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NIH grant 1R21AR088602-01: An Oleoyl Serine Derivative as an Innovative Therapeutic Approach for Osteoporosis
Institute: {'code': 'AR', 'abbreviation': 'NIAMS', 'name': 'National Institute of Arthritis and Musculoskeletal and Skin Diseases', 'admin_org_id': '12500006', 'admin_funding_url': ''}. PI: ROLAND E BARON. Award: $430816.
Start: 2026-09-18T00:00:00.
PROJECT SUMMARY
Fractures due to osteoporosis are common, as half of women over 50 years of age will suffer a fracture in their
remaining lifetime, leading to profound morbidity and increased mortality. Current guidelines for the management
of patients with osteoporosis recommend treatment of advanced disease — namely patients with very low bone
mineral density (BMD) and/or patients who have already suffered a fragility fracture. Thus, a major unmet need
in the management of osteoporosis is an option for primary prevention, analogous to the use of statins for
cardiovascular disease. Thus, the availability of a safe, orally available treatment to prevent bone loss and
osteoporosis could prompt a paradigm shift in osteoporosis management toward primary prevention. This
proposal aims to determine whether an orally available nutraceutical compound derived from olive oil, oleoyl α-
methyl serine (HU-671) — a derivative of oleoyl-serine (OS) designed to improve in vivo stability, can prevent
bone loss that occurs naturally and rapidly over time in adult female mice. The rationale for this proposal is
supported by prior studies showing that i) OS is present in bone tissue, ii) that exposure to OS and HU-671
promotes osteoblast proliferation and mineralization, as well as osteoclast apoptosis in vitro, and iii) that OS and
HU-671 rescues ovariectomy-induced bone loss in mice by increasing bone formation and decreasing bone
resorption, a rare pharmacologic profile. Though these preclinical studies have delivered OS and HU671 via
intraperitoneal injection, our preliminary data confirm the oral availability of HU-671 in rodents. Finally, we
previously showed that female C57Bl/6J mice exhibit notable trabecular bone loss from 8 to 16 weeks of age,
even in the absence of estrogen deficiency, thereby providing a suitable animal model to test whether treatment
with HU-671 can prevent aging-related bone loss. Thus, we propose to treat female C57Bl/6 mice with HU-671
(0.5 mg/kg/d, IP injection), HU-671 (1, 3, or 10 mg/kg, oral gavage) or vehicle beginning at 12 or 24 weeks of
age and continuing for 6 weeks. Treatment efficacy will be evaluated by in vivo longitudinal bone mass
measurements and ex vivo assessment of bone microstructure, quality and strength. To gain insight into the
mechanisms by which orally-delivered HU-671 influences bone metabolism, we will assess bone formation and
resorption via dynamic histomorphometry and serum markers of bone metabolism. We will also identify genes
and signaling pathways differentially affected by HU-671 by performing bulk RNASeq on bone cells (osteoblasts,
osteoclasts and osteocytes) exposed to HU-671 in vitro, and on the flushed femoral diaphysis of treated mice.
Successful completion of the aims will provide unique information about the potential development and ultimate
use of the HU-671 as a safe, orally available compound for the prevention of osteoporosis. Development of an
oral nutraceutical to prevent bone loss is a highly innovative concept that could alter the clinical paradigm of
osteoporosis management from treatment of advanced disease to one that incorporates prevention.document fetched 2026-09-27 02:45