Elsevier

Bone

Volume 44, Issue 1, January 2009, Pages 113-119
Bone

Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1–84

https://doi.org/10.1016/j.bone.2008.09.019Get rights and content

Abstract

Treatment with parathyroid hormone [PTH(1–84)] increases lumbar spine bone mineral density and decreases vertebral fractures, but its effects on bone microarchitecture are unknown. We obtained iliac crest biopsies from postmenopausal osteoporotic women given placebo (n = 8) or 100 μg PTH(1–84) for 18 (n = 8) or 24 (n = 7) months to assess cancellous and cortical bone formation and structure. At 18 months, cancellous bone volume (BV/TV) measured by microcomputed tomography and histomorphometry was 45–48% higher in subjects treated with PTH(1–84) versus placebo, a result of higher trabecular number (Tb.N) and thickness. The higher Tb.N appeared to result from intratrabecular tunneling. Connectivity density was higher and structure model index was lower, indicating a better connected and more plate-like trabecular architecture. Cancellous bone formation rate (BFR) was 2-fold higher in PTH(1–84)-treated subjects, primarily because of greater mineralizing surface. Osteoblast and osteoid surfaces were a nonsignificant 58% and 35%, respectively, higher with PTH(1–84) treatment. Osteoclast and eroded surface were unaffected by PTH(1–84). There were no effects of PTH(1–84) treatment on cortical thickness, or endocortical or periosteal BFR, but cortical porosity tended to be higher. Although cancellous BFR was lower at 24 than at 18 months, measures of cancellous and cortical bone structure were similar at both timepoints. The bone produced by PTH(1–84) had normal lamellar structure and mineralization with no abnormal histology. In conclusion, when compared with placebo, treatment of osteoporotic women with PTH(1–84) was associated with higher BV/TV and trabecular connectivity, with a more plate-like architecture, all consistent with the lower vertebral fracture incidence.

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

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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.

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