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Osteoporosis in Solid Organ Transplantation

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The detrimental effects of immunosuppressants on bone remodeling and bone quality (osteoporosis) are linked to bone loss following solid organ transplantation.

Written by

Dr. Palak Jain

Medically reviewed by

Dr. Pandian. P

Published At January 4, 2023
Reviewed AtDecember 28, 2023

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.

Frequently Asked Questions

1.

Which Transplantation Can Cause Severe Osteoporosis?

Bone marrow transplantation, or hematopoietic stem cell transplantation (HSCT), is most likely to lead to severe osteoporosis. This is because HSCT involves high doses of chemotherapy and radiation, which can damage the bone marrow and decrease bone density. Additionally, the use of glucocorticoids, a type of medication commonly used after HSCT to prevent graft-versus-host disease, can further contribute to the development of osteoporosis.

2.

Is Immunosuppressants Results in Osteoporosis?

Yes, immunosuppressants can cause osteoporosis. Immunosuppressant medications are often used to prevent transplanted organ rejection or treat autoimmune diseases. Still, they can also lead to bone loss and increase the risk of osteoporosis. This is because some immunosuppressants can interfere with the normal balance of bone remodeling, leading to decreased bone formation and increased bone resorption.

3.

Can Bone Marrow Transplant Results in Osteoporosis?

A bone marrow transplant (a hematopoietic stem cell transplant) can cause osteoporosis. The high doses of chemotherapy and radiation therapy used in the transplant process can damage the bone marrow and decrease bone density. In addition, corticosteroids and other medications commonly used to prevent or treat graft-versus-host disease after a transplant can further contribute to bone loss and osteoporosis.

4.

Is Tacrolimus Results in Osteoporosis?

Tacrolimus, a medication commonly used to prevent the rejection of transplanted organs, has been associated with an increased risk of osteoporosis. Although the exact mechanism is not fully understood, it is thought that Tacrolimus can interfere with the normal bone remodeling process, leading to decreased bone formation and increased bone resorption. In addition, long-term use of Tacrolimus can cause vitamin D deficiency, an important nutrient for bone health. As a result, people taking Tacrolimus may be at increased risk for osteoporosis. They should talk to their doctors about ways to monitor and manage their bone health, such as calcium and vitamin D supplementation, exercise, and regular bone density testing.

5.

How Organ Transplant Is Done?

Organ transplantation is a surgical procedure that involves replacing a damaged or diseased organ with a healthy organ from a donor. The patient is evaluated to determine if they are a suitable candidate for transplant, and if so, they are placed on a waiting list. Once a donor organ becomes available, the patient undergoes surgery to receive the transplant. The patient is then monitored closely to ensure that the new organ functions properly and that the body does not reject it. Immunosuppressant medications are often used to prevent the rejection of the new organ.

6.

What Is the Treatment of Osteoporosis?

The treatment of osteoporosis usually involves a combination of lifestyle changes and medications. Lifestyle changes include regular weight-bearing exercise, a calcium and vitamin D diet, and avoiding smoking and excessive alcohol consumption. Medications are used to slow down bone loss and improve bone density. The most commonly prescribed medications for osteoporosis are bisphosphonates, which help to slow bone loss, and medications known as selective estrogen receptor modulators (SERMs) and parathyroid hormone (PTH) analogs, which help to increase bone density.

7.

What Is the Effect of Osteoporosis on the Bone Matrix?

Osteoporosis is when bone mass loss and bone matrix deterioration result in weakened bones that are more prone to fracture. The bone matrix is the structural framework of the bone, made up of collagen fibers and mineral crystals. In osteoporosis, there is an imbalance in the normal bone remodeling process, with increased bone resorption (breakdown) by osteoclasts and decreased bone formation by osteoblasts. This results in a reduction of both collagen and mineral content of the bone matrix, leading to thinning of the bone and increased risk of fracture.

8.

What Is the Effect of Osteoporosis on the Body?

Osteoporosis can affect the body in several ways. The most common effect is an increased risk of bone fractures, particularly in the spine, hip, and wrist. These fractures can cause pain, disability, and a decreased quality of life. Osteoporosis can also cause posture and spinal curvature changes, leading to decreased height and chronic back pain. In severe cases, osteoporosis can cause compression fractures in the vertebrae, leading to spinal cord compression and nerve damage. Osteoporosis can also affect other body parts, such as the teeth and jaw, leading to an increased risk of tooth loss and gum disease.

9.

How to Diagnose Osteoporosis?

Osteoporosis is typically diagnosed using a combination of clinical evaluation, medical history, and imaging tests. The most commonly used imaging test for osteoporosis is a bone density scan, which measures the bone mineral density in the spine, hip, or wrist. The bone density scan typically uses dual-energy X-ray absorptiometry (DXA). It calculates a T-score, which compares a person's bone density to that of a healthy young adult of the same gender.

10.

What Is the Treatment of Osteoporosis in Kidney Transplant Patients?

The treatment of osteoporosis in kidney transplant patients includes lifestyle modifications such as exercise, quitting smoking, and reducing alcohol consumption, along with adequate calcium and vitamin D. Medications such as bisphosphonates and Teriparatide may also be used to increase bone density. Treatment should be tailored to the patient's needs and may require regular monitoring.

11.

Can Bone Marrow Use as a Transplant?

Yes, a bone marrow transplant can use a patient's bone marrow, an autologous bone marrow transplant. In this type of transplant, the patient's bone marrow is collected, treated, or purged to remove any cancerous or diseased cells and then frozen for later use. The patient then receives high-dose chemotherapy or radiation therapy to kill any remaining cancer cells or diseased bone marrow cells. After the chemotherapy or radiation therapy, the patient's previously collected bone marrow is thawed and infused back into the patient's body.

12.

Is Bone Marrow a Solid Organ?

No, bone marrow transplantation is not considered a solid organ transplant. Solid organ transplants typically refer to the transplantation of organs such as the heart, liver, lungs, kidneys, or pancreas, composed of complex tissues and structures. Bone marrow transplantation, on the other hand, involves the transplantation of hematopoietic stem cells found in the bone marrow and responsible for producing blood cells. While bone marrow is a vital and complex tissue, it is not considered a solid organ traditionally, as it does not have the same structural complexity or functionality as other solid organs.

13.

What Are the Three Major Risk Factors for Osteoporosis?

The three major risk factors for osteoporosis are:
- Age: The risk of osteoporosis increases with age, particularly in women who have gone through menopause.
- Gender: Women are at a higher risk of osteoporosis than men, partly because they have a lower peak bone mass and experience a rapid decline in bone density after menopause.
- Low Bone Density: Low bone density is a major risk factor for osteoporosis. Factors contributing to low bone density include a family history of osteoporosis, being thin or having a small frame, having a history of fractures, and certain medical conditions such as celiac disease, inflammatory bowel disease, or chronic kidney disease.

14.

What Is Recent Treatment of Osteoporosis?

A monoclonal antibody that works by inhibiting sclerostin, a protein that negatively regulates bone formation. By blocking sclerostin, Romosozumab increases bone formation and reduces bone resorption, leading to an overall increase in bone density. In clinical trials, Romosozumab has been shown to reduce the risk of new vertebral fractures by up to 73 % compared to placebo and to increase bone mineral density more than current osteoporosis medications such as bisphosphonates and Teriparatide.
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Dr. Pandian. P
Dr. Pandian. P

General Surgery

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