Question

1- Describe how would you treat osteoporosis? [Define negative feedback (5 pts), identify the control mechanisms for bone growth (5 pts, identify cells involved (1 pt for each cell)), and explain why treatment would work and how it would interfere with the feedback system(5 pts); 15 pts]

Answer 1

1) Medications used to treat osteoporosis are :-

- Estrogen

MOA:stimulates maturation of osteoblasts and prolongs their lifespan, inhibits and matures osteoclasts and shortens lifespan, inhibits the expression of RANK-L, decreasing osteoclast activity

Efficacy: showed small improvements in BMD, but also showed some concerning risks, so while it is effective therapy, it is NOT first line therapy for prevention or tx of osteoporosis

Adverse:CHD, stroke, breast cancer, VTE

- Raloxifene

MOA: SERM that binds estrogen receptor, but with different properties-->Estrogen like at bone (small improvement in bone density, prevent further loss), anti-estrogen at breast (decreased Breast CA risk), neutral at endometrium (no risk of endometrial hyperplasia)

Efficacy: decreased VERTEBRAL fx by 30-50%, no proven benefit for hip or other fx

Adverse: increased hot flashes and risk of thromboembolic disease

- Bisphosphonates (Alendronate, risendronate, ibandronate, zoledronic acid)

MOA: incorporate into matrix of bone, get reabsorbed by osteoclasts-->impair fxn and induce apoptosis. Induce small improvement in bone density, prevent further bone loss

Efficacy: prevent bone loss, small gains seen in clinical trials

Adv: upper GI symptoms/heartburn (oral only)-->take on empty stomach, 8 oz water, upright for 30 min post, Osteonecrosis of jaw (very rare, only with excessively high doses for metastatic cancer patients), atypical femoral necrosis: very rare, "slightly less rare" on bisphosphonates-->but the overall risk/benefit ratio still favors use!!

- Calcitonin

comes from thyroid parafollicular cells

has no significant activity in calcium balance in humans, but salmon derived: can decrease calcium levels acutely in tx of severe hypercalcemia, but effect is short-lived, has some minimal vertebral fx prevention data, has some data showing pain control in vertebral compression fx, given intranasally or subQ

Advantages: no real side effect (aside from allergy), so why not give it if it could help??

- Teriparatide

THE ONLY ANABOLIC AGENT!!

MOA: pulsatile PTH-->induce osteoblast>osteoclast-->net gains in bone density

PK: short-acting recombinant PTH 1-34, daily SubQ inj, approved for 2 year use with a 5-15% gain in BMD, decreases vertebral fx 65% and nonvertebral 50%

Early concern: certain rat strain showed increased osteosarcoma-->has not been subsequently shown

Since gains are quickly lost, must put them on maintenance therapy (bisphosphonate) when they are taken off teriparatide

2) NEGATIVE FEEDBACK. mechanism of homeostasis, where a change in stabilization of a set point that triggers a response that counteracts the initial change.

3) Bone growth mechanism :-