Elsevier

Bone

Volume 40, Issue 6, June 2007, Pages 1447-1452
Bone

Review
Skeletal actions of intermittent parathyroid hormone: Effects on bone remodelling and structure

https://doi.org/10.1016/j.bone.2006.09.008Get rights and content

Abstract

Intermittent administration of parathyroid hormone peptides has anabolic skeletal effects and reduces fracture risk in postmenopausal women with osteoporosis but the cellular and structural mechanisms by which these effects are mediated have not been fully established. In cancellous and endocortical bone, there is evidence that both modelling and remodelling-based formation contribute to the increase in bone mass although the contribution of these at different time points in the response to PTH has not been established. Despite the large increase in spine bone mineral density, however, significant increases in iliac crest cancellous bone volume and trabecular thickness have not been consistently demonstrated, possibly reflecting site-specific differences in PTH-induced skeletal effects and/or the large sampling and measurement variance associated with assessment of iliac crest cancellous bone volume and structure. In iliac crest cortical bone, increased cortical thickness has been demonstrated, due at least in part to increased endosteal bone formation; there is also some evidence for increased formation on periosteal surfaces. At some sites an increase in cortical porosity may also occur and the overall effects on cortical bone strength, particularly at the hip, remain to be established. Studies in iliac crest bone indicate a trend towards a lower mineralisation density of bone matrix and increased heterogeneity of mineralisation, consistent with new bone formation. In addition, there is a reduction in mineral crystallinity and a shift towards more divalent collagen cross-links, indicating a change towards a younger bone profile.

The potential clinical implications of these effects on bone are currently unknown. The stimulatory effect of PTH peptides on bone formation may favour their use in low turnover bone disease and in states of advanced bone loss. Furthermore, if beneficial effects on cortical bone strength are confirmed, efficacy at non-vertebral sites might be superior to those observed with antiresorptive drugs. Better definition of the effects of intermittent PTH administration on cancellous and cortical bone remodelling and structure at different skeletal sites may inform these speculations and is an important area for future research.

Introduction

The recent development of bone forming agents has provided an exciting new option for the prevention of osteoporotic fractures. Daily administration of parathyroid hormone (PTH) peptide 1-34 [1] and PTH 1-84 peptide [2] reduces vertebral fracture risk in postmenopausal women with osteoporosis and, for the former, a reduction in non-vertebral fractures has also been demonstrated. Given the predominantly catabolic skeletal effects of continuous PTH administration, the mechanisms by which intermittent administration produce anabolic effects are of considerable interest and have implications for the development of other bone forming agents.

Section snippets

Cellular and structural basis of anabolic skeletal effect of intermittent PTH: cancellous bone

In the spine, intermittent administration of PTH induces large increases in areal bone mineral density; for example, subcutaneous administration of 20 or 40 μg daily of recombinant human PTH peptide 1-34 to postmenopausal women with osteoporosis was associated with a 10–15% increase after a median treatment period of 19 months [1]. The magnitude of these changes suggests that there is a substantial increase in bone formation but the mechanisms by which this is achieved remain incompletely

Effects of intermittent PTH on cancellous bone microarchitecture

While antiresorptive agents maintain existing architecture [18], [19], anabolic agents have the potential to reverse structural disruption. Investigation of the effects of intermittent PTH therapy provides some evidence that may indeed occur, based on measurements on connectivity and trabecular shape. Thus, connectivity density in men and women with osteoporosis treated with PTH (1-34) increased after 3 years treatment [14], and in women with osteoporosis treated for a median of 19 months [17]

Effects of intermittent PTH on cortical bone

The small or even negative changes in bone mineral density at sites containing large proportions of cortical bone contrast sharply with the large increases observed at predominantly cancellous sites such as the spine [1], [23], [24]. This initially led to concerns that increases in cancellous bone mass might occur at the expense of cortical bone [20], [25], but subsequent studies indicate that at least at some skeletal sites, beneficial changes occur in cortical bone architecture and the

Effects of intermittent parathyroid hormone on the bone matrix/mineral composite

Aspects of bone composition and structure other than bone mass and architecture that may affect bone strength include matrix mineralisation and collagen cross-linking. The degree of mineralisation and its distribution is closely related to bone turnover, with an increase in both homogeneity and degree of mineralisation in bone from individuals treated with bisphosphonates [37], [38], [39]. Using quantitative back-scattered electron imaging and small angle X-ray scattering in paired iliac crest

Potential clinical implications of mechanisms underlying anabolic skeletal effect of intermittent PTH

The marked differences in mode of action between antiresorptive drugs and intermittent PTH have potential, although as yet unproven, therapeutic implications. The ability of PTH to stimulate bone remodelling and modelling suggests that it might be the treatment of choice in low turnover disease, for example in bone disease associated with long-term glucocorticoid therapy [41] and in some forms of renal osteodystrophy [42]. Delmas et al. [43] recently reported that teriparatide-induced fracture

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