Hypothesis

Long‑term NSAID use in older adults blunts the release of undercarboxylated osteocalcin (ucOCN) from resorption sites by inhibiting COX‑2‑derived prostaglandin E2, thereby weakening an osteokine‑driven endocrine circuit that supports insulin sensitivity, BDNF signaling, and cognitive resilience. Consequently, habitual analgesic consumption accelerates metabolic dysregulation and cognitive decline, effectively trading short‑term pain relief for faster biological aging.

Mechanistic rationale

• Bone microdamage during remodeling creates acidic resorption lacunae where COX‑2 in osteoclasts and osteocytes produces PGE2.
• PGE2 acts on EP4 receptors on neighboring osteocytes to stimulate ucOCN secretion into circulation [[https://pmc.ncbi.nlm.nih.gov/articles/PMC11059196/]].
• NSAIDs (especially selective COX‑2 inhibitors) blunt this PGE2 surge, reducing ucOCN release.
• Lower circulating ucOCN diminishes its endocrine actions: reduced insulin secretion/sensitivity [[https://pmc.ncbi.nlm.nih.gov/articles/PMC5349189/]] and weaker neuronal Gpr158‑BDNF signaling [[https://pmc.ncbi.nlm.nih.gov/articles/PMC11059196/]].
• The net effect is a shift toward higher fasting glucose, increased adiposity, and diminished neurotrophic support, phenotypes that correlate with accelerated frailty and cognitive loss.

Testable predictions

1. In epidemiological cohorts of adults ≥65 y, serum ucOCN will be inversely associated with cumulative NSAID dose (defined daily doses) after adjusting for age, sex, BMI, and comorbidities.
2. Participants in the highest NSAID‑use quartile will exhibit:
   • higher fasting glucose and HOMA‑IR,
   • lower plasma BDNF,
   • faster decline in gait speed and Mini‑Mental State Examination scores over 3‑year follow‑up.
3. In aged mice, chronic administration of a COX‑2‑selective NSAID will lower bone‑derived ucOCN, impair glucose tolerance, and reduce hippocampal BDNF compared with vehicle‑treated controls; genetic deletion of COX‑2 in osteoclasts will phenocopy these effects.
4. Exogenous ucOCN administration will rescue the metabolic and cognitive deficits induced by NSAID treatment in mice, confirming causality.

Falsifiability

If long‑term NSAID exposure does not predict lower ucOCN or if ucOCN levels fail to mediate the relationship between NSAID use and metabolic/cognitive decline, the hypothesis is refuted. Likewise, if COX‑2 inhibition in osteoclasts does not alter ucOCN release or downstream phenotypes in mice, the proposed mechanistic link is invalid.

Implications

Should the hypothesis hold, it suggests a reevaluation of analgesic guidelines in aging: balancing analgesia with preservation of bone‑derived endocrine signaling, perhaps via intermittent dosing, COX‑2‑sparing agents, or ucOCN supplementation.