Calcium homeostasis bone resorption
Osteoporosis is a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration with a subsequent increase in bone fragility and susceptibility to fracture. It affects an estimated 75 million people worldwide. In addition to the increased fracture risk, patients with osteoporosis often have severe spinal kyphosis, leading to disfiguration, respiratory and digestive complications, and pain. Osteoporosis is prevalent in the elderly and affects not only women, but men with a hip fracture prevalence of approximately one-third of that seen in women (International Osteoporosis Foundation, http://www.iofbonehealth.org/facts-and-statistics.html).
In osteoporosis, there is often an increase in bone turnover rate and an imbalance resulting from bone resorption exceeding bone formation. Therefore, the systems biology model being developed aims to characterize and subsequently predict expected rates of bone turnover due to both natural disease progression and therapeutic intervention, allowing for evaluation of affecting mechanisms. For example, this model can provide a priori insight into previously unexplored paths (or combinations of explored and unexplored paths) to identify targets suitable for therapeutic exploration. It provides a quantified magnitude of effect (e.g., % inhibition or stimulation of each pathway) needed to elicit therapeutic benefit, as well as the expected time course of on- and off-set of the effect. The model also can be explored for plausible mechanisms to explain clinical observations of therapeutic effects (e.g., possible mechanisms for the anabolic effect of intermittent PTH administration versus its catabolic effect following continuous administration, or evaluation of the time course of bone turnover marker (BTM) changes following discontinuation of therapy(ies)).
To date the model has been developed and evaluated for the following disease states and therapeutic interventions:
- Hyperparathyroidism (primary)
- Secondary hyperparathyroidism caused by progressive renal insufficiency
- Hypoparathyroidism
- Once-daily PTH therapy
- RANK-L inhibition
- Estrogen replacement therapy (initiation and withdrawal)
Presentations reviewing the model include: PAGE 2007 (poster): http://www.page-meeting.org/default.asp?abstract=1218 AAPS 2007
- poster: http://www.aapsj.org/abstracts/AM_2007/AAPS2007-003504.PDF
- Symposium presentation: Osteoporosis and Bone Disorders: A Showcase for Model-based Drug Development
- http://www.aapspharmaceutica.com/meetings/meeting.asp?id=118&size=big (no slides available)
2008 AAPS Biotech (Roundtable presentation on Disease Progression)
- The slides for 2008 AAPS Biotech meeting are now available on-line at:
- Slides from that meeting are posted at:
- http://aaps.org/meetings/meeting.asp?id=124
- http://mediaserver.aapspharmaceutica.com/nbc/NBC08/Tuesday/713/Riggs.pdf
Future development of the model will focus on:
- linkages to bone mineral density (BMD) and bone quality (site specific);
- inclusion oral vitamin D dosing;
- description of natural time-course of estrogen loss during menopause with link to longitudinal changes on bone remodeling, BMD and bone quality;
- expansion of osteoblast intracellular signaling pathways (e.g., WNT) to include sclerostin inhibition and serotonin involvement through Lrp5;
- development/ evaluation of long-term Ca malnutrition.
