Results from a novel longitudinal water/fat imaging study may have identified a key mechanism that explains how a third-generation bisphosphonate zoledronic acid (Reclast) protects bone loss.
Research in ovariectomized rats revealed that zoledronic acid reverses the bone marrow adipogenesis that occurs with estrogen depletion following menopause. Expression of the nuclear receptor gene PPAR-gamma-2 was also down-regulated with treatment, reported Guan-Wu Li, MD, of Shanghai University of Traditional Chinese Medicine, and colleagues.
The findings add to evidence indicating bisphosphonates exert anabolic effects through the stimulation of the osteogenic differentiation potential of marrow mesenchymal stem cells (MSC), as well as through the reduction in adipogenic differentiation, they wrote in Endocrinology.
"From the perspective of mechanisms, excess marrow fat may inversely impact bone formation because adipocytes and osteoblasts derive from common marrow MSCs," they observed.
MSCs are precursors of both adipocytes and osteoblasts, the researchers noted, adding that there is growing evidence that a reciprocal relationship exists between bone strength and marrow adiposity in conditions such as aging, menopause, anorexia nervosa, and chemotherapy-induced bone loss.
"Early zoledronic acid treatment has been found to fully preserve ovariectomy (OVX)-induced deterioration of bone micro-architecture and strength over time. However, there are no in vivo data concerning the effects of zoledronic acid treatment on marrow adiposity," the researchers wrote. "Because both osteoblasts and adipocytes are of mesenchymal origin, we hypothesized that zoledronic acid treatment might negatively impact marrow adipogenesis."
They tested their theory by examining the impact of zoledronic acid treatment on marrow adipose tissue in an OVX female rat model over 3 months, using water/fat separation shift-based MRI to assess changes.
Dual-energy x-ray absorptiometry and water/fat MRI were performed at baseline, 6 weeks, and 12 weeks after treatment to assess bone mineral density and marrow fat fraction. Some subjects were harvested during the study to obtain femurs and tibias for histology and histomorphometry. The uterus/body mass ratio was calculated by normalizing the uterine weight to the final body mass.
Serum biochemical markers, bone remodeling, and marrow adipocyte parameters were analyzed using biochemistry, histomorphometry, and histopathology. Osteoblast, adipocyte, and osteoclast-related gene expression in bone marrow were measured using reverse transcription polymerase chain reaction.
"The OVX [control] rats showed marked bone loss, first detected at 12 weeks, but estrogen deficiency resulted in a remarked increase in marrow fat fraction, first detected at 6 weeks compared with (non-OVX, untreated [SHAM]) rats (all P<0.001)," the researchers wrote. "The OVX controls had a substantially larger marrow fat area (+163.0%), mean adipocyte diameter (+29.5%), and higher adipocyte density (+57.3%) than the SHAM rats (all P<0.001)."
The extent of bone loss was greater in the vertebrae than in the femur.
However, zoledronic acid treatment to the OVX rats significantly suppressed bone resorption and returned adipocyte-related gene expression and marrow adipocyte parameters toward levels seen in SHAM animals, the researchers noted.
"The results of our study suggest that zoledronic acid has preventative effects on the deterioration of bone mass and suppressive effects on marrow adipogenesis induced by estrogen deficiency in rats in vivo," Li and colleagues wrote.
The findings also suggest that measuring marrow fat fraction may be useful for monitoring response to treatment with zoledronic acid.
"Recognizing the diagnostic limitations of densitometric techniques, our results suggest that the MRI-based analysis of marrow fat content might serve as a novel imaging tool for the noninvasive assessment of osteoporosis-related research," they wrote. "Future research should target integrating imaging findings with emerging insights into marrow adipocyte biology to understand the pathomechanisms that drive these changes."