A
phenylalanine (Phe)-restricted diet is indispensable to control the blood Phe for individuals with
phenylketonuria (PKU), who are also confronted with progressive bone impairment. Thus, the development of a low-Phe
protein substitute that could positively regulate bone metabolism is desired for their bone health. Our previous study reported the preparation of a low-Phe containing whey hydrolysate (LPH) from a selected
whey protein hydrolysate (TAH). However, the effect of LPH on the bone status is unknown. In this study, we used an ovariectomized (OVX) mice model to evaluate the anti-osteoporotic potential of
oral administration of
whey protein concentrate (WPC,
protein control), TAH, and LPH on bone physiology and bone metabolism. The results showed that after 12 weeks of treatment, the decreased bone mineral density, the deteriorated trabecular microarchitecture, and the reduced ultimate load due to
ovariectomy were significantly attenuated by two
whey protein hydrolysates (TAH and LPH); meanwhile, the
body weight, uterine weight, bone composition, and the femoral elastic load of OVX mice had not been significantly affected by whey samples. In addition, LPH and TAH dual-regulated bone remodeling in OVX mice through triggering osteogenesis (promoted the expression of runt-related
protein 2 (Runx2) and osteoformation markers) and inhibiting osteoresorption as well as
inflammation. The modulated
mitogen-activated protein kinase signaling and the inhibited nuclear factor κB signaling by LPH and TAH might relate to the dual-regulatory activities on bone. Overall, in the OVX mice model, LPH exerted higher osteoprotective potential than TAH of the same dose by activating the bone formation markers and inhibiting the inflammatory status. The current study demonstrated for the first time the potential use of a low-Phe whey hydrolysate, a
protein substitute for PKU individuals, in the prevention of
osteoporosis.