⒈ Bone Marrow Transplant Research Paper
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Bone Marrow Transplant for Leukemia - Robert and Jamie's Story
Indeed, histomorphometric analyses of iliac crest biopsy specimens from patients with OI who had received pamidronate therapy demonstrated increased cortical thickness and number of trabeculae but no increase in trabecular thickness. Although bisphosphonate treatment is well established for OI in children, data are limited on efficacy and on risk of harm when bisphosphonates are used in children with osteoporosis secondary to chronic illness such as cystic fibrosis, juvenile rheumatoid arthritis, or anorexia nervosa or in those who have had serious burns.
A recent systematic review of bisphosphonate therapy for children and adolescents with secondary osteoporosis concluded that too little evidence is available to support bisphosphonates as standard therapy, although treatment for periods of 3 years or less appears to be well tolerated. Finally, given the long skeletal half-life of bisphosphonates and evidence that pamidronate can be found in urine specimens up to 8 years after administration, care is warranted when considering bisphosphonate treatment for either adolescent or young girls who will reach reproductive maturity within a decade of treatment. At present, only limited, anecdotal data have assessed the safety of long-term pamidronate or other bisphosphonate treatment during fetal development. Among potential adverse clinical events associated with the use of bisphosphonates, none has received greater attention than ONJ.
Whereas the incidence of ONJ is estimated to be 1 to 10 per oncology patients, the risk of ONJ appears to be substantially lower among patients receiving oral bisphosphonate therapy for osteoporosis, with an estimated incidence of approximately 1 in 10, to 1 in , patient treatment years, although this estimate is based on incomplete data. Although use of bisphosphonates and development of ONJ have been temporally associated, a causal relationship has not been identified. Thus, despite the burgeoning scientific literature that has developed since the association between bisphosphonate therapy and ONJ was first reported in , many fundamental questions remain unanswered. As a first step in this process, a task force convened by the American Society for Bone and Mineral Research recently provided a standardized definition of ONJ as the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a health care professional.
In addition to the concern for ONJ, another concern with bisphosphonate therapy, which has recently come to light, is atrial fibrillation. In the HORIZON Pivotal Fracture Trial, in which patients were treated annually with IV zoledronic acid, a statistically significant increase in the incidence of serious atrial fibrillation defined as events resulting in hospitalization or disability or judged to be life-threatening was noted. Whether other bisphosphonate preparations are associated with increased rates of atrial fibrillation is currently unknown, but recent post hoc analysis of data from the pivotal Fracture Intervention Trials and from a large population-based case-control study suggest a correlation between alendronate administration and a slightly increased incidence of atrial fibrillation, although a larger population-based case-control study showed no evidence of an increased risk of atrial fibrillation or flutter with alendronate use.
Although increased rates of microfractures have been found in dogs treated with high doses of bisphosphonates, this finding does not appear to be common among postmenopausal women with osteoporosis treated with either oral or IV bisphosphonate therapy, 22 , although isolated cases of severely suppressed bone turnover and associated fractures have been reported. Hypocalcemia after bisphosphonate administration most frequently follows IV infusion and can occur in patients with high rates of osteoclast-mediated bone resorption such as in patients with either Paget disease of bone or a substantial skeletal tumor burden , previously unrecognized hypoparathyroidism, impaired renal function, or hypovitaminosis D before treatment.
This rate declines by more than half with each subsequent infusion, such that a rate of 2. Occasionally corticosteroids are of benefit. A relatively rare adverse effect of bisphosphonate therapy of which physicians should be aware is ocular inflammation conjunctivitis, uveitis, episcleritis, and scleritis. This complication has been found to occur with both oral and IV bisphosphonate therapy. In the largest retrospective study to date, an incidence of approximately 0. Although all oral and IV bisphosphonate preparations list musculoskeletal pain as a potential adverse effect in their prescribing information, the US FDA recently issued an alert highlighting the possibility of severe, incapacitating musculoskeletal pain that can occur at any point after initiation of bisphosphonate therapy.
Fewer than cases had been reported by late for alendronate and mid for risedronate in total. Other complications associated with the use of oral and IV bisphosphonate therapies are well recognized. Esophageal irritation and erosion can occur with oral bisphosphonate therapy, particularly in patients with known gastroesophageal reflux disease or esophageal stricture. Strict maintenance of an upright posture for 30 to 60 minutes after ingestion with a full glass of water, depending on the oral bisphosphonate, and the use of weekly rather than daily preparations are both likely to limit the risk of adverse effects.
For patients unable to tolerate oral bisphosphonates, IV preparations as noted previously are now FDA approved and not associated with gastroesophageal irritation. Bisphosphonate doses and infusion rates should be adjusted for patients with moderate to severe renal insufficiency. Particularly in patients who receive IV preparations, bisphosphonates can lead to rapid deterioration of renal function, , likely because of their local accumulation in the kidney. For patients with renal insufficiency who receive IV bisphosphonate therapy, renal function both before and after drug administration should be determined.
In patients with mild to moderate renal impairment, oral bisphosphonates rarely lead to further deterioration in renal function, likely because of their poor absorption across the gastrointestinal tract and thus limited short-term bioavailability. Bisphosphonates have been and continue to be used for other conditions without an FDA-approved indication for therapy. As noted, these include various pediatric populations with low bone mass, incident fractures, and prolonged immobility. Many healthy premenopausal women with either radiographic osteopenia or osteoporosis without fractures and postmenopausal women with osteopenia but without fractures now receive bisphosphonate therapy.
Until further studies address these important clinical questions, it is important to tell such patients that we currently lack sufficient data from well-controlled clinical trials to determine either benefits or risks assumed with these pharmacological interventions. Despite the good intentions of many practitioners to limit fractures in their patients by instituting bisphosphonate therapy, the importance of assuring adequate vitamin D and calcium intake both before and after starting bisphosphate therapy is frequently overlooked.
Hypovitaminosis D is common among many patient populations that are also prescribed bisphosphonate therapy and is particularly common among elderly patients who frequently have limited sun exposure, reduced dietary intake, or some renal impairment. This vitamin D insufficiency or deficiency limits dietary absorption of calcium, leading to secondary hyperparathyroidism and loss of skeletal calcium to maintain normocalcemia. Accordingly, among elderly women with osteoporosis, the persistence of secondary hyperparathyroidism blunted the increase in BMD in the lumbar spine in response to weekly alendronate.
Although guidelines for the maintenance of optimal vitamin D levels have changed substantially as we appreciate that vitamin D insufficiency and deficiency affect a far greater proportion of the population than previously recognized, recommendations for optimal calcium intake have been modified only slightly since being addressed by an expert panel convened by the National Institutes of Health in Since their introduction to clinical practice, bisphosphonates have transformed the clinical care of an array of skeletal disorders characterized by excessive osteoclast-mediated bone resorption.
Accordingly, the informed and judicious use of bisphosphonates confers a clear clinical benefit for carefully selected patients that outweighs the risks associated with bisphosphonate use. Maintenance of adequate calcium and vitamin D intake is crucial for all patients receiving bisphosphonate therapy. Individual reprints of this article are not available. National Center for Biotechnology Information , U. Mayo Clin Proc. Author manuscript; available in PMC Sep 1. Matthew T. Author information Copyright and License information Disclaimer.
Address correspondence to Matthew T. Copyright notice. The publisher's final edited version of this article is available at Mayo Clin Proc. See other articles in PMC that cite the published article. Abstract Bisphosphonates are primary agents in the current pharmacological arsenal against osteoclast-mediated bone loss due to osteoporosis, Paget disease of bone, malignancies metastatic to bone, multiple myeloma, and hypercalcemia of malignancy. Open in a separate window. Osteoporosis The most common clinical condition for which bisphosphonate therapy is used is osteoporosis, a skeletal condition characterized by compromised bone strength resulting in an increased risk of fracture.
Glucocorticoid-Induced and Transplant-Associated Osteoporosis Whereas bisphosphonates have become the primary therapeutic choice for treatment of postmenopausal osteoporosis, few recognize that glucocorticoid therapy leads to bone loss. Immobility-Induced Osteoporosis and Other Causes of Acute Bone Loss Immobilized patients, such as those with a recent spinal cord injury or cerebrovascular event, undergo rapid loss of bone, leading to a substantially increased risk of fracture, hypercalcemia, and frequently nephrolithiasis.
Paget Disease of Bone Whereas postmenopausal osteoporosis is characterized by generalized bone loss from increased osteoclast activity, Paget disease of bone involves 1 or more areas of disordered bone remodeling, in which accelerated osteoclast-mediated bone resorption is followed by imperfect osteoblast-mediated bone deposition. Bisphosphonates in Malignancy Many cancers are osteotropic and either metastasize to the skeleton including but not limited to primary malignancies of the breast, prostate, lung, or kidney or grow primarily within the bone marrow multiple myeloma , where this growth frequently leads to hypercalcemia, severe bone pain, skeletal destruction, and pathologic fractures.
Prostate Cancer Breast cancer is characterized by osteolytic lesions, but skeletal metastases from prostate cancer have been described as osteoblastic. Multiple Myeloma In multiple myeloma, clonal proliferation of malignant plasma cells within the bone marrow cavity results in osteolysis and skeletal destruction, accounting for much of the morbidity associated with the disease. Other Malignancies Use of bisphosphonates in other malignancies less frequently metastatic to bone, such as renal cell carcinoma, has been demonstrated to delay the onset and progression of skeletal disease, 99 suggesting that patients with clinical conditions less commonly believed to affect the skeleton can also benefit from bisphosphonate therapy.
Bisphosphonate Therapy for Children Although bisphosphonates have been used most extensively in adults, during the past decade they have become the mainstay of therapy for OI, a heritable skeletal disorder characterized by substantially diminished bone mass and severe fragility, usually resulting from mutations in the genes for type I collagen. Atrial Fibrillation In addition to the concern for ONJ, another concern with bisphosphonate therapy, which has recently come to light, is atrial fibrillation. Hypocalcemia Hypocalcemia after bisphosphonate administration most frequently follows IV infusion and can occur in patients with high rates of osteoclast-mediated bone resorption such as in patients with either Paget disease of bone or a substantial skeletal tumor burden , previously unrecognized hypoparathyroidism, impaired renal function, or hypovitaminosis D before treatment.
Severe Musculoskeletal Pain Although all oral and IV bisphosphonate preparations list musculoskeletal pain as a potential adverse effect in their prescribing information, the US FDA recently issued an alert highlighting the possibility of severe, incapacitating musculoskeletal pain that can occur at any point after initiation of bisphosphonate therapy. Other Potential Complications of Bisphosphonate Therapy Other complications associated with the use of oral and IV bisphosphonate therapies are well recognized. Acknowledgments We thank James M. Peterson for assistance with the figures.
Footnotes Individual reprints of this article are not available. References 1. Russell RG. Bisphosphonates: from bench to bedside. Ann N Y Acad Sci. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats. Calcif Tissue Res. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation.
J Biol Chem. Epub Dec 6. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Epub May 9. Hall A. Rho GTPases and the actin cytoskeleton. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. Alendronate Once-Weekly Study Group. Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis.
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Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Epub Apr 8. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. Alendronate for the treatment of osteoporosis in men. Effects of teriparatide, alendronate, or both on bone turnover in osteoporotic men. J Clin Endocrinol Metab. The importance of bisphosphonate therapy in maintaining bone mass in men after therapy with teriparatide [human parathyroid hormone 1—34 ] Osteoporos Int.
Epub Jun 3. Efficacy and safety of risedronate mg once a month in the treatment of postmenopausal osteoporosis. Zoledronic acid and clinical fractures and mortality after hip fracture. Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate. Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. Combination therapy for postmenopausal osteoporosis. Clin Endocrinol Oxf ; 56 5 — Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. Effect of parathyroid hormone 1—34 on fractures and bone mineral density in postmenopausal women with osteoporosis.
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Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. Individual fracture risk and the cost-effectiveness of bisphosphonates in patients using oral glucocorticoids. Rheumatology Oxford Mar; 46 3 — Epub Aug 9. Primary prevention of glucocorticoid-induced osteoporosis with intermittent intravenous pamidronate: a randomized trial. Intermittent intravenous ibandronate injections reduce vertebral fracture risk in corticosteroid-induced osteoporosis: results from a long-term comparative study. Epub Aug Intravenous pamidronate as treatment for osteoporosis after heart transplantation: a prospective study.
Prevention of bone loss in renal transplant recipients: a prospective, randomized trial of intravenous pamidronate. J Am Soc Nephrol. Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation. Effect of ibandronate on bone loss and renal function after kidney transplantation. Alendronate prevents further bone loss in renal transplant recipients. Short-term zoledronic acid treatment increases bone mineral density and marrow clonogenic fibroblast progenitors after allogeneic stem cell transplantation.
Epub Nov Pamidronate reduces bone loss after allogeneic stem cell transplantation. Epub Jul Zoledronic acid prevents bone loss after allogeneic haemopoietic stem cell transplantation. Intern Med J. Bone Marrow Transplant. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. Alendronate prevents bone loss in patients with acute spinal cord injury: a randomized, double-blind, placebo-controlled study. Epub Jan Intravenous pamidronate attenuates bone density loss after acute spinal cord injury.
Arch Phys Med Rehabil. Alendronate reduces periprosthetic bone loss after uncemented primary total hip arthroplasty: a prospective randomized study. Risedronate reduces postoperative bone resorption after cementless total hip arthroplasty. Epub Feb Whyte MP. Siris ES. Body JJ. Treatment and prevention of bone metastases and myeloma in bone disease. In: Favus MJ, editor. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials.
Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal-related event or progressive bone metastases despite first-line bisphosphonate therapy. MF Study Group. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.
Ann Oncol. Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. Cancer treatment-related bone loss: a review and synthesis of the literature. Curr Oncol. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. Treatment-related Adverse events resulting in a DLT will be summarized by maximum toxicity grade for each dose level of isatuximab.
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Matched Unrelated Donor Transplantation Bone marrow transplantation can be performed using one's own bone marrow or by using another person's bone marrow. Our team Wei Z. Shagun Arora MD Hematologist-oncologist. Miguel Cerejo DO Oncologist. Karen Chee MD Hematologist-oncologist. Alfred Chung MD Hematologist-oncologist. Patricia Cornett MD Hematologist. Lloyd Damon MD Hematologist. Karin Gaensler MD Hematologist. Kristen M. Hege MD Hematologist-oncologist. Jelena Kao MD Hematologist-oncologist. Lawrence D. Kaplan MD Hematologist-oncologist. Andrew D.
Leavitt MD Hematologist. Aaron C. Logan MD Hematologist. Akshiv Malhotra MD Medical oncologist. Thomas G. Martin MD Hematologist-oncologist. Rebecca L. Michael Pourdehnad MD Hematologist-oncologist. Julia Ramos MD Hematologist-oncologist. James L. Giselle Salmasi MD Hematologist.Effect of ibandronate on bone loss and renal Bone Marrow Transplant Research Paper after kidney Bone Marrow Transplant Research Paper. Sandy W. Journal of Applied Philosophy. As detailed in Figure 1, BRed Hunting Hat Analysis Bone Marrow Transplant Research Paper from PPi, nearly all bisphosphonates in current clinical use also have Bone Marrow Transplant Research Paper hydroxyl group attached to the central carbon termed the R 1 position. Krieger, Bone Marrow Transplant Research Paper of endocrinology at Mount Bone Marrow Transplant Research Paper Medical Center in New York City, achieved success with a partial brain transplant in mice.