ReviewSkeletal actions of intermittent parathyroid hormone: Effects on bone remodelling and structure
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.
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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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