Increased fatty acid availability improves the osteo-anabolic effects of intermittent parathyroid hormone (iPTH) in murine models

Osteoporosis is a major public health problem which results in reduced bone mineral density (BMD) and increased fracture risk. Osteoporosis-related fractures often lead to multiple comorbidities which can significantly reduce longevity and diminish one's quality of life. While anabolic agents that increase bone formation, such as parathyroid hormone (PTH), have aided in the management of osteoporosis, patients still experience adverse side-effects along with variations in therapeutic response. Therefore, continued development of refined therapeutic interventions as well as improving efficacy is necessary. Relative to this, the current experiments report on the ability to harness PTH's impact to modulate osteoblast bioenergetic capacity to promote bone formation by supplying fatty acid substrates to meet this energetic demand. To accomplish this, mice were fed a moderately 'high' fat diet (2.5×) or control fat, as to not induce metabolic perturbations, while treating with or without PTH for 4 weeks. This dietary regimen resulted in improved bone parameters in mice fed the high fat diet compared to control diet. To directly test the contribution of increased exogenous fatty acid substrates during PTH treatment, we next introduced oleic acid simultaneous to PTH treatment for 4 weeks, and again showed improved skeletal parameters compared to the vehicle-control treated mice. These data support previous publications that demonstrate the osteoanabolic responsiveness of osteoblasts to PTH requires fatty acid substrates. These data further expand on these findings, by providing evidence that PTH efficacy can be improved by supplying exogenous fatty acid substrates, either by dietary or direct interventions.