Nancy A. Melville

October 14, 2013

BALTIMORE — The contention that osteoporosis drugs can and should be used to prevent fracture in patients with chronic kidney disease (CKD), despite various continuing unknowns, received the support of about 75% of attendees at a debate on the topic here at the American Society of Bone and Mineral Research (ASBMR) Annual Meeting last week.

But in arguing for more restraint in using the drugs and convincing a greater percentage of attendees to switch to his side — calculated by a tally of text-in votes at the beginning and end of the discussion — Alastair R. McLellan, MD, FRCP, prevailed as the winner of the debate and of the society's annual "Golden Femur" award.

"The fact is we have no evidence that in patients with an estimated glomerular filtration rate [eGFR] of less than 50 there is any treatment that can reduce the incidence of hip, nonhip, or nonvertebral fractures, or even clinical vertebral fractures," said Dr. McLellan, from the Western Infirmary in Glasgow, Scotland, who argued on behalf of the European Calcified Tissue Society.

Representing the opposing argument for ASBMR was Sophie A. Jamal, MD, PhD, an associate professor of medicine at the University of Toronto and the director of the multidisciplinary osteoporosis research program at Women's College Hospital in Ontario.

"Fractures are extremely common in patients with CKD, and as clinicians, we need to recognize that our bottom line is to take care of patients," Dr. Jamal said. "There are plenty of data showing these drugs to be safe and effective for CKD patients with osteoporosis," she stressed.

Osteoporosis Still Most Common Cause of Fracture in CKD

The most common forms of CKD are stages 1 through 4, affecting as many as 26 million Americans, while about 750,000 have stage 5, Dr. Jamal explained.

While she acknowledged that many fractures in CKD are attributed to renal osteodystrophy, which can complicate the assessment, and that there are some other triggers, she stressed that the most common cause of fracture in all stages of CKD is still osteoporosis, and thus treatment to prevent fractures is possible.

By way of illustration she cited a meta-analysis from her own group showing bone-mineral density (BMD) to be significantly lower in dialysis patients with stage 5 CKD who have fractures than in those without fractures (Am J Kidney Dis. 2007;49:674-681). "If the fracture is due to osteoporosis, it makes absolute sense that we should treat these people like they have osteoporosis," she said.

And while osteoporosis drugs, including alendronate, ibandronate, and risedronate, are not recommended by the US Food and Drug Administration (FDA) for patients with impaired creatinine clearance, and zoledronic acid is contraindicated for such patients, Dr. Jamal argued that these recommendations are based on limited information. "The FDA recommendations came from rat renal-toxicity studies in high doses, as well as a lack of data in stage 4 and 5 CKD," she observed.

She went on to detail several studies showing reductions in fractures, improvements in BMD, and positive safety data up to 3 years for such drugs in patients with CKD up to stage 4.

One secondary analysis of alendronate in the placebo-controlled Fracture Intervention Trial (FIT), for instance, involving 581 women with severely reduced renal function (eGFR < 45 mL/min), concluded the drug is safe and effective in increasing BMD and decreasing fracture risk, she noted (J Bone Miner Res. 2007;22:503-508).

She added that the osteoporosis treatments raloxifene (Evista, Eli Lilly), denosumab (Prolia, Amgen), and parathyroid hormone (PTH) have no FDA warning or contraindication for this use.

"There are lots of post hoc studies that support treatment of osteoporosis with CKD. Alendronate, risedronate, raloxifene, and denosumab can be used in patients with stage 4 CKD for at least 3 years and PTH down to stage 3 for at least a year and a half," she noted.

Regarding stage 5 CKD, she did acknowledge a lack of clinical trial data for osteoporosis treatment but made the case that this hasn't stopped treatment in plenty of other disease scenarios.

For example, in the West of Scotland Coronary Prevention Study for pravastatin, only 1% of participants had diabetes, all were male, none had CKD, and all were under 64, "yet we use pravastatin in people with diabetes, in women, in patients with CKD, and in people over the age of 64," she observed.

Counterargument: The "Inconvenient Truth" Lies in the Unknown

In his counterargument, Dr. McLellan asserted that patients with CKD have important distinctions that set them apart from patients who have only osteoporosis.

"The inconvenient truth is that we know that patients with CKD are profoundly different," he emphasized, saying the disparities extend from how patients with CKD handle calcium and phosphate to their skeletal architecture and their more troublesome morbidity and mortality profile.

For example, the prevalence of hyperparathyroidism increases with progression from stage 2 to 4 or 5 CKD; when creatinine clearance is under 50, abnormal bone histomorphometry is common; and the all-cause mortality in stages 3, 4, and 5 is substantially higher than in stages 1 and 2, he said.

Plus, the data available on fractures in CKD patients are lacking and post hoc studies just don't suffice, he argued.

"I'm not against post hoc studies when it comes to evidence of what drugs can do, but I think you need to take them with a grain of salt — seldom are they able to address the right question, and they all use unblinded data." In addition, "the randomization strategy in these studies is somewhat abandoned; they selectively use data; they typically lack power; and they are often pharma-funded with an end point of informing marketing strategy rather than clinical practice," he asserted.

All of the trials of therapeutic agents described in Dr. Jamal's argument excluded patients with elevated PTH levels and, in general, raised more questions than answers, he argued.

"Call me cynical, but virtually all of these trials did record nonvertebral and clinical vertebral fracture outcomes, yet somehow none of the data made their way into these analyses," he said.

Also of key importance, said Dr. McLellan, was the method used to categorize CKD staging in many of these trials. Many used the Cockcroft-Gault equation, but use of the alternative Modification of Diet in Renal Disease (MDRD) method may have shown significantly different results, he said.

"The categorization of CKD at which fractures seem to occur is critically dependent on whether you calculate with the Cockcroft-Gault or the MDRD method," he observed.

Finally, the potential adverse effects associated with osteoporosis drugs in CKD run the gamut from reports of atypical femoral fractures with treatment with denosumab or bisphosphonates and a risk for hypercalcemia with denosumab, to the occasional potential for acute kidney injury or nephritic syndrome with alendronate, Dr. McLellan added.

Combined, the numerous unknowns about safety as well as efficacy should give physicians pause in prescribing such treatments to patients with CKD, he observed.

Bottom Line: Risk vs Benefit Remains Unknown

"When it comes to speaking to our patients about risk vs benefits of treatments, we really don't know to what extent renal disease increases their risk, and I think our patients in [this day and age] deserve some understanding of that," Dr. McLellan told delegates.

A member of the audience seemed to speak for many when he asked Dr. McLellan, "If you decide you shouldn't be treating these patients, what do you tell them?"

"First, I don't believe that life as we know it is a bisphosphonate-deficient state," Dr. McLellan said. "I seek the right grounds for justifying treatment in patients where I know I can reduce fractures, but if I have to say to them, 'We don't know, we lack evidence, and we maybe even need to think about strategies such as reducing fall risk,' well, so be it.

"I think we have to be honest with our patients and be very cautious until we have properly conducted clinical trials," he concluded.

In her rebuttal, Dr. Jamal responded that regarding PTH, elevations are not common until about stage 4 CKD, and she typically measures patients' PTH levels several times and will do a bone biopsy if the osteoporosis does not appear straightforward.

She seconded the assertion that clinicians should be frank with their patients — but encouraged treatment to prevent fractures with CKD whenever possible.

"[Like Dr. McLellan,] I also believe we have to be honest with our patients, but clinicians know darn well that randomized controlled data doesn't apply to the 95-year-old woman sitting in your office with hypertension that needs to be on a drug for longer than 2 years, and I think patients understand that," she said.

"If CKD patients are fracturing, they have an impaired quality of life and are at an excess risk of dying, and I think it is our responsibility to diagnose the cause of fractures in these patients, and if they have osteoporosis, we need to treat them."

Dr. Jamal has served as an advisor or consultant for Novartis Pharmaceuticals, Amgen, Warner Chilcott, Genzyme, Shire, and Cytochroma and has received grants for clinical research from Novartis Pharmaceuticals, Amgen, Warner Chilcott, Genzyme, Shire, and Cytochroma with Genzyme, Novartis. Dr. McLellan has disclosed no relevant financial relationships.

American Society for Bone and Mineral Research 2013 Annual Meeting. Presented October 4, 2013.


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