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Department of Molecular and Clinical Endocrinology and Oncology (L.T., G.L., A.C.), Division of Hematology (P.R., B.S., B.R., C.S.), Federico II University of Naples, 80131, Naples, Italy
Address all correspondence and requests for reprints to: Carmine Selleri, M.D., Division of Hematology, Federico II University of Naples, Via S. Pansini 5, 80131, Napoli, Italy. E-mail: selleri{at}unina.it.
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Abstract |
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In conclusion, short-term zoledronic acid treatment consistently improved both LS and FN BMD in transplanted patients who were at high risk for fast and/or persistent bone loss, partly by increasing the osteogenic progenitors in the stromal cell compartment.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Oral bisphosphonates are widely used for treating osteoporosis; they have been shown to improve bone mineral density (BMD) and decrease the rate of fractures in various patient populations (9, 10, 11, 12). However, the use of these drugs may be limited by poor gastrointestinal tolerance, variable oral bioavailability, and long-term compliance. Allo-SCT patients usually run into long-lasting and complex therapeutic regimens to prevent and treat several early and late complications related to the transplant procedure. About half of SCT patients suffer from graft-vs.-host disease (GVHD), with the gastrointestinal tract being one of the most frequent targets. For these patients, who may have reduced drug absorption, intermittent iv administration of bisphosphonates may be the treatment of choice. Zoledronic acid, a third-generation nitrogen-containing bisphosphonate, is the most potent member of the bisphosphonate family ever investigated in clinical trials (13). Because of its high potency, small doses and long intervals are sufficient enough to inhibit bone resorption and can easily be added to a complex therapeutic regimen in the posttransplant period.
Intravenous bisphosphonates have proven to be very effective in the treatment of menopausal and glucocorticoid-induced osteoporosis, malignant hypercalcemia, and Paget’s disease (14, 15, 16, 17, 18, 19). Clinical benefits in patients with cancer and multiple myeloma include bone pain improvement, reduction, and delay in skeletal complications (14, 19).
Previously, we have shown that bone loss continues for 3 yr after allo-SCT at both the lumbar spine (LS) and femoral neck (FN); it persisted up to 10 yr at FN, although improving mildly but significantly with time at LS (20). We have also documented that post-SCT bone damage is at least in part related to a severe and long-lasting deficit in the regenerating capacity of bone marrow stromal stem cells (20, 21).
The present study aimed at investigating the 12-month effect of short-term iv zoledronic acid administration on lumbar and femoral BMD, bone turnover markers, and clonogenic fibroblast progenitors belonging to the osteogenic stromal lineage in patients with low BMD or fast bone loss after allo-SCT for hematological malignancies.
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Patients and Methods |
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Thirty-two patients who had undergone allo-SCT at our institution were evaluated for BMD at the LS and FN, body mass index (BMI, kg/m2), gonadal status, serum osteocalcin, and urinary hydroxyproline excretion after a median period of 12.2 months (range, 6–18) since transplant. Immediately after the transplant, calcium (500 mg) and vitamin D (400 IU) supplementation had been administered orally and once daily to all patients, between 1900 and 2000 h and was continued for the whole observation period. The determination of densitometry and bone turnover markers was repeated after a median time span of 12.5 months (range, 10.3–13.1) since the first evaluation. Subsequently, 15 patients (group 1) affected by osteoporosis (n = 7) or rapidly progressing osteopenia (i.e. bone loss > 5%/yr) (n = 8) received 4 mg of zoledronic acid (Zometa; Novartis Pharmaceuticals Corp., Basel, Switzerland) iv as a 15-min infusion every 28 d for 3 months; seven patients in this group were suffering from extensive chronic GVHD (cGVHD). Another 15 patients (group 2), who were similar to the zoledronic acid cohort in terms of age, time since transplant, BMI, and gender, were reevaluated for bone turnover and BMD after the same span of time without receiving zoledronic acid. Two patients with Hodgkin’s disease who relapsed 13 and 15 months after allo-SCT were excluded from the study (Fig. 1
). To better point out the importance of bone loss within the first year after allografting, two healthy subjects for each case, matched by gender, age, and BMI were enrolled as controls, undergoing a single biochemical and densitometric evaluation. None of the controls received drugs known to interfere with bone metabolism. None of the participants had been given previous treatments for osteoporosis. Written informed consent was obtained from all patients and controls in accordance with the institutional guidelines, and the study was designed in accordance with the Declaration of Helsinki II on treatment of human subjects.
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Leukemia was the most common indication for allo-SCT. All patients had been successfully allo-transplanted with unmanipulated marrow from a human leukocyte antigen identical sibling. All patients underwent conditioning with the BU-CY2 regimen (busulfan, 16 mg/kg; cyclophosphamide, 120 mg/kg) and received cyclosporin A (CsA) (1 mg/kg·d by continuous iv infusion from d –1 to d + 20 and then 8 mg/kg·d orally) plus short-course methotrexate (10 mg/m2 on d +1, +3, and +6) as prophylaxis for GVHD. No patient had received radiation therapy. All patients with acute GVHD (aGVHD) and cGVHD were treated by methylprednisone (2 mg/kg·d and 1 mg/kg·d for 15 d in patients with aGVHD and cGVHD, respectively) and CsA (5 mg/kg·d) before the first evaluation of bone status. During the study, 53% of patients developed or had persistent cGVHD requiring immunosuppressive therapy as described above. As a significant correlation was found between corticosteroid treatment and bone damage at the initial evaluation, steroids were avoided whenever possible thereafter. During the study period, cGVHD was treated by CsA plus mycophenolate mofetil at a dose of 30 mg/kg·d; low-dose corticosteroids were continued in addition to these immunosuppressants in eight patients only. The median cumulative dose of steroids given to this cohort of patients before entry was equivalent to 6.5 g of prednisone (range, 0.8–22 g) for 3–36 months, whereas it was 1.5 ± 0.8 g for 2.5–5 months during the study. The median daily dose of prednisone equivalents administered during the study was 17.5 mg (range, 5–50 mg).
Gonadal status assessment
At study entry, all subjects underwent serum FSH, LH, 17ß-estradiol/testosterone determination in a single sample at 0800 h. In patients only, the same parameters were again evaluated every 6 months. All women were in the reproductive age. All measurements were performed by commercially available kits: FSH and LH with RIA (Biodata, Rimini, Italy), testosterone and estradiol using solid-phase chemiluminescent enzyme immunoassay (Diagnostic Products Corp., Los Angeles, CA). All controls were eugonadal females having regular menstrual cycles.
Bone metabolism assessment
Serum calcium, phosphorus, creatinine, alkaline phosphatase (ALP), intact PTH, and osteocalcin were determined in blood samples drawn at initial evaluation, at the end of the longitudinal study, before zoledronic acid administration, and after 12 months. Blood samples were collected in the morning after a 12-h fast. Urinary calcium, phosphorus, and hydroxyproline were assayed on the 24-h urinary collection. Standard dietary restrictions were observed by all individuals tested, starting 5 d before urinary collection. Intact PTH and serum osteocalcin levels were measured by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA), the detection limit of the latter being 0.35 mg/liter. Bone alkaline phosphatase was assayed by a direct immunoradiometric assay (Ostease, Hybritech, San Diego, CA). Hydroxyproline excretion was measured with HPLC. Blood chemistry profile, including Ca, P, ALP, urinary Ca excretion, and creatinine levels, were analyzed using a standard autoanalyzer.
Bone density assessment
Bone density was determined by dual-energy x-ray absorptiometry at the LS (L1–L4) and FN, using the Hologic QDR 1000 densitometer (Hologic, Inc., Waltham, MA). Individual BMD values were expressed as g/cm2 and Z-scores. Quality control was performed by daily scanning of an anthropomorphic spine phantom. The coefficient of variation was 1.7% for the LS and 2.1% for the FN. The reference population adopted in this study was the international pooled sample provided by the manufacturer; their data, however, did not differ significantly from those obtained on a local sample in a study performed when the device was set up (22).
Mesenchymal stem cell enrichment
Bone marrow was aspirated from the posterior iliac crest of 20 transplanted patients and 15 bone marrow donors into syringes containing heparin (O’Neil & Feldman, St. Louis, MO). Briefly, mesenchymal stem cells were enriched by incubating whole bone marrow with a cocktail of antibodies against glycophorin A, CD3, CD14, CD19, CD38, and CD66b for 20 min at 4 C, according to the manufacturer’s instructions (Rosette-Sep, StemCell Technologies Inc., Vancouver, Canada). Unagglutinated cells, after density gradient centrifugation using lymphocyte separation medium (Life Technologies, Gaithersburg, MD), were washed with Hanks’ balanced salt solution (HBSS) supplemented with 1% BSA and resuspended in HBSS/1% BSA. HBSS and BSA were purchased from Life Technologies.
Colony forming unit-fibroblast (CFU-F) assay
The in vitro CFU-F growth assay was performed using enriched mesenchymal stem cells as previously described (20, 21). Briefly, enriched mesenchymal stem cells were resuspended at a concentration of 1 x 106/ml in a specific medium (McCoy’s 5A modified medium containing 10% fetal bovine serum with L-glutamine) formulated for optimal mesenchymal stem cell expansion (Mesencult, StemCell Technologies) supplemented with 10–8 M dexamethasone (Sigma-Aldrich, Milwaukee, WI), allowing the recruitment of bone marrow mesenchymal cells to the osteoblastic lineage, and seeded at 4 x 105 cells/cm2 in 35-mm tissue culture plates. Fibroblast colony growth was evaluated after incubation at 37 C, 5% CO2 for 14 d in a humidified atmosphere. Aggregates of more than 50 characteristic fibroblastoid cells were scored in situ as CFU-F under an inverted microscope. Osteogenic differentiation of fibroblastoid colonies was further defined by their ability to express ALP activity after replating for 14 d at 5% CO2 in Mesencult medium supplemented with 10–8 M dexamethasone, 0.2 mM ascorbic acid, and 10 mM ß-glycerol phosphate (Sigma-Aldrich) and readhesion to plastic ware. All cultures were performed in triplicate.
Statistical analysis
Data are reported as mean ± SD unless otherwise specified. Statistical analysis was performed by the Student’s t test for paired and unpaired data, as appropriate, for the comparison between patients and controls and groups of treated and untreated patients. In the period before treatment, the association between BMD changes, immunosuppressive treatment duration and cumulative doses, and amenorrhea period were assessed by linear regression. Linear regression analysis was also used to analyze the relationship between increments of bone density and baseline BMD. Comparison of the variables within the same group was performed by the Friedman test. The significance was set at 5%.
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Results |
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In Table 1 we have summarized the clinical features, underlying malignancies, and details on previous treatments of the population of 32 patients at study entry. Ninety percent of women experienced ovarian failure (gonadotropin levels in the menopausal range and estradiol below the normal range of fertile women) with amenorrhea lasting at least 6 months as a consequence of chemotherapy. Eight women (53.3%) were receiving hormone replacement therapy (HRT) at the time of the first testing; this treatment had been started 6–12 months after SCT and was continued over the whole study period. The other women in whom this treatment was contraindicated or refused were not given any HRT until the end of the study. HRT consisted of oral administration of estradiol (2 mg/d) and dihydroprogesterone (10 mg/d) per 14 d per month (Femoston 2/10; Solvey Pharma SpA, Grugliasco, Italy).
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Longitudinal evaluation of BMD after SCT
There were no significant changes in the biochemical parameters of bone turnover during the observation period (Table 2). Baseline BMD values in the 32 patients were significantly lower than those of controls at both skeletal sites (P < 0.001) (Table 2). According to the World Health Organization criteria (23), osteoporosis was diagnosed in six patients (19%) and osteopenia in 10 (31%).
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). Although bone loss in male and female patients was not significantly different, males tended to lose more bone at FN (–6.4 ± 7.4 vs.–2 ± 8.33%), whereas bone loss in women was higher at LS (–4.16 ± 6.3 vs.–2.41 ± 8.56%). In the whole group of 32 patients at the first evaluation, adjusted femoral BMD values correlated with age (r = –0.6; P = 0.045) and BMI (r = 0.46; P = 0.013). At the second evaluation, femoral BMD continued to be significantly associated with BMI (r = 0.465; P = 0.017) but not with age. In women, lumbar BMD correlated inversely with the duration of amenorrhea both at the first and second evaluation. A borderline correlation was found between femoral BMD decrease and BMI (r = –0.41; P = 0.05), suggesting a mild protective effect of weight on FN BMD. A mild, not significant correlation was present between the amount of lumbar BMD decrease and cumulative dose of corticosteroids (r = –0.44; P = 0.067). Serum osteocalcin was slightly correlated with baseline lumbar BMD (r = –0.62; P = 0.055).
At study entry, lumbar BMD was lower in patients with cGVHD compared with patients without this complication (P < 0.05), whereas the difference was not revealed at the second evaluation. The amount of bone loss during the observation period was greater in patients with cGVHD but not significantly different from those without cGVHD (data not shown). A correlation at the very limit of significance was detected between CsA treatment duration and the amount of FN BMD decrease (r = 0.24; P = 0.05).
Effects of zoledronic acid on bone turnover and BMD after allo-SCT
During the treatment period, there was a significant decrease in hydroxyproline excretion (P < 0.0001) and an increase in bone alkaline phosphatase (P < 0.05); in addition, there was a trend toward a negative correlation between serum osteocalcin and baseline LS BMD, but this correlation did not quite reach statistical significance (r = –0.62; P = 0.055) (Table 3). Twelve months after the beginning of the treatment, an increase in BMD was observed at both LS and FN (9.8 and 6.47%; P < 0.001 and P < 0.005, respectively vs. baseline) (Fig. 2). The percentage and absolute increase in FN BMD were inversely correlated with pretreatment values at the same skeletal site (r = –0.778; P = 0.014 and r = –0.79; P = 0.01, respectively), indicating greater improvement in patients with lower initial bone density. On the other hand, in the untreated group of 15 patients, no significant change occurred in bone turnover markers (Table 3) and bone density at both LS (–2.1%) and FN (–2.3%) (P = not significant). The change in BMD between the treated and untreated groups was significant at both LS and FN (P < 0.00001), as was the difference in absolute BMD values after the 12-month treatment (P < 0.001 and P < 0.05 for LS and FN, respectively) (Table 3).
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Side effects, including flu-like symptoms, myalgia, and nausea, occurred in 12 patients (80%); they were generally mild and well controlled using 15 mg prednisone as premedication 1 h before zoledronic acid administration. Kidney function was carefully monitored every month, and the changes did not exceed 5% of the baseline levels over the whole observation period (Table 3).
Effects of zoledronic acid on marrow CFU-F cells
We have recently documented a severe and long-lasting decrease in marrow CFU-F cells after allo-SCT (20). In the present study, enriched mesenchymal stem cells were used to obtain CFU-F cells. At the baseline evaluation, the marrow compartment of CFU-F cells showed a 3- to 4-fold reduction in transplanted patients compared with normal donors [mean CFU-F/106 cells plated ± SEM: 9.9 ± 2.9 (range, 0–46) (n = 19) vs. 46.8 ± 4.4 (range, 29–59) (n = 15), respectively; P = 0.000009] (Fig. 3).
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). The difference in CFU-F cells at the second evaluation between treated and untreated patients was highly significant (P < 0.00001). |
Discussion |
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The major exposure to glucocorticoids and other immunosuppressive treatments in allo-SCT recipients occurs early after transplant for prevention and treatment of GVHD. Because the repopulating capacity of osteoblast precursors has also been proven to be related to cGVHD (20), patients affected by this complication seem to have multiple risk factors that predispose them to continuous bone loss (26). Moreover, all male patients on glucocorticoid treatment presented inhibited gonadal axis with consequent transient but likely metabolically relevant hypogonadism. The condition of hypogonadism and cGVHD largely overlapped in the whole population. Thus, it is difficult to evaluate the effects of these two factors separately, especially in men, where hypogonadism has a shorter duration and is milder than in women. Because the liver is one of the most frequent targets of cGVHD, an increase in liver enzymes often does not permit the introduction of replacement therapy for hypogonadism. Furthermore, currently there is a recommendation to not treat mild transient male hypogonadism.
Stern et al. (27) specifically evaluated the effects of cGVHD on bone mass over a 9-month period. An important average bone loss was shown in nine patients, (decrease, –9.5%) and was characterized by great individual variability (range, from +0.85 to –21.55%). Surprisingly, although the initial amount of bone loss was related to cGVHD presence in our study, the relationship was lost at longitudinal evaluation. After the initial observation of a relationship between BMD reduction and glucocorticoid exposure (20, 21), we started to treat cGVHD with the new immunosuppressive agent mycophenolate mofetil, known to cause less bone loss (28, 29). The most plausible hypothesis on absence of relationship between BMD values and GVHD consists of variable effects of different immunosuppressive regimens on bone metabolism. Other factors can be represented by a relatively short observation period (12 months) for a GVHD that is not severe. The only correlation at limit of significance was found between amount of FN bone loss and CsA treatment duration.
Most of the longitudinal studies investigated bone loss during the first year after SCT, comparing posttransplant BMD with pretransplant values. The sharpest bone loss at trabecular and cortical sites occurred within the first 6–12 months after allo-SCT. In our study, bone loss was evaluated comparing two BMD measurements performed after the transplant. The baseline evaluation that was done in a later stage after SCT can explain the lower rate of subsequent bone loss found in this study.
Considering previous data on the ineffectiveness of common interventions in preventing bone loss (6), transplanted patients need to be treated by highly potent, specific agents. Our study aimed to investigate the bone effects of iv zoledronic acid given as three monthly doses of 4 mg each in patients who had undergone allo-SCT. This produced beneficial effects on lumbar and femoral BMD, significantly higher than those obtained by oral bisphosphonates (30). Indeed, in our previous study, a treatment with risedronate for 12 months increased BMD at the LS by 5.9% and prevented bone loss at the FN (30). Zoledronic acid improved bone density also at cortical-rich bone (11).
In this study, zoledronic acid was given as three consecutive doses of 4 mg each because of the evidence of multifactorial, conspicuous, and persistent bone loss in long-term survivors after allo-SCT. With this schedule we had tried to obtain rapid and measurable effects on bone mass. Given the persistent bone loss at trabecular and cortical-rich skeletal sites in transplant recipients, zoledronic acid may be considered the treatment of choice in the near-transplant period for the prevention of bone loss. Moreover, given as intermittent short-lasting administration, this agent can be easily added to the complex therapeutic regimens generally administered to transplanted patients. Several infusion protocols have been used for the treatment of osteoporosis, but no standard regimen is available. In the study by Reid et al. (16), a total dose of 4 mg of zoledronic acid was administered during 1 yr with different schedules to menopausal women with low BMD. This caused a 4.3–5.1% and a 2.7–3.1% increase in LS and FN BMD, respectively, and was associated with a significant suppression of bone turnover markers (16). Another regimen was used in a multicenter study by Smith et al. (11) who investigated the effects of 4 mg of zoledronic acid repeated at 3-month intervals for 1 yr in men with nonmetastatic prostate cancer during androgen deprivation therapy; a 5.6% increase in lumbar BMD was observed.
Side effects were generally mild and well controlled by low-dose steroid premedication. No alteration in kidney function was detected at any time point during the study, and liver enzymes did not worsen during the treatment period. As a matter of fact, zoledronic acid has proven to have a lower nephrotoxic potential than pamidronate in rat models (31).
No conclusion can be made about fracture risk because this study is not sufficiently powerful to evaluate fracture incidence as a clinical end-point. Whether any treatment is able to reduce fracture risk after transplant still remains to be determined.
Beneficial effects on lumbar and femoral BMD of zoledronic acid treatment in our transplanted patients was associated with a significant improvement of the clonogenic fibroblast progenitors belonging to the osteogenic stromal lineage. Although the specific mechanisms whereby bisphosphonates exert their beneficial osteotropic effect are not yet completely clarified, it is generally accepted that they have a direct effect on osteoclasts, inducing their apoptosis (32, 33, 34), inhibiting their bone-resorbing activity (35), and blocking their precursor proliferation (36, 37, 38). This bisphosphonate-mediated antiresorptive action has been reported to be related to the inhibition of the osteoclastic mevalonate pathway (34). In addition, recent in vitro findings suggest that bisphosphonates have multiple effects on bone turnover; in fact, they may directly enhance osteoblast proliferation and differentiation (39, 40), prevent osteoblast apoptosis (41), and regulate osteoblast production of extracellular matrix proteins (42). All of these mechanisms may further contribute to the inhibitory effect on bone turnover.
Moreover, there is in vitro evidence that bisphosphonates increase osteoblastic production of osteoprotegerin, which is needed to neutralize the receptor activator of the nuclear factor-
B ligand (RANKL) essential for osteoclast formation and activation (43). Viereck et al. (43) have shown that in vitro pretreatment with pamidronate or zoledronate prevents the inhibitory effects of dexamethasone on osteoprotegerin production in the bone environment, suggesting that this mechanism may contribute to the bisphosphonate-induced enhancement of osteoclastic apoptosis in glucocorticoid-induced bone loss. The positive effects on osteoblasts may be particularly important in allo-transplanted patients, because previous evidence indicated a persistently reduced regenerative and functional capacity of osteoblast precursors (20, 26). Bisphosphonates were also demonstrated to stimulate in vitro formation of human and murine osteoblast precursors and of mineralized nodules, the latter probably through secretion of basic fibroblast growth factor stimulating CFU-F proliferation (42, 44). Our in vitro results are in line with these studies. We have used CFU-F, as they are well recognized as the initial cell source of early and late osteoblast precursors (45). A significant improvement of in vitro growth of osteogenic progenitors was induced by in vivo zoledronic acid administration. In untreated patients, the number of CFU-F colonies marginally improved, likely because of the time elapsed from the effects of cytotoxic drugs and transplant-related cytokine storm. The difference between spontaneous and zoledronate-induced improvement was highly significant. In agreement with a larger study (46), we have documented a recipient origin of clonogenic fibroblast progenitors also after zoledronic acid treatment (Selleri, C, unpublished data). The increase in BMD and clonogenic fibroblast progenitors was accompanied by a significant decrease in hydroxyproline excretion and by an increase in serum bone alkaline phosphatase, whereas osteocalcin increase was just below the limit of statistical significance. The increase in marrow osteogenic precursors and bone alkaline phosphatase without significant increase in serum osteocalcin could be explained by a strong in situ stimulatory effect of zoledronic acid on the osteoblastic compartment concentrated in local niches of the stromal microenvironment. Such a loose effect could be detectable as changes in serum bone formation markers. Indeed, controversial results were reported in serum osteocalcin levels during bisphosphonate treatment for posttransplant osteoporosis (47, 48, 49).
In conclusion, persistent multifactorial bone loss has been confirmed in patients up to 36 months after allo-SCT. The most important risk factors included persistently reduced regenerating capacity of the normal osteogenic cell compartment, ovarian failure, and the presence of cGVHD, requiring long-term immunosuppressive treatments. Zoledronic acid was easily manageable and effective in increasing densitometric values at both trabecular and cortical skeletal sites. At least part of this effect can be ascribed to the ability in reversing the persistent posttransplant reduction of the clonogenic fibroblast progenitors belonging to the osteogenic stromal lineage. Because iv bisphosphonates represent the most potent treatment option for posttransplant osteoporosis currently available, transplanted patients who are at high risk for fast and/or persistent bone loss should receive preventive treatment. Currently, the choice of oral/iv bisphosphonate administration in patients who had undergone allo-SCT should be made on the basis of individual clinical conditions, including the presence, grading, and localization of GVHD and prevalent site of bone loss.
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Footnotes |
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Abbreviations: Allo-SCT, Allogeneic stem cell transplantation; ALP, alkaline phosphatase; BMD, bone mineral density; CFU-F, colony-forming units fibroblast; CsA, cyclosporin A; FN, femoral neck; GVHD, graft-vs.-host disease (a, acute; c, chronic); HBSS, Hanks’ balanced salt solution; HRT, hormone replacement therapy; LS, lumbar spine.
This work was supported in part by grants from Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST), from Regione Campania and from Associazione Italiana Leucemie Linfomi (AIL) Salerno.
Received March 16, 2004.
Accepted October 28, 2004.
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