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* From the Division of Respirology, Department of Medicine, The Toronto Hospital, University of Toronto, Toronto, Ontario, Canada.
Correspondence to: Charles K.N. Chan, MD, FCCP, Head, Division of Respirology, The Toronto Hospital, General Division, 10-N220, Eaton Building, 200 Elizabeth St, Toronto, Ontario, M5G 2C4 Canada; e-mail: cchan{at}torhosp.toronto.on.ca
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Abstract |
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Patients and design: We conducted a prospective study of BMD in 28 patients with various end-stage respiratory diseases pretransplantation and 6 to 12 months posttransplantation. The BMD of the lumbar spine (LS) and femoral neck (FN) were measured. All 28 patients were treated only with vitamin D and calcium supplementation posttransplant. The primary endpoint was the percentage change in BMD. The secondary endpoint was the incidence of fractures posttransplant. A univariate analysis was conducted to determine the various risk factors associated with bone mass loss pretransplant and posttransplant.
Results: Prior to transplantation, moderate to severe bone disease was evident. The mean (± SD) pretransplant T score (the number of SDs from the peak bone mass) and Z score (the number of SDs from the age-matched mean) for the LS were -1.72 ± 1.37 and -1.44 ± 1.31, respectively. The mean pretransplant T score and Z score for the FN were -2.65 ± 1.01 and -1.5 ± 1.43, respectively. Within 6 to 12 months posttransplant, the mean BMD for the LS decreased by 4.76% (p < 0.001), while the mean BMD for the FN decreased by 5.3% (p < 0.001). Five of the 28 patients (18%) suffered osteoporotic fractures posttransplant, while no fractures were documented pretransplant. The cumulative steroid dose posttransplant was associated with a drop in BMD for the LS and FN (r = 0.39, p = 0.039 and r = 0.63, p < 0.001, respectively), while a negative association was found between cumulative steroid use pretransplant and baseline LS and FN T scores (r = -0.4, p = 0.02 and r = -0.43, p = 0.023, respectively).
Conclusion: Within 6 to 12 months after lung transplantation, there is a significant decrease in BMD at both the LS and FN levels (approximately 5%) despite vitamin D and calcium supplementation. This drop in BMD is associated with a relatively high incidence of osteoporotic fractures posttransplant.
Key Words: bone mineral density • corticosteroids • fractures • prospective study
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Introduction |
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Multiple studies have documented the degree of bone mass loss that occurs after kidney,3 4 5 6 heart,7 8 9 10 and liver transplantation.11 12 13 14 15 16 The magnitude of bone mass loss associated with lung transplantation, however, has been poorly studied to date. Only two studies have attempted to quantify the severity of the problem. A cross-sectional study by Aris et al17 revealed that 75% of post-lung transplant patients had bone mineral densities (BMDs) for the spine and femur that were below the fracture threshold (defined in that study as 2 SDs below the age-matched mean). The cross-sectional design of that study, however, did not allow the authors to assess the impact of transplantation on BMD in each subject. A small prospective study by Ferrari et al18 found that the BMD of the lumbar spine (LS) decreased by 4% within 3 to 6 months after transplantation, with no significant change in the BMD of the femoral neck (FN). Although 21 patients were recruited for this study, only 12 patients had their BMD measured posttransplant. The small and selected sample of study subjects likely played a role in the failure of the study to demonstrate any statistically significant correlation between the various osteoporotic risk factors and both pre- and posttransplant BMD.
We conducted a prospective study of BMD in 28 patients before and 6 to 12 months after they had undergone lung transplantation to establish the degree of bone mass loss, frequency of fractures, and risk factors associated with BMD loss after transplantation.
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Materials and Methods |
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The BMD of the LS and FN of 28 patients was measured pretransplant (mean, 4.9 months prior to transplantation) and within 6 to 12 months posttransplant (22 patients were measured at 6 months, 2 patients at 9 months, and 4 patients at 12 months), as the most critical period for bone loss following transplantation appears to be the first 6 months.3 4 5 6 7 8 9 19 We also recorded the number of osteoporotic fractures occurring posttransplantation in this population. As posttransplant prophylaxis for osteoporosis, all 28 patients were treated with vitamin D (400 IU/d) and calcium (1 g/d) alone.
In terms of the immunosuppression regime, cyclosporine, 3 mg/kg/d, was given perioperatively by continuous infusion, with conversion to the oral preparation as soon as it could be tolerated by the patient. The dose was adjusted to obtain a whole-blood trough level of 250 to 350 ng/mL in the first year and 200 to 250 ng/mL thereafter. Azathioprine was given in a dose of 1.0 to 2.0 mg/kg/d, keeping the WBC count > 3,500 cells/mL. The administration of systemic corticosteroids was started with methylprednisolone, 500 mg IV, before graft perfusion, followed by 0.5 mg/kg/d for the first 4 days. On the fourth day posttransplant, prednisone was started at 40 mg/d and was tapered to 5 mg every 5 days until a dose of 20 mg was reached during the first 3 months. Following the first 3 months, the dose of prednisone was further tapered until a long-term maintenance dose of 15 mg every other day was reached 1 year after the transplant. Acute rejection episodes were treated with IV methylprednisolone, 1 g/d for 3 consecutive days. This was followed by oral prednisone, 40 mg/d, on day 4, and was tapered to 5 mg every 5 days until the baseline dose was reached. A third episode of rejection in any individual was treated with antilymphocyte therapy.
Bone Mass Measurements
The BMDs of the LS (L1 to L4) and the FN were measured using
dual-energy x-ray absorptiometry (DEXA) (QDR, 1,000 W; Hologic;
Waltham, MA). Measurements were expressed as grams of bone mineral per
square centimeter of bone. Quality control was maintained by scanning
an anthropomorphic spine phantom daily. The coefficient of variation,
in vivo, for our DEXA was < 1% for the LS and 1.5% for
the FN. Bone mass changes posttransplant were expressed as percentages
of differences from baseline BMDs. The BMD results also were expressed
as T scores (the number of SDs from the peak bone mass) and Z scores
(the number of SDs from the age-matched mean). Osteoporosis was defined
as a BMD that was < 2.5 SDs below peak bone mass (ie, a T
score < -2.5), per the World Health Organization standard.
Fractures
The number of fractures was determined by chart review. New
fractures were diagnosed by radiographs of the affected areas as
indicated by clinical symptoms (ie, bony pain). Radiographic
screening for asymptomatic vertebral fractures was not performed in
this study population due to the high prevalence of preexisting disease
and lack of baseline radiographs.
Risk Factors for Osteoporosis
We performed a univariate analysis of the various osteoporotic
risk factors and the bone mass loss in order to gain insight into the
cause of lung transplant-related osteoporosis. The following six
potential risk factors were defined a priori: age; sex; body
mass index (BMI); steroid use; mobility; and smoking. BMI was measured
at the time of pretransplant measurement of BMD and at 6 months
posttransplant in all study subjects. Pretransplant smoking history was
determined by chart review and patient interview. The degree of
mobility was estimated from the results of the patients’ 6-min walk
test using the modified Bruce protocol, which was conducted at the time
of lung transplant assessment and at 6 months posttransplant. The
cumulative steroid dose used pretransplant and posttransplant was
calculated from a comprehensive chart review and was expressed as
milligrams of prednisone (1 mg of methylprednisolone = 1.25 mg
prednisone). Methylprednisolone was included in order to provide a true
estimate of total cumulative steroid exposure. Other established
osteoporotic risk factors including postmenopausal status and type of
pulmonary disease were not analyzed due to the relatively small sample
size.
Statistical Analysis
Data were analyzed using computer software (SAS, version 6.12
for Windows; SAS Institute; Cary, NC). The paired t test was
used to analyze the percentage of change in the LS and FN. A
correlation analysis between T score and the studied risk factors was
performed using Pearson’s correlation coefficient. Differences in mean
BMD by categorical factors were tested via two-sample t
test. All tests were two-tailed, and statistical significance was
considered for p < 0.05.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1-antitrypsin deficiency (one patient),
pulmonary hypertension (one patient), and idiopathic pulmonary fibrosis
(one patient). The mean pretransplant T scores for the LS and the FN
for these 5 patients were -1.86 and -2.9, respectively (compared with
-1.68 and -2.58, respectively, for the other 23 patients).
Furthermore, there was a mean decrease in BMD of 5.2% at the LS and
10.1% at the FN for these five patients.
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Discussion |
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The cause for the rapid loss of bone mass after transplantation is likely multifactorial, with the immunosuppressant medications, notably the corticosteroids, playing a major role.1 19 In our study, a statistically significant association was found between cumulative steroid use posttransplant and decrease in BMDs in the LS and the FN. Laboratory studies have demonstrated multiple mechanisms by which corticosteroids cause bone mass loss.20 21 22 Corticosteroids have a dual direct effect on bone: the inhibition of bone formation and the acceleration of bone resorption. The suppression of osteoblast function is accomplished by inhibiting the effect of insulin-like growth factor 1 on these cells20 and by preventing the formation of osteocalcin, a key noncollagenous matrix protein in bone, by osteoblasts.22 Increased bone resorption is caused by activation of the osteoclast cells, the mechanism for which is still unclear. The other mechanisms by which steroids may induce osteoporosis include the inhibition of intestinal calcium resorption, an increase in urinary calcium excretion, and a diminishment of ovarian and testicular function (resulting in hypogonadism).23 However, patients who received higher doses of steroids in our study experienced a greater number of rejection episodes and, thus, may have represented a cohort that was more ill.
Although steroids play a major role, there are likely many other factors that are associated with bone loss after lung transplantation. BMI and mobility are well-recognized osteoporotic risk factors. In the cross-sectional study by Aris et al,17 a positive association was found between BMI and posttransplant Z scores for the FN. Our study did not reveal a statistically significant association between either of these variables and a drop in BMD posttransplant. These variables may change rapidly within the first 12 months posttransplant and may be difficult to assess on a one-time basis. Other osteoporotic risk factors, including postmenopausal status and type of pulmonary disease, could not be analyzed due to the relatively small sample size. The dose of cyclosporine was not analyzed as a risk factor because the dose administered and serum levels were not closely correlated (the dose administered does not equal the dose absorbed). Furthermore, no association between cyclosporine levels and BMD loss has been found in clinical trials that have evaluated that endpoint.6 7 13
Our study did not evaluate the changes in BMD that occur after the first year after lung transplantation. In the only other prospective study, Ferrari et al18 found no drop in BMD after the initial 12 months after lung transplantation. This pattern appears to hold true in other organ transplant settings.5 7 13
Symptomatic osteoporotic fractures were detected in 5 of 28 patients (18%) within 6 to 12 months after undergoing transplantation. This result is comparable to the findings in the other studies that evaluated this clinical outcome. Ferrari et al18 reported that 2 of the 12 patients (17%) in their study experienced osteoporotic fractures. In the cross-sectional study by Aris et al,17 10 of the 55 patients (18%) experienced fractures after undergoing transplantation. In a retrospective study, however, Chaparro et al24 found that only 10 of 161 patients (6%) developed osteoporotic fractures. The retrospective nature of that study24 may have resulted in an underestimate of the number of fractures. In our study, three of the five patients experienced severely debilitating vertebral compression fractures that have significantly impacted their quality of life after undergoing transplantation.
Our study also documents the severity of bone disease that exists prior to lung transplantation. Thirty-two percent of our study patients had osteoporosis at the LS and 54% had osteoporosis at the FN before transplantation. In fact, only three patients (11%) had normal BMDs (defined as a T score > -1) at both the LS and FN. This pretransplant bone mass loss is likely multifactorial. Decreased mobility, corticosteroid use, and tobacco use are important risk factors for bone mineral loss in lung transplant candidates.25 For the cystic fibrosis patients, additional risk factors for osteoporosis include decreased vitamin D and calcium absorption, reduced sex hormone production, and increased levels of catabolic cytokines.26 Our study found a statistically significant inverse correlation between cumulative steroid use and baseline T scores for the LS and the FN, as well as an association between BMI and baseline T scores for the LS and the FN of borderline statistical significance. We were unable to find a statistically significant association between age, sex, smoking history, or mobility and pretransplant T scores.
In summary, our study demonstrated a statistically significant decrease in the BMD at both the LS and FN levels as well as a relatively high incidence of fractures (18%) within 6 to 12 months after patients underwent lung transplantation. These fractures occurred despite prophylactic posttransplant treatment with vitamin D and calcium. Clearly, other treatments aimed at preserving bone mass are needed in this patient population. Antiresorptive therapy with the bisphosphonate class of medication holds great promise. Several recently published randomized control trials have shown that etidronate, pamidronate, and alendronate prevent steroid-induced osteoporosis in patients requiring long-term steroid use.27 28 29 As a result, plans are underway to initiate a randomized trial at our center with this class of medication in transplant patients. A role for other agents in the transplant setting, including calcitonin and fluoride, requires further investigation.
The ultimate solution for the osteoporotic complication of lung transplantation, however, does not likely reside in the posttransplant setting alone. With only a modest drop in BMD (4 to 5%) and a relatively high fracture incidence (18%) posttransplant, our study strongly suggests that the moderate decrease in BMD associated with lung transplantation pushes patients with preexisting severe bone mass loss over the fracture threshold. Preventing the initial development of bone mass loss in this patient population years before patients undergo transplantation is clearly the key to avoiding bony complications posttransplant. Thus, one of the strongest messages derived from our study is directed at the clinicians who care for patients with various end-stage respiratory diseases many years prior to transplantation. Early screening for bone mass loss (with DEXA) and the institution of appropriate prophylactic therapy (ie, calcium/vitamin D possibly in conjunction with bisphosphonates) for these patients is needed.
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Footnotes |
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Received for publication March 4, 1999. Accepted for publication July 23, 1999.
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This article has been cited by other articles:
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  O. Tschopp, C. Schmid, R. Speich, B. Seifert, E. W. Russi, and A. Boehler Pretransplantation bone disease in patients with primary pulmonary hypertension. Chest, April 1, 2006; 129(4): 1002 - 1008. [Abstract] [Full Text] [PDF]
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C. E. Caplan-Shaw, S. M. Arcasoy, E. Shane, D. J. Lederer, J. S. Wilt, M. K. O'Shea, V. Addesso, J. R. Sonett, and S. M. Kawut Osteoporosis in Diffuse Parenchymal Lung Disease Chest, January 1, 2006; 129(1): 140 - 146. [Abstract] [Full Text] [PDF]
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 R. M. Aris, P. A. Merkel, L. K. Bachrach, D. S. Borowitz, M. P. Boyle, S. L. Elkin, T. A. Guise, D. S. Hardin, C. S. Haworth, M. F. Holick, et al. Guide to Bone Health and Disease in Cystic Fibrosis J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1888 - 1896. [Abstract] [Full Text] [PDF]
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S. M. Levine A Survey of Clinical Practice of Lung Transplantation in North America Chest, April 1, 2004; 125(4): 1224 - 1238. [Abstract] [Full Text] [PDF]
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