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Divisions of Endocrinology (K.K., M.J.V.) and Hematology (L.V., T.R.), Department of Medicine, and Departments of Obstetrics and Gynecology (K.L.) and Clinical Chemistry (H.A.), Helsinki University Central Hospital, FIN-00290 Helsinki, Finland
Address all correspondence and requests for reprints to: Dr. Matti Välimäki, M.D., Ph.D., Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland. E-mail: matti.valimaki{at}hus.fi.
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Abstract |
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Objective: The objective of the study was to test whether additional iv pamidronate would prevent bone loss associated with SCT more effectively than the combination of calcium, vitamin D, and sex steroid replacement therapy alone.
Setting. The study was carried out at the Helsinki University Central Hospital.
Patients, Design, Intervention: Ninety-nine adult recipients of allogeneic SCT were randomized by age and gender into two groups. In one group, the patients received 1000 mg calcium carbonate and 800 IU vitamin D daily, and females received estrogen and males received testosterone replacement therapy. In another group, the patients received the same treatments plus six iv infusions of 60 mg pamidronate before and 1, 2, 3, 6, and 9 months after SCT.
Main Outcome Measures: Bone mineral density (BMD) of the lumbar spine and the upper femur, measured by dual-energy x-ray absorptiometry, and bone turnover markers were followed for 12 months.
Results: In the pamidronate group, lumbar spine BMD remained stable but decreased in the other group by 2.9% at 12 months (P = 0.0084 between the groups over time). Total hip BMD reduced 5.1% in the pamidronate group and 7.8% in the other group by 12 months (P = 0.0015), and femoral neck BMD reduced 4.2 and 6.2%, respectively (P = 0.074). In the pamidronate group, serum type I procollagen amino-terminal propeptide (P = 0.032 between the groups over time) and urinary type I collagen amino-terminal telopeptide (P = 0.035) decreased 79 and 68% during the first 3 months, and remained lowered thereafter, but did not change in the other group.
Conclusions: The recipients of allogeneic SCT receiving additional pamidronate sustain less bone loss than those treated with calcium, vitamin D, and sex steroid replacement alone. Despite all the efforts, however, bone loss is not totally abolished at the hip.
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Introduction |
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Cyclosporine A (CyA) and glucocorticoids, used to prevent and treat graft-vs.-host disease (GVHD), have been considered as major reasons for SCT-associated bone loss (4, 11, 12). Glucocorticoids profoundly inhibit bone formation, with relatively minor effects on bone resorption (13). In contrast, studies of CyA in animals have demonstrated markedly increased bone formation and resorption (14). Other potential candidates to cause bone loss are the basic hematological disease (15), chemotherapy (16), total body irradiation (17, 18), or even GVHD itself (19). Recently, the impaired differentiation of stem cell stromal cells into osteoblasts after SCT was described (7). Myeloablative therapy together with immunosuppressive agents, GVHD, or poor nutritional status were assumed as reasons for the observation (7).
There are only few data on preventing bone loss after SCT. In our previous study, calcium alone or combined with calcitonin appeared to be ineffective (3). In one study, calcium, vitamin D, and estrogen replacement therapy for females did not prevent bone loss at the femoral sites (8). In another study, estrogen replacement therapy increased previously reduced lumbar BMD when started 13 months after SCT (20). Several studies suggest that bisphosphonates (pamidronate, alendronate, ibandronate, and etidronate) might be capable of preventing bone loss associated with solid organ transplantations (21, 22, 23, 24, 25, 26).
Except for one uncontrolled study with pamidronate (27), the efficacy of bisphosphonates in prevention of bone loss after SCT has not been evaluated to date, but in two studies, either risedronate or zoledronic acid was started for treatment of osteopenia or rapid bone loss 17–24 months after SCT (28, 29). Thus, we randomized 99 SCT recipients to receive either a basic prevention of osteoporosis alone or with additional iv pamidronate. We judged that, in addition to calcium and vitamin D, the basic prevention of osteoporosis included estrogen replacement for women and testosterone replacement for men, because SCT results in early menopause (30) and in lowered serum testosterone levels (3). We considered the inclusion of an untreated control group in this study unethical.
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Patients and Methods |
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One hundred fifteen consecutive adult patients undergoing allogeneic SCT for hematological malignancies except for myeloma were considered for the trial. BMD was not any inclusion or exclusion criteria. Nine patients refused and seven patients were excluded due to serum creatinine level above the reference limit. Thus, 99 patients were randomized by age and gender to receive or not to receive iv pamidronate (Fig. 1
). The characteristics of the patients are shown in Table 1.
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Acute GVHD was treated at its appearance, independently of its grade, with 10 mg/kg·d MP iv, divided into four doses. If the response was prompt, the dose was reduced to 2 mg/kg·d in 3 d; otherwise, it was halved with 3-d intervals thrice and according to the clinical situation thereafter. In the corticosteroid-resistant cases, Thymoglobuline was used as the second-line treatment.
Chronic GVHD was treated with a low dose of MP alone or in combination with CyA, thalidomide, or mycophenolate mofetil (MMF). Nine patients (four in the pamidronate group and five in the control group) received mycophenolate mofetil during the study, four of them due to side effects of CyA. Altogether, there were seven patients who did not receive MP at all during the study period (two in the pamidronate group and five in the other group).
Study design
Patients were randomized by age and sex to two treatment groups. In one group, the patients (19 women and 18 men) received 1000 mg calcium carbonate and 800 IU vitamin D daily (Ideos; Meda, Solna, Sweden). Two weeks after SCT, female patients started percutaneous estrogen replacement therapy using patches, which release 50 µg estradiol (Estraderm Matrix; Novartis, Basel, Switzerland) per 24 h and 10 mg oral hydroxyprogesterone acetate (Provera; Pfizer, Inc., Bohrs, Belgium) daily during the first 10 d of every month. At the same time, male patients started testosterone replacement therapy using patches, which release 2.5 or 5 mg testosterone per 24 h (Atmos; AstraZeneca, Gothenburg, Sweden). The dose of testosterone was adjusted on the basis of serum testosterone level at the start of medication. In another group, the patients (17 women and 18 men) received the same treatments mentioned above plus six iv infusions of 60 mg pamidronate (Aredia; Novartis), first just before and then 1, 2, 3, 6, and 9 months after SCT.
BMD of the lumbar spine (lumbar vertebrae L1–L4) and of the three femoral sites (femoral neck, trochanter, and total hip) was measured before and 6 and 12 months after SCT.
Serum was sampled for the determination of creatinine, ionized calcium, type I procollagen amino-terminal propeptide (PINP), type I collagen carboxy-terminal telopeptide (ICTP), type I collagen cross-linked carboxy-terminal telopeptide ß (CTX), tartrate resistant acid phosphatase 5b (TRACP5b), and estradiol in females and testosterone in males. Second void urine samples were collected for the determination of type I collagen amino-terminal telopeptide (NTX). Serum and urine samples were collected in the fasting state in the morning by 1000 h before and 1, 3, 6, and 12 months after SCT.
BMD measurements and spine x-rays
BMD was measured by dual-energy x-ray absorptiometry using Hologic QDR 1000 (Hologic, Waltham, MA) equipment. The precision of the method [coefficient of variation (CV)] was 0.9% at the lumbar spine and 1.2% at the femoral neck. Bone density was expressed as grams per square centimeter. Percentage changes from baseline were calculated for the measurements at 6 and 12 months. X-ray of the spine was taken before and 6 and 12 months after SCT. A 20% or more reduction in the height of the vertebra was considered as a fracture.
Assays
Intact PINP and ICTP were determined by RIA kits (Orion Diagnostica, Oulunsalo, Finland). The intraassay and interassay CVs for these assays ranged from 2–9%. Urinary NTX was measured by an automated chemiluminescence immunoassay (Vitros Eci; Ortho Clinical Diagnostics, Amersham, UK) with intraassay and interassay CVs ranging from 2–10%; the measured values were related to urinary creatinine excretion. Serum activity of TRACP5b was assessed by an immunoextraction method with BoneTRAP reagents (Suomen Bioanalytiikka Oy, Turku, Finland). Intraassay and interassay CVs were 6% or less at relevant concentrations. Serum CTX was assayed by an ELISA method (Serum CrossLaps ELISA; Nordicbioscience Diagnostics, Herlev, Denmark). Intraassay and interassay CVs of the method ranged from 7–10%. Serum testosterone was assayed by an automated luminoimmunoassay (Chiron Diagnostics, Medfield, MA) with intraassay and interassay CVs ranging from 4–7%. Serum estradiol was measured by a RIA kit (Orion Diagnostica) (intraassay and interassay CVs from 3–12%). For the determination of serum-ionized calcium, blood samples were centrifuged immediately after being drawn, and the serum was analyzed with routine methods within a few hours of blood collection (intraassay CV of 1.6%). Serum and urine creatinine were determined by the Jaffe method.
Lifestyle
Patients’ smoking history, alcohol consumption, and calcium intake from dairy products were asked by a questionnaire.
Statistics
Primarily, the study was aimed at studying the patients who completed six months of follow-up. Data with normal distributions are expressed as means with SD values; otherwise, the are expressed as medians with interquartile ranges. In comparisons between and within the study groups, normally distributed variables were studied using repeated-measures ANOVA. If the assumptions for repeated-measures ANOVA (even after log transformation) were not fulfilled, Geisser-Greenhouse adjusted P values were used. Two-sample t test or one-way ANOVA (percentage changes) were used as appropriate. The data not distributed normally after the log transformation were tested with Mann-Whitney U test or Kruskal-Wallis one-way ANOVA on ranks. BMD changes were also analyzed with ANOVA using percentage changes from baseline to 6- and 12-month time points. Pearson correlation coefficients were calculated between bone markers at different time points and bone loss at the total hip at 6 months. In the analyses of the bone marker data, log-transformed percentage changes from baseline to 1-, 3-, 6-, and 12-month time points were used. The analyses were performed using NCSS 2000 software (NCSS Statistical Software, Kaysville, UT) or SPSS 11.0 for Windows (SPSS, Inc., Chicago, IL).
Ethics
The Ethical Committee of the Department of Medicine, Helsinki University Central Hospital, approved the study. A written consent was obtained before randomization
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Results |
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). Another six patients stopped the study before the 12-months follow-up visit; five died, and, for one patient, bisphosphonate therapy was started outside the trial. Thus, altogether, 72 patients were followed at least for 6 months and comprised the actual study group. Sixty-six patients were followed for 12 months (Fig. 1).
The present study groups had similar distributions of the genders and the basic hematological diseases (Table 1). The groups did not differ in respect to body weight and height, alcohol, or calcium intake. Also, the total doses of MP and CyA used after the transplantation were similar (Table 1). At baseline, the present study groups had similar absolute and standardized (Z-scores) values for BMD at different measurement sites, as well as for bone turnover markers (Table 1). The mean Z-scores varied from –0.13 to 0.77 at four measurement sites of the two groups (Table 1). All of the bone treatments used were well tolerated. None stopped the study due to adverse events, and no major side effects were reported.
BMD
Figure 2 describes the percentage changes from baseline in BMD. Over time, the study groups differed significantly from each other in the lumbar spine (P = 0.0084), the trochanter (P = 0.0040), and the total hip (P = 0.0015) but not in the femoral neck (P = 0.074). In the pamidronate group, lumbar spine BMD remained stable but decreased in the other group by 3.2% (P = 0.005) at 6 months and by 2.9% (P = 0.031) at 12 months. In femoral neck BMD of the pamidronate group, the reductions were 2.5% (P = 0.001) and 4.2% (P < 0.001) at 6 and 12 months and, in the other group, were 4.9% (P < 0.001) and 6.2% (P < 0.001), respectively. The patients on pamidronate lost 3.8% of their trochanter BMD in 6 months (P < 0.001) and 4.9% in 12 months (P = 0.001). In the other group, the respective losses were 8.9% (P < 0.001) and 9.8% (P < 0.001). In the total hip, bone loss in the pamidronate group was 4.8% at 6 months (P < 0.001) and 5.5% at 12 months (P < 0.001) and, in the other group, was 7.6% (P < 0.001) and 7.8% (P < 0.001), respectively.
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The median percentage changes from baseline in the markers of bone turnover are shown in Fig. 3. Over time, the study groups differed from each other with respect to changes in serum PINP (P = 0.032) and urinary NTX (P = 0.035); the differences in serum CTX (P = 0.10) and TRACP5b (P = 0.077) were of borderline significance. A serum marker of bone formation PINP decreased 79% in the pamidronate group (P = 0.025) during the first 3 months and remained lowered by the end of the follow-up (P = 0.002); in the other group, PINP did not change significantly. Of the markers of bone resorption, urinary NTX decreased by 68% in the pamidronate group during the first 3 months (P = 0.014) and remained lowered by the end of follow-up (P = 0.026); in the other group, no significant changes were observed. In the pamidronate group, serum CTX dropped 49% (P = 0.054) below baseline at 3 months but was back at baseline at 6 months; in the other group, it did not show any significant changes. Serum ICTP doubled in the control group (P = 0.001) and increased by 61% in the pamidronate group (P < 0.001) during the first month. It was still elevated at 6 months (+48% in the pamidronate group, P < 0.001; +77% in the other group, P = 0.027) and nonsignificantly so at 12 months. Serum TRACP5b increased nonsignificantly by 40% in the pamidronate group (P = 0.16) and by 51% in the other group within the first month (P = 0.022). By the end of the follow-up, it decreased to 70% of the pre-SCT level in the pamidronate group (P = 0.073) and to the pre-SCT level in the other group.
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In the pamidronate group, bone loss at the total hip at 6 months was the greater, the higher serum ICTP levels were at 3 months (r = 0.53; P = 0.004) (Table 2). In those not receiving pamidronate urinary NTX at 1 month (r = 0.67; P < 0.0001) and serum TRACP5b at baseline and 1 and 3 months predicted bone loss at the total hip at 6 months (r = 0.49–0.61; P = 0.007–0.033) (Table 2).
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In males, no significant within-group changes or between-groups differences were observed in serum testosterone, which remained within the normal range (Fig. 4). In females, serum estradiol did not differ between the groups but fell 63% in the pamidronate group (P = 0.054) and 67% in the other group (P = 0.076) within the first month. Thereafter, it mainly remained within the target range of estrogen replacement therapy (0.10–0.30 nmol/liter) in both groups.
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Fractures
Eight patients experienced a radiologically verified vertebral fracture: three (8.6%) in the pamidronate group and five (13.2%) in control group.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Except for multiple myeloma, our study population presented those hematological patients who most commonly undergo allogeneic SCT. We judged that estrogen replacement with progesterone should be a part of the basic treatment of female patients because SCT causes early menopause and because there is a lot of evidence to show that hormone replacement therapy inhibits bone loss and prevents fractures in estrogen-deficient women (32, 33). Because in our previous study serum testosterone level decreased by 57% during the first month after SCT (3), we included testosterone replacement to the basic treatment of the male patients. This view was supported by the observation that hypogonadal men benefit from testosterone replacement with respect to their bone mass (34).
The present study is the first controlled one in which bisphosphonates have been used to prevent bone loss immediately after allogeneic SCT. Its rationale resides in previous studies in which bisphosphonates have been capable of preventing or reducing bone loss in association with solid organ transplantations. In kidney-transplant recipients, iv ibandronate or zoledronic acid either prevented bone loss or even improved BMD (25, 35). After cardiac transplantation, a single dose of pamidronate followed by cyclic etidronate reduced bone loss at the femoral neck and prevented it at the spine (22). Liver-transplant recipients with reduced bone mass before the procedure did not experience vertebral fractures when treated with iv pamidronate before and after transplantation; instead, 38% of untreated patients had new fractures (23). Lung-transplant recipients treated with cyclic etidronate had less bone loss at the spine than controls (26). In the latest study of cardiac-transplant recipients, oral alendronate and calcitriol equally decreased bone loss compared with untreated patients at both the spine and the femoral sites during the first posttransplant year (21).
In the present study, the efficacy of additional pamidronate to prevent bone loss was superior to the combination of calcium, vitamin D, and sex hormone replacement, on which patients sustained bone loss at all measurement sites. This loss was not less than in our previous study of SCT recipients who either did not receive any treatment or were treated with calcium alone or with calcitonin. This was the case despite the fact that the previous patients received higher doses of corticosteroids than the present controls (3). Pamidronate totally prevented the reduction in BMD at the spine but only decreased it at the femoral sites (not significantly in the femoral neck). The observation that, independently of treatment, bone loss after SCT dominates at the femoral sites over the lumbar spine is compatible with previous studies (3, 4, 5, 7). One explanation might reside in the different amounts of cortical bone at these sites (6, 36). Another explanation is that the dosage chosen for the trial was too low, but later on a similar regimen has been used with success in renal-transplant recipients (37).
As a sign of more powerful antiresorptive efficacy of pamidronate, serum PINP and urinary NTX decreased more in the pamidronate group than in the basic prevention group. Serum CTX did not follow the similar pattern of changes, but it has a great diurnal variation (38), which, despite our efforts to collect samples in the morning, might have affected the results. Serum ICTP behaved totally differently than the other resorption markers. It clearly rose in both groups shortly after SCT and remained elevated until the end of the follow-up. Furthermore, the study groups did not differ at all with respect to changes in ICTP.
In contrast to postmenopausal or corticosteroid-induced osteoporosis in which efficacious bisphosphonates totally abolish bone loss or even increase bone mass also at femoral sites (39, 40, 41, 42), in the present stem cell-transplant recipients, pamidronate in the combination with calcium, vitamin D, and sex hormone replacement was not capable of preserving bone mass at the hip. Recently, a similar finding was made by Shane et al. (21) on alendronate in heart-transplant recipients. Interestingly, when started not earlier than 17–24 months after SCT, risedronate or zoledronic acid either prevented additional bone loss or even increased BMD at the femoral neck (28, 29). High serum levels of ICTP might offer one mechanistic explanation for the relative inefficacy of bisphosphonates immediately after organ transplantations. ICTP is thought to reflect matrix metalloproteinase (MMP)-mediated bone resorption and CTX and NTX cathepsin-K-mediated resorption (43, 44, 45). Bisphosphonates inhibit cathepsin-K-mediated resorption and decrease NTX and CTX (45, 46, 47) but not serum ICTP. Consequently, an opportunity remains that MMP-mediated bone resorption significantly contributes to immediate bone loss in patients with organ transplantations, and this is not abolished by bisphosphonates. TRACP5b is a novel and specific marker of osteoclast function (48, 49) and should reflect both MMP- and cathepsin-K-mediated bone resorption by osteoclasts. In the pamidronate-treated patients, TRACP 5b was lowered below the pretransplantation level, but ICTP remained elevated 6–12 months after the procedure. Consequently, a question arises as to where the possibly increased MMP activity resides: in osteoclasts or possibly in osteoblasts (50, 51).
How the present findings are translated to changes in fracture incidence after SCT remains open. We (12) and others (8) have shown that BMD at the lumbar spine but not at the femoral sites recovers even without any treatment. An approximately 10% loss in proximal femur BMD persisting 4–6 yr after SCT (8, 12) might mean a 2- to 3-fold increase in hip fracture risk (52), but there is no current evidence to support this increased risk in recipients of SCT or solid organ transplants. Consequently, we are not capable of estimating the clinical significance and cost-effectiveness of prevention of bone loss in terms of reduced fracture incidence.
We conclude that the recipients of an allogeneic stem cell transplant receiving additional pamidronate sustain less bone loss than those treated with calcium, vitamin D, and sex hormone replacement at both the lumbar spine and the hip. Importantly, despite all of the efforts, bone loss is, however, not totally abolished at the hip.
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Footnotes |
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First Published Online March 29, 2005
Abbreviations: BMD, Bone mineral density; CTX, type I collagen cross-linked carboxy-terminal telopeptide ß; CV, coefficient of variation; CyA, cyclosporine A; GVHD, graft-vs.-host disease; ICTP, type I collagen carboxy-terminal telopeptide; MMP, matrix metalloproteinase; MP, methylprednisolone; NTX, type I collagen amino-terminal telopeptide; PINP, type I procollagen amino-terminal propeptide; SCT, stem cell transplantation; TRACP5b, tartrate resistant acid phosphatase 5b.
Received November 4, 2004.
Accepted March 23, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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, P < 0.05; 
