INTRODUCTION Osteoporosis and chronic kidney disease (CKD) are common conditions of older adults and often occur

concurrently. This follows population trends: (1) the older the person and the greater the degree of osteoporosis, the greater the risk of bone fracture2; and (2) the older the person, the higher the likelihood of having diabetes and high blood pressure, the 2 most prevalent causes of CKD.3-5 Osteoporosis has been associated with both hypertension and diabetes6; therefore, it should come as no surprise that older persons are likely to have both some degree of CKD and low BMD.7 In osteoporosis, BMD is decreased, bone microarchitecture is disrupted, and the amount and variety of proteins in bone are altered. Osteoporosis is defined by the World Health Organization in women as BMD 2.5 standard deviations less than peak bone mass (20-year-old healthy woman average) measured using DEXA. Osteoporosis is considered to result from an imbalance between factors that promote bone production and those that promote bone resorption, tilting the scales toward a net increase in bone breakdown. CKD is associated with abnormalities in calcium, phosphate, PTH, and vitamin D metabolism, all of which can adversely affect bone health. Increasingly, the broader definition of CKDmineral and bone disorder (CKD-MBD)8 is being used to describe the wide range of systemic mineral metabolism derangements associated with increased morbidity and mortality in this population.9 Treatment options for women and men with low BMD from osteoporosis have increased during the past several decades. These options now consist of a variety of pharmacologic therapies, including receptor selective estrogens, androgens, calcium and vitamin D, bisphosphonates, PTH, fluoride, and calcitonin, as well as dietary therapies, including phytoestrogens and soy, and also physical therapies, including weight-bearing or resistance exercises to improve balance, prevent falls, and increase the mechanical strength of the bone.10,11 However, some therapies for osteoporosis may be relatively contraindicated in patients with CKD. In this review, we discuss the evaluation and management of osteoporosis in patients who also have CKD, highlighting some of the more controversial therapies, such as use of bisphosphonates. OSTEOPOROSIS AND BONE DISEASES SPECIFIC TO THE CKD POPULATION Normal Bone Histologic Characteristics and Osteoporosis Bone is a complex 3-dimensional organ consisting of organic matrix, bone cells, and mineral salts. Factors associated with bone quality include quantifiable factors, such as bone mass and bone density, and qualitative factors, such as bone geometry (shape and size), microarchitectural features (cortical or trabecular connections), and molecular elements (collagen type and linkages, bone mineral composition, and crystal orientation). Bone also contains cells called osteoblasts, which deposit bone collagen and aid in bone mineralization, as well as osteoclasts, which break down bone mineral and collagen by secreting acids and digestive enzymes. In healthy adult bone remodeling, bone breakdown is balanced by bone formation. However, in osteoporosis, bone mineral and protein are normal, but the balance is shifted toward bone breakdown, leading to thinning of the 3-dimensional structure and increased fragility.10,11 Bone Disorders in CKD Individuals with progressive CKD invariably develop systemic deregulation of mineral and bone metabolism traditionally known as renal osteodystrophy, but more recently defined as CKDMBD.12 Although CKD-MBD now describes the wide range of systemic mineral metabolism derangements seen in people with CKD, the term renal osteodystrophy is used to specifically

describe the various abnormalities in bone histomorphologic characteristics caused by the characteristic disturbances in bone turnover, mineralization, and volume (called TMV, see Box 1) that develop as a consequence of CKD-MBD,8,12 whereas the definition of CKD-MBD also includes biochemical abnormalities and calcifications in vascular and other soft tissues.12 Bone volume is a new parameter used along with turnover and mineralization to describe renal osteodystrophy. Bone volume is a direct result of bone formation and resorption rates and is related directly to the porosity of bone and as such, to bone strength and bone fragility.13 The spectrum of histologic abnormalities in renal osteodystrophy includes adynamic disease, highturnover disease, mixed disease, and osteomalacia (see Box 2 for a glossary of terms). The nature of renal osteodystrophy shifts with the progression of kidney disease. Decreasing kidney function progressively disrupts the relationship among phosphorus, calcium, and their hormonal regulators, including PTH, 1,25 dihydroxyvitamin D,14 and the phosphaturic hormone fibroblast growth factor 23 (FGF-23). FGF-23 is secreted mainly by osteocyctes in response to increasing phosphate retention and acts to increase phosphate excretion.15 Increasing levels of FGF-23 eventually inhibit 1-_- hydroxylase production in the kidney, resulting in suppression of 1,25 dihydroxyvitamin D with the subsequent development of hypocalcemia and secondary hyperparathyroidism (SHPT). The dilemma for nephrologists is that CKD-MBD may coexist with osteoporosis, particularly in the elderly population in whom decreasing kidney function is prevalent. According to data from the NHANES III (Third National Health and Nutrition Examination Survey; 1988-1994), low BMD was much more prevalent in those with CKD than in those with normal kidney function.16 In addition, slightly _60% of women with a diagnosis of osteoporosis also had CKD stage 3, and 23% had CKD stage 4.16 Unfortunately, despite their very different pathophysiologic states, both osteoporosis and renal osteodystrophy independently increase bone fragility, presenting diagnostic and therapeutic challenges and collectively increasing the risk of fracture at all stages of CKD.17-20 METHODS FOR ASSESSING BONE Multiple methods are used to evaluate bone quantity and quality (Box 3). Probably the most common and inexpensive technology available to measure bone density is DEXA. Dual-Energy X-Ray Absorptiometry DEXA measures attenuation through the body tissues of low doses of x-ray, allowing the determination of both bone mineral content and bone area, from which BMD is calculated. In patients on hemodialysis therapy, DEXA of the lumbar spine often overestimates BMD, perhaps because of extraosseous densities, such as calcified blood vessels,21 or decreases in cortical and increases in trabecular bone in response to increased PTH levels,22 suggesting that the hip or forearm may be better sites for measuring BMD. Ameta-analysis in hemodialysis patients showed that at all BMD sites except the femoral neck, patients with fractures had significantly lower BMD than those without fractures.23 In one study of bone disease in CKD, half the participants had low BMD, which was associated with PTH levels _70 ng/mL.24 Although decreases in BMD are linked to increases in fracture incidence, 25 many fractures occur in patients who would not be considered osteoporotic on the basis of DEXA BMD.26,27 Partly for these reasons, the recent KDIGO (Kidney Disease: Improving Global Outcomes) guidelines do not recommend routinely testing BMD in patients with CKD stages 3-512; this lack of useful data supports the development and implementation of other technologies to better assess bone quality and strength.

Quantitative Computed Tomography Quantitative computed tomography (CT) detects the attenuation of x-rays as they pass through body tissues. In contrast to the 2-dimensional area measured using DEXA, quantitative CT measures (3-dimensional) volume. Quantitative CT images can separately measure cortical and trabecular bone geometry and morphology, an important feature because trabecular bone density decreases more in women than men with increasing age.28 In contrast to spine BMD using DEXA, quantitative CT can measure early increases in vertebral trabecular bone density after treatment with PTH.29 In one study of children with CKD and renal osteodystrophy who were undergoing bone biopsies, peripheral quantitative CT could distinguish the typical increases seen in trabecular bone BMD and decreases in cortical bone BMD.30 Magnetic Resonance Imaging Micromagnetic resonance imaging (MRI), the newest generation of high-resolution scanners, has been used to show the cortical thickening and loss of trabecular connectivity seen in dialysis patients with renal osteodystrophy. 31 This and other new MRI techniques may offer researchers a noninvasive method of studying the bone changes seen in renal bone disease. Ultrasound Quantitative ultrasound is a method for measuring appendicular skeletal density, most often in calcaneal bone, and may be a better technique than BMD using DEXA for predicting who will develop fractures.32 However, few studies have been done in patients with CKD. In those studies, the speed of sound transmission was decreased in patients with CKD or on dialysis therapy compared with healthy persons, was slowest in persons with the highest PTH levels,33,34 and in one small study, correlated negatively in only patients with biopsy-proven high-turnover disease. 35 Bone Biopsy The distinction between changes in bone caused by osteoporosis and those caused by CKDMBD can become more difficult to distinguish as CKD progresses into stages 4 and 5, and bone biopsy may be the only way to differentiate between the 2 conditons36 (Fig 1). The recent KDIGO guidelines suggest considering bone biopsy for unexplained fractures, persistent bone pain, unexplained hypophosphatemia, possible aluminum toxicity, and before therapy with bisphosphonates.12 One recent study of 2,340 biopsies carried out during a decade in Brazil and Uruguay suggested that hyperparathyroid bone disease is becoming more common,37 whereas the KDIGO guidelines suggest that the incidence of both osteitis fibrosa and adynamic bone disease is increasing.12 A biopsy sample of bone usually is obtained from the anterior iliac crest after double-tetracycline labeling. Tetracycline binds to newly formed bone at the unmineralized bone interface, where it is visible as a linear fluorescence. A second dose given 11-14 days after the first dose forms a second line. Measuring the distance between the 2 fluorescent labels allows calculation of the rate of bone formation during that interval.38 Discussion of histomorphometric criteria for distinguishing osteoporosis from CKD-MBD is beyond the scope of this article. The American Society for Bone and Mineral Research has developed standard criteria for differentiating among the various forms of metabolic bone disease.39

MANAGEMENT STRATEGIES FOR OSTEOPOROSIS IN PATIENTS WITH CKDMBD Making the appropriate diagnosis (ie, distinguishing renal metabolic bone abnormalities from those caused by osteoporosis) and correcting any metabolic derangements are necessary to adequately treat patients at risk of fractures from increased bone fragility. Treatment of osteoporosis is aimed at stabilizing or increasing bone mass and decreasing the risk of fracture, whereas treatment of CKD-MBD is centered on normalizing derangements in the PTHcalcium/phosphatevitamin D axis to maintain normal mineral metabolism and bone turnover. In the early stages of both conditions, some overlap occurs in prevention and treatment strategies (Table 1). The US Surgeon Generals recommended pyramidal approach to treatment41 can be followed to achieve the 4 major goals of osteoporosis treatment: prevention of fracture, stabilization or achievement of increased bone mass, alleviation of symptoms of fractures and skeletal deformity, and maximizing physical function.42 Lifestyle Changes Physical Activity and Exercise Although progressive load-bearing exercise has well-known osteogenic effects on bone metabolism in the adult and aged skeleton,43-45 even moderate-intensity walking may have beneficial effects. A modest increase in lumbar BMD was observed in a group of postmenopausal women with osteoporosis in response to moderateintensity walking.46 Unfortunately, there are no studies of the impact of exercise on bone in patients with CKD or end-stage renal disease (ESRD). Nevertheless, studies, including one of hemodialysis patients,47 show a positive correlation between muscle strength and BMD. Although effects of strength training on BMD have been equivocal in healthy populations,48 strength and muscle mass increase in response to strength training in patients with ESRD49 and thus may benefit bone. Fall Prevention More than 30% of individuals older than 60 years have at least 1 fall per year, and falls are the precipitating factor for nearly 90% of all fractures. 49 Common risks include problems often found in patients with CKD: previous falls, muscle weakness, dizziness or impaired balance, impaired vision, and medications (eg, sedatives, narcotics, analgesics, anticholinergics, and antihypertensives), as well as environmental factors, including obstacles and poor lighting. 50,51 A safety checklist to help patients identify and eliminate common household hazards is available from the National Osteoporosis Foundation (www.nof.org/patientinfo/fall_ prevention.htm).52 Dietary Changes Nutrition and Dietary Interventions A balanced nutritious diet with adequate caloric and protein intake is essential to maintain muscle mass and support normal growth and tissue regeneration, particularly in patients with CKD, because mechanical loading applied to the bone by muscle is directly responsible for bone formation and remodeling.53 Unfortunately, muscle mass typically is decreased as CKD progresses and muscle function deteriorates. Similarly, a decrease in lean body mass, which also occurs with aging, is an independent predictor of low BMD.54,55 Dietary Phosphate Restriction

Bone mineral existing in the body as calcium phosphate and phosphorus is as important as calcium in attaining and maintaining bone mass.56 Despite the relative efficiency of phosphorus absorption from the gut, there are circumstances in which phosphorus intake is insufficient for normal bone remodeling and may predispose to the development of osteoporosis. In patients with CKD, phosphorus-lowering treatment using binders, dietary protein restriction, or both is used in an attempt to control the increasing retention of phosphorus with disease progression, and inadequate phosphorus binding or restriction could possibly have adverse bone consequences. Slatopolsky et al57 showed several decades ago in dogs with progressive nephron reduction that maintaining the dogs on a low-phosphate diet prevented increases in PTH levels. More recently, Oste et al58 showed that despite having PTH levels in the reference range, rats with normal kidney function fed a high-phosphate diet had more osteoid formation and greater mineral apposition rates than rats with severe CKD (5/6 nephrectomy) fed a low-phosphate diet. Interestingly, rats with moderate CKD (1/2 nephrectomy) on a low-phosphate diet also had slower progression of CKD than rats on a higher phosphate diet (as well as lower PTH levels).59 Although higher serum phosphate levels in patients with CKD are associated with more rapid progression of kidney disease60-63 and recent research shows that serum phosphate levels at even the higher end of the reference range are associated with considerably increased risk of cardiovascular events and mortality in early stages of CKD,62,63 there is little information to date that decreasing serum phosphorus levels using dietary interventions or binders can change these outcomes.64 However, one study examining the effects of a very low-protein and phosphorusrestricted diet in patients with advanced kidney disease found that some patients experienced a decrease in bone formation rate resulting in bone loss that appeared to be the result of oversuppression of bone remodeling caused by relative hypoparathyroidism. 65 Subsequently, a study of predialysis patients with advanced stages of CKD who were placed on very low dietary protein and phosphorus-restricted diets for a mean duration of 5 years found that more than half the patients developed moderate to severe osteoporosis, even in those with normal bone turnover and despite the reversal of SHPT.66 This suggests that dietary phosphorus restriction through low-protein diets may increase the risk of the development of osteoporosis in patients with CKD despite the mitigation of renal osteodystrophy. Calcium and VitaminD Adequate vitamin D and calcium intake also are important for bone health; 25-hydroxyvitamin D insufficiency and deficiency are common in patients with CKD stage 3 and higher,67 but are not specifically related to GFR.15 Circulating levels of 1,25 dihydroxyvitamin D begin to decrease early in the time course of CKD, with reports of the earliest decreases beginning at a GFR just _90 mL/min/1.73 m2,68 and progressing as kidney mass and function decrease.68,69 SHPT develops in response to disruptions in the homeostatic control of PTH secretion by alterations in serum phosphorus, calcium, and 1,25 dihydroxyvitamin D associated with diminishing kidney function. PTH levels increase early in CKD, but can be suppressed by the administration of vitamin D sterols. The current focus of vitamin D treatment for the prevention of SHPT is on measuring its effects on bone metabolism and tissue calcification, as outlined in the current National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines70 and the recent KDIGO Clinical Practice Guidelines.12 In addition to the wellknown role of vitamin D in mineral homeostasis and bone metabolism, increasing evidence suggests that the pleiotropic extraskeletal actions of vitamin D on immune and endothelial function and cell-cycle regulation are clinically significant and low 25-hydroxyvitamin D levels should be treated. Adequate calcium intake undoubtedly is vital to bone mineralization, and a generally increased calcium requirement with aging has placed calcium supplementation at the

forefront in the prevention and treatment of osteoporosis. However, both population-based71 and recent interventional72- 74 studies show calcium supplementation to be associated with an increased incidence of cardiovascular disease. Results of these studies raise new concerns that this risk may outweigh the benefit of calcium supplementation to bone. Therefore both the KDOQI70 and KDIGO guidelines12 recommend that serum calcium levels be maintained within the reference range, and the KDOQI guidelines recommend that for patients with CKD stages 35, total elemental calcium intake (including both dietary calcium intake and calcium-based phosphate binders) not be _2,000 mg/d to decrease the risk of extraskeletal calcification. Pharmacologic Treatments for Osteoporosis in CKD Medications for osteoporosis generally are described as antiresorptive (ie, helping to prevent breakdown) or anabolic (ie, increasing bone mass). Evidence from clinical trials suggests both the efficacy and safety of US Food and Drug Administration (FDA)-registered pharmacologic agents for the treatment of osteoporosis in patients with age-related decreases in eGFR as low as 30 mL/min/1.73 m2 (ie, not CKD stage 4 or 5), but no evidence of CKD-MBD.36 However, because the severity of osteoporosis intersects with the development of CKD-MBD in the setting of worsening kidney disease, treatment decisions become more difficult. Because the pathogenesis of bone disease in patients with CKD-MBD is different from that of age-related or postmenopausal osteoporosis, extrapolation of results of studies in these populations may not be valid, with treatments considered safe in the general population posing increased concerns of long-term safety in patients with CKD who have evidence of CKD-MBD.12 Antiresorptive Agents Current FDA-approved antiresorptive drugs for the treatment and/or prevention of osteoporosis include bisphosphonates (alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid), estrogen/hormone therapy, calcitonin, and raloxifene. The latter is a selective estrogen receptor modulator (SERM) that interacts with the type of estrogen receptors found in bone. However, fewer data are available for this class of medications, which can be considered an emerging area. For patients with CKD stages 3-5 with biochemical abnormalities of CKD-MBD and low BMD, KDIGO guidelines recommend bone biopsy before the initiation of treatment with antiresorptive agents.12 Bisphosphonates. All bisphosphonates share a common structure (Fig 2); differing side chains for R1 and R2 alter both chemical and pharmacokinetic properties of the molecule. They have high affinity for bone mineral, binding strongly to hydroxyapatite and impairing osteoclast cell function by inhibiting enzyme activity.75 Intestinal absorption of bisphosphonates is _1%.75 When absorbed, the fraction not taken up by bone (40%-60%) is excreted unchanged through glomerular filtration and active proximal tubular secretion.76 Bisphosphonates accumulate in bone, with a half-life of more than 10 years,75 and gradually are released back into the circulation and taken up again or excreted. Recently, there is some question about the possibility of oversuppression of bone formation with long-term use of bisphosphonates,12 emphasizing the need for bone biopsy in patients with CKD to exclude lowboneturnover disease before starting bisphosphonate therapy. Severe hypocalcemia also has been reported when bisphosphonates have been used in patients with vitamin D deficiency,77,78 raising concern for patients with CKD-MBD not yet on vitamin D therapy. Current FDA warnings against using bisphosphonates in patients with GFR _30 mL/min/ 1.73 m2 were based on studies of rapid administration of high doses in rats resulting in histologic lesions in the kidney79 and acute kidney injury. 80,81 Although the presence of kidney disease was an

exclusion criterion in the large efficacy and safety trials for the current FDAapproved bisphosphonates, post hoc analyses using calculated eGFRs of participants showed that a considerable number of participants had agerelated kidney impairment. Published prospective trials of bisphosphonate use in patients with CKD stages 2-4 also generally excluded patients with metabolic abnormalities. Repeated analyses of several large risedronate82 and alendronate83 trials suggest that in the absence of laboratory indicators of CKD-MBD or other secondary causes of low BMD, use of bisphosphonates in patients with age-related CKD stages 2-4 is not nephrotoxic and results in a similar degree of decrease in fracture rate82,83 and increase in BMD83 as in women with normal kidney function. Similarly, the intravenous bisphosphonates (ibandronate and zoledronic acid) appear safe for use in patients with GFR _3035 mL/min/1.73 m2 and no evidence of CKD-MBD when administered as recommended,84 although a small subset of patients experienced a transient increase in serum creatinine levels (_0.5 to 2.0 mg/dL) that resolved before the subsequent annual injection. 85 Generally, ibandronate appears to have the smallest risk of nephrotoxicity86; however, there are case reports of significant nephrotoxicity in patients with normal kidney function with repeated use of high intravenous doses of zolendronate81 and particularly for pamidronate, for which a number of case reports and several case series have reported an association between higher doses of pamidronate and nephrotic syndrome, with collapsing focal segmental glomerulosclerosis as the most common pathologic finding. 86 In dialysis patients, one study showed an improvement in BMD with ibandronate, 2 mg, intravenously every 4 weeks for 48 weeks,85 and another small study showed that alendronate, 35 mg, every week for 6 weeks resulted in stabilization of hip BMD after 6 months compared with a loss of BMD in dialysis patients receiving placebo.87 Estrogen/hormone therapy. Estrogen exerts significant effects on the female skeleton and considerable evidence exists for a dominant role of estrogens in the bone turnover of men as well.88,89 Lack of estrogen increases osteoclastic bone re-sorption; in postmenopausal women, hormone replacement therapy increases bone mass and lowers the risk of fractures.90 In the Womens Health Initiative trial, hormone replacement therapy also increased serum calcitriol levels and decreased serum phosphorus levels.91 The investigators hypothesized that estrogen may cause the kidney to be more sensitive to the effects of PTH, decreasing tubular resorption of phosphorus and thus decreasing PTH levels.91 Premenopausal women with advanced CKD (stage 5) have a greater likelihood of premature and persistent amenorrhea, possibly because of impaired hypothalamic regulation of gonadotropin secretion, decreasing estradiol levels.92 Lower estradiol levels in these patients are associated with lower trabecular BMD and increased levels of bone resorption markers,93 and hormone replacement therapy has stabilized or increased BMD in premenopausal amenorrheic women on hemodialysis therapy.94 Estradiol pharmacokinetics are altered by CKD, and higher free and total estradiol levels are observed after oral estrogen administration in women with ESRD,95 suggesting that lower doses should be used. However, findings from the 1998 HERS (Heart and Estrogen- Progestin Replacement Study)96 and subsequent reports from theWomens Health Initiative in 200297 and 200498 showing increased risk of breast cancer, cardiovascular disease, and stroke that were not offset by benefits of fracture reduction require that the relative risk be considered carefully for each patient before the start of and during estrogen replacement therapy. Selective estrogen receptor modulators. Raloxifene, an estrogen agonist in bone, is the only SERM currently approved for the prevention and treatment of osteoporosis. Although only a small fraction of raloxifene is cleared by the kidney,99 a study evaluating treatment in men with impaired kidney function (median creatinine clearance, 33 mL/min/1.73 m2; range, 24-51 mL/min/ 1.73 m2) showed

increased levels and decreased clearance of raloxifene compared with findings in men with normal kidney function. Raloxifene decreases the risk of vertebral fractures by 30% in patients with prevalent vertebral fractures and by 50% in patients without prior vertebral fracture. 100 Retrospective analyses of data from a large clinical trial in postmenopausal women with agerelated impaired kidney function showed that women with eGFR _45 mL/min/1.73 m2 (n _ 1,480) were no more likely to experience adverse events than those with eGFR _60 mL/min/1.73 m2 (n _ 2,343).101 Lower baseline eGFR was associated with a greater increase in femoral neck BMD with raloxifene treatment However, only 55 women in this trial had an eGFR _30 mL/min/1.73 m2, and participants with increased PTH or low vitamin D levels were excluded. Treatment with raloxifene (60 mg/d for 1 year) in postmenopausal women on hemodialysis therapy with severe osteopenia or osteoporosis102 was associated with significant improvementin lumbar spine BMD, along with decreases in markers of bone resorption. Despite the increased risk of blood clots associated with raloxifene use,103 no venous thrombi, pulmonary emboli, or clotting problems with vascular access or dialysis catheters occurred throughout the year of treatment in this study. Calcitonin. Calcitonin inhibits renal phosphorus and increases renal calcium reabsorption, helping to decrease PTH hormone levels and inhibit osteoclast activity. Calcitonin, which can be given as an intranasal spray or by subcutaneous injection, increases BMD104,105 and decreases fracture incidence106 in women with established osteoporosis to a degree similar to the effect of SERMs, such as raloxifene. In rats with moderate CKD, calcitonin significantly decreased osteomalacia and other bone lesions independent of phosphorus intake.107 In hemodialysis patients, treatment with intranasal calcitonin (200 IU) administered with 1,25 dihydroxyvitamin D 3 times weekly resulted in a significantly greater increase in BMD and decrease in markers of bone resorption than seen with either drug alone.108,109 Long-term use of calcitonin can result in a gradual loss of skeletal response to its effects, reflecting the formation of antibodies against the exogenous calcitonin110 and receptor downregulation. 111 This has led to various therapeutic schemes using low doses given intermittently, ranging from as often as 3 times weekly to as infrequently as alternate years.112 Whether calcitonin could be used as an efficacious adjunctive therapy to preserve bone mass in patients with CKD with moderate to severe kidney disease has not been studied. Anabolic Agents The only anabolic medication currently approved by the FDAfor the management of osteoporosis is teriparatide, a recombinant formulation of PTH.113 Other anabolic medications associated with increases in bone turnover indices and BMD include testosterone and the testosterone- derived anabolic steroid nandrolone decanoate. Teriparatide. Teriparatide is a 34amino acid N-terminal fragment of human PTH and appears to contain all anabolic properties of the fulllength PTH. In the Fracture Prevention Trial, 1,637 postmenopausal women with mild (GFR, 50-79 mL/min/1.73 m2 using the Cockcroft- Gault equation) to moderately (GFR, 30-49 mL/ min/1.73 m2) impaired kidney function, but normal endogenous PTH levels, were randomly assigned to 20 or 40 mg of teriparatide or placebo. Compared with participants receiving placebo, those receiving teriparatide had dosedependent increases in BMD and decreased fracture risk. There was a similar incidence of kidney-related adverse events in both groups.114 All patients, regardless of baseline kidney function, developed transiently increased serum calcium levels _10.6 mg/dL 4-6 hours postinjection associated with increased urine calcium excretion.114 Use of teriparatide is contraindicated in patients with CKD with SHPT, although it might be a useful therapy in patients after parathyroidectomy with low BMD and/or fragility fractures. No information is available regarding the use of teriparatide in patients with CKD with adynamic bone disease. Testosterone. Hypogonadism is the most

common secondary cause of osteoporosis in men.115,116 Fifty-four percent of men with CKD stage 4 are reported to have low or low-normal testosterone levels,117 whereas _60% of men with ESRD have testosterone deficiency.118 Hypogonadal osteoporosis associated with low plasma 1,25 dihydroxyvitamin D levels, poor calcium absorption, and low serum calcium levels is reversed by treatment with testosterone.119 Testosterone acts through androgen receptors located on osteoblast cells to promote the proliferation and differentiation of osteoblasts and inhibit osteoclast recruitment.120,121 Trials to investigate the effects of testosterone replacement on BMD have produced mixed results; one study suggested a beneficial effect on lumbar spine BMD, but equivocal effects on femoral neck BMD.122 In addition to the increased risk of prostate cancer, testosterone may promote fluid retention and edema in patients with preexisting cardiac, kidney, or hepatic disease.123 This consideration is moot in dialysis patients. Nandrolone decanoate. Nandrolone decanoate is a derivative of testosterone synthesized to dissociate the anabolic effects from the androgenic effects. Like testosterone, nandrolone stimulates osteoblastic cell proliferation and differentiation and inhibits bone resorption by downregulating osteoclast activity. Nandrolone also increases intestinal and renal tubular calcium reabsorption.124 Although there are no specific reports of the effects of nandrolone on BMD in patients with CKD, studies of elderly patients with osteoporosis (ages _70 years) show that 50 mg every 3-4 weeks increases bone mineral content,125 increases BMD, and decreases fracture risk.126 In addition, nandrolone increases muscle mass in both predialysis patients with CKD127 and patients with ESRD on dialysis therapy,128,129 and, as described earlier, increased muscle mass has a well-known benefit on bone through its loading effect. FUTURE DIRECTIONS: DOES TREATMENT FOR OSTEOPOROSIS SLOW THE PROGRESSION OF CKD? Interestingly, some treatments that can improve bone function also have been associated with slowing the progression of kidney dysfunction. These include treatment of metabolic acidosis, 130 use of SERMs,131 low dietary phosphate, 57,58 and nitric oxide.132 Correction of Metabolic Acidosis The gradual development of mild metabolic acidosis as CKD progresses133 increases patients risks of bone loss. In an elegant series of experiments, Frick et al134 have shown in mouse calvariae that increasing concentrations of metabolic acids increases calcium flux from bone, effects that are only modulated, but not prevented, by altering vitamin D, PTH, or osteoclast function. Alkali therapy effectively decreases urinary calcium losses135 and bone resorption136 in healthy older adults and corrects abnormal bone cell function and increases BMD in children with distal renal tubular acidosis.137 Acidosis also stimulates catabolic pathways in muscle, leading to protein breakdown and muscle wasting.138 The current KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in CKD recommend that serum total carbon dioxide levels be _22 mEq/L, and if necessary, supplemental alkali salts should be given to achieve this goal.70 Nitric Oxide Supplementation Nitric oxide has prevented bone breakdown in ovariectomized rats and women.40 A small study comparing isosorbide dinitrate, 60 mg/d, with alendronate, 70 mg/wk, by Nabhan and Rabie139 showed equivalent increases in BMD in postmenopausal women after 1 year of treatment. More recently, analysis of participants in the Canadian Multicentre Osteoporosis Study showed significant positive associations between nitrate use and higher BMD.140 No study has investigated nitrate use in patients with CKD; however, these

agents often are administered to patients with endothelial dysfunction, a common problemin patients with CKD. CONCLUSIONS AND RECOMMENDATIONS Osteoporosis and CKD often coexist in patients. For patients with early CKD, many recommendations from the US Surgeon General for treatment of osteoporosis are similar to those for patients with CKD. As patients age and kidney function decreases, various bone metabolic factors, such as calcium, phosphate, vitamin D, and PTH levels, change, confounding the bone histologic picture of osteoporosis with the metabolic abnormalities of bone matrix and mineralization associated with increasing PTH and FGF-23 levels and decreasing 1,25 dihydroxyvitamin D levels. Although DEXA is widely used to determine the degree of BMD decrease, more precise modalities, such as quantitative CT and micro-MRI, may be more useful in patients who may have both osteoporosis and CKD-MBD. At present, bone biopsy remains the gold standard for diagnosis and is recommended before treating patients with the metabolic abnormalities of CKDMBD with many of the medications described. Multiple pharmacologic treatment options are available for patients with both CKD and osteoporosis, with a considerable degree of overlap between the 2 groups. However, available data apply to only patients with normal calcium/phosphate/ PTH levels and GFR _30 mL/min/1.73 m2. Data from trials in patients with MBD and more advanced CKD not yet on dialysis therapy are limited. The KDIGO guidelines summarize the paucity of method-qualified trials; accordingly, most of the guideline is composed of level 2 recommendations, rather than mandatory therapeutic approaches.Areas of future study include determining the best imaging modality for predicting fractures in patients withCKD-MBD,whether vascular calcifications identify patients who may benefit from specific treatments, and the relationship of specific treatments to clinical outcomes.12 CASE REVIEW Many options exist for the patient described at the beginning of this article, who is osteopenic by means of DEXA. Given that she has CKD stage 3-4 and biochemical abnormalities consistent with CKD-MBD, options to consider to better identify the problem(s) before initiating specific treatments are listed in Box 4. In this case, the patient refused to undergo bone biopsy. She was referred for nutritional counseling; pioglitazone therapy was changed to glyburide, 5 mg/d; and treatment with calcitriol, 0.25 mg/d, and isosorbide dinitrate, 20 mg, thrice daily was started, with resultant improvement in blood pressure to 120-130/70-75 mm Hg and a decrease in serum PTH level. ACKNOWLEDGEMENTS We thank Dr Jean Olson from the UCSF Department of Pathology for generous use of bone slides for this manuscript. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.