PTH: A future role in the management of osteoporosis?

Abstract

1x1 Y-I.IVI. YI.AI<S A ( i o 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 t o show that injections of Collip'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 o f 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 t o have contained only a small proportion o f 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 o n 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 (e.g. 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 anabolic 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 concu...

Pulsatile release of parathyroid hormone from an implantable delivery system

“…Interestingly, PTH also stimulates bone formation with a net anabolic effect under certain conditions, which makes PTH a desirable therapeutic agent for the treatment of osteoporosis [1,6,8,9]. The catabolic or anabolic action of PTH depends on the pattern of delivery: continuous exposure to PTH results in bone resorption, whereas intermittent administration (pulsatile release) of PTH increases bone formation.…”

“…Whereas continuous exposure to PTH results in bone resorption, intermittent administration (pulsatile delivery) of PTH improves bone micro-architecture, mineral density and strength [1,2,6]. The anabolic action makes PTH a particularly appealing agent to treat patients with osteoporosis [7][8][9][10][11]. In fact, the anabolic application of PTH is FDA-approved for stimulating bone formation, and it has been shown to reduce the risks of vertebral and non-vertebral fractures in postmenopausal women in clinical trials [3,7,12].…”

Inhibin and the regulation of bone mass

“…Indeed, the distinct InhA-suppressive actions observed after short-term in vivo or in vitro exposure versus InhA anabolic effects after long-term in vivo exposure are reminiscent of the welldocumented paradigm of continuous versus intermittent parathyroid hormone that has driven mechanistic studies by numerous investigators for decades [41][42][43][44][45]. Thus, the data clearly place inhibins in context with other endocrine biphasic regulators of bone metabolism, and have led to the hypothesis that the in vivo effects of InhA, like a host of other endocrine hormones, are pleiotropic, and that inhibins exert a bimodal effect on the skeleton ( Fig.…”

Parathyroid Hormone-Related Protein, Human Adipose-Derived Stem Cells Adipogenic Capacity and Healthy Obesity

“…PTHrP has been shown to induce bone formation (7). It interacts at G protein-coupled receptors, which are linked to the adenylyl cyclase/protein kinase A (PKA)-signaling system and the phospholipase C/protein kinase C (PKC) systems (8).…”