Calcium Homeostasis

Describe bone remodeling

1. Physiological process - old bone is removed by osteoclasts

2. New bone formed by osteoblasts

Difference between PTH and Calcitonin

1. PTH - acts on osteoblasts - activation of mature osteoclasts - increases calcium

2. Calcitonin - strongly inhibits bone-resorbing activity of osteoclasts - calcium decreases

Name 4 antiresorptive agents

1. Calcitonin

2. Bisphosphonates

3. Denosumab

4. Estrogens/SERMs

What is a calcimimetic agent?

Cinacalcet

Name 3 anabolic agents?

1. Teriparatide

2. Abaloparatide

3. Romosozumab

Describe the pathway of maturation of vit D

Calcitriol enhances calcium absorption in intestines/kidneys, bone resorption, and inhibits PTH

The main function of _________ is to lower blood calcium levels by inhibiting bone resorption and increases calcium excretion through the kidneys

Calcitonin - reduces blood calcium by opposing PTH

Bisphosphonates are used to treat hypercalcemia. They are ________ analogues - inhibit osteoclastic bone resorption

Pyrophosphate analogues

MED CHEM of bisphosphonates - what does R1 and R2 do?

1. R1: OH group - binding to bone is enhanced

2. R2: Determines drug’s effects on binding to hydroxyapatite

What are the two types of bisphosphonates? Name some examples?

1. Simple bisphosphonates

   1. Etidronate and Clodronate

2. Nitrogen-containing

   1. Risedronate, alendronate, ibandronate, zoledronate

Which of the following is not correct…

1. Bisphosphonates are pyrophosphate analogues

2. Non nitrogen bisphosphonates can be metabolized to non-hydrolyzable ATP

3. Alendronate structurally belongs to non-nitrogen containing bisphosphonates

4. Nitrogen containing bisphosphonates target osteoclast farnesyl pyrophosphate synthase

Alendronate is a nitrogen containing bisphosphonate

What is the difference between bisphosphonates and denosumab MOA?

Bisphosphonates typically provide persistent antiresorptive effect after discontinuation, while denosumab’s bone turnover is quickly reversible with discontinuation - transient rebound

How does denosumab work?

1. Human monoclonal antibody

2. Works as a RANK ligand INHIBITOR (inhibits RANKL-RANK)

3. Prevents development of osteoclasts → prevents bone resorption

What is cinacalcet and how does it work?

1. Cinacalcet mimics the action of calcium

   1. Allosterically activates the calcium sensing receptor

   2. Reduces PTH → decrease serum calcium levels

2. Used to treat hyperparathyroidism (CKD/dialysis)

Romosozumab is a humanized monoclonal antibody - how does it work?

1. Increases bone formation by osteoblasts AND decreases bone resorption by osteoclast

2. Works against sclerostin

   1. Inhibits genesis of osteoblasts as a WNT signaling inhibitor

   2. Decreases bone formation

   3. Romosozumab opposes this mechanism

What are PTH analogue drugs?

1. Teriparatide = recombinant PTH

2. Abaloparatide = parathyroid hormone-related protein analog

Bazedoxifene and raloxifene are both _____________ used to treat _______________ and prevent fractures in postmenopausal women

1. Selective estrogen receptor modulators (SERMS)

2. Treats osteoporosis

SERMs work by mimicking the effects of _________ (hormone) on __________, without stimulating the ______ or ______

1. Mimics estrogen on bones

2. Does NOT stimulate uterus or breast tissue

   1. Reduces the risk of invasive cancers at high risk

What is the difference between an anabolic and antiresorptive therapy?

1. Antiresorptive = slow bone remodeling and reduce bone loss

2. Anabolic = stimulate bone formation