Bone fracture is extremely common and can result in significant pain, deterioration of quality of life and even increased mortality. Hip fracture is particularly serious. The lifetime risk for a hip fracture has been estimated to amount to 17.5% for white women, and 6% for white men in the USA. During recent years the incidence of hip fractures has increased in the USA and almost all European and Asian countries. In part this trend may be explained by the longer life expectancy of the population. However, the age-adjusted incidence has also increased, suggesting that bone quality is decreasing. The increasing life expectancy and the increasing age-adjusted fracture incidence may result in a worldwide increase of hip fractures from an estimated 1.7 million cases in 1990 to between 8.2 million and 21 million cases in 2050. Following hip fracture, there is a 10-20% excess mortality during the first six months, whereas 50% of those who survive will be unable to walk unaided during the rest of their lives, and 25% will require long-term domesticiliary care. Hence there is a considerable need for improved treatments of fracture. Common causes of fracture are osteoporosis (see our recent analysis of this area), aging and bony metastases. The latter two conditions are associated with local hypoxia.

Bone remodeling occurs throughout life and involves the resorption of old bone by osteoclasts and the formation of new bone by osteoblasts. This process is important to prevent micro damage that results from skeletal stress during the rigors of daily life. Any substantial decrease in the rate of remodeling may increase the risk of spontaneous fractures because the skeleton's ability to repair itself is decreased. Both an increase in osteoclast and/or a decrease in osteoblast activity can detrimentally affect remodeling.

Hypoxia has been shown to increase osteoblast proliferation and to enhance production of angiogenic VEGF by these cells. Researchers at UCL in the United Kingdom have now published data describing the effect of hypoxia on osteoclast function. In their recent Journal of Cellular Physiology paper, this group reports the dramatic effect of hypoxia on osteoclast resorption; when cultured over 7-13 days in 2% oxygen the resorptive activity of murine osteoclasts increased by 21- and 9.5-fold respectively compared to cells cultured under normal oxygen levels. Likewise osteoclast formation was also increased. This effect was mirrored by a dramatic increase in Ca2+ release from murine clavarial bones maintained under 2% oxygen over a 3 day culture period, a process related to acidification and also the formation of arachidonic acid metabolites.

Bone hypoxia can occur under a number of conditions including: (1) fractures, which entail local disruption of blood supply; (2) inflammation, including arthritis; (3) infection; (4) tumors; (5) diabetic ischemia; (6) microvascular damage due to long-term smoking; (7) aging, where there is a progressive shift from endosteal to periosteal blood supply; (8) chronic respiratory failure or breathing air with a depleted oxygen content; (9) excessive exercise. The present study is important in that it indicates that hypoxia could directly stimulate bone resorption and an increased risk of fracture in a wide variety of different clinical conditions and targeting molecular aspects of the hypoxia-related osteoclast homeostasis could be of immense therapeutic benefit. The UCL group identifies cyclooxygenase as one such target since hypoxia-induced decalcification was inhibited by indomethacin. Cyclooxygenase inhibitors are frequently used for the treatment of many of the above mentioned diseases and therefore the effect of these inhibitors on osteoclast function may represent an important but as of yet under-estimated aspect of their overall therapeutic value.
Entry date Monday, June 30, 2003

Adapted from Arnett et al, J Cell Physiol. 2003 Jul;196(1):2-8.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk