November 2010

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In this Issue

Osteoporosis and Chronic Kidney Disease

Paul D. Miller, MD Distinguished Clinical Professor of Medicine Colorado Center for Bone Research and Kelly A. Trippe, MA, Managing Editor, Osteoporosis Clinical Updates.

Editor's Introduction

Osteoporosis, as defined by The National Institutes of Health Consensus Conference, may co-exist with renal bone disease or renal osteodystrophy - a histomorph-ometrically defined complex group of skeletal disorders caused by chronic kidney disease (CKD). Forms of osteodystrophy include severe hyperparathyroidism (or osteitis fibrosa cystica), adynamic bone disease, osteomalacia, and post-transplantation syndrome. Like osteoporosis, all forms of renal osteodystrophy can cause fragility fractures. The potential presence of one or more of these bone diseases makes treating renal-disease patients complex and difficult. How best to treat skeletal disease associated with renal insufficiency or failure is still a challenge despite all the therapies available for osteoporosis treatment. The lack of guidelines for drug use in these patients has long been an issue and remains so today. This issue of Osteoporosis: Clinical Updates brings into focus this clinical conundrum. It addresses many of the current questions about bone health and renal disease and updates present knowledge about pathology and therapy. -Angelo Licata, MD, PhD

 

Diagnosis and Treatment of Osteoporosis or Fragility Fractures in Patients with Chronic Kidney Disease

Paul D. Miller, MD with Kelly Trippe, MA

Chronic kidney disease (CKD) is associated with a range of distinctly different metabolic bone diseases, each with its own diagnostic and treatment considerations. Aging itself is associated with both reductions in glomerular filtration rate (GFR) and increased prevalence of osteoporotic fractures.[1, 2, 3, 4, 5, 6, 7] Fracture rates in patients throughout all of the National Kidney Foundation's five stages of CKD are higher than age-matched controls without CKD and are associated with higher mortality. This presents the clinician with a complex decision-making challenge: determining whether a fracture in CKD patients indicates osteoporosis, another bone disorder, or simply results from decreased GFR.

 

Defining CKD

In 2009, a working group of the National Kidney Foundation, Kidney Disease Improving Global Outcome (acronym KDIGO), developed a set of clinical practice guidelines for the management of patients with mineral and bone disorders related to chronic kidney disease, or CKD-MBD.[8]

The guidelines define CKD as kidney damage or glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 for three months or more, regardless of the cause of the kidney disease.[9] The stages of CKD are described by GFR ranging from high (stage 1 with GFR greater than or equal to 90) down to low (stage 5 with GFR less than 15, the level at which dialysis or transplantation may be necessary).[9]

 

The Five Stages of Chronic Kidney Disease
Stage Description GFR l/min/1.73 m2
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009 Aug;(113):S1-130.
1 Kidney damage with normal or ↑ GFR ≥90
2 Kidney damage with mild ↓ GFR 60-89
3 Moderate ↓ GFR 30-59
4 Severe ↓ GFR 15-29
5 Kidney failure <15
5D Kidney failure with dialysis <15

The KDIGO working group saw the need to address expanded understanding of the complex systemic impact of CKD. To that end, KDIGO created the term CKD-MBD (chronic kidney disease-mineral and bone disorder), defined as a systemic disorder of mineral and bone metabolism due to CKD that is manifested by one or a combination of the following factors:

CKD-MBD takes a wider view of the role of bone metabolism (turnover, mineralization, and volume [TMV]) than its local effects. For example, recent research suggests that bone turnover may be directly linked to risk of cardiovascular disease. This is because low bone turnover reduces bone's capacity for phosphorus uptake, causing high serum phosphorus, which leads to calcium-phosphorus deposition into vascular tissues, resulting in cardiovascular disease and heightened mortality.[11, 12]

US Renal Data System. USRDS 2007 Annual Report. Atlas of Chronic Kidney Disease and End Stage Renal Disease in the United States. 2007

Coresh J, Selvin E, Stevens LA, et. al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.

CKD-MBD may be caused by many diseases that affect the kidney or may be caused by decline in renal function due to aging. Age-related decline in renal function is common. Data from the Third National Health and Nutrition Examination Survey (NHANES III) indicates that, as age increases, otherwise healthy people may experience a steady decline in renal function measured by their estimated GFR (eGFR) by Cockcroft-Gault equation. NHANES III data showed that 39% of people 60 years and older had some form of CKD, with the greatest proportion of these in stage 3 CKD (20%).[13]

CKD-MBD is also associated with increased risk of fracture. The SOF study of 9000+ postmenopausal women found that in women with no intrinsic renal disease, age-related decline in kidney function was responsible for a near doubling of fracture risk in women with eGFR of less than 65 ml/min/1.73 m2 as compared to age-matched women with normal GFR.[14]

 

Causes of Fragility Fracture in CKD Patients

There are five causes of fracture in patients with CKD: severe hyperparathyroidism, adynamic bone disease, osteomalacia, post-transplantation syndrome, and osteoporosis. The risk of fracture increases with the severity of CKD. There is weak evidence that early stages of CKD (stages 1-3) increase risk of fragility fractures due to slight changes in bone turnover (mild hyperparathyroidism or low bone turnover). However, strong evidence exists that late stage CKD (stages 4-5) may be associated with fragility fractures from severe hyperparathyroidism, adynamic bone disease, and osteomalacia (very high or very low bone turnover). In addition, fragility fractures in this population convey a higher mortality risk than in persons with stage 1-3 CKD.[15]

 

Causes of Fracture in CKD Patients

  1. Hyperparathyroidism (severe)
  2. Adynamic bone disease
  3. Osteomalacia
  4. Post‐transplantation syndrome
  5. Osteoporosis

Atsumi K, Kushida K, Yamazaki K,et al. Risk factors for vertebral fractures in renal osteodystrophy. Am J Kidney Dis. 1999 Feb;33(2):287-93.
Stehman-Breen CO, Sherrard DJ, Alem AM, et al. Risk factors for hip fracture among patients with end-stage renal disease. Kidney Int. 2000 Nov;58(5):2200-5.
Fried LF, Biggs ML, Shlipak MG,et al. Association of kidney function with incident hip fracture in older adults. J Am Soc Nephrol. 2007 Jan;18(1):282-6.
Coco M, Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis. 2000 Dec;36(6):1115-21.
Nickolas TL, Leonard MB, Shane E. Chronic kidney disease and bone fracture: a growing concern. Kidney Int. 2008 Sep;74(6):721-31.

Osteoporosis may develop in patients with reduced GFR that is due either to age-related decline in renal function or to a specific form of intrinsic renal disease. Patients with CKD due to intrinsic renal disease have many risk factors for osteoporosis not related to age: chronic use of heparin (when on dialysis), use of gluocorticoids, hypogonadisim, hyperprolactinemia, poor nutrition, vitamin D deficiency, hyperparathyroidism, and metabolic acidosis. [16, 17, 18, 19] Determining whether a CKD patient's fracture is caused by osteoporosis or one of the other forms of renal bone disease is the first step in prescribing the most appropriate treatment.

It is important to recognize that most patients with postmenopausal or age-related osteoporosis may also have early stage CKD (stage 1 through early stage 3). Patients with more advanced stages of CKD (late stage 3-5D), in whom the biochemical abnormalities of mineral metabolism that define CKD-MBD may be present, may have renal osteodystrophy. Both idiopathic osteoporosis and CKD-MBD can lead to increased bone fragility and fractures, but these diseases have different pathophysiological backgrounds. Bone fragility is due to varying combinations of low bone mineral content and poor bone quality. Abnormalities in bone turnover, mineralization, and volume can lead to compromised bone quality even in patients with normal or high bone-mineral content. Measurement of bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) is of limited benefit in predicting fracture risk in patients with severe (stage 4-5) CKD-MBD. There is, however, agreement that DXA has the same value for women with stage 1-3 CKD as it has for postmenopausal women without CKD. [20, 21] The gold standard diagnostic tool for assessing the bone turnover component of CKD-MBD is transiliac bone biopsy based on quantitative histolomorphometric analysis.

 

Diagnosing Osteoporosis in CKD Patients

Osteoporosis is traditionally diagnosed as low BMD (T-score of -2.5 or lower) or low trauma fractures. In patients with early CKD (stage 1 to early stage 3), fractures are far more likely to be due to osteoporosis than to a specific form of CKD-MBD. Adynamic and osteomalacia forms of renal bone disease are uncommon before stage 3-5 CKD. [22, 23] Consequently, the same criteria used to diagnose osteoporosis in postmenopausal women with normal GFR may be used in patients with early CKD: presence of low-trauma fracture and/or T-score on DXA following World Health Organization cut points (T-score ≤-2.5), assuming there are no biochemical abnormalities suggesting the concomitant presence of CKD-MBD. [24]

How then is the diagnosis of osteoporosis made in patients with moderate to severe CKD (stage 4-5)? DXA is an inadequate methodology to predict risk in patients with more severe CKD because bone strength may be affected by one of the many different processes that lead to CKD-MBD not captured by two-dimensional DXA imaging. The presence of fragility fractures also won’t help, since all forms of severe CKD-MBD may cause fracture. At present, double tetracycline-labeled quantitative bone histomorphometry is the best diagnostic test, since biopsies provide indications of underlying pathophysiology as well as measurements of bone turnover, mineralization, and volume. [8] Once biopsy results rule out other forms of renal osteodystrophy and indicate low trabecular bone volume, the diagnosis of osteoporosis can be made. A great deal of work is currently being done examining the ability of other non-invasive radiological devices that can measure bone density, bone volume, geometry, and microarchitecture not captured by DXA including pQCT, high-resolution pQCT, and micro-magnetic resonance imaging. [25, 26]

What about biochemical markers? Measures of biomarkers parathyroid hormone (PTH) and bone-specific alkaline phosphatase (BASP) can be used in an attempt to discriminate between adynamic bone disease and severe hyperparathyroid-induced bone disease in groups of patients. [8] However, in individual patients, biochemical values may overlap, making specific diagnosis unclear. If there is any question as to the exact diagnosis, bone biopsy is still needed before treatment in order to avoid using an agent that may be contraindicated to treat osteoporosis in patients with GFR < 30 ml/min or in patients with adynamic or osteomalacic bone disease. [27] There are two aspects of BSAP and or PTH that may be useful in differential diagnosis: an elevated BSAP or an intact PTH six times or greater than the upper limit of normal is highly likely to exclude adynamic renal bone disease; values that are within the normal range do not. In the future, assays may be available to measure the osteoclast activity marker TRAP5b, providing a more sensitive gauge of bone resorption due to the fact that TRAP5b is cleared by the reticuloendothelial system and not the kidney.[28]

Options for Treating Osteoporosis in CKD Patients

Pharmacologic management of osteoporosis in patients with stages 1-3 CKD does not differ from that of postmenopausal women with normal GFR because clinical trials for osteoporosis treatments randomized patients down to GFR of 30 ml/min. FDA-approved antiresorptive and anabolic agents available for this population include the bisphosphonates (alendronate [Fosamax® and Fosamax Plus D™], ibandronate [Boniva®], risedronate [Actonel® and Actonel® with Calcium], zoledronic acid [Reclast®]), calcitonin-salmon (Fortical® and Miacalcin®), estrogen, the estrogen agonist/antagonist raloxifene [Evista®], as well as the anabolic agent teraparatide (Forteo™)[29]. In addition, densoumab (Prolia™), a fully human monoclonal antibody to Rank-Ligand, was recently approved by the FDA for treatment of osteoporosis in postmenopausal women with osteoporosis at high risk for fracture.

In patients with moderate CKD (stage 4) there is either no data or data based on post-hoc analysis of the postmenopausal osteoporosis clinical trials where patients had been randomized down to eGFR (by Cockgroft-Gault) to 15ml/min. Off-label use of the above-mentioned antiresorptive and anabolic agents may be potentially beneficial in patients with established osteoporosis in whom other forms of renal bone disease have been excluded and who are at very high risk for osteoporotic fractures. In such patients, the mortality risk of untreated osteoporosis is high as a consequence of fractures. Although no clinical trial data is yet available for use in this population, post-hoc analyses show efficacy and safety of risedronate, alendronate, and raloxifene down to GFR of 15 ml/min for a limited period of time -- through 3 years.[21, 30, 31, 32]

Bisphosphonates. The use of bisphosphonates in populations with decreased GFR entails important management considerations.[33] Current US FDA product labeling strongly advises against using oral bisphosphonates in patients with GFRs below 30 ml/min (Stage 4-5 CKD).[36] This FDA recommendation is based mostly on high-dose rat renal toxicity data and the knowledge that bisphosphonates are both filtered and secreted by renal tubules.[34] It is not based on any known detrimental effects of oral bisphosphonates in recommended doses on renal function in humans.[35] The graphics shown here represent one of the post-hoc analyses of oral risedronate safety and efficacy in patients with compromised renal function, from mild CKD (GFR ≥50- < 80 ml/min) down to severe CKD (GFR ≥30 ml/min). As you can see, a dose of 5 mg risedronate over two years, while not significantly changing creatinine clearance, did significantly reduce fractures equally across all stages of CKD.[36]

Miller PD et al JBMR 2005

Miller PD et al JBMR 2005

Miller PD et al JBMR 2005

Appropriate dosage depends in large part on the known pharmacokinetic characteristics of bisphosphonates. In a healthy person, 50% of an ingested dose of bisphosphonate is excreted by the kidney and 50% binds to bone. Since bisphosphonates may not be dialyzable, it therefore seems reasonable to use 50% of the approved dose to treat patients on dialysis who have fractured due to osteoporosis. However, skeletal retention of bisphosphonates may be elevated in patients with stage 5/5D CKD (GFR < 15 ml/min or on dialysis). Thus, even with a 50% dose reduction, the clinician might consider a shorter total duration of bisphosphonate therapy than is used for treating postmenopausal osteoporosis.[37]

In patients with stage 1-4 CKD, oral bisphosphonates seem to be safe at usual doses down to GFR levels of 15 ml/min, although this preliminary data needs confirmation by prospective studies.[39] However, as with treating any chronic condition over a prolonged time period, follow-up safety and efficacy monitoring is essential. In patients with stage 4 CKD (GFR 15-30 ml/min) who are given bisphosphonates, annual monitoring of serum creatinine concentrations should be done. In addition, clinicians should be observant of the theoretical unknowns surrounding long-term bisphosphonate use – both in patients with normal GFR and in patients with impaired GFR.

 

Boonen S, Sellmeyer DE, Lippuner K, et al. Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women. Kidney Int. 2008 Sep;74(5):641-8.

Intravenous bisphosphonates zoledronic acid and ibandronate have been shown to temporarily elevate creatinine levels. To avoid renal damage resulting from their use, a minimum 15-30 minute infusion time is advisable, and the patient should be off diuretics and well hydrated before an infusion of zoledronic acid.[38] In addition, FDA product labeling advises adjusting the dosage of intravenous zoledronic acid according to the patient’s pre-treatment GFR.

There have been no FDA post-marketing reports of acute renal failure with IV ibandronate as there have been with IV zoledronic acid. However, it is unknown if IV ibandronate is any safer than IV zoledronic acid since there have been no head-to-head comparative trials between the two with safety outcomes.[39]

Calcitonin-salmon. Calcitonin-salmon has been shown to be safe and can be employed in this population regardless of CKD stage of renal function. However, it has also been shown to have a less robust effect on vertebral fracture risk than other agents and, because calcitonin has not been shown to reduce risk of non-vertebral fracture, it has limited appropriateness for patients at higher risk for non-vertebral fracture.

Denosumab. Densoumab (Prolia™) was recently approved for treatment of osteoporosis in postmenopausal women at high risk of fracture (which is defined as a history of osteoporotic fracture or multiple risk factors for fractures) and for patients for whom other treatments have failed or are not tolerated. Denosumab is a human monoclonal antibody that specifically targets a mediator of bone turnover. Denosumab may prove to be an attractive option for patients with CKD since it is not cleared by the kidney but is metabolized by the reticuloendothelial system and has a fast on-set, off-set mechanism of action on bone tissue. [40] In addition, in a post-hoc analysis of the registration clinical trial, denosumab was found safe and effective for three years in patients with eGFR down to 15 ml/min.[41] Prospective studies will define the potential renal safety for denosumab in patients with even more severe renal failure. [42]

Estrogen. Data from the Women’s Health Initiative confirm the efficacy of estrogen in reducing the risk of both vertebral and hip fracture.[43] It is possible that lower-dose estrogen may be effective in preventing bone loss in postmenopausal women with CKD. However, since estrogen may increase the risk for endometrial bleeding, stroke, and deep vein thrombosis, it is best avoided especially in the stage 5 CKD population. For similar reasons, raloxifene may not be an ideal agent either. [44]

Raloxifene. Analysis of data from the large three-year multicenter, randomized, placebo-controlled MORE trial found raloxifene’s documented benefits to bone (decreased fracture risk, increased BMD) were similar in women with normal kidney function and in those with CKD, regardless of estimated GFR. In addition, rates of adverse effects were comparable for placebo and raloxifene groups across all CKD levels. (Patients with more severe CKD had more adverse events with or without raloxifene.)

Teriparatide. Data from clinical trials on safety and effectiveness of teriparatide (recombinant human PTH [1-34]) at 20 or 40 µg/day show no adverse effect on GFR in patients with mild to moderate impairment of renal function (eGFR down to 30 ml/min). In fact, GFR goes up a little because PTH is a vasodialator and increases renal blood flow.[45] Contraindications to teriparatide treatment in patients with mild to moderate CKD include elevated pretreatment PTH, hypercalcemia, and unexplained elevated bone-specific alkaline phosphatase. There is currently no data on use of PTH in patients with GFR < 30 ml/min.

Miller PD, Schwartz EN, Chen Pet al. Teriparatide in postmenopausal women with osteoporosis and mild or moderate renal impairment. Osteoporos Int. 2007 Jan;18(1):59-68.

 

Other Management Considerations

Treatment of patients with osteoporosis and CKD should include the broader recommendations of calcium and vitamin D replacement applicable to patients with normal postmenopausal osteoporosis: 1200-1500 mg/day of elemental calcium and adequate vitamin D replacement to maintain 25-hydroxyvitamin D levels at least to values of 30 µg/ml. [46] Special vitamin D analogues that are often used by nephrologists to reduce PTH levels in patients with CKD (e.g., 1,25 dihydroxyvitamin D) should be employed only by specialists familiar with their use, since their effects need to be carefully monitored.[20]

 

 

CASE 1: 72-Year-Old Postmenopausal Woman with -3.0
T-Score at the Hip and Two Vertebral Fractures

The first patient we will discuss represents a very common clinical presentation. An otherwise healthy 72-year-old Caucasian postmenopausal woman consults her clinician because she has had bone mineral density measurement done as a part of a health screening. (Note: The United States Prevention Services Task Force recommends osteoporosis screening in all postmenopausal women 65 and older regardless of additional risk factors). [47] The patient was surprised to find that she has osteoporosis by World Health Organization (WHO) criteria, due to a femoral neck T-score of -3.0.

What Are the Findings on Clinical Assessment?

The patient has been postmenopausal for 22 years and has never taken hormone replacement therapy. Her weight is 102 lbs. She has a stadiometer-measured height of 5 foot 2 inches and reports that when she was 25 years of age, she had a measured height of 5 foot 5 inches. Assuming accuracy of the earlier measurement, the patient has lost 3 inches in height. Based on this height loss, her clinician orders an AP and lateral thoracic and lumbar spine x-ray. The x-ray reveals two moderate vertebral compression fractures. Based on WHO criteria this patient has severe osteoporosis, since the presence of vertebral fractures, even when asymptomatic, predicts a much greater risk for future vertebral and non-vertebral fractures. [48, 49, 50] Laboratory workup is negative for secondary conditions that may cause osteoporosis and bone fragility. Her serum creatinine concentration is measured as 1.3 mg/dl (normal laboratory reference range: 0.5-1.5 mg/dl).

Should the Clinician Measure this Patient's Glomerular Filtration Rate (GFR)?

Currently, measurement of a patient's GFR is not a standard of care for patients presenting with postmenopausal osteoporosis who have serum creatinine concentration within the laboratory's normal reference range. However, as pointed out earlier, GFR may be below 30 ml/min in many seemingly healthy postmenopausal women over age 70. Furthermore, the common commercial laboratory reporting of eGFR by the Modification of Diet in Renal Disease equation is creating a realization among clinicians that many people do have low GFR even though their serum creatinine concentration is normal. This raises questions about management with any pharmacological agent that has FDA restrictions at specific levels of renal function.

For the purpose of early CKD detection, the National Kidney Foundation endorses automatic reporting of eGFR on commercial laboratory reports before management decisions are made regarding the use of bisphosphonates in patients with marginal eGFRs (e.g. ~25 ml/min). Because reduction in kidney function may not be reflected by serum creatinine concentration, clinicians should first perform a well-hydrated 24-hour urine assessment for creatinine clearance. Aging is associated with a decline in the function of many biological systems and the kidneys are no exception. As GFR declines to even 50% of its baseline normal level, serum creatinine concentration will double from baseline. [51, 52]

Serum creatinine is derived from the breakdown of the muscle precursor creatine. As muscle mass declines (also often an age-related development), the source of serum creatinine declines as well. As a result, older patients may often have serum creatinine concentrations within the normal range of a reference laboratory and yet have GFRs below 30 ml/min. As we said above, FDA labeling recommends avoiding bisphosphonates in patients with GFRs below 30-35 ml/min. In reality, due to occult renal dysfunction, many clinicians are probably administering oral bisphosphonates to patients with GFRs below 30-35 ml/min without realizing it.

What Should the Clinician Do?

Clinicians should strongly consider measuring GFR in patients over age 70 being assessed for PMO, male osteoporosis, or glucocorticoid-induced osteoporosis because serum creatinine concentration may not accurately reflect these patients' real GFR. In clinical medicine, 24-hour urine collection for GFR calculations by creatinine clearance is the ideal method for determining GFR. However, 24-hour urine collections may be cumbersome, especially for the elderly. Calculating GFR indirectly, by easily performed office-based calculations, can be substituted for GFR determinations by creatinine clearance. [20, 53, 54] Both the Cockcroft-Gault and the MDRD (modification of diet in renal disease) calculations of GFR are highly correlated to GFR determinations by creatinine clearance. [53] (See Table below for equations.)

What if the Clinician Discovers a GFR of 20 ml/min in this Patient? What's Next?

In patients with stage 1-3 CKD, the WHO criteria for fragility fractures can be used for diagnosis of osteoporosis. Patients with stage 4 CKD (GFR between 15 and 30 ml/min) who present with PMO and age-related reductions in GFR, rather than a pre-existing intrinsic renal disease, may not need an in-depth work-up for secondary causes of renal osteodystrophy assuming their basic laboratory work-up for PMO is unremarkable. Secondary causes of renal osteodystrophy are rare in patients with stage 1-4 CKD (e.g., severe hyperparathyroidism, osteomalacia, or adynamic bone disease).

When Should the Clinician Refer to a Specialist?

Patients with stage 4 CKD suspected of having a form of renal osteodystrophy or CKD-MBD rather than PMO due to, for example, elevated PTH levels and all patients who present with PMO but have a GFR below 15 ml/min (stage 5 CKD) should be referred to a specialist. The histologically defined forms of renal bone disease — especially adynamic bone disease, osteomalacia, aluminium bone disease, and severe secondary or tertiary hyperparathyroidism — become more prevalent the longer a patient lives with stage 5 CKD. Mild secondary hyperparathyroidism (intact PTH levels >65 pg/ml but < 150 pg/ml) can be seen in stage 3 and 4 CKD. Bone biopsies may show mild hyperparathyroid bone in these PTH ranges as well. However, many elderly patients with PMO also have elevations in PTH for reasons other than reduced GFR (e.g., low 25 hydroxyvitamin D levels, inadequate calcium intake, or calicium malabsorption from a condition such as celiac disease). Stage 4 CKD patients in whom a clinician determines that PTH is elevated due to reduced renal function alone should be referred, as should all stage 5 CKD patients.

Specialists knowledgeable about renal bone disease diagnosis and management should then measure both 25 hydroxyvitamin D levels and 1,25 dihydroxyvitamin D levels, serum phosphorus and calcium concentrations, and 1-84 intact PTH levels. In patients who require double-tetracycline-labeled quantitative bone histomorphometry for reasons previously outlined, a biopsy should be done. In patients with stage 4 or 5 CKD presenting with PMO who have low 1,25 dihydroxyvitamin D levels associated with elevated PTH levels, specialists could consider using one of the vitamin D analogues or cinacalcet, which are designed to directly reduce PTH production.

How Should this Patient Be Treated?

This patient has a GFR of 20 ml/min (stage 4 CKD), a normal PTH level, and was deemed to have postmenopausal osteoporosis, since other workup for secondary causes for osteoporosis were negative. Her treatment should include a total 1500 mg/day of calcium and adequate vitamin D. The adequacy of vitamin D replacement has become an intense issue recently. There is increasing recognition of the high prevalence of 25 hydroxyvitamin D deficiency in the elderly population. Although the current RDA (recommended dietary allowance) for vitamin D supplementation in the United States is 400 IU/day, this dose recommendation often must be modified in order to achieve a desirable serum level of 25 hydroxyvitamin D (>30 µg/ml).

What FDA-Approved Pharmacological Therapy for PMO Would Be Best Suited to this Patient?

Because this patient is at high risk for additional fractures based on her age, low BMD, and prevalent fractures, all options should be considered. For a patient such as this, who has a high risk not only for future vertebral fractures but also for nonvertebral fractures, a bisphosphonate or teriparatide could be considered. A bisphosphonate could reduce risk of both vertebral and nonvertebral facture, while teriparatide could be considered for off-label use (GFR < 30 ml/min) because her endogenous 1-84 PTH level and alkaline phosphatase are normal.

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CASE 2: 81-Year-Old Caucasian Male who Recently Suffered a Hip Fracture

The second case we will discuss is that of an 81-year-old Caucasian male who recently suffered a hip fracture from a fall. His physical examination was significant for "frailty" defined clinically and a body mass index of 19 kg/m2 (weight 110 pounds and height of 5 foot 11 inches). His T-score at the femoral neck was -5.0. The patient's laboratory data were normal, and he had a normal serum creatinine concentration of 1.3 mg/dl (normal: 0.8-1.5 mg/dl). The patient has taken an oral bisphosphonate for more than one year and has had no change in spine or hip BMD. As a result, he has been referred to an osteoporosis specialist.

What Does this Patient's Workup by Osteoporosis Specialists Indicate?

The osteoporosis specialists discovered that the patient's 24-hour-urine calcium excretion was 30 mg/day on duplicate measurements, despite a daily intake of 2000 mg of calcium as calcium citrate. His creatinine clearance was 18 ml/min (Stage 4 CKD), despite a normal serum creatinine concentration. In addition, his 25 hydroxyvitamin D level was normal, his celiac antibody tests were negative, and he had a mildly elevated parathyroid hormone level of 80 pg/ml (normal 10-65 pg/ml), which is consistent with the decrease in GFR. The osteoporosis experts recommended continuing bisphosphonate therapy.

Because of his low GFR (on 24-hour urine assessment), the patient was referred to a nephrologist who observed that he had a normal urinalysis, no proteinuria, a normal renal ultrasound, and no clinical risk factors for CKD. The nephrologist advised discontinuing bisphosphonate treatment because of the patient's CKD and because he was "not responding to treatment anyway."

Who Is Correct? Why Wasn’t CKD Detected on Initial Serum Creatinine Concentration?

Serum creatinine concentration is the usual means to assess renal function in clinical practice. Current standards of care do not recommend measuring a creatinine clearance before starting oral bisphosphonates, even though the current FDA label suggests avoiding oral bisphosphonates in patients with glomerular filtration rates below 30-35 ml/min. Serum creatinine concentration may be a poor indicator of normal renal function in elderly patients with low muscle mass since it is derived from skeletal muscle metabolism. In patients with low muscle mass, serum creatinine levels can fall within a normal reference range even in the presence of low GFR. These situations are aided by calculation of an eGFR.

What Factors Could Be Affecting this Patient's GFR?

Many elderly patients have a low GFR as a function of aging. As a result, a large proportion of the elderly population we treat for postmenopausal osteoporosis may have a low GFR even to levels where oral bisphosphonates are not advised by the FDA. Yet these low GFR levels may go undetected because of serum creatinine concentrations in the normal reference range, a common observation in the elderly. A recent report suggests that oral risedronate is safe and effective in approved doses for postmenopausal osteoporosis down to GFR levels of 15 ml/min. [34] IV zoledronic acid may be considered off-label in very high risk patients with well established osteoporosis. Slowing down the infusion rate may help to avoid issues of toxicity. It seems from the oncology literature that any renal tubular damage may be related to the CMax (peak concentration of the drug) rather than the AUC (area under the curve). Slowing the infusion rate down to 30 minutes mitigates potential renal damage.

What Does the Patient's Low Calcium Excretion Tell Us?

The patient's low calcium excretion may reflect poor calcium intake, low calcium preparation bioavailability, or celiac disease — all of which may cause low calcium excretion, and none of which our patient had. The low urine calcium excretion may also be due to the patient’s low GFR, which induces low absolute urine calcium excretion. As the filtered calcium load declines (GFR x serum calcium concentration) so does the urinary calcium excretion.

How Should We Interpret the Patient’s Unchanged BMD?

The lack of change in the patient's BMD over the year of treatment may not indicate treatment non-response. Stable BMD may be a perfectly acceptable therapeutic end-point. There is only a slight difference in fracture risk reduction between patients with stable BMD and patients with increased BMD, given good compliance, persistence of bisphosphonate use, and exclusion of secondary conditions that could mitigate BMD response. The real concern is the patient who loses BMD beyond the least-significant change (LSC). In both alendronate and risedronate datasets, more fractures occurred in those who lost BMD than in those who did not.

What Management Plan Can Be Recommended for this Patient?

Assuming that secondary causes for osteoporosis have been excluded and the patient is compliant, it is probably not necessary to change a thing. The clinician can simply continue to monitor BMD, fractures, and serum creatinine over time and reassure the patient. Urine and serum bone resorption markers can be measured for an indication of whether the bisphosphonate is suppressing bone resorption. However, resorption markers should be interpreted with caution since most of the published resorption marker data has not prespecified a population with GFR under 30 ml/min.

SUMMARY 

Clinicians frequently encounter patients with varying degrees of CKD who suffer fragility fractures. Guidance is needed in the management of these patients. In patients with stages 1-3 CKD, management decisions can be made in the same manner as with patients who have normal GFR as long as there are no biochemical abnormalities suggesting CKD-MBD.

In stage 4 CKD and in high risk patients who appear to have osteoporosis and not CKD-MBD, off-label use of bisphosphonates for a limited period of time could be considered. Before initiating therapy in a patient with stage 5/5D CKD, it is even more important to be as certain as possible what type of renal bone disease the patient has. This is ideally accomplished by performing a transiliac bone biopsy after tetracycline labeling. If biopsy excludes adynamic, aluminum bone disease, or osteomalacia and the patient has a low trabecular bone volume or evidence of microarchitectural damage, it is reasonable to treat with bisphosphonates, raloxifene, or teriparatide, but only in very high risk patients and in patients with fractures where their mortality risk is very high. Consider prescribing oral bisphosphonates at doses approximately 50% below the currently approved doses and IV bisphosphonates administered in infusion times of no less than 15-30 minutes and used for a limited period of time (2-3 years). If biopsy is not possible, classification of the patient on the basis of serum concentrations of PTH 1-84 and bone-specific alkaline phosphatase is the next best option, recognizing that biochemical classification may not accurately predict histological bone disease in the individual patient.

Revised by Paul D. Miller, MD and Kelly A. Trippe, MA. Managing Editor (2010) Original by Paul D. Miller, MD (2005). Editor-in-chief Angelo Licata, MD, PhD.

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The National Osteoporosis Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.  The National Osteoporosis Foundation designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Editorial Board

The Osteoporosis Clinical Updates Editorial Board is comprised of medical specialists, nonspecialists, and a variety of other healthcare professionals involved in research in and management of osteoporosis.

DISCLOSURE OF COMMERCIAL SUPPORT
It is the policy of the National Osteoporosis Foundation (NOF) to ensure balance, independence, objectivity, and scientific rigor in all its sponsored publications and programs. NOF requires the disclosure of the existence of any significant financial interest or any other relationship the sponsor, Editorial Board or Guest Contributors have with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. All authors and contributors to this continuing education activity have disclosed any real or apparent interest that may have direct bearing on the subject matter of this program.

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STATEMENT ON OFF-LABEL USE

Please be advised that any publication of the Osteoporosis Clinical Updates that discusses off-label use of any medications or devices will be disclosed to the participant.

EDITORIAL BOARD DISCLOSURES

Editor-in-Chief
Angelo Licata, MD, PhD
Director, Center Space Medicine
Department of Endocrinology
Cleveland Clinic 
Disclosures: Speaking/Teaching: Eli Lilly, Novartis, Amgen, Consulting: Merck

Adrienne Berarducci, PhD, ARNP, BC 
Associate Professor
University of South Florida and 
Azure Medical Group
Disclosure: No relationships to disclose

Carolyn J. Bolognese, RN, CDE
Bethesda Health Research Center
Disclosure: Consulting: Amgen, Merck
Speaking/Teaching: Amgen, Merck

JoAnn Caudill, RT, BD, CDT
Bone Health Program Manager
Redwood / Erickson Retirement Communities
Disclosures: No relationships to disclose

Peggy Doheny, PhD, RN, CNS, ONC
Professor and Adult CNS Program Director
Kent State University College of Nursing
Disclosures: No relationships to disclose

Patricia Graham, MD, PC
Owner, Physical Medicine and Rehabilitation / Integrative Medicine
Disclosures: No relationships to disclose

Craig Langman, MD
Head, Kidney Diseases
Childrens Memorial Hospital
Professor, Feinberg School of Medicine
Northwestern University
Disclosure: No relationships to disclose

Barbara Messinger-Rapport, MD, PhD
Director, Center for Geriatric Medicine of the Medicine Institute
Cleveland Clinic
Disclosure: No relationships to disclose

Paul D. Miller, MD
Distinguished Clinical Professor of Medicine
Colorado Center for Bone Research
Disclosures: Consulting: Warner Chilcott, Baxter, Genentech, Eli Lilly, Merck, Novartis, Amgen, GlaxoSmithKline
Speaking/Teaching: Warner Chilcott, Genentech, Eli Lilly, Merck, Novartis, Amgen
Advisory Committee: Warner Chilcott, Genentech, Eli Lilly, Merck, Novartis, Amgen
Research/Grants: Warner Chilcott, Eli Lilly, Merck, Novartis, Amgen

Jeri Nieves, PhD
Associate Professor of Clinical Epidemiology
Columbia University, Helen Hayes Hospital
Disclosure: Consulting: Merck

Mary Beth O’Connell, PharmD, BCPS
Associate Professor, Wayne State University
Eugene Applebaum College of Pharmacy and Health Sciences
Disclosures: Research Grants: Merck

Carol Sedlak, PhD, RN, CNS, ONC, CNE
Professor & Nurse Educator Program Director
Kent State University College of Nursing
Disclosures: No relationships to disclose

Kathy M. Shipp, PT, MHS, PhD 
Assistant Professor, Division of Physical Therapy 
Department of Community and Family Medicine 
Duke University School of Medicine 
Disclosure: Speaking/Teaching: Amgen

Andrea Sikon, MD, FACP, CCD, NCMP
Chair, Department of Internal Medicine
Cleveland Clinic
Disclosure: Stockholder: Amgen, Pfizer

Kelly Trippe, MA
Managing Editor, Osteoporosis Clinical Updates
National Osteoporosis Foundation
Disclosure: No relationships to disclose

Susan Randall, RN, MSN, FNP-BC
Senior Director, Science and Education
National Osteoporosis Foundation
Disclosure: No relationships to disclose