The effect of protein on osteoporosis and risk of bone fracture is complex. Calcium loss from bone occurs at protein intake below requirement when individuals are in negative protein balance, suggesting that too little protein is dangerous for bone health.[29] IGF-1, which contributes to muscle growth, also contributes to bone growth, and IGF-1 is modulated by protein intake.[6] However, at high protein levels, a net loss of calcium may occur through the urine in neutralizing the acid formed from the deamination and subsequent metabolism of methionine and cysteine. Large prospective cohort studies have shown a slight increase in risk of bone fracture when the quintile of highest protein consumption is compared to the quintile of lowest protein consumption.[3] In these studies, the trend is also seen for animal protein but not plant protein, but the individuals differ substantially in animal protein intake and very little in plant protein intake.