Chronic kidney disease (CKD) patients have an increased risk of fractures (Figure 1). For example, in elderly patients hip fractures are twice as common in those with CKD-stage 3 as in those with normal renal function. Dialysis patients have four times as many hip fractures as expected for their age.
Thus, the problem is clear, but the solution is not.1 Patients with the mineral and bone disorder seen with CKD (CKD-MBD) have complex abnormalities in bone physiology.2
Osteoporosis is a disease of reduced bone mass and reduced bone strength. There is some overlap between “ordinary” osteoporosis and CKD-MBD, but they are different diseases—just as hemolytic anemia and iron-deficiency anemia have similar manifestations but different physiology (Table 1).
Although there have been studies involving thousands of patients with osteoporosis, very few of these have included any patients with CKD-MBD. In fact, for the major new osteoporosis medications, the studies were designed to exclude those with renal disease. Nevertheless, because serum creatinine was used as an exclusion criterion and the patients were elderly, many subjects had CKD-stage 3.3-5
They had normal serum PTH, alkaline phosphatase, calcium and phosphate and thus did not have the biochemical abnormalities that herald the advanced mineral and bone disorders associated with CKD-MBD. These patients respond to osteoporosis medications and can be treated the same as other elderly persons with osteoporosis.
Published studies of osteoporosis therapies in patients with CKD stages 4-5 are very limited. For the KDIGO (Kidney Disease: Improving Global Outcomes) report, a literature review with pre-specification of 50 patients and six months duration found only one paper about raloxifene,6 and none using bisphosphonates. Since then, one trial of alendronate that enrolled 50 subjects was published.7 Unfortunately, there are no ongoing studies listed in ClinicalTrials.gov using osteoporosis medications in patients with CKD stage 4 or 5.
Predicting fracture rate in CKD
Bone density in patients with CKD-stage 5 is only weakly predictive of fractures.8 This is different from studies in patients with postmenopausal osteoporosis, in whom a standard deviation decrease in bone density by dual energy X-ray absorptiometry is associated with a doubling of the risk of a fragility fracture. There are several possible reasons for the poor performance of these tests in the kidney patients.
Bone density tends to be worse in cortical sites and normal or even increased in cancellous sites, whereas in ordinary osteoporosis bone is lost in both locations. CKD patients also may have poor quality bone, so they can suffer fractures even without severe loss of bone mass. Low bone density is seen in patients with osteomalacia, even when their bone volume is normal. Many CKD patients have been treated with glucocorticosteroids, which also can cause fractures despite a deceivingly normal bone density.
Although nontraumatic fractures may still occur in patients with a normal bone density, a low bone density is always worrisome. Patients with fragility fractures with or without low bone density present a challenge to the nephrologist. Since there is not enough evidence from clinical trials to decide on therapies, the only choice is to follow physiological principles and to be careful to do no harm.
The first therapeutic steps in a patient with fractures or bone density in the “osteoporotic” range (hip T-score lower than -2.5) are to correct the known associated problems with the mineral and bone disorder seen in CKD-MBD. It is difficult but important to simultaneously treat abnormalities in serum calcium, phosphate, and parathyroid hormone (PTH).
The new KDIGO guidelines have extensively reviewed studies about medications that can help achieve this.1 Careful attention to these “standard” problems will help with the bones, and many patients with fractures have abnormalities that can be improved with greater attention to phosphate control using diet, dialysis, and medications. Hyperparathyroidism increases bone resorption, especially in the cortical bone of the forearm and the hip, and excessively high PTH levels can be controlled with vitamin D analogs or cinacalcet.
Lower vitamin D Levels
Many dialysis patients are deficient in vitamin D. They are not eating dairy products, and the specific nephrology vitamins do not contain vitamin D. Patients often do not get adequate sunlight exposure. It had been thought that 25-hydroxyvitamin D—25(OH)D—levels were not important in patients who were taking calcitriol or vitamin D analogues because they had adequate amounts of the active hormone, and only the kidney (and possibly some granuloma cells) had 1-alpha-hydroxylase.
However, it has been documented that many cells can convert 25(OH)D into 1,25(OH)2D intracellularly without secretion of the 1,25(OH)2D, so that serum levels did not reflect the actual activity. This is seen in skeletal muscle, T-cells, and parathyroid cells. The optimal serum level of 25(OH)D in dialysis patients is not yet determined, particularly if the patients are receiving analogs, but until ongoing studies are completed, it makes sense to aim for a level of 20 to 50 ng/dL. This is the range associated with the lowest mortality in men and women from the general population.
Bones respond to mechanical forces, and many patients with CKD-stage 4-5 do not get much weight-bearing exercise. Walking, stair-climbing and dancing, as well as back extension exercises, should be encouraged in these patients. Exercise programs have not been shown to reduce fractures in large trials, but they make a lot of sense and can also improve cardiovascular and mental health.