentiation, such as IGF1, Vitamin D receptor, FGF23, and bone morphogenetic protein-7. Receptor activator of nuclear factor-kappabeta ligand levels improved with calcitriol treatment but without changes in osteoprotegerin suggesting an enhancement of osteo/chondroclastogenesis and mineralization. Overall, both daily and intermittent calcitriol had similar effects on endochondral bone growth in phosphorus-loaded rats with renal failure."

Calcitriol is the active form of Vitamin D and is the form of Vitamin D with low levels in Osteomalacia.  So perhaps it is not FGF23 that is causing the reactivation of growth plates but rather the low Vitamin D.

The cells in the mans bone may have regressed to a chondrogenic phenotype due to less Vitamin D rather than new stem cells differentiating into chondrocytes in the growth plate.

We need to find more information about this 54-year old man.  It seems that FGF-23 may actually reduce height in growing individuals but it may lower Vitamin D to regress bone cells to a chondrogenic phenotype.  The question is whether this way will help people grow taller or not.

Did the 54-year old man grow taller is the question?  Maybe by cycling between high and low levels of Vitamin D by manipulating FGF23 you can induce height growth.  And in the transition from cartilage to bone you may gain a little height each time.

Iron may affect FGF-23 levels.

Iron status and fibroblast growth factor-23 in Gambian children.

"A relationship between iron and fibroblast growth factor-23 (FGF23) metabolic pathways has been proposed. Iron deficiency anaemia is prevalent in The Gambia and concentrations of fibroblast growth factor-23 FGF23 are elevated in a large percentage of Gambian children with rickets-like bone deformity. We speculate that low iron status may be involved in the aetiology of Gambian rickets[low iron may elevate FGF23]. The aim of this study was to determine if there was a relationship between haemoglobin, as a marker of iron status, and FGF23 in samples from children with and without a history of rickets-like bone deformities in The Gambia. We conducted a retrospective analysis of studies carried out from 2006 to 2008 in children from a rural community in The Gambia where iron deficiency anaemia is endemic and where elevated circulating concentrations of FGF23 have been found. To investigate the relationship between circulating FGF23 and haemoglobin concentrations we used an age-adjusted linear regression model on data from children <18y of age with a family or personal history of rickets-like bone deformity (BD) (n=108) and from the local community (LC) (n=382). We found that circulating concentration of FGF23 was inversely correlated with haemoglobin concentration. This effect was more pronounced in BD children compared with LC children. Anaemia and elevated FGF23 were more prevalent in BD children compared to LC children."

"inverse relationship between ferritin and FGF23 concentrations"

"the role of iron in the processing and excretion of the FGF23 molecule in the kidney"

"When looking at the children with a personal or a family history of rickets-like bone deformities (BD) there was no difference between Index children (n = 32) or their siblings (n = 76) in any variables before and after age-adjustments were made, with the exception of height where the BD siblings tended to be taller than the index children"<-so more evidence than FGF-23 increases height

Rickets kids were taller than their non-rickets siblings but not children from the local community(LC).

"BD children had higher 1,25(OH)2D, and lower Hb than LC children"

"After adjusting for age, all children with high FGF23 (> 125 RU/ml) were shorter, tended to be heavier and had a greater BMI than children with FGF23 concentrations within the normal range"<-but maybe kids with FGF23 grow taller for longer and end with a greater adult height?

"iron may act on FGF23 pathways in the following ways; firstly by inhibiting the cleavage of the intact FGF23 molecule and secondly in assisting the clearance of FGF23 fragments by the kidney"