Romosozumab as Treatment for Severe Osteoporosis in Heart and Lung Transplant Recipients

Abstract

Background: Osteoporosis is common in transplant recipients, and fracture risk is high. Standard treatment is with anti-resorptive medications. Despite high fracture rates, there are limited data on the use of anabolic bone therapies in transplant recipients. Aim: To evaluate skeletal outcomes after treatment with romosozumab for 12 months in heart and lung transplant recipients. Methods: Retrospective analysis of transplant recipients who completed 12 months of romosozumab treatment at a single centre. Results: Six transplant recipients completed 12 months of romosozumab treatment, commenced after a median of 3 years post transplant (range 2–20). Four patients (66%) were still receiving prednisolone treatment at the time of starting romosozumab. All patients had a history of fracture and had previously received anti-resorptive therapy (4 with zoledronate, 2 with denosumab for >2 years). Following completion of romosozumab treatment, all patients were consolidated with zoledronate or denosumab. Bone mineral density (BMD) was measured prior to and after completion of romosozumab treatment. The median baseline lumbar spine (LS) T-score was −2.3 SD (range −3.1 to +0.9) and total femur T-score was −2.2 SD (range −2.9 to −1.6). Most (5/6) patients experienced an increase in BMD at the LS (median change +7.1%). Most (5/6) patients did not experience clinically significant change in total femur BMD, apart from one patient who experienced a 9% gain. Three patients (50%) experienced subsequent fractures during (1/3) or after completing (2/3) romosozumab treatment. Conclusions: These cases demonstrate severe osteoporosis in transplant recipients. Most patients in our case series had improvement in LS BMD following romosozumab treatment, yet new fractures still occurred during follow-up. The appropriate use of romosozumab in heart and lung transplant patients with osteoporosis requires further study.

1. Introduction

Osteoporosis is common in solid organ transplant recipients, contributed to by the underlying disease necessitating transplant and side effects of immunosuppressive medications required after organ transplantation [1,2]. Fracture rates of up to 40% have been reported in heart and lung transplant recipients [3,4]. Indeed, in a recent study of 10,783 transplant recipients, heart and lung transplant recipients had a 4-fold greater fracture risk compared to a matched non-transplant population [5]. Standard treatment for osteoporosis in heart and lung transplant recipients is with anti-resorptive medications, such as bisphosphonates [1,2]. However, despite liberal use of bisphosphonates, the incidence of fractures and associated morbidity in heart and lung transplant recipients remains high [4,6].

Anabolic therapies for osteoporosis, namely teriparatide and romosozumab, are superior to bisphosphonates for fracture prevention, but there are limited reports of their use in transplant patients. There are case reports of the use of teriparatide, a recombinant human parathyroid hormone that stimulates osteoblast activity, to treat osteoporosis in heart and lung transplant recipients [7,8]. To date, no cases of romosozumab use in transplant recipients exist. Romosozumab is a monoclonal antibody that binds to sclerostin and inhibits its action, administered monthly subcutaneously. Romosozumab reduces vertebral fractures compared to placebo and alendronate in postmenopausal women [9,10] and improves bone mineral density compared to placebo in men [11]. Data for romosozumab treatment of glucocorticoid-induced osteoporosis are limited to small retrospective cohorts, and there are no published data on bone-related outcomes of transplant recipients treated with romosozumab [12,13].

Here we report on skeletal outcomes in heart and lung transplant recipients after treatment with romosozumab for 12 months. In each case, romosozumab was prescribed by the treating clinician after discussion with the patient. The indication for treatment was severe osteoporosis defined as a new fracture occurring despite treatment with an anti-resorptive agent. The option of romosozumab or teriparatide was discussed with patients.

2. Materials and Methods

This is a case series of heart and lung transplant recipients who completed 12 months of romosozumab at a single centre. Medical records of transplant recipients attending the transplant endocrine clinic were reviewed to determine the exposed cohort. The study was approved by the St Vincent’s Hospital Human Research and Ethics Committee via the low–negligible risk pathway (2024/ETH01508). The ethics approval date was 18 July 2024.Data were extracted from hospital electronic and paper records.

Baseline data included age, sex, details of the transplant, bone mineral density (BMD), fracture history, and previous anti-resorptive medication exposure. BMD before and after the completion of romosozumab was measured on a GE LUNAR Prodigy densitometer (Madison, WI, USA). Fracture history during and after romosozumab treatment was collected. Data are expressed as a median (range) or number (percentage). Due to the small sample size, no statistical analysis was performed.

3. Results

Six transplant recipients (median age 57 (range 49–75) years; 67% female) completed 12 months of romosozumab treatment. There were two heart transplant recipients, two bilateral lung transplant recipients, one single lung transplant recipient, and one combined heart–lung transplant recipient. Baseline characteristics are shown in

Table 1. Baseline characteristics.

Baseline Characteristic	Result
Age (years)	57 (49–75)
Male sex	2 (33)
Time since transplant (years)	3 (2–20)
Bone mineral density (T-score)
Lumbar spine	−2.3 (−3.1–+0.9)
Total femur	−2.2 (−2.9–−1.6)
Femoral neck	−2.6 (−2.8–−2.0)
Number of fractures	4 (2–6)
Fracture location
Vertebral	5 (83)
Hip	0 (0)
Other	6 (100)
Anti-resorptive therapy immediately prior to romosozumab
Zoledronate	3 (50)
Denosumab	3 (50)

Data expressed as median (range) or number (percentage).

. Romosozumab was commenced after a median of 3 years post transplant (range 2–20). Standard immunosuppression included tacrolimus, mycophenolate mofetil, and a tapering course of prednisolone. Four patients (66%) were still receiving prednisolone treatment at the time of starting romosozumab, all at a dose of 5 mg daily. The remaining two patients had received prednisolone for one year following transplant. All patients received calcium supplementation with calcium carbonate 1200 mg daily, or calcium citrate 500 mg daily, and vitamin D supplementation with cholecalciferol 1000–2000 international units daily. All patients had a history of fracture, with a majority (5/6) having had at least one vertebral fracture; other fractures included ribs (n = 5), fibula (n = 2), and humerus (n = 1). All had previously received anti-resorptive therapy (3 with zoledronate for >3 years, 3 with denosumab for >2 years).

BMD was measured prior to and after completion of romosozumab. The median baseline lumbar spine (LS) T-score was −2.3 SD, with 50% (n = 3) having an LS T-score ≤ −2.5 SD; the median total femur T-score was −2.2 SD, with 33% (n = 2) having a T-score ≤ −2.5 SD; the median neck of femur T-score was −2.6 SD, with 67% (n = 4) having a T-score ≤ −2.5 SD. The median change in LS BMD after 12 months of treatment was +7.1% (interquartile range (IQR) 6.1–7.4) (Figure 1). Most patients (5/6) experienced a net increase in LS BMD, although a single patient experienced a 16% decrease in LS BMD without an obvious cause. The median change in total proximal femur BMD after romosozumab treatment was +0.6% (IQR 0.0–2.3) (Figure 2). Most (5/6) patients did not experience a clinically significant change in total proximal femur BMD, apart from one patient who experienced a 9% gain.

Following completion of romosozumab treatment, all patients were consolidated with zoledronate or denosumab. Three patients (50%) experienced subsequent fractures during (1/3) or after completing (2/3) romosozumab treatment. Post-treatment fractures included vertebral (n = 1) and distal radius (n = 2).

4. Discussion

We have reported bone density and fracture outcomes for six heart and lung transplant recipients treated with romosozumab for severe osteoporosis. This is the first reported use of romosozumab in transplant recipients. Most patients had a measurable improvement in LS BMD but not total femur BMD following romosozumab treatment. New fractures occurred in half the cohort despite treatment with a potent anabolic agent known to significantly reduce fracture risk in non-transplant patients with osteoporosis. No adverse cardiovascular events occurred during treatment.

Although osteoporosis and fractures are common after heart and lung transplants, there are no specific guidelines for optimal treatment [1,2]. Small studies support the use of bisphosphonates in transplant recipients; however, other agents should be assessed due to persistently high fracture rates. Post-transplant care is complex with competing priorities but, as the number of transplant recipients increases and survival rates continue to improve, the management of comorbidities such as osteoporosis becomes more important.

In non-transplant populations, romosozumab has been shown to have potent anabolic effects on bone density and significant anti-fracture efficacy in patients with severe osteoporosis and high risk of fracture. The FRAME study demonstrated BMD improvements and reduction in vertebral fractures with romosozumab compared to placebo in postmenopausal women [9]. Additionally, the ARCH study showed fracture and BMD benefit using romosozumab compared to alendronate, an oral bisphosphonate [10]. Improvement in BMD with romosozumab compared to placebo has also been demonstrated in older men with osteoporosis [11]. Like the FRAME and ARCH studies, our cohort contained postmenopausal women and older men. However, we did not observe the same degree of BMD improvement in our patients, probably due to the additional pathological impact of post-transplant factors on BMD and fracture risk that are not present in traditional osteoporosis patient cohorts and the use of prior anti-resorptive therapy.

The sequence of romosozumab use following bisphosphonate or denosumab therapy likely limits the potential BMD gains [14]. All the participants in our cohort had received >2 years of anti-resorptive therapy prior to commencing romosozumab, which may have contributed to the heterogeneity in their responses. Additionally, one patient experienced a loss of LS BMD during treatment with romosozumab. This patient had been treated with denosumab for 4 years prior to romosozumab, as well as having a distant history of three doses of zoledronic acid, which may have contributed to the lack of BMD gain.

Immunosuppressant agents are required to minimise rejection of the transplanted organ; however, these agents affect bone metabolism [1]. Glucocorticoid use is well established as a risk factor for osteoporosis, causing excessive bone resorption and impaired bone formation. In our cohort, 66% had ongoing exposure to glucocorticoids, with the remaining two patients having had 12 months of exposure to glucocorticoids following transplant. There are two studies reporting on romosozumab as a treatment for glucocorticoid-induced osteoporosis [12,13]. One demonstrated that romosozumab was comparable to denosumab in BMD gain at the spine and hip, with no difference in new fracture rates, whereas the other showed superior LS BMD gain with romosozumab [12,13]. Both of these studies consisted of a subgroup of patients previously exposed to bisphosphonates or denosumab. In patients on prednisolone ≥5 mg daily exposed to bisphosphonate therapy prior to romosozumab, bone mineral density gain was blunted compared with those not exposed to prior bisphosphonates [13]. There are conflicting data on the contribution of tacrolimus and mycophenolate to bone loss; however, their role as glucocorticoid-sparing agents in transplant recipients is likely overall beneficial [1].

The other available anabolic agent is teriparatide, a recombinant human parathyroid hormone that stimulates osteoblast activity. We previously reported our experience with teriparatide in lung transplant recipients at our institution but, as yet, there are no head-to-head studies of teriparatide and romosozumab in glucocorticoid-induced or transplant-related osteoporosis [7]. Future studies of these agents in transplant recipients are warranted.

There is concern about the cardiovascular safety of romosozumab, as the ARCH trial showed an imbalance in serious cardiovascular-adverse events in patients randomised to romosozumab when compared to alendronate [10]. However, no cardiovascular-adverse event difference was seen in the FRAME trial when romosozumab was compared to placebo [9]. Conversely, real-world electronic medical record data comparing cardiovascular events in people prescribed romosozumab or teriparatide showed fewer adverse cardiovascular events with romosozumab use [15]. Nevertheless, cardiovascular health needs to be closely monitored in transplant recipients, and this is an important outcome for further assessment of romosozumab use in this population. It has been suggested that romosozumab use in heart transplant recipients is inadvisable [2]. However, cardiac transplant recipients undergo regular cardiovascular monitoring and should be free from coronary artery disease at the time of transplant. Therefore, until further evidence is available, an individualised risk assessment should be undertaken to establish suitability for treatment with romosozumab. In our cohort, the patients were counselled on the possible association with adverse cardiovascular events.

This case series is limited by the small cohort of six patients. Transplant recipients are excluded from most large clinical trials, and very few clinical trials exist assessing osteoporosis management in heart and lung transplant recipients [1,2]. A comparator group was not available for this series, and a prospective randomised trial comparing different osteoporosis treatments in transplant recipients is needed. This high-risk population should not be excluded from potential therapeutic options simply because a lack of data is available.

5. Conclusions

Our case series highlights that severe osteoporosis is prevalent in heart and lung transplant recipients and that anti-osteoporosis therapies may be less effective in these patients. Furthermore, fracture risk remains high, and patients continue to fracture despite treatment with potent anti-resorptive and anabolic medication. The appropriate use and timing of anabolic agents, such as romosozumab and teriparatide, in the treatment of osteoporosis is an important area for further study in transplant recipients.