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Osteoporosis in patients with CKD: a diagnostic dilemma.

Osteoporosis in patients with chronic kidney disease (CKD) is a complex problem, with diagnostic criteria and treatment plans often debated. The debate focuses on how best to assess for osteoporosis in patients with CKD, and if and how to plan therapy.

Clinicians and researchers concur that the diagnosis of osteoporosis in patients with CKD is only definitive with bone biopsy, but bone biopsy is neither practical nor accessible in many clinical settings and is often cost prohibitive (Miller, 2014). Without a definitive diagnosis, the question is whether or not the clinician should consider therapy for osteoporosis in patients with CKD. The debate creates a practice dilemma, especially when faced with an aging population and an increasing incidence of fragility fractures. This article discusses the dilemma as seen from the perspective of nephrology clinicians on differentiating osteoporosis from other bone mineral disorders in patients with progressive CKD.

The Dilemma

Changes in mineral metabolism and bone structure develop early as a consequence of CKD and worsen with progressive loss of kidney function (Chauhan, Kelepouris, Chauhan, & Vaid, 2012). The condition is known as CKD mineral and bone disorder (CKD-MBD) and may result in fragility and low impact fractures that can mimic osteoporotic fractures (Gordon & Frassetto, 2010). Differentiating the cause of a fragility fracture is important because the pathophysiology and management differs vastly between osteoporosis and CKD-MBD. Not all clinicians appreciate the significance or evidence of CKD-MBD in their patients and may insist on treatment of osteoporosis when, in fact, the intervention could do more harm than good (Gordon & Frassetto, 2010; Stehman-Breen, 2004). It is important for clinicians to understand the biochemical and histological changes that occur in progressive CKD in order to understand that pharmacological interventions for osteoporosis may or may not be concordant with best practices in CKD management.

Significance to Nephrology Nursing

Osteoporosis and CKD are common conditions, especially in older adults, and both may be associated with substantial morbidity. The diseases follow population trends for the aging patient; the older the patient, the higher the risk for CKD, osteoporosis, and fracture (Gordon & Frassetto, 2010). The aging population in the United States (U.S.) is growing, so this topic and our patients deserve this attention.

Important Definitions

Osteoporosis

Osteoporosis is a disease in which bones become fragile and are more likely to fracture because they lose density as measured by the amount of calcium and minerals in the bone (Masi, 2008). The World Health Organization (WHO) (2004) defined osteoporosis in women as bone mineral density (BMD) of a T score threshold of -2.5 standard deviation (SD) less than peak bone mass (20-year-old healthy woman average) best measured using dual energy X-ray absorptiometry (DXA). Osteoporosis results from an imbalance between bone production and bone resorption, with the imbalance tilting toward resorption (McCance, Huether, Brashers, & Rote, 2010).

CKD

CKD is the gradual loss of kidney function. It causes abnormalities in calcium, phosphate, parathyroid hormone, and vitamin D metabolism, all of which affect bone health (Centers for Disease Control and Prevention [CDC], 2013).

CKD-MBD

CKD-MBD is the systemic mineral metabolism derangements found in the CKD population. CKD-MBD includes abnormalities in calcium, phosphorus, parathyroid hormone, or vitamin D; bone turnover, mineralization, volume, liner growth, or strength; and/or vascular or other soft tissue calcification found in patients with CKD (Liu, Yen, Lang, Yan, & Lu, 2013). The emphasis in CKD-MBD is on the systemic nature of the disease, affecting bone, vascular, and other soft tissues (Ott, 2010).

Osteodystrophy

Osteodystrophy describes the various abnormalities in bone histo-morphology caused by bone turnover, mineralization, and volume that develops as a consequence of more severe forms of CKD-MBD (Kidney Disease: Improving Global Outcomes [KDIGO] CKD-MBD Work Group, 2009).

Bone Volume

Bone volume is a parameter used along with bone turnover and mineralization to describe renal osteodystrophy. Bone volume is a direct result of bone formation and resorption rates, and is related to the porosity, strength, and fragility of bone (Gordon & Frassetto, 2010).

Adynamic Bone Disease

Adynamic bone disease is char acterized by low rates of bone formation and resorption, and is primarily a disease of bone turnover (Gordon & Frassetto, 2010).

High Turnover Bone Disease

High turnover bone disease is often associated with secondary hyperparathyroidism and classically has high rates of bone formation and resorption (Gordon & Frassetto, 2010).

National Kidney Foundation Stages of CKD

The National Kidney Foundation (NKF) stages of CKD are shown in Table 1.

Epidemiology of Osteoporosis and CKD

Osteoporosis and CKD are common conditions of older adults and often occur concurrendy (Gordon & Frassetto, 2010). Osteoporosis is the most common type of bone disease in the general population (National Institutes of Health [NIH], 2015). A study released in by the National Osteoporosis Foundation (2014) revealed that up to 54% of the American population is affected by osteoporosis or low bone mass. The study estimated that among adults aged 50 years and older, 10.3% (10.2 million) had osteoporosis and 43.9% (43.4 million) had low bone mass in 2010. When combined, the estimated number of adults with osteoporosis and low bone mass was 53.6 million, representing approximately 54% of the U.S. adult population aged 50 years and older. It is estimated that about one half of all women over age 50 years will fracture the hip, wrist, or vertebra during their lifetime. Hip fractures, long considered more devastating than any other type of osteoporotic fracture, occur at a rate of about two million per year in the U.S. and have been projected to increase to three million by 2025 (Burge et al, 2007).

In 2007, Burge et al. estimated that osteoporotic fractures cost the U.S. healthcare system between $17 billion and $20 billion, annually. These direct medical costs represent a greater burden on national healthcare costs than the projected annual costs of stroke, breast cancer, diabetes, or chronic lung disease (CDC, 2013).

The prevalence of CKD was reported to be 14.8% in 2011-2014, with CKD Stage 3 being the most prevalent stage (United States Renal Data System [USRDS], 2016). End stage CKD is associated with an increased risk of low-trauma fractures and associated mortality. Research studies show the relationship of decreased eGFR with an increase in hip fractures regardless of age, and show an even greater risk in women over age 65 years with moderate to severe CKD (Miller, 2014). An example is in a case-cohort study of women age 65 years and older demonstrating higher hip fracture rates in those with eGFR of 45 to 59 mL/min/1.73[m.sup.2] as compared to women with a eGFR greater than 60 mL/min/[1.73.sup.2] (Miller, 2014).

Pathophysiology of Osteoporosis

Bone is living tissue that is constantly being replaced, as is true with all cells. Bone consists of the matrix, bone cells (osteoblasts, which aids in laying down new bone; osteoclasts, which break down and remove old bone), and mineral salts (Liu et al., 2013). In healthy adult bone remodeling, bone breakdown is balanced with new bone formation. However, in osteoporosis, the balance shifts toward breakdown and leads to a reduction in bone density or mass. The bone that remains is histologically and biochemically normal, but there is not enough of it to support skeletal integrity (Gordon & Frassetto, 2010; McCance et al., 2010). Osteoporosis develops when the remodeling cycle is disrupted. This can happen as rapid bone loss or slow bone loss (Barliya, 2013).

The process of bone turnover resorption of old bone and creation of new bone--is compromised in the aging body and especially in women after menopause, which increases the propensity for fractures. As estrogen levels decrease in menopause, bone resorption increases caused by an increased lifespan of osteoclasts and decreased life span of osteoblasts (Chauhan et al., 2012).

Risk Factors for Osteoporosis and Fractures

The NIH (2015) identifies several interacting risk factors for osteoporosis and fragility fractures that are classified as clinical, medical, behavioral, nutritional, and genetic.

* Clinical. Normal aging and peak bone mass (defined in adolescences and early adulthood), low body weight, and/or low percentage of total body fat. A history of hyperthyroidism, previous fracture, and impaired vision are other clinical risk factors.

* Medical. Gastrointestinal disorders, such as malabsorption and irritable bowel disease; hematological disorders, such as thalassemia and pernicious anemia; hypogonadal states (amenorrhea); and chronic use of certain medications, such as glucocorticoids.

* Behavioral. Tobacco use, low levels of activity, increased alcohol use (greater than seven ounces per week) and excessive caffeine intake.

* Nutritional. Dietary calcium intake of less than 1,000 to 1,200 mg daily, especially in lean men and women. Vitamin D deficiency.

* Genetic factors. Race, especially in Caucasian and Asian women over age 50 years. The lowest hip fracture rate and highest mean bone mineral density has been reported in black women (Lane, 2006; NIH, 2015).

Pathophysiology of CKD-MBD

CKD-MBD includes abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular calcifications. Renal osteodystrophy occurs in patients with advanced CKD and includess hyperparathyroidism-mediated high turnover bone disease, adynamic bone disease, osteomalcia, and mixed uremic osteodystrophy (Miller, 2014). As kidney function declines, there is progressive deterioration in bone-mineral homeostasis and changes in levels of PTH, 25-hydroxy-vitamin D, 1,25-dihydroxy vitamin D, and fibroblast growth factor-23 (FGF 23), causing incremental increases in phosphorus and reabsorption into bone and soft tissue (Bushinsky, Gallant, & Kelepouris, 2013).

Serum PTH level changes can begin occurring in early stage CKD, even as early as an eGFR just below 70 mL/min/ 1.73[m.sup.2]. Short of bone biopsy, there is no absolute way to diagnosis which type of CKD-MBD exists. However, bone-specific alkaline phosphatase (BSAP) can be used to help evaluate bone disease in patients with CKD because markedly high or low values predict underlying bone turnover.

Diagnosing Osteoporosis in CKD

Diagnosis of osteoporosis in the general population is made in two ways: the presence of a low trauma fracture or a standard deviation T score as measured by DXA that meets the WHO criteria (Miller, 2014). In patients with CKD and a low trauma fracture, the question or diagnosis to be made is, "Was the fracture caused by osteoporosis or CKD-MBD?" In patients with CKD with a higher eGFR (greater than 30 mL/min/1.73[m.sup.2]), disorders of CKD-MBD are less common, and the use of T scoring may be more reliable in assessing fracture risk (Miller, 2014). The NKF Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guideline on definition, evaluation, and classification of renal osteodystrophy agrees that the diagnosis in this case can be made based on fracture history or the WHO criteria as in the general population (Uhlig et al., 2010).

However, the diagnosis of osteoporosis in patients with a lower eGFR (30 mL/min/1.73[m.sup.2] or less), especially in the older population, can be trickier. Fragility fractures, reduced GFR, and low T scores on DXA are common in the older patient. These patients may have osteoporotic bone and bone mineral disorders related to CKD. There is uncertainty in relating the WHO criteria to these patients to assess fracture risk (Miller, 2014; Ott, 2010).

Generally, nephrology researchers and clinicians agree that in patients with an eGFR greater than 30 mL/min/1.73[m.sup.2], the WHO criteria or evidence of previous low impact fracture may be safely used to diagnosis and plan treatment for osteoporosis if there is no evidence of hyperparathyroidism or hyperphosphatemia that signals coexisting CKD-MBD. However, in patients with eGFR of 30 mL/min/1.73[m.sup.2] or less who have low T scores or history of a low trauma fracture, the diagnosis of osteoporosis can only be made by excluding other CKD-MBD disease (Miller, 2014).

Diagnostic Evaluation for Coexisting CKD-MBD

According to Miller (2009), patients with an eGFR less than 60 mL/min/1.73[m.sup.2] and low T scores (-2.5 or greater), and/or a low trauma fracture, the evaluation begins with the determination of the cause of the fracture. Exclusion of adynamic bone disease is paramount because many popular pharmacological agents approved for the treatment of osteoporosis have a mechanism of action that lowers bone turnover, and in adynamic bone disease, there is already no bone turnover. Treatment with these drugs in the setting of a dynamic done disease can lead to systemic CKD-MBD and vascular calcifications (Miller, 2014). Therefore:

* If the biochemical tests for calcium, phosphorous, PTH, and 25-hydroxy vitamin D are normal and the eGFR is greater than 30 mL/min/ 1.73[m.sup.2], the diagnosis of osteoporosis is safe, and pharmacological treatment may be considered if there is a history of low trauma fracture and/or low T score. If biochemical tests are positive for bone mineral derangement, management of the underlying condition is required prior to the initiation of pharmacological treatments for osteoporosis.

* In patients with an eGFR of 30 mL/min/1.73[m.sup.2] or less, it is recommended to measure BSAP in addition to calcium, phosphorous, PTH, and 25-hydroxy vitamin D because of their increased risk to CKD-MBD. Quantifying BSAP may be helpful in diagnosing adynamic bone disease because BSAP is derived from osteoblast activity. Look for a low BSAP of 7 ng/mL or less and a PTH below 100 pg/mL in adynamic bone disease. In addition, look for higher serum calcium in a dynamic bone disease (Miller, 2009). There is a strong recommendation that a diagnosis of osteoporosis may be made in CKD Stages 4-5 only after ruling out CKD-MBD. The goal of treatment in this setting is the prevention or control of CKD-MBD by managing secondary hyperparathyroidism, preventing over-suppression of PTH, and treating acidosis and vitamin D deficiency (Miller, 2014).

* Bone biopsy remains the gold standard for differentiating bone diseases in patients with CKD (Miller, 2014).

In Summary

In summary, routine bone mineral density testing is not recommended to assess fracture risk and make a diagnosis of osteoporosis in patients with an eGFR of 30 mL/min/1.73[m.sup.2] or less. However, bone mineral density testing may be useful in patients with an eGFR of 30 mL/min/1.73[m.sup.2] and higher without evidence of CKD-MBD as a baseline when pharmacological treatment for osteoporosis is being considered. In these few and select patients, the baseline measurement and two years into pharmacological treatment would be recommended (Miller, 2014).

Treatment of Osteoporosis

The goal of osteoporosis treatment is fracture prevention, whether secondary or tertiary. Diet, nutrition, and lifestyle in general are important factors affecting bone health. Pharmacological therapies or drugs used for the treatment for osteoporosis are generally classified as antiresorptive (helping to prevent bone breakdown) or anabolic (increasing bone mass) to prevent fracture or refracture. The anti-fracture benefits of Food and Drug Administration (FDA)-approved drugs have been mostly studied in the post-menopausal female population. Bisphosphonates are the most widely prescribed drugs for the prevention and treatment of osteoporosis, and their effects can last for years. The effects of non-bisphosphonate agents are temporary and wane almost immediately upon discontinuation. This is one reason bisphosphonates are so readily prescribed by primary and women's care providers (Cosman, 2014).

Pharmacological treatment decisions and duration of therapy must be individualized. After three to five years of intervention, a comprehensive risk assessment should be performed. Include an interval fracture history, assessment for new chronic diseases or medication changes, height measurement, bone mineral density testing, and vertebral imaging if a decrease in height is documented. Continuation of therapy decisions can then be considered in those who remain at high risk after the initial treatment period (Cosman et al., 2014).

Conclusion

Patients with CKD have complex bone and mineral problems that can exacerbate as kidney disease progresses. Patients with CKD are at an increased risk for bone loss and fractures, and sorting out the cause is also complex. The potential for doing harm is significant in this population and signals the need to comprehensively assess each patient before initiating or agreeing to a treatment plan that includes pharmacological agents. Ensuring that decisions for continuation of treatment are documented with evidence is also important and is an opportunity for collaboration with primary care.

When a patient with CKD suffers a frailty fracture, the question must always be asked, "Is this osteoporosis, or is it another mineral bone disorder associated with CKD?" As clinicians, it is crucial that we understand the disease and why typical testing like bone density may not be enough to guide treatment decisions.

Ann Hallock, DNP, APRN, CNP, CNN, is an Assistant Professor, School of Nursing, Armstrong State University, Savannah, GA; a member of ANNA's Dogwood Chapter; and is currently serving on the ANNA National Conference Planning Committee.

Statement of Disclosure: The author reported no actual or potential conflict of interest in relation to this continuing nursing education activity.

Note: The Learning Outcome, additional statements of disclosure, and instructions for CNE evaluation can be found on page 18.

References

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Burge, R., Dawson-Hughes, B., Solomon, D., Wong, J., King, A., & Tosteson, A. (2007). Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. Journal of Bone and Mineral Research, 22(3), 465-475.

Bushinsky, D.A., Gallant, K.M., & Kelepouris, E. (2013). Management of bone-mineral-vascular disorders: Insights into chronic kidney disease and cardiovascular disease. Presented at the National Kidney Foundation 2013 Spring Clinical Mettings, Orlando, FL. Retrieved from http://www.staging. medscape.org/viewarticle/808537_ transcript

Centers for Disease Control and Prevention (CDC). (2013). Osteoporosis. Retrieved from http://www.cdc.gov/ nchs/fastats/osteoporosis.htm

Chauhan, V., Kelepouris, E., Chauhan, N., & Vaid, M. (2012). Current concepts and management strategies in chronic kidney disease-mineral and bone disorder. South Medical Journal, 105(9), 479-485.

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Gordon, P.L., & Frassetto, L. (2010). Management of osteoporosis in CKD Stages 3 to 5. American Journal of Kidney Diseases, 55(5), 941-956.

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Table 1
GFR Categories

GFR
Category           GFR                    Terms

G1         Greater than 90        Normal or high
           mL/min/1.73[m.sup.2]

G2         60 to 89               Mildly decreased
           mL/min/1.73[m.sup.2]   (relative to young
                                  adult level)

G3a        45 to 59               Mildly to moderately
           mL/min/1.73[m.sup.2]   decreased

G3b        30 to 44               Moderately to severely
           mL/min/1.73[m.sup.2]   decreased

G4         15 to 29               Severely decreased
           mL/min/1.73[m.sup.2]

G5         Less than 15           Kidney failure
           mL/min/1.73[m.sup.2]

Sources: Kidney Disease Improving Global Outcomes (KDIGO), 2013;
National Kidney Foundtation (NKF), 2015.
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Publication:Nephrology Nursing Journal
Date:Jan 1, 2017
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