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NDT Advance Access originally published online on May 15, 2006
Nephrology Dialysis Transplantation 2006 21(8):2075-2077; doi:10.1093/ndt/gfl245
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Translational Nephrology

Anti-RANKL therapy—implications for the bone-vascular-axis in CKD? Denosumab in post-menopausal women with low bone mineral density*

Ralf Westenfeld, Markus Ketteler and Vincent M. Brandenburg

RWTH University Hostipal, Nephrology and Iumunology, Aachen, NRW, Germany

Correspondence and offprint requests to: Ralf Westenfeld, MD, Department of Nephrology and Clinical Immunology, University Hospital Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany. Email: ralf.westenfeld{at}rwth-aachen.de

Keywords: chronic kidney disease; osteoporosis; osteoprotegerin; RANKL; vascular calcification

Less than a decade ago substantial changes in our understanding of bone metabolism emerged by the discovery of the outstanding importance of the osteoprotegerin (OPG)–receptor activator of nuclear factor-{kappa}B (RANK)—RANK ligand (RANKL) system for bone cell regulatory processes. The OPG–RANK–RANKL axis is the biochemical correlate for the well-known ‘coupling’ in bone remodelling: a strongly linked interplay between continuously ongoing bone degradation and bone formation—in other words between osteoblastic and osteoclastic activity [1,2].

In this locally active, triangular system, RANKL exerts the action of an osteoclastic activator, enhancing both differentiation as well as functional status of osteoclasts and hence increasing bone resorptive activity. In contrast, osteoprotegerin (nomen est omen) functions as a soluble decoy receptor for RANKL and thus antagonizes RANKL action with the net effect of bone resorption inhibition. Preservation of the RANKL-to-OPG balance is of critical importance for bone remodelling and preservation of bone mass.

The importance of the OPG–RANK–RANKL system may extend to vascular health [3]. OPG-deficient mice develop both premature and severe osteoporosis as well as arterial calcifications in the aorta and renal arteries, predominantly occurring in the medial layer of these vessels [4]. Transgenic overexpression of OPG in OPG–/– mice [5] or parenteral OPG administration in animal models of rapidly progressive arterial calcification (Warfarin-treatment, vitamin D toxicity) [6] also revealed a combined vasculo- and osteoprotective role of OPG. Maintenance of bone mineralization and prevention of vascular calcification are obviously closely linked. Epidemiological studies have clearly shown that patients with osteoporosis are prone to vascular calcification and vice versa [7].

Is a safe and effective pharmaceutical influence of the human OPG–RANK–RANKL system feasible? A very recent publication says ‘yes’.

In a February issue of the New England Journal of Medicine, McClung and colleagues [8] report a phase 2 study of the efficacy of various doses of denosumab for treatment of post-menopausal osteopenia and osteoporosis. Denosumab is a neutralizing human monoclonal antibody to RANKL, mimicking the biological function of OPG. In a cohort of 412 post-menopausal women with low bone density, the efficacy of seven different dosing regimens of denosumab were tested compared with placebo and a standard dose of the bisphosphonate alendronate, respectively. Denosumab was administered intermittently either every 3 or every 6 months. The antibody strongly inhibited bone resorption as judged by up to 88% reduction in the levels of serum C-telopeptide, with a rapid onset of action 3 days after administration and with a sustained, but reversible antiresorptive effect. At 1 year, denosumab treatment significantly increased bone mineral density, especially in the lumbar spine (+3.0 to +6.7%) and to a minor extent in the total hip and the distal radius. These changes due to denosumab treatment were at least comparable and somewhat superior to those induced by alendronate and revealed dose-dependency. Apart from the established increment of dyspepsia during bisphosphonate treatment, no significant differences in adverse events were observed between the treatment groups. In summary, the report by McClung added a promising and presumably safe antiresorptive agent to the currently available drug armatorium for the treatment of osteopenia and osteoporosis in post-menopausal women.

What are the potential implications for patient-care in nephrology? Can we regard denosumab as a ‘magic bullet’ for our end-stage renal disease (ESRD) patients, of whom the majority display a reduced bone mineral density [9] with concomitantly increased fracture rates [10] and with an excess of cardiovascular calcification and mortality burden [11]?

Regrettably, it is as yet not guaranteed, if such a magic bullet will hit its target. First, renal osteodystrophy and the affiliated demineralization in chronic kidney disease (CKD) is a broad spectrum of disease conditions with two extreme variants warranting special attention: (1) adynamic bone disease (ABD), i.e. low-turnover bone disease, and (2) osteitis fibrosa, i.e. high-turnover bone disease as the histological equivalent of renal hyperparathyroidism (HPT) [12]. It is a noteworthy fact that ABD has been continuously catching up with HPT in the last decade in terms of prevalence in ESRD patients [13].

In states of high-turnover bone disease with characteristically increased bone resorption—in other words with a disequilibrium in the RANKL–OPG balance in favour of the former factor—denosumab treatment may probably be of value to rapidly suppress osteoclast mediated bone-resorption for a prolonged period of time. Indeed, it has recently been shown in a rat model of renal insufficiency and hyperparathyroidism that OPG administration diminishes PTH action on bone [14]. Moreover, as underscored by the small decreases of serum calcium levels in denosumab-treated subjects [8], additive denosumab administration for treatment of severe secondary hyperparathyroidism may diminish the risk of hypercalcaemia with concomitant calcitriol therapy—although this clearly remains to be proven. A similar approach has been described for the combination of calcitriol and the anti-osteoclastic, anti-resorptive agent pamidronate [15].

On the other hand, ABD is characterized histopathologically by a diminished cellular activity of both osteoblasts and osteoclasts and is suspected to be related to increased fracture and mortality rates [16]. As demonstrated by McClung et al. [8], denosumab treatment is presumably associated not only with a decrease in osteoclast activity, but also with a subsequent decrement in osteoblast activity as judged by diminished bone-specific alkaline phosphatase serum levels. Thus, denosumab bears the risk of aggravating ABD by further reducing bone remodelling activity. The hazard of over-depression of bone metabolism is supported by findings of Coco and colleagues [17] who discovered very low bone turnover in renal transplant recipients treated with pamidronate. The association of reduced osteoblastic surfaces in bone histomorphometry accompanied by enhanced vascular calcification further underscores a potential causal link between low bone turnover and cardiovascular morbidity in haemodialysis patients [18]. Conflicting results have been published regarding serum levels of circulating OPG in dialysis patients with low-turnover bone disease compared with those with high-turnover bone disease [19,20].

The second reason for speculating rather cautiously about the potential of denosumab treatment in ESRD is the unclear role of OPG in human vascular disease. Quite unexpectedly, serum levels of the presumed calcification inhibitor OPG correlated directly, and not inversely, with the severity of vascular disease in the normal population and with the magnitude of vascular calcification in an ESRD cohort, respectively [21,22]. The issue of whether high serum OPG levels in patients with vascular disease reflect counter-regulation and an endogenous defence effort, or in contrast a driving pro-calcificatory force of OPG in humans is still unresolved [3]. It is noteworthy that high OPG, as well as low RANKL, serum levels were recently found to be independently linked to increased mortality in ESRD patients [23]. However, to make matters worse and even more complex, the relative risk association between OPG serum levels and mortality appeared to be U-shaped in a subgroup of inflamed dialysis patients (CRP >10mg/l) [23].

In conclusion, there is a rapidly growing understanding of the complex interplay concerning the regulation of bone formation as orchestrated by a number of bone regulatory proteins, e.g. OPG, RANKL, the Wnt-pathway, bone morphogenetic proteins, and others. CKD significantly and specifically contributes to a disequilibrium of bone turnover, even with consequences leading to vascular pathology [24]. At this time, the potential of antagonizing RANKL in post-menopausal osteoporosis can be regarded as a major therapeutic breakthrough and as a biology-based cause-and-effect-related approach. There is as well stimulating hope that the availability of denosumab as a novel treatment tool may find its place and use in the spectrum of bone and vascular disease in CKD, but it is too early to oversee all the consequences of such an approach.

Conflict of interest statement. None declared.



   Notes
 
*Comment on McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006; 354: 821–831 Back



   References
Top
 References
 

  1. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165–176[CrossRef][Web of Science][Medline]
  2. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423: 337–342[CrossRef][Medline]
  3. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 2004; 95: 1046–1057[Abstract/Free Full Text]
  4. Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260–1268[Abstract/Free Full Text]
  5. Min H, Morony S, Sarosi I, et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 2000; 192: 463–474[Abstract/Free Full Text]
  6. Price PA, June HH, Buckley JR, Williamson MK. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol 2001; 21: 1610–1616[Abstract/Free Full Text]
  7. Hak AE, Pols HA, van Hemert AM, Hofman A, Witteman JC. Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol 2000; 20: 1926–1931[Abstract/Free Full Text]
  8. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006; 354: 821–831[Abstract/Free Full Text]
  9. Taal MW, Masud T, Green D, Cassidy MJ. Risk factors for reduced bone density in haemodialysis patients. Nephrol Dial Transplant 1999; 14: 1922–1928[Abstract/Free Full Text]
  10. Ball AM, Gillen DL, Sherrard D, et al. Risk of hip fracture among dialysis and renal transplant recipients. JAMA 2002; 288: 3014–3018[Abstract/Free Full Text]
  11. Ketteler M, Wanner C, Metzger T, et al. Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia. Kidney Int 2003; [Suppl]: S84–S87
  12. Hruska KA, Teitelbaum SL. Renal osteodystrophy. N Engl J Med 1995; 333: 166–174[Free Full Text]
  13. Malluche HH, Mawad H, Monier-Faugere MC. The importance of bone health in end-stage renal disease: out of the frying pan, into the fire? Nephrol Dial Transplant 2004; 19 Suppl 1: i9–i13
  14. Padagas J, Colloton M, Shalhoub V, et al. The receptor activator of nuclear factor-kappaB ligand inhibitor osteoprotegerin is a bone-protective agent in a rat model of chronic renal insufficiency and hyperparathyroidism. Calcif Tissue Int 2006; 78: 35–44[Medline]
  15. Torregrosa JV, Moreno A, Mas M, Ybarra J, Fuster D. Usefulness of pamidronate in severe secondary hyperparathyroidism in patients undergoing hemodialysis. Kidney Int 2003; [Suppl]: S88–S90
  16. Coco M, Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis 2000; 36: 1115–1121[Web of Science][Medline]
  17. Coco M, Glicklich D, Faugere MC, et al. Prevention of bone loss in renal transplant recipients: a prospective, randomized trial of intravenous pamidronate. J Am Soc Nephrol 2003; 14: 2669–2676[Abstract/Free Full Text]
  18. London GM, Marty C, Marchais SJ, et al. Arterial calcifications and bone histomorphometry in end-stage renal disease. J Am Soc Nephrol 2004; 15: 1943–1951[Abstract/Free Full Text]
  19. Haas M, Leko-Mohr Z, Roschger P, et al. Osteoprotegerin and parathyroid hormone as markers of high-turnover osteodystrophy and decreased bone mineralization in hemodialysis patients. Am J Kidney Dis 2002; 39: 580–586[Web of Science][Medline]
  20. Coen G, Ballanti P, Balducci A, et al. Serum osteoprotegerin and renal osteodystrophy. Nephrol Dial Transplant 2002; 17: 233–238[Abstract/Free Full Text]
  21. Schoppet M, Al Fakhri N, Franke FE, et al. Localization of osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand, and receptor activator of nuclear factor-kappaB ligand in Monckeberg's sclerosis and atherosclerosis. J Clin Endocrinol Metab 2004; 89: 4104–4112[Abstract/Free Full Text]
  22. Nitta K, Akiba T, Uchida K, et al. Serum osteoprotegerin levels and the extent of vascular calcification in haemodialysis patients. Nephrol Dial Transplant 2004; 19: 1886–1889[Abstract/Free Full Text]
  23. Morena M, Terrier N, Jaussent I, et al. Plasma osteoprotegerin is associated with mortality in hemodialysis patients. J Am Soc Nephrol 2006; 17: 262–270[Abstract/Free Full Text]
  24. Hruska KA, Saab G, Chaudhary LR, et al. Kidney–bone, bone–kidney, and cell–cell communications in renal osteodystrophy. Semin Nephrol 2004; 24: 25–38[CrossRef][Web of Science][Medline]
Received for publication: 28. 3.06
Accepted in revised form: 5. 4.06


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