Module 29

Question 1

1. One class of drugs for the treatment of osteoporosis is the bisphosphonates. Etidronate (Didronel), alendronate (Fosamax, structure shown below) and risedronate (Actonel) are the agents currently available. How do these agents work? What is the bioavailability of alendronate and what factors affect it? What is the dosing regimen, and why is it different for etidronate and alendronate? What is the major complication of alendronate treatment and how can it be prevented? What type of fracture do bisphosphonates appear to increase?

Answer 1

• These agents work by inhibition of osteoclasts, which are the cells involved in breaking down bone as bones are continually restructured. This changes the balance of bone resorption to bone building to favor bone formation.
  
  • A drug that is mostly charged can still be well absorbed if there is a significant proportion that is uncharged. However, a phosphonate is more highly charged than a carboxylic acid, and there are two phosphonates as well as a basic amino group. Therefore, oral absorption is quite poor, less than 1%, although this is still sufficient to allow these drugs to be dosed orally.
    ○ However, most things further decrease absorption so bisphosphonates have to be taken with plain water; in fact it should not even be hard water that contains a significant amount of minerals. The bisphosphonates are also very corrosive, and if a patient takes a bisphosphonate and then lies down, it can reflux into the esophagus and cause very serious esophagitis.
  • Alendronate is more potent and selectively inhibits osteoclasts. In contrast etidronate is less potent and must be given at higher doses. At the higher doses etidronate also inhibits osteoblasts, which form new bone. In order to prevent too much inhibition of osteoblasts, etidronate dosing is interrupted periodically to allow more bone formation.
  • Even though bisphosphonates decrease the risk of bone fractures, with chronic use they are associated with fractures straight across the femur. They are also associated with osteonecrosis, especially of the jaw, in which the bone basically dies. Therefore, bisphosphonates are often stopped after a few years of treatment. The half life of bisphosphonates in bones is measured in years; therefore, they exert their effects for a long time.

Question 2

What two other types of drugs are used for the prevention of osteoporosis?

Answer 2

parathyroid hormone, calcitonin, and testosterone. However, the major alternative drugs are estrogen or SERMs such as raloxifene, and a new agent, denosumab, which is an antibody that inhibits RANKL and prevents the development of osteoclasts.

Question 3

What is the optimal calcium intake in postmenopausal women?

Answer 3

• The answer to that question is unknown. In the past, high doses of calcium were recommended to decrease the risk of osteoporosis; however, the absorption of calcium is controlled, and data indicate that high doses of calcium do not decrease the risk of osteoporosis. There is epidemiological evidence that high calcium intake increases the risk of cardiovascular disease; however, association does not prove causation, and there does not appear to be any clear dose/response relationship.

Question 4

What other drugs can affect bone metabolism?

Answer 4

• Chronic administration of corticosteroids is a major risk factor for osteoporosis.
  
  • Some anticonvulsants and chronic use of proton pump inhibitors also appear to increase the risk of fractures.
    Thiazide diuretics decrease the renal excretion of calcium; they are associated with a decrease in fractures and calcium oxalate renal stones.