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Editorial |
Departments of Diabetes and Endocrinology and Medicine The University of Melbourne The Royal Melbourne Hospital Parkville 3050, Victoria, Australia
Address all correspondence and requests for reprints to: Peter R. Ebeling, M.D., FRACP, Departments of Diabetes and Endocrinology and Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville 3050, Victoria, Australia. E-mail: peter.Ebeling{at}mh.org.au.
Osteoporosis is an important potential long-term complication of both solid-organ and stem-cell transplantation (SCT) (1). SCT is now the most common form of transplantation. The majority of patients undergoing SCT are young and will survive for many years after transplant. However, bone disease after SCT differs from that after solid organ transplantation. There are specific effects of the SCT on bone marrow stromal cells, patients are generally young, the interval between diagnosis and SCT is short, and the pre-SCT treatment often also affects bone (2).
Post-SCT bone loss is important because it is associated with an increased risk of fragility fractures and avascular necrosis. The incidence of new vertebral fractures varies from 4–16% in the first year and up to 10.6% within 3 yr of SCT (3). Significant height loss also occurs in the first 12 months after SCT. Data on the incidence of long-term nonvertebral fractures after SCT are absent. Avascular necrosis is the most serious complication of SCT and develops in 10–20% of allogeneic SCT (allo-SCT) survivors a median of 12 months after SCT (4). The femoral head is most often affected, and frequently more than one site may be affected. It is less common after autologous SCT (auto-SCT), occurring in 1.9% of patients. The cumulative glucocorticoid dose is the most important risk factor. Age but not sex is also important. In one study (5), femoral neck bone loss was also greater in men with avascular necrosis of the femoral head. Avascular necrosis appears to be related to decreased numbers of bone marrow colony forming unit-fibroblast (CFU-f) colonies in vitro but not to bone mineral density (BMD) values (5). Avascular necrosis may be facilitated by a deficit in bone marrow stromal stem cell regeneration and low osteoblast numbers after SCT.
The pattern of bone loss occurring after SCT is also distinctive. Our group was the first of many to show that dramatic bone loss from the proximal femur occurs within the first 12 months of allo-SCT (5). Spinal bone loss is lower and partial recovery of bone mass occurs at this site from 6–12 months after SCT. This contrasts with bone loss in recipients of auto-SCT, in whom spinal bone loss is transient with recovery to baseline, and bone loss from the femoral neck is less than after allo-SCT but persists in the long term (6). A persistent decrease in bone mass at the proximal femur is the striking finding after SCT, being greater following allo-SCT than auto-SCT. The reason for this characteristic post-SCT pattern of bone loss targeting the proximal femur is unclear.
The factors predisposing to post-SCT bone loss are complex. The main factors are immunosuppressive therapy with glucocorticoids and cyclosporine A, used to prevent and treat graft-vs.-host disease; the effects of cytokines; and a stromal cell defect affecting the osteoblast precursor cell, colony forming unit CFU-f (fibroblast), which may persist for 12 yr after SCT. The underlying hematological disease and its treatment, myeloablative chemotherapy, total body irradiation, hypogonadism complicating chemotherapy (often permanent in females and transient in males after allo-SCT), and vitamin D deficiency and secondary hyperparathyroidism, may also contribute. The combined effects of high-dose glucocorticoid therapy and defective osteoblast differentiation are to profoundly decrease bone formation, whereas cyclosporine A, hypogonadism, and secondary hyperparathyroidism increase bone remodeling.
Because of the high prevalence of osteoporosis, osteopenia, and abnormal bone and mineral metabolism in patients awaiting SCT and the morbidity caused by osteoporosis after transplantation, all candidates for SCT would benefit from an evaluation of bone health. BMD of the hip and spine should be measured before transplantation, preferably at the time of acceptance to the waiting list. Spine radiographs should be performed to detect prevalent fractures. If BMD is low, an evaluation for secondary causes of osteoporosis should be undertaken and, if detected, should be treated specifically. However, most cases will be related to myeloablative chemotherapy and glucocorticoids. All patients should receive the recommended daily allowance of calcium and vitamin D (1000–1500 mg of calcium and 400–800 IU of vitamin D). Bisphosphonates are now one of the most commonly used drugs to treat osteoporosis. They predominantly act to inhibit the action of osteoclasts and induce their apoptosis. However, bisphosphonates may also reduce osteoblast apoptosis. Oral and iv bisphosphonates have also been successfully used to prevent bone loss after solid organ transplantation.
The study by Karenen et al. (7) published in this issue is important because it is the largest study of bisphosphonate therapy after allo-SCT published to date. These investigators attempted to prevent bone loss after allo-SCT by administering iv pamidronate therapy at doses similar to those used to prevent glucocorticoid-induced bone loss (60 mg before, then at 1, 2, 3, 6, and 9 months after allo-SCT). The doses were staggered to give the highest doses when bone loss is greatest in the first 3–6 months after SCT. All patients also received calcium carbonate (1000 mg) and vitamin D (800 IU) per day and sex hormone replacement with either transdermal estradiol and oral hydroxyprogesterone acetate or transdermal testosterone beginning 2 wk after SCT. They showed that allo-SCT recipients treated with iv pamidronate sustained less bone loss at the lumbar spine, total hip, and femoral neck sites than those treated with calcium, vitamin D, and sex hormone replacement alone. Bone resorption and bone formation markers were also reduced by pamidronate therapy. However, despite these efforts, bone loss from the hip was not completely prevented by pamidronate therapy. This is in contrast to the successful use of iv or oral bisphosphonates to prevent bone loss after cardiac and kidney transplantation (1). Intravenous pamidronate therapy has also been associated with a lower incidence of vertebral fractures after liver transplantation. Recently, it was reported that oral alendronate or calcitriol also equally decreased bone loss from the spine and femoral neck in comparison with untreated patients in the first year after cardiac transplantation (8).
It is unclear why the combination of pamidronate, calcium, vitamin D, and sex hormone replacement did not preserve hip bone mass in allo-SCT recipients. Karenen et al. (7) showed a discrepancy in the response of bone resorption markers to pamidronate treatment. C-telopeptide and N-telopeptide both reflect cathepsin-K-mediated osteoclastic bone resorption, which was inhibited by bisphosphonates, whereas serum type I collagen C-terminal telopeptide, reflecting matrix metalloproteinase-mediated bone resorption, was not. The authors postulate that the increased matrix metalloproteinase activity may be an effect of osteoblasts and is unaffected by bisphosphonate therapy. Another possible cause is that the dose of pamidronate was suboptimal. Additional studies of higher pamidronate doses are therefore required before concluding that pamidronate therapy is ineffective in reducing bone loss after allo-SCT.
The pattern of increased bone resorption and decreased bone formation present in SCT recipients is reminiscent of the pattern of changes in bone turnover seen in multiple myeloma. In this disease, an osteoblast-derived protein, Dickkopf-1 (DKK1), is elevated and antagonizes the Wnt signaling system to reduce bone formation and increase the development of osteolytic lesions (9). In multiple myeloma, increased DKK1 levels are also associated with elevated IL-6 levels. IL-6 is one of the cytokines that increases early after SCT. It is therefore tempting to speculate that increased DKK-1 levels may contribute to the unusual pattern of bone loss after SCT and also to its resistance to pamidronate therapy. No data are currently available measuring DKK-1 levels after SCT, and additional investigations are required.
Other more potent bisphosphonates may prove to be effective in preventing bone loss from the hip after SCT. In a prospective randomized 12-month study of risedronate on bone mass and turnover in patients who had undergone allo-BMT at least 6 months before, spine BMD increased in patients on risedronate and decreased in those taking placebo (10). All patients received calcium and vitamin D. At the femoral neck, BMD did not change significantly in patients on risedronate but decreased in those on placebo. However, it is not clear from this study whether risedronate would also prevent the rapid early bone loss from the femoral neck occurring after BMT.
A recent small study of three monthly doses of 4 mg zoledronic acid iv administered a median of 12 months after SCT in patients with osteoporosis or rapidly progressing osteopenia showed marked increases in spinal and femoral BMD of 10% and 6%, respectively (11). However, treatment was commenced after the most rapid phase of bone loss had occurred in all patients. Interestingly, after zoledronate there was also an increase in ex vivo growth of bone marrow osteoblast precursor cells, CFU-f, suggesting this potent bisphosphonate may be effective at improving osteoblast recovery and increasing osteoblast numbers after SCT. Additional larger studies comparing different doses of zoledronate are now required to confirm these findings, particularly when treatment is commenced immediately before allo-SCT. Such studies will also need to address the safety of zoledronic acid therapy in this patient group, given the recent identification of the very uncommon, but serious, complication of jaw osteonecrosis complicating potent bisphosphonate therapy (12). This is particularly important in this patient group, given that many allo-SCT recipients are young.
Other treatments shown to be ineffective in preventing bone loss after SCT are calcium and vitamin D, calcitonin, or sex hormone replacement. Future treatment options may include sc injections of human antibodies to receptor activator of nuclear factor 
B ligand. This treatment may be effective at preventing bone loss after SCT because this final pathway mediates the effects of hormone deficiency and cytokines on osteoclasts. Its efficacy remains to be tested in allo-SCT recipients, but the safety and efficacy of this treatment are currently being investigated in women with postmenopausal osteoporosis.
This study represents an important first step in preventing bone loss after SCT. The authors are to be congratulated for performing such a well-planned study. Additional work is now required to elucidate the mechanisms underlying this distinctive pattern of posttransplantation bone loss, as well as the optimal and safest strategies for its prevention.
Footnotes
Abbreviations: allo-SCT, Allogeneic SCT; auto-SCT, autologous SCT; BMD, bone mineral density; CFU-f, colony forming unit-fibroblast; DKK1, Dickkopf-1; SCT, stem-cell transplantation.
Received May 13, 2005.
Accepted May 23, 2005.
References
This article has been cited by other articles:
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  L. Tauchmanova, A. Colao, G. Lombardi, B. Rotoli, and C. Selleri REVIEW: Bone Loss and Its Management in Long-Term Survivors from Allogeneic Stem Cell Transplantation J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4536 - 4545. [Abstract] [Full Text] [PDF]
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A. P. Grigg, P. Shuttleworth, J. Reynolds, A. P. Schwarer, J. Szer, K. Bradstock, C. Hui, R. Herrmann, and P. R. Ebeling Pamidronate Reduces Bone Loss after Allogeneic Stem Cell Transplantation J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3835 - 3843. [Abstract] [Full Text] [PDF]
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