What we don't know about osteoporosis.

Bone remodeling Our current understanding is that postmenopausal osteoporosis results from a bone remodeling imbalance with bone resorption exceeding bone formation and that the medications approved for osteoporosis treatment all work by modulating bone remodeling in a favorable way. This is almost certainly correct, yet there is much more to be learned about bone remodeling that might enhance our understanding of the drugs we now use, improve their safety, and assist in developing new ones. A vast gap remains in our understanding of bone remodeling at the cellular level. There is much to learn about the molecular regulators that determine differentiation, activity, and survival of osteoclasts, osteoblasts, and osteocytes. As knowledge of cellular and molecular mediators of “crosstalk” between bone and muscle advances, new approaches to reducing fracture risk may emerge. In addition to enhanced understanding on the cellular level, we must learn how to best modulate remodeling and for how long to continue an intervention. Bisphosphonates are unique among osteoporosis medications in having a long skeletal retention time with persistence of antiresorptive effect (for an uncertain, and almost certainly variable, duration of time) after discontinuation. This has resulted in the concept of bisphosphonate “holidays” where patients discontinue treatment, hopefully continuing to benefit from anti-fracture efficacy for an undefined length of time while having an improved safety profile. Given the paucity of data supporting bisphosphonate holidays, uncertainty remains on when, if ever, and for whom, to start a holiday, when to end it, and how to monitor patients during a holiday. It is not clear how best to treat a patient who has been on longterm bisphosphonate therapy (e.g., 10 years or more) and remains at high risk for fracture, particularly if a full course of treatment with teriparatide has previously been administered. Finally, enhanced understanding of bone remodeling It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so. Mark Twain, American humorist, 1835–1910.