O Future Directions

Serotonin Regulation of Bone Formation

The low-density lipoprotein (LDL)-receptor-related protein 5 (Lrp5) is a regulator of bone remodeling (balanced osteoblast and osteoclast activity). Among its functions is limiting biosynthesis of serotonin in the gut. Using knockout mice models that are deficient in Lrp5, increased serotonin levels results in decreased bone formation. The site of approximately 95% of the body's serotonin production is the gut, and this serotonin cannot cross the blood-brain barrier. Most of the gut-produced serotonin is taken up by platelets with much of the remainder possibly affecting bone formation by controlling osteoblast proliferation.15 Consistent with this model is the observation that patients taking selective serotonin reuptake inhibitors (SSRIs), where there is increased peripheral serotonin, can have reduced bone mass.16

Monoclonal Antibodies

A monoclonal antibody target for the treatment of osteoporosis is the RANKL, which is the essential mediator of os-teoclasts. As pointed out in the osteoporosis discussion, the loss of calcium by increased osteoclastic activity and decreased osteoclast apoptosis is opposed by a RANKL inhibitor, osteoprotegerin a 401-amino acid glycoprotein, and a member of the TNF superfamily. Rather than develop a pharmaceutically acceptable osteoprotegerin, a fully human monoclonal antibody, denosumab, that binds to the RANKL preventing its binding to RANK is being evaluated for the treatment of osteoporosis. The reported result is inhibition of all stages of osteoclast activity.17 It is important to keep a perspective when administering drugs that interfere with the immune system over long periods of time. RANKL is part of the normal bone remodeling process as well as with pathological bone loss. The key is balance, and this will require long-term studies in patients with post-menopausal osteoporosis.

# review questions #

1. Name the two cell lines responsible for bone remodeling and function of each.

2. What is found in the large bones and what is its function?

3. How does osteoporosis differ from osteomalacia?

4. How does the site of action of the non-N-bisphosphonates differ from the N-containing bisphosphonates?

5. What is the basis for the adverse reactions seen with administration of calcitonin-salmon?

6. What is teriparatide?

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