Skeletal Lead from the Leaded Petrol Era and Its Potential Role in Neurodegenerative Disease: Hypothesis and Research Agenda

The widespread use of leaded petrol during the twentieth century resulted in substantial population exposure to lead, particularly among individuals growing up in urban environments during peak emissions. Although the phase-out of leaded petrol markedly reduced environmental and blood-lead concentrations, historically absorbed lead can remain stored in the skeleton for decades. Bone remodelling releases accumulated lead into circulation, potentially contributing to continuing endogenous exposure during ageing, menopause, pregnancy, lactation and other periods of increased bone turnover. Epidemiological studies have associated cumulative lead exposure with cognitive decline, dementia and amyotrophic lateral sclerosis (ALS), although the specific contribution of skeletal lead mobilisation to neurodegenerative disease remains uncertain. This paper examines whether interventions modifying bone turnover or calcium availability could reduce endogenous lead exposure associated with historical leaded petrol emissions. Preliminary human evidence suggests that alendronate, a bisphosphonate that inhibits bone resorption, can reduce circulating lead concentrations, with lead-isotope evidence consistent with reduced skeletal mobilisation. Romosozumab, a monoclonal antibody that stimulates bone formation and suppresses resorption, represents another potential intervention, although its effects on circulating lead remain uninvestigated. Randomised controlled trials have also demonstrated that calcium supplementation can reduce blood-lead concentrations in some pregnant and lactating women, potentially through reduced gastrointestinal absorption and altered skeletal mobilisation. However, its effectiveness among older adults with elevated skeletal lead burdens remains uncertain. We propose controlled investigations incorporating skeletal lead measurements, serial blood-lead concentrations, bone turnover markers, dietary calcium assessment and lead-isotope analysis to determine whether pharmacological and nutritional interventions produce sustained reductions in endogenous exposure. Particular attention should be given to historically exposed ageing populations and menopause-associated skeletal lead mobilisation. Establishing whether these interventions reduce circulating lead is a necessary first step before investigating potential neurological benefits. Neither bone-modifying therapies nor calcium supplementation has been demonstrated to prevent lead-associated neurodegenerative disease.