Changing bone patterns with progression of chronic kidney disease
2016; Elsevier BV; Volume: 89; Issue: 2 Linguagem: Inglês
10.1016/j.kint.2015.12.004
ISSN1523-1755
AutoresTilman B. Drüeke, Ziad A. Massy,
Tópico(s)Vitamin D Research Studies
ResumoIt is commonly held that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy in patients with chronic kidney disease. Osteitis fibrosa is a high-turnover bone disease resulting mainly from secondary hyperparathyroidism, and mixed uremic osteodystrophy is in addition characterized by a mineralization defect most often attributed to vitamin D deficiency. However, there is ancient and more recent evidence that in early chronic kidney disease stages adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients. This could be due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/β-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4. The development of high-turnover bone disease would occur only later on, when serum PTH levels are able to overcome peripheral PTH resistance and the other inhibitory factors of bone formation. Whether FGF23 and Klotho play a direct role in the transition from low- to high-turnover bone disease or participate only indirectly via regulating PTH secretion remains to be seen. It is commonly held that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy in patients with chronic kidney disease. Osteitis fibrosa is a high-turnover bone disease resulting mainly from secondary hyperparathyroidism, and mixed uremic osteodystrophy is in addition characterized by a mineralization defect most often attributed to vitamin D deficiency. However, there is ancient and more recent evidence that in early chronic kidney disease stages adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients. This could be due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/β-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4. The development of high-turnover bone disease would occur only later on, when serum PTH levels are able to overcome peripheral PTH resistance and the other inhibitory factors of bone formation. Whether FGF23 and Klotho play a direct role in the transition from low- to high-turnover bone disease or participate only indirectly via regulating PTH secretion remains to be seen. Following the first description of osteitis fibrosa cystica by Davies in 19151Davies H.M. Osteitis fibrosa cystica.Proc R Soc Med. 1915; 8: 34PubMed Google Scholar and the discovery by Bauer and his colleagues of its association with parathyroid gland overactivity in 1930,2Bauer W. Albright F. Aub J.C. A case of osteitis fibrosa cystica (osteomalacia?) with evidence of hyperactivity of the para-thyroid bodies. Metabolic Study Ii.J Clin Invest. 1930; 8: 229-248Crossref PubMed Google Scholar Albright’s group postulated in 1937 that phosphate retention and concomitant blood calcium lowering in patients with chronic kidney disease (CKD) might cause parathyroid hyperplasia and renal osteitis fibrosa.3Albright F. Drake T.G. Sulkowitch H.W. Renal osteitis fibrosa cystica.Bull Johns Hopkins Hosp. 1937; 60: 377-399Google Scholar To the best of our knowledge, the term renal osteodystrophy was coined in the 1940s.4Liu S.H. Chu H.I. Treatment of renal osteodystrophy with dihydrotachysterol (A.T.10) and iron.Science. 1942; 95: 388-389Crossref PubMed Google Scholar, 5Norman J.S. Perlman R. Bastable S. Renal osteodystrophy.J Am Med Assoc. 1947; 133: 771-773Crossref PubMed Google Scholar Very early the question arose whether renal bone disease might also be due to vitamin D deficiency or resistance to its action, with the histologic expression of osteomalacia.2Bauer W. Albright F. Aub J.C. A case of osteitis fibrosa cystica (osteomalacia?) with evidence of hyperactivity of the para-thyroid bodies. Metabolic Study Ii.J Clin Invest. 1930; 8: 229-248Crossref PubMed Google Scholar The subsequent elegant studies by Bricker and Slatopolsky et al. led to the “trade-off hypothesis.”6Bricker N.S. On the pathogenesis of the uremic state. An exposition of the “trade-off hypothesis.”.N Engl J Med. 1972; 286: 1093-1099Crossref PubMed Google Scholar, 7Slatopolsky E. Caglar S. Pennell J.P. et al.On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog.J Clin Invest. 1971; 50: 492-499Crossref PubMed Google Scholar It suggests that in the setting of CKD the progressive loss of functioning nephrons brings into play a number of compensatory mechanisms, including an increase in parathyroid hormone (PTH) secretion in response to the progressive inability of the kidneys to excrete appropriate amounts of phosphate, delaying the occurrence of hyperphosphatemia. This theory, together with the frequent observation of severe secondary hyperparathyroidism in patients with end-stage renal disease (ESRD) undergoing dialysis therapy, led to the common belief that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy observed as nephropathies progress from early to more advanced stages of CKD. Although the predominance of these 2 forms of renal osteodystrophy was certainly true for patients with ESRD in the 1960s and early 1970s, the situation changed dramatically in the 1980s, at least in many regions of the world, as a consequence of aluminum intoxication. This new disease was mainly, although not exclusively, observed in patients undergoing long-term hemodialysis treatment. It was characterized by peculiar types of osteomalacia or adynamic bone disease,8Ward M.K. Feest T.G. Ellis H.A. et al.Osteomalacic dialysis osteodystrophy: evidence for a water-borne aetiological agent, probably aluminium.Lancet. 1978; 1: 841-845Abstract PubMed Scopus (0) Google Scholar and often accompanied by microcytic anemia9Touam M. Martinez F. Lacour B. et al.Aluminium-induced, reversible microcytic anemia in chronic renal failure: clinical and experimental studies.Clin Nephrol. 1983; 19: 295-298PubMed Google Scholar and encephalopathy.10Alfrey A.C. LeGendre G.R. Kaehny W.D. The dialysis encephalopathy syndrome. Possible aluminum intoxication.N Engl J Med. 1976; 294: 184-188Crossref PubMed Google Scholar It was mainly induced by heavy aluminum contamination of tap water used for hemodialysis in certain geographic areas.8Ward M.K. Feest T.G. Ellis H.A. et al.Osteomalacic dialysis osteodystrophy: evidence for a water-borne aetiological agent, probably aluminium.Lancet. 1978; 1: 841-845Abstract PubMed Scopus (0) Google Scholar It could also be caused by the oral intake of high amounts of aluminum-containing phosphate binders.11Andreoli S.P. Bergstein J.M. Sherrard D.J. Aluminum intoxication from aluminum-containing phosphate binders in children with azotemia not undergoing dialysis.N Engl J Med. 1984; 310: 1079-1084Crossref PubMed Google Scholar Another possible etiologic factor in the pathogenesis of adynamic bone disease was the increasingly vigorous use of active vitamin D sterols and analogs in the subsequent decade, with considerable overlap between the tail end of the aluminum epidemic and the overzealous use of active vitamin D compounds.12Coburn J.W. An update on vitamin D as related to nephrology practice: 2003.Kidney Int Suppl. 2003; : S125-S130Abstract Full Text Full Text PDF PubMed Google Scholar, 13Hernandez J.D. Wesseling K. Salusky I.B. Role of parathyroid hormone and therapy with active vitamin D sterols in renal osteodystrophy.Semin Dial. 2005; 18: 290-295Crossref PubMed Scopus (0) Google Scholar Fortunately, the incidence of this “iatrogenic” disease has rapidly waned as a consequence of better dialysis water purification and the declining prescription of aluminum-containing phosphate chelators to patients with CKD. It has become exceptional at present. We will not address here this iatrogenic disease. With the progression of CKD a series of changes occur in bone and mineral metabolism that are encompassed by the term CKD-MBD,14Moe S. Drueke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Abstract Full Text Full Text PDF PubMed Scopus (875) Google Scholar a systemic disorder due to CKD that is manifested by either 1 or a combination of the following: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and vascular or other soft tissue calcification. According to this definition, renal osteodystrophy is an alteration of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by bone histomorphometry. The majority of studies devoted to renal osteodystrophy have been done in patients with ESRD, that is, in the setting of long-term exposure to the uremic milieu with complex, major disturbances of mineral and endocrine metabolism. The availability of studies on renal osteodystrophy in patients with less advanced stages of CKD is much more limited. Therefore, knowledge on the development and progression of renal bone disease in CKD stages 3 to 5 before the start of renal replacement therapies is relatively scarce. Fortunately, in recent years there has been an increasing number of studies using either light microscopy or physical imaging techniques in these patients. Moreover, in the nephrology community there has been a progressive shift from a predominant interest in the X-ray and histologic aspects of renal bone disease associated with parathyroid overfunction and vitamin D deficiency toward an earlier assessment of bony changes that may favor the occurrence of fractures, under the concomitant influence of conditions leading to osteoporosis as observed in the general population. The quest for a better understanding of underlying mechanisms has evolved together with an increasing interest in fracture prevention and treatment. In the past, the perception of uremic bone was mainly that of a passive organ suffering from the disturbances of mineral and hormonal metabolism associated with CKD. Interestingly, in recent years this perception has changed to that of an endocrine organ that also plays an active part in the cardiovascular complications and metabolic anomalies occurring with the progression of CKD.15Vervloet M.G. Massy Z.A. Brandenburg V.M. et al.Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders.Lancet Diabetes Endocrinol. 2014; 2: 427-436Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar In this Review we present a synthesis of studies that examined changes in bone-related serum parameters with the progression of CKD, alterations of bone structure and protein expression, and possible interactions of CKD-linked disturbances of mineral and endocrine metabolism with changes in bone structure. The contribution of experimental animal studies to a better understanding of the skeletal changes observed with the progression of CKD is discussed only briefly. A personal interpretation of the possible causes underlying the sequential features of renal osteodystrophy is provided. They include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin;15Vervloet M.G. Massy Z.A. Brandenburg V.M. et al.Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders.Lancet Diabetes Endocrinol. 2014; 2: 427-436Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 16Evenepoel P. Rodriguez M. Ketteler M. Laboratory abnormalities in CKD-MBD: markers, predictors, or mediators of disease?.Semin Nephrol. 2014; 34: 151-163Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 17Moe S.M. Drueke T. Lameire N. Eknoyan G. Chronic kidney disease-mineral-bone disorder: a new paradigm.Adv Chronic Kidney Dis. 2007; 14: 3-12Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 18Morena M. Jaussent I. Dupuy A.M. et al.Osteoprotegerin and sclerostin in chronic kidney disease prior to dialysis: potential partners in vascular calcifications.Nephrol Dial Transplant. 2015; 30: 1345-1356Crossref PubMed Scopus (0) Google Scholar variable increases in advanced glycation end products (AGEs),19Gajjala P.R. Fliser D. Speer T. et al.Emerging role of post-translational modifications in chronic kidney disease and cardiovascular disease.Nephrol Dial Transplant. 2015; 30: 1814-1824Crossref PubMed Scopus (12) Google Scholar, 20Gugliucci A. Menini T. The axis AGE-RAGE-soluble RAGE and oxidative stress in chronic kidney disease.Adv Exp Med Biol. 2014; 824: 191-208Crossref PubMed Scopus (0) Google Scholar, 21Mallipattu S.K. Uribarri J. Advanced glycation end product accumulation: a new enemy to target in chronic kidney disease?.Curr Opin Nephrol Hypertens. 2014; 23: 547-554Crossref PubMed Scopus (4) Google Scholar oxidative stress markers including advanced oxidation protein products,19Gajjala P.R. Fliser D. Speer T. et al.Emerging role of post-translational modifications in chronic kidney disease and cardiovascular disease.Nephrol Dial Transplant. 2015; 30: 1814-1824Crossref PubMed Scopus (12) Google Scholar, 22Descamps-Latscha B. Witko-Sarsat V. Nguyen-Khoa T. et al.Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients.Am J Kidney Dis. 2005; 45: 39-47Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 23Tucker P.S. Dalbo V.J. Han T. Kingsley M.I. Clinical and research markers of oxidative stress in chronic kidney disease.Biomarkers. 2013; 18: 103-115Crossref PubMed Scopus (0) Google Scholar and protein carbamylation products;19Gajjala P.R. Fliser D. Speer T. et al.Emerging role of post-translational modifications in chronic kidney disease and cardiovascular disease.Nephrol Dial Transplant. 2015; 30: 1814-1824Crossref PubMed Scopus (12) Google Scholar, 24Kalim S. Karumanchi S.A. Thadhani R.I. Berg A.H. Protein carbamylation in kidney disease: pathogenesis and clinical implications.Am J Kidney Dis. 2014; 64: 793-803Abstract Full Text Full Text PDF PubMed Google Scholar, 25Verbrugge F.H. Tang W.H. Hazen S.L. Protein carbamylation and cardiovascular disease.Kidney Int. 2015; 88: 474-478Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar increases in numerous other compounds summarized under the term “uremic toxins”;26Barreto F.C. Stinghen A.E. de Oliveira R.B. et al.The quest for a better understanding of chronic kidney disease complications: an update on uremic toxins.J Bras Nefrol. 2014; 36: 221-235Crossref PubMed Google Scholar, 27Moradi H. Sica D.A. Kalantar-Zadeh K. Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease.Am J Nephrol. 2013; 38: 136-148Crossref PubMed Scopus (26) Google Scholar, 28Vanholder R. Schepers E. Pletinck A. et al.The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review.J Am Soc Nephrol. 2014; 25: 1897-1907Crossref PubMed Scopus (0) Google Scholar decreases in serum concentrations of 25 OH vitamin D and 1,25 diOH vitamin D;29Levin A. Bakris G.L. Molitch M. et al.Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.Kidney Int. 2007; 71: 31-38Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar, 30Lucas P.A. Woodhead J.S. Brown R.C. Vitamin D3 metabolites in chronic renal failure and after renal transplantation.Nephrol Dial Transplant. 1988; 3: 70-76PubMed Google Scholar, 31Pavik I. Jaeger P. Ebner L. et al.Secreted Klotho and FGF23 in chronic kidney disease stage 1 to 5: a sequence suggested from a cross-sectional study.Nephrol Dial Transplant. 2013; 28: 352-359Crossref PubMed Scopus (0) Google Scholar and decreases in serum and or tissue concentrations of αKlotho.32Barker S.L. Pastor J. Carranza D. et al.The demonstration of alphaKlotho deficiency in human chronic kidney disease with a novel synthetic antibody.Nephrol Dial Transplant. 2015; 30: 223-233Crossref PubMed Scopus (12) Google Scholar, 33Hu M.C. Kuro-o M. Moe O.W. Klotho and chronic kidney disease.Contrib Nephrol. 2013; 180: 47-63Crossref PubMed Scopus (22) Google Scholar, 34Tsuchiya K. Nagano N. Nitta K. Klotho/FGF23 axis in CKD.Contrib Nephrol. 2015; 185: 56-65PubMed Google Scholar FGF23 processing appears to change with CKD progression. Although circulating FGF23 undergoes cleavage in patients with normal kidney function and in those with mild CKD,35Bhattacharyya N. Wiench M. Dumitrescu C. et al.Mechanism of FGF23 processing in fibrous dysplasia.J Bone Miner Res. 2012; 27: 1132-1141Crossref PubMed Scopus (0) Google Scholar most circulating FGF23 in dialysis patients is in its full-length form.36Shimada T. Urakawa I. Isakova T. et al.Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active.J Clin Endocrinol Metab. 2010; 95: 578-585Crossref PubMed Scopus (107) Google Scholar It remains to be seen whether CKD-associated alterations in mineral and endocrine metabolism or other factors are responsible for this change in FGF23 catabolism. The serum levels of secreted frizzled-related protein 4 (sFRP4) do not change with the progression of CKD or the development of hyperphosphatemia.37Pande S. Ritter C.S. Rothstein M. et al.FGF-23 and sFRP-4 in chronic kidney disease and post-renal transplantation.Nephron Physiol. 2006; 104: p23-p32Crossref PubMed Scopus (0) Google Scholar Finally, the role of circulating Dickkopf-1 (Dkk1) is still uncertain, with either no changes38Cejka D. Herberth J. Branscum A.J. et al.Sclerostin and Dickkopf-1 in renal osteodystrophy.Clin J Am Soc Nephrol. 2011; 6: 877-882Crossref PubMed Scopus (110) Google Scholar, 39Thambiah S. Roplekar R. Manghat P. et al.Circulating sclerostin and Dickkopf-1 (DKK1) in predialysis chronic kidney disease (CKD): relationship with bone density and arterial stiffness.Calcif Tissue Int. 2012; 90: 473-480Crossref PubMed Scopus (67) Google Scholar or a slight decrease18Morena M. Jaussent I. Dupuy A.M. et al.Osteoprotegerin and sclerostin in chronic kidney disease prior to dialysis: potential partners in vascular calcifications.Nephrol Dial Transplant. 2015; 30: 1345-1356Crossref PubMed Scopus (0) Google Scholar of mean serum values in patients with CKD. Table 1 summarizes the possible role of bone-related, CKD-modified circulating parameters in bone formation, mineralization, and resorption.Table 1Possible associations of bone-related, CKD-modified blood parameters with bone formation, mineralization, and resorptionParameterDirection of change in boneFormationMineralizationResorptionMetabolic acidosis↓↓↑High PTH↑Normal↑↑High FGF23???High osteocalcin↑NormalHigh osteoprotegerin↑↓High sclerostin↓Low 25 OH vitamin D↓↓Low 1,25 diOH vitamin D↑↓↑Low Klotho↑?↑CKD, chronic kidney disease; FGF23, fibroblast growth factor 23; Klotho, soluble αKlotho; PTH, parathyroid hormone. Open table in a new tab CKD, chronic kidney disease; FGF23, fibroblast growth factor 23; Klotho, soluble αKlotho; PTH, parathyroid hormone. The interpretation of measured values of many of the previously mentioned parameters in terms of their biologic activity in CKD is hampered by the fact that they often are present in the circulation not only as entire hormones or growth factors but also as fragments thereof, with sometimes actions opposite to the full-length molecule. Moreover, they may undergo oxidation, AGE-transformation, or carbamylation, which also may greatly alter biologic activity.19Gajjala P.R. Fliser D. Speer T. et al.Emerging role of post-translational modifications in chronic kidney disease and cardiovascular disease.Nephrol Dial Transplant. 2015; 30: 1814-1824Crossref PubMed Scopus (12) Google Scholar, 40Hocher B. Armbruster F.P. Stoeva S. et al.Measuring parathyroid hormone (PTH) in patients with oxidative stress: do we need a fourth generation parathyroid hormone assay?.PLoS One. 2012; 7: e40242Crossref PubMed Scopus (0) Google Scholar, 41Stinghen AE, Massy ZA, Vlassara H, et al. Uremic toxicity of advanced glycation end products in CKD [e-pub ahead of print]. J Am Soc Nephrol. http://dx.doi.org/10.1681/ASN.2014101047.Google Scholar Bone histomorphometry informs bone turnover, mineralization, and volume, and, indirectly, bone quality.42Moorthi R.N. Moe S.M. Recent advances in the noninvasive diagnosis of renal osteodystrophy.Kidney Int. 2013; 84: 886-894Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar However, bone biopsy findings reflect skeletal status only at a single time point. Moreover, a biopsy taken from the iliac crest does not necessarily reflect changes at other sites of the skeleton. Another problem is that historically bone histomorphometry has evaluated only changes in trabecular bone, although cortical bone thickness and porosity are equally important in determining fracture risk. This is especially important in CKD, as hyperparathyroidism can cause thinning in the cortex.43Leonard M.B. A structural approach to skeletal fragility in chronic kidney disease.Semin Nephrol. 2009; 29: 133-143Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Simultaneously in the trabeculae, increased remodeling and increased bone volume may be observed, although new trabeculae may be irregular and lack connectivity and strength.43Leonard M.B. A structural approach to skeletal fragility in chronic kidney disease.Semin Nephrol. 2009; 29: 133-143Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Despite these and other issues, bone biopsy remains the gold standard for the diagnosis of the different types of renal osteodystrophy. Histomorphometry studies of static and dynamic bone parameters have been performed much less frequently in patients with CKD before the stage of ESRD than in patients on renal replacement therapy. Most importantly, knowledge of the initial changes of bone structure in CKD stages 2 and 3 is scarce, and the probable influence of different nephropathy types remains ill-understood. It has long been known that slowly progressive renal disease such as chronic interstitial nephritis or pyelonephritis is more frequently associated with osteomalacia or mixed renal osteodystrophy than more rapidly progressive forms of glomerulonephritis.44Mora Palma F.J. Ellis H.A. Cook D.B. et al.Osteomalacia in patients with chronic renal failure before dialysis or transplantation.Q J Med. 1983; 52: 332-348PubMed Google Scholar In the following, we present some of the studies that we think have made important contributions to this issue, without any claim to completeness. As early as in 1976, Malluche et al.45Malluche H.H. Ritz E. Lange H.P. et al.Bone histology in incipient and advanced renal failure.Kidney Int. 1976; 9: 355-362Abstract Full Text PDF PubMed Google Scholar performed a bone histomorphometry study in 50 German patients with various stages of CKD, ages 20 to 61 years, 19 males and 31 females. Their creatinine clearance (glomerular filtration rate) values ranged from 80 to 6 ml/min per 1.73 m2, that is, CKD stages 2 to 5 according to present nomenclature. The underlying renal diseases were glomerulonephritis (19 patients); renal malformation, pyelonephritis, or both (21 patients); polycystic kidney disease (6 patients); and other or unknown causes (4 patients). The bone biopsies of patients with incipient CKD exhibited evidence of PTH excess, with empty osteoclastic lacunae and woven osteoid. Figure 1 shows that the prevalence of woven osteoid, an early expression of osteitis fibrosa, was increasing with decreasing glomerular filtration rate (GFR). However, there was wide interpatient variability at different CKD stages. Notably, even some patients with GFR values as high as 60 to 80 had woven osteoid. Osteoclastic surface resorption was abnormally high when GFR fell below 50 and endosteal fibrosis appeared below 30 ml/min per 1.73 m2. Using tetracycline double labeling the authors also found evidence of a mineralization defect reflecting osteomalacia in many but not all patients. However, since osteomalacia, which was previously thought to precede osteitis fibrosa,46Stanbury S.W. Bony Complications of Renal Disease. Blackwell Scientific Publications, Oxford, UK1967Google Scholar was not consistently observed in all patients, this hypothesis could not be confirmed, although it also could not be definitively excluded. Finally, the authors were unable to recognize a correlation between the nature of renal disease and the severity of histologic lesions. They concluded that despite the absence of frankly increased numbers of osteoclasts, the accumulation of empty resorption cavities as well as the appearance of woven osteoid even in early CKD stages was compatible with an early stimulatory effect of PTH in the skeleton. In 1996, Coen et al.47Coen G. Mazzaferro S. Ballanti P. et al.Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure: a cross-sectional study.Nephrol Dial Transplant. 1996; 11: 813-819Crossref PubMed Google Scholar reported findings of a cross-sectional, retrospective bone histomorphometry study in 76 unselected Italian CKD patients on conservative treatment, ages 18 to 72 years, 44 males and 32 females, with serum creatinine levels ranging from 1.2 to 11.4 mg/dl and a mean ± SD creatinine clearance of 20 ± 12 ml/min per 1.73 m2. The causes of CKD were chronic glomerulonephritis in 43 patients, tubulointerstitial nephritis in 16, polycystic kidney disease in 7, and other or unknown in 9 among them. Eleven patients had non–insulin-dependent diabetes mellitus. None had received corticosteroids in the preceding 12 months. None were receiving anticoagulant and anticonvulsive medication or nonsteroidal anti-inflammatory drugs at the time of bone biopsy. None of them were prescribed native vitamin D, calcitriol, or aluminum-containing phosphate binders. The main findings were normal bone in 10 patients, low-turnover, adynamic bone disease in 9 (all negative for histochemical aluminum staining), mild mixed osteodystrophy in 26, predominant osteomalacia in 7, advanced mixed osteodystrophy in 22, and predominant hyperparathyroidism in 2. Notably, patients with adynamic bone disease had a less severe degree of CKD than the other subgroups, with intact PTH values above the upper normal limit, and normal serum calcium. Osteomalacia was found in patients with more advanced CKD stages, together with a tendency toward hypocalcemia and more severe metabolic acidosis. A GFR of 20 ml/min was indicative of a demarcation line between the patients with osteomalacia and those with adynamic bone disease. Based on these findings the authors postulated that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD. The 2 reports above appear to be contradictory, at least in part, especially with respect to the prevalence of osteomalacia and adynamic bone disease in CKD patients not yet on dialysis. Reports by other research groups of that time do not allow further clarification of this issue. Thus Dahl et al.48Dahl E. Nordal K.P. Attramadal A. et al.Renal osteodystrophy in predialysis patients without stainable bone aluminum. A cross-sectional bone-histomorphometric study.Acta Med Scand. 1988; 224: 157-164Crossref PubMed Google Scholar reported that osteomalacia was extremely rare in the predialysis stage, while Mora Palma et al.44Mora Palma F.J. Ellis H.A. Cook D.B. et al.Osteomalacia in patients with chronic renal failure before dialysis or transplantation.Q J Med. 1983; 52: 332-348PubMed Google Scholar found a high percentage of cases with osteomalacia, mainly in association with chronic tubulointerstitial nephritis and prevailing metabolic acidosis. The types of underlying nephropathy responsible for a more or less rapid progression of CKD and accompanying metabolic and endocrine abnormalities probably explain these differences in prevalence. Whether oral intake of aluminum-containing phosphate binders has contributed to the osteomalacia in at least some of these patients is unclear. Finally, different diagnostic criteria used to define osteomalacia may also account for the observed difference.47Coen G. Mazzaferro S. Ballanti P. et al.Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure: a cross-sectional study.Nephrol Dial Transplant. 1996; 11: 813-819Crossref PubMed Google
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