Fragility fractures in chronic kidney disease: An opinion-based approach
ABSTRACTWhen a patient with chronic kidney disease suffers a fragility fracture, a key question is whether the patient has osteoporosis or, instead, renal osteodystrophy. Bone densitometry does not help in this distinction: biochemical tests, and sometimes also bone biopsy, are needed. However, even if the patient has osteoporosis, we have little evidence to guide our treatment decisions in cases of advanced chronic kidney disease.
KEY POINTS
- If the patient’s glomerular filtration rate (GFR) is at least 30 mL/min/1.73 m2 and if no biochemical test results suggest renal osteodystrophy, osteoporosis can be diagnosed if the T score is less than −2.5 or if the patient has had a fragility fracture. These criteria can also probably be applied, though with less certainty, if the patient’s GFR is as low as 15.
- If the patient’s GFR is less than 15 or if he or she is on dialysis, biochemical profiling often cannot distinguish among the heterogeneous forms of renal bone disease. In some cases of severe chronic kidney disease with fractures, bone biopsy is needed to rule out renal osteodystrophy and to diagnose osteoporosis by exclusion.
- In the author’s opinion, in patients with severe chronic kidney disease and fractures who have “osteoporosis” by exclusion, off-label use of bisphosphonates is an option, but only after very careful consideration.
Bisphosphonates in stage 1–3 chronic kidney disease
There is prospective evidence that patients with an age-related reduction in GFR down to 30 mL/min benefit from oral and intravenous bisphosphonates, since all of the clinical trials that led to the approval of bisphosphonates included patients with GFRs as low as this.54–57 Bisphosphonates seem to have an excellent safety profile as measured by renal adverse events in patients with a GFR of 30 mL/min or greater.52–59
From the intravenous bisphosphonate studies, it appears that ibandronate (Boniva) at the approved dose of 3 mg intravenously every 3 months and zoledronic acid (Reclast) 5 mg once a year given over 15 minutes are safe in patients with a GFR greater than 30 or 35 mL/min.
However, the safety of these drugs might not be the same in patients with preexisting renal parenchymal disease (eg, in diabetes) or in patients using other agents that could affect renal function (eg, nonsteroidal antiinflammatory drugs). Therefore, caution is still needed when deciding to use intravenous bisphosphonates in specific higher-risk renal subpopulations.
In the clinical trials of zoledronic acid, a substantial proportion of patients had diabetes, and no difference was seen in adverse renal effects between diabetic and nondiabetic patients. Also, GFRs declined equally between the treated and placebo groups over time and were no different at the end of 3 years.55 However, in patients in whom serum creatinine was measured 9 to 11 days after the infusion of zoledronic acid, there was a small but statistically significant transient increase in serum creatinine concentration (0.5–2.0 mg/dL above baseline) after the second annual infusion. 58 The serum creatinine concentrations returned to their baseline values in all of these patients before the next annual infusion.
It is important that infusions of zoledronic acid be given no faster than over 15 minutes. More rapid infusion has been associated with acute renal failure, suggesting that the tubular damage that mimics acute tubular necrosis is related to the maximal concentration and not to the area under the curve. I infuse zoledronic acid over 30 minutes in patients with normal renal function or in those with stage 1, 2, or 3 chronic kidney disease.
Teriparatide
Teriparatide’s approval trial did not require baseline measurements of GFR, but patients were enrolled only if their baseline serum creatinine concentrations were less than 2.0 mg/dL.60 In a post hoc analysis, a small subset of patients had GFRs as low as 30 mL/min as estimated by the Cockcroft-Gault equation. In these patients, teriparatide 20 or 40 μg/day had an anabolic effect as measured by increases in osteoblast activity markers and bone mineral density, similar to that seen in patients with higher estimated GFRs and without any adverse renal effects.61
There are no data on using teriparatide in stage 4 or 5 chronic kidney disease, and I emphasize that in all of the clinical trials of teriparatide, all patients, even those with estimated GFRs as low as 30 mL/min, had normal baseline serum intact parathyroid hormone levels. It is possible that the bone biologic response could differ between patients with chronic kidney disease who have an elevated as compared with a normal serum parathyroid hormone level. This issue should be investigated.
TREATING OSTEOPOROSIS IN STAGE 4 OR 5 CHRONIC KIDNEY DISEASE
Treatment decisions are more difficult in patients with stage 4 and especially stage 5 chronic kidney disease who have had fragility fractures. This is even the case when the clinician has determined to the best of his or her ability that the patient has osteoporosis rather than renal osteodystrophy.
There are no prospective data showing any of the approved drugs to be effective in treating osteoporosis in patients whose GFRs are lower than 30 mL/min. However, a post hoc analysis of pooled data from nine clinical trials62 found that risedronate (Actonel) 5 mg/day reduced the incidence of new vertebral fractures. Another post hoc analysis, from the Fracture Intervention Trial,63 found that alendronate (Fosamax) 5 mg/day for the first 2 years and 10 mg/day for the 3rd year reduced the incidence of all clinical fractures. In neither of these post hoc analyses did the drug affect the serum creatinine concentration. The patients—postmenopausal women—had GFRs as low as 15 mL/min as estimated by the Cockcroft-Gault equation. Similar post hoc data have been published on raloxifene (Evista).64
There are no data on the efficacy (reduction in fracture risk) or safety of any bisphosphonate in patients with GFRs lower than 15 mL/min (stage 5 chronic kidney disease). Nevertheless, the question often arises when fragility fractures occur in this population. Here, only opinion and controversy exist, and we fervently await good science and randomized prospective data.
How to manage renal bone disease after transplantation is a distinctly separate issue in which bisphosphonate use may be even more controversial than in end-stage renal disease.65,66
In my opinion, patients without fractures with stage 5 chronic kidney disease should not be given bisphosphonates or teriparatide offlabel. Treating only on the basis of low bone mineral density and other risk factors seems to be associated with greater risk than benefit.
In stage 5 patients suffering fragility fractures, a bisphosphonate may be considered, but only after renal osteodystrophy has been thoroughly ruled out, which most often requires a bone biopsy.43,67,68 In skilled hands, transiliac bone biopsy is a safe procedure with little morbidity.
If osteoporosis appears to be the cause of the fracture, and if one chooses to use a bisphosphonate and the patient gives his or her informed consent, then I would give half the usual dose and restrict the therapy to no more than 3 years. The reason for halving the dose is based on the known pharmacokinetics of bisphosphonates in people with normal renal function: 50% of a given dose goes to bone and 50% is excreted by the kidney. Furthermore, the dialyzability of bisphosphonates has not been well studied. Limiting the treatment to 3 years is based on the unknown but probably greater bone retention of bisphosphonates when excretion is impaired.
I must emphasize that these approaches are not based on any evidence of efficacy, but rather are considered in extreme cases of often-recurrent fragility fractures in which the fractures per se pose a great risk of morbidity and death. These approaches should be clearly discussed with the patient, undertaken by specialists knowledgeable in complex metabolic bone disease management, and initiated only after the skeletal fragility disorder is well characterized.
SUMMING UP
No consensus exists on the criteria for diagnosing osteoporosis in stage 4 or 5 chronic kidney disease.
In higher-risk patients in stage 1, 2, or 3 chronic kidney disease who have osteoporosis, it appears that any drug approved for osteoporosis can be used, eg, a bisphosphonate, teriparatide, or both.
Considerations for management are far more complex in stage 4 or 5 because of the increased prevalence of other metabolic bone diseases and renal osteodystrophy, and because the World Health Organization criteria cannot be used to diagnose osteoporosis. In stage 5, the differential diagnosis requires careful analysis of a broad range of biochemical markers of bone turnover and, at times, quantitative bone histomorphometry, especially if one is considering using a bisphosphonate. It is unknown if bisphosphonates, by reducing bone turnover in a preexisting low-bone-turnover state, would help or harm bone or would lead to less or more cardiovascular disease. These questions must be addressed by better science and prospective data.
In the future, newer noninvasive radiologic tools to measure microstructure and mineralization of bone promise to help us better understand osteoporosis and renal osteodystrophy in a noninvasive manner.
In clinical practice, at the current time and with current limited knowledge, treatment of osteoporosis in stage 4 or 5 chronic kidney disease is opinion-based. Nevertheless, in very specific clinical cases of severe fragility fractures that, by themselves, may cause disability and death, bisphosphonates should be considered by experts in bone metabolism and, as with any off-label application, after careful informed discussions with the patient.
