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Exp Clin Endocrinol Diabetes 2011; 119(09): 519-524
DOI: 10.1055/s-0031-1284365
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© J. A. Barth Verlag in George Thieme Verlag KG Stuttgart · New York

Paget’s Disease of Bone and Calcium Homeostasis: Focus on Bisphosphonate Treatment

S. A. Polyzos
1   Second Medical Clinic, Medical School, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
,
A. D. Anastasilakis
2   Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece
,
P. Makras
3   Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA Hospital, Athens, Greece
,
E. Terpos
4   Department of Clinical Therapeutics, School of Medicine, University of Athens, Athens, Greece
› Author Affiliations
Further Information

Publication History

received 17 April 2011
firstdecision 17 April 2011

accepted 12 July 2011

Publication Date:
02 August 2011 (online)

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Abstract

Paget’s disease of bone (PDB) is the second most common metabolic bone disease. Bisphosphonates (BPs) are currently the drugs of choice for PDB. PDB and osteomalacia are both common in the elderly. The concept of relative vitamin D deficiency in patients with PDB was suggested long ago, but it has not yet elucidated. Both diseases predispose to fractures, but their combined action to fragility has not been studied yet. The older BPs, mainly etidronate, further inhibit bone mineralization. Mineralization defects have also been described in patients with PDB treated with pamidronate. Moreover, hypocalcemia and secondary hyperparathyroidism after treatment with BPs have been described in PDB. Hypocalcemia seems to be more severe after treatment with the more potent, intravenous zoledronic acid, which is currently the treatment of choice for PDB. The counteracting hyperparathyroidism pathophysiologically intends to increase renal reabsorption of calcium and 1.25-dihydroxy vitamin D production and to stimulate osteoclasts in order to prevent long-term hypocalcemia. However, the effect of PTH on osteoclasts is, at least partly, restricted in patients taking BPs. Secondary hyperparathyroidism is a potentially detrimental condition, especially in patients already suffering from another bone disease. Serum calcium and vitamin D deficiency should be restored before BP treatment and calcium and vitamin D administration should be possibly continued for longer after achieving normocalcemia, which may shorten the duration of secondary hyperparathyroidism.

Quick summary:

Mineralization defects and hypocalcemia with secondary hyperparathyroidism have been described in patients with Paget’s disease of bone treated with bisphosphonates. Secondary hyperparathyroidism may be a potentially detrimental condition for patients with Paget’s disease of bone.

Key words

bisphosphonate - hyperparathyroidism - hypocalcemia - Paget’s disease - vitamin D
 

  • References

  • 1 Adamson BB, Gallacher SJ, Byars J et al. Mineralisation defects with pamidronate therapy for Paget’s disease. Lancet 1993; 342: 1459-1460
    CrossrefPubMedGoogle Scholar
  • 2 Avramidis A, Polyzos SA, Moralidis E et al. Scintigraphic biochemical, and clinical response to zoledronic acid treatment in patients with Paget’s disease of bone. J Bone Miner Metab 2008; 26: 635-641
    CrossrefPubMedGoogle Scholar
  • 3 Barker DJ, Gardner MJ. Distribution of Paget’s disease in England, Wales and Scotland and a possible relationship with vitamin D deficiency in childhood. Br J Prev Soc Med 1974; 28: 226-232
    PubMedGoogle Scholar
  • 4 Boonen S, Lips P, Bouillon R et al. Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 2007; 92: 1415-1423
    CrossrefPubMedGoogle Scholar
  • 5 Boyce BF, Smith L, Fogelman I et al. Focal osteomalacia due to low-dose diphosphonate therapy in Paget’s disease. Lancet 1984; 1: 821-824
    PubMedGoogle Scholar
  • 6 Brown JP, Hosking DJ, Ste-Marie L et al. Risedronate, a highly effective, short-term oral treatment for Paget’s disease: a dose-response study. Calcif Tissue Int 1999; 64: 93-99
    CrossrefPubMedGoogle Scholar
  • 7 Chennuru S, Koduri J, Baumann MA. Risk factors for symptomatic hypocalcaemia complicating treatment with zoledronic acid. Intern Med J 2008; 38: 635-637
    CrossrefPubMedGoogle Scholar
  • 8 Cooper C, Harvey NC, Dennison EM et al. Update on the epidemiology of Paget’s disease of bone. J Bone Miner Res 2006; 21 (Suppl. 02) 3-8
    CrossrefPubMedGoogle Scholar
  • 9 Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008; 336: 1298-1302
    CrossrefPubMedGoogle Scholar
  • 10 Crawford BA, Kam C, Pavlovic J et al. Zoledronic acid prevents bone loss after liver transplantation: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2006; 144: 239-248
    PubMedGoogle Scholar
  • 11 Cremers SC, Eekhoff ME, Den HJ et al. Relationships between pharmacokinetics and rate of bone turnover after intravenous bisphosphonate (olpadronate) in patients with Paget’s disease of bone. J Bone Miner Res 2003; 18: 868-875
    CrossrefPubMedGoogle Scholar
  • 12 Cundy T, Bolland M. Paget disease of bone. Trends Endocrinol Metab 2008; 19: 246-253
    CrossrefPubMedGoogle Scholar
  • 13 Cundy T, Wattie D, King AR. High-dose pamidronate in the management of resistant Paget’s disease. Calcif Tissue Int 1996; 58: 6-8
    CrossrefPubMedGoogle Scholar
  • 14 de Seze S, Durand C. Maladie de Paget et Carence Calcique. Rev Rhum 1945; 12: 193-217
    PubMedGoogle Scholar
  • 15 Devogelaer JP, Bergmann P, Body JJ et al. Management of patients with Paget’s disease: a consensus document of the Belgian Bone Club. Osteoporos Int 2008; 19: 1109-1117
    CrossrefPubMedGoogle Scholar
  • 16 Evans RA, Dunstan CR, Hills E et al. Pathologic fracture due to severe osteomalacia following low-dose diphosphonate treatment of Paget’s disease of bone. Aust N Z J Med 1983; 13: 277-279
    CrossrefPubMedGoogle Scholar
  • 17 Eyres KS, Marshall P, McCloskey E et al. Spontaneous fractures in a patient treated with low doses of etidronic acid (disodium etidronate). Drug Saf 1992; 7: 162-165
    CrossrefPubMedGoogle Scholar
  • 18 Fenton AJ, Gutteridge DH, Kent GN et al. Intravenous aminobisphosphonate in Paget’s disease: clinical, biochemical, histomorphometric and radiological responses. Clin Endocrinol (Oxf) 1991; 34: 197-204
    CrossrefPubMedGoogle Scholar
  • 19 Gibbs CJ, Aaron JE, Peacock M et al. Osteomalacia in Paget’s disease treated with short term, high dose sodium etidronate. Br Med J (Clin Res Ed) 1986; 292: 1227-1229
    CrossrefPubMedGoogle Scholar
  • 20 Gutteridge DH, Retallack RW, Ward LC et al. Clinical, biochemical, hematologic, and radiographic responses in Paget’s disease following intravenous pamidronate disodium: a 2-year study. Bone 1996; 19: 387-394
    CrossrefPubMedGoogle Scholar
  • 21 Harris ST, Gertz BJ, Genant HK et al. The effect of short term treatment with alendronate on vertebral density and biochemical markers of bone remodeling in early postmenopausal women. J Clin Endocrinol Metab 1993; 76: 1399-1406
    CrossrefPubMedGoogle Scholar
  • 22 Heaney RP, Dowell MS, Hale CA et al. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 2003; 22: 142-146
    CrossrefPubMedGoogle Scholar
  • 23 Hosking D, Lyles K, Brown JP et al. Long-term control of bone turnover in Paget’s disease with zoledronic acid and risedronate. J Bone Miner Res 2007; 22: 142-148
    CrossrefPubMedGoogle Scholar
  • 24 Joshi SR, Ambhore S, Butala N et al. Paget’s disease from Western India. J Assoc Physicians India 2006; 54: 535-538
    PubMedGoogle Scholar
  • 25 Kannan S, Mahadevan S, Sathya A et al. A tale of three diseases of the bone. Singapore Med J 2008; 49: 263-265
    PubMedGoogle Scholar
  • 26 Kimmel DB. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res 2007; 86: 1022-1033
    CrossrefPubMedGoogle Scholar
  • 27 Labinson P, Taxel P. Multiple fractures in a woman receiving 24 years of etidronate treatment for Paget’s disease. Conn Med 2007; 71: 269-273
    PubMedGoogle Scholar
  • 28 Lanham-New SA, Buttriss JL, Miles LM et al. Proceedings of the Rank Forum on Vitamin D. Br J Nutr 2011; 105: 144-156
    CrossrefPubMedGoogle Scholar
  • 29 Lu KC, Yeung LK, Lin SH et al. Acute effect of pamidronate on PTH secretion in postmenopausal hemodialysis patients with secondary hyperparathyroidism. Am J Kidney Dis 2003; 42: 1221-1227
    CrossrefPubMedGoogle Scholar
  • 30 MacGowan JR, Pringle J, Morris VH et al. Gross vertebral collapse associated with long-term disodium etidronate treatment for pelvic Paget’s disease. Skeletal Radiol 2000; 29: 279-282
    CrossrefPubMedGoogle Scholar
  • 31 Mehrotra B. Bisphosphonates – role in cancer therapies. J Oral Maxillofac Surg 2009; 67: 19-26
    PubMedGoogle Scholar
  • 32 Merlotti D, Gennari L, Martini G et al. Comparison of Different Intravenous Bisphosphonate Regimens for Paget’s Disease of Bone. J Bone Miner Res 2007; 22: 1510-1517
    CrossrefPubMedGoogle Scholar
  • 33 Nagant de Deuxchaisnes C, Maldague B, Malghem J et al. The Action of the Main Therapeutic Regimes on Pagets-Disease of Bone, with A Note on the Effect of Vitamin-D Deficiency. Arthritis Rheum 1980; 23: 1215-1232
    CrossrefPubMedGoogle Scholar
  • 34 Nancollas GH, Tang R, Phipps RJ et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 2006; 38: 617-627
    CrossrefPubMedGoogle Scholar
  • 35 Papapetrou PD. Bisphosphonate-associated adverse events. Hormones (Athens) 2009; 8: 96-110
    PubMedGoogle Scholar
  • 36 Polyzos SA, Anastasilakis AD, Litsas I et al. Profound hypocalcemia following effective response to zoledronic acid treatment in a patient with juvenile Paget’s disease. J Bone Miner Metab 2010; 28: 706-712
    CrossrefPubMedGoogle Scholar
  • 37 Polyzos SA, Anastasilakis AD, Terpos E. Paget’s disease of bone: emphasis on treatment with zoledronic acid. Expert Rev Endocrinol Metabolism 2009; 4: 424-434
    PubMedGoogle Scholar
  • 38 Polyzos SA, Anastasilakis AD, Terpos E. Transient secondary hyperparathyroidism following intravenous infusion of zoledronic acid. Support Care Cancer 2009; 17: 1329-1330
    CrossrefPubMedGoogle Scholar
  • 39 Ralston SH, Langston AL, Reid IR. Pathogenesis and management of Paget’s disease of bone. Lancet 2008; 372: 155-163
    CrossrefPubMedGoogle Scholar
  • 40 Reid IR, Miller P, Lyles K et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 2005; 353: 898-908
    CrossrefPubMedGoogle Scholar
  • 41 Russell RG. Bisphosphonates: from bench to bedside. Ann NY Acad Sci 2006; 1068: 367-401
    CrossrefPubMedGoogle Scholar
  • 42 Sayin M, Yazici G. Hyperparathyroidism secondary to zoledronic acid infusion: case report. Support Care Cancer 2009; 17: 469-470
    CrossrefPubMedGoogle Scholar
  • 43 Shankar S, Hosking DJ. Biochemical assessment of Paget’s disease of bone. J Bone Miner Res 2006; 21 (Suppl. 02) 22-27
    CrossrefPubMedGoogle Scholar
  • 44 Siris E, Weinstein RS, Altman R et al. Comparative study of alendronate versus etidronate for the treatment of Paget’s disease of bone. J Clin Endocrinol Metab 1996; 81: 961-967
    CrossrefPubMedGoogle Scholar
  • 45 Siris ES, Clemens TP, McMahon D et al. Parathyroid function in Paget’s disease of bone. J Bone Miner Res 1989; 4: 75-79
    PubMedGoogle Scholar
  • 46 Sparidans RW, Twiss IM, Talbot S. Bisphosphonates in bone diseases. Pharm World Sci 1998; 20: 206-213
    CrossrefPubMedGoogle Scholar
  • 47 Stewart GO, Gutteridge DH, Price RI et al. Prevention of appendicular bone loss in Paget’s disease following treatment with intravenous pamidronate disodium. Bone 1999; 24: 139-144
    CrossrefPubMedGoogle Scholar
  • 48 Stuckey BG, Lim EM, Kent GN et al. Bisphosphonate therapy for Paget’s disease in a patient with hypoparathyroidism: profound hypocalcemia, rapid response, and prolonged remission. J Bone Miner Res 2001; 16: 1719-1723
    CrossrefPubMedGoogle Scholar
  • 49 van Staa TP, Selby P, Leufkens HG et al. Incidence and natural history of Paget’s disease of bone in England and Wales. J Bone Miner Res 2002; 17: 465-471
    CrossrefPubMedGoogle Scholar
  • 50 Vuorimies I, Toiviainen-Salo S, Hero M et al. Zoledronic Acid Treatment in Children with Osteogenesis Imperfecta. Horm Res Paediatr 2011; 75: 346-353
    CrossrefPubMedGoogle Scholar
  • 51 Whitson HE, Lobaugh B, Lyles KW. Severe hypocalcemia following bisphosphonate treatment in a patient with Paget’s disease of bone. Bone 2006; 39: 954-958
    CrossrefPubMedGoogle Scholar
  • 52 Williams ED, Barr WT, Rajan KT. Relative vitamin D deficiency in Paget’s disease. Lancet 1981; 1: 384-385
    PubMedGoogle Scholar