Effects of Bisphosphonate Administration on the Bone Mass in Immune Thrombocytopenic Purpura Patients Under Treatment With Steroids

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1 Effects of Bisphosphonate Administration on the Bone Mass in Immune Thrombocytopenic Purpura Patients Under Treatment With Steroids Clinical and Applied Thrombosis/Hemostasis 16(6) ª The Author(s) 2010 Reprints and permission: sagepub.com/journalspermissions.nav DOI: / Shosaku Nomura, MD, 1 Yoshiyuki Kurata, MD, 2 Yoshiaki Tomiyama, MD, 2 Takayuki Takubo, MD, 3 Minoru Hasegawa, MD, 3 Katsuyasu Saigo, MD, 4 Masakatsu Nishikawa, MD, 5 Satoshi Higasa, MD, 6 Yasuhiro Maeda, MD, 7 and Kunio Hayashi, MD 8 Abstract Immune thrombocytopenic purpura (ITP) is an acquired hemorrhage condition involving accelerated platelet consumption caused by antiplatelet autoantibodies. Although various therapeutic strategies are used to treat patients with ITP, the standard treatment method is steroid therapy. The most important problem with steroid administration may be a prolonged use tendency in many cases, because there are many refractory chronic patients. To elucidate the effects of glucocorticoid on bone mineral density (BMD) in patients with ITP, we retrospectively evaluated the relationship between BMD and the total dose of glucocorticoid or the mean daily dose given. We observed decreased BMD in 66.7% of the patients with ITP to whom glucocorticoid was given, although normal bone BMD was observed in 28.6% of patients with ITP treated without steroids. The mean level of BMD was markedly decreased in steroid-treated patients compared with nonsteroid-treated patients (P <.01). The relationship between BMD and the total dose of glucocorticoid (P ¼.023) or the mean daily dose revealed a negative correlation (P ¼.022). Administration of bisphosphonate revealed a significant increase in bone mass in patients at 6 and 12 months after the start of bisphosphonate treatment, despite the aggravation of thrombocytopenia. In conclusion, glucocorticoid-induced osteoporosis was observed in patients with ITP, similar to situation seen in patients with other diseases. Bisphosphonate may be an effective agent for the prevention and treatment of glucocorticoid-induced osteoporosis in patients with ITP scheduled to receive long-term steroid treatment. Keywords immune thrombocytopenic purpura, bisphosphonate, steroid, bone mass, quality of life Introduction Immune thrombocytopenic purpura (ITP) is an acquired hemorrhage condition of accelerated platelet consumption caused by antiplatelet autoantibodies. 1 In addition to markedly shortened platelet survival, impaired platelet production is also responsible for thrombocytopenia in ITP. 2 Recently, various new therapeutic strategies such as rituximab and thrombopoietin-like agents are used for the treatment of patients with ITP. 2-4 However, the standard treatment method is a steroid therapy. 5 The most important problem about steroid administration may be a prolong-used tendency in many cases because there are many refractory chronic patients. However, there is a report that the incidence of patients with ITP aged 60 years or older has been increasing in recent years. 6 Given the fact that ITP is a disease common among women and increasing in the elderly population, glucocorticoid-induced osteoporosis in patients with ITP is important in considering the patient s prognosis. Therefore, in recent studies, high doses of steroids for short periods of time is advocated in patients with ITP. 2,5 1 Division of Hematology, Kishiwada City Hospital, Osaka, Japan 2 Department of Blood Transfusion, Osaka University, Osaka, Japan 3 Department of Hematology, Osaka Medical College, Osaka, Japan 4 Department of Blood Transfusion, Kobe University, Kobe, Hyogo, Japan 5 Department of Hematology, Mie University, Tsu, Mie, Japan 6 Department of Hematology, Hyougo Medical College, Hyogo, Japan 7 Department of Hematology, Kinki University, Hiroshima, Japan 8 Division of Hematology, Hirakata Kouseikai Hospital, Osaka, Japan Corresponding Author: Shosaku Nomura, Division of Hematology, Kishiwada City Hospital, 1001 Gakuhara-cho, Kishiwada, Osaka , Japan. shosaku-n@mbp.ocn.ne.jp 622

2 Nomura et al 623 As tests for the assessment of osteoporosis have become widely available in recent years, osteoporosis associated with the administration of corticosteroids (hereinafter, steroids) has become a focus of attention. Because osteoporosis is common in the elderly population and vertebral compression fracture and femoral neck fracture lead to a decline in the quality of life (QOL), its prevention is important. It is widely known that osteoporosis can be caused by steroids. The fracture risk in patients with glucocorticoid-induced osteoporosis increases with escalation of steroid dose and is likely to occur especially in vertebral bones. 7 It has been reported that the bone mineral density (BMD) in fractured bones in patients with glucocorticoid-induced osteoporosis is higher than that in fractured in patients with primary osteoporosis, and even if the loss of BMD is slower, the fracture risk of patients with glucocorticoid-induced osteoporosis is higher than that of patients with primary osteoporosis. 8 Based on these backgrounds, we examined the relationship between steroids and BMD in patients with ITP and fluctuations of bone metabolism markers by administering bisphosphonate in patients under long-term treatment with steroids. We report the results of our examination. Materials and Methods Patients In 25 patients with ITP (6 men, 19 women) aged 19 to 75 years old in whom the BMD was measured, the history of steroid administration (presence or absence of steroid administration, total dose, and average daily dose) from the time of onset of ITP to the time of BMD measurement was investigated retrospectively, and its relationship with the BMD was examined. Of these, 6 were treated with Kami-kihi-to, 4 with danazol, and 5 with Helicobactor pylori eradication therapy. However, there were no long-term drugs other than steroids. Concerning the steroid treatment, the steroid doses were calculated as prednisolone-equivalent doses. The usual dosages of steroids used for chronic ITP were 5 to 30 mg/d. The duration of treatment was calculated from the start of steroid administration to the time of the BMD measurement, and the average daily dose was calculated by dividing the total steroid dose during this period by the duration. Measurements of BMD As for BMD measurement, the BMD from the second to fourth lumbar vertebrae (L2-4) was measured by dual-energy x-ray absorptiometry (DXA). 9 For comparison of the BMD between the groups treated and groups not treated with steroids, the measured values were classified into normal, osteopenia, and osteoporosis levels according to the Diagnostic Criteria for Primary Osteoporosis (year 2000 version) laid down by the Japanese Society for Bone and Mineral Metabolism. The Mann-Whitney U test was used to determine the significance of differences between the 2 groups. Because men and postmenopausal women are also subject to measurements of the BMD, BMD is expressed as the deviation score (z score) from the mean values in a sex- and age-matched healthy control group. z score ¼ðMeasured values Mean valueþ= SDðSD : standard deviationþ Effects of Bisphosphonate In the next step, among the 32 patients with ITP, 27 patients (4 men, 23 women) aged 19 to 75 years old in whom the BMD was measured after obtaining informed consent were treated with alendronate to examine the clinical effects of bisphosphonates in ITP patients with glucocorticoid-induced osteoporosis The BMD and bone metabolism markers in these patients were then examined prospectively. The markers of bone metabolism were examined at the start of the drug (bisphosphonate) administration and at 6 and 12 months after the start of the drug administration. The markers of bone metabolism measured were the serum level of bone-specific alkaline phosphatase (hereinafter, BAP) and urinary level of collagen type 1 cross-linked N-telopeptides (hereinafter, NTX). Mann-Whitney U test was used to test the significance of the differences between the 2 groups. All study protocols were approved by the Institutional Review Board (IRB) of our institutions, and written informed consent was obtained from each patient prior to the start of the trial. Results Bone mass was examined according to the Diagnostic Criteria for Primary Osteoporosis (year 200 revision) laid down by the Japanese Society for Bone and Mineral Metabolism. There were 18 patients in the steroid administration group and 7 patients who were not on steroid treatment; the mean ages of the patients in the 2 groups were and years, respectively, with no significant difference in age between the 2 groups. The average total dose and average daily dose (as predonisolone-equivalent dose) in the steroid treatment group were and mg, respectively. The platelet count was /mL in the steroid treatment group, which was higher than /mL in the group not under steroid treatment. Among the patients in the steroid treatment group, 8 had taken either active vitamin D or vitamin K2 (Table 1). In relation to the distribution of the bone mass in the 2 groups, the frequencies of both osteopenia and osteoporosis were higher in the steroid treatment group than in the group not treated with steroids, although no significant difference in the distribution was observed between the 2 groups (Table 2). Then, the changes in the bone mass (z score) were examined as a function of the steroid dose. Comparison of the average BMD between the steroid treatment group and the group not treated with steroids revealed that the average BMD in the former was significantly lower ( ) than that in the 623

3 624 Clinical and Applied Thrombosis/Hemostasis 16(6) Table 1. Patient Characteristics a Steroid group Nonsteroid group P value n 18 7 Men/women (no) 14/4 5/2 NS Age (years) NS BMI (kg/m 2 ) NS Duration (year) NS Steroid dosage Total dose (mg) Therapy duration (day) Daily dose (mg) Platelet count (10 4 /mm) NS Total number of patients For osteoporosis by VD3 8 0 NOTE: BMI ¼ body mass index. a Data are shown as mean + SD. P value, steroid group versus nonsteroid group. Table 2. Distribution of Bone Mineral Density a Steroid group Nonsteroid group Normal >80%* of YAM 6 (33.3) 5 (71.4) Osteopenia 70>, <80%* of YAM 5 (27.8) 1 (14.3) Osteoporosis <70%* of YAM 7 (38.9) 1 (14.3) NOTE: YAM ¼ Young Adult Mean (mean value of women aged years) ():% a Primary osteoporosis is classified according to the diagnostic criteria for this disease: the presence of a prior fracture and the percentage value of bone density compared with YAM. Mann-Whitney U test: NS. *T score (%) ¼ (Observed value /YAM) 100. latter ( ). In the examination of the BMD as a function of the average daily steroid dose, the BMD was in the group receiving less than 5 mg daily, in the group receiving 5 to 10 mg daily, in the group receiving 10 to 15 mg daily, and in the group receiving more than 15 mg daily (Figure 1). In regard to the relationship between the total steroid dose and the bone mass, the bone mass decreased as the total steroid dose increased. A negative correlation was observed between the total steroid dose and the bone mass (Figure 2). In the relationship between the daily steroid dose and the bone mass, the bone mass decreased as the daily steroid dose increased. In addition, a negative correlation was observed between the daily steroid dose and the bone mass (Figure 3). Alendronate was administered as the drug of first choice to patients recommended treatment for osteoporosis based on the guidelines of the Japanese Society for Bone and Mineral Metabolism, and its effects were examined. The serum level of the bone metabolism marker BAP was significantly lower in the group treated with alendronate than in the 5 patients in the steroid treatment group not treated with alendronate ( vs , P <.05). No differences were observed in the platelet count at the start of the drug administration and at 6 months and 12 months Figure 1. Impact of steroid treatment on bone mineral density (BMD). Mean level of BMD was decreased in steroid-treated patients compared with steroid nontreated patients. Figure 2. Correlation between total steroid dose and bone mineral density (BMD). Negative correlation between BMD and total steroid dose. 624

4 Nomura et al 625 Figure 3. Correlation between daily steroid dose and bone mineral density (BMD). Relationship between BMD and daily steroid dose revealed negative correlation. after the start of the drug administration between the alendronate group and the control group (data not shown). In the alendronate group, the bone mass was % relative to the young adult mean (YAM) at the start of alendronate therapy but increased significantly to 2.8% + 1.4% at 6 months and 3.0% + 5.4% at 12 months after the start of treatment. The urinary level of the NTX, a bone resorption marker demonstrated an upward trend in the control group, while it decreased significantly in the alendronate group to 75.3% % at 6 months and at 12 months after the start of alendronate therapy, relative to the level at the start of the drug administration (Figure 4). The serum level of BAP decreased at 6 months and at 12 months after the start in both the control and the alendronate group and no differences were observed within both groups (data not shown). Discussion The secondary causes of osteoporosis have been classified into endocrine, nutritional drug-induced, immobility-related, congenital, and other causes. Glucocorticoid-induced osteoporosis is the most frequency-encountered form of secondary osteoporosis and poses a clinical problem in many cases. Rheumatoid arthritis is the most common underlying diseases causing glucocorticoid-induced osteoporosis; other common underlying diseases include collagen diseases, such as systemic lupus erythematosus, autoimmune diseases, bronchial asthma, and nephritic syndrome. According to the survey conducted by American College of Rheumatology in 1996, there are an estimated 20 million patients with osteoporosis in the United States, about 20% of which have glucocorticoid-induced osteoporosis. In regard to the underlying pathogenetic mechanism in glucocorticoid-induced osteoporosis, the direct actions of steroids on the bone are considered the most important. 13 When the administered steroid dose is relatively high, hyperparathyroidism may also be involved. Steroids act on osteoblastic cells Figure 4. u-ntx%. u-ntx did not increase in alendronate group. to inhibit the formation of bone matrix, causing disorder of bone mineralization and inhibiting bone formation. In addition, inhibition of small intestinal Ca absorption and of renal tubular Ca reabsorption by steroids may lead to hyperparathyroidism, which is considered to promote bone absorption. Van Staa et al 7 showed that the risks of bone fracture in patients with glucocorticoid-induced osteoporosis increase with escalating steroid dose and that the fracture risk is particularly high in the long bones. It has also been shown that after long-term steroid use in the elderly population, the BMD continues to decline even after discontinuation of the steroid. 8 Diagnosis and treatment guidelines were proposed in foreign countries based on these results According to these reports, treatment is indicated if a new bone fracture is found in a patient during oral steroid treatment for longer than 3 months or in patients with an existing fracture scheduled to receive steroid treatment. Even without fractures, if the BMDofapatientislessthan80% of the YAM value, that is, less than the bone mass loss, treatment is indicated. Treatment is also recommended for persons with normal bone mass scheduled to receive a prednisolone-equivalent dose of more than 5 mg daily. Bisphosphonates are considered the drugs of first choice for the treatment of glucocorticoid-induced osteoporosis. 18,19 While there are numerous reports of the effects of steroid treatment on the bones in various diseases, all these are systemic diseases, and there is the possibility that the disease itself might also affect the BMD. Unlike chronic rheumatism or SLE, the clinical manifestation of ITP is limited to the decrease of the platelet count, with no systemic symptoms. Patients with ITP are thus considered the most suitable for the examination of glucocorticoid-induced osteoporosis. In this study, we conducted a retrospective examination of the effects of steroids on the bone mass in patients with ITP. The results revealed a high rate of osteopenia or osteoporosis (66.7%), diagnosed based on the diagnostic criteria for primary osteoporosis, in the group receiving steroid treatment. There were no differences in the patient background characteristics between the group 625

5 626 Clinical and Applied Thrombosis/Hemostasis 16(6) receiving steroid treatment and the group not treated with steroids; thus, it was considered that the risk of BMD loss was higher in the group receiving steroid treatment. In addition, after the elimination of confounding factors by expressing the BMD as z scores, which represent deviation scores from the mean values in sex- and age-matched participants, significant bone mass as compared with that in the group not treated with steroids was confirmed in the group receiving steroid treatment. The bone mass was also higher in patients receiving higher daily doses. Based on the above, as in other diseases treated with steroids, it was concluded that the risk of bone mass loss is increased with the administration of steroids in patients with ITP. Particular attention to bone mass loss and the elevated risk of bone fractures should be paid in patients receiving large doses of steroids. Based on this background, we treated ITP patients with bone mass loss to osteopenia or osteoporosis levels with alendronate and followed their progress. Our results revealed a significant increase of the bone mass in these patients at 6 months and 12 months after the start of alendronate treatment as compared with that at the start of alendronate treatment. Although the urinary levels of NTX, a bone resorption marker, demonstrated an upward trend in the control group, the levels decreased significantly in patients treated with alendronate, at 6 months and 12 months after the start of the treatment, relative to the levels at the start of alendronate administration. In other words, it was considered that bone resorption was inhibited by alendronate, preventing any increase in urinary NTX levels in patients treated with alendronate. However, the serum levels of the bone formation marker, BAP, also increased in the patients treated with alendronate at 6 months and 12 months after the start of the treatment. This result suggests that alendronate may have no effect on bone formation. Thus, based on our results, bisphosphonate appear to be useful for the prevention and treatment of glucocorticoid-induced osteoporosis in patients with ITP, because improvement of the serum and urinary levels of bone metabolism markers was observed following the administration of a bisphosphonate to patients with ITP on steroid treatment. Because the effects of steroids on bone are mainly exerted via effects on bone resorption, it may be reasonable to treat patients with steroid-induced osteoporosis with a bisphosphonate, which inhibits bone resorption. For patients with ITP under long-term steroid treatment or those who are scheduled for long-term treatment, aggressive treatment with a bisphosphonate may be expected to contribute to an improvement in the QOL of these patients. However, once bisphosphonate are incorporated into bone, they can remain there for up to 12 years without deteriorating. 20,21 Therefore, we should pay attention to the risk of osteonecrosis of the jaws (ONJ) due to bisphosphonate treatment. 22 Our study has some limitations: it was small sample size, and some clinical parameters were not routinely recorded. Furthermore, we could not investigate the effects of patient s sex or age in the current study. Further confirmation of these observations in larger studies would be useful. Conclusion Bone mass loss was confirmed in patients with ITP under long-term steroid treatment, as in patients with other diseases being treated with steroids, and thus the baseline BMDs should be measured prior to initiation of long-term steroids. In addition, alendronate may be an effective agent for the prevention and treatment of glucocorticoid-induced osteoporosis in patients with ITP scheduled to receive long-term steroid treatment. Declaration of Conflicting Interest The authors declared no conflicts of interest with respect to the authorship and/or publication of this article. References 1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346(13): George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost. 2006;4(8): Bussel JB. Treatment of immune thrombocytopenic purpura in adults. Semin Hematol. 2006;43(3 suppl 5):S3-S Psaila B, Bussel JB. Refractory immune thrombocytopenic purpura: current strategies for investigation and management. Br J Haematol. 2008;143(1): Stasi R, Evangelista ML, Stipa E, Buccisano F, Venditti A, Amadori S. Idiopathic thrombocytopenic purpura: current concepts in pathophysiology and management. Thromb Haemost. 2008;99(1): Frederiksen H, Schmidt K. The incidence of idiopathic thrombocytopenic purpura in adults increase with age. Blood. 1999;94(3): Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of oral corticpsteroids and risk of fracture. J Bone Miner Res. 2000;15(6): Clowes JA, Peel N, Eastell R. Glucocorticoid-induced osteoporosis. Curr Opin Rheumatol. 2001;13(4): Cram P, Schlechte J, Christensen A. A randomized trial to assess the impact of direct reporting of DXA scan results to patients on quality of osteoporosis care. J Clin Densitom. 2006;9(4): Sosa M, Hernandez D, Segarra MC, Gómez A, de la Peña E, Betancor P. Effect of two forms of alendronate administration upon bone mass after two years of treatment. J Clin Densitom. 2002;5(1): Sawka AM, Thabane L, Papaioannou A, Gafni A, Hanley DA, Adachi JD. A systemic review of the effect of alendronate on bone mineral density in men. J Clin Densitom. 2005;8(1): Bruder JM, Ma JZ, Wing N, Basler J, Katselnik D. Effects of alendronate on bone mineral density in men with prostate cancer treated with androgen deprivation therapy. J Clin Densitom. 2006;9(4): Patschan D, Loddenkemper K, Buttgereit F. Molecular mechanisms of glucocorticoid-induced osteoporosis. Bone. 2001;29(6):

6 Nomura et al American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis; 2001 update. Arthritis Rheum. 2001;44(7): Eastell R, Reid DM, Compston J, et al. A UK consensus group on management of glucocorticoid-induced osteoporosis: an update. J Intern Med. 1998;244(4): Adachi JD, Olszynski WP, Hanley DA, et al. Management of corticosteroid-induced osteoporosis. Semin Arthritis Rheum. 2000;29(4): Brown JP, Josse RG clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ. 2001;167(10 suppl):s1-s Reid IR. Glucocorticoid-induced osteoporosis: assessment and treatment. J Clin Densitom. 1998;1(1): Hanley DA, Ioannidis G, Adachi JD. Etrironate therapy in the treatment and prevention of osteoporosis. J Clin Densitom. 2000;3(1): Cheng A, Mavrokokki A, Carter G, et al. The dental implications of bisphosphonates and bone disease. Aust Dent J. 2005; 50(4 suppl 2):S4-S Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144(10): Font RG, Garcia MLM, Martinez JMO. Osteochemonecrosis of the jaws due to bisphosphonate treatments: update. Med Oral Patol Oral Cir Bucal. 2008;13(5):E318-E