Ketogenic diet sex-dependent effects on rat bone marrow cells during development and β-HB protection in hypoglycemia

The ketogenic diet (KD) is a high-fat, moderate-protein, and low-carbohydrate diet. Initially prescribed for drug-resistant epilepsy, KD has become popular for weight reduction in patients with diabetes and obesity, who are often affected by reduced bone mass. However, KD's impact on bone marrow cells remains largely unexplored. Here, we show the effects of low protein KD on bone marrow cells (BMCs) during pregnancy, lactation, and postnatal development in 30-day-old Wistar rat offspring. KD consumption in female juvenile rat offspring supported BMC osteogenic differentiation and inhibited osteoclast activity, while in male rat BMCs it reduced bone regenerative potential. This was observed despite a strongly reduced body weight in both sexes. The addition of the primary ketone body β-hydroxybutyrate (β-HB) to juvenile and adult rat BMC cultures in a low glucose culture medium effectively promoted extracellular matrix mineralization and proliferation of rat BMCs and reversed the negative impact of low glucose on BMC viability, inflammation, and osteoclast activity. Given the above, we recommend considering the potential sex differences when implementing restrictive diets and their consequences during pregnancy. Our results also highlight the distinct effects of low glucose and β-HB on the osteogenesis of juvenile and adult rat BMCs, which suggests caution in considering short-term KD or fasting for bone-related therapies.