Osteoporosis in Solid Organ Transplantation

Introduction

For several diseases, such as acute and chronic liver failure, end-stage renal illness, end-stage pulmonary disease, and heart failure, solid organ transplantation has established itself as a viable therapeutic alternative. Bone disease has become a frequent side effect of organ transplantation due to the rising number of transplanted organs and the better lifespan of transplant recipients. Up to half of the transplant recipients have osteoporosis, and in some facilities, nearly a third of patients have vertebral fractures (solid organs are organs that are not hollow and thus referred to as solid organs example - the liver, pancreas, spleen, adrenal glands).

What Are the Causes of Osteoporosis, Followed by Organ Transplantation?

Various factors influence the pathophysiology of osteoporosis following organ transplantation.

These consist of the following:

1. Vitamin D deficiency.

2. Secondary hypothyroidism.

3. Malnutrition.

4. Immobilization.

5. Glucocorticoids.

6. Hypogonadism.

7. Pre-existing bone disease.

8. Cyclosporin (immunosuppressant).

How Can Pre-transplant Bone Disease Lead To Osteoporosis?

According to several studies, up to 50 percent of transplant patients have a pre-existing bone condition, and fractures are more common in this group than in the general population. Alcohol misuse, hypogonadism, a lack of vitamin D, and hyperbilirubinemia have all been linked to hepatic osteodystrophy. In individuals with congestive heart failure, variables include vitamin D inadequacy, renal insufficiency, and the use of loop diuretics contribute to bone damage.

Smoking and long-term use of glucocorticoids increase the risk of bone disease in lung transplant patients. For cystic fibrosis patients, in particular, vitamin D deficiency brought on by intestinal malabsorption and hypogonadism is crucial. In contrast to the underlying pathology of the bone marrow, pre-transplant exposure to chemotherapeutic drugs or whole-body radiation.

Patients with end-stage renal disease frequently have a bone mineral disease (chronic kidney disease - bone mineral density), which can be divided into three groups depending on the morphology seen in bone histomorphometry studies.

1. Secondary hyperparathyroidism and accelerated bone turnover cause osteitis fibrosa.

2. Osteomalacia is brought on by a lack of vitamin D, which reduces bone mineralization.

3. Adynamic bone disease develops due to excessive PTH (Parathyroid hormone) suppression and reduced bone remodeling.

How Do Corticosteroids Cause Osteoporosis in Patients Who Have Had Organ Transplants?

The primary ways that corticosteroids cause bone loss are by the direct suppression of osteoblast activities, increased osteoblast death, and increased osteoclast activation by boosting RANK (receptor activator of nuclear factor kappa - B) ligand activity. Corticosteroid also causes numerous other negative consequences that are harmful to the bones.

The most significant of them is how Corticosteroids affect calcium metabolism, which causes a reduction in intestinal calcium absorption and increases calcium loss from the kidneys, both of which promote secondary hyperparathyroidism and accelerate bone loss. In addition, corticosteroids enhance bone resorption by suppressing the hypothalamic-pituitary-gonadal axis, which causes hypogonadism. Additionally, Corticosteroids raise the risk of fractures by causing significant myopathy.

How Does Immuno-Suppressant (Calcineurin Inhibitors) Cause Osteoporosis in Patients Who Have Had an Organ Transplant?

Since Corticosteroids are typically administered concurrently to patients receiving Calcineurin inhibitors, such as Tacrolimus and Cyclosporine, it is uncertain how these medications will affect the human skeleton. Even though Calcineurin inhibitors stimulated osteoblasts and osteoclasts in murine models, the bone resorption rate was significantly higher than the rate of bone creation, causing a net increase in bone resorption in patients who have had an organ transplant.

How Do Immobilization and Malnutrition Affect Osteoporosis in Patients With an Organ Transplant?

Many patients undergo a disease-related decompensation accompanied by decreased physical activity and malnutrition while they wait on the transplant waiting list, which is getting longer and longer. These issues may harm skeletal health if the proper remedies are not made. Lengthy hospital stays following transplantation was connected with severe bone loss.

What Does the Hypothalamic-Pituitary-Gonadal (Hpg) Axis Involve?

Testosterone levels drop in many heart transplant patients after surgery, but they usually return to normal within the first year. Even though the Hypothalamic-Pituitary-Gonadal axis and sex steroid metabolism were significantly altered before liver transplantation, most patients see a return to normal physiological function. 48 to 80 percent of women, especially those who underwent liver transplantation for acute liver failure, resume their regular menstrual cycles. The Hypothalamic-Pituitary-Gonadal axis is restored in many men and premenopausal women after renal transplantation to correct the hyperprolactinemia caused by uremia.

How Does Vitamin D and PTH (Parathyroid Hormone) Involve?

Although this is likely connected to the use of vitamin D supplements, prospective studies in patients who have undergone liver, heart, and lung transplants show that serum 25 - hydroxyvitamin D (Vitamin D) levels progressively rise from the low levels seen before transplant to normal levels. Following liver transplant recipients prospectively, a gradual rise in the serum parathyroid hormone concentration was observed. However, there was no change in the mildly raised parathyroid hormone levels following cardiac transplantation. Although the mechanisms underlying the elevated serum parathyroid hormone levels are not well understood, they may be partly responsible for up to 20 percent of transplant recipients who have decreased renal function.

During the initial six months following a kidney transplant, recipients' blood parathyroid hormone concentrations gradually decline. But 25 to 43 percent of patients with serum creatinine levels less than 1.5 mg/dl milligrams (mg) per decilitre (dL) one year after grafting are found to have persistent hyperparathyroidism, perhaps due to the hyperplastic parathyroid glands' gradual involution. Longer time on dialysis and greater parathyroid hormone levels are pretransplant risk factors for persistent hyperparathyroidism in renal transplant recipients. Glomerular filtration rate of less than 70 ml/min (milliliter per minute), Cyclosporine use, and low serum 25 - hydroxyvitamin D levels are posttransplantation predictors.

How Does BMD (Bone Mineral Density) After Transplantation Get Affected?

After solid organ transplantation, the first year shows significant drops in bone mineral density at the lumbar spine and femoral neck. This decline primarily affects the first three to six months after grafting and is most likely caused by the high doses of glucocorticoids administered soon. The lumbar spine (cancellous bone), a characteristic feature of glucocorticoid-induced bone loss, experiences early bone loss. Following that, the lumbar spine bone loss rate slows, stabilizing by 6 to 12 months and even showing some improvement after liver, lung, and heart transplantation. After the first six months, femoral neck bone loss may be more significant than at the lumbar spine. After the initial, quick, and considerable decrease in bone mineral density in the first six months, there may be a subsequent, ongoing loss of about 1 percent each year for up to eight years following kidney transplantation.

What Physical Symptoms Are Present in Patients With Osteoporosis Following Transplantation?

1. Bone pain.

2. Low-impact fractures.

3. Bone deformities.

What Investigation Needs to Be Done Before Organ Transplantation to Lower the Prevalence of Osteoporosis After an Organ Transplant?

Compared to the general population, transplant individuals have a higher frequency of bone disease. Thus these patients should be assessed and treated adequately before the transplant.

Several guidelines for evaluating transplant individuals are made depending on the underlying illness process and the transplanted organ. The 2013 guidelines published by the American Association for the Study of Liver Diseases and the American Society of Transplantation advise that all patients slated for liver transplantation get a bone density scan (DXA scan) and, if osteoporosis is discovered, get treated before the transplant. After a kidney transplant, KDIGO (Kidney Disease Improving Global Outcomes) guidelines from 2017 advise routinely monitoring calcium, phosphorus, vitamin D, and parathyroid hormone levels until levels stabilize.

Most authors suggest that the following tests be performed for evaluation on all transplant individuals:

1. Bone density scan to detect osteopenia or osteoporosis.

2. To check for vertebral fractures, doctors may use thoracic and lumbar spine radiographs or a vertebral fracture assessment (VFA) via a bone density scan.

3. Examining patients for vitamin D insufficiency and secondary causes of osteoporosis such as hyperparathyroidism, alcoholism, persistent smoking, hypogonadism, and harmful drugs like Heparin and loop diuretics.

What Treatment Plan Should Be Taken for Osteoporosis Transplantation?

Osteoporosis detected in the post-transplantation phase is treated by addressing its secondary causes and starting pharmacologic therapy. The first medication of preference is Bisphosphonate treatment. Patients with weak renal function (GFR 30 mL/min) may benefit from Denosumab as an alternate treatment. When Bisphosphonates are contraindicated for patients with impaired renal function, Teriparatide is an additional medication that may be used. Teriparatide's anabolic actions are especially beneficial for patients with adynamic bone disease, characterized by a low rate of bone turnover. Alternative medications for the treatment of post-transplantation osteoporosis that do not respond to Bisphosphonate therapy include Denosumab and Teriparatide.

Recognizing and addressing all of the secondary causes of osteoporosis mentioned under pre-transplantation bone disorders is essential. Hyperparathyroidism, a lack of vitamin D, hypogonadism, and Cyclosporin exposure are a few of the leading causes. For all transplant patients, adequate calcium and vitamin D supplementation is essential before and after transplantation. It's also important to make the proper lifestyle changes, like giving up alcohol and smoking, improving nutrition, and becoming more active. The smallest dose of Cyclosporine required to prevent rejection should be administered to patients. Due to their high prevalence in patients undergoing kidney transplantation, inflation in parathyroid hormones and vitamin D levels is particularly useful in preventing bone loss during this procedure.

Conclusion

A number of interconnected variables, including pre-transplant bone disease, immunosuppressive medications, and lifestyle choices, cause the pathophysiology of osteoporosis in transplant recipients. As bone loss and fracture incidence are highest just after transplantation, early risk factor identification and prompt implementation of preventative interventions are required to reduce the likelihood of fractures. Effective therapies combine post-transplantation measures, such as exercise, calcium and vitamin D replenishment, and antiresorptive agents started before or shortly after transplantation, to overcome Glucocorticoid-induced rapid bone loss. Pre-transplantation measures are used to treat pre-existing bone disease.