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Weekly clodronate treatment prevents bone loss and vertebral fractures in women with subclinical Cushing’s syndrome

Journal of Endocrinological Investigation volume 32, pages 390–394 (2009)Cite this article

Abstract

Introduction: Chronic mild endogenous glucocorticoid excess has been shown to cause bone loss and to increase fracture risk in both post-menopausal and premenopausal women. Currently, it is unclear if patients with subclinical Cushing’s syndrome (SCS) with osteoporosis or osteopenia may benefit from antiresorptive treatment and the type of therapy to be given. Objective: This pilot randomized study was aimed at evaluating the effects of 12-month im administration of clodronate (100 mg every week) on vertebral and femoral bone mineral density (BMD), bone turnover markers and on subjective pain in premenopausal women with SCS due to adrenal incidentalomas. Methods: Forty-six women (age, 43.1 ±7.7 yr) with SCS due to adrenal incidentaloma and osteoporosis/osteopenia were randomized to receive clodronate plus supplement of Calcium (500 mg daily) and Vitamin D3 (800 mg daily) (group 1, no.=23) or supplements only (group 2, no.=23). Both groups were similar in terms of age, body mass index, cortisol levels, BMD values, and bone turnover markers. All of the women were re-evaluated after 12 months. Results: After 12 months of treatment, in group 1, a significant increase in lumbar BMD occurred (p=0.04), while bone turnover markers decreased by about one third (p<0.05). In group 2, bone turnover markers did not change and BMD values slightly decreased (p=ns). The differences in bone turnover markers and in lumbar BMD between the two groups were significant (p<0.05, all). No new vertebral fracture occurred in group 1, while in group 2 the spine radiographies revealed 2 new fractures and a worsening of two pre-existent fractures. An improvement in subjective back pain, assessed by visual analogue scale pain score was observed in group 1 (from 4.3±2.7 to 2.9±2.0; p<0.05) but not in group 2 (from 4.4±3.1 to 4.2±3.4; p=ns). No significant changes occurred in cortisol secretion or clinical picture of the SCS during the study. Conclusions: Intramuscular administration of clodronate effectively increased lumbar BMD values, preserved bone mass at the femoral neck, stabilized vertebral fracture index, and decreased subjective back pain in pre-menopausal women with SCS. Since the untreated group continued to lose bone, antiresorptive treatment should be considered in patients with SCS, according to the prevision of surgical treatment, prevalent fractures, BMD values, age, concomitant morbidities, and desire for pregnancy.

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References

  1. Terzolo M, Osella G, Ali A, et al. Subclinical Cushing’s syndrome in adrenal incidentaloma. Clin Endocrinol (Oxf) 1998, 48: 89–97.

    Article  CAS  Google Scholar 

  2. Rossi R, Tauchmanovà L, Luciano A, et al. Subclinical Cushing’s syndrome in patients with adrenal incidentaloma. Clinical and biochemical features. J Clin Endocrinol Metab 2000, 85: 1440–8.

    PubMed  CAS  Google Scholar 

  3. Tsagarakis S, Vassiliadi D, Thalassinos N. Endogenous subclinical hypercortisolism: Diagnostic uncertainties and clinical implications. J Endocrinol Invest 2006, 29: 471–82.

    PubMed  Article  CAS  Google Scholar 

  4. Catargi B, Rigalleau V, Poussin A, et al. Occult Cushing’s syndrome in type-2 diabetes. J Clin Endocrinol Metab 2003, 88: 5808–13.

    PubMed  Article  CAS  Google Scholar 

  5. Hermus AR, Smals A, Swinkels LM, et al. Bone mineral density and bone turnover before and after cure of Cushing’s syndrome. J Clin Endocrinol Metab 1995, 80: 2859–65.

    PubMed  CAS  Google Scholar 

  6. Khanine V, Fournier JJ, Requeda E, Luton JP, Simon F, Crouzet J. Osteoporotic fractures at presentation of Cushing’s disease: two case reports and literature review. Joint Bone Spine 2000, 67: 341–5.

    PubMed  CAS  Google Scholar 

  7. Freehill AK, Lenke LG. Severe kyphosis secondary to glucocorticoid-induced osteoporosis in a young adult with Cushing’s disease. A case report and literature review. Spine 1999, 24: 189–93.

    PubMed  Article  CAS  Google Scholar 

  8. Vestergaard P, Lindholm J, Jèrgensen JO, et al. Increased risk of osteoporotic fractures in patients with Cushing’s syndrome. Eur J Endocrinol 2002, 146: 51–6.

    PubMed  Article  CAS  Google Scholar 

  9. Tauchmanovà L, Pivonello R, Di Somma C, et al. Bone demineralization and vertebral fractures in patients with endogenous cortisol excess: role of disease etiology and gonadal status. J Clin Endocrinol Metab 2006, 91: 1779–84.

    PubMed  Article  CAS  Google Scholar 

  10. Chiodini I, Guglielmi G, Battista C, et al. Spinal volumetric bone mineral density and vertebral fractures in female patients with adrenal incidentalomas: the effects of subclinical hypercortisolism and gonadal status. J Clin Endocrinol Metab 2004, 89: 2237–41.

    PubMed  Article  CAS  Google Scholar 

  11. Tauchmanovà L, Pivonello R, De Martino MC, et al. Effects of sex steroids on bone in women with subclinical or overt endogenous hypercortisolism. Eur J Endocrinol 2007, 157: 359–66.

    PubMed  Article  CAS  Google Scholar 

  12. Mazziotti G, Angeli A, Bilezikian JP, Canalis E, Giustina A. Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol Metab 2006, 17: 144–9.

    PubMed  Article  CAS  Google Scholar 

  13. Compston JE. Emerging consensus on prevention and treatment of glucocorticoid-induced osteoporosis. Curr Rheumatol Rep 2007, 9: 78–84.

    PubMed  Article  CAS  Google Scholar 

  14. McCloskey E, Selby P, Davies M, et al. Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res 2004, 19: 728–36.

    PubMed  Article  CAS  Google Scholar 

  15. McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 2007, 22: 135–41.

    PubMed  Article  CAS  Google Scholar 

  16. Russell RG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone 1999, 25: 97–106.

    PubMed  Article  CAS  Google Scholar 

  17. Frediani B, Falsetti F, Baldi F, Acciai C, Filippou G, Marcolongo R. Effects of 4-year treatment with once-weekly clodronate on prevention of corticosteroid-induced bone loss and fractures in patients with arthritis: evaluation with dual-energy X-ray absorptiometry and quantitative ultrasound. Bone 2003, 33: 575–81.

    PubMed  Article  CAS  Google Scholar 

  18. Muratore M, Santacesaria G, Quarta E, Calcagnile F, Cosentino L, Muratore L. Prevention with clodronate of osteoporosis secondary to inhaled corticosteroid treatment in patients with chronic asthmatic bronchitis. Int J Clin Pharmacol Res 2000, 20: 61–4.

    PubMed  CAS  Google Scholar 

  19. Herrala J, Puolijoki H, Liippo K, et al. Clodronate is effective in preventing corticosteroid-induced bone loss among asthmatic patients. Bone 1998, 22: 577–82.

    PubMed  Article  CAS  Google Scholar 

  20. Genant HK, Jeras M. Assessment of prevalent and incident vertebral fractures in osteoporosis research. Osteoporos Int 2003, 14 (Suppl 3): S43–55.

    PubMed  Google Scholar 

  21. Terzolo M, Bovio S, Reimondo G, et al. Subclinical Cushing’s syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am 2005, 34: 423–39.

    PubMed  Article  Google Scholar 

  22. Nancollas GH, Tang R, Phipps RJ, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 2006, 38: 617–27.

    PubMed  Article  CAS  Google Scholar 

  23. Di Somma C, Colao A, Pivonello R, et al. Effectiveness of chronic treatment with alendronate in the osteoporosis of Cushing’s disease. Clin Endocrinol (Oxf) 1998, 48: 655–62.

    Article  Google Scholar 

  24. Canalis E. Mechanisms of glucocorticoid action in bone: implications for glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 2006, 81: 3441–7.

    Google Scholar 

  25. O’Brien CA, Jia D, Plotkin LI, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 2004, 145: 1835–41.

    PubMed  Article  CAS  Google Scholar 

  26. Fromigué O, Body JJ. Bisphosphonates influence the proliferation and the maturation of normal human osteoblasts. J Endocrinol Invest 2002, 25: 539–46.

    PubMed  Article  Google Scholar 

  27. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 1999, 104: 1363–74.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  28. Im GI, Qureshi SA, Kenney J, Rubash HE, Shanbhag AS. Osteoblast proliferation and maturation by bisphosphonates. Biomaterials 2004, 25: 4105–15.

    PubMed  Article  CAS  Google Scholar 

  29. Itoh F, Aoyagi S, Furihata-Komatsu H, et al. Clodronate stimulates osteoblast differentiation in ST2 and MC3T3-E1 cells and rat organ cultures. Eur J Pharmacol 2003, 477: 9–16.

    PubMed  Article  CAS  Google Scholar 

  30. Selander K, Lehenkari P, Väänänen HK. The effects of bisphosphonates on the resorption cycle of isolated osteoclasts. Calcif Tissue Int 1994, 55: 368–75.

    PubMed  Article  CAS  Google Scholar 

  31. Plotkin LI, Manolagas SC, Bellido T. Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their antiapoptotic effects on osteoblasts/osteocytes with novel analogs. Bone 2006, 39: 443–52.

    PubMed  Article  CAS  Google Scholar 

  32. Saviola G, Santoro L. Clodronate in erosive osteoarthritis of the hand: efficacy for pain and function recovery. G Ital Med Lav Ergon 2000, 22: 328–31.

    PubMed  CAS  Google Scholar 

  33. Rovetta G, Monteforte P, Balestra V. Intravenous clodronate for acute pain induced by osteoporotic vertebral fracture. Drugs Exp Clin Res 2000, 26: 25–30.

    PubMed  CAS  Google Scholar 

  34. Varenna M, Zucchi F, Ghiringhelli D, et al. Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized, double blind, placebo controlled study. J Rheumatol 2000, 27: 1477–83.

    PubMed  CAS  Google Scholar 

  35. Bonabello A, Galmozzi MR, Canaparo R, Serpe L, Zara GP. Long-term analgesic effect of clodronate in rodents. Bone 2003, 33: 567–74.

    PubMed  Article  CAS  Google Scholar 

  36. McCloskey EV, Dunn JA, Kanis JA, MacLennan IC, Drayson MT. Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol 2001, 113: 1035–43.

    PubMed  Article  CAS  Google Scholar 

  37. Ippoliti G, Pellegrini C, Campana C, et al. Clodronate treatment of established bone loss in cardiac recipients: a randomized study. Transplantation 2003, 75: 330–4.

    PubMed  Article  CAS  Google Scholar 

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Affiliations

  1. Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Via S. Pansini n.5, 80131, Naples, Italy

    L. Tauchmanova MD, PhD, E. Guerra, R. Pivonello, M. C. De Martino, M. De Leo, G. Lombardi & A. Colao

  2. Department of Gynecology, Federico II University of Naples, Naples, Italy

    F. Caggiano

Authors
  1. L. Tauchmanova MD, PhD
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  2. E. Guerra
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  3. R. Pivonello
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  4. M. C. De Martino
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  5. M. De Leo
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  6. F. Caggiano
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  7. G. Lombardi
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  8. A. Colao
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Correspondence to L. Tauchmanova MD, PhD.

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Tauchmanova, L., Guerra, E., Pivonello, R. et al. Weekly clodronate treatment prevents bone loss and vertebral fractures in women with subclinical Cushing’s syndrome. J Endocrinol Invest 32, 390–394 (2009). https://doi.org/10.1007/BF03346473

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Key-words

  • Clodronate
  • osteopenia
  • osteoporosis
  • subclinical Cushing’s syndrome