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Review Question - QID 5899

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QID 5899 (Type "5899" in App Search)
A researcher is working on Medication A, a drug FDA-approved for the treatment of osteoporosis in men and women. It is an anti-resorptive agent that inhibits the formation, function and survival of osteoclasts. It does not bind to calcium hydroxyapatite. At 1-year after the initial dose, tissue levels are non-detectable. It can be used in the presence of cancer metastases to bone. What is Medication A?

Denosumab

51%

1375/2693

Alendronate

33%

901/2693

Abaloparatide

2%

57/2693

Teriparatide

10%

278/2693

Strontium ranelate

2%

56/2693

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Denosumab is FDA-approved for the treatment of osteoporosis in men and women. It inhibits the formation, function and survival of osteoclasts (OC). It does not bind to calcium hydroxyapatite. At 1-year after the initial dose, tissue levels are non-detectable.

Denosumab is a human monoclonal antibody against RANKL. By binding RANKL, it prevents interaction of RANKL with RANK (on OC and osteoclast precursors, OCP), and inhibits OC-mediated bone resorption, and the formation, function and survival of OC. In contrast, bisphosphonates bind to calcium hydroxyapatite in bone, and decrease resorption by decreasing function and survival (but not formation) of OC.

Vaananen et al. reviewed the cell biology of OC. During bone resorption, 3 membrane domains appear: ruffled border, sealing zone and functional secretory domain. The resorption cycle starts with migration, bone attachment, polarization (formation of membrane domains), dissolution of hydroxyapatite, degradation of organic matrix, removal of degradation products from resorption lacuna, and apoptosis of the OC or return to the non-resorbing stage.

Boyce et al. reviewed the regulation of osteoclasts and their functions. OCPs are held in bone marrow by chemokines e.g. stroma-derived factor-1 (SDF1) and attracted to blood by sphingosine-1 phosphate (S1P) (increased in synovial fluid of patients with RA). All aspects of osteoclast formation and functions are regulated by M-CSF and RANKL. More recent studies indicate that osteoclasts and their precursors regulate immune responses and osteoblast formation and functions by means of direct cell-cell contact through ligands and receptors, such as ephrins and Ephs, and semaphorins and plexins, and through expression of clastokines.

Warriner and Saag reviewed the diagnosis and treatment of osteoporosis. They defined osteoporosis as T-score of = -2.5 or a history of fragility fracture. Incident hip and vertebral fractures increase future risk of these fractures (hazard ratio 7.3 and 3.5, respectively).

Cummings et al. compared subcutaneous denosumab (60mg every 6mths) vs placebo in prevention of fractures in 7868 osteoporotic (T-score -2.5 to -4.0) postmenopausal women. They found that denosumab reduced risk of vertebral fracture by 68% (risk ratio, 0.32), hip fracture by 40% (hazard ratio 0.6), nonvertebral fracture by 20% (hazard ratio 0.8). There was no increased risk of cancer, infection, delayed fracture healing, cardiovascular disease, osteonecrosis of the jaw or adverse reactions. They concluded that it was useful for reduction of fractures in osteoporotic women.

The video shows the action of denosumab (prolia). Illustration A shows the different osteoclast zones.

Incorrect Answers:
Answers 2: Alendronate (and other bisphosphnates) inhibit resorption of bone, decrease function and survival of osteoclasts. Because of binding to calcium hydroxyapatite, they are detectable years after dosing. They reduce function and survival of OC, but do not affect the formation of osteoclasts.
Answer 3: Abaloparatide is a PTH analog that has completed phase III trials for osteoporosis. As of mid-2016, it is not yet approved for treatment of osteoporosis.
Answer 4: Teriparatide (recombinant PTH 1-34) is the only anabolic (not antiresorptive) agent approved for osteoporosis treatment. It is administered by daily subcutaneous injection. Osteosarcoma, cancer metastases to bone and Paget's disease are contraindications.
Answer 5: Strontium ranelate (marketed as Protelos or Protos) both increases deposition of new bone by osteoblasts and reduces the resorption of bone by osteoclasts ("dual action bone agent", DABA). It is not FDA approved for use in the United States. Increased risk of myocardial infarction has been detected.

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