Bone Strength and Surrogate Markers: The First, Second, and Third Fiddle

Ever since the publication of the United States fluoride clinical trial data showing that the studied dose of fluoride therapy in postmenopausal osteoporosis (PMO) induced a linear increase in spinal bone mineral density (BMD) but without a reduction in fracture risk,(1) registration for all subsequent therapies for the treatment of PMO required evidence for fracture risk reduction as the primary endpoint—the first fiddle.(2) The previous preemptive role that this surrogate marker (pharmacologically-induced increase in BMD) had held as the indicator for improvement in bone strength now became the second fiddle. In a symphony orchestra the second fiddle plays a less robust role to the first fiddle — changes in BMD became the less robust endpoint for risk reduction and it now became the second fiddle for registration of therapies for the treatment of PMO….