Bone-targeted estrogen delivery reverses postmenopausal osteoporosis in mice

Postmenopausal osteoporosis is a condition that weakens bones, making them brittle and prone to fracture. Taking the hormone estradiol can reverse these effects, but it may also increase endometrial and uterine cancer risks. Researchers publishing in ACS’ Nano Letters developed a two-layer shell to encapsulate the hormone so it bypasses the uterus and releases only within an osteoporotic bone. Tests of the drug-delivery system showed improved bone density in treated mice without uterine side effects.

After some people reach menopause, their estrogen production declines significantly. Because estrogen is critical to reducing bone resorption and promoting bone growth, postmenopausal osteoporosis can result. Treatment for this type of osteoporosis is typically estradiol — a form of the estrogen hormone — but most is broken down before reaching the bones. To deliver estradiol directly to the bones, Xi Chen, Changsheng Liu and Jiajing Zhou caged the hormone in materials that allow the molecules to bypass the uterus and other organs, activating only when the parcels enter the acidic environment of weakening bones.

The researchers first coated estradiol with peptides that are naturally drawn toward the calcium ions found in bones. Then they placed the peptide-coated molecules into tiny, cage-like structures that combined tannic acid, which blocks cells that dissolve bone tissue, and magnesium ions, which improve bone structure and promote cells that create bone tissue. In lab tests, the two-layer coatings stayed intact in neutral pH solutions, like in the bloodstream, but dissolved and released the tannic acid, magnesium ions and drug contents in acidic solutions, akin to microenvironments affected by bone loss.

In a study on mice with postmenopausal osteoporosis, Chen and colleagues injected animals twice weekly with the new caged estradiol, regular estradiol, or a saline solution. After 4 weeks of treatment, mice that received the caged estradiol injections achieved bone density values higher than pre-osteoporosis levels without uterine side effects. Fluorescence imaging of these mice confirmed that the hormone concentrated only in the weakened bones. With further development, the researchers say this new drug-delivery system could lead to more effective treatment of postmenopausal osteoporosis in humans.

“This system not only enhances therapeutic efficacy but also significantly reduces the risk of uterine side effects associated with traditional estrogen therapy,” shares Chen. “Our next focus will be developing an oral double-coated estradiol pill.”

The authors acknowledge funding from the National Natural Science Foundation of China, the National Key Research & Development Project of China, the Basic Science Center Project of the National Natural Science Foundation of China, and the Fundamental Research Funds for the Central Universities.

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