Mechanism of Action

Gallium In Bone

Gallium reduces bone loss by inhibiting calcium resorption from bone. Preclinical evidence suggests that the mechanism of gallium action is multifactorial and different from other current therapies used to treat bone loss, such as estrogen, selective estrogen receptor modulators (SERMs), denosumab, calcitonin, or bisphosphonates (e.g., Zometa^® or Fosamax^®). Gallium preferentially accumulates in metabolically active regions of bone, inhibits osteoclast-mediated bone resorption, and favorably alters bone mineral composition and properties.

The safety and efficacy of an oral gallium compound have not been established for any use.

• MOA
• Normal Bone Remodeling

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  The active ingredient in oral gallium (ionic gallium [Ga3+]) has potent anti-resorptive activity and mild anabolic effects on bone tissue.  The compound is reversibly incorporated into regions of high metabolic skeletal activity.  Using synchrotron-generated x-ray microscopy, contour maps in animals treated for 14 days showed that the highest levels concentrate in metabolically active regions of bone (i.e., metaphyseal and epiphyseal regions) where remodeling occurs. Conversely, extremely low levels are found in mid-cortical regions where skeletal metabolic activity and calcium turnover are low.

   

  Gallium regulates the activity of cells responsible for bone resorption (osteoclasts) in a non-toxic manner.  A principal mechanism whereby osteoclasts dissolve bone is via acidification of mineralized bone matrix.  Gallium has been shown to significantly inhibit ATPase-dependent hydrogen ion transport in this cell, thereby markedly inhibiting the acidification of mineralized matrix, hence reducing bone dissolution.  This effect (i.e., a marked decrease in activity of the proton pump) is currently believed to be the principal mechanism responsible for the drug's anti-resorptive action.

  In vivo, the drug promotes hydroxyapatite maturation, producing bone particles of increased density and somewhat larger or more perfect crystallites with greater calcium and phosphate content and lower carbonate content.  These changes are associated with a significant decrease in the solubility of treated bone in acidic buffer solutions, suggesting that even short-term (2-week) treatment renders bone significantly more resistant to dissolution. 

  Gallium may also exert mild anabolic effects on new bone production.  Injection of radiolabeled calcium into gallium-treated rodents demonstrates significantly enhanced accretion of new calcium into bone relative to controls.  These findings suggest that gallium treatment may enhance mineralization of newly-forming bone in addition to decreasing bone resorption.  Gallium also significantly enhanced the synthesis and content of Type-I collagen, the major protein found in skeletal matrix.  In summary,
  these dual effects (i.e., a decrease in bone resorption and [possibly] an increase in new bone formation) may account for the very high clinical potency of the active ingredient.

  Genta’s oral gallium compounds are investigational agents undergoing testing to evaluate safety and efficacy in the treatment of various conditions associated with bone loss. Studies are currently planned to examine the potential role of these compounds in a variety of clinical indications.
  

• Bone Remodeling

  Bone is a living tissue that is constantly being remodeled in response to the stresses of daily life. However, certain regions (i.e., the ends of long bones and in the middle interior regions of all bones) are more active than other sites (the outer cortex). The bone remodeling process is dynamic and generally in equilibrium, whereby bone resorption (breakdown) is generally balanced by new bone formation.

  

   

   

  Many diseases are associated with accelerated bone loss, including osteoporosis, cancer, Paget’s disease, and others. In some diseases, the alteration in the bone remodeling equilibrium is subtle and slow, while in others it is very rapid and acute. For example, in osteoporosis, the most prevalent bone-losing condition, the process of bone loss extends over a period of years (even decades) before the disease manifests itself. Conversely, in cancer-related hypercalcemia, bone is being lost at such a rapid rate that it overwhelms the kidney’s ability to excrete calcium from the system. In this condition, the calcium level in the blood can rise to levels that can quickly become fatal.

  Genta’s oral gallium compounds are investigational agents undergoing testing to evaluate safety and efficacy in the treatment of various conditions associated with bone loss. Studies are currently planned to examine the potential role of these compounds in a variety of clinical indications.