Chronic kidney disease (CKD) affects 23 million people in the United States, or 14% of the population. Worldwide, the prevalence of CKD is estimated at 8% to 16% of the population. CKD is associated with numerous morbidities and complications, one of which is mineral and bone disorder (CKD-MBD), a spectrum of disorders previously known as renal osteodystrophy (Figure 1). Primary care providers need to be aware of the pathogenesis and pathophysiology of CKD-MBD and should be able to screen for, diagnose, and treat this complication.
The Kidney Disease Outcomes Quality Initiative (KDOQI) from the National Kidney Foundation (NKF) in 2002 released guidelines that stratified CKD into five stages (Table 1) and outlined complications, treatment, and other management strategies associated with each stage.1 These guidelines significantly changed the day-to-day management of CKD, for the first time providing standards for evaluating and treating CKD. The guidelines were most recently updated in 2012.1,2 Kidney Disease Global Outcomes (KDIGO), established by the International Society of Nephrologists and managed by the NKF, has endorsed the KDOQI guidelines but also has published its own guidelines, which sometimes differ from KDOQI's.3
Most complications of CKD begin to be symptomatic or evident in serum markers in stage 3. Before that, even as nephrons are injured or destroyed, patients have adequate glomerular filtration rate (GFR) and physiologic function, and the nephrons begin to hyperfilter as they try to compensate for their declining numbers.4 The patient remains asymptomatic and unaware of loss of kidney function, even as GFR falls and serum creatinine begins to rise above normal. However, once the estimated GFR (eGFR) falls to 60 mL/min/1.73 m2 or lower (stage 3), corresponding to a serum creatinine of about 2 mg/dL, normal homeostatic physiologic mechanisms begin to deteriorate.
One of the most difficult and time-consuming complications of CKD is managing concomitant bone disease, a complex disorder that typically becomes problematic in stages 3 and 4.1 Guidelines vary somewhat for patients on peritoneal or hemodialysis (stage 5D), which will not be discussed in this article.
In normally functioning kidneys, about 90% of plasma phosphate is filtered and excreted.5 However, in patients with CKD, disorders that lead to CKD-MBD (including secondary hyperparathyroidism, hyperphosphatemia, decreased intestinal calcium absorption and disordered vitamin D metabolism) begin in stage 2 but do not become clinically detectable until late stage 3 or early stage 4.6-8
Levels of parathyroid hormone (PTH) are regulated by a negative feedback loop with serum calcium levels. Low serum calcium stimulates the parathyroid glands to secrete PTH; high serum calcium inhibits PTH secretion. However, in patients with CKD, osteocytes and osteoblasts secrete increased levels of fibroblast growth factor 23 (FGF23).9 FGF23 maintains normal serum phosphate levels by reducing phosphate reabsorption in the tubules. FGF23 also reduces phosphate absorption in the small intestine through decreased vitamin D (calcitriol) production. These mechanisms maintain normal serum calcium and phosphorus levels early in CKD, even as the patient's PTH level rises. The patient's serum calcium and pH levels generally remain within normal limits until GFR declines to less than 50 mL/min/1.73 m2 late in stage 3.7,10,11
By stage 3 CKD, which corresponds to a 50% decline in kidney function, 60% of patients have developed an elevated PTH level.10 This stimulates the nephrons to excrete phosphorus and stimulates bones to release calcium, resulting in ongoing bone resorption, remodeling, and redistribution, and (rarely) osteitis fibrosa (Table 2).
PTH also stimulates the proximal tubules in the kidneys to produce calcitriol in a further attempt to increase calcium levels and counteract the effect of FGF23 on calcitriol levels. However, despite rising levels of PTH, the kidneys' ability to activate vitamin D decreases as nephrons are lost, and PTH becomes ineffective. Hyperphosphatemia further suppresses production of calcitriol.8 As PTH remains elevated, receptors on the bones downregulate, which results in skeletal resistance to its calcemic action. As eGFR continues to decline, adaptive mechanisms no longer are able to maintain calcium-phosphorus homeostasis. The end result is hyperphosphatemia and secondary hyperparathyroidism (Figure 2). Some patients can develop tertiary hyperparathyroidism, in which PTH remains high and cannot be controlled medically, probably due to parathyroid hyperplasia. Parathyroidectomy is the only treatment for this condition.5,12,13
Bone is weakened further by metabolic acidosis, which usually occurs in stage 4 CKD due to decreased secretion of hydrogen ions into, and decreased reabsorption of bicarbonate ions from, the tubular fluid.8 As a compensatory mechanism, calcium is drawn from the bone to buffer the excess hydrogen ion, further worsening bone mineral density.14
Some causes of CKD require treatment with high-dose and/or prolonged courses of corticosteroids (lupus nephritis, Goodpasture syndrome, focal segmental glomerulosclerosis, membranous nephropathy, minimal change disease, or membranoproliferative glomerulonephritis), further weakening bone through other complex mechanisms. Aluminum-containing medications previously used as phosphate binders to treat hyperphosphatemia in patients with CKD caused osteomalacia and are no longer used in the United States for treating CKD.
Alterations in bone turnover contribute to decreased skeletal mechanical competence, which can result in fractures and diminished capacity to bear loads. The most common fractures are fragility fractures of the vertebrae, femoral neck of the hip, or the wrist (Colles fractures).15 From a symptomatic perspective, patients experience bone pain, increased risk of pathologic fractures, joint stiffness, proximal muscle weakness, spontaneous tendon rupture, and decreases in mobility and strength.11 Subsequently, patients can become disabled, have a reduced quality of life, be hospitalized more frequently, and may die prematurely.
Cardiovascular disease is the leading cause of death in patients with CKD. Hyperphosphatemia has been shown to stimulate osteoblasts and vascular calcification, particularly of arteries and cardiac valves.6 This extraosseous calcification, theorized to be driven by the metabolic derangements of CKD-MBD, starts early in CKD and increases as kidney function decreases. Calcification is more severe and accelerated in patients with CKD compared with healthy patients.7 Hyperphosphatemia may be caused by the early upregulated production in the diseased kidneys of substances including wingless/integration 1 inhibitors, Dickkopf-1, sclerostin, and secreted klotho, which regulates osteocyte FGF23 secretion.6
In mice also treated with a phosphate binder, administering a monoclonal antibody that neutralized Dickkopf-1 prevented vascular calcification, which offers the possibility of simultaneous treatments for CKD-MBD and CKD-induced vascular calcification.6,7 More research is needed in this area.
Given the spectrum of disorders described in Table 2, no single diagnostic procedure or test can accurately evaluate CKD-MBD. Abnormalities in bone matrix probably begin to occur at an eGFR of about 60 mL/min/1.73 m2 (late stage 2) but may not be clinically detectable in bone and plasma until the eGFR declines to 40 to 50 mL/min/1.73 m2.6 KDIGO recommends using three parameters (collectively called TMV) to assess bone pathology: bone turnover (high or low), mineralization (high or low), and volume (normal or abnormal) (Table 2). This system emphasizes the importance of multiple parameters when assessing bone quality because treatment can vary with the type of bone disease present.
- Bone turnover measurements assess bone formation rate via tetracycline labeling, which is not used in the clinical setting. Low bone turnover is characterized by changes in microstructure; high bone turnover manifests as changes in composition and mechanical properties.8
- Mineralization reflects the amount of unmineralized osteoid and is assessed by bone scan, which is unreliable in patients with CKD-MBD because calcified soft tissue creates artifact and complicates interpretation of the test.16
- Bone volume is the fraction of a given volume occupied by mineralized bone, and reflects the activity of osteoblasts (bone formation) and osteoclasts (bone resorption). A bone biopsy is the gold standard for determining bone volume but is not routinely recommended.17
Given the complexity of CKD-MBD, serum laboratory tests and imaging studies do not adequately predict underlying bone histology.3 The most accurate method of diagnosing the nature of bone disease remains biopsy, which can assess TMV but is impractical on a widespread basis.3 Bone biopsy frequently is unnecessary because a precise histologic diagnosis often does not alter treatment plans. However, KDIGO recommends performing a bone biopsy (not graded) on patients with CKD stages 3 to 5 in the following situations: unexplained fractures, elevated levels of calcium and/or low levels of phosphorus, persistent bone pain, possible aluminum toxicity, and before starting therapy with bisphosphonates.3 In 2010 KDOQI provided a commentary on this recommendation, stating that a pool of proficient pathologists would be needed to interpret the biopsies, which may not be available or practical. They recommended that “bone biopsy should be considered in patients for whom the cause of clinical symptoms and biochemical abnormalities is not certain and for whom the effect of treatment on bone needs to be assessed.”7
KDOQI recommends beginning to monitor the metabolic abnormalities that accompany CKD-MBD in stage 3. To assess bone health without doing a biopsy, KDIGO recommends measuring serum PTH or bone-specific alkaline phosphatase; markedly high or low values of these parameters indicate the degree of bone turnover.3 In its commentary, KDOQI stated that the value of alkaline phosphatase in clinical decision making is unproven at this time, but that monitoring PTH and alkaline phosphatase levels may be useful to estimate bone turnover, especially in patients with very abnormal values.7 Unfortunately, the lack of strong objective evidence for the utility of these parameters leaves clinicians with no definitive method for how best to monitor bone health and density. Monitoring serum PTH is accepted clinical practice at this time.
In addition to evaluating bone with PTH level, clinicians must screen patients for biochemical abnormalities associated with secondary hyperparathyroidism, including hypocalcemia, hyperphosphatemia, and low calcidiol level. Calcidiol is the preferred assay for measuring vitamin D because of its long half-life and because it reflects both dietary intake and skin synthesis of vitamin D.3 KDOQI notes that the rate of change and severity of laboratory abnormalities are highly variable among patients and that no data support a specific testing frequency.7 KDOQI guidelines recommend monitoring patterns and temporal trends and rechecking based on clinical judgment (Table 3).7 KDIGO agrees that the presence and magnitude of abnormalities, trends in levels, and rates of CKD progression should dictate monitoring in actual practice (Table 4).3
In patients with evidence of CKD-MBD (biochemical abnormalities and/or fragility fractures), KDIGO and KDOQI do not recommend routine bone mineral density testing (either with bone-density scanning or quantitative CT or MRI) in patients with stages 3 through 5 CKD, stating that routine testing does not predict fracture risk in patients with CKD as it does in the general population, and does not predict the type of CKD-MBD.3 If a patient has a fragility fracture, bone biopsy is recommended before starting bisphosphonate therapy.3,7 Bone-density scanning is recommended only for patients with stage 1 or 2 CKD who have had a fragility fracture or have risk factors for osteoporosis, including female sex, age, white or Asian race, smoking history, excessive alcohol consumption, family history, low intake of calcium and/or vitamin D, and sedentary lifestyle. Treatment is the same as for the general public.18
Treatment of CKD-MBD varies with the primary metabolic abnormality, the specific type of bone disease, and the severity of the underlying kidney dysfunction. When deciding how to treat, assess multiple metabolic parameters including serum phosphorus, calcium, PTH, and calcidiol levels. The goals are to maintain blood levels of calcium and phosphorus as close to normal as possible, to prevent or treat established hyperparathyroidism (the optimal PTH level is not known), prevent parathyroid hyperplasia, and avoid oversuppressing bone turnover to prevent inducing adynamic bone disease.3,8 Initial treatment of secondary hyperparathyroidism in patients not on dialysis involves a combination of dietary phosphate restriction and phosphate binders, with or without calcium.
Table 5 lists KDIGO recommendations for management of biochemical abnormalities in patients with CKD. Both KDIGO and KDOQI recommend checking laboratory results more frequently after making a therapeutic change and evaluating calcium and phosphorus levels separately, rather than the calcium-phosphorus product.3,7
Hyperphosphatemia also has been associated with the development of secondary hyperparathyroidism, reduced serum calcitriol levels, abnormal bone remodeling, and soft-tissue calcification.7 KDIGO notes that high normal serum phosphorus levels have been associated with increased cardiovascular risk and mortality in patients who do not have CKD and in patients with stage 3 CKD. Because no evidence exists that lowering serum phosphorus to a specific target range improves outcomes, KDIGO states that recommended goals must be based on observational data.3 A recent study of 13,000 patients from the Third National Health and Nutrition Examination Survey found that patients in the highest quartile of fasting serum phosphorus had a 74% increased risk of all-cause mortality and a twofold increased risk of cardiovascular mortality compared with those in the lowest quartile.19 However, the authors note that this was an observational study, with all its limitations, and patients' PTH and FGF23 levels were unknown.19 Once hyperphosphatemia occurs, the initial intervention is to limit patients' dietary phosphorus intake to 800 to 1,000 mg/day or less.1 Prescribe a phosphate binder and refer patients to a registered dietitian or nutritionist for education and help in planning meals that do not compromise optimum nutrition.3Many foods that may need to be restricted are good sources of protein, such as dairy products, meat, poultry, fish, nuts, beans, and grains.3
Some phosphate binders contain calcium. KDIGO notes that no evidence exists to favor one phosphate binder over another, and recommends choosing an agent that improves all clinical parameters, not just phosphorus.3 The therapeutic choice should take into account the patient's CKD stage, presence of other components of CKD-MBD, other medications the patient is taking, and potential adverse reactions. As per the KDIGO guidelines, if a patient is hypocalcemic, either calcium acetate or calcium carbonate is acceptable, and their costs are much lower than the agents that do not contain calcium.
Calcium citrate is not recommended in patients with CKD because it enhances aluminum absorption.3 However, if the patient has one or more of the following: known arterial calcification, adynamic bone disease, persistently low serum PTH level, high normal serum calcium level, and/or is taking vitamin D, KDIGO recommends using calcium-based phosphate binders with caution and possibly restricting the dose of the binder and/or vitamin D.3 Patients who are hypercalcemic should receive agents that do not contain calcium (such as sevelamer carbonate or lanthanum carbonate), which also can be used in normocalcemic patients whose calcium may be high-normal. Lanthanum carbonate does not cause a decrease in serum bicarbonate level, and is the preferred agent in patients with metabolic acidosis.
In its 2010 response to the KDIGO guidelines, KDOQI stated that although phosphate binders lower serum phosphorus levels, no randomized controlled trials have examined whether treating hyperphosphatemia to specific treatment goals improves clinical outcomes.7 KDOQI also noted that phosphate binders cause gastrointestinal adverse reactions and contribute to the high pill burden of patients with CKD because they have to be taken with every meal and snack. KDOQI recommends maintaining phosphorus levels in the normal range rather than establishing a specific target value.7
Calcium-based phosphate binders may contribute to vascular calcification, which has major implications for patient mortality. Because phosphate binders must be taken frequently, patients may exceed the maximum recommended daily calcium intake. The KDIGO guidelines suggest using an abdominal radiograph to detect vascular calcification and an echocardiogram to detect valvular calcification.3 However, KDOQI does not recommend imaging, noting that the vascular calcification seen in patients with CKD may be different from that seen in patients with atherosclerosis who do not have CKD, and that patients cannot be stratified into risk groups for treatment.7 KDIGO recommends restricting the dosage of calcium-based phosphate binders in patients with persistent or recurrent hypercalcemia.3 The 2002 KDOQI guidelines state that daily intake of calcium from phosphate binders should not exceed 1,500 mg and that daily intake of calcium from phosphate binders plus diet should not exceed 2,000 mg.1 The KDOQI workgroup notes that although no trial data support these numbers, the recommendation remains, based on expert opinion. The phosphate binder dose should be titrated to maintain normal phosphorus and calcium levels; at this time, controlling serum phosphorus and PTH levels is the best way to normalize serum calcium.7 More studies are needed to more firmly establish safe daily intake parameters for calcium.7
Vitamin D deficiency is associated with elevated PTH levels and may worsen the manifestations of secondary hyperparathyroidism in patients with CKD stages 3 and 4.3 If the patient's PTH is elevated and/or serum calcium is low, measure the calcidiol level. KDIGO recommends treating deficiency and insufficiency as per the general population, although some endocrinologists differ.20 Although vitamin D deficiency has known adverse reactions, including rickets and osteomalacia, the risks associated with insufficiency are less clear, and no consensus exists about what is a sufficient or toxic level.3,5 Because vitamin D deficiency may be an underlying cause of elevated PTH in patients with stage 3 or 4 CKD, KDIGO recommends measuring and supplementing these patients as per guidelines for the general public.3 KDIGO does not recommend a target or threshold level of calcidiol but notes that no data suggest that the presence of CKD alters recommended levels.3
Vitamin D analogues have not been shown to be clinically superior to calcitriol, so any of the available oral agents are acceptable.7 The goal is to maintain the patient's serum calcium level within normal limits. Patients whose serum calcidiol level is 20 to 30 ng/mL (vitamin D insufficiency) should receive 8,000 to 10,000 international units [IU] of vitamin D supplementation per week and have their calcium and phosphorus levels checked every 3 months.20 Patients with vitamin D deficiency (less than 20 ng/mL) should be supplemented with 100 IU for every 0.7 ng/mL that their level is below normal.20 Check calcium and phosphorus levels every 3 months and reduce the patient's calcidiol dose as appropriate to maintain these electrolytes within target ranges. Patients who are vegans may prefer vitamin D2, which is made from ultraviolet irradiation of yeast, over vitamin D3, which is made from irradiation of lanolin.21
Whether patients with CKD should be treated with bisphosphonates or other osteoporosis medications depends on the nature of the bone disease, the patient's history of fragility fractures, reversibility of the biochemical abnormalities, and progression of CKD. KDOQI recommends that clinicians considering osteoporosis medication for a patient obtain a bone biopsy to establish the type of bone disease present, then treat only patients with increased bone resorption, stable GFR without abnormalities of vitamin D metabolism and PTH, and in whom the risk of fracture outweighs the long-term risk of inducing irreversible low bone turnover.7 Osteoporosis treatment for patients with stage 3 CKD and normal PTH should be the same as for the general population.3 Bisphosphonates taken orally achieve maximum resorption of bone within 3 months of initiation, a rate that remains steady throughout treatment. IV bisphosphonates work more rapidly, with a sustained effect measured by biochemical markers for 2 years. The estimated half-life of all these drugs is 10 years.22
As with many aspects of CKD, the optimal approach is unclear, due to a lack of evidence about:
- the best method of diagnosing CKD-MBD
- to what degree biochemical abnormalities should be treated (intensive versus less-intensive approach)
- optimal serum levels of phosphorus and PTH
- whether correcting low serum calcidiol levels improves outcomes, and if so, which vitamin D supplement formulation is best
- whether phosphate binders improve survival, and if so, which agents are preferred
- if calcium-containing phosphate binders contribute to vascular calcification, and if so, can the risk be quantified
- whether treatment with bisphosphonates, teriparatide, or raloxifene reduces fractures or vascular calcification
- if efforts to reverse adynamic bone disease affect clinical outcomes.3
Future research efforts should focus on decreasing levels of FGF23 with the early use of phosphate binders, before serum levels of phosphorus become abnormal, in an attempt to reduce vascular calcification, CKD progression, and mortality.10 Other studies are focusing on neutralizing Dickkopf-1 with antibody therapy, which has been shown to prevent vascular dedifferentiation, vascular calcification, and renal osteodystrophy and decrease levels of sclerostin.6 Human trials are needed, and future treatment may involve both.
CKD-MBD and its inherent pathophysiologic mechanisms are increasingly recognized as key factors in the high mortality of CKD.6 CKD-MBD is characterized by biochemical abnormalities, abnormalities in bone turnover, mineralization, growth, and/or strength, and vascular calcification. Despite the complexity of the issues, patients with CKD should be monitored for biochemical signs of mineral bone disease and treated for hyperphosphatemia, and, to the extent possible, every effort should be made to prevent or treat secondary hyperparathyroidism.
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6. Fang Y, Ginsberg C, Seifert M, et al. CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. J Am Soc Nephrol
7. Uhlig K, Berns JS, Kestenbaum B, et al. KDOQI US commentary on the 2009 KDIGO clinical practice guideline for the diagnosis, evaluation, and treatment of CKD-mineral and bone disorder (CKD-MBD). Am J Kidney Dis
8. Martin KJ, González EA. Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol
9. Isakova T, Wolf MS. FGF23 or PTH: which comes first in CKD. Kidney Int
10. Oliveira RB, Cancela AL, Graciolli FG, et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy. Clin J Am Soc Nephrol
11. Hasegawa H, Nagano N, Urakawa I, et al. Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. Kidney Int
12. Qunibi WY, Henrich WL. Overview of chronic kidney disease-metabolic bone disease (CKD-MBD). UpToDate
13. Fuleihan GE, Silverberg SJ. Clinical manifestations of primary hyperparathyroidism. UpToDate
14. Kovesdy CP. Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease. UpToDate
16. Toussaint ND, Elder GJ, Kerr PG. Bisphosphonates in chronic kidney disease: balancing potential benefits and adverse effects on bone and soft tissue. CJASN
17. Ott SM. Histomorphometric measurements of bone turnover, mineralization, and volume. Clin J Am Soc Nephrol
20. Dawson-Hughes B. Vitamin D deficiency in adults: definition, clinical manifestations, and treatment. UpToDate
22. Kennel KA, Drake MT. Adverse effects of bisphosphonates: implications for osteoporosis management. Mayo Clin Proc
23. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int
Keywords:Copyright © 2016 American Academy of Physician Assistants
chronic kidney disease; mineral bone disorder; hyperphosphatemia; secondary hyperparathyroidism; phosphate binders; adynamic bone disease