| BackgroundOsteoporosis is a generalized metabolic disease characterized by progressive loss of bone mass and micro-architectural deterioration of bone tissue, leading to bone fragility and increasing the risk of fracture, mainly in the spine and femora. The use of anti-resorptive agents reduces the risk of fractures in patients with osteoporosis. Elemental gallium is a potent inhibitor of bone resorption that acts to maintain or restore bone mass. Gallium has certain physicochemical properties that are relevant to bone physiology. Gallium readily adsorbs to hydroxyapatite and it is rapidly incorporated into osteogenic foci and within cells in metabolically active tissues, Therapeutic doses of gallium result in trace level accumulation in bone. By virtue of these biologic effects, gallium compounds are potentially useful treatments for a variety of diseases that are characterized by accelerated bone loss, including cancer-related hypercalcemia, bone metastases, Paget's disease, and postmenopausal osteoporosis. However, the side effect associated with gallium limits its role as a therapeutic agent for osteoporosis treatment. Organic gallium is one potent way to reduce gallium-associated toxicity and maintain its effect. Yeast has a certain enrichment ability that can convert inorganic elements to organic species and can be used as a gallium carrier. The present study was carried out to investigate the possible role of organic gallium in preventing osteoporosis.ObjectiveThe purpose of this study was to verify the effect of organic gallium on ovariectomized osteopenic rats.MethodThirty Wistar female rats used were divided into three groups:(1) sham-operation rats (control), (2) ovariectomized (OVX) rats with osteopenia, and (3) OVX rats with osteopenia treated with organic gallium. Treatments were performed over an 8-week period. At sacrifice, the fifth lumbar vertebral body, one tibia, one femur, and the fourth lumbar vertebrae were removed, subjected to micro-CT for determination of trabecular bone structure, and then processed for histomorphometry to assess bone turnover. The femoral neck was used for mechanical compression testing. The left femur and L-4 vertebra bone were processed for mineral content measurement. Serum samples were stored at-80℃for future analyses.ResultsMicro-CT After 8 weeks of organic gallium treatment, trabecular bone volume of OVX+gallium group increased by 37.4% (P＜0.05) compared with the OVX+vehicle group, and this bone volume was similar to that of the sham+vehicle group (Table 1). Trabecular number of organic gallium treatment group was significantly lower than in the sham+vehicle group. However,-trabecular thickness increased by 27.6% compared to the sham+vehicletreated group, increased by 48.7% compared with the OVX+vehicle group. Cortical thickness was 32.2% greater in organic gallium (P<0.05) compared to OVX+vehicle group Histomorphometry revealed analysis of cancellous bone volume (BV/TV). At the end of the study, BV/TV in the lumbar vertebrae of PBS-treated OVX rats was 47.5% reduced compared with that in shams (P＜0.05). Organic gallium significantly increased BV/TV in the lumbar vertebrae of OVX rats In the proximal tibial metaphysis, OVX caused 47.4% decrease in BV/TV compared with shams (P＜0.05). Organic gallium cause a significant 145.5% increase in BV/TV (P＜0.05). Histomorphometry also revealed interesting differences in the cellular response to therapies. At the end of the 8-week treatment period, osteoblast surface in the lumbar vertebrae was not affected by OVX or any treatment. A different cellular response was observed in the proximal tibial metaphysis. Organic gallium treatment caused a 3-fold increase in osteoblast surface compared with that in vehicle-treated OVX rats (P＜0.05). The average maximum fracture loading to the femoral necks was 29.3% lower in the salinetreated OVX group compared with the sham-control group. Femoral neck strength in organic gallium-treated OVX groups was higher than that in the saline-treated OVX group.The mineral content in the examined bones of the ovariectomized control animals was significantly reduced compared to the results obtained for the sham-operated controls. The administration of organic gallium to the ovariectomized animals increased significantly the mineral content in the examined bones when compared to the ovariectomized group. Plasma Calcium and Phosphorus Measurements The effects of treatment with organic gallium on plasma total calcium and inorganic phosphate concentrations. OVX rats treated with organic gallium had mean values for serum calcium and serum phosphorus (10.01±0.4 and 5.20±0.2 mg/dl, respectively). These values were significantly lower than those of vehicle-treated control (13.23±0.3 and 8.88±0.4 mg/dl, respectively).ConclusionThese data provide an important proof of concept that organic gallium may represent a powerful approach to treating or reversing severe osteoporosis in humans. |
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