Epiphyseal (growth) plates are zones of proliferating and hypertrophic chondrocytes near the ends of long bones. These regions drive longitudinal growth during childhood and adolescence.
Fibroblast growth factor receptor 3 (FGFR3) is a membrane receptor that modulates growth by binding fibroblast growth factors such as
FGF18 and
FGF9. Once activated, FGFR3 triggers
MAPK and
STAT signaling cascades that decrease chondrocyte proliferation and accelerate differentiation.
Too much FGFR3 signaling shortens bones (as in achondroplasia). Removing FGFR3 function lengthens bones in animal models.
In mid‑puberty (Tanner stage IV), estrogen rises and pushes the growth plates toward senescence and closure.
(Which I why aromatase inhibitors should be paired but ill get into that another time)
Blocking FGFR3 at this stage could prolong chondrocyte proliferation, slow epiphyseal fusion, and increase final height. Preclinical studies with selective FGFR3 inhibitors have shown increases in femur and tibia length when given before closure.
Recifercept – a soluble decoy receptor that binds FGF ligands and prevents them from activating FGFR3. It was administered by weekly subcutaneousinjections at roughly 1 mg/kg in early trials. Development halted after phase II.
Infigratinib – an oral tyrosine kinase inhibitor of FGFR1–3. In achondroplasia children, about 0.128 mg/kg/day increased height velocity by ~1.5 cm/year. Doses up to 0.25 mg/kg/day are being tested.
Vofatamab – a monoclonal antibody that blocks the extracellular domain of FGFR3. It was used in oncology at 10–20 mg/kg IV every few weeks. Proposed for growth plate modulation but not trialed in adolescents.
Vosoritide – a C‑type natriuretic peptide analog that activates guanylate cyclase and inhibits the MAPK pathway downstream of FGFR3. Approved for achondroplasia; 15 µg/kg/day subcutaneously increases growth velocity by ~1.6 cm/year.
(Ill get into cnp analogs in another thread)
Meclozine – an antihistamine found to attenuate FGFR3 signaling in cell models. Doses around 1–2 mg/kg twice daily increased long‑bone length in mice. Safety in adolescents for height is untested.
Statins – cholesterol‑lowering drugs that improved chondrogenesis and bone growth in achondroplasia models. Mechanism may involve BMP signaling. Typical cholesterol doses were used in animal studies; human data are lacking.
InhibitorMechanismTypical Dosage
Recifercept
Decoy receptor for FGF ligands~1 mg/kg weeklySubcutaneousDiscontinued development
Infigratinib
FGFR1–3 tyrosine kinase inhibitor0.128–0.25 mg/kg/dayOralPhase II pediatric trials
Vofatamab
FGFR3 monoclonal antibody10–20 mg/kg every few weeksIntravenousUsed in oncology
VosoritideC‑type natriuretic peptide analog
15 µg/kg/daySubcutaneousApproved for achondroplasia
MeclozineAntihistamine;
downstream MAPK inhibition1–2 mg/kg twice dailyOralAnimal data only
Statins
Cholesterol synthesis inhibitors; possible BMP modulationStandard dosesOralExperimental use
Bone age influences how much additional height can be gained by blocking FGFR3.
Estrogen exposure increases with age, driving plates toward closure.
The earlier the intervention, the greater the potential gain.
14 years – Mid‑puberty
Growth plates are thick and proliferative; FGFR3 blockade could add several centimeters. This stage offers the highest potential.
15 years – Mid‑late puberty
Plates are thinning; growth slows. FGFR3 inhibition still helps but estrogen now accelerates closure.
16 years – Late puberty
Plates are nearly exhausted; benefits are modest unless estrogen production is suppressed (e.g., with aromatase inhibitors).
17 years - typically end of puberty
Most plates have fused; little to no height can be added by inhibiting FGFR3.
Hyperphosphatemia and mineral imbalance –
FGFR signaling affects kidney handling of phosphate via FGF23. Inhibitors can cause phosphate retention and lower vitamin D levels. Check serum phosphate, calcium, and vitamin D during treatment.
Hepatic and renal function –
FGFR inhibitors are metabolized and excreted through liver and kidneys. Routine liver function tests and serum creatinine are prudent.
Gastrointestinal and appetite changes –
Mild dyspepsia, decreased appetite, and flatulence have been reported. Monitor weight and nutritional status.
Osteochondromas and abnormal growth
FGFR3 normally restricts chondrocyte proliferation. Complete suppression can lead to benign cartilage tumors and dysregulated bone overgrowth. Orthopedic evaluation and imaging help detect such problems early.
Hormonal modulation –
Estrogen drives epiphyseal closure. Combining FGFR3 inhibitors with aromatase inhibitors delays estrogen formation and can further prolong growth plates. Testosterone is converted to estrogen via aromatase, suppressing this step slows closure.
Supportive nutrition –
Adequate calcium, protein, and vitamin D are required for osteoblast function and bone mineralization. Ensure dietary intake meets increased growth demands.
0nce the growth plates have fused, further inhibition of FGFR3 does not provide additional height. Terminate therapy when radiographs confirm epiphyseal closure and continue regular follow‑up to monitor bone health.
TheCoolDude2000 for the idea
