Bone Loss and Increased Fractures After Organ Transplantation

Bone disease after an organ transplantation is a much more common problem in transplant recipients than most patients realize. It is, however, something that should be understood, preferably before one opts for an organ transplantation, so that preventive measures can be taken. At its most minor, bone disease in such situations could cause bone pain, but in extreme cases could lead to fractures. Obviously, that would greatly impact a patient's quality of life and could increase the risk of death as well.

Despite the kidneys' role in bone formation, it is not just patients with kidney failure (who receive a kidney transplant) who are high-risk for bone disease and fractures. Most organ transplant patients (including recipients of kidney, heart, lung, liver, and bone marrow transplants) could develop complications including fractures, bone pain, osteoporosis, etc. However, the risks might vary based on the organ involved. For instance, the frequency of fractures in kidney transplant recipients could be anywhere from 6%  to 45%, as opposed 22 to 42% for recipients of heart, lung, or liver transplants.

As mentioned above, the incidence will vary by the organ transplanted. A retrospective study of 86 patients who received kidney transplants found that recipients had a five-fold increase in the risk of fractures in the first 10 years after receiving a kidney, as opposed to the average person. Even after 10 years of follow-up, the risk was still two-fold. This suggests that the increased risk of fracture continues long-term after kidney transplantation.

Fractures, however, are just one extreme example of bone disease after an organ transplant. Osteoporosis is a common feature as well. We see this across different kinds of organ transplants with varying frequency—kidney (88%), heart (20%), liver (37%), lung (73%), and bone marrow (29% of transplant recipients).

One surprising feature when it comes to post-transplantation bone loss is how quickly patients lose their bone mass. Lung, kidney, heart, and liver transplant recipients can lose 4 to 10% of their bone mineral density (BMD) within the first 6 to 12 months after organ transplantation. To better appreciate this, compare this statistic to the rate of bone loss in a postmenopausal osteoporotic woman, which is just 1 to 2% per year.

Looking at it from a simplistic standpoint, bone loss in people who receive organ transplants is due to factors that exist prior to the organ transplant, as well as rapid bone loss that occurs after organ transplantation.

Generic risk factors that increase bone loss that apply to pretty much anyone, obviously are relevant here as well. These include:

• Vitamin D deficiency
• Smoking
• Diabetes
• Advanced age

Let's look at some specific risk factors based on the organ failure involved.

Risk factors in patients who have advanced kidney disease include:

• Vitamin D deficiency
• Frequent use of steroids (which cause bone loss), as a treatment for a variety of kidney diseases
• High acid levels in the blood, called metabolic acidosis
• High levels of parathyroid hormone in the blood (called secondary hyperparathyroidism), which leads to accelerated calcium loss from the bone

Risk factors in patients who have liver disease include:

• Malnutrition, often seen in liver failure patients 
• Cholestasis
• Low testosterone levels or hypogonadism

Risk factors in patients who have lung disease include:

• Frequent use of steroids, to treat diseases of the lung, like COPD or asthma
• Smoking, a major risk factor for osteoporosis and bone loss
• High acid levels, because of carbon dioxide retention in the blood

Risk factors in patients who have heart disease include:

• Frequent use of water pills, or diuretics, which can cause calcium loss from the bone. Examples include medications like furosemide and torsemide.
• Reduced physical activity, a common feature in patients with heart disease

Pre-transplant risk factors that cause bone loss will usually persist to a certain degree even after organ transplantation. However, certain new risk factors come into play after a patient with organ failure receives a new organ transplant. These factors include:

• Steroid use: After patients have received an organ transplant, they require medications to suppress their immune system from "rejecting" the new organ. Steroids happen to be one of these drugs. Unfortunately, steroids reduce new bone formation by inhibiting a particular type of bone cell called "osteoblast." They also increase bone loss by stimulating another kind of cell called "osteoclast." In other words, when you're on steroids, you are burning the candle at both ends. There are other mechanisms that steroids influence, which are beyond the scope of this article (something called increased up-regulation of Receptor Activator of Nuclear Factor kappa-B) which will cause bone loss.
• Calcineurin inhibitor use: Just like steroids, these are another common category of medications that are used in preventing transplant organ rejection. These medications include cyclosporine, tacrolimus, etc. These can cause increased bone loss but typically will also interfere with the kidneys' ability to turn vitamin D into a usable form (which is essential for bone formation), something called activation.

The "gold standard" test to assess the presence of bone disease in transplant recipients is a bone biopsy, which entails sticking a needle into the bone and looking at it under a microscope to make a diagnosis. Since most patients are not big fans of sticking thick needles into their bones, non-invasive tests are used for an initial assessment. Although the well known DEXA scan (used to assess bone mineral density) is a common test used to assess bone health in the general population, its ability to predict the risk of fractures in the organ transplant population is not proven. From a practical standpoint, the test is still prescribed and recommended by major organizations that like the American Society of Transplantation and KDIGO.

Other supportive or ancillary tests include tests for markers of bone turnover like serum osteocalcin and bone-specific alkaline phosphatase levels. Like the DEXA scan, none of these have been studied in their ability to predict fracture risk in transplant patients.

General measures are applicable to the general population, as much as they are to a transplant recipient. These include weight-bearing exercise, smoking cessation, nutritional guidance with calcium and vitamin D supplementation.

Specific measures target risk factors specific to organ transfer recipients and include:

• Avoiding steroids, if possible, as part of the cocktail of drugs used to prevent transplant organ rejection. However, this needs to be weighed against an increased risk of organ rejection.
• A common category of medications that are often recommended for this problem is something called "bisphosphonates," which are used for preventing and treating steroid-induced bone loss in the general population. Although some studies have shown these medications to be effective in preventing and treating post-transplant bone loss, none of the data have proven that bisphosphonates have the ability to reduce the risk of actual fractures.