J Nephrol DOI 10.1007/s40620-017-0397-7
REVIEW
Adynamic bone disease is a predominant bone pattern in early stages of chronic kidney disease Ziad Massy1,2 · Tilman Drueke2
Received: 3 February 2017 / Accepted: 29 March 2017 © Italian Society of Nephrology 2017
Abstract Chronic kidney disease (CKD) is complicated by disturbances of mineral and bone metabolism which start early in the course of the disease. It has long been assumed that high turnover bone lesions induced by secondary hyperparathyroidism are the predominant type of renal osteodystrophy from the start. However, there is increasing evidence in favor of the view that in early CKD stages low bone turnover is prevailing, with adynamic bone disease being the predominant form. Since serum parathyroid hormone levels increase progressively early on, and the most probable explanation is resistance to the skeletal action of this hormone. An early inhibition of the Wnt pathway with an increase in sclerostin and other inhibitors of Wnt signaling may be involved. Finally, a variety of other uremic toxins such as indoxyl sulfate and phosphate may play an important role in the pathogenesis of the low turnover bone disease observed in early stages of CKD. The optimal strategies to prevent and to treat adynamic bone disease in incipient CKD yet need to be defined. Targeting uremic toxins such as sclerostin, phosphate, and indoxyl sulfate may be relevant.
* Ziad Massy [email protected] 1
Division of Nephrology, Ambroise Paré Hospital, APHP, Versailles Saint-Quentin-en-Yvelines University (Paris-Ilede-France-Ouest University, UVSQ), 9 avenue Charles de Gaulle, 92104 Boulogne Billancourt and Villejuif Cedex, France
2
Inserm U‑1018, Team 5, Paris-Sud University (UPS) and Versailles Saint-Quentin-en-Yvelines University (ParisIle-de-France-Ouest University, UVSQ), Villejuif, France
Keywords Renal osteodystrophy · Adynamic bone disease · Early CKD · PTH · FGF23 · Uremic toxins · Indoxyl sulfate Patients with chronic kidney disease (CKD) suffer from different types of bone disease, including osteitis fibrosa, osteomalacia, mixed lesions, adynamic bone disease (ADB), and osteoporosis. Collectively, they are summarized under the term renal osteodystrophy, which is part of the mineral and bone disorder associated with CKD (CKDMBD). Bone histomorphometry assessment remains the gold standard for the distinction of the different forms of renal osteodystrophy. However, bone biopsies are not well accepted by the patients. This makes their performance impractical in clinical routine. Since parathyroid hormone (PTH) is a major regulator of bone turnover in CKD and its serum level reflects, at least to some extent, impaired bone cell activity, both the KDOQI and the KDIGO guidelines suggest to use the serum level of PTH for the clinical distinction of high from low bone turnover disease in patients with CKD [1, 2]. Another reason for the use of PTH as a biomarker is that secondary hyperparathyroidism can be controlled by established medical prevention and therapy. There is no doubt that extremely high serum PTH levels are associated with high bone turnover, and extremely low levels with low bone turnover. An annoying issue, however, is that there is a large range of PTH, comprised between approximately 2 and 9 times the upper limit of normal values, in which the relationship between PTH levels and bone histomorphometry findings in patients with end-stage renal disease (ESRD) is uncertain. This is the reason why the KDIGO guideline of 2009 [1] recommended to maintain intact PTH (iPTH) levels within this large window, ie between 550 and 150 pg/mL. Above the upper limit the
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presence of high-turnover bone disease including osteitis fibrosa and some forms of osteoporosis is highly probable, while below lower limit the presence of low-turnover bone disease including ADB, osteomalacia and other forms of osteoporosis can be suspected with a reasonable degree of certainty. Serum iPTH levels between 150 and 550 pg/mL in ESRD patients are compatible with all forms of renal osteodystrophy, including normal bone structure and mixed lesions, as shown in a remarkable bone histomorphometry study reported by Barreto et al. in 2008 [3]. These Brazilian authors made the unexpected observation that a high proportion among their 97 chronic hemodialysis patients had low-turnover bone disease, essentially ABD, despite relatively high serum iPTH levels, >300 pg/mL. Conversely, a smaller number among these hemodialysis patients highturnover bone disease in presence of relatively low iPTH levels,
REVIEW
Adynamic bone disease is a predominant bone pattern in early stages of chronic kidney disease Ziad Massy1,2 · Tilman Drueke2
Received: 3 February 2017 / Accepted: 29 March 2017 © Italian Society of Nephrology 2017
Abstract Chronic kidney disease (CKD) is complicated by disturbances of mineral and bone metabolism which start early in the course of the disease. It has long been assumed that high turnover bone lesions induced by secondary hyperparathyroidism are the predominant type of renal osteodystrophy from the start. However, there is increasing evidence in favor of the view that in early CKD stages low bone turnover is prevailing, with adynamic bone disease being the predominant form. Since serum parathyroid hormone levels increase progressively early on, and the most probable explanation is resistance to the skeletal action of this hormone. An early inhibition of the Wnt pathway with an increase in sclerostin and other inhibitors of Wnt signaling may be involved. Finally, a variety of other uremic toxins such as indoxyl sulfate and phosphate may play an important role in the pathogenesis of the low turnover bone disease observed in early stages of CKD. The optimal strategies to prevent and to treat adynamic bone disease in incipient CKD yet need to be defined. Targeting uremic toxins such as sclerostin, phosphate, and indoxyl sulfate may be relevant.
* Ziad Massy [email protected] 1
Division of Nephrology, Ambroise Paré Hospital, APHP, Versailles Saint-Quentin-en-Yvelines University (Paris-Ilede-France-Ouest University, UVSQ), 9 avenue Charles de Gaulle, 92104 Boulogne Billancourt and Villejuif Cedex, France
2
Inserm U‑1018, Team 5, Paris-Sud University (UPS) and Versailles Saint-Quentin-en-Yvelines University (ParisIle-de-France-Ouest University, UVSQ), Villejuif, France
Keywords Renal osteodystrophy · Adynamic bone disease · Early CKD · PTH · FGF23 · Uremic toxins · Indoxyl sulfate Patients with chronic kidney disease (CKD) suffer from different types of bone disease, including osteitis fibrosa, osteomalacia, mixed lesions, adynamic bone disease (ADB), and osteoporosis. Collectively, they are summarized under the term renal osteodystrophy, which is part of the mineral and bone disorder associated with CKD (CKDMBD). Bone histomorphometry assessment remains the gold standard for the distinction of the different forms of renal osteodystrophy. However, bone biopsies are not well accepted by the patients. This makes their performance impractical in clinical routine. Since parathyroid hormone (PTH) is a major regulator of bone turnover in CKD and its serum level reflects, at least to some extent, impaired bone cell activity, both the KDOQI and the KDIGO guidelines suggest to use the serum level of PTH for the clinical distinction of high from low bone turnover disease in patients with CKD [1, 2]. Another reason for the use of PTH as a biomarker is that secondary hyperparathyroidism can be controlled by established medical prevention and therapy. There is no doubt that extremely high serum PTH levels are associated with high bone turnover, and extremely low levels with low bone turnover. An annoying issue, however, is that there is a large range of PTH, comprised between approximately 2 and 9 times the upper limit of normal values, in which the relationship between PTH levels and bone histomorphometry findings in patients with end-stage renal disease (ESRD) is uncertain. This is the reason why the KDIGO guideline of 2009 [1] recommended to maintain intact PTH (iPTH) levels within this large window, ie between 550 and 150 pg/mL. Above the upper limit the
13
Vol.:(0123456789)
presence of high-turnover bone disease including osteitis fibrosa and some forms of osteoporosis is highly probable, while below lower limit the presence of low-turnover bone disease including ADB, osteomalacia and other forms of osteoporosis can be suspected with a reasonable degree of certainty. Serum iPTH levels between 150 and 550 pg/mL in ESRD patients are compatible with all forms of renal osteodystrophy, including normal bone structure and mixed lesions, as shown in a remarkable bone histomorphometry study reported by Barreto et al. in 2008 [3]. These Brazilian authors made the unexpected observation that a high proportion among their 97 chronic hemodialysis patients had low-turnover bone disease, essentially ABD, despite relatively high serum iPTH levels, >300 pg/mL. Conversely, a smaller number among these hemodialysis patients highturnover bone disease in presence of relatively low iPTH levels,
