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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2870
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4536-4545
Copyright © 2007 by The Endocrine Society

REVIEW

REVIEW: Bone Loss and Its Management in Long-Term Survivors from Allogeneic Stem Cell Transplantation

Libuse Tauchmanovà, Annamaria Colao, Gaetano Lombardi, Bruno Rotoli and Carmine Selleri

Departments of Molecular and Clinical Endocrinology and Oncology (L.T., A.C., G.L.) and Biochemistry and Medical Biotechnology (B.R., C.S.), Federico II University of Naples, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Libuse Tauchmanovà, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, via S. Pansini 5, 80131 Naples, Italy. E-mail: tauchman{at}unina.it.


   Abstract
Top
 Abstract
Introduction
 Clinical Studies
 Hypothesis on the Systemic...
 Bone Marrow Microenvironment and...
 Prevention and Treatment of...
 Management of Patients
 Conclusions
 References
 
Context: Recently, great efforts have been made to understand the pathogenesis of bone loss after allogeneic stem cell transplant (allo-SCT) and possible treatments.

Evidence Acquisition: A literature search of the MEDLINE database was performed to find articles in English using the search terms "allogeneic stem cell transplant" or "bone marrow transplant," in combination with "bone loss," "osteoporosis treatment," "osteoblast," "cytokines," or "osteoprotegerin." Reference lists from the articles retrieved were also evaluated for relevant information.

Evidence Synthesis: Bone mineral density at the lumbar spine, but not at the femur, can improve or even recover several years after SCT. Multiple risk factors for posttransplant bone loss have been recently identified: abnormalities in the immune system function and their treatments, reduced production of growth factors, osteoclast activation by increased cytokine release, and decreased number and function of osteoblast precursors within the stromal stem cell compartment. Pamidronate was partially successful in preventing posttransplant bone loss, whereas both oral and parenteral bisphosphonates had beneficial effects on documented osteoporosis in long-term survivors.

Conclusions: There is clear evidence that transplant-related bone loss is a multifactorial, early, and possibly long-lasting disorder. All patients who have already received allo-SCT should be evaluated as to their bone status and treated with appropriate supportive measures and specific treatments as soon as abnormalities are detected. Although preventive antiresorptive treatments are only partially effective, they should be started in all patients before or at the time of allo-SCT, regardless of their bone mineral density values, and continued at least for the first year after transplant.


   Introduction
Top
 Abstract
 Introduction
Clinical Studies
 Hypothesis on the Systemic...
 Bone Marrow Microenvironment and...
 Prevention and Treatment of...
 Management of Patients
 Conclusions
 References
 
BONE LOSS IS a long-lasting complication of both solid organ and stem cell transplants (SCT). SCT is currently the most common form of transplantation; it is associated with specific features of bone damage that are related to the type of patient, underlying diseases, pretransplant treatments, and general health conditions after grafting. Patients undergoing SCT are generally young, have a short interval between disease diagnosis and transplant, and have already undergone several cycles of chemotherapy; they are treated with additional high-dose chemotherapy with or without radiotherapy as conditioning regimens for SCT (1). Although patients after allogeneic (allo)-SCT do not receive life-long immunosuppressive treatments, unlike patients undergoing solid organ transplants, their immune system seems to be even more dysregulated. Allo-SCT represents the only condition in which a large number of immunocompetent donor cells are infused into the host. These cells are believed to cause a graft-vs.-tumor reaction, which represents an important contribution for disease eradication. However, in about half of the patients, it causes acute and/or chronic graft-vs.-host disease (cGvHD), which shares multiple pathogenic and clinical features with degenerative and autoimmune diseases (2, 3). Acute GvHD and exacerbations of cGvHD require temporary high doses of immunosuppressive therapy. In addition, abnormalities of the immune system and their treatments influence bone remodeling and bone mass directly and indirectly.


   Clinical Studies
Top
 Abstract
 Introduction
 Clinical Studies
Hypothesis on the Systemic...
 Bone Marrow Microenvironment and...
 Prevention and Treatment of...
 Management of Patients
 Conclusions
 References
 
Bone loss is more severe and occurs over a longer time frame after allo-SCT than after autologous (auto)-SCT. In the latter, spinal bone loss is mostly transient because baseline values are rapidly recovered. Decreases in femoral bone mineral density (BMD) last longer in both types of transplants (4, 5). Both auto- and allo-SCT are performed for similar underlying hematological malignancies and are preceded by identical pretransplant treatment protocols and conditioning regimens. The most important differences between these two settings are related to an involvement of the immune system, which include 1) a prolonged and greater posttransplant cytokine release in allo-SCT patients, 2) onset of acute or cGvHD in about half of allo-transplanted subjects, and 3) a more frequent use of immunosuppressive treatments in the allogeneic setting (2, 3). Indeed, greater bone damage in survivors of allo-SCT may be related to a greater derangement of their immune system. This hypothesis is based on recent reports describing negative effects on bone of immune system disorders in different populations of patients (6).

About 25 studies have been published describing the features of bone loss consequent to allo-SCT; more than half of them are prospective (Table 1Go). They provide important information on the temporal sequence of bone loss at different skeletal sites. Most of these studies evaluated bone mass for 1–3 yr after SCT; the longest follow-up period reached 12 yr (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). However, only a small number of patients were followed for periods of time longer than 2–3 yr after allografting. All of the reports described an early stage of rapid demineralization (within 6–12 months) at all skeletal sites, followed by an improvement in lumbar BMD (predominantly trabecular bone), whereas bone loss at the femoral neck (predominantly cortical bone) persisted up to 48–120 months after SCT (5, 7, 19, 20). The rates of bone loss during the first posttransplant year ranged between 6.2 and 12% at the femoral neck, 3 and 17% at the spine, and 3.1 and 3.8% at whole-body scan (1, 17, 21). The prevalence of osteopenia/osteoporosis ranged from 29–75% at the lumbar spine and from 33–59% at the femoral neck (1, 5, 7, 21). As for bone turnover, bone formation markers decreased immediately after allo-SCT, whereas resorption markers increased later on and both recovered within 12 months (11, 22). This is an important observation, because abnormalities in bone turnover have been widely recognized as an independent risk factor for fractures, regardless of BMD behavior (23). The incidence of new vertebral fractures varied from 4–16% during the first year after SCT (4, 10, 11) and was 10.6% within 3 yr after SCT (18). However, no data are available on nonvertebral fractures and long-term risk of vertebral fractures. We can estimate that approximately 10% BMD loss at the proximal femur, persisting 4–6 yr after SCT (4, 14), might suggest a 2- to 3-fold increase in hip fracture risk (24).


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  		TABLE 1. Risk factors reported in large studies on bone mass in adult patients after allogeneic stem cell transplant

 

   Hypothesis on the Systemic Etiology of Post-SCT Bone Loss
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 Abstract
 Introduction
 Clinical Studies
 Hypothesis on the Systemic...
Bone Marrow Microenvironment and...
 Prevention and Treatment of...
 Management of Patients
 Conclusions
 References
 
Concerning the etiology of bone loss consequent to allo-SCT, the first studies classified this disorder as a specific type of steroid-induced osteoporosis. Cortisol excess exerts direct and indirect effects on bone, enhancing its resorption first and inhibiting bone formation thereafter, with a rapid bone loss at both trabecular and cortical sites and evidence of increased fracture risk at any skeletal site (25, 26). Posttransplant bone loss is prevalent and more persistent at the femoral neck. Although most of the authors showed a significant correlation between lumbar/femoral BMD and both total and daily steroid doses, glucocorticoids are only one of the contributing factors to bone loss consequent to allo-SCT. Secondary hypogonadism and a direct contribution of chemotherapy and radiotherapy were recognized early as important risk factors (12, 19). Other immunosuppressive therapies, including cyclosporin A (CsA) and tacrolimus, may also cause bone damage (11, 18), although to a lesser extent. Studies on the effects of CsA in animals demonstrated an increase in both bone formation and resorption (27). In humans, CsA-induced bone loss occurred principally at sites rich in cortical bone, and its degree was related to the duration of exposure (11, 18); there are no clinical data on the effects of the newer immunosuppressive agents such as tacrolimus and mofetil mycophenolate.

Currently, it is clear that SCT-related bone loss must be considered as a multifactorial disorder. There is consistent evidence that major risk factors include myeloablative conditioning regimens, marked cytokine release at the time of transplant, high-dose glucocorticoid and CsA therapy, gonadal failure, and reduced mobility (1, 28, 29). Additionally, altered kidney, liver, and bowel function may result in reduced absorption and abnormal metabolism of calcium and vitamin D (1, 28, 29).

Several studies have pointed to the relationship between cGvHD and the most severe forms of bone loss (5, 7, 9, 30). Stern et al. (9) specifically evaluated the effects of cGvHD on bone mass in nine patients over a 9-month period; they found significant bone loss (average decrease, –9.5% between the third and the 12th posttransplant month), characterized by great individual variability (from +0.85% to –21.55%). Patients with cGvHD of grade II or higher had greater lumbar bone loss than patients with GvHD of grade I or lower. In our experience, lumbar BMD was lower in patients affected by cGvHD and started to improve approximately 24 months after SCT, without complete recovery (5, 7). This is in agreement with the clinical observation that cGvHD generally disappears and immunosuppressive treatments can be progressively tapered and withdrawn within 24–36 months after transplant (2).

Finally, an early decline in the production of growth factors may contribute to post-SCT bone loss (20, 22). A reduction of serum IGF-I and fibroblast growth factor 2 was observed during 3 wk after transplant and returned to baseline within 3 months (22). Serum IGF-I levels at 3 wk and 3 months predicted the amount of bone loss at the proximal femur during the first 12 months after SCT (22).

Other possible mechanisms for posttransplant bone loss may consist of osteoclast activation by increased systemic or local cytokine production. Enhanced release of granulocyte-macrophage colony-stimulating factor, IL-6, and TNF-{alpha} was observed and was triggered by both myeloablative treatments and transplant (31). In recent studies, the amounts that IL-6, IL-7, and TNF-{alpha} increased during the first 3 wk after allo-SCT predicted the amount of bone loss during the first 12 months after transplant (30, 32).

We found an increase in the levels of serum interferon-{gamma} and TNF-{alpha} but not of IL-6 in patients who were evaluated 12–72 months after allo-SCT; no relationship was observed between IL-6 and BMD values (33). These findings suggest that cytokines may play an important role in bone loss immediately after grafting, whereas their production and influence on BMD decrease thereafter. However, there are also patients who continue to lose their bone mass years after SCT. The reasons for the peculiar pattern of persistent bone loss consequent to allo-SCT, targeting principally the proximal femur, still need to be clarified. Other risk factors may be revealed in the future.


   Bone Marrow Microenvironment and Mechanisms of Bone Loss Consequent to Allo-SCT
Top
 Abstract
 Introduction
 Clinical Studies
 Hypothesis on the Systemic...
 Bone Marrow Microenvironment and...
Prevention and Treatment of...
 Management of Patients
 Conclusions
 References
 
Three centers (including ours) observed a severe and persistent posttransplant reduction in the number and function of osteoblastic precursors within the bone marrow, suggesting that the inability to regenerate a normal osteogenic cell compartment may partly explain the reason for persistent bone damage after allo-SCT (5, 34, 35).

Bone is the only tissue that is constantly regenerated by a process of osteoclast-mediated resorption and osteoblast-induced replacement. An impaired balance between these two processes is the primary cause of osteoporosis. Bone and bone marrow are anatomically and functionally related tissues; the precursors for bone cells, osteoblasts and osteoclasts, originate in the marrow. Their normal production is necessary for osteogenesis and bone remodeling. Radiotherapy was the first treatment to be documented as causing bone loss, by diminishing osteocyte and osteoblast function (36). Later on, chemotherapy was reported to impair the function of bone cell precursors (37). Finally, SCT preceded by myeloablative conditioning regimens was found to delay the repopulation of bone microenvironment (5, 7, 34, 38). We have reported a significantly reduced number of osteoblastic precursors within the bone marrow, which correlated with both lumbar and femoral BMD; moreover, the functional capacity of these cells to produce a confluent stroma was reduced (5). Immunostaining for alkaline phosphatase, i.e. an enzyme involved in mineralization, was also reduced. These data suggest that, in addition to radio-/chemotherapy, the SCT procedure itself causes severe and persistent quantitative and qualitative impairment of the osteoblastic precursors within the stromal stem cell compartment. The inability to regenerate a normal osteogenic cell compartment may in part account for the persistent bone damage after allo-SCT (5).

Finally, cGvHD was associated with a significantly lower number of osteoblastic precursors (5, 7). The exact reason that patients affected by cGvHD have greater damage to the osteogenic cell marrow compartment is still unclear. However, it is difficult to separate the effects of cGvHD from those of its treatments, because glucocorticoids also decrease osteoblastic proliferation and activity (25, 39). Moreover, endocrine disorders consequent to allo-SCT, which include reduction of anabolic hormones such as GH, IGF-I, and dehydroepiandrosterone sulfate can further contribute to bone loss (40, 41, 42).

As mentioned above, osteoclastic activation may be triggered by increased systemic or local cytokine production. In a study by Lee et al. (43), serum type I collagen carboxyl-terminal telopeptide (ICTP), a bone resorption marker, correlated with bone marrow plasma IL-6 but not TNF-{alpha} levels at 3 wk after SCT. These data confirm the influence of both the immune system activation and increased marrow IL production on posttransplant bone loss.

An alteration in the balance between the receptor activator of the nuclear factor-{kappa}B ligand (RANKL) and osteoprotegerin (OPG) was shown to be critical in the pathogenesis of osteoporosis (44). Serum OPG (sOPG) was found to be increased in various conditions characterized by bone loss, including post-SCT status (21, 45, 46); this increase has been explained as a possible homeostatic mechanism limiting the more rapid bone loss (47); however, the exact skeletal and nonskeletal contributions to circulating OPG are far from clear.

An increase in sOPG and soluble RANKL (sRANKL) during the first 3 wk and a decline within 3 months after transplant was described by Baek et al. (32). The amount of sRANKL and sRANKL/OPG changes correlated with those of the bone turnover marker ICTP. Other authors reported posttransplant increases in sOPG at 3–6 months without changes in sRANKL (22, 47). However, no correlation was observed between the posttransplant behavior of sOPG, sRANKL, and BMD (30, 32, 33, 48). We evaluated OPG and sRANKL in serum and marrow plasma in long-term survivors (12–72 months) after allo-SCT (33). Serum OPG was significantly higher in patients than controls and correlated with circulating interferon-{gamma} levels. On the contrary, in marrow plasma and in conditioned media (after 1 and 3 months of culture of marrow mesenchymal-derived osteogenic cells), OPG levels were lower in patients than controls. sRANKL did not differ between patients and controls in serum and in bone marrow plasma; however, the OPG-to-RANKL ratio in situ was significantly lower in patients. No correlation was observed between sOPG and marrow OPG and sRANKL levels and densitometric values.

We concluded that the serum OPG/RANKL values do not express the condition of the bone marrow microenvironment in patients after allo-SCT. sOPG may be sustained by several alternative sources, whereas in the marrow niches, they are mainly produced by mesenchymal-derived osteoblastic cells that appear substantially reduced after transplant. A locally low OPG-to-RANKL ratio is likely to promote bone resorption. Our data need to be confirmed in a larger series of transplanted patients and at various time points during the posttransplant follow-up. More studies are also essential to clarify the biological mechanisms underlying the impaired OPG production that causes abnormal bone remodeling after allo-SCT. Factors that are currently known to influence the posttransplant balance of bone marrow cell precursors are summarized in Fig. 1Go.


Figure 1
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  		FIG. 1. Main factors influencing bone remodeling after transplant. A, Systemic and local factors that influence the stromal compartment after allogeneic SCT. The whole stromal cell compartment and osteoblastic differentiation from mesenchymal cells are inhibited by multiple factors after allo-SCT; the function of osteoblasts is also decreased. The reduction of osteoblastic precursors together with several systemic and local factors decrease OPG production. On the contrary, RANKL production increases through the effects of multiple factors, including trafficking of activated lymphocytes. Consequently, the RANKL/OPG ratio increases within the bone marrow microenvironment, and this enhances bone resorption. The OPG/RANKL pathway seems to be the most important one in maintaining the balance of bone remodeling. B, Principal systemic and local factors that control bone remodeling after stem cell transplant in both genders. Different systemic factors may directly increase bone resorption after SCT: cytokine storm, granulocyte-colony stimulating factor (G-CSF), immunosuppression, immobilization and impaired metabolism, and gastrointestinal absorption of calcium and vitamin D. Reduced calcium and vitamin D may cause secondary hyperparathyroidism that further triggers bone resorption. Increased RANKL-to-OPG ratio is induced by multiple factors, which promotes bone resorption by enhancing osteoclastogenesis and osteoclast activation and by prolonging the survival of preexisting osteoclasts. Furthermore, chemotherapy, radiotherapy, and GvHD inhibit gonadal secretion of sex steroids, whereas glucocorticoids have inhibitory effects on the production of both gonadal and adrenal sex steroids. A decrease in estrogens and androgens leads to increased bone resorption. Some factors may influence bone turnover either directly or through the RANKL/OPG pathway.

 

   Prevention and Treatment of Bone Loss after Allo-SCT
Top
 Abstract
 Introduction
 Clinical Studies
 Hypothesis on the Systemic...
 Bone Marrow Microenvironment and...
 Prevention and Treatment of...
Management of Patients
 Conclusions
 References
 
It should be emphasized that transplant-related bone loss is an early event, and currently, no therapy is able to completely restore lost bone mass. Therefore, the concept of prevention emerges. There is general agreement that in allo-transplanted patients, it is necessary to promptly start appropriate preventive measures, including calcium and vitamin D supplementation and sex steroid replacement for hypogonadism, whenever possible. Patients should be advised to adopt nonpharmacological preventive measures, i.e. healthy lifestyle, physical activity, smoking cessation, and measures to prevent falls (eye exam, attention to environmental conditions, and exercise to improve muscle coordination and proprioception).

However, calcium, either alone or combined with calcitonin, was ineffective in preventing bone loss during the first posttransplant year (Table 2Go) (12, 49). Despite lack of efficacy when used alone, adequate doses of calcium and vitamin D supplements should be given to all patients undergoing SCT, because their absorption is poor and their metabolism could be altered.


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  		TABLE 2. Effects of treatments on bone loss after allo-SCT

 
Physiological levels of sex hormones are important for bone homeostasis in both genders. Estrogens inhibit osteoclast activity and promote osteoclast apoptosis. Androgens may directly affect osteoblast differentiation and at least in part act on bone after being converted to estrogens by aromatization. Therefore, persistent hypogonadism should be treated with hormone replacement therapy (HRT) in both genders whenever possible. As to the effects of HRT, BMD improvement was observed in 13 hypogonadal women after auto- or allo-SCT, when estrogens were introduced approximately 13 months after transplant (50). In two other studies, calcium, vitamin D, and HRT did not prevent bone loss at the lumbar spine and proximal femur (11, 21). In our series of long-term hypogonadal female survivors after allo-SCT, HRT (estradiol, 2 mg daily orally or 50 µg in transdermal administration, associated with progestins) together with supplementation of calcium (500–1000 mg daily) and vitamin D (400–800 IU daily) failed to improve bone mass at either the lumbar spine or the femoral neck (51).

The ineffectiveness of the preventive measures in posttransplant bone loss suggested the need for more appropriate and potent drugs. Oral and parenteral bisphosphonates (BPs) (pamidronate, alendronate, ibandronate, and etidronate) were effective in preventing bone loss after solid organ transplants (52, 53). Oral BPs currently represent the standard of care for menopausal and glucocorticoid-induced osteoporosis. However, BPs are poorly absorbed from the gastrointestinal tract (54, 55, 56), and oral use is contraindicated in immobilized patients (56). For these reasons, they can hardly be administered during the posttransplant period, and their introduction later on can be troublesome in patients with gastrointestinal cGvHD. There is only one study on the use of oral BPs in long-term survivors after allo-SCT. Risedronate treatment was started 17–24 months after grafting and significantly improved lumbar BMD within 12 months; it also prevented additional bone loss at the femoral neck (57).

Intermittent parenteral formulations of many BPs have been available for years and have been used to treat osteoporosis in controlled clinical trials in various settings, including patients after allo-SCT. In patients with osteoporosis or rapidly progressing osteopenia (bone loss > 5%/yr), the administration of zoledronic acid at three monthly doses of 4 mg each increased BMD significantly at both the lumbar spine (+9.8%) and femoral neck (+6.4%) (58). The treatment was started after a median period of 12.2 (range, 6–18) months after SCT, and the patients were reevaluated 12 months after the beginning of treatment (58). A flaw of this study was that the patients were not randomized and started the treatment at different times after allo-SCT. D’Souza et al. (59) evaluated the effects of a single 4-mg zoledronic acid infusion in an open uncontrolled study in 12 allo-SCT patients with osteoporosis or rapidly declining BMD. Most of the patients (nine of 12) received zoledronic acid within the first year after transplant. Twelve months after the infusion, total hip BMD increased in 75% of patients by a median of +3.3% (range, –20.4 to +14.8%), and femoral neck BMD increased in 11 of 12 patients by a median of +1.4% (range, –22.2 to +33.6%). Surprisingly, spinal BMD increased in only four patients, whereas it was stable in four and decreased in another four cases; median lumbar BMD decreased by 2.8% (range, –27.6 to +24.4%). The authors concluded that zoledronic acid may reduce bone loss in most patients after allo-SCT. However, there is a discrepancy between these results and all the other reports describing a greater increase in spinal rather than femoral BMD during BP administration.

The first randomized controlled study in which BPs were used to prevent bone loss soon after allo-SCT was published by Kananen et al. (49). Sixty-six (33 in each group) recipients of allo-SCT completed a 12-month follow-up. The treatment group received six iv infusions of 60 mg pamidronate (before and 1, 2, 3, 6, and 9 months after SCT); both groups were given HRT for hypogonadism and received 1 g calcium and 800 IU vitamin D daily. Lumbar spine BMD remained stable in the pamidronate group and decreased by 2.9% in the untreated group, total hip BMD was reduced by 5.1% in the pamidronate group and by 7.8% in the untreated group, and femoral BMD decreased by 4.2 and 6.2%, respectively. At 12 months, the BMD differences between the two groups remained significant at the lumbar spine and total hip but not at the femoral neck. The authors concluded that pamidronate prevented bone loss at the lumbar spine and reduced it at femoral sites in allo-SCT recipients. Bone turnover rates were also better controlled by adding pamidronate to the treatment scheme of calcium, vitamin D, and sex steroid replacement.

Similar results were obtained by Grigg et al. (60) in his randomized study on 116 patients; bone loss was well prevented at the lumbar spine but only partially at the femoral neck with monthly iv administration of 90 mg pamidronate for 12 months, starting within a week of the commencement of the pretransplant chemotherapy. Treatment benefits were greater in patients receiving high-dose glucocorticoids (daily prednisolone dose > 10 mg) and prolonged cyclosporin therapy; however, most of the improvements achieved were lost within 12 months after stopping pamidronate.

Whereas zoledronic acid increased both lumbar and femoral BMD in long-term allo-SCT survivors (51, 61), pamidronate was unable to preserve bone mass at the hip in the early posttransplant period (49, 60). Kananen et al. (49) tried to explain the relative inefficacy of BPs in the early posttransplant period by their effects on bone remodeling. She observed reduced serum levels of type I collagen amino-terminal telopeptide and cross-linked carboxyl-terminal telopeptide β, which mirror the effects of cathepsin-K-mediated resorption, but also found unchanged ICTP levels, which express the matrix metalloproteinase-mediated activity. Thus, BPs were supposedly unable to abolish the matrix metalloproteinase-mediated bone resorption early after allo-SCT. Moreover, the dose of pamidronate used by the authors might be insufficient in the posttransplant period. Another hypothesis was raised by Ebeling (62): pamidronate therapy was unable to reverse defective osteoblast functioning after transplant, which could have been responsible for the bone loss at the proximal femur.

In our experience, a significant increase in ex vivo growth of bone marrow osteoblast precursors in the colony-forming unit fibroblast assay was found in a majority of patients (nine of 12) 12 months after the beginning of zoledronic acid treatment (58). The immunostaining for alkaline phosphatase also increased during the treatment period. However, these patients started the therapy after the most rapid phase of bone loss (6–18 months after allo-SCT). Therefore, it is still unclear whether zoledronic acid, the most potent BP currently available for clinical use, is effective in the prevention of early posttransplant bone loss and whether it permits a stimulation of osteoblast precursors early after grafting.

BPs are generally considered antiresorptive agents that act on osteoclasts, inducing their apoptosis, inhibiting their resorptive activity, and blocking their precursor proliferation (63, 64, 65). However, recent in vitro findings suggested that BPs have multiple effects on bone turnover; at low concentrations, they directly enhance osteoblast proliferation and differentiation (66, 67), prevent osteoblast apoptosis at the genomic level (68, 69), and regulate osteoblast production of extracellular matrix proteins (70). Moreover, there is evidence that BPs in vitro increase osteoblastic production of OPG (71, 72). Kananen et al. observed a significant reduction of serum RANKL concentrations in transplanted patients on pamidronate therapy when compared with untreated patients. A milder and more transient posttransplant increase in the OPG levels was observed in treated patients when compared with untreated ones (48). However, the effects of BPs on the OPG/RANKL pathway after allo-SCT needs further investigation.

There are no data on the effects of BPs on fractures after allo-SCT because none of the available studies was sufficiently powered. Moreover, there are no available data on fracture risk in recipients of allo-SCT after more than 1 yr from transplant. Consequently, we are unable to estimate the clinical significance and cost effectiveness of bone loss prevention in terms of long-lasting protection from fractures after allo-SCT.

It is still unclear how long a young transplanted patient with osteoporosis should be treated and what happens after BP withdrawal. In open studies on menopausal osteoporosis, the lumbar and femoral BMD remained stable for 2 yr after stopping long-term treatments (73, 74). We suspect that bone mass may not be maintained for long after BP withdrawal in transplanted patients. Indeed, Grigg et al. (60) showed that bone loss reappeared at the spine and femoral neck but not at the total hip during the second year after withdrawal of high-dose pamidronate therapy. To the best of our knowledge, no case of osteonecrosis of the jaw has been reported in allo-SCT patients with diseases other than multiple myeloma. This is likely attributable to a short duration of iv BP treatment in each study.

Currently, most of the treatments for osteoporosis are able to prevent or stop bone loss, but they fail to reverse it. PTH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) is the only anabolic therapy for osteoporosis. It is contraindicated in patients with malignancies localized to bone and in those whose bones have received radiotherapy; therefore, there is no experience with these agents in patients after allo-SCT. Strontium ranelate has been shown to have both inhibitory effects on osteoclasts and stimulatory effects on osteoblasts (75, 76). However, there is no experience with its use in patients with malignancies or those who have received a transplantation. New therapies for osteoporosis, such as injections of human monoclonal antibodies to RANKL (denosumab), are under development. This treatment seems to be promising in preventing bone loss after SCT because its mechanism of action involves pathways disturbed by glucocorticoids, hypogonadism, and cytokines (77).

As mentioned above, risk factors that have been recently discovered for posttransplant bone loss include increased cytokine release, decreased growth factor production, and reduced repopulating capacity of osteoblast precursors. It is difficult to come up with a specific therapy for the first two conditions; although cytokine production can be reduced by immunosuppressive treatments, it may directly affect the bone negatively. Some growth factors are available for clinical use, but their administration to patients with malignancies may be risky. Therefore, we have to hope for future agents that can promote the differentiation of mesenchymal cells into the osteoblastic lineage. There is some recent evidence that PTH and PTH-related protein may direct osteoblastic rather than adipogenic commitment of mesenchymal cells in vitro (78, 79).


   Management of Patients
Top
 Abstract
 Introduction
 Clinical Studies
 Hypothesis on the Systemic...
 Bone Marrow Microenvironment and...
 Prevention and Treatment of...
 Management of Patients
Conclusions
 References
 
Due to a high prevalence of bone loss and abnormal mineral metabolism in patients undergoing allo-SCT, every candidate ideally should be evaluated for bone status. Lumbar and femoral BMD should be measured before transplantation, and spine x-rays should be performed to detect prevalent fractures. Secondary causes of bone loss should be looked for and addressed in patients who before transplant have decreases in BMD.

Bone status should also be evaluated in all patients who underwent allo-SCT in the past, because some of them may have reduced BMD years after grafting. A specific treatment should be started immediately in patients with osteoporosis and/or fractures.

All patients undergoing SCT should receive the recommended daily dose of calcium (1.0–1.5 g daily) and vitamin D3 (≥800 IU daily), because hypovitaminosis D was found in nearly all patients after transplantation and recovered after at least 1 yr (17). Indeed, food intake and gastrointestinal absorption are reduced after SCT. Vitamin D deficiency may cause secondary hyperparathyroidism, which further triggers bone loss. There is no experience with parenteral use of vitamin D3 after SCT. Standard vitamin D3 (cholecalciferol) is currently recommended for osteoporosis treatment, although some authors successfully used its biologically active form (calcitriol) during the first year after transplant (60). More research regarding the optimal form of vitamin D after SCT is needed.

Management of sex hormone replacement can be complex. As stated before, about half of patients are affected by cGvHD, and the intestine, liver, and skin are among the most frequently involved sites (2). The localization and severity of cGvHD should be taken into consideration when deciding on timing and type of HRT or testosterone administration, because their absorption can be reduced and liver metabolism impaired. Moreover, it can be difficult to combine immunosuppressive treatments and sex hormone replacement. Beside reduced absorption, there can be other reasons accounting for the ineffectiveness of HRT; higher doses of estrogens are probably needed to replace gonadal insufficiency and prevent bone demineralization in young women with ovarian damage induced by antiblastic therapies (51). This hypothesis is further supported by previous reports that standard HRT doses for women after physiological menopause are unable to prevent fractures in otherwise healthy women with premature ovarian failure (80). In males, a decrease in serum testosterone is mostly transient and disappears weeks to months after grafting (81, 82). In our experience, testosterone was reduced in about one third of patients up to 1 yr after SCT (61). Grigg et al. (60) found the mean testosterone levels at the lower limit of the normal range at 3 and 6 months after SCT, with a recovery within 12 months.

BPs represent the most common treatment for bone loss in subjects after solid organ transplantation. On the contrary, there is no general agreement regarding the prevention of osteoporosis in patients undergoing allo-SCT. In our opinion, prevention with parenteral BPs is advisable, because these drugs were shown to ameliorate bone loss in the early posttransplant period when bone resorption is strongly increased by multiple factors. In long-term survivors who are unaffected by gastrointestinal cGvHD, oral BPs can also be used. Stronger data currently exist on the effects of pamidronate, because it has been more frequently used. More studies are required to assess the efficacy of zoledronic acid in preventing bone loss after allo-SCT.

BMD measurement and spine x-ray should be repeated 12 months after SCT in either treated or untreated patients. In the first group, it is important to measure the effects of treatment to decide whether to continue or interrupt it; in untreated patients, the BMD reevaluation allows physicians to determine the amount of bone loss consequent to transplant and eventually introduce a specific therapy. A subsequent follow-up should be individualized, according to the preexistent quantity of bone loss and the general clinical condition of each patient.


   Conclusions
Top
 Abstract
 Introduction
 Clinical Studies
 Hypothesis on the Systemic...
 Bone Marrow Microenvironment and...
 Prevention and Treatment of...
 Management of Patients
 Conclusions
References
 
Bone loss is an important early and potentially long-lasting complication of allo-SCT, with a multifactorial pathogenesis. Several new risk factors have been recently identified and include a dysregulation of the immune system and its treatments, reduced production of growth factors, osteoclastic activation by increased cytokine release, and reduced number and function of osteoblastic precursors within the bone marrow. Alterations in the RANKL/OPG balance seem to be crucial in the pathogenesis of posttransplant bone resorption, but more direct studies are needed.

The reduced repopulating capacity of osteoblast precursors seems to be a very important factor for persistent bone loss after allo-SCT and is probably influenced by the effects of chemotherapy/radiotherapy, by concomitant endocrine disorders, immunosuppressive treatments, and disorders in the balance of cytokines and growth factors.

The clinical experience of all transplant centers shows that there is a high incidence of reduced BMD and vertebral fractures during the first posttransplant year. BMD at the lumbar spine, but not at the femur, may spontaneously improve or even completely recover in some patients several years after SCT. However, it is unclear to which extent this improvement is a true recovery in bone mass and quality. Indeed, we should always exclude a false increase in BMD due to arthrosis or fractured collapsed vertebrae. Patients affected by cGvHD seem to be at greater risk of continuous bone loss due to multiple risk factors and should be periodically monitored even years after SCT.

There is sufficient evidence that common preventive measures for bone loss are ineffective in patients after allo-SCT, and specific treatments must be used. However, calcium and vitamin D supplementation, sex steroid replacement, and nonpharmacological preventive measures should be introduced whenever possible. Shortly after allo-SCT, iv pamidronate was able to prevent early bone loss at the lumbar spine and to reduce it at the proximal femur; zoledronic acid improved femoral BMD in an uncontrolled study. In long-term survivors, after the most rapid period of bone loss, both risedronate and zoledronic acid improved lumbar BMD, but only zoledronic acid was able to increase femoral BMD. All these studies were underpowered for the investigation of fracture risk.

As for patient management, all patients who received allo-SCT should be evaluated for their bone status and treated as soon as abnormalities are detected. Despite the evidence of only partial effectiveness of preventive antiresorptive treatments, it is reasonable to start parenteral BP administration before or at the time of allo-SCT in all patients, regardless of their pretransplant BMD values, and continue them at least for the first year after transplant.


   Acknowledgments
 
We are indebted to Mrs. Rosanna Scala and Mr. Alfonso Gruosso for their help in editing the manuscript.


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online October 2, 2007

Abbreviations: Allo, Allogeneic; auto, autologous; BMD, bone mineral density; BP, bisphosphonate; cGvHD, chronic graft-vs.-host disease; CsA, cyclosporin A; HRT, hormonal replacement therapy; ICTP, collagen I carboxyl-terminal telopeptide; OPG, osteoprotegerin; RANKL, receptor activator of the nuclear factor-{kappa}B ligand; SCT, stem cell transplant; sOPG, serum OPG; sRANKL, soluble RANKL.

Received December 27, 2006.

Accepted September 25, 2007.


   References
Top
 Abstract
 Introduction
 Clinical Studies
 Hypothesis on the Systemic...
 Bone Marrow Microenvironment and...
 Prevention and Treatment of...
 Management of Patients
 Conclusions
 References
 

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