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Review
. 2017 May 18;8(43):75646-75663.
doi: 10.18632/oncotarget.17980. eCollection 2017 Sep 26.

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation

Luisella Cianferotti  1 , Francesco Bertoldo  2 , Marco Carini  3 , John A Kanis  4 , Alberto Lapini  3 , Nicola Longo  5 , Giuseppe Martorana  6 , Vincenzo Mirone  5 , Jean-Yves Reginster  7 , Rene Rizzoli  8 , Maria Luisa Brandi  1
Affiliations
Review

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation

Luisella Cianferotti et al. Oncotarget. .

Abstract

Androgen deprivation therapy is commonly employed for the treatment of non-metastatic prostate cancer as primary or adjuvant treatment. The skeleton is greatly compromised in men with prostate cancer during androgen deprivation therapy because of the lack of androgens and estrogens, which are trophic factors for bone. Men receiving androgen deprivation therapy sustain variable degrees of bone loss with an increased risk of fragility fractures. Several bone antiresorptive agents have been tested in randomized controlled trials in these patients. Oral bisphosphonates, such as alendronate and risedronate, and intravenous bisphosphonates, such as pamidronate and zoledronic acid, have been shown to increase bone density and decrease the risk of fractures in men receiving androgen deprivation therapy. Denosumab, a fully monoclonal antibody that inhibits osteoclastic-mediated bone resorption, is also effective in increasing bone mineral density and reducing fracture rates in these patients. The assessment of fracture risk, T-score and/or the evaluation of prevalent fragility fractures are mandatory for the selection of patients who will benefit from antiresorptive therapy. In the future, new agents modulating bone turnover and skeletal muscle metabolism will be available for testing in these subjects.

Keywords: ADT; FRAX; androgen deprivation therapy; osteoporosis; zoledronic acid.

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Conflict of interest statement

CONFLICTS OF INTEREST All authors declare no conflict of interest related to the subject of this paper. More general disclosures: L.C. lecture fees: Abiogen Pharma. B.F. advisory board, consulting fees: Abiogen, Amgen, Bayer, Italfarmaco; lecture fees: Abiogen Pharma, Amgen, Lilly. K.J.A. reports grants from Amgen, grants from Lilly, non-financial support from Medimaps, grants from Unigene, non-financial support from Asahi, grants from Radius Health. Outside the submitted work, he is the architect of FRAX but has no financial interest. R.J.Y.: consulting fees or paid advisory boards: Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merck, Nycomed, NPS, Theramex, UCB; lecture fees when speaking at the invitation of a commercial sponsor: Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed, Novo-Nordisk, Nolver; grant Support from Industry: Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva, Lilly, Novartis, Roche, GlaxoSmithKline, Amgen, Servier. B.M.L. consulting fees and grants from Alexion, Abiogen, Amgen, Bruno Farmaceutici, Eli Lilly, MSD, NPS, Shire, SPA and Servier.

Figures

Figure 1
Figure 1. Effects of sex steroids on bone
Androgens like T can be converted via aromatization to estrogens and can thus activate both AR and ERα. In males, both AR and ERα maintain cortical and trabecular bone in adult male. Estrogens increases osteoblast number and activity, inhibit osteocyte apoptosis, reduces the number and activity of osteoclasts. Androgen directly increase number and function of osteoblasts and inhibit apoptosis of osteocytes. Osteoclasts apparently do not express AR. Trabecular bone formation is increased by ERα in males, whereas both ERα and AR can inhibit trabecular bone resorption. ERα inhibits endosteal bone resorption and with GH/IGF-1 (probably via central aromatization of androgens) stimulates periosteal bone formation). The action of GH/IGF-1 axis in particularly evident during puberty. E2 : estradiol; T: testosterone; DHT dihydrotestosterone; Era: estrogen a-receptor; AR: androgen receptor; OB: osteoblast; OC osteocyte; OCL :osteoclast; GH: growth hormone; IGF-1: insulin growth-factor;.
Figure 2
Figure 2. Mechanisms of bone loss in men with prostate cancer receiving androgen deprivation therapy
Androgen deprivation therapy reduces testosterone levels and indirectly the estrogen levels in man. The low serum and tissue levels of estrogen increase bone turnover increasing the number of BMU and increasing the number of osteoclasts. The low levels of estrogen increase endosteal reabsorption and cortical porosity. Androgen and estrogen deficiency reduces the thickness and the number of trabeculae and high bone turnover reduce trabecular connectivity, predisposing to bone fragility. Sarcopenia increases risk of falls and indirectly impairs bone metabolism. E2 : estradiol; T: testosterone; DHT dihydrotestosterone; Era: estrogen a-receptor; AR: androgen receptor; OB: osteoblast; OC osteocyte; OCL :osteoclast; GH: growth hormone; IGF-1: insulin growth-factor; ADT: Androgen deprivation therapy; Dotted-line: lack of action
Figure 3
Figure 3. IOF’s algorithm for the management of non-metastatic bone disease in prostate cancer patients receiving ADT (modified from ref. 16)
Figure 4
Figure 4. Assessment of fracture risk in countries with high access to DXA: FRAX-based assessment threshold (solid line) and FRAX-based intervention thresholds (dotted line) (reproduced from ref. 100)
See this image and copyright information in PMC

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