Ann Thorac Surg 1999;67:130-133
© 1999 The Society of Thoracic Surgeons
Original Articles
Progression of steroid-associated osteoporosis after heart transplantation
Jochen Cremer, MDa,
Martin Strüber, MDa,
Ingrid Wagenbreth, MDa,
Johannes Nischelsky, MDb,
Stefanos Demertzis, MDa,
Thomas Graeter, MDa,
Conny Abraham, PhDa,
Axel Haverich, MDa
a Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Hannover, Germany
b Division of Radiology, Hannover Medical School, Hannover, Germany
Accepted for publication June 24, 1998.
Address reprint requests to Dr Cremer, Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Carl Neuberg Str. 1, 30625 Hannover, Germany
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Abstract
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Background. Osteoporosis has been recognized as an important side effect of long-term and of pulsed steroid application after heart transplantation.
Methods. In June 1989 a prospective clinical trial was started to study bone demineralization by quantitative computed tomographic scan. All patients received vitamin D and calcium. In group I (n = 30) synthetic calcitonin (40 Medical Research Council Standard Units subcutaneously per day was administered in 14-day cycles, whereas group II patients (n = 31) received a placebo preparation. Repeat trabecular and cortical quantitative computed tomographic scans of the thoracic (T12) and lumbar spine (L1, L2, L3) were obtained within 48 weeks after heart transplantation.
Results. Expressed as the means of T12, L1, L2, and L3, trabecular bone density decreased significantly from 100 ± 24 to 79 ± 29 mg/mL within 3 weeks after heart transplantation, followed by a further reduction to 67 ± 29 mg/mL after 3 months in the calcitonin group. The values for cortical bone density decreased significantly from 229 ± 37 to 202 ± 40 mg/mL (calcitonin) 3 weeks after heart transplantation. Comparable results were obtained in the placebo group. In both groups bone density remained stable thereafter. Intergroup differences were not of statistical significance.
Conclusions. In heart transplant recipients progressive trabecular bone demineralization is limited to the first 3 postoperative months. Thereafter, bone density remained stable. A positive effect of synthetic calcitonin in addition to prophylactic calcium and vitamin D application could not be proved by repeat quantitative computed tomography.
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Introduction
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With reliable donor organ protection, elaborated operative techniques, and nearly standardized maintenance immunosuppression, heart transplantation (HTx) has become a routine procedure resulting in excellent perioperative and intermediate survival rates. Along with increasing success in posttransplantation survival, attention was directed to improvement in achievable life quality after HTx, which is often impaired by adverse effects of basic maintenance immunosuppression. Consistent with discussed limitations of posttransplantation life quality, osteoporosis has been recognized as a major problem responsible for pain-dependent immobilization and bone fractures [1, 2], even in younger individuals. Incidence and progression of osteoporosis is assumed to be associated with long-term maintenance steroid administration as part of the commonly applied basic immunosuppression in addition to cyclosporine and azathioprine, as well as with frequently applied high-dose steroid therapy for rejection treatment [1, 2]. As avoidance of long-term steroid medication may result in increased rejection rates and progressive impairment of long-term graft function, but conversely, adaptation to the remaining immunosuppressants would cumulatively increase organ toxicity, the question arises as to whether prevention of steroid-associated osteoporosis is possible. To evaluate progression of osteoporosis in HTx recipients and efficacy of two preventive protocols, vertebral bone density was measured by frequently applied single-energy quantitative computed tomography (SEQCT) in 61 prospectively randomized patients [3].
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Patients and methods
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In 74 consecutive patients with end-stage heart disease, HTx was performed between June 1989 and March 1992. Inclusion criteria for the study were adult age, informed consent, and an uneventful early postoperative course as indicated by extubation within 3 days after transplantation and no catecholamine requirement after the fourth postoperative day. Exclusion criterion for both HTx and the study was the presence of vertebral fractures before transplantation. Sixty-one recipients (51 men and 10 women) were included in the study. All recipients completed the intended follow-up of 48 weeks. Trabecular and cortical bone density were measured by SEQCT performed preoperatively and every 3 weeks for the first 12 weeks, and every 4 weeks until 48 weeks. Trabecular and cortical bone density were expressed as mean values ± standard deviation of the mean of thoracic vertebra 12 (T12) and lumbar vertebrae 1 to 3 (L1, L2, L3).
All patients were prospectively (double-blind) randomized into two groups by computer-generated random number technique, receiving subcutaneously administered synthetic eel calcitonin (elcitonin, Hafslund Nycomed Pharma Wien, Vienna, Austria; 40 Medical Research Council Standard Units subcutaneously per day) or placebo preparation at 14-day intervals for 48 weeks. A 2-week interval with daily injections was alternated with a 2-week interval without injections. Because patients were unable to perform self-administered injections, no subcutaneous applications were scheduled for Saturdays and Sundays. In addition to elcitonin or placebo injections, calcium (2 x 500 mg calcium per day orally, Sandoz, Nürnberg, Germany) and vitamin D (1, 25 dihydroxycholecalciferol, 0.25 mg every other day orally) were given. Distribution of sex, age, and underlying diseases was similar in both groups (Table 1).
Technique of single-energy quantitative computed tomography
Single-energy quantitative computed tomography (somatom DR, Siemens AG, Forcheim, Germany) was applied for vertebral bone density measurements as described elsewhere [1, 3, 4]. In the supine position, the imaging process was performed at 8-mm slices within the region of interest, exposing at 125 kV peak with 520 mA/s for 7 seconds. Integrated phantom sections were used as reference. Density was measured as trabecular and cortical bone density of vertebrae T12, L1, L2, and L3.
Immunosuppressive regimen
The basic immunosuppression protocol included a triple-drug regimen consisting of cyclosporin A (trough level, 200 to 300 ng/mL, specific radioimmunoassay), azathioprine (2 mg · kg-1 · d-1), and prednisone (starting with 0.5 mg · kg-1 · d-1 and being tapered down to 0.2 mg · kg-1 · d-1 within the first month). For postoperative induction therapy anti-thymocyte-globulin (R-ATG) or OKT III were given. Episodes of moderate rejection were usually treated with pulsed doses of methylprednisolone (3 x 500 to 1,000 mg i.v.). Anti-thymocyte-globulin (3 x 100 mg i.v.) and OKT III (7 to 14 x 5 mg i.v.) were only administered in cases with severe rejection.
The study protocol was revised and permitted by the institutional ethics committee and was in concordance with local governmental regulations. Informed patient consent was obtained preoperatively in each case.
Statistical analysis
Trabecular and cortical bone density values were expressed as mean values ± standard deviation of T12, L1, L2, and L3. Analysis of variance for repeated measurements was performed using SPSS statistical program. A p value of < 0.05 was considered statistically significant.
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Results
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The steroid medication as part of the basic immunosuppression was similar in both groups after 1, 3, 6, 9, and 12 months with a comparable trend of dose reduction in both groups (Fig 1). In addition frequency and distribution of steroid-treated rejection episodes were comparable with more than 70% of treatment courses within the first 3 months and a mean methylprednisolone dose of 1.68 ± 0.5 g (elcitonin) and 1.74 ± 0.54 g (placebo) per course.
Trabecular bone density in the elcitonin group decreased from 100.3 ± 23.8 to 79.8 ± 29 mg/mL (p = 0.002) within 3 weeks. A further reduction to 67.4 ± 29.4 mg/mL was found after 3 months (p = 0.004). In the placebo group trabecular bone density was 109.1 ± 21.5 mg/mL before HTx and decreased to 85.1 ± 21 mg/mL (p = 0.006) after 3 weeks and to 75.7 ± 25.1 mg/mL after 3 months (p = 0.015). Thereafter trabecular bone density remained comparatively stable with values higher than 60 mg/mL in both groups (Fig 2). Intergroup analysis revealed no significant differences comparing placebo and treatment group.
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Fig 2. Course of trabecular bone density (mean of T12, L1, L2, and L3) in the elcitonin and placebo groups. (*p < 0.05.)
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For cortical bone density a significant decrease was found after 3 weeks (Fig 3): In the elcitonin group mean cortical density of 229 ± 37 mg/mL was obtained before transplantation and 202 ± 40 mg/mL after 3 weeks (p = 0.030). In the placebo group 234 ± 31 mg/mL was measured before HTx and 209 ± 33 mg/mL after 3 weeks (p = 0.011). The remaining data appeared stable in both groups, varying between 184 and 211.7 mg/mL. Intergroup differences were not of statistical significance. When comparing men and women within each group and between the groups, also no differences were found. Dividing the complete male study population (independent of the treatment group) into men older than 40 years (n = 41) and 40 years or younger (n = 10), significantly higher values (p = 0.03) for trabecular bone density were found in younger individuals before and after transplantation (Fig 4), whereas these male subgroups did not differ in cortical bone density. Thus, indicating men older than 40 years as a risk group (n = 41) we compared these individuals depending on elcitonin or placebo administration, but were unable to find significant differences. Clinically no bone fracture occurred during the observation period in either group.
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Fig 3. Course of cortical bone density (mean of T12, L1, L2, and L3) in the elcitonin and placebo groups. (*p < 0.05.)
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Fig 4. Course of trabecular bone density (mean of T12, L1, L2, and L3) in men older or younger than 40 years independent of elcitonin treatment. (*p < 0.05.)
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Comment
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Spine fractures and consequent immobilization in our historical HTx recipients occurred frequently within the first 6 months after HTx and were also reported by other groups [1, 2]. Because of this finding a prospective, randomized, double-blind, clinical trial comparing two preventive treatment protocols was initiated. Because of the high incidence of osteoporotic lesions and attendant morbidity in our historical recipients without any preventive treatment, we did not include such a control group in the study. Supported by data on the positive effects of synthetic calcitonin in treatment of osteoporosis [5], especially in postmenopausal osteoporosis [6], the aim of the study was to evaluate the efficacy of elcitonin in addition to preventive treatment with calcium and vitamin D. Repeat SEQCT is the established method for quantification of bone loss before and after transplantation with respect to reproducibility and accuracy [3].
Using this method, we were able to demonstrate decreased preoperative trabecular bone density of the spine in patients undergoing HTx as reported by others [1]. Under triple therapy for maintenance immunosuppression (azathioprine, cyclosporine, and prednisone), posttransplant progression of trabecular bone demineralization predominantly occurred within the first 3 months after transplant. An early onset of bone loss after HTx was reported by other groups who studied the recipients twice a year [7, 8].
Whether steroid treatment and cyclosporine administration, which evidently also acts on bone metabolism [2, 7, 9], are determinants of progressive osteoporosis remains open to debate, but the highest progression of demineralization occurred with the highest dosage of maintenance and pulsed steroids. In contrast cyclosporine levels were kept stable within the first 6 months.
Owing to the fact that women represent only a small proportion in our HTx patients we were unable to identify them, and especially postmenopausal women, as a risk group. Men older than 40 years, however, demonstrated significantly, decreased trabecular bone density when compared with younger male individuals. This finding is confirmed by data of Muchmore and coworkers [1], who also applied repeat SEQCT in HTx recipients with and without antiosteoporosis treatment in a nonrandomized fashion. In contrast to their results [1], we could not reveal treatment success as indicated by increase of bone density or neomineralization.
In a recent study Shane and associates [10] reported the association of lower serum concentration of vitamin D metabolites and higher bone turnover with more rapid bone loss after cardiac transplantation. In part a high bone remodeling is induced by cyclosporin A [11]. Because calcitonin was shown to be effective in diseases characterized by increased bone turnover, such as Paget’s disease [12], a beneficial effect of the combination of vitamin D and elcitonin was expected in our study. However, we were unable to find any beneficial effect of elcitonin added to the basic prophylaxis consisting of vitamin D and calcium. A similar result was reported for patients on long-term corticosteroids for rheumatic, immunologic, or respiratory disease [13]: prophylactic administration of calcitriol (dihydroxyvitamin D3) and calcium prevented bone loss in the lumbar spine. Also in this study no additional effect of calcitonin was found. In addition, vitamin D supplementation was defined as the most effective drug in the prevention of bone loss after HTx [14]. A possible explanation for the lack of effect of elcitonin is the antibody formation and development of resistance, as was described for porcine and synthetic salmon calcitonin [15]. As a synthetic product elcitonin resistance may not be as common as porcine calcitonin resistance, but antibody formation may occur with long-term use. In addition, we speculate that the pharmacologic effect on the bone of direct inhibition of bone resorption may be counteracted by the direct effect on the kidney of increased calcium excretion.
Our clinical evaluation comparing the current control group with historic controls with no treatment at all, however, clearly showed a dramatic decrease of osteoporosis-related morbidity. This observation is supported by the results of Van Cleemput and colleagues [16], who reported recently on 4 of 24 heart transplant recipients with symptomatic fractures of the lumbar spine and the femoral neck within 24 months after transplantation. In another group of 24 patients who received calcium and vitamin D supplements no such events occurred.
As the major reduction of bone mineral density occurs within the first 3 months after transplantation, prophylactic treatment with vitamin D and calcium may be of the greatest importance during the first 6 to 12 months after transplantation, but additional factors must be considered. Osteopenia is already present in many patients awaiting HTx. Immobilization and use of high-dose loop diuretics in severe congestive heart failure are identified as primary contributors of bone loss [17]. After the initial phase of HTx, the need for loop diuretics may decrease and the ability and performance of exercise increase. A protocol of resistance exercise training in cardiac recipients was shown to restore bone mineral density effectively toward pretransplant levels [18].
In conclusion, this study, as well as our past experience of high bone morbidity in heart tranpslant recipients without prophylactic treatment, suggests the prophylactic prevention of osteoporosis in all HTx recipients at least for 3 to 6 months after transplantation. A body of evidence is established in the literature for the importance of vitamin D supplementation as the most effective drug. The administration of calcium is effective too, but further studies are required to identify a possible synergistic effect of calcium in combination with vitamin D. Elcitonin failed to improve bone loss in our study as calcitonin did in corticosteroid-induced osteoporosis, and therefore it is not recommended for prophylactic use after HTx. In addition, control of body weight, as well as participation of HTx recipients in physical posttransplantation exercise programs, needs attention to prevent orthopedic complications.
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References
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Abstract
Introduction
