Adverse Skeletal Effects of Drugs -- Beyond Glucocorticoids
Adverse Skeletal Effects of Drugs -- Beyond Glucocorticoids
The direct negative effects of agents such as methotrexate, doxorubicin and cisplatin on bone turnover, particularly through depletion of osteoblast precursors, have been demonstrated in animal models and in vitro studies. In children, chemotherapy may reduce bone growth and final height, and possibly BMD. This may result in permanently reduced BMD and an increased risk of fracture in adulthood. In premenopausal women, the deleterious effects of chemotherapy are predominantly the result of chemotherapy-induced ovarian failure, which is associated with rapid bone loss in the first 6–12 months following chemotherapy. There may be some direct effect of chemotherapy as evidenced by reduced BMD in postmenopausal women receiving chemotherapy. Men treated with combination chemotherapy for Hodgkin's lymphoma and haematologic malignancy had reduced BMD; however, some had evidence of mild hypogonadism. In another study, men who had previously received chemotherapy for lymphoma or testicular cancers did not have reduced BMD. There are no fracture data for any of these populations. Currently, there are no evidence-based protocols for managing bone health in patients undergoing chemotherapy. Intravenous bisphosphonates are effective in preventing chemotherapy-induced bone loss in children and premenopausal women. In children exposed to chemotherapy, monitoring of growth and assessment of BMD in adulthood may be reasonable.
The tyrosine kinase inhibitors (TKI), imatinib, nilotinib and dasatinib, used in the treatment of chronic myeloid leukaemia (CML), and gastrointestinal stromal cells tumour (GIST), substantially improve the prognosis of the underlying disease. Their molecular targets (PDGFR, c-abl, c-kit) are present in bone and "bystander effects" on bone and calcium metabolism have been observed.In vitro these drugs inhibit osteoblast proliferation but not function, and osteoclastogenesis. Data from animal studies demonstrate reduced bone formation and bone mass after treatment with imatinib. The most consistent effects in patients are alterations in calcium and phosphate metabolism and development of mild secondary hyperparathyroidism. In a prospective study, imatinib therapy was associated with altered bone remodelling, but BMD was stable or increased compared with baseline values. In patients treated with nilotinib, BMD tended to be higher than normative values. Overall, data in adults are largely reassuring regarding the skeletal safety of short- or long-term use of imatinib for treatment of CML or GIST. In children, imatinib also leads to development of secondary hyperparathyroidism and dysregulation of bone remodelling and may inhibit linear growth. Some authors recommend periodic monitoring of calcium and phosphate metabolism in patients receiving TKIs, but the current data do not suggest a need to monitor bone health in adults. In children, there may be negative effects on growth, but the nature and magnitude of this effect is unclear, and further studies are necessary before recommendations can be made.
Cyclosporine A (CsA) and tacrolimus are immunosuppressive drugs used to prevent graft rejection following solid organ transplantation and to treat autoimmune disorders.In vitro, CsA inhibits osteoblasts, particularly at high doses, and osteoclasts, and animal studies suggest a detrimental effect of both CsA and FK506 on bone. The specific skeletal effects of calcineurin inhibitors are difficult to evaluate in humans as they are generally used with glucocorticoids, which are associated with bone loss and an increased risk of fracture. Studies examining CsA monotherapy and some studies of regimens combining CsA and glucocorticoids have shown neutral or protective effects on BMD and fracture. As it is likely that those patients receiving calcineurin inhibitors will undergo monitoring and treatment for osteoporosis as a result of concomitant glucocorticoid use and disease-related risk factors, additional surveillance is unnecessary.
Antiretroviral therapy (ART) (also known as highly active antiretroviral therapy (HAART) consists of the combination of at least three classes of antiretroviral (ARV) drugs. As a result of the effectiveness of this treatment, patients with HIV have a life expectancy similar to the noninfected population and the focus has shifted to managing the long-term complications of HIV and ART, which may include adverse effects on skeletal health. The small number of preclinical studies investigating the effects of ART suggests an increase in osteoclast function, with inhibition of osteoblast function. In patients with HIV infection, the prevalence of low BMD is increased. However, low BMD is present at the time of diagnosis or very early in the course of the disease, and most of the difference in BMD is attributable to lower body weight, suggesting that HIV infection per se does not significantly affect bone health. Whether ART importantly affects skeletal health is uncertain. Initiation of ART induces increases in markers of bone turnover and causes accelerated bone loss in the first 2 years, particularly if treatment includes tenofovir. The mechanisms of these effects are unclear, and they may be attributable to the direct effects on bone cells seen in in vitro studies, vitamin D insufficiency or urinary phosphate wasting. Subsequently, however, changes in BMD tend to be positive in ART-treated cohorts and not different to those reported in non-HIV-infected controls. In a pooled analysis of randomized controlled trials of ART, fracture rates were similar in patients established on ART compared with those who were ART-naïve, but were higher in the first 2 years after initiation of ART. Overall, these results suggest that ART may activate osteoclast function with an increase in bone turnover and a fall in BMD in the first 2 years of treatment. The subsequent stabilization of BMD and lack of data showing an increase rate of fracture in the longer term are reassuring. At present, the available evidence suggests that younger healthy adults with adequately treated HIV infection do not need specific skeletal investigation or treatment, and older HIV-infected adults can be assessed and managed as per the existing guidelines for the general population.
Chemotherapeutic Agents
Chemotherapy
The direct negative effects of agents such as methotrexate, doxorubicin and cisplatin on bone turnover, particularly through depletion of osteoblast precursors, have been demonstrated in animal models and in vitro studies. In children, chemotherapy may reduce bone growth and final height, and possibly BMD. This may result in permanently reduced BMD and an increased risk of fracture in adulthood. In premenopausal women, the deleterious effects of chemotherapy are predominantly the result of chemotherapy-induced ovarian failure, which is associated with rapid bone loss in the first 6–12 months following chemotherapy. There may be some direct effect of chemotherapy as evidenced by reduced BMD in postmenopausal women receiving chemotherapy. Men treated with combination chemotherapy for Hodgkin's lymphoma and haematologic malignancy had reduced BMD; however, some had evidence of mild hypogonadism. In another study, men who had previously received chemotherapy for lymphoma or testicular cancers did not have reduced BMD. There are no fracture data for any of these populations. Currently, there are no evidence-based protocols for managing bone health in patients undergoing chemotherapy. Intravenous bisphosphonates are effective in preventing chemotherapy-induced bone loss in children and premenopausal women. In children exposed to chemotherapy, monitoring of growth and assessment of BMD in adulthood may be reasonable.
Tyrosine Kinase Inhibitors
The tyrosine kinase inhibitors (TKI), imatinib, nilotinib and dasatinib, used in the treatment of chronic myeloid leukaemia (CML), and gastrointestinal stromal cells tumour (GIST), substantially improve the prognosis of the underlying disease. Their molecular targets (PDGFR, c-abl, c-kit) are present in bone and "bystander effects" on bone and calcium metabolism have been observed.In vitro these drugs inhibit osteoblast proliferation but not function, and osteoclastogenesis. Data from animal studies demonstrate reduced bone formation and bone mass after treatment with imatinib. The most consistent effects in patients are alterations in calcium and phosphate metabolism and development of mild secondary hyperparathyroidism. In a prospective study, imatinib therapy was associated with altered bone remodelling, but BMD was stable or increased compared with baseline values. In patients treated with nilotinib, BMD tended to be higher than normative values. Overall, data in adults are largely reassuring regarding the skeletal safety of short- or long-term use of imatinib for treatment of CML or GIST. In children, imatinib also leads to development of secondary hyperparathyroidism and dysregulation of bone remodelling and may inhibit linear growth. Some authors recommend periodic monitoring of calcium and phosphate metabolism in patients receiving TKIs, but the current data do not suggest a need to monitor bone health in adults. In children, there may be negative effects on growth, but the nature and magnitude of this effect is unclear, and further studies are necessary before recommendations can be made.
Calcineurin Inhibitors
Cyclosporine A (CsA) and tacrolimus are immunosuppressive drugs used to prevent graft rejection following solid organ transplantation and to treat autoimmune disorders.In vitro, CsA inhibits osteoblasts, particularly at high doses, and osteoclasts, and animal studies suggest a detrimental effect of both CsA and FK506 on bone. The specific skeletal effects of calcineurin inhibitors are difficult to evaluate in humans as they are generally used with glucocorticoids, which are associated with bone loss and an increased risk of fracture. Studies examining CsA monotherapy and some studies of regimens combining CsA and glucocorticoids have shown neutral or protective effects on BMD and fracture. As it is likely that those patients receiving calcineurin inhibitors will undergo monitoring and treatment for osteoporosis as a result of concomitant glucocorticoid use and disease-related risk factors, additional surveillance is unnecessary.
Antiretroviral Therapy
Antiretroviral therapy (ART) (also known as highly active antiretroviral therapy (HAART) consists of the combination of at least three classes of antiretroviral (ARV) drugs. As a result of the effectiveness of this treatment, patients with HIV have a life expectancy similar to the noninfected population and the focus has shifted to managing the long-term complications of HIV and ART, which may include adverse effects on skeletal health. The small number of preclinical studies investigating the effects of ART suggests an increase in osteoclast function, with inhibition of osteoblast function. In patients with HIV infection, the prevalence of low BMD is increased. However, low BMD is present at the time of diagnosis or very early in the course of the disease, and most of the difference in BMD is attributable to lower body weight, suggesting that HIV infection per se does not significantly affect bone health. Whether ART importantly affects skeletal health is uncertain. Initiation of ART induces increases in markers of bone turnover and causes accelerated bone loss in the first 2 years, particularly if treatment includes tenofovir. The mechanisms of these effects are unclear, and they may be attributable to the direct effects on bone cells seen in in vitro studies, vitamin D insufficiency or urinary phosphate wasting. Subsequently, however, changes in BMD tend to be positive in ART-treated cohorts and not different to those reported in non-HIV-infected controls. In a pooled analysis of randomized controlled trials of ART, fracture rates were similar in patients established on ART compared with those who were ART-naïve, but were higher in the first 2 years after initiation of ART. Overall, these results suggest that ART may activate osteoclast function with an increase in bone turnover and a fall in BMD in the first 2 years of treatment. The subsequent stabilization of BMD and lack of data showing an increase rate of fracture in the longer term are reassuring. At present, the available evidence suggests that younger healthy adults with adequately treated HIV infection do not need specific skeletal investigation or treatment, and older HIV-infected adults can be assessed and managed as per the existing guidelines for the general population.