Reducing the Risk of Osteoporotic Fractures Following Lung Transplantation

By Sarah Keller, MD

People don’t always consider bone health in relation to end-stage pulmonary disease and lung transplantation, but it is important to do so. Medications and comorbidities associated with lung disease elevate risks for osteoporosis (OP) and bone fracture. The high-dose glucocorticoid (GC) therapy that follows transplantation can sharply affect bone loss and increase the likelihood of fractures, leading to lengthy hospital stays or even death.

Proactive bone-health management may reduce morbidity and mortality in lung transplant patients, but a more widespread understanding of the risks is needed.
A recent study by Cleveland Clinic’s Osteoporosis and Metabolic Bone Disease Center identifies strong predictors of post-transplant fracture and highlights the importance of osteoporosis management before and after transplant.

Our research team also analyzed post-transplant use of denosumab — an inhibitor of receptor activator of nuclear factor kappa-Β ligand (RANKL) — and found it was associated with a 65% reduction in the odds of having an osteoporosis-related fracture.

Background

From 1992 to 2001, the median survival after lung transplant (LT) in the U.S. was 4.7 years. From 2010 to 2017, that rose to 6.7 years, and the risk of fracture from related OP has increased along with it.

Bone health studies of LT patients have been limited, but risk factors for OP and fractures among this population include lung disease pathology; low body mass index; a sedentary lifestyle; chronic hypoxia/hypercapnia; tobacco and alcohol use; medications (use of glucocorticoids, loop diuretics and calcineurin inhibitors); calcium and vitamin D deficiencies; inadequate post-transplant ambulation and rehabilitation; and acute and chronic organ rejection that requires increased GC doses.

In end-stage pulmonary disease, OP and fragility fractures can occur before LT or as a complication soon after transplant, or later. In a meta-analysis, the incidence of vertebral fractures was 19.5% before transplant and 50.4% after.¹ In the first year post-LT, the rate of fracture was 18% to 37%.²

Vertebral fractures are common and can cause compression and curvature of the spine and reduced lung capacity. In older patients, hip fractures carry the greatest mortality risk. Consequences can include stress-related strokes or heart attacks that take place at the time of the break or afterward. A broken hip may lead to surgery, which can put a patient at risk for blood clots or bleeding related to blood thinners.

During recovery, patients may spend a long time sedentary, which raises cardiovascular risk and can cause loss of independence.

Given the odds of developing serious osteoporosis and fracture, we know that the long-term health of patients who undergo lung transplant depends in part on protecting their bone health.

Study details

Our team’s retrospective cohort study was conducted at Cleveland Clinic’s transplant center, and included adults who had lung transplants between Jan. 1, 2010, and Dec. 30, 2020. Patients who died within the first year after transplant and those who had a previous lung transplant were excluded. Out of 1,223 patients who had transplants, 1,054 met the inclusion criteria.

Before transplant, 366 patients (35%) had osteopenia; 254 patients (24%) had osteoporosis; and 131 patients (12%) had had at least one fracture, most commonly vertebral (67; 51%). Pre-LT, 403 patients had been treated with these OP medications:
• Abaloparatide, 4
• Alendronate, 225
• Denosumab, 17
• Ibandronate, 40
• Raloxifene, 2
• Risedronate, 29
• Teriparatide, 26
• Zoledronic Acid, 67

After transplant, there were 243 fractures. Additionally, 641 patients received post-LT OP medications:
• Abaloparatide, 8
• Alendronate, 292
• Calcitonin, 4
• Denosumab, 195
• Ibandronate, 28
• Pamidronate, 4
• Raloxifene, 2
• Risedronate, 18
• Teriparatide, 38
• Zoledronic acid, 101

Among denosumab patients, there were 11 episodes of hypocalcemia (one hospitalization) and 23 patients (12%) had cellulitis. In the denosumab fracture analysis, there were a total of 182 fractures. (Fractures that occurred before or after the denosumab treatment were excluded.) Of those fractures, 21 were in patients who had received denosumab and 161 were in patients who had not. Use of denosumab was associated with 65% (OR: 0.35, 95% CI: 0.21-0.58) lower risk of post-transplant fracture after adjusting for other covariates.

In addition, we found that pre-transplant osteopenia, osteoporosis and
a history of smoking and alcohol use are strong predictors of posttransplant
fracture.

Cleveland Clinic's program

Along with Annmarie Miranda, PC-C, our research team included Abby Abelson, MD; Marie Budev, DO; Chad Deal, MD; Komal Mushtaq, MD; Adil Vural, MD; and Chao Zhang.

Our results underscore the need for bone-health programs such as Cleveland Clinic’s, which was launched in 2002 through a cooperative relationship between transplant and metabolic bone specialists.

Every Cleveland Clinic patient who is considered for lung transplant is evaluated in our clinic for overall bone health, which includes a detailed medical history to reveal risk factors, bone-density scans and imaging. For every transplant patient, we develop a medication and follow-up plan.

Patients who go through lung transplants need not have their health jeopardized by osteoporosis-related fracture and frailty. Today, we have some medications that can decrease the risk of fracture by nearly 70%. Expert bone-health care before and after surgery can help improve the chances of a strong recovery.

References

1. Caffarelli et al., Journal of Clinical Medicine. 2020. 9(9)
2. Stein et al. Endocrinology and Metabolism Clinics of North America. 2007.
07.008