BACKGROUND-Mortality is increased after a hip fracture, and strategies that improve outcomes are needed.

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Parathyroid hormone-related protein (PTHrP) was discovered as a result of a search for the circulating factor secreted by cancers which causes the common paraneoplastic syndrome humoral hypercalcemia of malignancy. Since the identification of the peptide in 1982 and the cloning of the cDNA in 1987, it has become clear that PTHrP is a prohormone that is posttranslationally cleaved by prohormone convertases to yield a complex family of peptides, each of which is believed to have its own receptor. It is also clear that the PTHrP gene is expressed not only in cancers but also in the vast majority of normal tissues during adult and/or fetal life. In contrast to the situation in humoral hypercalcemia of malignancy in which PTHrP plays the role of a classical "endocrine" hormone, under normal circumstances PTHrP plays predominantly paracrine and/or autocrine roles. These apparent physiological functions are also complex and appear to include 1) regulation of smooth muscle (vascular, intestinal, uterine, bladder) tone, 2) regulation of transepithelial (renal, placental, oviduct, mammary gland) calcium transport, and 3) regulation of tissue and organ development, differentiation, and proliferation. In this review, the discovery of PTHrP, the structure of its gene and its cDNAs, and the posttranslational processing of the initial translation products are briefly reviewed. Attention is then focused on a detailed organ system-oriented review of the normal physiological functions of PTHrP.

We used data from the Fracture Intervention Trial to assess the relationship change in bone turnover after 1 year of alendronate or placebo treatment and subsequent hip, non-spine, and spine fracture risk among 6186 postmenopausal women. In the alendronate group (n ‫؍‬ 3105), greater reductions in one or more biochemical marker were associated with a lower risk of fracture.Introduction: There are few data on the relationship between short-term change in biochemical markers of bone turnover and non-spine fracture risk among bisphosphonate-treated women, and the clinical use of such measurements is unknown. Materials and Methods:We measured biochemical markers of bone turnover (bone-specific alkaline phosphatase [bone ALP], intact N-terminal propeptide of type I collagen, and C-terminal crosslinked telopeptide of type 1 collagen) and BMD of the spine and hip at baseline and after 1 year of alendronate or placebo. During a mean follow-up of 3.6 years, 72 hip, 786 non-spine, and 336 vertebral fractures were documented. Results and Conclusions: Each 1 SD reduction in 1-year change in bone ALP was associated with fewer spine (odds ratio ϭ 0.74; CI: 0.63, 0.87), non-spine (relative hazard [RH] ϭ 0.89; CI: 0.78, 1.00; p Ͻ 0.050), and hip fractures (RH ϭ 0.61; CI: 0.46, 0.78). Alendronate-treated women with at least a 30% reduction in bone ALP had a lower risk of non-spine (RH ϭ 0.72; CI: 0.55, 0.92) and hip fractures (RH ϭ 0.26; CI: 0.08, 0.83) relative to those with reductions Ͻ30%. We conclude that greater reductions in bone turnover with alendronate therapy are associated with fewer hip, non-spine, and vertebral fractures, and the effect is at least as strong as that observed with 1-year change in BMD.

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