Pharmacology of Osteoporosis

Question 1

Where is bone mineral density (BMD) typically measured to predict osteoporosis? What is the measure at which osteoporosis is diagonsed?

Answer 1

Femoral neck (predicts risk of hip fractures), or the spine

2.5 standard deviations below the mean for young women in BMD

Question 2

What are the recommendations for vitamin D and calcium supplementation? Give the exact values you want to hit?

Answer 2

Generally only needed in those nutritionally deficient, which is easy to be when taking antiresorptive agents (prevent freeing of calcium from bone) like those used for osteoporosis

1000mg of Ca for adults, with 1200mg if <50 in women

600 IU of vitamin D for adults, with 800 IU if <70 in women

Question 3

What are the adverse effects of calcium supplementation? How is it given?

Answer 3

Only increased risk of kidney stones and GI distress

- generally given as calcium carbonate or citrate with food

Question 4

What are the bisphosphonates and their mechanism of action?

Answer 4

Drugs ending in -DRONATE, prevent or treat osteoporosis by decreasing bone resorption by binding active sites of bone remodeling on osteoclasts (osteoclasts will grab drug instead of hydroxyapatite)

Question 5

Most of the bisphosphonates are given orally. Which is not? What do these serve to do?

Answer 5

Zoledronic acid is given once yearly via IV, or once every two years to prevent osteoporosis

Reduce the risk of vertebral and non-vertebral fractures

Question 6

When and how should bisphosphonates be taken?

Answer 6

Oral agents such as alendronate should be taken after an overnight fast with plain water, since many things can limit their absorption

They should also be taken upright to prevent the upper GI side effects

Question 7

What are the common side effects of bisphosphonates? More severe?

Answer 7

Upper GI side effects: esophagitis, acid reflux, esophageal ulcers (think of the rusty rod in the neck of the dino).

Also common: hypocalcemia due to antiresorptive properties (supplement with vitamin D and Ca+2)

Severe: Osteonecrosis of jaw (jaw falling off dino), esophageal cancer

Question 8

Which drug is a monoclonal antibody to RANKL expressed on osteoblasts, which stimulates osteoclast differentiation?

Answer 8

Denosumab (think dino-suit-man taking away crank-drill (RANKL) from the osteoclast kid)

Question 9

How are the side effects of Denosumab different from bisphosphonates?

Answer 9

Allergic reactions at injection site, and also denosumab is safe in impaired renal function (bisphosphonates can cause acute renal failure)

Otherwise, the same minus the GI side effects

Question 10

What drugs are the selective estrogen receptor modulators (SERMs)?

Answer 10

-oxifenes

Includes Raloxifene (think relax in Sketchy) and Bazedoxifene

Question 11

How do the SERMs work?

Answer 11

They are agonists of estrogens in bone (inhibits osteoclasts) -> relax sign inhibiting osteoclasts

They also have less cancer risk than normal estrogens because they antagonize estrogen action in the breast and uterus (can be used as chemotherapies for these cancers)

Question 12

What are the side effects of SERMs?

Answer 12

Hot flashes, peripheral edema (fluid retention like all estrogens), increased risk of venous thromboembolism (same clotting propensity increase as estrogens)

Question 13

What is the mechanism of action of Calcitonin and why is it rarely used for osteoporosis now?

Answer 13

Directly inhibits osteoclasts (reduce calcium levels) and causes excretion of Ca+2 in the kidneys (reduce calcium levels).

Mainly used in hypercalcemia
-> rarely used due to serious allergic reactions and increased risk of malignancy

Question 14

What are the mechanisms of action of parathyroid hormone? Think bone and kidney. What inhibits it?

Answer 14

1. Stimulates osteoblasts and short-term bone formation
2. Long-term, stimulates osteoblasts to recruit new osteoclasts for bone breakdown and an increase in blood calcium
3. Parathyroid hormone stimulates reabsorption of calcium in exchange for phosphate in the kidney
4. Parathyroid hormone stimulates conversion to calcitriol in kidney
   - > PTH is inhibited by high calcium levels and vitamin D

Question 15

How is active vitamin D made?

Answer 15

7-DHC in skin is converted to vitamin D3 in skin (or D3 / D2 eaten in diet)

D3 converted to 25-OH-D3 in liver.

25-OH-D3 converted to 1,25-OH-D3 (calcitriol, active) in kidney, under control of PTH

Question 16

What are the actions of active vitamin D?

Answer 16

Stimulates calcium and phosphate reabsorption in the kidney

2. Stimulates osteoblasts and stimulates osteoclasts, increase bone turnover
3. Blocks PTH (reduces bone breakdown overall)
4. Increases intestinal absorption of calcium and phosphate

Question 17

What drug is a PTH analog and how does it treat osteoporosis?

Answer 17

Teriparatide (TA in sketchy), think Terry PARA

Once daily injections in short bursts will promote osteoblast bone formation without stimulate of osteoclast bone degradation
-> not an antiresorptive agent

Also acts in kidney

Question 18

What are the most likely adverse effects of teriparatide?

Answer 18

Hypercalcemia and hypercalciuria -> bone resorption is not inhibited, and teriparatide also enhances resorption of Ca+2 in the kidney like PTH + stimulates vitamin D production

Question 19

What is the most likely adverse effect of calcitriol?

Answer 19

Hypercalcemia -> due to increased Ca+2 resorption and faster bone turnover