Effect of Immunosuppression on the Hybrid Skeleton of Vascularized Composite Allotransplants?

To date, the long-term effects of immunosuppression on the hybrid skeleton (donor/recipient) of vascularized composite allotransplants (VCAs) have not been adequately investigated. At the same time, a significant body of literature recognizes osteoporosis and bone demineralization as significant complications following solid organ transplantations. Immunosuppressive medications, specifically glucocorticoids and calcineurin-inhibitors (eg, tacrolimus), are thought to be major contributors.[1] Glucocorticoids induce upregulation of osteoclasts with concomitant inhibition of osteoblast activity.[1] Furthermore, calcineurin-inhibitors inhibit osteoblast growth.[1] These cells are central to bone remodeling and skeletal health.[1]

Bone loss has been recognized as soon as 6 months following solid organ transplantations. Sixty percent of patients display an osseus mineral density less than the fracture threshold by 18 months.[1] The most common fracture sites include the lower limbs, spine, and ribs.[1]

Of note, bone is an integral component of all hand transplants. In addition, facial VCAs incorporate increasingly greater osseus elements. Initial face transplants were essentially restricted to soft tissue replacements. Nevertheless, subsequent experience revealed the critical role of skeletal support to reduce ptosis and maximize aesthetics and function. The impact of immunosuppressive medications on the hybrid skeleton (donor/recipient) of VCAs may be significant. Specifically, skeletal integration, bone strength, mineralization, and dentition may be affected.

We conducted a review of available literature. Diep et al reviewed the literature for all described facial allograft revisions.[2] They found revisions of the craniofacial skeleton in 15 (35%) of 43 face transplants as of August 2020.[2] Most revisions were performed in the first 6 months following transplantation.[2] Nevertheless, bone density and strength were not analyzed.[2]

Previous reports describe only “fibrous bony union” at the donor/recipient skeletal interface.[3] Moreover, a case of fracture involving the donor mandible and nose 8-years after face transplantation has recently been described.[3]

Petruzzo et al utilized high-resolution peripheral quantitative computed-tomography scans to analyze bone density in four hand VCAs.[4] They identified decreased trabecular density and decreased cortical thickness in three out of four patients.[4] Lantieri et al, on the other hand, describe no bone density loss on long-term follow-up of four bone-containing face transplants.[5] Nevertheless, how quantitative analysis of skeletal density was assessed in this latter study is not well described.[5] Moreover, recently this same group reported the fracture of the donor skeleton described above.[3]

The bones of the hand may be more comparable to the bones cited as common places for fractures following solid organ transplantations. In contrast, facial bones (eg, maxilla or mandible) are structurally and developmentally different. Perhaps immunosuppressive medications possess differential or selective osseus predilection based on bone structure and embryologic origin. Nevertheless, the current literature lacks sufficient studies to prove or refute these assumptions.

We encourage face and hand transplant teams to study and analyze the long-term fate of the hybrid skeleton in greater detail. Bone health is vital to maintain the structural integrity of the graft and sustain successful surgical outcomes. VCA is an exciting advancement in reconstructive surgery. Further evolution mandates continued research to improve outcomes and reduce side-effects.

Disclosure

The authors have no financial interest to declare in relation to the content of this article.