doi: 10.1111/jop.12176

J Oral Pathol Med © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd wileyonlinelibrary.com/journal/jop

REVIEW ARTICLE

Chronic kidney disease–mineral bone disorder: an update on the pathology and cranial manifestations Erich J. Raubenheimer1, Claudia E. E. Noffke2, Hilde D. Hendrik3 1

Oral Pathology and Consultant for Metabolic Bone Diseases, School of Oral Health Sciences, University of Limpopo, Pretoria, South Africa; 2 Oral and Maxillofacial Radiology, School of Oral Health Sciences, University of Limpopo, Pretoria, South Africa; 3 Oral Biology, School of Oral Health Sciences, University of Limpopo, Pretoria, South Africa

Chronic kidney disease–mineral bone disorder (CKDMBD) is a syndrome encompassing skeletal and extra skeletal changes associated with chronic kidney disease. It progresses silently until an advanced clinical stage when complications impact on the quality of life and survival rates of patients. The maxillofacial manifestations are unique and may play an important role in the early identification of changes which could influence the management of these patients. The goal of this review is to highlight the maxillofacial features, pathology, and principles of management of CKD-MBD. J Oral Pathol Med (2014) Keywords: bone mineral disorder; chronic kidney disease

Introduction Chronic kidney disease (CKD) is a growing international public health problem affecting 5–10% of the population of the world (1). The classical skeletal changes are the consequences of progressive metabolic derangements resulting from kidney failure. Although the skeletal pathology is well documented, the long-term survival of CKD patients resulting from current management strategies is focussing the attention on the extra skeletal changes, which have become prognostic determinants in a significant number of cases. The term Chronic kidney disease–mineral and bone disorder (CKD-MBD) was recommended in 2006 to address the broader clinical syndrome encompassing bone-, mineraland soft tissue calcific abnormalities in CKD patients (2). This manuscript focusses on the craniofacial manifestations and pathology of CKD-MBD. The figures were all retrieved from patients diagnosed by the Metabolic Bone Disease Unit at the University of Limpopo. The main goal is to provide those involved in oral diagnoses with an Correspondence: Erich J Raubenheimer, School of Oral Health Sciences, Medunsa Campus, University of Limpopo, 0204, South Africa. Tel: +27 12 5214839, Fax: +27 12 5215274, E-mail: [email protected] Accepted for publication January 31, 2014

understanding of the pathogenesis of CKD-MBD and facilitate the identification of complications which may influence the course of the disease.

Early biochemical changes Progressive CKD with loss of functioning kidney mass results in a suspension of the last step in the hydroxylation of vitamin D2 (25OHvitD) to active vitamin D3 (1,25 (OH)2vitD) by renal a-1- hydroxylase. The deficiency of vitamin D3 leads to decreased retention of calcium by the renal tubules and a reduction of calcium absorption from the gastrointestinal tract. The subsequent hypocalcemia induces secondary hyperparathyroidism with the release of parathyroid hormone (PTH) which results in a quantifiable increase of active osteoclasts in bone with release of skeletal calcium (3). The up-regulation of bone metabolism elaborates fibroblast growth factor 23 (FGF23) whose major functions are to induce the catabolism of vitamin D2 and inhibit renal tubular phosphate reabsorption (4). The net effects are a lowering of blood calcium, elevation of phosphate concentrations and progressive bone loss.

Early skeletal changes in CKD-MBD The earliest microscopic evidence of the osteoclastic response to PTH is aptly described as ‘tunneling’ resorption(5) (Fig. 1) and is below the detection limit of conventional radiology. The first radiologic change is represented by intracortical and subendosteal resorption facets (6). As skeletal catabolism progresses, the resorbed bone is replaced by fibrous connective tissue, a microscopic feature described as “osteitis fibrosa” (Fig. 2). This change is particularly detrimental to the growing skeleton. The microscopic differential diagnosis includes fibrous dysplasia which is distinguished by its relative absence of osteoclasts. Due to the up-regulation of bone metabolism, scintigraphy shows an increased tracer uptake and this metabolic state is referred to as ‘high turnover uremic osteodystrophy’(7) (Fig. 3). The earliest radiological sign of jaw bone involvement is resorption of the cortices and lamina dura

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Figure 3 High turnover osteodystrophy. Bone scintigraphy showing increased uptake in the jaws and skull (740MBq 99m Tc MDP injected intravenously, three phase bone scan and SPECT imaging, duration 119 sec).

Figure 1 Tunneling resorption in hyperparathyroidism. Note the osteoclasts (black arrows) on the endosteal surface of the cortical bone (H&E stain, 9400).

Figure 4 Ground glass to granular radiological pattern. Note the poor definition of cortices, inferior alveolar canal and lamina dura. Figure 2 Early stage of osteitis fibrosa. Advanced resorption of bony trabecula (osteoclasts are indicated with arrows) and fibrous replacement of the resorbed bone (star) (H&E stain, magnification 9200).

and ultimately effacement of the bony trabecula with a ground-glass appearance (Fig. 4). With appropriate management of the CKD patient, mineral homeostasis and PTH concentrations should normalize and skeletal catabolism should be suspended. Coarsening of trabecula, manifesting radiologically with a salt and pepper appearance, may occur in cases where the balance is in favor of bone anabolism (Fig. 5).

Advanced skeletal changes in CKD-MBD In CKD patients with persistent hypocalcemia and secondary hyperparathyroidism due to inappropriate management, J Oral Pathol Med

resilience to therapy or those with tertiary hyperparathyroidism, skeletal catabolism advances. In tertiary hyperparathyroidism, the parathyroid glands remain active and may fail to respond to a correction of the serum calcium concentrations. This autonomous state of parathyroid function is particularly prevalent in patients on long-term dialysis and is an indication for parathyroidectomy (8). Tertiary hyperparathyroidism is characterized by high concentrations of PTH, hypercalcemia and accelerated skeletal catabolism refractive to conservative management. The risk of pathological fractures and metastatic calcification of soft tissues now becomes a prognostic consideration (see extra skeletal complications). Well-defined skeletal radiolucencies develop after prolonged hyperparathyroidism and are described as ‘osteiitis fibrosa cystica’ or ‘brown tumors of hyperparathyroidism.’ The brown coloration is

Chronic kidney disease–mineral bone disorder Raubenheimer et al.

Figure 5 Salt and pepper appearance of osteitis fibrosa. Note the absence of the lamina dura and the appearance of cotton-wool like radiopacities in the calvarium. The white arrows indicate a calcified carotid artery.

due to the presence of hemosiderin pigment and is not a distinctive feature as it is shared with other giant cell lesions of bone (9).

Atypical skeletal manifestations of CKD-MBD Although the pathogenesis outlined above explains the course of skeletal changes in the majority of CKD patients, other skeletal manifestations have also been described. ‘Adynamic bone disease’ is a term used to refer to a complete absence of cellular activity on bone surfaces in a CKD patient with low to normal PTH concentrations (Fig. 6). This manifestation is often seen in CKD patients that are on dialysis or those treated rigorously with calcium and vitamin D derivatives (8). A radiological appearance of

osteoporosis may be seen in some patients with elevated PTH concentrations. Although the pathogenesis in this setting remains unclear, it has been suggested that the uremic state results in a down regulation of PTH receptors on bone cells (10). In practice, some patients may show a mixture of the classical manifestations and the term ‘mixed bone disease’ is used to describe this hybrid manifestation of skeletal changes in CKD (7). In a small cohort of CKD patients, enlargement of the facial bones occur. This manifestation has been described in the literature as ‘leontiasis ossea’, a term originally coined by Virchow in 1864 for the clinical appearance of patients with chronic periostitis secondary to facial leprosy (11). It is therefore not unexpected that the term was applied to other common causes for facial bone enlargement like fibrous dysplasia and Paget’s disease of bone. From a radiological perspective, the differential diagnosis of cranial uremic leontiasis ossea should include fibrous dysplasia in children, while Paget’s disease of bone should be considered in adults. Apart from the microscopical difference mentioned previously, osteitis fibrosa is distinguished from fibrous dysplasia, both of which may show a ground-glass radiological appearance, by its poor cortico-medullary definition (12). Pagets disease affects adults and shows three distinctive phases: lytic, intermediate and sclerotic. The lack of replacement of the bone marrow implies that the fat signal of marrow will be preserved on T1-weighted MRI sequences of Pagets disease (13), in contrast to osteitis fibrosa and fibrous dysplasia where the fat signal will disappear due to the fibrous replacement of the fat cells in the marrow. Although radionuclide bone scintigraphy is currently superseded as the technique of choice by FDGPET for the identification of skeletal foci of increased metabolic activity (14–16), it is still widely used in the identification of occult skeletal metastases. The role of all techniques that identify foci of metabolic activity in the differentiation between fibrous dysplasia (17), Pagets disease of bone (14), disseminated malignancies and osteitis fibrosa is, however, limited as all three conditions manifest with increased tracer uptake and these investigations should not be interpreted in isolation.

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Extra skeletal complications

Figure 6 Adynamic bone disease. Note the absence of metabolic activity on the trabecular bone surfaces (H&E stain, magnification 9100).

Prolonged hypercalcemia as a result of tertiary hyperparathyroidism causes soft tissue and vascular calcifications. Calcified carotid arterial plaques are often seen on extra oral dental radiographs in patients with hyperparathyroidism (Fig. 5) and have been reported as a validated risk indicator for future cardiovascular events (18). Cardiovascular impairment due to coronary and valvular calcifications is associated with more than half the deaths in patients on long-term renal dialysis (19, 20). CKD results in impairment of the glomerular filtration rate with subsequent accumulation of the catabolytes of metabolism, several of which impact negatively on cell functions and bone metabolism. One such catabolyte is b-2 microglobulin, which is deposited as amyloid in bone and periarticular soft tissue (21, 22) (Fig. 7). b-2 microglobulin has been shown to stimulate osteoclasts (23) and has been associated with a significantly higher femoral fracture risk (24) and J Oral Pathol Med

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and other life-threatening complications develop. An understanding of the early bone and soft tissue changes is of paramount importance in monitoring the progress of the disease and the institution of an appropriate management regime.

References

Figure 7 b-2 microglobulin amyloidosis (between arrows) in periarticular muscle in CKD-MBD (H&E stain, magnification 9200).

destructive arthropathy. The destructive arthropathies and radiolucencies in bone due to b-2 microglobulin amyloidosis are difficult to distinguish radiologically from foci of osteitis fibrosa (22) and histological confirmation thereof is indicated.

Management of CKD-MBD The comprehensive management of CKD-MBD is not within the scope of this review and readers are referred to a recently reported clinical practice guideline for detailed information in this regard (25). In principle, management is aimed at the restoration of kidney functions through dialysis or renal transplantation and the re-establishment of normal blood calcium concentrations with among others vitamin D supplementation. Secondary hyperparathyroidism can be addressed through the control of calcium intake, diasylate calcium content and the use of calcimimetic drugs which mimic the action of calcium, thereby reducing parathyroid activity (26). If managed successfully, blood calcium concentrations return to normal, secondary hyperparathyroidism is corrected and PTH over-production suspended. Osteoclasts become de-activated, bone catabolism ceases and the risk for cardiovascular calcifications is averted. Tertiary hyperparathyroidism may, however, be non-responsive to these measures and require parathyroidectomy to correct. During the preparation for parathyroidectomy, ultrasound is reliable as the first imaging modality due to the fact that the normal parathyroid glands are not visible with this technique (27). 99mTc scans, particularly 99mTc – sestamibi, which offers lower radiation exposure and higher detection efficiency (27), are indicated for the accurate detection of the hyperactive parathyroids and are particularly valuable in the identification of parathyroids located at an ectopic site.

Conclusions Bone catabolism in chronic kidney disease is clinically silent until an advanced stage when skeletal incapacitation J Oral Pathol Med

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J Oral Pathol Med

Chronic kidney disease-mineral bone disorder: an update on the pathology and cranial manifestations.

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a syndrome encompassing skeletal and extra skeletal changes associated with chronic kidney d...
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