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Bone Disease in Elderly Individuals With CKD
Bone Disease in Elderly Individuals With CKD Sheru Kansal and Linda Fried Bone disease can lead to significant morbidity and mortality for those who are afflicted by it, irrespective of etiology. Two very prevalent causes of bone disease that contribute to this are osteoporosis and chronic kidney disease (CKD). The modern era has seen important advances in the understanding and management of these processes, but in elderly patients with CKD it remains a complex issue that has yet to be clearly defined. Changes in mineral metabolism that accompany the loss of renal function result in a spectrum of bone disease that occurs concomitantly with bone loss secondary to aging. As such, the traditional paradigms used to manage bone disease may not be appropriate for these patients. With the aging dialysis population, a better understanding of these 2 processes and their interplay deserves more attention. Q 2010 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Renal osteodystrophy, Osteoperosis, Chronic kidney disease, Bone mineral density
B
one disease can lead to significant morbidity and mortality for those who are afflicted by it, irrespective of etiology. Two very prevalent causes of bone disease that contribute to this are osteoporosis and chronic kidney disease (CKD). The modern era has seen important advances in the understanding and management of these processes, but in elderly patients with CKD it remains a complex issue that has yet to be clearly defined. Changes in mineral metabolism that accompany the loss of renal function result in a spectrum of bone disease that occurs concomitantly with bone loss secondary to aging. As such, the traditional paradigms used to manage bone disease may not be appropriate for these patients. With the aging population and the marked prevalence of CKD in the elderly, a better understanding of these 2 processes and their interplay deserves more attention. Bone disorders associated with CKD were traditionally referred to as renal osteodystrophy. This umbrella term encompassed a wide variety of bone disorders including ostesitis fibrosa, osteomalacia, adynamic bone disease (ABD), and mixed uremic dystrophy. With improvement in our understanding of the under-
From Renal Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA; and Renal Section, VA Pittsburgh Healthcare System, Pittsburgh, PA. Address correspondence to Sheru Kansal, MD, Renal Electrolyte Division, University of Pittsburgh, 2550 Scaife Hall, Pittsburgh, PA 15261. E-mail: [email protected] Ó 2010 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 doi:10.1053/j.ackd.2010.05.001
lying disease process, a new classification system, referred to as CKD-mineral and bone disorder (CKD-MBD), has emerged. CKDMBD takes into consideration the systemic consequences of altered mineral metabolism as well as bony abnormalities. Additionally, the traditional nomenclature has been replaced with a quantitative assessment of the histomorphometry of CKD-related bone disease based on the parameters of turnover, mineralization, and volume.1 Osteoporosis is uniformly a disease of low bone mineral density (BMD) and microarchitectural disruption and fragility.2 It is extremely common, with an estimated prevalence of around 10 million people in the United States, according to the National Women’s Health Information Center. Moreover, its prevalence is expected to grow exponentionally over the next decade. The World Health Organization (WHO) has defined diagnostic thresholds for low bone mass and osteoporosis on the basis of BMD measurements compared with a young adult reference population (T-score) based on dual energy X-ray absorptiometry (DEXA). A BMD between 1 and 2.5 standard deviations (T-score) below the mean for young adults is classified as osteopenia; a T-score greater than 2.5 is classified as osteoporosis. Consensus guidelines on management in women are based on large epidemiologic studies which have been extrapolated for use in men. Patients with significant CKD were systematically excluded from these studies and at present their management is unclear. As other articles in this issue have described, CKD is more common in the elderly population. Because osteoporosis prevalence also
Advances in Chronic Kidney Disease, Vol 17, No 4 (July), 2010: pp e41-e51
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increases with age, older individuals with CKD may have both osteoporosis and CKD-MBD. In the following review, we present the current understanding of age-related bone disease and bone abnormalities associated with CKD. We also attempt to reconcile the clinical dilemma of managing bone disease in elderly patients with CKD, based on the existing literature.
Bone Remodeling Bone is a complex and dynamic organ. It is constantly being remodeled with bone resorption and bone formation. Remodeling is stimulated in a variety of situations, including normal growth, as a response to stress so as to increase bone strength where appropriate, in fractures, and in metabolic processes that seek to either mobilize or store calcium. Bone remodeling is regulated by both local (e.g., cytokines, osteoprotegerin, receptor activator for nuclear factor kb) and systemic factors (e.g., parathyroid hormone, vitamin D, estrogen).3 Typically, bone resorption is tightly coupled with bone formation so that the net effect on mass is negligible. When these processes become uncoupled, bone disease tends to develop. There are 2 types of bone in the human skeleton. Cortical bone comprises 80% of the skeleton and constitutes the outer part of all skeletal structures; it is dense and compact and slower to turn over. Trabecular bone is less dense and more metabolically active. It is found at the end of long bones (i.e., appendicular skeleton), in bodies of vertebrae, and inner portions of large flat bones.3
Epidemiology of Osteoporosis Bone loss in the elderly people is typically related to advancing age and estrogen deficiency. In this context, it is not surprising that postmenopausal women have the highest prevalence of osteoporosis. Bone mass peaks in late adolescence and is generally maintained though adulthood, with bone resorption matching bone formation. Bone loss tends to begin in midlife for both men and women, although the rates of loss are markedly different. A recent longitudinal study following BMD in both men and women found
an accelerated period of bone loss in women during the perimenopausal period.4 A second period of accelerated loss occurred after the age of 70, which correlated with accelerated bone loss in men.4 The accelerated perimenopausal bone loss involves mainly trabecular bone, whereas the slower bone loss in men and women involves both cortical and trabecular bone.5 Estrogen is implicated in the perimenopausal decline in BMD. It inhibits bone resorption and its deficiency results in rapid bone loss. The mechanism by which it exerts its effect on bone is not entirely clear. It does not inhibit osteoclastic bone resorption in vitro systems, but is thought to affect osteoclastogenesis and osteoclast function through its effects on local factors, including IL-1 and tumor necrosis factor and IL-2 to interleukin-2.6 Men suffer from age-related bone loss as women do, but they only account for 20% of prevalent cases of osteoporosis.7 Men tend to attain a higher peak bone mass and are spared from the accelerated loss that occurs in women during the perimenopausal period. This is evident clinically as the incidence of fractures seems to increase about 10 years later in men (after age 70) and the overall incidence is lower when compared with women. However, men tend to have a higher mortality when they do suffer a fracture.8,9 Similar to women, estrogen seems to be related to agerelated bone loss in men. Elimination of endogenous testosterone and estrogen through gonadotropin-releasing hormone agonist and aromatase inhibitor with physiologic replacement and subsequent withdrawal of one or both resulted in increased bone resorption, with the withdrawal of estrogen having the greatest effect.10 Also, higher serum estrogen concentrations are associated with higher bone density in men, independent of their serum androgen concentrations.11 Numerous other risk factors for the development of osteoporosis have been identified in addition to those of age and gender (Table 1). Men in particular tend to have an identifiable secondary cause of osteoporosis. Epidemiologic surveys suggest that a secondary cause can be found in a maximum of 60% of men, whereas in postmenopausal women, secondary causes can be identified in a maximum of 30%.12,13 Many of these risk factors
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Bone Disease and CKD in the Elderly
Table 1. Risk Factors Associated With the Development of Osteoporosis Endocrine diseases Hypogonadism Hypercortisolism Hyperthyroidism Hyperparathyroidism Vitamin D deficiency Growth hormone deficiency Diabetes mellitus Gasterointestinal diseases Malabsorption syndromes Inflammatory bowel disease Gastrectomy Cirrhosis Alactasia Chronic biliary obstruction Hematologic disorders Multiple myeloma Lymphoma Leukemia Chronic hemolytic anemia Disseminated carcinoma Systemic mastocylosis
Connective tissue diseases Marfan’s syndrome Osteogenesis imperfecta Ehlers-Danlos syndrome Homocystinuria Rheumatoid arthritis
Medications Heparin Glucocorticoids Cyclosporine Anticonvulsants (i.e., phenytoin) Thyroxine GnRH analogs Chemotherapy Miscellaneous Alcoholism Immobilizations Anorexia nervosa Hypercalciuria
are common in individuals with CKD, but it remains controversial whether CKD itself predisposes to the development of osteoporosis.
it increases resorption and releases calcium. There are also other mechanisms at play in this process that are complex with significant cross-talk. For example, hyperphosphatemia has been shown to directly promote PTH excretion by increasing gene expression. It may also directly inhibit calcitriol formation in the kidney.15 PTH excretion may also be enhanced through skeletal resistance to the calcemic effect of PTH that occurs because of downregulation of PTH receptors. Calcitriol deficiency and hyperphosphatemia may also contribute to this skeletal resistance.16 The Study to Evaluate Early Kidney Disease data suggest that biochemical evidence of these changes typically tends to occur when GFR drops below 30 mL/min, although abnormalities in PTH can be seen earlier (Fig 1). Similar findings have been reported in the Kidney Education and Evaluation Program and National Health and Nutrition Examination Survey (NHANES) as well.17-19 The milieu of altered phosphorous and calcium homeostasis that accompanies the decline in GFR has systemic effects, but it is the increased secretion of PTH that has the most significant effect on bone. Chronically elevated PTH levels cause bone resorption through osteoclasts. Because only osteoblasts express PTH receptors, osteoclast activation likely occurs through cellular interactions and various cytokines.20 If left unchecked, elevated levels of PTH lead to osteitis fibrosa, characterized Biochemical evidence of CKD-MBD and eGFR 60 50
Renal Function and its Effect on Bone As glomerular filtration rate (GFR) declines, the filtered load of phosphate decreases and phosphate retention ensues. The normal response is to increase phosphate excretion. This is initially accomplished with increasing levels of fibroblast growth factor-23 which promotes renal phosphate excretion and decreases renal synthesis of 1-a-hydroxylase, resulting in calcitriol deficiency.14 Hypocalcemia then ensues which, in turn, stimulates parathyroid hormone (PTH) excretion. PTH acts on the distal tubule to further promote phosphate excretion as well as on bone where
eGFR > 60 mL/min 60 < eGFR <= 30 eGFR < 30 mL/min
40 30 20 10 0 Hypocalcemia
Hyperphosphatemia
Hyperparathyroid
Percent
Figure 1. Biochemical evidence of CKD-MBD by eGFR. Hypocalcemia, Ca ,8.4 mg/dL; Hyperphosphatemia, PO4 .4.6 mg/dL; Hyperparathyroidism, iPTH .65 pg/mL. Data derived from Levin colleagues.17
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by marrow fibrosis and high bone turnover because of increased activity of both osteoblasts and osteoclasts. The prevalence of these changes increases as renal function declines. Based on bone histomorphometry, 41.2% of patients with CKD stage 3 or 4 and 61.4% with CKD stage 5 had osteitis fibrosa.21 The effect of osteitis fibrosa on BMD is unclear but may be dependent on the site. A study on patients with primary hyperparathyroidism found reductions in BMD in sites of predominantly cortical bone, such as the radius and femur, whereas sites of predominantly trabecular bone, such as the lumbar spine, were normal.22 A similar pattern in BMD has been observed in patients with severe CKD as measured by quantitative computerized tomography (QCT), although a study that looked at markers of bone metabolism and BMD could find no correlations between PTH levels and BMD at the lumbar spine or femoral neck.23,24 A recent study analyzed the association of PTH and BMD in hemodialysis patients and found that in patients with PTH levels .100 pg/mL, PTH was negatively correlated with BMD at all sites, including the lumbar spine.25
Epidemiology of Bone Disease in CKD Osteitis fibrosa has traditionally been the most common form of bone disease associated with kidney disease, but over the past few decades the prevalence of ABD has increased, with a rate of 20% to 50% reported in hemodialysis patients.26 Those on peritoneal dialysis have even higher rates of ABD (Fig 2). It is characterized by a low turnover state, with bone biopsy findings of inactive osteoblasts and mineralization with decreased osteoclasts and resorptive surfaces. The principle factor in its pathogenesis appears to be related to oversuppression of PTH, which is likely the result of multiple factors. An iatrogenic component stems from higher calcium loads from calcium-based phosphate binders. For those on peritoneal dialysis, almost constant exposure to a high calcium dialysate predisposes to ABD. The use of activated vitamin D has contributed to the increasing prevalence of ABD as well. Diabetes and advancing age are recognized risk factors for ABD and the pathogenesis in this
Prevalence of types of bone disease 60 Hemodialysis Peritoneal dialysis
50
40
30
20
10
0 Normal
Mild
OF
Mixed
ABD
OM
Figure 2. Prevalence of types of bone disease in patients with ESRD. Data derived from Moe and colleagues.27
population may not be simply related to oversuppression of PTH.28 The reason for their propensity to develop ABD is not entirely clear. One study showed that under poor glycemic control, diabetics without renal disease tended to have lower calcium and PTH levels.29 The accumulation of advanced glycosylation end products may induce osteoblast apoptosis resulting in a low turnover state as well.30 Many of these patients are vitamin D deficient, particularly the elderly population, resulting in decreased osteoblastic activity. Reduced circulating sex hormones and oxidative stress may also play a role in the development in ABD in the elderly people.31 The effect of a low turnover state on BMD may be dependant on the site examined, as is the case with states of high turnover. In a pediatric population, those with low turnover lesions had higher cortical bone density and lower trabecular density as compared with those with high turnover lesions when BMD was measured by QCT and bone turnover was assessed by PTH levels.32 However, a recent study found that in hemodialysis patients with PTH levels ,100 pg/mL, BMD was variable at all sites measured, including the radius, femur, and lumbar spine.25 In patients with mild to moderate renal dysfunction who may not have significant perturbations in phosphate and calcium metabolism, BMD tends to be lower than the general population. Data from NHANES III were analyzed for the occurrence of renal dysfunction in patients with osteoporosis. With
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the Cockcroft–Gault equation, 61% of adult women with osteoporosis had CKD stage 3.33 It is unclear whether this overlap was because of a direct effect of decreased renal function or because both CKD and bone loss increase with aging. A separate analysis of the NHANES data found that the association between CKD and lower BMD disappeared when adjusted for age, sex, and weight, suggesting no direct effect of kidney dysfunction on BMD.34 However, data from the Cardiovascular Health Study did find that although kidney function was not associated with lower BMD at baseline, kidney dysfunction, as assessed by cystatin-C, was associated with a more rapid loss of BMD at the hip over time and this association persisted in men when adjusted for age, race, lean mass, and fat mass.35
Fracture Risk The main clinical consequence of bone disease is fracture, the rates of which are increased as compared with the general population, in both osteoporosis and CKD. Fractures are responsible for a significant medical and economical burden as they are associated with an increased mortality in both populations.36,37 Half of all women over the age of 50 and 1 in 5 of their male counterparts will suffer an osteoporotic fracture in their lifetime.38 Although age, BMD, and prior fracture tend to
be the strongest predictors of future fractures, other risk factors include alcohol and cigarette use, low body weight, glucocorticoid therapy, and a family history of fractures.39 Vertebral fractures are the most common. They tend to be asymptomatic and found incidentally on plain films of the chest or abdomen. Hip fractures are less common but tend to portend a poorer prognosis as they are associated with higher mortality rates.40 Epidemiological surveys have clearly shown on increased fracture risk among patients with CKD. Men and women on hemodialysis have a 4-fold increased risk of hip fracture as compared with the general population.41 Risk factors included traditional osteoporotic fracture risks as well as time on dialysis.41 Attempts to evaluate the relationship of fracture with PTH or type of renal osteodystrophy have yielded inconsistent results (Table 2). Patients with pre-dialysis CKD are at risk as well. One study in particular did find that women with mild to moderate kidney dysfunction had an increased risk of hip fracture. In those with an eGFR 45 to 59 mL/min the hazards ratio was 3.93, whereas those with an eGFR ,45 had a hazards ratio of 7.17.51 An assessment tool to estimate fracture risk with or without information on BMD has been developed by the WHO.52 The main risk factors affecting the score are age and BMD. Other risk factors in the model include
Table 2. Studies of the Relationship of Type of Renal Osteodystrophy and PTH With Fracture Study (Reference) 42
Piraino et al
(n ¼ 31)
Population Dialysis
Arau´jo et al43 (n ¼ 2340)
Dialysis
Gerakis et al44 (n ¼ 62) Atsumi et al45 (n ¼ 137)
Hemodialysis Hemodialysis, Male
Coco et al46 (n ¼ 1272)
Dialysis
Block et al47 (n ¼ 40,538)
Hemodialysis
Danese et al48 (n ¼ 9007)
Dialysis
Jadoul et al49 (n ¼ 12,782) Mitterbauer et al50 (n ¼ 1774)
Hemodialysis Hemodialysis
Finding* BMD was not predictive of fracture but type of bone disease was (ABD . OF) Low PTH level (,150 pg/mL) predicted ABD Higher rate of fractures with OM but no difference in ABD, OF, MBD Higher fracture rate in ABD Highest vertebral fracture risk in lowest PTH tertile and lowest in middle tertile Highest fracture risk with PTH ,65 and lowest with PTH between 195-500 PTH and phosphorus directly associated with risk of hospitalization for fracture Fracture risk at PTH showed U shaped association, there was no association of calcium or phosphorus with fracture Fracture RR 1.7 if PTH.900 vs PTH 150-300 No relation between fracture risk and PTH
*ABD ¼ adynamic bone disease, OF ¼ osteitis fibrosa, BMD ¼ bone mineral density.
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corticosteroid use, rheumatoid arthritis, and smoking. They appear to be mediated mainly through their effect on BMD, so if BMD is known the addition of these factors to the algorithm has little effect on the score.52 The score was derived from international prospective studies of over 40,000 patients for 4 years and validated in over 2,30,000 who were followed up for 5 years. Fracture risk was 4.2 times higher for every standard deviation increase in the risk score.53 However, the tool does not account for alterations in kidney function and may not be applicable to patients with CKD. Moreover, the cohorts that the tool is based on selected patients randomly and made no mention of baseline renal function. The level of evidence for a relationship between BMD and fracture risk in patients with significant CKD is not as strong as compared with the general population. There is a lack of longitudinal studies, but several cross-sectional studies have looked at the relationship between BMD and fracture risk in this population. They did not find an association of low BMD with fracture in individuals with CKD.54 A recent meta-analysis found no increased risk of hip fracture with lower BMD at the hip, whereas the BMD at the spine and radius was lower in those who had a fracture at these sites.55 The reasons for the poor relationship of BMD and fractures in severe CKD is not clear, but may be related to the varying effects on PTH on bone that were previously outlined. Fracture risk is related to bone strength. Although BMD accounts for 60% to 70% of the variation in bone strength, it is a surrogate measure. Other factures, such as bone architecture, are not accounted for.56 In light of this, the most recent KDIGO (Kidney Disease: Improving Global Outcomes) guidelines do not recommend BMD testing in patients with CKD stages 3–5D.27
Evaluation and Management of Osteoporosis in the Elderly Population With CKD Current recommendations for the screening of osteoporosis in the general population vary but most agree that all women aged .65 years undergo screening DEXA. Guidelines vary for women aged ,65 years, but most groups
recommend a screening DEXA in premenopausal women with risk factors. The National Osteoporosis Foundation and International Society for Clinical Densitometry are the only groups that comment specifically on screening in men and both recommend that all men aged .70 years be screened regardless of risk factors.57-60 As noted, KDIGO guidelines do not recommend routine BMD testing in patients with CKD stages 3–5D who have evidence of CKD-MBD because BMD does not predict fractures well nor has any treatments been shown to reduce fractures in this population. Whether this should apply to all patients with CKD stage 3 (e.g., stage 3A), who make up the largest proportion of older individuals with CKD, is unclear. Quantitative computed tomography provides information on BMD and distinguishes between cortical and trabecular bone and may be of more use in patients with CKDMBD. A cross-sectional study of hemodialysis patients did find that cortical BMD measurements by QCT were better at discriminating fracture risk as compared with trabecular BMD by QCT and DEXA measurements.61 However, routine use of QCT is not recommended at this time and the assessment of bone health in patients with CKD-MBD is limited to biochemical analysis of 25-hydroxyvitamin D, phosphorous, calcium, and PTH. Therapy of osteoporosis in the general population consists of nonpharmacologic and pharmacologic modalities. Nonpharmacologic therapy consists of exercise, lifestyle modifications including cessation of smoking and reduction in alcohol intake, and adequate dietary calcium and vitamin D intake. Exercise can also improve muscle strength and balance, leading to a decreased risk of falls and fractures.62,63 Although no studies have specifically looked at the role of exercise on bone disorders in CKD, one study found that walking improved BMD because of suppression of bone turnover suggesting that walking may help patients with highturnover bone disease.64 In those with lowturnover bone disease, low impact exercise may increase bone volume through minimodeling which is a concept that dynamic external stress may stimulate bone formation in otherwise adynamic bone.65 Similarly, the effects of
Bone Disease and CKD in the Elderly
smoking and alcohol intake have not been specifically studied in regard to bone disease in CKD. However, given the other benefits associated with smoking cessation and limiting alcohol intake, it seems reasonable to recommend them in elderly patients with CKD and bone disease. Supplementation with calcium and vitamin D is a standard therapy, both in the prevention and management of osteoporosis. The elderly people are at significant risk of vitamin D deficiency. They tend to have inadequate dietary intake as well as a decreased ability for cutaneous synthesis.66 Several studies have shown a benefit on BMD with supplementation, whereas the effect on fractures has been mixed. The largest of these studies showed a small but significant improvement in BMD with supplementation and no significant reduction in fractures. A subgroup analysis showed a significant reduction in fractures in compliant patients.67 Patients with CKD tend to have a high prevalence of vitamin D deficiency as well. The role of supplementation is unclear because there is no evidence that this improves outcomes, although in patients with moderate renal dysfunction and vitamin D deficiency, supplementation may improve PTH levels.68 Dialysis patients have a diminished ability to convert 25-hydroxyvitamin D to its active metabolite, suggesting that supplementation would be of no benefit on bone. However, dialysis patients with vitamin D deficiency tend to have more severe secondary hyperparathyroidism.69 There is also limited evidence that suggests low vitamin D levels are associated with increased early mortality in dialysis patients.70 In kidney transplant patients, a small randomized study found that the use of calcitriol with calcium decreased post-transplant bone loss.71 However, another study did not find a beneficial effect on bone loss.72 The main concern with supplementation of either calcium or vitamin D is in the development of hypercalcemia, which is associated with ABD and extraosseous calcifications in patient with moderate to severe renal dysfunction. However, this was not borne out in a study of hemodialysis patients who were supplemented with ergocalciferol.73 As noted, patients with CKD stages 1-3 typically do not have biochemical evidence of CKD-MBD and supplementation
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is reasonable in this population. For patients with advanced renal dysfunction, supplementation may be beneficial if a nutritional deficiency exits. Pharmacologic therapy is an important adjunct in the treatment of age-related bone loss. In the general population, options include bisphosphonates, raloxifene, and teriparatide. Bisphosphonates reduce bone resorption through their inhibitory action on osteoclasts. They have been extensively studied and shown to improve BMD and reduce fracture rates, making many regard them as first line agents in the treatment of osteoporosis. However, these studies have specifically excluded patients with elevated creatinine or PTH. The prescribing information generally recommends that these medications not be used in individuals with a creatinine clearance ,30 mL/min. Two post hoc analyses have been published to address this issue and their results are summarized in Table 3. Both showed improvements in lumber BMD as well as reductions in vertebral fractures in patients with renal impairment.74,75 This has lead KDIGO to recommend that the use of bisphosphonates in those with CKD stages 1-3 and osteoporosis, who do not have biochemical evidence of CKD-MBD, be the same as the general population. Patients with CKD stage 4 are not included in this recommendation because of the paucity of evidence in this group. For patients with CKD stages 4-5D with low BMD, additional studies such as bone biopsy are recommended before treatment with bisphosphonates owing to the observation that some patients with this degree of renal dysfunction developed ABD after being treated with alendronate.78 Raloxifene is another option in the treatment of osteoporosis. It is an anti-resorptive agent that has been shown to be effective in the management of osteoporosis. As with the trials on bisphosphonates, studies on raloxifene excluded patients with severe renal dysfunction and those with biochemical evidence of CKD-MBD, making their role in this population unclear. A post hoc analysis was done on the Multiple Outcomes of Raloxifene Evaluation trial to assess efficacy in patient with reduced eGFR (Table 3), which found improved vertebral and hip BMD with reduced
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Table 3. Efficacy of Anti-osteoporotic Medications Changes in BMD (Percent Change Difference) Renal Function Jamal et al74 (Risendronate) eGFR $ 45 (n ¼ 5877) eGFR , 45 (n ¼ 581) Miller et al75 (Alendronate) 80 . eGFR $ 50 (n ¼ 4353) 30 # eGFR , 50 (n ¼ 4071) eGFR , 30 (n ¼ 572) Ishani et al76 (Raloxifene) eGFR $ 60 (n ¼ 2343) 45 # eGFR , 59 (n ¼ 3493) eGFR , 45 (n ¼ 1480) Miller et al77 (Teriparatide) eGFR . 80 (n ¼ 885) 50 # eGFR , 79 (n ¼ 648) 30 # eGFR , 49 (n ¼ 83)
Lumbar
Fractures (OR)
Femoral
Vertebral
Other 0.81 (0.70-0.94) 0.78 (0.51-1.2)
6.6 6.7
4.5 5.0
0.50 (0.32-0.76) 0.72 (0.31-1.7)
4.1 4.8 5.6
N/A N/A N/A
0.32 (0.14-0.46)* 0.45 (0.31-0.57)* 0.56 (0.11-0.78)*
0.9† 0.9† 1.0†
0.6† 0.7† 1.0†
0.64 (0.43-0.94) 0.45 (0.34-0.59) 0.78 (0.54-1.11)
0.92 (0.69-1.23) 1.02 (0.80-1.30) 0.84 (0.60-1.17)
8.5-11‡ 7.5-14.5‡ 9-13‡
1.7-2.7‡ 1.2-3.2‡ 1.5‡
0.43 (0.25-0.73)* 0.21 (0.12-0.40)* 0.27 (0.07-1.09)*
0.53 (0.26-1.05)* 0.39 (0.18-0.84)* x
N/A N/A N/A
*Relative risk. †Annualized percentage change. ‡Teriparatide 20 mcg/day - Teriparatide 40 mcg/day. xNo nonvertebral fractures in either group.
incident of vertebral fracture in patients with renal impairment.76 One study evaluated raloxifene in ESRD patients with a low T-score and after 1 year, treated patients had a significant improvement in vertebral BMD.79 Because of its small sample size and surrogate endpoint, it is not incorporated into the KDIO guidelines which are the same as those for bisphosphonates. Teripartide is a recombinant human 1-34 PTH that is anabolic with regard to bone when given intermittently. The Fracture Prevention Trial showed that it increased BMD and reduced the risk of both vertebral and nonvertebral fractures, but like previous studies on anti-osteoporotic medications it excluded those with significant renal impairment and abnormalities in bone metabolism.77 To assess its efficacy in patients with CKD, a post hoc analysis of this trial was performed that divided patients on the basis of renal function (Table 3). This analysis found that it decreased fracture incidence among all groups while increasing BMD in all groups similarly. On the basis of this data, KDIGO guidelines again recommend that patients with CKD stages 1-3 without biochemical evidence of CKD-MBD be treated the same as the general population with regard to teriparatide. There are no data on the use of teriparatide in CKD stage 3 with
evidence of CKD-MBD or CKD stages 4-5D. Theoretical, it may exacerbate preexisting HPT while benefiting those with ABD, but there are no data to support this. In patients with CKD stage 3 and biochemical evidence of CKD-MBD, treatment must be individualized. The clinical trials on bisphosphonates, raloxifene, and teriparatide excluded patients with abnormal PTH and their benefits cannot be assumed to apply to this population. However, it may be reasonable to consider therapy in patients who are high risk of fracture after PTH is corrected, but the risk of inducing ABD must be weighed against any benefit.
Conclusion Bone disease in elderly patients with CKD is a problem. It is common and causes significant morbidity and mortality. This is complicated by our lack of understanding on the interplay of age-related bone loss and renal osteodystrophy. On the basis of current evidence, those with mild CKD who have not manifested biochemical evidence of CKD-MBD can be treated for age-related bone loss much in the same way as the general population. In those with advanced CKD, there is no good evidence to help guide therapy. As the
Bone Disease and CKD in the Elderly
population continues to age, this is will continue to be a topic of concern that future research will need to address.
17.
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of calcitriol and the effect of parathyroidectomy. Kidney Int 40:1063-1068, 1991 Levin A, Bakris GL, 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 71:31-38, 2007 Clase CM, Kiberd BA, Garg AX: Relationship between glomerular filtration rate and the prevalence of metabolic abnormalities: Results from the Third National Health and Nutrition Examination Survey (NHANES III). Nephron Clin Pract 105:c178-c184, 2007 Vassalotti JA, Uribarri J, Chen SC, et al: Trends in mineral metabolism: Kidney Early Evaluation Program (KEEP) and the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Am J Kidney Dis 51(4 Suppl 2):S56-S68, 2008 Murray TM, Rao LG, Divieti P, et al: Parathyroid hormone secretion and action: Evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl- terminal ligands. Endocr Rev 26:78-113, 2005 Lehmann G, Ott U, Kaemmerer D, et al: Bone histomorphometry and biochemical markers of bone turnover in patients with chronic kidney disease stages 3-5. Clin Nephrol 70:296-305, 2008 Moosgaard B, Christensen SE, Vetsergaard P, et al: Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism. Clin Endocrinol 68: 707-715, 2008 Tsurusaki K, Ito M, Hayashi K: Differential effects of menopause and metabolic disease on trabecular and cortical bone assessed by peripheral quantitative computed tomography (pQCT). Br J Radiol 73:14-22, 2000 Sit D, Kadiroglu AK, Kayabasi H, et al: Relationship between bone mineral density and biochemical markers of bone turnover in hemodialysis patients. Adv Ther 24:987-995, 2007 Ambrus C, Almasi C, Berta K, et al: Bone mineral density and parathyroid function in patients on maintenance hemodialysis. Int Urol Nephrol (in press) Andress DL: Adynamic bone in patients with chronic kidney disease. Kidney Int 73:1345-1354, 2008 Moe SM, Drueke TB, Block GA, et al: KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney DiseaseMineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 113:S1-S130, 2009 Pei Y, Hercz G, Greenwood C, et al: Risk factors for renal osteodystrophy: A multivariant analysis. J Bone Miner Res 10:149-156, 1995 Thalassinos NC, Hadjiyanni P, Tzanela M, et al: Calcium metabolism in diabetes mellitus: Effect of improved blood glucose control. Diabet Med 10: 341-344, 1993 Alikhani M, Alikhani Z, Boyd C, et al: Advanced glycation end-products stimulate osteoblastic apoptosis via MAP kinase and cytosolic apoptotic pathways. Bone 40:345-353, 2007 Almedia M, Han L, Martin-Millan M, et al: Skeletal involution by age-associated oxidative stress and it’s
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33.
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38.
39. 40.
41.
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43.
44.
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47.
48.
49.
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acceleration by loss of sex steroids. J Biol Chem 282: 27285-27297, 2007 Lima EM, Goodman WG, Kuizon BD, et al: Bone density measurements in pediatric patients with renal osteodystrophy. Pediatr Nephrol 18:554-559, 2003 Klawansky S, Komaroff E, Cavanaugh PF, et al: Relationship between age, renal function and bone mineral density in the US population. Osteoporos Int 14:570-576, 2003 Hsu CY, Cummings SR, McCulloch CE, et al: Bone mineral density is not diminished by mild-moderate renal insufficiency. Kidney Int 61:1814-1820, 2002 Fried LF, Shlipak MG, Stehman-Breen C, et al: Kidney function predicts the rate of bone loss in older individuals: The Cardiovascular Health Study. J Gerontol A Biol Sci Med Sci 61:743-748, 2006 Mittalhenkle A, Gillen DL, Stehman-Breen CO: Increased risk of mortality associated with hip fracture in the dialysis population. Am J Kidney Dis 44: 672-679, 2004 Ioannidis G, Papaioannou A, Hopman WM, et al: Relation between fractures and mortality: Results from the Canadian Multicentre Osteoporosis Study. CMAJ 181:265-271, 2009 van Staa TP, Dennison EM, Leufkens HG, et al: Epidemiology of fractures in England and Wales. Bone 29: 517-522, 2001 Kanis JA, Borgstrom F, De Laet C, et al: Assessment of fracture risk. Osteoporos Int 16:581-589, 2005 Holroyd C, Cooper C, Dennison E: Epidemiology of osteoporosis. Best Pract Res Clin Endocrinol Metab 22:671-685, 2008 Alem AM, Sherrard DJ, Gillen DL, et al: Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int 58:396-399, 2000 Piraino B, Chen T, Cooperstein L, et al: Fractures and vertebral bone mineral density in patients with renal osteodystrophy. Clin Nephrol 30:57-62, 1988 Arau´jo SM, Ambrosoni P, Loba˜o RR, et al: The renal osteodystrophy pattern in Brazil and Uruguay: An overview. Kidney Int 63(Suppl 85):S54-S56, 2003 Gerakis A, Hadjidakis D, Kokkinakis E, et al: Correlation of bone mineral density with the histological findings of renal osteodystrophy in patients on hemodialysis. J Nephrol 13:437-443, 2000 Atsumi K, Kushida K, Yamazaki K, et al: Risk factors for vertebral fractures in renal osteodystrophy. Am J of Kidney Dis 33:287-293, 1999 Coco M, Rush H: Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis 36:1115-1121, 2000 Block GA, Klassen PS, Lazarus JM, et al: Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15:2208-2218, 2004 Danese MD, Kim J, Doan QV, et al: PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis. Am J Kidney Dis 47:149-156, 2006 Jadoul M, Albert JM, Akiba T, et al: Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the dialysis outcomes and practice patterns study. Kidney Int 70:1358-1366, 2006
50. Mitterbauer C, Kramar R, Oberbauer R: Age and sex are sufficient for predicting fractures occurring within 1 year of hemodialysis treatment. Bone 40:516-521, 2006 51. Ensrud KE, Lui LY, Taylor BC, et al: Renal function and risk of hip and vertebral fractures in older women. Arch Intern Med 167:133-139, 2007 52. Dawson-Hughes B: National Osteoporosis Foundation Guide Committee: A revised clinician’s guide to the prevention and treatment of osteoporosis. J Clin Endocrinol Metab 93:2463-2465, 2008 53. Kanis JA, Johnell O, Oden A, et al: FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 19:385-397, 2008 54. Nickolas TL, Leonard MB, Shane E: Chronic kidney disease and bone fracture: A growing concern. Kidney Int 74:721-731, 2008 55. Jamal SA, Hayden JA, Beyene J: Low bone mineral density and fractures in long-term hemodialysis patients: A meta-analysis. Am J Kidney Dis 49:674-681, 2007 56. Ammann P, Rizzoli R: Bone strength and its determinants. Osteoporos Int 14(Suppl 3):S13-S18, 2003 57. The National Osteoporosis Foundation Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at, http://www.nof.org/professionals/ NOF_Clinicians_Guide.htm 58. Baim S, Binkley N, Bilezikian JP, et al: Official positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom 11:75-91, 2008 59. Hodgson SF, Watts NB, Bilezikian JP, et al: American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract 9:544, 2003 60. U.S. Preventive Services Task Force. Guide to Clinical Preventive Services (3rd ed). Available at: www.ahrq. gov/clinic/uspstfix.htm 61. Jamal SA, Gilbert J, Gordon C, et al: Cortical pQCT measures are associated with fractures in dialysis patients. J Bone Miner Res 21:543-548, 2006 62. Hourigan SR, Nitz JC, Brauer SG, et al: Positive effects of exercise on falls and fracture risk in osteopenic women. Osteoporos Int 19:1077-1086, 2008 63. Kemmler W, von Stengel S, Engelke K, et al: Exercise effects on bone mineral density, falls, coronary risk factors, and health care costs in older women: The randomized controlled Senior Fitness and Prevention (SEFIP) Study. Arch Intern Med 170:179-185, 2010 64. Yamazaki S, Ichimura S, Iwamoto J, et al: Effect of walking exercise on bone metabolism in postmenopausal women with osteopenia/osteoporosis. J Bone Miner Metab 22:500-508, 2004 65. Ubara Y, Tagami T, Nakanishi S, et al: Significance of minimodeling in dialysis patients with a dynamic bone disease. Kidney Int 68:833-839, 2005 66. MacLaughlin J, Holick MF: Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 76:1536-1538, 1985
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67. Jackson RD, LaCroix AZ, Gass M, et al: Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 354:669-683, 2006 68. Kooienga L, Fried L, Scragg R, et al: The effect of combined calcium and vitamin D3 supplementation on serum intact parathyroid hormone in CKD. Am J Kidney Dis 53:408-416, 2009 69. Ghazali A, Fardellone P, Pruna A, et al: Is low plasma 25-(OH) vitamin D a major risk factor for hyperparathyroidism and Looser’s zones independent of calcitriol? Kidney Int 55:2169-2177, 1999 70. Wolf M, Shah A, Gutierrez O, et al: Vitamin D levels and early mortality in incident hemodialysis patient. Kidney Int 72:1004-1013, 2007 71. Josephson MA, Schumm LP, Chiu MY, et al: Calcium and calcitriol prophylaxis attenuates posttransplant bone loss. Transplantation 78:1233-1236, 2004 72. Cueto-Manzano AM, Konel S, Freemont AJ, et al: Effect of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation. Am J Kidney Dis 35:227-236, 2000 73. Saab G, Young DO, Gincherman Y, et al: Prevalence of vitamin D deficiency and the safety and effectiveness of monthly ergocalciferol in hemodialysis patients. Nephron Clin Pract 105:c132-c138, 2007
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74. Jamal SA, Bauer DC, Ensrud KE, et al: Alendronate treatment in women with normal to severely impaired renal function: An analysis of the Fracture Intervention Trial. J Bone Miner Res 22:503-508, 2007 75. Miller PD, Roux C, Boonen S, et al: Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: A pooled analysis of nine clinical trials. J Bone Miner Res 20:2105–2015, 2005 76. Ishani A, Blackwell T, Jamal SA, et al: The effect of raloxifene treatment in postmenopausal women with CKD. J Am Soc Nephrol 19:1430-1438, 2008 77. Miller PD, Schwartz EN, Chen P, et al: Teriparatide in postmenopausal women with osteoporosis and impaired renal function. Osteoporos Int 18:59-68, 2007 78. Amerling R, Harbord N, Winchester JF, et al: Bisphosphonate use in chronic kidney disease associated with adynamic bone disease. Abstract from the ISN Nexus Symposium on the Bone and the Kidney; October 12-15, 2006; Copenhagen, Denmark 79. Herna´ndez E, Valera R, Alonzo E, et al: Effects of raloxifene on bone metabolism and serum lipids in postmenopausal women on chronic hemodialysis. Kidney Int 63:2269-2274, 2003
B
one disease can lead to significant morbidity and mortality for those who are afflicted by it, irrespective of etiology. Two very prevalent causes of bone disease that contribute to this are osteoporosis and chronic kidney disease (CKD). The modern era has seen important advances in the understanding and management of these processes, but in elderly patients with CKD it remains a complex issue that has yet to be clearly defined. Changes in mineral metabolism that accompany the loss of renal function result in a spectrum of bone disease that occurs concomitantly with bone loss secondary to aging. As such, the traditional paradigms used to manage bone disease may not be appropriate for these patients. With the aging population and the marked prevalence of CKD in the elderly, a better understanding of these 2 processes and their interplay deserves more attention. Bone disorders associated with CKD were traditionally referred to as renal osteodystrophy. This umbrella term encompassed a wide variety of bone disorders including ostesitis fibrosa, osteomalacia, adynamic bone disease (ABD), and mixed uremic dystrophy. With improvement in our understanding of the under-
From Renal Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA; and Renal Section, VA Pittsburgh Healthcare System, Pittsburgh, PA. Address correspondence to Sheru Kansal, MD, Renal Electrolyte Division, University of Pittsburgh, 2550 Scaife Hall, Pittsburgh, PA 15261. E-mail: [email protected] Ó 2010 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 doi:10.1053/j.ackd.2010.05.001
lying disease process, a new classification system, referred to as CKD-mineral and bone disorder (CKD-MBD), has emerged. CKDMBD takes into consideration the systemic consequences of altered mineral metabolism as well as bony abnormalities. Additionally, the traditional nomenclature has been replaced with a quantitative assessment of the histomorphometry of CKD-related bone disease based on the parameters of turnover, mineralization, and volume.1 Osteoporosis is uniformly a disease of low bone mineral density (BMD) and microarchitectural disruption and fragility.2 It is extremely common, with an estimated prevalence of around 10 million people in the United States, according to the National Women’s Health Information Center. Moreover, its prevalence is expected to grow exponentionally over the next decade. The World Health Organization (WHO) has defined diagnostic thresholds for low bone mass and osteoporosis on the basis of BMD measurements compared with a young adult reference population (T-score) based on dual energy X-ray absorptiometry (DEXA). A BMD between 1 and 2.5 standard deviations (T-score) below the mean for young adults is classified as osteopenia; a T-score greater than 2.5 is classified as osteoporosis. Consensus guidelines on management in women are based on large epidemiologic studies which have been extrapolated for use in men. Patients with significant CKD were systematically excluded from these studies and at present their management is unclear. As other articles in this issue have described, CKD is more common in the elderly population. Because osteoporosis prevalence also
Advances in Chronic Kidney Disease, Vol 17, No 4 (July), 2010: pp e41-e51
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increases with age, older individuals with CKD may have both osteoporosis and CKD-MBD. In the following review, we present the current understanding of age-related bone disease and bone abnormalities associated with CKD. We also attempt to reconcile the clinical dilemma of managing bone disease in elderly patients with CKD, based on the existing literature.
Bone Remodeling Bone is a complex and dynamic organ. It is constantly being remodeled with bone resorption and bone formation. Remodeling is stimulated in a variety of situations, including normal growth, as a response to stress so as to increase bone strength where appropriate, in fractures, and in metabolic processes that seek to either mobilize or store calcium. Bone remodeling is regulated by both local (e.g., cytokines, osteoprotegerin, receptor activator for nuclear factor kb) and systemic factors (e.g., parathyroid hormone, vitamin D, estrogen).3 Typically, bone resorption is tightly coupled with bone formation so that the net effect on mass is negligible. When these processes become uncoupled, bone disease tends to develop. There are 2 types of bone in the human skeleton. Cortical bone comprises 80% of the skeleton and constitutes the outer part of all skeletal structures; it is dense and compact and slower to turn over. Trabecular bone is less dense and more metabolically active. It is found at the end of long bones (i.e., appendicular skeleton), in bodies of vertebrae, and inner portions of large flat bones.3
Epidemiology of Osteoporosis Bone loss in the elderly people is typically related to advancing age and estrogen deficiency. In this context, it is not surprising that postmenopausal women have the highest prevalence of osteoporosis. Bone mass peaks in late adolescence and is generally maintained though adulthood, with bone resorption matching bone formation. Bone loss tends to begin in midlife for both men and women, although the rates of loss are markedly different. A recent longitudinal study following BMD in both men and women found
an accelerated period of bone loss in women during the perimenopausal period.4 A second period of accelerated loss occurred after the age of 70, which correlated with accelerated bone loss in men.4 The accelerated perimenopausal bone loss involves mainly trabecular bone, whereas the slower bone loss in men and women involves both cortical and trabecular bone.5 Estrogen is implicated in the perimenopausal decline in BMD. It inhibits bone resorption and its deficiency results in rapid bone loss. The mechanism by which it exerts its effect on bone is not entirely clear. It does not inhibit osteoclastic bone resorption in vitro systems, but is thought to affect osteoclastogenesis and osteoclast function through its effects on local factors, including IL-1 and tumor necrosis factor and IL-2 to interleukin-2.6 Men suffer from age-related bone loss as women do, but they only account for 20% of prevalent cases of osteoporosis.7 Men tend to attain a higher peak bone mass and are spared from the accelerated loss that occurs in women during the perimenopausal period. This is evident clinically as the incidence of fractures seems to increase about 10 years later in men (after age 70) and the overall incidence is lower when compared with women. However, men tend to have a higher mortality when they do suffer a fracture.8,9 Similar to women, estrogen seems to be related to agerelated bone loss in men. Elimination of endogenous testosterone and estrogen through gonadotropin-releasing hormone agonist and aromatase inhibitor with physiologic replacement and subsequent withdrawal of one or both resulted in increased bone resorption, with the withdrawal of estrogen having the greatest effect.10 Also, higher serum estrogen concentrations are associated with higher bone density in men, independent of their serum androgen concentrations.11 Numerous other risk factors for the development of osteoporosis have been identified in addition to those of age and gender (Table 1). Men in particular tend to have an identifiable secondary cause of osteoporosis. Epidemiologic surveys suggest that a secondary cause can be found in a maximum of 60% of men, whereas in postmenopausal women, secondary causes can be identified in a maximum of 30%.12,13 Many of these risk factors
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Table 1. Risk Factors Associated With the Development of Osteoporosis Endocrine diseases Hypogonadism Hypercortisolism Hyperthyroidism Hyperparathyroidism Vitamin D deficiency Growth hormone deficiency Diabetes mellitus Gasterointestinal diseases Malabsorption syndromes Inflammatory bowel disease Gastrectomy Cirrhosis Alactasia Chronic biliary obstruction Hematologic disorders Multiple myeloma Lymphoma Leukemia Chronic hemolytic anemia Disseminated carcinoma Systemic mastocylosis
Connective tissue diseases Marfan’s syndrome Osteogenesis imperfecta Ehlers-Danlos syndrome Homocystinuria Rheumatoid arthritis
Medications Heparin Glucocorticoids Cyclosporine Anticonvulsants (i.e., phenytoin) Thyroxine GnRH analogs Chemotherapy Miscellaneous Alcoholism Immobilizations Anorexia nervosa Hypercalciuria
are common in individuals with CKD, but it remains controversial whether CKD itself predisposes to the development of osteoporosis.
it increases resorption and releases calcium. There are also other mechanisms at play in this process that are complex with significant cross-talk. For example, hyperphosphatemia has been shown to directly promote PTH excretion by increasing gene expression. It may also directly inhibit calcitriol formation in the kidney.15 PTH excretion may also be enhanced through skeletal resistance to the calcemic effect of PTH that occurs because of downregulation of PTH receptors. Calcitriol deficiency and hyperphosphatemia may also contribute to this skeletal resistance.16 The Study to Evaluate Early Kidney Disease data suggest that biochemical evidence of these changes typically tends to occur when GFR drops below 30 mL/min, although abnormalities in PTH can be seen earlier (Fig 1). Similar findings have been reported in the Kidney Education and Evaluation Program and National Health and Nutrition Examination Survey (NHANES) as well.17-19 The milieu of altered phosphorous and calcium homeostasis that accompanies the decline in GFR has systemic effects, but it is the increased secretion of PTH that has the most significant effect on bone. Chronically elevated PTH levels cause bone resorption through osteoclasts. Because only osteoblasts express PTH receptors, osteoclast activation likely occurs through cellular interactions and various cytokines.20 If left unchecked, elevated levels of PTH lead to osteitis fibrosa, characterized Biochemical evidence of CKD-MBD and eGFR 60 50
Renal Function and its Effect on Bone As glomerular filtration rate (GFR) declines, the filtered load of phosphate decreases and phosphate retention ensues. The normal response is to increase phosphate excretion. This is initially accomplished with increasing levels of fibroblast growth factor-23 which promotes renal phosphate excretion and decreases renal synthesis of 1-a-hydroxylase, resulting in calcitriol deficiency.14 Hypocalcemia then ensues which, in turn, stimulates parathyroid hormone (PTH) excretion. PTH acts on the distal tubule to further promote phosphate excretion as well as on bone where
eGFR > 60 mL/min 60 < eGFR <= 30 eGFR < 30 mL/min
40 30 20 10 0 Hypocalcemia
Hyperphosphatemia
Hyperparathyroid
Percent
Figure 1. Biochemical evidence of CKD-MBD by eGFR. Hypocalcemia, Ca ,8.4 mg/dL; Hyperphosphatemia, PO4 .4.6 mg/dL; Hyperparathyroidism, iPTH .65 pg/mL. Data derived from Levin colleagues.17
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by marrow fibrosis and high bone turnover because of increased activity of both osteoblasts and osteoclasts. The prevalence of these changes increases as renal function declines. Based on bone histomorphometry, 41.2% of patients with CKD stage 3 or 4 and 61.4% with CKD stage 5 had osteitis fibrosa.21 The effect of osteitis fibrosa on BMD is unclear but may be dependent on the site. A study on patients with primary hyperparathyroidism found reductions in BMD in sites of predominantly cortical bone, such as the radius and femur, whereas sites of predominantly trabecular bone, such as the lumbar spine, were normal.22 A similar pattern in BMD has been observed in patients with severe CKD as measured by quantitative computerized tomography (QCT), although a study that looked at markers of bone metabolism and BMD could find no correlations between PTH levels and BMD at the lumbar spine or femoral neck.23,24 A recent study analyzed the association of PTH and BMD in hemodialysis patients and found that in patients with PTH levels .100 pg/mL, PTH was negatively correlated with BMD at all sites, including the lumbar spine.25
Epidemiology of Bone Disease in CKD Osteitis fibrosa has traditionally been the most common form of bone disease associated with kidney disease, but over the past few decades the prevalence of ABD has increased, with a rate of 20% to 50% reported in hemodialysis patients.26 Those on peritoneal dialysis have even higher rates of ABD (Fig 2). It is characterized by a low turnover state, with bone biopsy findings of inactive osteoblasts and mineralization with decreased osteoclasts and resorptive surfaces. The principle factor in its pathogenesis appears to be related to oversuppression of PTH, which is likely the result of multiple factors. An iatrogenic component stems from higher calcium loads from calcium-based phosphate binders. For those on peritoneal dialysis, almost constant exposure to a high calcium dialysate predisposes to ABD. The use of activated vitamin D has contributed to the increasing prevalence of ABD as well. Diabetes and advancing age are recognized risk factors for ABD and the pathogenesis in this
Prevalence of types of bone disease 60 Hemodialysis Peritoneal dialysis
50
40
30
20
10
0 Normal
Mild
OF
Mixed
ABD
OM
Figure 2. Prevalence of types of bone disease in patients with ESRD. Data derived from Moe and colleagues.27
population may not be simply related to oversuppression of PTH.28 The reason for their propensity to develop ABD is not entirely clear. One study showed that under poor glycemic control, diabetics without renal disease tended to have lower calcium and PTH levels.29 The accumulation of advanced glycosylation end products may induce osteoblast apoptosis resulting in a low turnover state as well.30 Many of these patients are vitamin D deficient, particularly the elderly population, resulting in decreased osteoblastic activity. Reduced circulating sex hormones and oxidative stress may also play a role in the development in ABD in the elderly people.31 The effect of a low turnover state on BMD may be dependant on the site examined, as is the case with states of high turnover. In a pediatric population, those with low turnover lesions had higher cortical bone density and lower trabecular density as compared with those with high turnover lesions when BMD was measured by QCT and bone turnover was assessed by PTH levels.32 However, a recent study found that in hemodialysis patients with PTH levels ,100 pg/mL, BMD was variable at all sites measured, including the radius, femur, and lumbar spine.25 In patients with mild to moderate renal dysfunction who may not have significant perturbations in phosphate and calcium metabolism, BMD tends to be lower than the general population. Data from NHANES III were analyzed for the occurrence of renal dysfunction in patients with osteoporosis. With
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the Cockcroft–Gault equation, 61% of adult women with osteoporosis had CKD stage 3.33 It is unclear whether this overlap was because of a direct effect of decreased renal function or because both CKD and bone loss increase with aging. A separate analysis of the NHANES data found that the association between CKD and lower BMD disappeared when adjusted for age, sex, and weight, suggesting no direct effect of kidney dysfunction on BMD.34 However, data from the Cardiovascular Health Study did find that although kidney function was not associated with lower BMD at baseline, kidney dysfunction, as assessed by cystatin-C, was associated with a more rapid loss of BMD at the hip over time and this association persisted in men when adjusted for age, race, lean mass, and fat mass.35
Fracture Risk The main clinical consequence of bone disease is fracture, the rates of which are increased as compared with the general population, in both osteoporosis and CKD. Fractures are responsible for a significant medical and economical burden as they are associated with an increased mortality in both populations.36,37 Half of all women over the age of 50 and 1 in 5 of their male counterparts will suffer an osteoporotic fracture in their lifetime.38 Although age, BMD, and prior fracture tend to
be the strongest predictors of future fractures, other risk factors include alcohol and cigarette use, low body weight, glucocorticoid therapy, and a family history of fractures.39 Vertebral fractures are the most common. They tend to be asymptomatic and found incidentally on plain films of the chest or abdomen. Hip fractures are less common but tend to portend a poorer prognosis as they are associated with higher mortality rates.40 Epidemiological surveys have clearly shown on increased fracture risk among patients with CKD. Men and women on hemodialysis have a 4-fold increased risk of hip fracture as compared with the general population.41 Risk factors included traditional osteoporotic fracture risks as well as time on dialysis.41 Attempts to evaluate the relationship of fracture with PTH or type of renal osteodystrophy have yielded inconsistent results (Table 2). Patients with pre-dialysis CKD are at risk as well. One study in particular did find that women with mild to moderate kidney dysfunction had an increased risk of hip fracture. In those with an eGFR 45 to 59 mL/min the hazards ratio was 3.93, whereas those with an eGFR ,45 had a hazards ratio of 7.17.51 An assessment tool to estimate fracture risk with or without information on BMD has been developed by the WHO.52 The main risk factors affecting the score are age and BMD. Other risk factors in the model include
Table 2. Studies of the Relationship of Type of Renal Osteodystrophy and PTH With Fracture Study (Reference) 42
Piraino et al
(n ¼ 31)
Population Dialysis
Arau´jo et al43 (n ¼ 2340)
Dialysis
Gerakis et al44 (n ¼ 62) Atsumi et al45 (n ¼ 137)
Hemodialysis Hemodialysis, Male
Coco et al46 (n ¼ 1272)
Dialysis
Block et al47 (n ¼ 40,538)
Hemodialysis
Danese et al48 (n ¼ 9007)
Dialysis
Jadoul et al49 (n ¼ 12,782) Mitterbauer et al50 (n ¼ 1774)
Hemodialysis Hemodialysis
Finding* BMD was not predictive of fracture but type of bone disease was (ABD . OF) Low PTH level (,150 pg/mL) predicted ABD Higher rate of fractures with OM but no difference in ABD, OF, MBD Higher fracture rate in ABD Highest vertebral fracture risk in lowest PTH tertile and lowest in middle tertile Highest fracture risk with PTH ,65 and lowest with PTH between 195-500 PTH and phosphorus directly associated with risk of hospitalization for fracture Fracture risk at PTH showed U shaped association, there was no association of calcium or phosphorus with fracture Fracture RR 1.7 if PTH.900 vs PTH 150-300 No relation between fracture risk and PTH
*ABD ¼ adynamic bone disease, OF ¼ osteitis fibrosa, BMD ¼ bone mineral density.
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corticosteroid use, rheumatoid arthritis, and smoking. They appear to be mediated mainly through their effect on BMD, so if BMD is known the addition of these factors to the algorithm has little effect on the score.52 The score was derived from international prospective studies of over 40,000 patients for 4 years and validated in over 2,30,000 who were followed up for 5 years. Fracture risk was 4.2 times higher for every standard deviation increase in the risk score.53 However, the tool does not account for alterations in kidney function and may not be applicable to patients with CKD. Moreover, the cohorts that the tool is based on selected patients randomly and made no mention of baseline renal function. The level of evidence for a relationship between BMD and fracture risk in patients with significant CKD is not as strong as compared with the general population. There is a lack of longitudinal studies, but several cross-sectional studies have looked at the relationship between BMD and fracture risk in this population. They did not find an association of low BMD with fracture in individuals with CKD.54 A recent meta-analysis found no increased risk of hip fracture with lower BMD at the hip, whereas the BMD at the spine and radius was lower in those who had a fracture at these sites.55 The reasons for the poor relationship of BMD and fractures in severe CKD is not clear, but may be related to the varying effects on PTH on bone that were previously outlined. Fracture risk is related to bone strength. Although BMD accounts for 60% to 70% of the variation in bone strength, it is a surrogate measure. Other factures, such as bone architecture, are not accounted for.56 In light of this, the most recent KDIGO (Kidney Disease: Improving Global Outcomes) guidelines do not recommend BMD testing in patients with CKD stages 3–5D.27
Evaluation and Management of Osteoporosis in the Elderly Population With CKD Current recommendations for the screening of osteoporosis in the general population vary but most agree that all women aged .65 years undergo screening DEXA. Guidelines vary for women aged ,65 years, but most groups
recommend a screening DEXA in premenopausal women with risk factors. The National Osteoporosis Foundation and International Society for Clinical Densitometry are the only groups that comment specifically on screening in men and both recommend that all men aged .70 years be screened regardless of risk factors.57-60 As noted, KDIGO guidelines do not recommend routine BMD testing in patients with CKD stages 3–5D who have evidence of CKD-MBD because BMD does not predict fractures well nor has any treatments been shown to reduce fractures in this population. Whether this should apply to all patients with CKD stage 3 (e.g., stage 3A), who make up the largest proportion of older individuals with CKD, is unclear. Quantitative computed tomography provides information on BMD and distinguishes between cortical and trabecular bone and may be of more use in patients with CKDMBD. A cross-sectional study of hemodialysis patients did find that cortical BMD measurements by QCT were better at discriminating fracture risk as compared with trabecular BMD by QCT and DEXA measurements.61 However, routine use of QCT is not recommended at this time and the assessment of bone health in patients with CKD-MBD is limited to biochemical analysis of 25-hydroxyvitamin D, phosphorous, calcium, and PTH. Therapy of osteoporosis in the general population consists of nonpharmacologic and pharmacologic modalities. Nonpharmacologic therapy consists of exercise, lifestyle modifications including cessation of smoking and reduction in alcohol intake, and adequate dietary calcium and vitamin D intake. Exercise can also improve muscle strength and balance, leading to a decreased risk of falls and fractures.62,63 Although no studies have specifically looked at the role of exercise on bone disorders in CKD, one study found that walking improved BMD because of suppression of bone turnover suggesting that walking may help patients with highturnover bone disease.64 In those with lowturnover bone disease, low impact exercise may increase bone volume through minimodeling which is a concept that dynamic external stress may stimulate bone formation in otherwise adynamic bone.65 Similarly, the effects of
Bone Disease and CKD in the Elderly
smoking and alcohol intake have not been specifically studied in regard to bone disease in CKD. However, given the other benefits associated with smoking cessation and limiting alcohol intake, it seems reasonable to recommend them in elderly patients with CKD and bone disease. Supplementation with calcium and vitamin D is a standard therapy, both in the prevention and management of osteoporosis. The elderly people are at significant risk of vitamin D deficiency. They tend to have inadequate dietary intake as well as a decreased ability for cutaneous synthesis.66 Several studies have shown a benefit on BMD with supplementation, whereas the effect on fractures has been mixed. The largest of these studies showed a small but significant improvement in BMD with supplementation and no significant reduction in fractures. A subgroup analysis showed a significant reduction in fractures in compliant patients.67 Patients with CKD tend to have a high prevalence of vitamin D deficiency as well. The role of supplementation is unclear because there is no evidence that this improves outcomes, although in patients with moderate renal dysfunction and vitamin D deficiency, supplementation may improve PTH levels.68 Dialysis patients have a diminished ability to convert 25-hydroxyvitamin D to its active metabolite, suggesting that supplementation would be of no benefit on bone. However, dialysis patients with vitamin D deficiency tend to have more severe secondary hyperparathyroidism.69 There is also limited evidence that suggests low vitamin D levels are associated with increased early mortality in dialysis patients.70 In kidney transplant patients, a small randomized study found that the use of calcitriol with calcium decreased post-transplant bone loss.71 However, another study did not find a beneficial effect on bone loss.72 The main concern with supplementation of either calcium or vitamin D is in the development of hypercalcemia, which is associated with ABD and extraosseous calcifications in patient with moderate to severe renal dysfunction. However, this was not borne out in a study of hemodialysis patients who were supplemented with ergocalciferol.73 As noted, patients with CKD stages 1-3 typically do not have biochemical evidence of CKD-MBD and supplementation
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is reasonable in this population. For patients with advanced renal dysfunction, supplementation may be beneficial if a nutritional deficiency exits. Pharmacologic therapy is an important adjunct in the treatment of age-related bone loss. In the general population, options include bisphosphonates, raloxifene, and teriparatide. Bisphosphonates reduce bone resorption through their inhibitory action on osteoclasts. They have been extensively studied and shown to improve BMD and reduce fracture rates, making many regard them as first line agents in the treatment of osteoporosis. However, these studies have specifically excluded patients with elevated creatinine or PTH. The prescribing information generally recommends that these medications not be used in individuals with a creatinine clearance ,30 mL/min. Two post hoc analyses have been published to address this issue and their results are summarized in Table 3. Both showed improvements in lumber BMD as well as reductions in vertebral fractures in patients with renal impairment.74,75 This has lead KDIGO to recommend that the use of bisphosphonates in those with CKD stages 1-3 and osteoporosis, who do not have biochemical evidence of CKD-MBD, be the same as the general population. Patients with CKD stage 4 are not included in this recommendation because of the paucity of evidence in this group. For patients with CKD stages 4-5D with low BMD, additional studies such as bone biopsy are recommended before treatment with bisphosphonates owing to the observation that some patients with this degree of renal dysfunction developed ABD after being treated with alendronate.78 Raloxifene is another option in the treatment of osteoporosis. It is an anti-resorptive agent that has been shown to be effective in the management of osteoporosis. As with the trials on bisphosphonates, studies on raloxifene excluded patients with severe renal dysfunction and those with biochemical evidence of CKD-MBD, making their role in this population unclear. A post hoc analysis was done on the Multiple Outcomes of Raloxifene Evaluation trial to assess efficacy in patient with reduced eGFR (Table 3), which found improved vertebral and hip BMD with reduced
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Kansal and Fried
Table 3. Efficacy of Anti-osteoporotic Medications Changes in BMD (Percent Change Difference) Renal Function Jamal et al74 (Risendronate) eGFR $ 45 (n ¼ 5877) eGFR , 45 (n ¼ 581) Miller et al75 (Alendronate) 80 . eGFR $ 50 (n ¼ 4353) 30 # eGFR , 50 (n ¼ 4071) eGFR , 30 (n ¼ 572) Ishani et al76 (Raloxifene) eGFR $ 60 (n ¼ 2343) 45 # eGFR , 59 (n ¼ 3493) eGFR , 45 (n ¼ 1480) Miller et al77 (Teriparatide) eGFR . 80 (n ¼ 885) 50 # eGFR , 79 (n ¼ 648) 30 # eGFR , 49 (n ¼ 83)
Lumbar
Fractures (OR)
Femoral
Vertebral
Other 0.81 (0.70-0.94) 0.78 (0.51-1.2)
6.6 6.7
4.5 5.0
0.50 (0.32-0.76) 0.72 (0.31-1.7)
4.1 4.8 5.6
N/A N/A N/A
0.32 (0.14-0.46)* 0.45 (0.31-0.57)* 0.56 (0.11-0.78)*
0.9† 0.9† 1.0†
0.6† 0.7† 1.0†
0.64 (0.43-0.94) 0.45 (0.34-0.59) 0.78 (0.54-1.11)
0.92 (0.69-1.23) 1.02 (0.80-1.30) 0.84 (0.60-1.17)
8.5-11‡ 7.5-14.5‡ 9-13‡
1.7-2.7‡ 1.2-3.2‡ 1.5‡
0.43 (0.25-0.73)* 0.21 (0.12-0.40)* 0.27 (0.07-1.09)*
0.53 (0.26-1.05)* 0.39 (0.18-0.84)* x
N/A N/A N/A
*Relative risk. †Annualized percentage change. ‡Teriparatide 20 mcg/day - Teriparatide 40 mcg/day. xNo nonvertebral fractures in either group.
incident of vertebral fracture in patients with renal impairment.76 One study evaluated raloxifene in ESRD patients with a low T-score and after 1 year, treated patients had a significant improvement in vertebral BMD.79 Because of its small sample size and surrogate endpoint, it is not incorporated into the KDIO guidelines which are the same as those for bisphosphonates. Teripartide is a recombinant human 1-34 PTH that is anabolic with regard to bone when given intermittently. The Fracture Prevention Trial showed that it increased BMD and reduced the risk of both vertebral and nonvertebral fractures, but like previous studies on anti-osteoporotic medications it excluded those with significant renal impairment and abnormalities in bone metabolism.77 To assess its efficacy in patients with CKD, a post hoc analysis of this trial was performed that divided patients on the basis of renal function (Table 3). This analysis found that it decreased fracture incidence among all groups while increasing BMD in all groups similarly. On the basis of this data, KDIGO guidelines again recommend that patients with CKD stages 1-3 without biochemical evidence of CKD-MBD be treated the same as the general population with regard to teriparatide. There are no data on the use of teriparatide in CKD stage 3 with
evidence of CKD-MBD or CKD stages 4-5D. Theoretical, it may exacerbate preexisting HPT while benefiting those with ABD, but there are no data to support this. In patients with CKD stage 3 and biochemical evidence of CKD-MBD, treatment must be individualized. The clinical trials on bisphosphonates, raloxifene, and teriparatide excluded patients with abnormal PTH and their benefits cannot be assumed to apply to this population. However, it may be reasonable to consider therapy in patients who are high risk of fracture after PTH is corrected, but the risk of inducing ABD must be weighed against any benefit.
Conclusion Bone disease in elderly patients with CKD is a problem. It is common and causes significant morbidity and mortality. This is complicated by our lack of understanding on the interplay of age-related bone loss and renal osteodystrophy. On the basis of current evidence, those with mild CKD who have not manifested biochemical evidence of CKD-MBD can be treated for age-related bone loss much in the same way as the general population. In those with advanced CKD, there is no good evidence to help guide therapy. As the
Bone Disease and CKD in the Elderly
population continues to age, this is will continue to be a topic of concern that future research will need to address.
17.
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