Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1–84☆
Introduction
The anabolic action of intermittent injections of full-length parathyroid hormone (PTH) 1–84 in skeletal tissues has been recognized for many decades, but an increase in bone mass was first demonstrated in osteoporotic humans in 1980 using the human PTH(1–34) peptide [1]. The ability of PTH(1–84), PTH(1–34), and other amino-terminal fragments and analogs of PTH(1–84) and PTH-related protein to increase bone mineral density (BMD) in humans is now well accepted, particularly at skeletal sites such as the spine that contain substantial amounts of cancellous bone [2], [3]. Large, randomized, placebo-controlled trials of PTH(1–34) and PTH(1–84) have not only demonstrated a large increase in lumbar spine BMD, but also a significant reduction in the incidence vertebral fractures [4], [5].
Iliac crest bone biopsies from the small early studies of PTH(1–34) by Reeve et al. [1] and Bradbeer et al. [6] showed substantial 53–70% increases in cancellous bone volume (BV/TV) after 6 to 24 months of treatment, with indications of accelerated bone formation. However, more recent larger studies with PTH(1–34) of 1 to 3 year duration have seldom confirmed these earlier findings [7], [8], [9]. In contrast, a significant increase in cortical thickness has been described in all studies of PTH(1–34) in which this was quantified [7], [8], [9].
PTH(1–84) treatment of ovariectomized (OVX) rhesus monkeys for 16 months increased cancellous BFR, BV/TV, and bone strength at lumbar vertebrae and at the proximal femur [10], [11]. The effects of PTH(1–84) treatment on bone at the iliac crest of humans have not been investigated. In this study we performed histomorphometric and microcomputed tomography (μCT) measurements of cancellous and cortical bone from iliac crest biopsies from postmenopausal osteoporotic women who were treated with placebo or PTH(1–84) for up to 24 months.
Section snippets
Patient selection and PTH(1–84) treatment protocol
Subjects participating in this bone biopsy study were recruited from the TOP study, a large multicenter, double-blind, randomized, placebo-controlled study that evaluated the fracture prevention efficacy of treatment with PTH(1–84) for 18 months in osteoporotic women who were at least one year postmenopausal prior to entry into the study [5]. Those 45–54 years of age had to have a BMD T-score at lumbar spine, total hip, or femoral neck of ≤ − 3.0 (or ≤ − 2.5 with a prevalent vertebral fracture)
Demographics
At baseline there were no statistically significant differences between the 3 groups in age, years postmenopausal, and height, or in spine, total hip or femoral neck BMD. However, subjects who were treated with PTH(1–84) for 24 months were significantly heavier than those who received placebo. In general, the women who provided a biopsy were comparable to the entire TOP study population (Table 1). In subjects from whom biopsies were obtained, there were nonsignificant trends towards increased
Discussion
The ability of PTH(1–84) and PTH(1–34) treatment to increase lumbar spine BMD and to reduce the incidence of vertebral fractures in postmenopausal osteoporotic women has been reported previously [2], [3], [4], [5], [15]. However, there have been few clinical biopsy studies that have explored the mechanisms responsible for the increases in BMD with PTH(1–34) and the safety of such treatment in bone and, prior to this report, none with PTH(1–84).
The number of evaluable iliac crest biopsies
References (29)
Developments in parathyroid hormone and related peptides as bone-formation agents
Curr. Opin. Pharmacol.
(2002)- et al.
Histomorphometric evidence for increased bone turnover without change in cortical thickness or porosity after 2 years of cyclical hPTH(1–34) therapy in women with severe osteoporosis
Bone
(2000) - et al.
Trabecular architecture in iliac crest bone biopsies: intra-individual variability in structural parameters and changes with age
Bone
(1988) - et al.
Intratrabecular tunneling increases trabecular number throughout the skeleton of ovariectomized rhesus monkeys treated with parathyroid hormone 1–84
Bone
(2008) - et al.
Effects of daily treatment with parathyroid hormone 1–84 on density, architecture and biomechanical properties of cortical bone in adult ovariectomized rhesus monkeys
Bone
(2007) - et al.
Treatment with human parathyroid hormone (1–34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys (Macaca fasicularis)
Bone
(2001) - et al.
Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial
Br. Med. J.
(1980) - et al.
Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use
Endocr. Rev.
(2005) - et al.
Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis
N. Engl. J. Med.
(2001) - et al.
Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial
Ann. Intern. Med.
(2007)
Treatment of osteoporosis with parathyroid peptide (hPTH 1–34) and oestrogen: increase in volumetric density of iliac cancellous bone may depend on reduced trabecular spacing as well as increased thickness of packets of newly formed bone
Clin. Endocrinol. (Oxf)
Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study
J. Bone Miner. Res.
Recombinant human parathyroid hormone (1–34) [teriparatide] improves both cortical and cancellous bone structure
J. Bone Miner. Res.
Treatment of skeletally-mature ovariectomized rhesus monkeys with parathyroid hormone 1–84 for 16 months increases bone formation and density and improves trabecular architecture and biomechanical properties at the lumbar spine
J. Bone Miner. Res.
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Preliminary data was presented at the Sun Valley Hard Tissue Workshop in August 2005 and an extended abstract was published in the Journal of Musculoskeletal and Neuronal Interactions 2005;5:356–7.