Mineral and bone disorders are frequently found after kidney transplantation. Determining what is occurring in the bone of a transplant patient is exceedingly complicated as it involves pre-transplant bone disease, post-transplant immunosuppression, and kidney function. In a recent article published in the American Journal of Kidney Diseases, Alshayeb et al review mineral and bone disorders following kidney transplantation. Corresponding author Dr. Stuart Sprague (SS) from the Chicago Pritzker School of Medicine discusses this topic with Dr. Vinay Nair (eAJKD), eAJKD Advisory Board member
eAJKD: What is the most common type of bone pathology following kidney transplantation?
SS: The most common bone disorder is hard to qualify since it frequently parallels the individual patient’s pre-transplant bone disease category. If a patient comes in with severe hyperparathyroid, or high turnover bone disease, they tend to have that initially. If they come in with low turnover, they tend to have that. Following transplant, when we’ve done biopsies, within six months or so the bone turnover decreases and patients tend towards a low bone turnover state. In terms of other metabolic disorders that are seen following transplantation, hypophosphatemia and hypercalcemia are common within the first six months to a year.
eAJKD: As there is a trend towards lower bone turnover, what is the target PTH for a post-transplant patient? In other words, should we follow KDOQI guidelines for CKD, or should it be different in this population?
SS: That is a very difficult question to answer and I believe somewhat controversial. I don’t think PTH post-transplantation or even in CKD is necessarily a good surrogate to tell you what is exactly going on in the bone. Most transplant patients will have a slightly elevated parathyroid hormone, often about 110 or 120. And generally, in the few biopsies that are done, the turnover seems to be normal. I think where it gets problematic is when someone has a PTH of 100 and a calcium of 11. In these patients more than six months or a year post-transplant, high turnover or hyperparathyroid-related bone disease is a common finding.
I have a tendency to recommend bone biopsies a little more frequently at a year or so after transplantation when you have very murky biochemical parameters and/or fractures. Independent of the type of lesion that’s in the bone, fractures seem to be very common following transplantation.
eAJKD: How would you suggest evaluating a postmenopausal patient several years after transplant who has osteoporosis based on DEXA scan? What would your workup include?
SS: I find that there is some utility in checking a bone’s specific alkaline phosphatase to get a sense of bone turnover. I also find it useful to check osteocalcin, which sometimes gives you an indication of osteoblastic activity. What I find critical is checking 24-h urine calcium and phosphate. If you have someone who has a PTH of 110 pmol/L and they’re spilling 300 mg/24 h of calcium in their urine, then you know that they have hypercalciuria that’s likely coming from the bone. Then you have to evaluate if it is because there’s high turnover in the bone, which you may be able to tell by the level of PTH and/or the serum calcium and phosphorous, or because the bone is somewhat adynamic and they’re taking in too much calcium. The vitamin D status also has to be appropriate.
eAJKD: When would you suggest performing a bone biopsy?
SS: I recommend a bone biopsy in post-transplant patients that have frequent fractures and biochemical parameters that don’t fit the common findings. The common scenario is someone who has a PTH between 80 and 150 pmol/L, a calcium between about 10 and 11 mg/dL, a phosphorous that’s within the normal range, and multiple fractures. The bone density is low, and they are on a low dose of steroids. Interestingly, I am unable to predict whether they’re going to have high turnover disease, in which case, I would treat them with a bisphosphonate. If the calcium’s high and the phosphate is low, I may treat the hyperparathyroidism with cinacalcet or recommend a limited parathyroidectomy. Half of patients with those parameters have adynamic appearing bone, and I have had anecdotal success giving them a modified course of teriparatide.
eAJKD: Reviewing the literature and reading your editorial, bone formation and osteoblastic activity seems to be decreased while the resorptive activity seems to be high normal. How can you increase the bone formation? One paper with teriparatide did not show any improvement in bone density. Do more studies need to be performed with teriparatide?
SS: Anecdotally, I have three patients with bone biopsies pre and post the teriparatide that have shown improvement. But what has been remarkable in our experience of eight or ten patients who were fracturing before teriparatide, they stop fracturing once treated. And when you take them off teriparatide, six or seven months later, they start fracturing again.
I don’t repeat bone density in these patients anymore because I don’t find it to be very helpful. I want to make a caveat that I wouldn’t recommend doing what I just described without having pre-treatment bone biopsies in order to support the decision to use teriparatide. You clearly want to see low bone formation rate.
eAJKD: I have seen a couple patients with hypercalcemia and hypovitaminosis D. How do you treat such patients?
SS: I believe they should be replenished (with 25-vitamin D) to 30, independent of the calcium. I don’t think there’s a lot of data that vitamin D replacement makes hypercalcemia worse. As a matter of fact, I think you need to get vitamin D levels to about 80 or 100 ng/mL before hypercalcemia worsens. You may actually see some attenuation of the parathyroid hormone level as you correct the vitamin D level. I’m not convinced that the hypercalcemia we see is a function of hyperparathyroid bone disease.
eAJKD: Have you ever used nasal calcitonin to prevent bone loss? Is there any data using it in post-transplant?
SS: I am not aware of any data. I find the use of calcitonin to be effective more as an analgesic after an acute usually spinal fracture. If you have someone who has acute hypercalcemia from some sort of metastatic lesion or other disease in the bone, you could use calcitonin to get it down. But for the long-term treatment of osteoporosis, it has not shown to be very beneficial.
eAJKD: What do you see as the future of treating metabolic bone disease? Do you believe that any of the drugs on the horizon are going to make a big difference? Or do you think it’s going to be the same treatment armamentarium and we will need to individualize therapy with what we have?
SS: In terms of approaching patients, we are going to have to individualize therapy. In terms of what is in the future, diagnostically, MicroMRI is on the horizon and may give us a virtual bone biopsy. In terms of drugs, we have denosumab, which is an anti-RANKL antibody that’s now being used for osteoporosis. Some of the anecdotal reports of in patients with CKD show it to be very effective. There is a little bit of concern about trying it in transplant patients since it is a monoclonal antibody and increases the risk slightly of infections. There is an osteoblastic growth factor which is in early phases of development that may also be a potential therapeutic tool in this patient population. I think we need to understand the role of cinacalcet a little more because it may have other beneficial effects on the skeleton, not just related to biochemical effects.