Chapter 14: Disease and Abnormalities in Elderly Patients With CKD

Harmeet Singh

Division of , Brody School of Medicine, Greenville, North Carolina

An 81-yr-old African-American woman with end- issue problematic to define. in CKD is stage (ESKD) who has been on he- only a part of the constellation of metabolic bone modialysis for 10 yr seeks a consultation with you. problems. Therefore, its diagnosis and manage- Her primary physician obtained a dual-energy x- ment may differ from general population. ray absorptiometry (DEXA) scan and asked her to are more severely affected in CKD than that from discuss the results with her nephrologist for further normal aging. In a patient with renal osteodystro- management. She is diagnosed with osteoporosis phy, there is the potential for low BMD to coexist based on her T-scores of Ϫ5.1 (AP spine), Ϫ4.1 (left with an enormous range of functional abnormali- femoral neck), and Ϫ5.4 (left total hip). Her last ties. These range from high turnover bone lesions in dialysis laboratory results show serum calcium is patients with uncontrolled to 10.7 mg/dl, intact (PTH) is severely reduced bone remodeling activity in pa- 207 pg/ml, phosphorus is 5.7 mg/dl, and alkaline tients with adynamic . This is in con- phosphatase (ALP) is 122 IU/L. She receives pari- trast to the non-CKD patient with osteoporosis calcitol 5 mg intravenously on three where bone remodeling is not severely affected. times per week. (CKD)-related bone dis- ease is known as renal or uremic . It IMPACT ON QUALITY OF LIFE is associated with derangements in bone and min- eral metabolism that leads to abnormal regulation Patients with CKD-MBD and osteoporosis are as- of calcium, phosphorous, , and PTH. It sociated with increased risk of fractures and are at a encompasses a spectrum of conditions that are clas- high risk of cardiovascular disease.2 The overall in- sified based on bone biopsy findings including os- cidence of hip fractures among dialysis patients is teitis fibrosa (high turnover disease), mixed uremic about four-fold higher than that expected for gen- osteodystrophy, (low turnover dis- eral population. The risk is increased in both men ease), and adynamic bone disease. KDIGO (kidney and women.3 Fractures may limit ambulation, lead- disease: improving global outcomes) has proposed ing to loss of independence and chronic pain, to define CKD-related bone and mineral metabolic thereby decreasing quality of life. Mortality risk in abnormalities in the context of a systemic disorder dialysis patients with hip fracture is twice that of called CKD–mineral and bone disorder (CKD- patients without hip fracture.4 Women who are 65 MBD).1 yr of age and older and have moderate renal dys- Osteoporosis is a condition characterized by low function (eGFR Ͻ 60 ml/min per 1.73 m2) are also bone mass leading to reduced bone strength and an at an increased risk of hip fractures.5 In addition to increased risk of fractures. Hip, spine, and wrist are the traditional risk factors, several risk factors for most commonly affected. The WHO definition of low BMD have been identified in the CKD popula- osteoporosis is based on bone mineral density tion such as , ethnicity, trans- (BMD) measurements. The NIH consensus state- plant status, and duration of dialysis.6 ment refers to osteoporosis as a skeletal disorder characterized by compromised bone strength pre- disposing to increased risk of fracture. Correspondence: Harmeet Singh, Division of Nephrology, Brody School of Medicine, 2355 W. Arlington Boulevard, Greenville, NC Osteoporosis and renal osteodystrophy may co- 27834. E-mail: [email protected] exist in elderly patients with CKD, which makes the Copyright ᮊ 2009 by the American Society of Nephrology

American Society of Nephrology Curriculum 1 EVALUATION diagnostic test for determining the type of bone disease asso- ciated with CKD is iliac crest bone biopsy with double tetracy- Assessment of bone strength in an elderly patient with CKD is cline labeling and bone histomorphometric analysis. Bone his- complex. The initial evaluation of CKD-related bone and min- tology shows information about turnover, mineralization, and eral disorders should include serum biomarkers and noninva- volume and may be helpful in guiding therapy. Bone biopsy is sive imaging. Bone histomorphometric analysis might be not performed routinely in clinical practice because it is inva- needed in some cases. Bone strength is represented by two sive, available in limited centers, and requires special expertise main features: and bone quality. Bone density can and an experienced pathologist for interpretation. However, it be measured using several different radiologic techniques, but should be considered in patients with Stage 5 CKD who have bone quality is difficult to assess because it depends on archi- (1) fractures with minimal or no trauma (pathologic frac- tecture, turnover, and mineralization. Correlation of BMD tures); (2) intact plasma PTH levels between 100 and 500 with bone histology is poor. pg/ml (11.0 to 55.0 pmol/L; in CKD Stage 5) with coexisting conditions such as unexplained hypercalcemia, severe bone Serum Biomarkers pain, or unexplained increases in bone alkaline phosphatase Surrogate markers of bone metabolism such as serum intact activity; and (3) suspected aluminum bone disease, based on PTH, calcium (preferably ionized), phosphorus, alkaline clinical symptoms or history of aluminum exposure.2 Bone phosphatases, and bicarbonate levels should be obtained ini- biopsy should be strongly considered before starting bisphos- tially. High intact PTH levels may correlate with high turnover phonate therapy in patients with Stage 5 CKD. bone disease. The optimal target level for intact PTH in CKD is not known. TREATMENT Noninvasive Imaging Several imaging tools are available to assess includ- Whether the standard agents used for osteoporosis in general ing DEXA scan, quantitative computed tomography (qCT), population can be applied to patients with CKD is unclear. The and heel ultrasound. The value of BMD in evaluation of CKD- management of osteoporosis includes addressing modifiable related bone disease is not well established. risk factors and using pharmacologic agents. DEXA scan is most commonly used to assess bone mass. It (1) Smoking cessation is strongly recommended. Excess al- can only detect overall density but not quality of the bone. cohol consumption should be avoided. According to WHO definition, a T-score of Ϫ2.5 is defined as (2) Exercise: Moderate weight-bearing physical activity has osteoporosis. The extension of this definition to groups other been associated with improvement in bone density and reduc- than postmenopausal Caucasian women is controversial. Be- tion in risk of hip fractures. However, in older women, the cause of vascular and extraskeletal in CKD, the benefit is modest. interpretation may be affected by artifacts. However, it is com- (3) Calcium and vitamin D requirements: Vitamin D defi- monly used because of low cost, accuracy, and wide availabil- ciency is common in older adults especially during winter. It ity. The distal radius may be the preferred site in CKD pa- may be related to reduced synthesis, inadequate intake, dietary tients.7 KDOQI recommends use of DEXA to measure BMD in restrictions, and inactive lifestyle in dialysis patients. 25(OH- patients with fractures and in those with known risk factors for )Vitamin D deficiency is associated with increased iPTH levels, osteoporosis. reduced BMD, and increased rate of hip fractures. The extra- renal effects of vitamin D are also receiving increasing atten- Quantitative CT tion. Low 25(OH)vitamin D levels may be associated with in- Information regarding use of qCT in assessing BMD in pa- creased risk of cardiovascular events in patients with peritoneal tients with CKD is limited. It has the advantage of distinguish- dialysis (PD)9 and higher risk of myocardial infarction in ing outer dense cortical bone from inner spongy trabecular men.10 The optimal serum 25(OH)vitamin D concentration bone. Hyperparathyroidism leads to sclerotic thickening of needed to maintain bone health has not been established. Cal- trabecular bone with increased BMD but stimulates resorption cium and vitamin D supplementation has been reported to in cortical bone with significant reductions in BMD. Thinning result in small improvement in hip bone density. It did not of the cortical bone results in increased risk of fractures. A significantly reduce hip fractures but increased the risk of kid- small study has reported association of radius cortical param- ney stones.11 In CKD Stages 3 and 4, KDOQI recommends eters with fractures in hemodialysis patients. qCT is more ex- maintaining 25(OH)vitamin D levels above 30 ng/ml by sup- pensive than DEXA and results in greater exposure to radia- plementation with ergocalciferol. In CKD Stages 3 to 5, total tion.8 elemental calcium intake including dietary and calcium based binders should not exceed 2000 mg/d. The National Osteopo- Bone Biopsy rosis Foundation recommends a daily calcium intake of 1200 It remains the gold standard for diagnosis of renal osteodys- mg and vitamin D intake of 800 to 1000 IU/d for adults 50 and trophy and assessment of bone architecture. The most accurate older.

2 Geriatric Nephrology Curriculum American Society of Nephrology (4) Role of : Bisphosphonates are effective hypercalcemia and increased uric acid levels.16 Safety data in dial- in treating osteoporosis, but their use in CKD Stages 4 and 5 is ysis patients or severe renal insufficiency are not available. controversial. No data are available that proves that bisphos- The above case shows difficult real-life situations faced by phonates reduce risk of fractures in dialysis patients with os- clinicians where no guidelines are available to recommend de- teoporosis. Use of bisphosphonates in CKD has been linked to finitive treatment strategies. If this patient develops , acute renal failure, and progressive renal and pathologic fractures, bone biopsy could be considered. disease. It is imperative to make a correct diagnosis before Some authors have suggested careful use of low-dose bisphos- treatment is initiated because bisphosphonates are not indi- phonates in this situation, although data are extremely limited. cated in adynamic or osteomalacic bone disease. Bone biopsy is A bone biopsy should be obtained to rule out adynamic disease recommended before using bisphosphonates. Alterations in before considering treatment with bisphosphonates. Conser- calcium, phosphorous, vitamin D deficiency, and hyperpara- vative measures including mild weight-bearing exercise, thyroidism should be addressed before starting bisphospho- smoking cessation, and avoiding alcohol should be encour- nates. Bisphosphonates have been used in the setting of renal aged. Fall prevention risk assessment and counseling should be transplant to prevent bone loss in the posttransplant period. In provided. small studies, alendronate, risedronate, clodronate, and iban- dronate have been shown to be safe to use in CKD. Some au- thors recommend using bisphosphonates for short periods of CONCLUSION time (2 to 3 yr) in the CKD population, although there is no evidence that it will result in reduction of fractures.12 Age-related bone loss is an important part of assessment in the (5) Calcitonin: Calcitonin binds to osteoclasts and inhibits growing aging dialysis and CKD population. Osteoporosis and . It has a low side effect profile and can be given renal osteodystrophy may coexist in the elderly CKD population, intranasally. It could help protect bone mass when used along making diagnosis and management complicated. The DEXA scan with calcium and vitamin D supplementation, especially in the is most commonly used to diagnose osteoporosis. Management posttransplant population.13 of osteoporosis includes addressing modifiable risk factors and (6) Estrogen/progestin therapy has fallen out of favor be- pharmacologic approaches. Patients with CKD are at greater risk cause of increased risk of breast cancer, stroke, and thrombo- for osteoporosis than general population. Osteoporotic fractures embolism. It may be an option in women who are not able to have significant morbidity and negative impact on quality of life. tolerate other forms of treatment. More data are needed to address the optimal management of (7) Selective estrogen receptor modulators (SERM): In a mineral and bone disorders in the elderly. subgroup analysis, raloxifene was associated with a greater in- crease in spine BMD, a reduction in vertebral fractures, and no effect on nonvertebral fractures compared with placebo. It was TAKE HOME POINTS safe to use in women with osteoporosis and mild to moderate • Bone disease in elderly persons with CKD is complicated by co-exis- 14 CKD over the 2- to 3-yr observation period. Some SERMs tence of renal osteodystrophy and osteoporosis may increase the risk of deep venous thrombosis (DVT) and • Patients with CKD-MBD and osteoporosis are at increased risk of pulmonary embolism. Therefore, these agents should be fractures and higher risk of cardiovascular disease avoided in women with active or history of DVT. They may • Hip fractures in dialysis patients is associated with doubling of mortality • also increase the risk of death caused by stroke in postmeno- Bone biopsy is the gold standard for diagnosis of renal osteodystrophy and assessment of bone architecture pausal women with coronary heart disease. More information • Although bisphosphonates are increasingly being used in the post renal is needed on long-term safety and efficacy of these agents in transplant setting for prevention of bone loss, there is no evidence that CKD. it results in reduction of incidence of fractures (8) : It is a that increases the sensi- tivity of calcium-sensing receptors in the parathyroid gland to calcium, thereby playing a role in regulation of PTH levels. It DISCLOSURES helps in improving bone histology, reducing bone turnover, None. and reducing fibrosis in patients with secondary hyperparathy- roidism. Some studies indicated that it may lower the risk of , fracture, and cardiovascular hospitaliza- REFERENCES tion.15 Side effects include gastrointestinal intolerance and hy- pocalcemia, which may lead to seizures. *Key References (9) Anabolic agents: A new class of anti-osteoporosis drugs are 1. Moe S, Dru¨ eke T, Cunningham J, Goodman W, Martin K, Olgaard K, now available that stimulate bone formation. A subgroup analysis Ott S, Sprague S, Lameire N, Eknoyan G; Kidney Disease: Improving of patients with mild to moderate CKD included in the fracture Global Outcomes (KDIGO): Improving global outcomes (KDIGO). Def- inition, evaluation, and classification of renal osteodystrophy: a posi- prevention trial showed that teriparatide significantly increased tion statement from Kidney Disease: Improving Global Outcomes lumbar spine and femoral neck BMD. Adverse effects included (KDIGO). Kidney Int 69: 1945–1953, 2006*

American Society of Nephrology Geriatric Nephrology Curriculum 3 2. NKF: K/DOQI clinical practice guidelines for bone metabolism and 10. Giovannucci E, Liu Y, Hollis BW, Rimm EB: 25-hydroxyvitamin D and disease in chronic kidney disease. Am J Kidney Dis 42(Suppl 3): risk of myocardial infarction in men: a prospective study. Arch Intern S1–S202, 2003* Med 168: 1174–1180, 2008 3. Alem AM, Sherrard DJ, Gillen DL, Weiss NS, Beresford SA, Heck- 11. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, bert SR, Wong C, Stehman-Breen C: Increased risk of hip fracture Bassford T, Beresford SA, Black HR, Blanchette P, Bonds DE, Brunner among patients with end-stage renal disease. Kidney Int 58: 396– RL, Brzyski RG, Caan B, Cauley JA, Chlebowski RT, Cummings SR, 399, 2000 Granek I, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, 4. Mittalhenkle A, Gillen DL, Stehman-Breen CO: Increased risk of mor- Johnson KC, Judd H, Kotchen JM, Kuller LH, Langer RD, Lasser NL, tality associated with hip fracture in the dialysis population. Am J Limacher MC, Ludlam S, Manson JE, Margolis KL, McGowan J, Ock- Kidney Dis 44: 672–679, 2004 ene JK, O’Sullivan MJ, Phillips L, Prentice RL, Sarto GE, Stefanick ML, 5. Ensrud KE, Lui LY, Taylor BC, Ishani A, Shlipak MG, Stone KL, Cauley Van Horn L, Wactawski-Wende J, Whitlock E, Anderson GL, Assaf AR, JA, Jamal SA, Antoniucci DM, Cummings SR; Osteoporotic Fractures Barad D; Women’s Health Initiative Investigators: Women’s Health Research Group: Osteoporotic Fractures Research Group. Renal func- Initiative Investigators. Calcium plus vitamin D supplementation and tion and risk of hip and vertebral fractures in older women. Arch Intern the risk of fractures. N Engl J Med 354: 669–683, 2006 Med 167: 133–139, 2007 12. Miller PD: Is there a role for bisphosphonates in chronic kidney dis- 6. Stehman-Breen CO, Sherrard DJ, Alem AM, Gillen DL, Heckbert SR, ease? Semin Dial 20: 186–190, 2007* Wong CS, Ball A, Weiss NS: Risk factors for hip fracture among 13. El-Agroudy AE, El-Husseini AA, El-Sayed M, Mohsen T, Ghoneim MA: patients with end-stage renal disease. Kidney Int 58: 2200–2205, 2000 A prospective randomized study for prevention of postrenal transplan- 7. Yamaguchi T, Kanno E, Tsubota J, Shiomi T, Nakai M, Hattori S: tation bone loss. Kidney Int 67: 2039–2045, 2005 Retrospective study on the usefulness of radius and lumbar bone 14. Ishani A, Blackwell T, MORE Investigators: The effect of raloxifene density in the separation of hemodialysis patients with fractures from treatment in postmenopausal women with CKD. J Am Soc Nephrol 19: those without fractures. Bone 19: 549–555, 1996 1430–1438, 2008 8. Jamal SA, Gilbert J, Gordon C, Bauer DC: Cortical pQCT measures 15. Cunningham J, Danese M, Olson K, Klassen P, Chertow GM: Effects of are associated with fractures in dialysis patients. J Bone Miner Res the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, 21:543–548, 2006 and health-related quality of life in secondary hyperparathyroidism. 9. Wang AY, Lam CW, Sanderson JE, Wang M, Chan IH, Lui SF, Sea MM, Kidney Int 68: 1793–1800, 2005 Woo J: Serum 25-hydroxyvitamin D status and cardiovascular out- 16. Miller PD, Schwartz EN, Chen P, Misurski DA, Krege JH: Teriparatide comes in chronic peritoneal dialysis patients: a 3-y prospective cohort in postmenopausal women with osteoporosis and mild or moderate study. Am J Clin Nutr 87:1631–1638, 2008 renal impairment. Osteoporos Int 18: 59–68, 2007

4 Geriatric Nephrology Curriculum American Society of Nephrology REVIEW QUESTIONS: BONE DISEASE AND CALCIUM 4. Which of the following statements is false ABNORMALITIES IN ELDERLY PATIENTS WITH CKD a. Calcitonin has been shown to protect bone mass in post transplant patients when used along with bisphospho- 1. Incidence of hip fractures among dialysis patients compared nates, calcium and vitamin D with general population is about b. SERMs increase the risk of DVT and thrombosis therefore a. Two-fold should not be used in patients with active or history of b. Four-fold DVT c. Six-fold c. Some studies indicate that Cinacalcet may lower the risk of d. Eight-fold parathyroidectomy, fracture and cardiovascular hospital- ization 2. Risk of mortality in dialysis patients from hip fracture com- d. A subgroup analysis of the patients with mild to moderate pared with those without hip fracture is CKD included in fracture prevention trial showed that a. Not affected treipartide significantly increased lumbar spine density b. Doubled and femoral neck BMD c. Tripled d. Quadroupled 5. Bisphophonates are increasingly being used in the posttrans- plant setting. Bisphosphonates 3. Bone strength is a function of bone density and quality; the a. Reduce incidence of fractures in the posttransplant period best test for the assessment of bone quality is b. Reduce posttransplant bone loss a. DEXA scan c. Can be safely used in failed transplant patients who return b. Quantitative CT to dialysis c. Bone biopsy d. Can potentally benefit patients with adynamic bone dis- d. Serum intact PTH ease

American Society of Nephrology Geriatric Nephrology Curriculum 5