Modeling of bone formation and resorption mediated by parathyroid hormone: response to estrogen/PTH therapy

Model Structure

Bone is a highly organised tissue which provides support and protection. In order to maintain its structural integrity, many new cells must be continually produced and, as such, bone provides an environment for hemopoiesis. Osteoblasts are responsible for the bone formation while osteoclasts are responsible for bone resorption. Knowledge of how the proliferation and differentiation of these two cell types are controlled is important for our understanding of the processes involved in the the growth and degeneration of the human skeleton. Throughout life the skeleton is being remodelled. After maximal skeletal mass has been reached the final adult phase begins, characterised by a continuous loss of boss mass, with the rate of loss increasing with age. Severe bone loss, together with the spontaneous fracturing of the remaining bone, characterised the condition known as osteoporosis.

The prevention and reversal of bone loss requires an in depth understanding of the remodelling process in bone, including the mechanisms underlying bone formation and resorption, and the effects of hormones such as estrogen and parathyroid hormone (PTH). Estrogen deficiency catalyses the pathogenesis of osteoporosis, and it is well established that estrogen administration can prevent post-menopausal bone loss. However, the mechanisms by which estrogen exerts these effects are not fully understood, and estrogen therapy is associated with certain risks and side effects.

To avoid the undesirable risks and side effects associated with estrogen therapy, PTH has been proposed as an alternative therapeutic agent that can replace lost bone and restore bone strength. However, while pulsatile PTH exposure results in bone formation, paradoxically, continuous PTH administration causes net bone loss. To date, the mechanisms underlying these two phenomena remain poorly understood. To address this issue Rattanakul et al. have developed a mathematical model which describes the differentiation of osteoblastic and osteoclastic populations in the bone, based on the differential effects of PTH. They also consider the effects of different estrogen treatment patterns.

Schematic diagram depicting the Rattanakul et al 2003 model - effects of PTH on osteoclast differentiation by osteoblasts. Exogenous application of PTH, and the effects of oestrogen, are also depicted.

The complete original paper reference is cited below:

Modeling of bone formation and resorption mediated by parathyroid hormone: response to estrogen/PTH therapy, Chontita Rattanakul, Yongwimon Lenbury, Nateetip Krishnamara, and David J. Wollkind, 2003, BioSystems , 70, 55-72. (Full text and PDF versions of the article are available to journal subscribers on the BioSystems website.) PubMed ID: 12753937

This model has been translated into three variant CellML models; the first represents the core model and describes changes in the concentration of PTH, the number of osteoclasts and the number of osteoblasts. The second model builds on this foundation to consider the effects of exogenous PTH administration - both continuous and pulsatile. Finally the third model considers the effects of estrogen administration.