Bone-related Complications Research Articles

Supportive Therapies in Multiple Myeloma

The outlook for patients with myeloma has improved dramatically over the past few years largely because of improvements in supportive care, the use of high-dose therapy, and the introduction of the novel agents thalidomide, bortezomib, and lenalidomide. These new treatment options have changed the natural history for patients with myeloma, but clinicians must consider treatment-related toxicities. Some of the most common short- and long-term toxicities include the development of peripheral neuropathy, hematologic complications, thrombosis, and bone-related complications, such as fracture and osteonecrosis of the jaw. Careful consideration of patient-reported symptoms and appropriate dose modification or prophylaxis to prevent the development of toxicity are critical, and will result in improved quality of life and better tolerance of delivered therapy.

Risk factors for bone loss with prostate cancer in Korean men not receiving androgen deprivation therapy

Preexisting bone loss in men with prostate cancer is an important issue due to the accelerated bone loss during androgen deprivation therapy (ADT). In addition, a high prostate-specific antigen (PSA) level has been reported to be related to bone metabolism. This study assessed the factors associated with osteoporosis in Korean men with non-metastatic prostate cancer before undergoing ADT. The study enrolled patients admitted for a prostate biopsy because of a high PSA or palpable nodule on a digital rectal examination. We divided the patients (n = 172) according to the results of the biopsy: group I, non-metastatic prostate cancer (n = 42) and group II, benign prostatic hypertrophy (BPH; n = 130). The lumbar bone mineral density (BMD) was evaluated using quantitative computed tomography. The demographic, health status, lifestyle, body mass index (BMI), serum testosterone concentration, and disease variables in prostate cancer (Gleason score, clinical stage, and PSA) were analyzed prospectively to determine their effect on the BMD. The estimated mean T-score was higher in group I than in group II (-1.96 +/- 3.35 vs. -2.66 +/- 3.20), but without statistic significance (p = 0.235). The significant factors correlated with BMD in group I were a high serum PSA (Beta = -0.346, p = 0.010) and low BMI (Beta = 0.345, p = 0.014) in the multiple linear regression model. Also old age (r = -0.481, p = 0.001), a high serum PSA (r = -0.571, p < 0.001), low BMI (r = 0.598, p < 0.001), and a high Gleason's score (r = -0.319, p = 0.040) were the factors related to BMD in the correlation. The significant factors correlated with BMD in group II were old age (Beta = -0.324, p = 0.001) and BMI (Beta = 0.143, p = 0.014) in the multiple linear regression model. The risk factors for osteoporosis in men with prostate cancer include a low BMI, and elevated serum PSA. Monitoring BMD from the outset of ADT is a logical first step in the clinical strategy to avoid or minimize potential bone-related complications in these patients.

Bone-related events in breast cancer

Breast cancer most frequently causes bone metastases in solid tumors. It has been known that there is a vicious cycle consisting of tumor cells, osteoblasts, osteoclasts and various humoral factors in osteolytic lesions. Although systemic therapy is a main treatment of bone metastases, local therapies, such as radiotherapy and surgical therapy, are also promptly needed when bone-related complications occur. In recent years, anti-osteoclast agents, bisphosphonates significantly contribute to the delay of occurrence of bone-related complications. Postoperative adjuvant therapy significantly reduces the incidence of recurrence in breast cancer patients. Chemotherapy and LH-RH agonists cause ovarian function suppression in premenopausal patients, and aromatase inhibitors cause estrogen deprivation in postmenopausal patients. These effects cause unbalance of bone metabolism, loss of bone density and increase in the incidence of fractures. Improvement of these bone-related adverse effects and careful follow-ups are needed for breast cancer patients.

Molecular aspects of osteopathy in type 1 Gaucher disease: correlation between genetics and bone density

Bone-related complications in Gaucher disease are considered to be poorly responsive to specific enzyme replacement therapy. Polymorphisms of candidate genes associated with low bone density were investigated to see whether they are correlated with bone mineral density (BMD) and bone involvement in Gaucher disease. Genotyping for polymorphisms in candidate genes (interleukins 1alpha and 1beta, interleukin-1 receptor antagonist; cytochrome P450; collagen 1A1; low-density Lipoprotein Receptor; bone morphogenic protein 4; vitamin D receptor; and estrogen receptor 2beta) were performed using standard methodologies. BMD was measured by dual energy X-ray absorptiometry (DXA). One hundred and ninety-four patients and 100 controls were genotyped for the above polymorphisms. Thirteen haplotypes were obtained, with several correlations with BMD in patients; also, a haplotype (T889-T3954-C511-240VNTR of IL1) was significantly correlated with T-scores and Z-score for femur neck and lumbar spine (p = 0.01) in patients. Haplotypes of bone-specific candidate genes associated with BMD may predict severity of these features in Gaucher disease.

Cancer-associated bone disease

Patients with cancer are at risk for many events involving the skeleton, including metastatic disease of bone and treatment-related bone loss. Cancer-related therapies that can affect bone include hormonal therapy, chemotherapy, and the use of glucocorticoids. Screening for bone loss, with lifestyle modifications and the early use of anti-osteoporosis therapies such as bisphosphonates, may decrease bone loss and reduce the risk of fracture. This article reviews risk factors and mechanisms associated with cancer-related bone loss and metastases as well as strategies for the detection of bone-related complications of cancer and therapies to treat these complications. This article focuses on the more common cancers with adverse skeletal effects: breast cancer, prostate cancer, and multiple myeloma.

Podocyte injury associated glomerulopathies induced by pamidronate

Pamidronate has been demonstrated to decrease bone-related complications in multiple myeloma and delay progression of the disease. This has led to its use in supportive and maintenance therapy of myeloma in conjunction with steroids and chemotherapy. It has also been selectively used in patients with breast cancer and other neoplasms. We report on five patients who developed glomerular disease induced by pamidronate. Pamidronate was the only drug common to all patients. Tests for hepatitis B and C and human immunodeficiency virus (HIV) were negative for all patients. The first two patients received a high dose of pamidronate for 8 weeks, whereas the other three patients were on monthly therapy for a prolonged period of time. Sources of data included chart review and pathologic analysis of kidney biopsy. Three patients were female and two were males and all were Caucasian, ranging in age from 58 to 71 years. Renal biopsy findings included minimal change disease in two, focal segmental glomerulosclerosis in two, and collapsing focal segmental glomerulosclerosis in one. Immunofluorescence was essentially negative in all cases. Electron microscopy showed variable podocyte injury and extensive foot process effacement. There was no evidence of multiple myeloma-related renal disease. After the biopsy, pamidronate was discontinued and renal function stabilized in all patients except the one with the collapsing variant of focal segmental glomerulosclerosis who required hemodialysis. Three patients had resolution of proteinuria, one patient continued to have proteinuria without deterioration in renal function. Pamidronate has been mainly associated with collapsing focal segmental glomerulosclerosis. This report expands that relationship and adds other glomerular diseases linked with podocyte injury. Additional studies are needed to define the cause of the variability of renal histology with this agent.

Novel approaches to the management of bone metastases

Standard management of breast cancer metastatic to bone includes systemic chemotherapy and, if applicable, hormone therapy, as well as radiotherapy for control of pain or prevention of pathologic fractures. In addition, orthopedic surgical procedures are used to prevent or correct pathologic fractures in weight-bearing areas of the osseous skeleton. Inhibitors of osteoclast function, including bisphosphonates and gallium nitrate, have been shown in clinical trials to decrease bone-related complications. Consequently, bisphosphonates have become an integral part of the management of bone metastases from breast cancer. Improved understanding of the biology of osteoclastogenesis led to the identification of osteoprotegerin as a critical modulator of osteoclast activity. The clinical evaluation of several osteoprotegerin preparations has shown therapeutic effects as measured by significant reductions in biochemical markers of bone resorption. Monoclonal antibodies to RANK ligand and parathyroid hormone-related protein, as well as Src kinase inhibitors, are also currently under clinical evaluation.

Emerging bone problems in patients infected with human immunodeficiency virus.

Recently, a high incidence of osteopenia and osteoporosis has been observed in individuals infected with human immunodeficiency virus (HIV). This problem appears to be more frequent in patients receiving potent antiretroviral therapy. Other bone-related complications in HIV-infected individuals, including avascular necrosis of the hip and compression fracture of the lumbar spine, have also been reported. People living with HIV have significant alterations in bone metabolism, regardless of whether they are receiving potent antiretroviral therapy. The underlying mechanisms to account for these observations remain unknown, although studies are underway to examine the relationship between the bone abnormalities and other complications associated with HIV and antiretroviral therapy. HIV-infected patients with osteopenia or osteoporosis should be treated similarly to HIV-seronegative patients with appropriate use of nutritional supplements (calcium and vitamin D) and exercise. Hormone replacement and antiresorptive therapies might be also indicated.

Soft-tissue flap coverage maximizes limb salvage after allograft bone extremity reconstruction.

Limb salvage after extremity tumor ablation may include the use of allograft bone. The primary complication of this method is infection of the allograft, which can lead to limb loss in up to 50 percent of cases. The purpose of this study is to evaluate the efficacy of primary muscle flap coverage in the setting of allograft bone limb salvage surgery. This study is a prospective review of all patients with flap coverage of extremity allografts over the 10-year period 1991 to 2001. There were 20 patients (11 male and nine female patients) with an average age of 28 years (range, 6 to 72 years). Flap coverage was primary in 16 patients and delayed in four. Delayed coverage was performed for failed wounds that did not have a primary soft-tissue flap. Pathologic findings included osteosarcoma in nine patients, Ewing sarcoma in five patients, malignant fibrohistiocytoma in two patients, chondrosarcoma in two patients, synovial sarcoma in one patient, and leiomyosarcoma in one patient. Allograft reconstruction was performed for the upper extremity in 12 patients and for the lower extremity in eight patients. Flap reconstruction was accomplished with 20 pedicle flaps in 17 patients (latissimus dorsi, 12; gastrocnemius, four; soleus, three; and fasciocutaneous flap, one) and four free flaps (rectus abdominis, three; latissimus dorsi, one) in four patients. All pedicled flaps survived. There was one flap failure in the entire series, which was a free rectus abdominis flap. This case resulted in the only limb loss noted. The follow-up period ranged from 1 to 50 months (average, 12.35 months). At the time of final follow-up, three patients were dead of disease and 17 were alive with intact extremities. The overall limb salvage rate in the setting of bone allograft and soft-tissue flap coverage was 95 percent (19 of 20). Reoperation for bone-related complications was required in 50 percent (two of four) of cases receiving delayed flap coverage compared with 19 percent (three of 16) of patients with primary flap coverage (statistically not significant). The results of this study support the use of soft-tissue flap coverage for allograft limb reconstruction. In this series, no limb was lost in the setting of a viable flap. Reoperation was markedly reduced in the setting of primary flap coverage. Pedicled or microvascular transfer of well-vascularized muscle can be used to wrap the allograft and minimize devastating wound complications potentially leading to loss of allograft and limb.

Effect of Low-dose Enzyme Replacement Therapy on Bones in Gaucher Disease Patients with Severe Skeletal Involvement

ABSTRACT Gaucher disease, the most common glycolipid storage disorder, is characterized by hepatosplenomegaly and skeletal involvement. Enzyme replacement therapy in both the high- and low-dose regimens has been shown to be effective in reducing the organomegaly and improving the hematological parameters of symptomatic patients with type I disease. Herein we report subjective and objective responses of bone-related complications after 2 to 4 years of low-dose enzyme replacement therapy in 14 adult type I patients with severe skeletal involvement pre-treatment. We discuss our results relative to those reported in patients on the high-dose regimen, as well as with reference to a single patient who developed new avascular necrosis despite objective improvement in radiological studies.

Anterior mandibulotomy for oral and oropharyngeal tumours

In the last six years, anterior mandibulotomy was used to approach tumours of the oropharynx and oral cavity in 39 cases. Twenty-six of these had primary lesions in the anterior two-thirds of the tongue. Eight cases had lesions in the base tongue, three in the cheek, and two in the tonsil. Twenty-six cases had T3 tumours, nine had T2 lesions, and four had T4 tumours. Twenty-five patients received post-operative radiotherapy. In 16 cases the mandibulotomy was combined with a marginal mandibulectomy. In 23 cases reconstruction was carried out using a pectoralis major myocutaneous flap. Adequate margins on histopathology obtained in all but eight patients. Bone-related complications occurred in only three patients, all of whom were previously irradiated. Thus the anterior mandibulotomy provides excellent exposure for oral and oropharyngeal tumours, with low complication rate, and avoidance of segmental mandibulectomy.