Fragility Fractures and Osteoporosis in Chronic Kidney Disease

Salam et al AJKD Fig 1

Fig 1 Salam et al AJKD, © National Kidney Foundation.

In a recent review in AJKD, Salam et al describe the pathophysiology of fragility fractures in the chronic kidney disease (CKD) population, and the challenges in diagnosing and treating this condition. Corresponding author Dr. Syazrah Salam (SS) discussed this important topic with eAJKD Contributor Dr. Magdalena Madero (eAJKD).

eAJKD: What diagnostic tool would you recommend to identify coexistent chronic kidney disease-mineral and bone disorder (CKD-MBD) and osteoporosis?

SS: We often suspect these two conditions co-exist in advanced CKD patients with biochemical evidence of CKD-MBD and low bone mineral density (BMD) on DXA. Bone biopsy is the only tool (gold standard) we currently have to confirm the diagnosis of renal osteodystrophy and/or osteoporosis in this group of patients. In clinical practice, we only perform a bone biopsy if it is going to change our management, for example, to rule out renal osteodystrophy prior to initiating anti-resorptive therapy. Bone biomarkers, which reflects bone turnover, are often high in this group of patients due to accumulation and therefore unreliable in differentiating adynamic bone disease from normal/high bone turnover. DXA has its limitations and BMD may be overestimated in CKD as discussed in the review. Although several studies showed that DXA has the ability to predict fracture risk in CKD, it is important to note that patients with bone mineral abnormalities were excluded from these studies. Therefore, low BMD on DXA only raises suspicion of osteoporosis but it is not diagnostic in this subset of patients.

eAJKD: Given the difficulties of performing bone biopsies in our CKD population, could you highlight the scenarios where bone biopsies should be recommended?

SS: We believe that bone biopsy should only be performed if the result would change patient management. For example, bone biopsy is highly recommended to rule out renal osteodystrophy in patients with advanced CKD prior to initiating anti-resorptive agents. Despite expertise in performing bone biopsy in our center, patients rarely agree to this procedure.

eAJKD: In your review, you describe a higher amount of bone biopsy-proven adynamic bone disease (ABD) in the hemodialysis population. You mention this may be related to the use of PTH-suppressive therapies. Do you think diagnostic bone tools should be implemented before prescribing cinacalcet in this population?

SS: In the UK, cinacalcet is used in dialysis patients with refractory secondary hyperparathyroidism with PTH >800 pg/mL despite standard therapy and in whom surgical parathyroidectomy is contra-indicated. These patients are more likely to have high bone turnover, although the specificity is improved with high bone alkaline phosphatase. The only diagnostic tool is bone biopsy but we don’t think this should be implemented prior to using cinacalcet as the aim of using cincalcet is to bring the PTH level within the KDIGO recommended PTH range (i.e., 2-9 times the upper limit of normal for the assay). Unfortunately, adynamic bone and high bone turnover can be present even in this recommended range, and the use of vitamin D can further suppress PTH.

eAJKD: You describe a recent association between hyponatremia and osteoporosis. Do you have a potential mechanism to explain this association?

SS: Early studies by Bergstrom and Wallace indicated that approximately a third of the body’s sodium is stored in bone matrix along with calcium and phosphate, and is released during bone resorption. Barsony et al described the possible sodium signalling mechanisms in osteoclasts, which may explain the association with osteoporosis. Using cell culture of preosteoclasts and primary bone marrow monocytes from rats, the group showed that lowering the extracellular sodium ion concentration ([Na+]) increases osteoclast formation and its resorptive activity. Chronic reduction in extracellular [Na+] dose-dependently decreases intracellular calcium without depleting the endoplasmic reticulum calcium stores and may prevent osteoclast apoptosis. Furthermore, they also found that chronic reduction in extracellular [Na+] dose-dependently decreases cellular uptake of radio-labelled ascorbic acid. The cells in culture medium with reduced ascorbic acid showed the same osteoclastogenic effect of low [Na+]. These mechanisms support the concept that chronic hyponatraemia could lead to chronic sodium loss from bone and bone demineralization through increased osteoclastic bone resorption.

eAJKD: Would you consider denosumab as the first line in treatment for osteoporosis in advanced CKD patients?

SS: I would consider denosumab in patients with advanced CKD and DXA evidence of osteoporosis as long as bone biopsy has ruled out renal osteodystrophy. We might still consider it in patients with mild increases in bone turnover, but certainly not in oesteitis fibrosa, ABD, or osteomalacia. Denosumab is a humanized monoclonal antibody that targets RANKL, thereby reducing osteoclastic bone resorption. In the pivotal FREEDOM study of 7868 post-menopausal women with osteoporosis, denosumab reduced the risk of both vertebral and non-vertebral fractures. Although the pharmacokinetics of denosumab are not fully understood, it does not appear to be filtered or actively excreted by the kidney suggesting that it may be an effective alternative therapy to bisphosphonates in CKD stages 4-5. A post-hoc analysis of the FREEDOM study demonstrated that treatment efficacy did not differ between CKD stages 1-4. However, only a small number (73 subjects) had CKD stage 4, and patients with abnormal PTH were excluded from the study.

To view the article abstract or full-text (subscription required), please visit AJKD.org.

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