Sunday, December 9, 2012

Teriparatide (Forteo®) Safety: What are the Risks for Osteosarcoma??

Teriparatide, the bone-building medication produced by Eli Lilli (Forteo®) and approved by the FDA in 2002, is now in its tenth year of use for the treatment of osteoporosis. Teriparatide has been shown in numerous studies to provide great benefit to patients with severe bone loss and high risk for fracture. It not only increases bone mineral density by increasing bone mass (not just density) but it also substantially reduces fracture risk. Common side effects of teriparatide are headaches, nausea and vomiting but the real concern has been that of bone cancer. During safety studies, rats given teriparatide for 2 years (which is most of their lifetime) at dosages 3 to 58-fold that of human doses, frequently developed oseteosarcomas, the most common primary malignant bone tumor seen in humans. Because of this, teriparatide carries a "black box warning" and is limited to 2 years of use.

When teriparatide was approved by the FDA, one of the stipulations was that there be a postmarketing evaluation of the potential association between teriparatide and osteosarcoma. Thus, the establishment of the Osteosarcoma Surveillance Study, an ongoing 15-year surveillance study. In this months issue of the Journal of Bone and Mineral Research, Andrews et al. (2012) report on the findings half-way through this study. "After 7 years of the study, there were no osteosarcoma patients who had a prior history of teriparatide treatment. Thus, approximately halfway through this 15-year study, the study has not detected a pattern indicative of a causal association between teriparatide treatment and osteosarcoma in humans."

In another article, Capriani, et al. (2012) tell us that there are differences in rat versus human bone metabolism that are important for understanding why teriparatide does not pose a substantial risk for osteosarcoma to humans. In their perspective article in the Journal of Bone and Mineral Research, they explain: "The rat is a species that models [* see below] its skeleton for virtually its entire life [about 2 to 3 years]. The modeling is associated with lifetime skeletal growth. When exposed to an osteoanabolic [bone building] agent like PTH [teriparatide], the rat responds exuberantly with a profound increase in endocortical and trabecular bone mass and a significant reduction in marrow space. Older studies from the 1930s showed that the entire marrow space can be obliterated by chronic exposure of rats to PTH [parathyroid hormone]. The ever-growing rat skeleton, therefore, is a developing organ harboring immature and potentially tumorigenic [cancerous] cells that might respond to PTH [teriparatide] with uncontrolled behavior, losing its capacity for ordered modeling or growth. In contrast to rat skeletal physiology, the mature adult human skeleton remodels itself on a continual basis. Modeling essentially ceases as a normal occurrence after skeletal maturity has been reached."

In other words, after humans reach the age of 21 or so, modeling of bone ceases and remodeling becomes the predominant form of bone activity. It is because of this important difference between rat and human bone physiology that teriparatide presents less risk of cancer to humans. In addition, studies with macaque monkeys exposed to dosages of up to 40 times that of the human dose did not show evidence of osteosarcoma formation.

* Bone modeling and remodeling are different. In bone modeling, which occurs predominantly when a child is growing, bone resorption and formation are not coupled in their actions and bone is undergoing a change in size and shape (i.e. children are growing). Bone remodeling is quite different and is a process where the old, worn-out bone seen in adults is replaced with new bone (i.e. adults are not growing but their bones are simply in need of constant repair). In remodeling, the resorption and formation phases are coupled and are taking place in the same bone surface area.

Andrews EB, et al., 2012. The US Postmarketing Surveillance Study of adult osteosarcoma and teriparatide: Study design and findings from the first 7 years, Journal of Bone and Mineral Research 27(12):2429-2437.

Capriani C, et al., 2012. Safety of osteoanabolic therapy: A decade of experience. Journal of Bone and Mineral Research 27(12):2419-2428.
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