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Bone health in patients with brain tumors
Surgical Neurology 68 (2007) 525 – 533 www.surgicalneurology-online.com
Neoplasm
Bone health in patients with brain tumors Arnaldo Neves Da Silva, MDa, Ailleen Heras-Herzig, MDb, David Schiff, MDa,4 Divisions of aNeuro-Oncology, Neurology Department, and bEndocrinology and Metabolism, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA Received 30 June 2006; accepted 28 November 2006
Abstract
Background: Several factors, including the use of antiepileptic drugs, glucocorticoids, anticoagulants, chemotherapy, radiation therapy, and hemiplegia-associated osteopenia, render patients with brain tumor susceptible to bone disease. Methods: The authors review the pathophysiology of these factors and their impact upon bone integrity. Results: Steps that can be taken to minimize or eliminate bone morbidity including measurement of bone mineral density at treatment onset, adequate calcium intake, vitamins D and K supplementation, adequate sunlight exposure, weight-bearing exercises, fall prevention, avoidance of antiepileptic drugs linked to osteopenia, and judicious use and choice of glucocorticoids and anticoagulants are suggested. Conclusions: Medical management of osteoporosis related to brain tumor treatment with bisphosphonates, teriparitide, and calcitonin is beneficial, as is kyphoplasty for symptomatic vertebral compression fractures. D 2007 Elsevier Inc. All rights reserved.
Keywords:
Brain tumors; Osteoporosis; Antiepileptic drugs; Glucocorticoids; Anticoagulants; Calcium; Vitamin D; Biphosphonates
1. Introduction It is well known that cancer treatments may affect bone health. Several published articles examine bone diseases related to the use of AEDs, radiation therapy, anticoagulants, chemotherapy, GCs, and hemiplegia-associated osteopenia. However, to our knowledge, no article has reviewed the impact of brain tumors and their management upon bone health. A review of these aspects and the steps that
Abbreviations: AED, antiepileptic drug; BCNU, bis-chloronitrosourea (carmustine); BMD, bone mineral density; CCNU, cyclohexyl chloroethyl nitrosourea (lomustine); CSF, cerebrospinal fluid; DXA, dual-energy x-ray absorptiometry; FDA, Food and Drug Administration; GC, glucocorticoid; LMWH, low-molecular-weight heparin; MGP, matrix Gla protein; MTX, methotrexate; PCNSL, primary central nervous system lymphoma; PTH, parathyroid hormone; WHO, World Health Organization. 4 Corresponding author. Tel.: +1 434 9824415; fax: +1 434 9824467. E-mail addresses: [email protected] (A.N. Da Silva)8 [email protected] (A. Heras-Herzig)8 [email protected] (D. Schiff). 0090-3019/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2006.11.065
can be taken to minimize or eliminate bone morbidity seems appropriate. Bone is in a constant process of remodeling, under the influence of systemic hormones and local bone-derived growth factors [38]. Bone consists of 2 physically and biologically distinct structures: cortical bone, which is most abundant in the long bones of the appendicular skeleton and comprises 85% of the total bone, and cancellous or trabecular bone, which represents the remaining 15% of the skeleton and is most abundant in the vertebral bodies. Every week, humans recycle 5% to 7% of their bone mass. The remodeling process helps maintain a blood calcium level that is important for many physiologic processes including coagulation, muscle contraction, nerve function, and cell division. One percent of the body calcium is extraskeletal and available for these functions; the remaining 99% is confined within the bones. The remodeling process is activated every time blood calcium levels drop so that the available calcium for those important physiologic functions is restored. The other reason for bone remodeling
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is to reshape the skeleton in response to stressors, such as gravity and weight-bearing exercises. The opposite activities of 2 cells are accountable for bone remodeling: osteoblasts and osteoclasts. Osteoclasts break down bone, converting the calcium salts to a soluble form that passes easily into the blood. Osteoblasts produce the organic fibers into which the calcium salts are deposited. Therefore, osteoclasts resorb the old bone and osteoblasts form new bone; balance of activity of these 2 cells is necessary for the bone mass to remain constant. PTH is a major hormone involved in bone remodeling. When plasma calcium is low, PTH increases the mobilization of calcium and phosphate from bone into the extracellular fluid; it stimulates the formation of more osteoclasts and stimulates osteoclast and osteocytic activity, resulting in increased calcium in the plasma. Vitamin D plays an essential role in maintaining a healthy mineralized skeleton. Sunlight causes the photoproduction of vitamin D3 in the skin, which is sequentially metabolized in the liver and kidney to 1,25-dihydroxyvitamin D. The major role of 1,25-dihydroxyvitamin D is to keep the serum calcium and phosphorus concentrations within the normal range to maintain essential cellular functions and to promote mineralization of the skeleton [44]. Bone mineral density measurement is widely used to diagnose osteoporosis and predict the risk of fractures [30]. Currently, the criterion-standard method to measure BMD is the use of DXA [54]. The DXA consists of 2 x-ray beams with differing energy levels aimed at a patient’s bone: the soft tissue is subtracted out, and the BMD can be determined from the absorption of each beam by bone. The DXA is primarily used to measure BMD at the lumbar spine and femoral neck, composed primarily of trabecular bone; at the total hip, a mix of cortical and trabecular bone; and at the distal radius, where cortical bone predominates [54,71]. According to the WHO, osteoporosis is defined as a BMD T-score at any site less than or equal to 2.5; and osteopenia is defined as a BMD T-score between 1 and 2.5. The T-score is the number of standard deviations above or below mean bone mass values for a healthy 30-year-old of the same sex who is at the peak bone mass [67]. In children, who have not achieved peak bone mass, Z-scores are most useful because these represent standard deviations below or above a sex- and age-matched control group. However, anyone with an insufficiency fracture is presumed to have osteoporosis regardless of bone density measurements. As bone undergoes constant turnover, increased bone turnover has been proposed as a potential risk factor for fractures [58]. Increased bone turnover can presumably increase bone loss and weaken bone architecture. Serum markers of bone formation include bone alkaline phosphatase, osteocalcin, and the C- and N-terminal propeptides of type I collagen. Urine bone resorption markers include breakdown products of type I collagen such as pyridinium cross-links (pyridinoline and deoxypyridinoline) and the Cand N-telopeptides of type I collagen. Although levels of
those markers represent rates of bone remodeling, that information is not as reliable as BMD testing; therefore, these levels cannot confirm the presence or absence of osteoporosis and cannot be used as a substitute for BMD testing [9]. 2. Antiepileptic drugs Initial studies of patients on AEDs suggested abnormalities of bone metabolism, although the fact that they were conducted on institutionalized patients exposed them to certain biases including poor nutrition, lack of sunlight exposure, low vitamin D intake, use of adjuvant regimens such as acetazolamide and ketogenic diet, concomitant use of other hepatic microsomal enzyme-inducing drugs, and lack of physical activity [22,39,82,100]. More recently, several studies on ambulatory patients also found disorders of bone and mineral metabolism, confirmed radiographically and biochemically [2,26,27,72,76,96,105]. Biochemical evidence of bone disease in patients taking AEDs is reflected in hypocalcemia, hypophosphatemia, decreased serum vitamin D metabolites, hyperparathyroidism, and elevated markers of bone resorption and formation [71]. Several mechanisms have been proposed to explain bone disease associated with the use of different AEDs. Induction of the cytochrome P-450 system, resulting in increased vitamin D catabolism, is the most accepted [2,16,91,104]. The increased conversion of vitamin D into inactive metabolites in the liver reduces its bioavailability and thereby limits absorption of calcium in the gut, leading to hypocalcemia and increased circulating PTH. The PTH increases the mobilization of calcium stores as a result of increased bone turnover. This mechanism is linked to the use of phenobarbital, phenytoin, and carbamazepine. Several studies report conflicting results when evaluating the effects of carbamazepine, which suggests that its role in bone metabolism has not been fully elucidated [71]. On the other hand, a study with 40 patients on long-term therapy with sodium valproate, which is an inhibitor of the cytochrome P-450, also showed decreased levels of serum calcium, low levels of vitamin D metabolites, increased markers of bone resorption and formation, and decreased BMD, suggesting that non–P-450 system mechanisms may play a role in bone loss [85]. Decreased intestinal absorption of calcium was found in rats treated with phenytoin, a finding not corroborated in rats treated with phenobarbital, suggesting that impaired calcium absorption is a possible mechanism of bone loss in patients treated with phenytoin [51]. Moreover, inhibition of cellular response to PTH, or PTH resistance, was demonstrated in fetal rats treated with phenytoin and phenobarbital. This could lead to hypocalcemia, a frequent finding in patients using AEDs [39]. Another proposed mechanism is abnormal bone resorption and formation. Evidence supporting this
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hypothesis includes the fact that increased bone resorption was found in neonatal mouse calvaria treated with phenytoin and one of its metabolites (5-[4-hydroxyphenyl]-5-phenylhydantoin) [97]. In addition, phenytoin and carbamazepine, at concentrations equivalent to therapeutic doses for epilepsy, have been demonstrated to inhibit the proliferation of human osteoblast-like cells [28]. These findings indicate that AEDs can cause an imbalance between bone resorption and formation, leading to increased bone loss. Phenytoin accelerates vitamin K metabolism by inducing cytochrome P-450, and vitamin K deficiency can also cause bone loss [10]. Vitamin K is a cofactor in posttranslational carboxylation of several bone proteins, in particular osteocalcin, a bone formation marker. Rats treated with phenytoin had more bone loss over a 5-week period than did rats treated with phenytoin and vitamin K2 (menatretenone), a form of vitamin K [70,72]. These findings suggest that long-term phenytoin exposure may inhibit bone formation via vitamin K deficiency. Deficiency of calcitonin, a hormone produced by the parafollicular or C cells in the thyroid gland that suppresses the resorption of bone by inhibiting the activity of osteoclasts, is also associated with AED treatment [39,103]. Calcitonin deficiency may accelerate bone turnover. The concomitant use of multiple AEDs is associated with a high risk of bone disease [34,72]. This is of particular importance because brain tumors are a common cause of poorly controlled seizures and use of multiple AEDs [42]. A recent publication studied the use of AEDs and the risk of fracture and concluded that patients with long-term use of AEDs, particularly women, indeed have an increased risk of fractures but did not find any differences between users of AEDs that do and do not induce the cytochrome P-450 system [95]. Newer AEDs such as lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide have been approved by the FDA in the last 10 years; and although they seem to have less adverse effects on bone health, further experimental and clinical studies need to be done to assess their effects on bone density and fracture risk [53]. 3. Glucocorticoids Glucocorticoid-induced osteoporosis is a leading cause of medication-induced osteoporosis and the second in general after postmenopausal osteoporosis [36]. It is known that 30% to 50% of chronic GC users will eventually develop fractures [1,19,24,66]. In patients with brain tumor, corticosteroids are the principal drug to control brain swelling. They are often used before, during, and after neurosurgical procedures and during radiation therapy, and sometimes are required for long periods of time until adequate control of vasogenic edema is achieved. They are also an integral part of some chemotherapy regimens.
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Prolonged use of GC accelerates bone loss, which is greatest in the first year of therapy when up to 20% of trabecular bone may be lost. Most deleterious effects occur during the first 3 months of GC therapy. Individuals with a high rate of bone remodeling, including children, may have a high bone loss rate. On the other hand, van Staa et al concluded that the risk of corticosteroid-induced fractures is more strongly related to daily dose than to cumulative dose, suggesting that the adverse skeletal effects of oral corticosteroids are acute rather than chronic [102]. The principal cause of bone loss in the context of GC therapy is a decrease in osteoblastic bone formation and, to a lesser degree, an increase in osteoclast bone resorption. Osteoblastic bone formation can be caused by impairment in osteoblastic cell function and replication; decrease in type I collagen synthesis, skeletal growth factors, and binding proteins; and increase in osteoblast apoptosis [36,69,73,108]. An increase in osteoclastic bone resorption is likely caused by a decrease in sex hormone production and an increase in PTH due to secondary hyperparathyroidism. High-dose GC leads to abnormalities in hypothalamic gonadotropin-releasing hormone secretion, resulting in a decrease in pituitary gonadotropin, and sex-steroid production by the ovaries and testis. In addition, GC leads to a negative calcium balance because of increased urinary calcium excretion and decreased intestinal absorption with a resultant secondary hyperparathyroidism [7,36,62,81,83]. In summary, GC directly and indirectly reduces the function and number of osteoblasts and increases the number and activity of osteoclasts, resulting in decreased bone formation and accelerated bone loss. Therefore, the risk of fractures in patients with brain tumors, although unreported in the literature, is likely high. Another serious complication of GC therapy is GCinduced osteonecrosis. This complication has been described both in patients receiving long-term GC therapy and in cancer patients under regimens of chemotherapy and GC, but there are no reports of this complication in the brain tumor literature [68,111]. The femoral head is the most common site followed by the humeral head, femoral condyle, tibial plateau, and talus. In most series, GCinduced osteonecrosis occurs between 20 and 40 months after the beginning of treatment. The mechanism of this disabling complication is not completely understood, and 2 hypotheses have been postulated. The first proposes that an increase in fat within the marrow cavity leads to increased intraosseous pressure, resulting in vascular occlusion and subsequent osteonecrosis. The second hypothesis postulates that fat emboli occlude the microvasculature, leading to ischemia, avascularity, fluid extravasation, and osteonecrosis. 4. Anticoagulants Patients with brain tumor, in particular those with meningiomas and high-grade gliomas, are prone to venous
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thromboembolic events. Consequently, prophylactic therapy is aggressively used before, during, and after surgery. Patients with malignant gliomas have a 10% to 36% incidence of symptomatic thromboembolic events [12,15,18,20,79], which reached 60% with routine screening in one study [90]. Several studies reported a variety of abnormal hemostatic parameters in patients with brain tumor, including increased platelet adhesion; hyperfibrinogenemia; shortened thromboelastogram; decreased levels of clotting factors II, V, and VII; and also increased fibrinolysis, although the only consistent finding in the hemostatic profile of patients with brain tumor is an elevated prothrombin time [88,89]. Experimentally, a consumptive coagulopathy was demonstrated in a glioblastoma multiforme model [88,89]; and a direct association between glioma invasiveness, high levels of plasminogen activators, fibrinolysis inhibitors, and also plasmin inhibitors (CSF a 1-antitrypsin) in tissue cultures has also been suggested [87,88]. Long-term use of heparin and sodium warfarin (4hydroxycoumarin), commonly used for the prophylaxis and treatment of thromboembolic events, is associated with bone loss and fractures [11,20,21,43,61,63,92]. Several studies link the prolonged use of heparin to a decreased BMD, but the percentage of patients who will develop a symptomatic fracture remains unknown [4,20,60,92]. Heparin-induced osteoporosis may be caused by overactivation of osteoclasts by PTH, decreased activity of osteoblasts, increased bone resorption as a result of collagen activation, and disturbances in vitamin D metabolism [107]. Using animal models, Muir et al concluded that heparin decreases trabecular bone volume both by decreasing the rate of bone formation and increasing the rate of bone resorption [63]. Petilla et al suggested, based upon a 3-year follow-up of women treated with heparin during pregnancy, that the negative influence of heparin on BMD may be permanent [75]. Low-molecular-weight heparins induce less bleeding and have a more predictable dose-response compared with heparin. A recent study indicates that the risk of bone loss with LMWHs still exists but seems to be lower than that with heparin [35], a finding also confirmed in animal studies [64]. On the other hand, Wawrzynska et al [107] suggest that long-term prophylaxis with anticoagulants seems to be consistent with a more prominent BMD decrease with LMWHs than with vitamin K antagonists. Warfarin exerts its anticoagulant effect by interfering with vitamin K metabolism in hepatocytes, thus blocking the posttranslational c-carboxylation of specific glutamate residues in vitamin K–dependent clotting factors II, VII, IX, and X [92,110]. Several extrahepatic vitamin K–dependent proteins such as osteocalcin, MGP, and protein S are found within bone [110]. These actions account for warfarin’s teratogenic effect on bones [74], but there is no strong evidence that warfarin causes deleterious effects on adult bone. Recently, Barnes et al found significantly reduced bone density in children with congenital heart disease
treated with long-term warfarin therapy, although a multifactorial etiology was not excluded [5]. Two large epidemiological studies have generated conflicting results. Jamal et al, comparing 102 patients placed on warfarin for at least 2 years with warfarin nonusers, found no effect on bone density and/or fracture incidence [47]. In contrast, Caraballo et al, in a retrospective cohort study, followed 572 women who were 35 years or older at their first lifetime venous thromboembolism event. They found that long-term exposure to oral anticoagulation was associated with an increased risk of vertebral and rib fractures when compared with the number of fractures expected from sex- and age-specific fracture incidence rates for the general population [11]. Several factors may explain these differences. Caraballo et al found bone loss related to warfarin on ribs and vertebrae, a site not studied by Jamal et al. In addition, Jamal et al excluded any patients with evident signs of osteoporosis from either groups. And finally, the average age in the study of Jamal et al was 12 years older than the average age in the study of Caraballo et al, raising the possibility that any effect of warfarin on bone could have been masked by age-related bone loss. Animal data support a deleterious effect of warfarin on bone health. Simon et al, using warfarin doses within the therapeutic range for humans in animal models, concluded that warfarin produced a reduction in cancellous bone volume by decreasing rates of bone formation and increasing rates of bone resorption [93]. Recently, fondaparinux, a new antithrombotic drug that specifically inhibits factor Xa, was found to lack the inhibitory effects of heparin on primary human osteoblasts in vitro when administered at a concentration that reflected high-dose clinical treatment [40]. Further studies are needed to assess whether fondaparinux is indeed not associated with bone loss in vivo.
5. Chemotherapy The role of chemotherapy in the treatment of nervous system malignancy has been continuously increasing. To our knowledge, no data have been published about bone loss related to chemotherapic drugs commonly used in brain tumor treatment such as nitrosoureas (BCNU, CCNU) or temozolomide. There are reports of increased incidence of fractures among children after use of MTX for leukemia, although many of these children probably received GCs as well [3]. The mechanism of action of MTX on bone at a cellular level remains unclear, although MTX affects bone cell mechanotransduction by interfering with integrinmediated signaling [25]. Wheeler et al demonstrated that rats treated with MTX displayed depressed cancellous and longitudinal bone growth with decreased bone volume, bone formation, and osteoblast activity, and with increased osteoclast activity [109]. High-dose MTX is part of the standard treatment of PCNSL; and any effects on bone may
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be particularly pertinent because the median age of patients with PCNSL is approximately 60 years, when the incidence of osteopenia and osteoporosis is high. This area merits further study. 6. Radiation therapy Bone loss after radiation therapy targeting brain tumors is not clinically significant because the skull is not a weight-bearing bone. Radiation therapy may be used in the spinal axis for prophylaxis and treatment of leptomeningeal spread of medulloblastomas, ependymomas, germinomas, high-grade gliomas, and metastatic tumors. Krishnamoorthy et al found that children who have undergone irradiation to posterior fossa and craniospinal axis for medulloblastomas and ependymomas have diminished total body and lumbar spine BMD [52]. Gilsanz et al described a significant decrease in lumbar BMD in children who had been treated with chemotherapy and whole brain radiation therapy for acute lymphoblastic leukemia: BMD was decreased when compared with a group of patients who had chemotherapy only [32]. Mithal et al demonstrated that adult survivors of childhood medulloblastoma had decreased BMD in lumbar spine and femoral neck [59]. These studies suggest that radiation therapy, besides its negative effects on bone growth, may play a role in reducing bone deposition or increasing bone resorption and also imply that the BMD decrease is not restricted to the radiotherapy field. 7. Hemiplegia-associated osteopenia It has been extensively demonstrated in patients who have had a stroke that bone mass is significantly reduced on the hemiplegic side [86]. Data show that 4% to 15% of hip fractures occur as a late complication of stroke and that 79% of these occur in the hemiplegic side [14,65,78]. Reduction in mechanical stress on bone inhibits osteoblast-mediated bone formation and accelerates osteoclast-mediated bone resorption especially of cancellous bone, leading to disuse osteoporosis [98]. Ultimately, the bone becomes atrophic, fragile, and predisposed to fractures. Lower limb weakness with gait disturbance, triceps weakness, and visual impairment are also common after strokes, predisposing patients to falls and osteoporotic fractures [37,77]. Although there are no literature citations linking brain tumor–associated hemiplegia and bone loss or increased incidence of fractures, it is probable that hemiplegiaassociated osteoporosis is a significant problem in these populations as well. 8. Recommendations To deliver the best care possible to patients with brain tumors, the risk of bone loss related to the treatment needs to be addressed; and the recommendations sum-
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Table 1 Prevention of bone loss and fractures Perform BMD testing at the beginning of treatment. Adequate calcium intake: 1000 mg daily (19-50 years), 1200 mg daily ( N 50 years) Patients with diagnosed osteoporosis should receive 1500 mg of calcium daily. Vitamin D supplementation: 200 IU (patients younger than 50 years), 400 IU (patients between 50 and 70 years), 600 IU (older than 70 years) Multivitamin tablet containing vitamin K Adequate sunlight exposure Weight-bearing and resistance-training exercises to prevent proximal muscles weakness Fall prevention When feasible, avoid antiseizure medications that induce cytochrome P-450 (phenobarbital, phenytoin, carbamazepine, and primidone). Discontinue GCs when feasible. Patients receiving steroids for more than 3 months should be considered for treatment. Oral anticoagulation seems to be less deleterious to the bone than LMWH and unfractioned heparin.
marized on Tables 1 and 2 should be part of standard neuro-oncology care. Ideally, all patients with brain tumor initiating treatment should undergo BMD testing, particularly those with tumors compatible with a long-term life expectancy. Patients with T-scores b 2.0 should be treated, and those with T-scores b 1.5 should be treated if there are other associated risks including anticoagulation therapy, GC use, use of antiseizure medications that induce cytochrome P-450 (phenobarbital, phenytoin, carbamazepine, and primidone), or neurological deficits that can predispose to falls. Extensive data suggest that calcium intake reduces bone loss and suppresses bone turnover. Food sources of calcium include dairy products (milk, yogurt, and cheeses). The estimated adequate daily calcium intake for men and women is 1000 mg/d (19-50 years) and 1200 mg/d (51 years and older) [29]. Vitamin D supplementation is inexpensive and also recommended in doses of 200 IU for adults younger than 50 years, 400 IU for those between 50 and 70 years old, and 600 IU for those older than 70 years, especially in those who have vitamin D deficiency or lack of sunlight exposure [29]. Multivitamin tablets usually contain 400 IU of vitamin D, and many calcium tablets also contain vitamin D. Considering the risks of skin cancer caused by sunlight exposure, short trips outside in sunny days and 30 to 60 minutes of exposure on rainy days should be incorporated to a daily routine [86]. In patients with vitamin D deficiency or insufficiency, defined as a 25-hydroxyvitamin D concentration of less than 30, treatment with high doses of vitamin D may be indicated. These patients may require treatment with ergocalciferol 50 000 U 1 to 2 times a week for 8 to 12 weeks to become vitamin D repleted. In addition, these patients oftentimes require maintenance treatment with ergocalciferol 50 000 U once monthly. Adequate vitamin K levels are important for optimal carboxylation of osteocalcin. Conditions in which the
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Table 2 Medical treatment of bone loss and fractures Bisphosphonate therapy has been demonstrated to increase bone density and reduce fracture risk in patients receiving GCs. Teriparitide (PTH fragments, hPTH I-34) has been demonstrated to increase bone mass and bone cross-sectional area in GC-treated patients. No fracture data are available at present. Teriparitide and biphosphonates can be used in patients taking AEDs or anticoagulants who need treatment of osteoporosis. Calcitonin has only been shown to decrease risk of fractures in lumbar spine, not in the hip. At present, there are no data on its use in patients receiving GCs. Kyphoplasty may be used for patients with symptomatic vertebral compression fractures.
vitamin K metabolism or nutrition is impaired, such as longterm phenytoin therapy, have been associated with reduced bone mass [70,72]. Therefore, recommendation of a daily multivitamin tablet is entirely justified. Exercise is widely accepted to help maintain bone mass and is an important part of any osteoporosis treatment or prevention program [94]. In particular, weight-bearing and resistance-training exercises have been demonstrated to increase balance and coordination, which are important to prevent falls. Examples of weight-bearing exercises are walking, jogging, hiking, dancing, and stair climbing. Exercises also are important to prevent proximal muscle weakness that occurs in steroid myopathy [6,45]. The use of anticonvulsant prophylaxis in newly diagnosed brain tumors has been controversial. The American Academy of Neurology Guideline recommends that because of lack of efficacy and their potential adverse effects, prophylactic AEDs should not be used routinely in patients with newly diagnosed brain tumors [33]. Furthermore, given the abundant number of AEDs, the physician should consider avoiding those that induce the cytochrome P-450 pathway including phenytoin, carbamazepine, phenobarbital, and primidone; these are linked with decreased bone mass after long-term treatment [2,16,91,104]. Evidence suggests that much of the bone loss related to AEDs can be treated or prevented by administration of calcium and vitamin D [101]. Antiepileptic drugs induce vitamin D deregulation; therefore, these patients often need more than 5 times the dietary reference intakes [17]. Screening of all adults who will receive long-term AED therapy with measurement of baseline serum calcium, phosphate, and 25-hydroxy vitamin D levels and alkaline phosphatase concentrations as well as assessment of BMD is also recommended [41]. Teriparitide (PTH fragments, hPTH I-34) and bisphosphonates can be used in patients taking AEDs diagnosed with osteoporosis. The management of steroid-induced osteoporosis relies upon studies in patients treated for chronic diseases such as rheumatoid arthritis, asthma, and cancers that produce longterm survivors. As a general rule, all patients who will be receiving steroids at doses equivalent to prednisone 7.5 mg/d (dexamethasone 1.2 mg) or greater for more than 3 months should be treated with a combination of calcium and
vitamin D supplementation and bisphosphonates or teriparitide therapy [8,23,57,84,106]. Although some strategies such as improved calcium intake along with vitamin D and blocking steroid-induced hypercalciuria with thiazide diuretics have been proposed, the only way to minimize the effects of steroids on bone is to discontinue steroid therapy or use the lowest possible daily dose for the shortest possible time [56]. Discontinuation of steroids is followed by a rebound increase in osteoblastic function [46]. Bisphosphonate therapy has been shown to increase bone density and reduce fracture risk in patients receiving GC therapy [49,84]. Teriparitide has been demonstrated to increase bone mass and bone cross-sectional area in GCtreated patients, although fracture data are not yet available [49,80]. Currently, a large randomized phase III study is under way comparing the efficacy of teriparatide with alendronate on lumbar spine BMD in GC-induced osteoporosis. Calcitonin has only been shown to decrease risk of fractures in lumbar spine, not in the hip; and as yet, there are no data on its use in patients receiving GCs [13]. In patients requiring long-term anticoagulation and who have a high risk of bleeding, in older patients, or in patients for whom periodic monitoring of coumarin therapy is difficult, the use of LMWH carries a lower risk of bone loss than unfractioned heparin. For patients with no contraindication to oral anticoagulation, LMWH seems not to have any advantage over warfarin particularly given the higher costs and the need for administration by injection [89]. In patients on unfractioned heparin therapy, discontinuation is the best way to prevent or treat osteoporosis [46,56], although teriparitide and biphosphonates can also be used in patients with diagnosed osteoporosis. In our institution, kyphoplasty has been the treatment of choice for patients with acute vertebral compression fractures due to osteoporosis that are complicated by underlying pain or postural deformity. This technique is a modification of percutaneous vertebroplasty and consists of the inflation of a balloon into the collapsed vertebral body to restore vertebral body height before fracture stabilization with bone cement [31,55,99]. Kyphoplasty has 2 advantages over percutaneous vertebroplasty: it attempts to restore vertebral body height and reduce spinal deformity. Recent data confirm that kyphoplasty provides a safe and effective treatment of pain and disability [48,50]. 9. Conclusion In patients with brain tumor and in those with other chronic diseases that threaten bone health, prevention is the best way to avoid complications from bone loss. Adequate calcium intake, vitamin D supplementation, sunlight exposure, exercise, fall prevention, use of AEDs that do not induce cytochrome P-450, and cautious use of GCs and anticoagulants are measures that should be kept in mind when dealing with patients with brain tumor.
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When bone loss or its feared complications are diagnosed, medical treatment of osteoporosis with bisphosphonates and teriparitide should be implemented. Osteoporosis treatment research is one of the most prosperous and growing fields in medicine, giving us hope that more effective drugs will soon be available. In patients with symptomatic vertebral fractures, kyphoplasty has been shown to improve pain, restoring vertebral body height and reducing spinal deformity.
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Commentary The authors of this article provide an excellent review of bone physiology and the multiple factors that adversely affect the bone health of patients diagnosed with and being treated for malignant glioma. The pain and disability associated with vertebral compression fractures and avascular necrosis of the hip, in particular, contribute to the overall decline in independent function and quality of life from which patients with brain tumor all too often suffer. The degenerative bone conditions outlined in this article, as well as the development of steroid-related diabetes, alopecia, fatigue, deconditioning, disfiguring cushingoid features, and sudden death from deep vein thrombosis–related pulmonary embolus, are unfortunately common comorbidities for patients already burdened with a tragic terminal diagnosis. The prescription for prevention outlined in this article is simple and easy to follow and should stimulate thought for managing other preventable deleterious adverse effects of treatment. We, as neuro-oncologists, share the view that if we cannot yet cure malignant glioma, we can be champions for our patients by keeping them neurologically and otherwise physically well for as long as possible so they can best enjoy what little time they may have left. Lynn Stuart Ashby, MD Barrow Neurological Institute Phoenix, AZ 85013, USA
Neoplasm
Bone health in patients with brain tumors Arnaldo Neves Da Silva, MDa, Ailleen Heras-Herzig, MDb, David Schiff, MDa,4 Divisions of aNeuro-Oncology, Neurology Department, and bEndocrinology and Metabolism, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA Received 30 June 2006; accepted 28 November 2006
Abstract
Background: Several factors, including the use of antiepileptic drugs, glucocorticoids, anticoagulants, chemotherapy, radiation therapy, and hemiplegia-associated osteopenia, render patients with brain tumor susceptible to bone disease. Methods: The authors review the pathophysiology of these factors and their impact upon bone integrity. Results: Steps that can be taken to minimize or eliminate bone morbidity including measurement of bone mineral density at treatment onset, adequate calcium intake, vitamins D and K supplementation, adequate sunlight exposure, weight-bearing exercises, fall prevention, avoidance of antiepileptic drugs linked to osteopenia, and judicious use and choice of glucocorticoids and anticoagulants are suggested. Conclusions: Medical management of osteoporosis related to brain tumor treatment with bisphosphonates, teriparitide, and calcitonin is beneficial, as is kyphoplasty for symptomatic vertebral compression fractures. D 2007 Elsevier Inc. All rights reserved.
Keywords:
Brain tumors; Osteoporosis; Antiepileptic drugs; Glucocorticoids; Anticoagulants; Calcium; Vitamin D; Biphosphonates
1. Introduction It is well known that cancer treatments may affect bone health. Several published articles examine bone diseases related to the use of AEDs, radiation therapy, anticoagulants, chemotherapy, GCs, and hemiplegia-associated osteopenia. However, to our knowledge, no article has reviewed the impact of brain tumors and their management upon bone health. A review of these aspects and the steps that
Abbreviations: AED, antiepileptic drug; BCNU, bis-chloronitrosourea (carmustine); BMD, bone mineral density; CCNU, cyclohexyl chloroethyl nitrosourea (lomustine); CSF, cerebrospinal fluid; DXA, dual-energy x-ray absorptiometry; FDA, Food and Drug Administration; GC, glucocorticoid; LMWH, low-molecular-weight heparin; MGP, matrix Gla protein; MTX, methotrexate; PCNSL, primary central nervous system lymphoma; PTH, parathyroid hormone; WHO, World Health Organization. 4 Corresponding author. Tel.: +1 434 9824415; fax: +1 434 9824467. E-mail addresses: [email protected] (A.N. Da Silva)8 [email protected] (A. Heras-Herzig)8 [email protected] (D. Schiff). 0090-3019/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2006.11.065
can be taken to minimize or eliminate bone morbidity seems appropriate. Bone is in a constant process of remodeling, under the influence of systemic hormones and local bone-derived growth factors [38]. Bone consists of 2 physically and biologically distinct structures: cortical bone, which is most abundant in the long bones of the appendicular skeleton and comprises 85% of the total bone, and cancellous or trabecular bone, which represents the remaining 15% of the skeleton and is most abundant in the vertebral bodies. Every week, humans recycle 5% to 7% of their bone mass. The remodeling process helps maintain a blood calcium level that is important for many physiologic processes including coagulation, muscle contraction, nerve function, and cell division. One percent of the body calcium is extraskeletal and available for these functions; the remaining 99% is confined within the bones. The remodeling process is activated every time blood calcium levels drop so that the available calcium for those important physiologic functions is restored. The other reason for bone remodeling
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is to reshape the skeleton in response to stressors, such as gravity and weight-bearing exercises. The opposite activities of 2 cells are accountable for bone remodeling: osteoblasts and osteoclasts. Osteoclasts break down bone, converting the calcium salts to a soluble form that passes easily into the blood. Osteoblasts produce the organic fibers into which the calcium salts are deposited. Therefore, osteoclasts resorb the old bone and osteoblasts form new bone; balance of activity of these 2 cells is necessary for the bone mass to remain constant. PTH is a major hormone involved in bone remodeling. When plasma calcium is low, PTH increases the mobilization of calcium and phosphate from bone into the extracellular fluid; it stimulates the formation of more osteoclasts and stimulates osteoclast and osteocytic activity, resulting in increased calcium in the plasma. Vitamin D plays an essential role in maintaining a healthy mineralized skeleton. Sunlight causes the photoproduction of vitamin D3 in the skin, which is sequentially metabolized in the liver and kidney to 1,25-dihydroxyvitamin D. The major role of 1,25-dihydroxyvitamin D is to keep the serum calcium and phosphorus concentrations within the normal range to maintain essential cellular functions and to promote mineralization of the skeleton [44]. Bone mineral density measurement is widely used to diagnose osteoporosis and predict the risk of fractures [30]. Currently, the criterion-standard method to measure BMD is the use of DXA [54]. The DXA consists of 2 x-ray beams with differing energy levels aimed at a patient’s bone: the soft tissue is subtracted out, and the BMD can be determined from the absorption of each beam by bone. The DXA is primarily used to measure BMD at the lumbar spine and femoral neck, composed primarily of trabecular bone; at the total hip, a mix of cortical and trabecular bone; and at the distal radius, where cortical bone predominates [54,71]. According to the WHO, osteoporosis is defined as a BMD T-score at any site less than or equal to 2.5; and osteopenia is defined as a BMD T-score between 1 and 2.5. The T-score is the number of standard deviations above or below mean bone mass values for a healthy 30-year-old of the same sex who is at the peak bone mass [67]. In children, who have not achieved peak bone mass, Z-scores are most useful because these represent standard deviations below or above a sex- and age-matched control group. However, anyone with an insufficiency fracture is presumed to have osteoporosis regardless of bone density measurements. As bone undergoes constant turnover, increased bone turnover has been proposed as a potential risk factor for fractures [58]. Increased bone turnover can presumably increase bone loss and weaken bone architecture. Serum markers of bone formation include bone alkaline phosphatase, osteocalcin, and the C- and N-terminal propeptides of type I collagen. Urine bone resorption markers include breakdown products of type I collagen such as pyridinium cross-links (pyridinoline and deoxypyridinoline) and the Cand N-telopeptides of type I collagen. Although levels of
those markers represent rates of bone remodeling, that information is not as reliable as BMD testing; therefore, these levels cannot confirm the presence or absence of osteoporosis and cannot be used as a substitute for BMD testing [9]. 2. Antiepileptic drugs Initial studies of patients on AEDs suggested abnormalities of bone metabolism, although the fact that they were conducted on institutionalized patients exposed them to certain biases including poor nutrition, lack of sunlight exposure, low vitamin D intake, use of adjuvant regimens such as acetazolamide and ketogenic diet, concomitant use of other hepatic microsomal enzyme-inducing drugs, and lack of physical activity [22,39,82,100]. More recently, several studies on ambulatory patients also found disorders of bone and mineral metabolism, confirmed radiographically and biochemically [2,26,27,72,76,96,105]. Biochemical evidence of bone disease in patients taking AEDs is reflected in hypocalcemia, hypophosphatemia, decreased serum vitamin D metabolites, hyperparathyroidism, and elevated markers of bone resorption and formation [71]. Several mechanisms have been proposed to explain bone disease associated with the use of different AEDs. Induction of the cytochrome P-450 system, resulting in increased vitamin D catabolism, is the most accepted [2,16,91,104]. The increased conversion of vitamin D into inactive metabolites in the liver reduces its bioavailability and thereby limits absorption of calcium in the gut, leading to hypocalcemia and increased circulating PTH. The PTH increases the mobilization of calcium stores as a result of increased bone turnover. This mechanism is linked to the use of phenobarbital, phenytoin, and carbamazepine. Several studies report conflicting results when evaluating the effects of carbamazepine, which suggests that its role in bone metabolism has not been fully elucidated [71]. On the other hand, a study with 40 patients on long-term therapy with sodium valproate, which is an inhibitor of the cytochrome P-450, also showed decreased levels of serum calcium, low levels of vitamin D metabolites, increased markers of bone resorption and formation, and decreased BMD, suggesting that non–P-450 system mechanisms may play a role in bone loss [85]. Decreased intestinal absorption of calcium was found in rats treated with phenytoin, a finding not corroborated in rats treated with phenobarbital, suggesting that impaired calcium absorption is a possible mechanism of bone loss in patients treated with phenytoin [51]. Moreover, inhibition of cellular response to PTH, or PTH resistance, was demonstrated in fetal rats treated with phenytoin and phenobarbital. This could lead to hypocalcemia, a frequent finding in patients using AEDs [39]. Another proposed mechanism is abnormal bone resorption and formation. Evidence supporting this
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hypothesis includes the fact that increased bone resorption was found in neonatal mouse calvaria treated with phenytoin and one of its metabolites (5-[4-hydroxyphenyl]-5-phenylhydantoin) [97]. In addition, phenytoin and carbamazepine, at concentrations equivalent to therapeutic doses for epilepsy, have been demonstrated to inhibit the proliferation of human osteoblast-like cells [28]. These findings indicate that AEDs can cause an imbalance between bone resorption and formation, leading to increased bone loss. Phenytoin accelerates vitamin K metabolism by inducing cytochrome P-450, and vitamin K deficiency can also cause bone loss [10]. Vitamin K is a cofactor in posttranslational carboxylation of several bone proteins, in particular osteocalcin, a bone formation marker. Rats treated with phenytoin had more bone loss over a 5-week period than did rats treated with phenytoin and vitamin K2 (menatretenone), a form of vitamin K [70,72]. These findings suggest that long-term phenytoin exposure may inhibit bone formation via vitamin K deficiency. Deficiency of calcitonin, a hormone produced by the parafollicular or C cells in the thyroid gland that suppresses the resorption of bone by inhibiting the activity of osteoclasts, is also associated with AED treatment [39,103]. Calcitonin deficiency may accelerate bone turnover. The concomitant use of multiple AEDs is associated with a high risk of bone disease [34,72]. This is of particular importance because brain tumors are a common cause of poorly controlled seizures and use of multiple AEDs [42]. A recent publication studied the use of AEDs and the risk of fracture and concluded that patients with long-term use of AEDs, particularly women, indeed have an increased risk of fractures but did not find any differences between users of AEDs that do and do not induce the cytochrome P-450 system [95]. Newer AEDs such as lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide have been approved by the FDA in the last 10 years; and although they seem to have less adverse effects on bone health, further experimental and clinical studies need to be done to assess their effects on bone density and fracture risk [53]. 3. Glucocorticoids Glucocorticoid-induced osteoporosis is a leading cause of medication-induced osteoporosis and the second in general after postmenopausal osteoporosis [36]. It is known that 30% to 50% of chronic GC users will eventually develop fractures [1,19,24,66]. In patients with brain tumor, corticosteroids are the principal drug to control brain swelling. They are often used before, during, and after neurosurgical procedures and during radiation therapy, and sometimes are required for long periods of time until adequate control of vasogenic edema is achieved. They are also an integral part of some chemotherapy regimens.
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Prolonged use of GC accelerates bone loss, which is greatest in the first year of therapy when up to 20% of trabecular bone may be lost. Most deleterious effects occur during the first 3 months of GC therapy. Individuals with a high rate of bone remodeling, including children, may have a high bone loss rate. On the other hand, van Staa et al concluded that the risk of corticosteroid-induced fractures is more strongly related to daily dose than to cumulative dose, suggesting that the adverse skeletal effects of oral corticosteroids are acute rather than chronic [102]. The principal cause of bone loss in the context of GC therapy is a decrease in osteoblastic bone formation and, to a lesser degree, an increase in osteoclast bone resorption. Osteoblastic bone formation can be caused by impairment in osteoblastic cell function and replication; decrease in type I collagen synthesis, skeletal growth factors, and binding proteins; and increase in osteoblast apoptosis [36,69,73,108]. An increase in osteoclastic bone resorption is likely caused by a decrease in sex hormone production and an increase in PTH due to secondary hyperparathyroidism. High-dose GC leads to abnormalities in hypothalamic gonadotropin-releasing hormone secretion, resulting in a decrease in pituitary gonadotropin, and sex-steroid production by the ovaries and testis. In addition, GC leads to a negative calcium balance because of increased urinary calcium excretion and decreased intestinal absorption with a resultant secondary hyperparathyroidism [7,36,62,81,83]. In summary, GC directly and indirectly reduces the function and number of osteoblasts and increases the number and activity of osteoclasts, resulting in decreased bone formation and accelerated bone loss. Therefore, the risk of fractures in patients with brain tumors, although unreported in the literature, is likely high. Another serious complication of GC therapy is GCinduced osteonecrosis. This complication has been described both in patients receiving long-term GC therapy and in cancer patients under regimens of chemotherapy and GC, but there are no reports of this complication in the brain tumor literature [68,111]. The femoral head is the most common site followed by the humeral head, femoral condyle, tibial plateau, and talus. In most series, GCinduced osteonecrosis occurs between 20 and 40 months after the beginning of treatment. The mechanism of this disabling complication is not completely understood, and 2 hypotheses have been postulated. The first proposes that an increase in fat within the marrow cavity leads to increased intraosseous pressure, resulting in vascular occlusion and subsequent osteonecrosis. The second hypothesis postulates that fat emboli occlude the microvasculature, leading to ischemia, avascularity, fluid extravasation, and osteonecrosis. 4. Anticoagulants Patients with brain tumor, in particular those with meningiomas and high-grade gliomas, are prone to venous
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thromboembolic events. Consequently, prophylactic therapy is aggressively used before, during, and after surgery. Patients with malignant gliomas have a 10% to 36% incidence of symptomatic thromboembolic events [12,15,18,20,79], which reached 60% with routine screening in one study [90]. Several studies reported a variety of abnormal hemostatic parameters in patients with brain tumor, including increased platelet adhesion; hyperfibrinogenemia; shortened thromboelastogram; decreased levels of clotting factors II, V, and VII; and also increased fibrinolysis, although the only consistent finding in the hemostatic profile of patients with brain tumor is an elevated prothrombin time [88,89]. Experimentally, a consumptive coagulopathy was demonstrated in a glioblastoma multiforme model [88,89]; and a direct association between glioma invasiveness, high levels of plasminogen activators, fibrinolysis inhibitors, and also plasmin inhibitors (CSF a 1-antitrypsin) in tissue cultures has also been suggested [87,88]. Long-term use of heparin and sodium warfarin (4hydroxycoumarin), commonly used for the prophylaxis and treatment of thromboembolic events, is associated with bone loss and fractures [11,20,21,43,61,63,92]. Several studies link the prolonged use of heparin to a decreased BMD, but the percentage of patients who will develop a symptomatic fracture remains unknown [4,20,60,92]. Heparin-induced osteoporosis may be caused by overactivation of osteoclasts by PTH, decreased activity of osteoblasts, increased bone resorption as a result of collagen activation, and disturbances in vitamin D metabolism [107]. Using animal models, Muir et al concluded that heparin decreases trabecular bone volume both by decreasing the rate of bone formation and increasing the rate of bone resorption [63]. Petilla et al suggested, based upon a 3-year follow-up of women treated with heparin during pregnancy, that the negative influence of heparin on BMD may be permanent [75]. Low-molecular-weight heparins induce less bleeding and have a more predictable dose-response compared with heparin. A recent study indicates that the risk of bone loss with LMWHs still exists but seems to be lower than that with heparin [35], a finding also confirmed in animal studies [64]. On the other hand, Wawrzynska et al [107] suggest that long-term prophylaxis with anticoagulants seems to be consistent with a more prominent BMD decrease with LMWHs than with vitamin K antagonists. Warfarin exerts its anticoagulant effect by interfering with vitamin K metabolism in hepatocytes, thus blocking the posttranslational c-carboxylation of specific glutamate residues in vitamin K–dependent clotting factors II, VII, IX, and X [92,110]. Several extrahepatic vitamin K–dependent proteins such as osteocalcin, MGP, and protein S are found within bone [110]. These actions account for warfarin’s teratogenic effect on bones [74], but there is no strong evidence that warfarin causes deleterious effects on adult bone. Recently, Barnes et al found significantly reduced bone density in children with congenital heart disease
treated with long-term warfarin therapy, although a multifactorial etiology was not excluded [5]. Two large epidemiological studies have generated conflicting results. Jamal et al, comparing 102 patients placed on warfarin for at least 2 years with warfarin nonusers, found no effect on bone density and/or fracture incidence [47]. In contrast, Caraballo et al, in a retrospective cohort study, followed 572 women who were 35 years or older at their first lifetime venous thromboembolism event. They found that long-term exposure to oral anticoagulation was associated with an increased risk of vertebral and rib fractures when compared with the number of fractures expected from sex- and age-specific fracture incidence rates for the general population [11]. Several factors may explain these differences. Caraballo et al found bone loss related to warfarin on ribs and vertebrae, a site not studied by Jamal et al. In addition, Jamal et al excluded any patients with evident signs of osteoporosis from either groups. And finally, the average age in the study of Jamal et al was 12 years older than the average age in the study of Caraballo et al, raising the possibility that any effect of warfarin on bone could have been masked by age-related bone loss. Animal data support a deleterious effect of warfarin on bone health. Simon et al, using warfarin doses within the therapeutic range for humans in animal models, concluded that warfarin produced a reduction in cancellous bone volume by decreasing rates of bone formation and increasing rates of bone resorption [93]. Recently, fondaparinux, a new antithrombotic drug that specifically inhibits factor Xa, was found to lack the inhibitory effects of heparin on primary human osteoblasts in vitro when administered at a concentration that reflected high-dose clinical treatment [40]. Further studies are needed to assess whether fondaparinux is indeed not associated with bone loss in vivo.
5. Chemotherapy The role of chemotherapy in the treatment of nervous system malignancy has been continuously increasing. To our knowledge, no data have been published about bone loss related to chemotherapic drugs commonly used in brain tumor treatment such as nitrosoureas (BCNU, CCNU) or temozolomide. There are reports of increased incidence of fractures among children after use of MTX for leukemia, although many of these children probably received GCs as well [3]. The mechanism of action of MTX on bone at a cellular level remains unclear, although MTX affects bone cell mechanotransduction by interfering with integrinmediated signaling [25]. Wheeler et al demonstrated that rats treated with MTX displayed depressed cancellous and longitudinal bone growth with decreased bone volume, bone formation, and osteoblast activity, and with increased osteoclast activity [109]. High-dose MTX is part of the standard treatment of PCNSL; and any effects on bone may
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be particularly pertinent because the median age of patients with PCNSL is approximately 60 years, when the incidence of osteopenia and osteoporosis is high. This area merits further study. 6. Radiation therapy Bone loss after radiation therapy targeting brain tumors is not clinically significant because the skull is not a weight-bearing bone. Radiation therapy may be used in the spinal axis for prophylaxis and treatment of leptomeningeal spread of medulloblastomas, ependymomas, germinomas, high-grade gliomas, and metastatic tumors. Krishnamoorthy et al found that children who have undergone irradiation to posterior fossa and craniospinal axis for medulloblastomas and ependymomas have diminished total body and lumbar spine BMD [52]. Gilsanz et al described a significant decrease in lumbar BMD in children who had been treated with chemotherapy and whole brain radiation therapy for acute lymphoblastic leukemia: BMD was decreased when compared with a group of patients who had chemotherapy only [32]. Mithal et al demonstrated that adult survivors of childhood medulloblastoma had decreased BMD in lumbar spine and femoral neck [59]. These studies suggest that radiation therapy, besides its negative effects on bone growth, may play a role in reducing bone deposition or increasing bone resorption and also imply that the BMD decrease is not restricted to the radiotherapy field. 7. Hemiplegia-associated osteopenia It has been extensively demonstrated in patients who have had a stroke that bone mass is significantly reduced on the hemiplegic side [86]. Data show that 4% to 15% of hip fractures occur as a late complication of stroke and that 79% of these occur in the hemiplegic side [14,65,78]. Reduction in mechanical stress on bone inhibits osteoblast-mediated bone formation and accelerates osteoclast-mediated bone resorption especially of cancellous bone, leading to disuse osteoporosis [98]. Ultimately, the bone becomes atrophic, fragile, and predisposed to fractures. Lower limb weakness with gait disturbance, triceps weakness, and visual impairment are also common after strokes, predisposing patients to falls and osteoporotic fractures [37,77]. Although there are no literature citations linking brain tumor–associated hemiplegia and bone loss or increased incidence of fractures, it is probable that hemiplegiaassociated osteoporosis is a significant problem in these populations as well. 8. Recommendations To deliver the best care possible to patients with brain tumors, the risk of bone loss related to the treatment needs to be addressed; and the recommendations sum-
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Table 1 Prevention of bone loss and fractures Perform BMD testing at the beginning of treatment. Adequate calcium intake: 1000 mg daily (19-50 years), 1200 mg daily ( N 50 years) Patients with diagnosed osteoporosis should receive 1500 mg of calcium daily. Vitamin D supplementation: 200 IU (patients younger than 50 years), 400 IU (patients between 50 and 70 years), 600 IU (older than 70 years) Multivitamin tablet containing vitamin K Adequate sunlight exposure Weight-bearing and resistance-training exercises to prevent proximal muscles weakness Fall prevention When feasible, avoid antiseizure medications that induce cytochrome P-450 (phenobarbital, phenytoin, carbamazepine, and primidone). Discontinue GCs when feasible. Patients receiving steroids for more than 3 months should be considered for treatment. Oral anticoagulation seems to be less deleterious to the bone than LMWH and unfractioned heparin.
marized on Tables 1 and 2 should be part of standard neuro-oncology care. Ideally, all patients with brain tumor initiating treatment should undergo BMD testing, particularly those with tumors compatible with a long-term life expectancy. Patients with T-scores b 2.0 should be treated, and those with T-scores b 1.5 should be treated if there are other associated risks including anticoagulation therapy, GC use, use of antiseizure medications that induce cytochrome P-450 (phenobarbital, phenytoin, carbamazepine, and primidone), or neurological deficits that can predispose to falls. Extensive data suggest that calcium intake reduces bone loss and suppresses bone turnover. Food sources of calcium include dairy products (milk, yogurt, and cheeses). The estimated adequate daily calcium intake for men and women is 1000 mg/d (19-50 years) and 1200 mg/d (51 years and older) [29]. Vitamin D supplementation is inexpensive and also recommended in doses of 200 IU for adults younger than 50 years, 400 IU for those between 50 and 70 years old, and 600 IU for those older than 70 years, especially in those who have vitamin D deficiency or lack of sunlight exposure [29]. Multivitamin tablets usually contain 400 IU of vitamin D, and many calcium tablets also contain vitamin D. Considering the risks of skin cancer caused by sunlight exposure, short trips outside in sunny days and 30 to 60 minutes of exposure on rainy days should be incorporated to a daily routine [86]. In patients with vitamin D deficiency or insufficiency, defined as a 25-hydroxyvitamin D concentration of less than 30, treatment with high doses of vitamin D may be indicated. These patients may require treatment with ergocalciferol 50 000 U 1 to 2 times a week for 8 to 12 weeks to become vitamin D repleted. In addition, these patients oftentimes require maintenance treatment with ergocalciferol 50 000 U once monthly. Adequate vitamin K levels are important for optimal carboxylation of osteocalcin. Conditions in which the
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Table 2 Medical treatment of bone loss and fractures Bisphosphonate therapy has been demonstrated to increase bone density and reduce fracture risk in patients receiving GCs. Teriparitide (PTH fragments, hPTH I-34) has been demonstrated to increase bone mass and bone cross-sectional area in GC-treated patients. No fracture data are available at present. Teriparitide and biphosphonates can be used in patients taking AEDs or anticoagulants who need treatment of osteoporosis. Calcitonin has only been shown to decrease risk of fractures in lumbar spine, not in the hip. At present, there are no data on its use in patients receiving GCs. Kyphoplasty may be used for patients with symptomatic vertebral compression fractures.
vitamin K metabolism or nutrition is impaired, such as longterm phenytoin therapy, have been associated with reduced bone mass [70,72]. Therefore, recommendation of a daily multivitamin tablet is entirely justified. Exercise is widely accepted to help maintain bone mass and is an important part of any osteoporosis treatment or prevention program [94]. In particular, weight-bearing and resistance-training exercises have been demonstrated to increase balance and coordination, which are important to prevent falls. Examples of weight-bearing exercises are walking, jogging, hiking, dancing, and stair climbing. Exercises also are important to prevent proximal muscle weakness that occurs in steroid myopathy [6,45]. The use of anticonvulsant prophylaxis in newly diagnosed brain tumors has been controversial. The American Academy of Neurology Guideline recommends that because of lack of efficacy and their potential adverse effects, prophylactic AEDs should not be used routinely in patients with newly diagnosed brain tumors [33]. Furthermore, given the abundant number of AEDs, the physician should consider avoiding those that induce the cytochrome P-450 pathway including phenytoin, carbamazepine, phenobarbital, and primidone; these are linked with decreased bone mass after long-term treatment [2,16,91,104]. Evidence suggests that much of the bone loss related to AEDs can be treated or prevented by administration of calcium and vitamin D [101]. Antiepileptic drugs induce vitamin D deregulation; therefore, these patients often need more than 5 times the dietary reference intakes [17]. Screening of all adults who will receive long-term AED therapy with measurement of baseline serum calcium, phosphate, and 25-hydroxy vitamin D levels and alkaline phosphatase concentrations as well as assessment of BMD is also recommended [41]. Teriparitide (PTH fragments, hPTH I-34) and bisphosphonates can be used in patients taking AEDs diagnosed with osteoporosis. The management of steroid-induced osteoporosis relies upon studies in patients treated for chronic diseases such as rheumatoid arthritis, asthma, and cancers that produce longterm survivors. As a general rule, all patients who will be receiving steroids at doses equivalent to prednisone 7.5 mg/d (dexamethasone 1.2 mg) or greater for more than 3 months should be treated with a combination of calcium and
vitamin D supplementation and bisphosphonates or teriparitide therapy [8,23,57,84,106]. Although some strategies such as improved calcium intake along with vitamin D and blocking steroid-induced hypercalciuria with thiazide diuretics have been proposed, the only way to minimize the effects of steroids on bone is to discontinue steroid therapy or use the lowest possible daily dose for the shortest possible time [56]. Discontinuation of steroids is followed by a rebound increase in osteoblastic function [46]. Bisphosphonate therapy has been shown to increase bone density and reduce fracture risk in patients receiving GC therapy [49,84]. Teriparitide has been demonstrated to increase bone mass and bone cross-sectional area in GCtreated patients, although fracture data are not yet available [49,80]. Currently, a large randomized phase III study is under way comparing the efficacy of teriparatide with alendronate on lumbar spine BMD in GC-induced osteoporosis. Calcitonin has only been shown to decrease risk of fractures in lumbar spine, not in the hip; and as yet, there are no data on its use in patients receiving GCs [13]. In patients requiring long-term anticoagulation and who have a high risk of bleeding, in older patients, or in patients for whom periodic monitoring of coumarin therapy is difficult, the use of LMWH carries a lower risk of bone loss than unfractioned heparin. For patients with no contraindication to oral anticoagulation, LMWH seems not to have any advantage over warfarin particularly given the higher costs and the need for administration by injection [89]. In patients on unfractioned heparin therapy, discontinuation is the best way to prevent or treat osteoporosis [46,56], although teriparitide and biphosphonates can also be used in patients with diagnosed osteoporosis. In our institution, kyphoplasty has been the treatment of choice for patients with acute vertebral compression fractures due to osteoporosis that are complicated by underlying pain or postural deformity. This technique is a modification of percutaneous vertebroplasty and consists of the inflation of a balloon into the collapsed vertebral body to restore vertebral body height before fracture stabilization with bone cement [31,55,99]. Kyphoplasty has 2 advantages over percutaneous vertebroplasty: it attempts to restore vertebral body height and reduce spinal deformity. Recent data confirm that kyphoplasty provides a safe and effective treatment of pain and disability [48,50]. 9. Conclusion In patients with brain tumor and in those with other chronic diseases that threaten bone health, prevention is the best way to avoid complications from bone loss. Adequate calcium intake, vitamin D supplementation, sunlight exposure, exercise, fall prevention, use of AEDs that do not induce cytochrome P-450, and cautious use of GCs and anticoagulants are measures that should be kept in mind when dealing with patients with brain tumor.
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When bone loss or its feared complications are diagnosed, medical treatment of osteoporosis with bisphosphonates and teriparitide should be implemented. Osteoporosis treatment research is one of the most prosperous and growing fields in medicine, giving us hope that more effective drugs will soon be available. In patients with symptomatic vertebral fractures, kyphoplasty has been shown to improve pain, restoring vertebral body height and reducing spinal deformity.
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Commentary The authors of this article provide an excellent review of bone physiology and the multiple factors that adversely affect the bone health of patients diagnosed with and being treated for malignant glioma. The pain and disability associated with vertebral compression fractures and avascular necrosis of the hip, in particular, contribute to the overall decline in independent function and quality of life from which patients with brain tumor all too often suffer. The degenerative bone conditions outlined in this article, as well as the development of steroid-related diabetes, alopecia, fatigue, deconditioning, disfiguring cushingoid features, and sudden death from deep vein thrombosis–related pulmonary embolus, are unfortunately common comorbidities for patients already burdened with a tragic terminal diagnosis. The prescription for prevention outlined in this article is simple and easy to follow and should stimulate thought for managing other preventable deleterious adverse effects of treatment. We, as neuro-oncologists, share the view that if we cannot yet cure malignant glioma, we can be champions for our patients by keeping them neurologically and otherwise physically well for as long as possible so they can best enjoy what little time they may have left. Lynn Stuart Ashby, MD Barrow Neurological Institute Phoenix, AZ 85013, USA