Radiopharmaceuticals for Bone

  1. A and P of the bone
    1. Bone consists of an outer layer of cortical bone that imparts shape and strength. Internal to the cortical bone is spongy cancellous (trabecular) bone. Cancellous bone contains marrow, which is composed of fat and hematopoietic elements. The articulating surfaces of bone are covered with a layer of cartilage. Blood vessels penetrate the cortex and permeate the cancellous bone. A fibrous and cellular envelope covers the bone tissue surfaces. This envelope, consisting of the periosteum externally and the endosteum internally, contains the osteocytes, which are pluripotent in bone remodeling.
    2. Collagen fibers give bone its tensile strength and provide centers for deposition of inorganic salts. Principal inorganic salts in bone are amorphous calcium phosphate (ACP) and hydroxyapatite (HA). ACP is believed to be a precursor to HA.
    3. Osteocytes function as osteoblasts (bone-forming) or osteoclasts (bone resorption). During bone production, osteoblasts synthesize an osteoid matrix and collagen fibers. ACP precipitates on their surfaces to form HA crystals. ACP is a mixture of hydrated calcium phosphates of varying Ca/P molar ratios consisting mainly of calcium monohydrogen phosphate (CaHPO 4, Ca/P = 1.0), octacalcium phosphate (Ca 4H(PO 4) 3, Ca/P = 1.33) and tricalcium phosphate (Ca3(PO 4) 2, Ca/P = 1.5). ACP salts are converted into crystallized HA (Ca 10(OH) 2(PO 4) 6, Ca/P = 1.66).
    4. HA has a large surface area (200 m 2/g) that provides an enormous opportunity for adsorption and surface exchange of a variety of ions. These include Sr +2, Pb +2, Ra +2, and Mg +2 for Ca +2; F - that exchanges for OH -; and CO 3 2-, citrate, phosphate esters, diphosphonates and pyrophosphates, which exchange with phosphate.
  1. Compounding- Radiopharmaceuticals are prepared by adding the required amount of Tc-99m sodium pertechnetate to a sterile lyophilized kit containing a mixture of stannous ion and the appropriate ligand.
    1. Radiocolloid is favored if the ratio of phosphate to tin is too low and the pH of the reaction mixture is too high. Although adding excess tin can counteract radiocolloid formation, large amounts of tin have been shown to interfere with brain imaging for up to 2 weeks, with use of 99mTcO4-.
      1. Bone kits prepared with reduced levels of tin were unstable producing free pertechnetate.
      2. Oxidative degradation (atmospheric and dissolved oxygen) and radiolytically generated free radicals promoted this instability.
      3. Nitrogen purging and addition of the antioxidants ascorbic acid or gentisic acid help stabilize these kits.
      4. Only gentisic acid can be used in pyrophosphate kits, because the presence of ascorbic acid causes the formation of a Tc-99m ascorbate complex that results in renal images.
      5. Addition of these agents provides an H atom to RO· and RO 2· free radicals resulting in a nonreactive molecule (RO 2H).
  1. Localization – Fluoride anion reacts with bone by isomorphous exchange of fluoride with hydroxyl in HA. Tc-99m phosphate and phosphonate complexes interact with bone by binding to calcium ions in bone ACP (chemisorption). EHDP, MDP and HDP are all geminal diphosphonate (both phosphate moieties are attached to the same carbon).   Binding to calcium is highest when one of the remaining two sites is hydroxyl and the other hydrogen (HDP). This tridentate face is optimal for calcium binding. Although EHDP has a similar structure, its methyl group imparts steric hindrance.
  2. Clinical use – Evaluation of metastatic disease, infection, and traumatic injury (20 mCi).
  3. Biodistribution – Rapidly distributed in the body and by 3 hours most of the activity is located in the skeleton, urine, and blood. Bone activity at this time is about 45% and 55% for EHDP and MDP, respectively. Although not clinically significant, HDP has 20% higher bone uptake than MDP.
  4. Excretion – The 3 h urine accumulation in humans is 43% for PPI, 56% for EHDP and 59% for MDP.

Tc-99m Medronate Injection (Tc-99m MDP)

  1. Compounding – A sterile aqueous solution prepared from a lyophilized kit containing medronic acid and stannous chloride. Several kits are formulated with gentisic or ascorbic acid to protect the relatively labile complex from degradation by oxygen and radiolytically generated free radicals. Radiochemical purity should be ≥ 90%.
  2. The kit is prepared by adding the specified amount of activity and volume of Tc-99m sodium pertechnetate and mixing for a maximum of 1 –2 m.

Tc-99m Oxidronate (Tc-99m HDP)

  1. Compounding – A sterile aqueous solution prepared from a kit that contains oxidronate sodium (3.15 mg), stannous chloride dihydrate (0.297 mg), gentisic acid (0.84 mg) as an antioxidant stabilizer, and sodium chloride (30 mg), sealed under nitrogen. The kit should be stored at 20 – 25 °C before and after labeling.
  2. The kit is prepared by adding up to 300 mCi of Tc-99m sodium pertechnetate in 3 – 6 mL and mixing for 30 s. The pH of the reconstituted product is 4 – 5.5 and is stable for 8 h. Radiochemical purity should be ≥ 90%.

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