Inhaled Corticosteroids and OsteoporosisInhaled corticosteroids Inhalationssteroid og osteoporose are the cornerstones in the management of bronchial asthma and some cases of chronic obstructive pulmonary disease. Although ICS are claimed to have low side effect profiles, at high doses they can cause systemic adverse effects including bone inhalationssteroid og osteoporose such as osteopenia, osteoporosis and osteonecrosis. Corticosteroids have detrimental effects on function and survival of osteoblasts and osteocytes, and with the prolongation of osteoclast survival, induce metabolic bone disease. Glucocorticoid-induced osteoporosis GIO can be associated with major complications such as vertebral and neck of femur fractures. ACR recommends bisphosphonates along with calcium and vitamin D supplements as the first-line agents for GIO management.
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Inhaled corticosteroids ICS are the cornerstones in the management of bronchial asthma and some cases of chronic obstructive pulmonary disease. Although ICS are claimed to have low side effect profiles, at high doses they can cause systemic adverse effects including bone diseases such as osteopenia, osteoporosis and osteonecrosis.
Corticosteroids have detrimental effects on function and survival of osteoblasts and osteocytes, and with the prolongation of osteoclast survival, induce metabolic bone disease.
Glucocorticoid-induced osteoporosis GIO can be associated with major complications such as vertebral and neck of femur fractures. ACR recommends bisphosphonates along with calcium and vitamin D supplements as the first-line agents for GIO management.
ACR recommendations can be applied to manage patients on ICS with a high risk of developing metabolic bone disease. This review outlines the mechanisms and management of ICS-induced bone disease. Inhaled corticosteroids ICS have been used for the long-term management of asthma and chronic obstructive pulmonary disease COPD over the past few decades. ICS are claimed to predominantly exert local effects in the airways with minimal systemic side effects, compared to enteral or parenteral steroids, making them the therapeutic agents of choice for the control of these chronic respiratory illnesses.
Although systemic side effects are few with ICS, they do occur in a significant number of patients when used in high doses [ 1 ]. The reported systemic adverse effects related to chronic use of ICS include suppression of the hypothalamo-pituitary-adrenal axis, cataracts, thinning and bruising of the skin, adrenal insufficiency, growth retardation in children, Cushing syndrome and osteoporosis [ 1 , 2 ].
The incidence of systemic effects varies with the type of ICS used. The effects of ICS on bone health have given rise to much attention in recent years, particularly with the increasing prevalence of aged population worldwide, as poor bone health and its complications are strongly associated with reduced quality of life. This review outlines the effects of ICS on bone health and therapeutic strategies. Bone tissue is composed of collagen, matrix proteins, calcium hydroxyapatite, and three types of cells: Osteoclasts are responsible for bone resorption, whilst osteoblasts form the bone.
Osteocytes are the main cells involved in the bone remodelling process through regulation of the other two cell types by their stimulation or inhibition [ 3 ]. Osteocytes are capable of detecting microdamage in the bone tissues and initiating repair in the damaged region [ 4 ]. A number of cytokines and growth factors are involved in the regulation of these complex processes which enables normal bone physiology and anatomy to be maintained.
There exists a delicate balance between bone formation and bone resorption in a healthy individual, and anything that disturbs this balance results in abnormal bone structure and function. Bone loss that results from osteoclast overactivity causes osteopenia in the early stages, and in the later stages, osteoporosis. Similarly, abnormal osteoblast function results in decreased bone formation and consequently osteopenia or osteoporosis develops.
Osteoblasts originate from the bone marrow-derived mesenchymal stem cells and osteoclasts from the haemopoietic stem cells [ 5 , 6 ]. Osteoblasts produce RANKL that binds to the trans-membrane receptor RANK on the osteoclast precursors and activate them to differentiate into mature osteoclasts [ 5 , 6 ]. The bone-forming osteoblasts and bone-degrading osteoclasts constitute a functional unit that determines the integrity and the strength of normal skeletal tissues. Mature osteoblasts secrete the bone matrix that becomes mineralized under the influence of calcium, phosphate and vitamin D [ 6 ].
RANKL produced by osteoblasts results in activation of the osteoclasts by the mechanism described above, and therefore appropriate remodelling of the mineralised bone occurs through osteoclast-mediated bone resorption, thus maintaining normal physiology in a healthy individual.
Glucocorticoids cause a reduction of osteoblastogenesis, increase osteoblast apoptosis and reduce their ability for bone formation [ 9 , 10 ]. Glucocorticoid administration has been demonstrated to switch the osteogenic potential of the bone marrow mesenchymal stem cells to adipogenic differentiation that causes reduction of osteoblastogenesis [ 11 , 12 ].
Increased production of reactive oxygen species induced by steroids leads to osteoblast apoptosis [ 13 ]. Studies in mouse models showed that activation of glucocorticoid receptors in osteoblasts resulted in a reduction of bone mass, trabecular thickness, osteoblast numbers and colony forming units [ 14 ].
Steroid-induced suppression of osteoblast-derived cytokines such as interleukin 11 was also found to impair osteoblast differentiation [ 14 ]. Glucocorticoids also suppress osteoclastogenesis [ 10 , 14 , 15 ]. The suppression of osteoclast formation may be mediated through the glucocorticoid receptors in the osteoblasts and osteoclasts [ 14 , 15 ]. However, unlike in the case of osteoblasts, steroids do not cause osteoclast apoptosis and can prolong osteoclast survival.
Steroids may also inhibit bone resorption efficiency of osteoclasts by interfering with their cytoskeleton formation in response to macrophage colony stimulating factor [ 15 ]. Osteocytes are also affected by corticosteroids. Apoptosis of the osteocytes by administration of corticosteroids in the mouse model was first demonstrated by Weinstein et al. Increased osteocyte lacunar size and loss of mineral around the osteocytes have also been demonstrated in steroid treated animal models [ 16 ].
Increased osteocyte autophagy was proposed as a mechanism by which glucocorticoids induced osteocyte apoptosis. Reductions in the blood flow to the bone canalicular system, and the water content of bone tissues are the other adverse consequences of steroids in the skeletal system [ 9 , 10 ]. Steroids may also affect the production and signalling of various cytokines and growth factors that control normal bone physiology.
Steroid treatment is the most common cause of secondary osteoporosis and iatrogenic metabolic bone disease [ 10 , 20 ]. The prevalence of low bone mineral density BMD can be as high as Steroid-induced bone disease was found to be associated with fewer numbers of osteoblasts and higher prevalence of apoptotic osteocytes in histological studies [ 9 , 24 , 25 ].
Excess osteocyte apoptosis is associated with reductions in the vascular endothelial growth factor, angiogenesis, interstitial fluid and the strength of skeletal tissues [ 26 ]. The loss of bone strength related to steroid use occurs before the loss of BMD that is peculiar to steroid-induced bone disease [ 20 ]. Although glucocorticoids directly suppress osteoclasto-genesis, the prolongation of osteoclast lifespan, in conjunct-ion with a decrease in lifespan of the osteoblasts, result in significant bone loss in long-term steroid users.
Osteopenia is the stage of significant bone loss that results in low BMD, assessed by dual-energy x-ray absorptiometry DEXA scan showing T scores between -1 and Chronic steroid use showed a dose-response pattern in bone strength - a cumulative prednisone exposure of greater than 11 mg was associated with low BMD odds ratio 8. Continued exposure of steroid is expected to result in worsening bone loss leading to osteoporosis. The World Health Organization WHO defines osteo-porosis as a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures.
Osteoporosis or low BMD affects approximately 52 million people in the United States, and approximately one in five men experience an osteoporotic fracture in their lifetime [ 28 ]. The most common sites involved are the vertebral bodies and neck of femur. Osteoporotic fractures are associated with significant mortality and morbidity in the sufferers, especially older individuals. Recent data from the United Kingdom shows that the one-year all-cause mortality compared to controls following a hip fracture is 3.
Therefore, physicians who prescribe corticosteroids for long-term use should consider the healthcare implications related to osteoporosis. Osteonecrosis is the other metabolic bone disease related to chronic steroid use. The disease can occur as early as within 36 days of 16 mg daily dose of oral methylprednisolone with a cumulative dose of mg [ 32 ]. Glucocorticoid-induced osteonecrosis is the most common complication of steroid use that receives medi-claim compensations from litigation suits in the US [ 33 ].
The pathogenic mechanisms underlying steroid-induced osteonecrosis were thought to be increased bone marrow fat that causes an increased intra-osseous pressure and decreased bone perfusion, fat embolism and hypercoagulability, reducing blood flow to the femoral head, and resultant fatigue fractures [ 32 , 34 ].
However, recent evidence suggests the role of osteocyte apoptosis in the causation of osteonecrosis [ 34 - 36 ]. Cumulative osteocyte apoptosis over a prolonged period disrupts the normal function of the osteocyte-lacunar-canalicular system of the bone that leads on to a sequence of events resulting in the joint collapse [ 37 ].
Although the systemic bioavailability of ICS is claimed to be minimal, they tend to occur in a significant number of ICS users, especially among those who receive large doses.
Even after adjustments for covariates such as age, body mass index, smoking, self-reported health, alcohol drinks per week , calcium, PASE physical activity scale for the elderly score, coronary artery disease, stroke, and diabetes, the mean annual percentage in the BMD loss in COPD and asthma patients was significantly higher in patients on ICS compared to controls 0.
Men in this cohort study on ICS showed a 2-fold elevated risk of osteoporotic vertebral fractures. ICS use in childhood was also found to be associated with a decrease in BMD of the lumbar spine and the femoral neck after adjustments for covariates such as age, sex, pubertal stage, height, weight, and use of systemic steroids at late school age [ 40 ]. Osteonecrosis related to ICS use is very uncommon and available data is limited only to case reports [ 41 - 44 ].
Concomitant use of oral steroids for exacerbation of primary lung conditions such as asthma and COPD increases the risk of osteonecrosis from ICS. Corticosteroids are metabolised in the liver by Cytochrome P enzyme mainly CYP3A4 system and the medications that induce this enzyme system may increase the systemic bioavailability of steroids leading to toxicity.
Increasing use of anti-retroviral medications such as retonavir, which are powerful CYP3A4 inducers, have been found to be associated with a higher risk of ICS-related osteonecrosis [ 43 , 44 ]. The systemic bioavailability of ICS differs with the type of steroid molecule, particle size, and mode of inhaler technique used. The systemic toxicity also depends on the pharmaco-kinetic and pharmaco-dynamic properties of the steroid molecule used.
Although newer ICS molecules with lower systemic bioavailability such as CIC were shown to have negligible effects on the bone metabolism and turn over [ 45 ], there are no head-to head comparative trials examining the potential harmful effects of different ICS agents currently available in the market, on bone health. Therefore, vigilance from medical practitioners is essential for the early identification and management of ICS-related bone disease, and also for preventive strategies.
The adverse consequences of ICS on bone metabolism can retard growth in children with a reduction of effective adult height in chronic users, especially those who are on higher doses. The follow-up study of the CAMP trial showed that the initial decrease in attained height associated with the use of ICS in pre-pubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative [ 47 ].
Because of the lack of, or incomplete reporting of growth velocity in the majority of ICS trials in the paediatric age-groups, a recent Cochrane review recommended systematic documentation of growth effects of ICS in all future clinical trials [ 48 ]. Prompt and early recognition of metabolic bone disease that can complicate long-term use of ICS is of paramount importance because of the adverse health implications of established disease.
Patients on moderate to large doses of ICS are particularly vulnerable and require evaluation for adverse metabolic effects on bones. Chronic respiratory illnesses as such can be associated with reductions in the BMD [ 49 ]. Repeated use of rescue oral corticosteroids for exacerbations of chronic respiratory disease augments the bone disease related to ICS use.
Litigations related to the lack of communication between healthcare professionals and patients on the skeletal complications from corticosteroids are not rare [ 33 ], although physicians often ignore the importance of these discussions.
Loss of height may be an early indicator of vertebral compression fractures from osteoporosis and therefore, assessment of height may be helpful for the initial diagnostic work up. Prevalent vertebral fractures are associated with an increased risk of future fractures [ 20 ].
A thorough history of previous falls and back pain may be helpful in identifying antecedent trauma that may increase the fracture risk in cases with established osteoporosis. History about the duration of respiratory illness, alcohol intake, smoking status, amount of daily exercise, calcium and vitamin D intake, previous fragility fractures, family history of osteoporotic fractures and menstrual history in females should be obtained. An assessment of the nutritional status and the body mass index BMI should be done in all cases.
Assessments of renal function, liver function and levels of calcium, phosphate, parathyroid hormone and vitamin D are useful for the initial laboratory work up. Plain radiographs may be useful to detect established fractures. BMD measurement is insensitive for initial risk assessment because of the mismatch between bone quantity and bone quality in osteoporosis related to steroid use [ 50 ].
BMD data can be useful in follow up of cases after the initial intervention. The WHO fracture risk scoring algorithm FRAX score has limitations in patients with steroid-induced osteoporosis as it underestimates the risk of fractures in patients on steroids as the duration and cumulative dose of steroids that substantially increase the fracture risk, are not included in the scoring system [ 20 ].
Although relatively rare when compared to oral or intra-articular steroid use, patients on ICS who report persistent hip, knee, or shoulder pain should be evaluated to rule out the possible occurrence of osteonecrosis as a complication. Established cases demonstrate severe pain on movement of the joint along with tenderness and reduced range of mobility. A subchondral crescent sign may be seen on plain radiographs in the late stages of the disease [ 32 ]. Magnetic resonance imaging MRI is the investigation of choice for diagnosing these signs [ 51 ].
Computed tomography of the affected site or arthroscopy of the joint may be necessary for establishing the diagnosis in patients who are unable to undergo MRI. There are no formal guidelines for the evaluation and management of bone disease in patients on ICS.