Selective serotonin-reuptake inhibitors (SSRIs) antagonize the serotonin (5-hydroxytryptamine) transporter (5-HTT), and are frequently prescribed to children and adolescents to treat depression. However, recent findings of functional serotonergic pathways in bone cells and preliminary clinical evidence demonstrating detrimental effects of SSRIs on bone growth have raised questions regarding the effects of these drugs on the growing skeleton. The current work investigated the impact of 5-HTT inhibition on the skeleton in: 1) mice with a null mutation in the gene encoding for the 5-HTT; and 2) growing mice treated with a SSRI. In both models, 5-HTT inhibition had significant detrimental effects on bone mineral accrual. 5-HTT null mutant mice had a consistent skeletal phenotype of reduced mass, altered architecture, and inferior mechanical properties, whereas bone mineral accrual was impaired in growing mice treated with a SSRI. These phenotypes resulted from a reduction in bone formation without an increase in bone resorption and were not influenced by effects on skeletal mechanosensitivity or serum biochemistries. These findings indicate a role for the 5-HTT in the regulation of bone accrual in the growing skeleton and point to a need for further research into the prescription of SSRIs to children and adolescents.

Using a mechanical loading program to induce bone adaptation, we found that small (<2-fold) changes in the structural properties of the rat ulna increased its fatigue resistance >100-fold. This indicates that a moderate exercise program may be an effective preventative strategy for stress fractures.Introduction: There are currently limited preventative strategies for stress fractures. Because stress fracture risk is directly influenced by skeletal properties, it has been hypothesized that modification of these properties using a mechanical loading program may positively influence risk. The aim of this study was to investigate whether the bone changes associated with a mechanical loading program can enhance skeletal fatigue resistance. Materials and Methods: Site-specific mechanical loading was performed on one forearm of adult female Sprague-Dawley rats using the axial compression loading model. Loading was performed 3 days/week for 5 consecutive weeks to induce adaptation. The loaded and nonloaded ulnas in each animal were removed after the loading program, and their material and structural properties were determined. The ulna pairs were subsequently loaded until fatigue failure at the same constant peak axial load. Results: Mechanical loading induced consistent and predictable changes in the structural properties of loaded ulnas, with the largest change being a nearly 2-fold increase in midshaft minimum second moment of area (I MIN ). The mechanical-loading induced bone changes resulted in a >100-fold increase in fatigue resistance in loaded ulnas, with resistance being exponentially related to the structural properties of the ulna. Conclusions: This study found that by enhancing the structural properties of a bone through a mechanical loading program, its fatigue resistance could be significantly improved. This indicates that an exercise program aimed at modifying bone structure may be used as a possible prevention strategy for stress fractures.

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