1x1 YI. IVI. YI. AI< S A (io ii significant cvcnt took place for the S clinical management of osteoporo successful surgical fixation was first described for the management of hip fracture.'" A slightly earlier event was the publication of the first experimental study to show that injections of Col-lip's parathyroid hormone extract (PTE) could increase bone density in the young rat.'2) The first development quickly revolutionized the surgical management of hip fracture whereas the second has so far only revolutionized, for some of us, our expectations of what might be achieved for patients with spinal osteoporosis. How can the pace of medical as distinct from surgical development have been so slow? The problems encountered were both conceptual and practical. PTE, now known to have contained only a small proportion of PTH, found its first clinical use in the treatment of hypoparathyroidism, but it was quickly displaced by vitamin 11 and AT10 (dihydrotachysterol) because it required in, jections-which were sometimes accompanied by; I local reaction-because its effect wore off, and because of its expense.'.''At the conceptual level, investigators following up the results of Bauer, Aub, and Ahright'" were intrigued by the sequential development of osteitis fibrosa and" Morble Bone Disease,"'"') which was not recognized in clinical hyperparathyroidism" until some 40 years later, and then only as a rarity.'".') Burrows, following a scholarly and detailed investigation at Yale,'4'concluded in 1938 that the then competing theories of the Albright school (that PTH had its main action on phosphate transport by the renal tubular cell) and other theories that emphasized a direct bony action of PTH on osteoclasts'x~"''or through increased acid production''I'were incapable of explaining the experimental results. He postulated that the anabolic actions of PTH were the result of the actions of a second biochemical messenger and concluded that it would be necessary to obtain pure PTH to discover whether this second messenger was an antibody-like substance directed at impurities in PTE, or part of some other intrinsic biological mechanism that for unknown reasons did not routinely find expression in clinical hyperparathyroidism.

Over 30 years elapsed before it became possible to use near-pure PTH and its synthetic fragments (eg hPTH 1-34) experimentally, following the development of improved extraction procedures for bovine PTH 1-84 and the sequencing and synthesis of the 1-34 amino terminal end of the molecule by Potts and his collaborators."" By then calcitonin had been discovered, but the experiments of Kalu et al. showed that it was not contamination of PTE by calcitonin but PTH itself that was responsible for the ana-bolic actions seen previously with daily PTE injcctions in young rats,'"'a result quickly confirmed by Walker."" At about the same time, Parsons and Reit''') demonstrated calcium retention with low dose infusions of purified PTH to dogs and, following the earlier extensive use of PTE in man and the concurrent absence of an adequate animal model of osteoporosis, the stage was set for the first clinical experiments with hPTH 1-34 in patients.("'."'This issue of the Journal contains reports of two studies in which human parathyroid hormone hPTH 1-X4'1x'or rat rPTH 1-34"") was administered long-term to ovariectomized rats as a daily or 6 days-a-week injection. The objective of Mitlak's study'") was to explore the dose-and time-dependency of the response of femur endosteal bone (assessed by peripheral quantitative tomography, pQCT) as well as spinc and whole body cortical plus cancellous bone (assessed by dual X-ray absorptiometry, DXA), in relation to estimates of …