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.
Biochemical markers of bone metabolism
In chronic kidney disease, the bone biochemical tests that nephrologists usually assess during the course of declining renal function are the serum levels of:
- Phosphorus
- Parathyroid hormone
- Calcium
- Other electrolytes
- Total alkaline phosphatase or bone-specific alkaline phosphatase
- 1,25 dihydroxyvitamin D.
In postmenopausal osteoporosis, the biochemical markers of bone turnover that are measured to reflect baseline levels of bone turnover or change in bone turnover in response to drug therapy are:
- The serum or urine collagen cross-links N-telopeptide (NTx) and C-telopeptide (CTx), markers of bone resorption
- Bone-specific alkaline phosphatase (an osteoblast activity marker)
- Serum osteocalcin, a bone formation marker
- Propeptide type 1 collagen (P1NP), a marker of osteoblast activity, highly correlated with bone formation
- 25-hydroxyvitamin D levels.
Biochemical markers of bone turnover cannot be used to diagnose osteoporosis. They can, however, provide clinical guidance as to whether a patient has high or low bone turnover and whether therapy is affecting bone turnover.28–36 Although these markers have value in making these distinctions in groups of patients, they are less sensitive and specific for classifying an individual patient’s bone turnover status.
Bone-specific alkaline phosphatase, parathyroid hormone, and adynamic bone disease
If a patient’s bone-specific alkaline phosphatase level is elevated, adynamic bone disease is highly unlikely. Assuming that other causes of this elevated level (eg, Paget disease of bone, metastatic cancer) have already been excluded, the elevated level could represent either osteomalacia or hyperparathyroid bone disease.
However, a “normal” bone-specific alkaline phosphatase level does not exclude adynamic bone disease, whereas a low level is more often associated with low bone turnover.
An elevated parathyroid hormone level does not exclude adynamic renal bone disease, but a low level (< 150 pg/mL) suggests a lowbone-turnover state. A level six times or more greater than the upper limit of normal is far more likely to be associated with high bone turnover.
Thus, in clinical practice, patients with stage 4 or 5 chronic kidney disease who have elevated bone-specific alkaline phosphatase or very high parathyroid hormone values do not have adynamic bone disease. Furthermore, once other causes of these aberrant biochemical abnormalities have been defined, then “high-bone-turnover osteoporosis” may be a consideration. Certainly, in my opinion, if bone turnover markers suggest low bone turnover, bone biopsy is necessary before starting an antiresorptive agent.35
Quantitative bone histomorphometry
Double tetracycline-labeled quantitative histomorphometry is still the only accepted way to measure turnover, mineralization, and volume in clinical practice.43–45 A committee of the American Society for Bone and Mineral Research has developed histomorphometric criteria for distinguishing among the different types of metabolic bone diseases (osteomalacia, adynamic bone disease, hyperparathyroid bone disease).12 These criteria can be used to distinguish among the various metabolic bone diseases that accompany stage 5 chronic kidney disease, including adynamic bone disease.43,46–48
For patients in stage 5 who have had a fragility fracture, adynamic bone disease should be excluded before the off-label use of an osteoporosis drug that reduces bone turnover, such as a bisphosphonate, calcitonin, estrogen, a selective estrogen receptor modulator, or denosumab (anti-RANK ligand antibody). While there is no evidence, for example, that starting a bisphosphonate in a patient who already has adynamic bone disease is detrimental to either bone strength or systemic vascular calcification (which may be linked to low bone turnover),49 it seems unreasonable to do so until solid prospective data clarify the harm or benefit.50 Preliminary experimental and clinical data suggest that bisphosphonates may even reduce progression of extraosseous calcification and inhibit the development of atherosclerosis.50
Hence, quantitative bone histomorphometry can discriminate among the various forms of renal osteodystrophy. If a distinct form of renal osteodystrophy is not present in a patient with stage 4 or 5 chronic kidney disease who has had a fracture and who, on biopsy, has a low trabecular bone volume, the patient probably has osteoporosis by exclusion.
TREATING OSTEOPOROSIS IN STAGE 1–3 CHRONIC KIDNEY DISEASE
As previously mentioned, patients who have fragility fractures in stage 1, 2, or 3 chronic kidney disease are more likely to have osteoporosis than renal osteodystrophy as the cause of their impaired bone strength. Although several articles have described a higher risk of fragility fractures in patients with age-related reduction in renal function than in agematched patients with normal renal function, the specific metabolic bone disease other than osteoporosis accounting for this bone fragility has not been defined.6
Hence, patients with osteoporosis who are in stage 1, 2, or 3 chronic kidney disease and do not have a known biochemical abnormality that might suggest some form of renal osteodystrophy can and should be considered for treatment with approved drugs that reduce the risk of fractures in postmenopausal, male, or glucocorticoid-induced osteoporosis.51–53 In clinical trials, these agents were shown to be effective in patients with serum creatinine concentrations as high as 2.0 mg/dL or a GFR as low as 30 mL/min, as estimated by the Cockcroft-Gault equation.
While all of the approved agents show evidence of reducing the risk of vertebral fractures, patients at higher risk of fractures or those who have already suffered a nonvertebral fracture are more often considered candidates for treatment with a bisphosphonate or teriparatide (Forteo), both of which have shown evidence of reducing the risk of all fractures.
