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Bone Health and Osteoporosis: A Report of the Surgeon General.
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As bone fracture is the final manifestation of bone loss, its risk should be estimated prior to the start of a specific therapy in a young IBD patient. An increase in the site-specific relative risk was estimated to be as high as 1.
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The risk for hip and spine fractures was 1. The risk of vertebral fracture was double RR 2. The risk of spine fracture was higher compared to risk of hip fracture in this latter study 1. To complicate judging the significance of bone loss in the diagnostic workup further, one should keep in mind that a direct relationship between bone loss and fracture is not so obvious in IBD patients compared to the general population.
The relationship between the risk of fracture and bone loss is comparable to the relationship between atherosclerosis and high cholesterol concentration in the general population, while risk of fracture was observed to be independent from bone mineral density BMD in some recent trials [ 19 , 20 ]. In this review we try to summarize the available literature on the therapy of IBD-related bone loss, while taking into consideration the aforementioned conflicting data on the epidemiological and diagnostic debates.
There are some factors which might predispose IBD patients for bone loss. Genetic influence, cytokine mediated pathogenesis of IBD, low body mass index, hypogonadism, malabsorption, extensive intestinal surgery and corticosteroid therapy are the most important ones. Some of them, like gender, age, and previous bowel resection [ 21 ] are not impressive.
Proved metabolic bone disease at diagnosis of IBD [ 22 ] is suspicious for factors like genetics, which are also unimpressive factors. There are some experimental data highlighting the common pathogenic pathways of IBD and the related bone loss [ 23 , 24 ]. Increased cytokine load of the bones might potentiate bone resorption [ 25 - 27 ].
Efficacious anti-inflammatory treatment of the basic disease may decrease the amount of this pathogenic factor, however this is not a bone-specific therapeutic approach. Different studies showed that systemic corticosteroid therapy is not the main cause of IBD-related bone loss [ 9 , 19 ]. Despite this observation, use of corticosteroids does influence the bone metabolism and increases fracture risk in IBD patients [ 28 ]. Taking the other well-known side-effects of steroid therapy into consideration, the elimination is essential for the prevention of bone loss.
Moreover, budesonide can cause bone loss as well [ 29 ]. Patients on long-term budesonide therapy are regarded to be steroid dependent [ 30 ], and this condition needs further therapeutic consideration - in any case. There are conflicting results in the literature on smoking as a risk factor for bone loss in IBD patients [ 26 , 31 ]. Due to its unfavorable effects on IBD itself, its cessation is mandatory, and might also lead to an improved bone metabolism in IBD patients.
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Bernstein et al [ 32 ] observed that changes in body mass correlate with changes in BMD. Based on these findings, it essential to optimize the nutritional status and preserve or augment muscle mass in IBD patients for the prevention of bone loss and fractures. Benefits of regular, low-impact exercise on bone mass have been proven in the early randomized controlled trial of Robinson et al [ 34 ], as well. Moreover, low intensity exercise is beneficial from a general health perspective in patients with inactive or mild CD [ 35 ].
Calcium Ca and Vitamin D are essential for healthy bone metabolism. Vitamin D exists mainly in two forms: Vitamin D3 is produced mainly in the skin from 7-dehydrocholesterol due to exposure to sunlight, but a small amount is obtained from the food, while vitamin D2 originates from plant sources. Vitamin D3 is transported to the liver, and hydrolyzed by the Vitamin D hydroxylase enzyme. It is a substrate of another enzyme 1a-hydroxylase located in the proximal tubule of the kidney, and Vitamin D3 is metabolized as 1,25a OH 2 Vitamin D3.
As Vitamin D3 can be produced endogenously, as long as the subject has access to adequate sunlight regularly, some authors state that it is not necessary to put this vitamin in the diet [ 36 ]. At the same time, extensive UV radiation exposure could have a role in the formation of skin cancer and melanoma, even in azathioprine treated IBD patients.
Optimizing the balance between sun exposure and dietary vitamin D needs are discussed [ 37 ]. It is concluded that taking into consideration the relatively high recommended serum Vitamin D level and its proven beneficial effects on skeletal health and other suspected beneficial effects regarding diabetes [ 38 ], reduction in mortality from cancers [ 39 ] and prevention of autoimmune diseases [ 40 ], it is favorable to increase the daily dietary intake of Vitamin D.
The absorption was related to the extent of resected small-bowel segment in one study [ 47 ]. Intestinal absorption of hydroxycholecalciferol was proved to be greater compared to absorption of cholecalciferol. Despite the well-described malabsorption of Vitamin D in IBD, the increase of its supplementation seems to be doubtful. Berstein et al [ 49 ] tested the benefits of Ca and Vitamin D supplementation mg plus IU in 17 corticosteroid-dependent IBD patients and compared its efficacy to placebo.
Supplementation therapy conferred no significant benefit to bone density at 1 year in those patients.
In our previous study, Ca and active vitamin D supplementation had beneficial effects by changing short-term bone turnover markers in CD patients [ 51 ]. Leslie et al [ 52 ] observed that correlation between serum vitamin D levels and BMD at the lumbar spine and hip, and gain in total body BMD between baseline and approximately 2 years later was positively correlated to serum levels of vitamin D. The authors concluded that early optimization of vitamin D may play an important role in preventing IBD-related bone disease.
All the therapeutic recommendations regarding vitamin D supplementation originate from our experiences in the general population. Cranney et al [ 54 ] performed a meta-analysis regarding the efficacy and safety of vitamin D treatment related to bone loss. They concluded that further high quality studies are needed to answer this question even in the average population.
This study observed some connection between 25 OH Vitamin D concentrations and beneficial bone health outcomes, but an optimal threshold for serum Vitamin D concentration was not defined. Moreover, as Vitamin D and Ca were supplemented in parallel in most of the studies, their effect is not separable. A Cochrane Collaboration meta-analysis did not observe beneficial effects of Vitamin D with regards to fracture incidence RR 1.
Vitamin D and Ca reduced the risk of hip fracture incidence RR 0. Finally, the guideline of the AGA [ 12 ], and the BSG [ 13 ] recommends to maintain normal Vitamin D serum levels, but there is no strict therapeutic guide in any of them. The recent ECCO guideline offers Vitamin D and Ca supplementation to all patients receiving corticosteroid therapy for more than 12 weeks [ 56 ].
Beyond the bones, Vitamin D seems to have some other beneficial effects apart from preserving bone density. It has immunregulatory effects, and its clinical benefits have been widely studied recently and discussed elsewhere [ 57 , 58 ]. Taking into considerations these additional effects, normal serum Vitamin D concentrations seems to be a desireable aim to achieve in every IBD patient.
Bisphosphonates are potent antiresorptive agents in postmenopausal osteoporosis and also have a fracture preventive effect in the general population. The efficacy of this drug type has also been proved in different subsets of IBD patients. In the previous era when long-term corticosteroid therapy was still an acceptable option for patients with IBD, its efficacy was studied widely in this patient population. DEXA control was performed 12 and 24 months later.
Triple therapy was proved to be superior compared to Vitamin D and Ca supplementation alone regarding femoral trochanter and total hip bone mineral density at month 12, moreover, this trend was more pronounced at month Efficacy of risedronate was observed to be more significant in non-smokers, those who had been on corticosteroid therapy in the previous year and current users of immunosuppressants.
A double-blind placebo controlled trial was designed to evaluate the efficacy of risedronate on bone mass in IBD in [ 61 ]. Patients received mg Ca with 5 mg of risedronate or placebo. Compared to the placebo group risedronate resulted in a 2. Risedronate therapy was regarded as an effective therapy to improve bone mass in these patients.
There was no difference between the placebo and risedronate treated group regarding the adverse events. Efficacy of intravenous ibandronate was investigated in IBD-related bone loss also. DEXA measurements were performed at the start of the study and 2. Lumbar T-score increased in both therapeutic groups. The authors concluded that as bisphosphonates are the standard for care in osteoporosis, and this agent decreases fracture risk, data we do not have for sodium-fluoride; CD patients with osteoporosis can be treated safely with intravenous ibandronate.
However, the same authors published another paper in the same year [ 63 ] showing that additional sodium fluoride or ibandronate had no benefit over Ca and cholecalciferol alone in managing reduced BMD in CD. Control DEXA was performed 1. During this period of time no treatment regimen was superior in any group or between-group analyses. None of the therapeutic regimens caused any remarkable side effects.
The same German group conducted a study with use of zoledronate in patients starting corticosteroid therapy [ 64 ]. Patients received 60 mg prednisolone per day as an induction therapy due to relapse of their disease and were randomized to receive 4 mg intravenous zoledronate or placebo. The BMD change under placebo and zoledronate The authors offer to start this bisphosphonate therapy at the time of the steroid induction, but there is no suggestion regarding the offered duration.
Myeloma bone disease: Pathophysiology and management
Further comparison should be performed regarding the actually recommended Vitamin D and Ca supplementation regime versus zoledronate to clarify this issue. The benefit of aledronate therapy was also investigated in steroid dependant CD patients in a small Japanese study [ 65 ]. Aledronate improved the BMD with 2. Thirty-two patients were randomized to receive 10 mg aledronate daily or placebo for 12 months in a Danish study [ 66 ].
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Most of the patients had osteopenia, and the minority of them had osteoporosis. Mean BMD of the lumbar spine showed an increase of 4. BMD of the hip increased by 3. Guidelines of the AGA and BSG could not take these novel results into consideration, and also experience with bisphosphonates was limited at the time of their introduction. As male hypogonadism and female postmenopausal state have major roles in the pathogenesis of bone loss, HRT is a reliable therapeutic approach both to prevent and treat osteopenia.
Malnutrition and chronic illness can cause menstrual dysfunction in women. Corticosteroid use has an impact on the normal gonadal function and showed to be associated with low testosterone production. Clements et al [ 70 ] conducted a two-year prospective study with postmenopausal women suffering from CD or UC. As all patients were postmenopausal women, this early study just proves the safety of HRT.
Due to the results of the Women's Health Initiative showing that risks from the HRT more cardiovascular, thrombotic and breast cancer events outweigh the benefits decrease risk of colorectal cancer and hip fractures the overall gain of this therapeutic approach is questionable. Khalili et al [ 71 ] conducted a prospective cohort study in , postmenopausal women without a prior history of IBD. Compared with women who never used hormones, the multivariate-adjusted HR for UC was 1.
The risk of UC increased with longer duration of hormone use and decreased with time since discontinuation. The effect was independent of the type of the hormones estrogen alone or combined with progestin. Data of sixty-five postmenopausal women receiving HRT were analyzed in this retrospective study. However, risks of different types of HRT should be considered regarding prevention of bone loss.
The use of estrogen therapy without progesterone progestin may be associated with an increased risk of endometrial cancer. Combined therapies specifically oral conjugated equine estrogen plus medroxyprogesterne acetate can increase the risk of stroke, invasive breast cancer, dementia, gallbladder disease, deep vein thrombosis and pulmonary embolism [ 73 ].
There is a lack of data in the literature regarding the influence of testosterone replacement in male IBD patients. No independent effect of testosterone deficiency was observed on bone parameters. Authors concluded that estrogen deficiency might have a role in the pathogenesis of bone loss in male IBD patients, analogous to postmenopausal female subjects.
There is no current guideline regarding the hormone replacement in IBD patients, however the proper hormone substitution is essential in boys with IBD and delayed growth and puberty, and testosterone substitution is associated with an advance in pubertal status and an improvement in growth [ 76 ]. This strategy can also potentiate normal bone formation. There is no data regarding effects of selective estrogen receptor modulators in IBD patients.
In contrast to other agents used to treat bone loss, sodium fluoride ameliorates bone formation instead of decreasing bone resorption. Its efficacy was compared to Ca and Vitamin D therapy [ 50 ], and to parameters of bone density. Sodium fluoride was not protective against vertebral fractures and increased the number of non-vertebral fractures in postmenopausal women [ 77 ], so its use is not recommended [ 78 ]. Low parathormone levels were described in IBD patients in different studies [ 79 - 81 ]. Similarly to sodium fluoride, parathormone is a bone anabolic therapeutic agent. Parathyroid treatment was compared to HRT in corticosteroid-induced bone loss by Lane et al in a one-year long randomized controlled trial conducted in postmenopausal women [ 82 ].
Parathyroid therapy enhanced the BMD by 9. The benefit of HRT was negligible in this setting. Although parathyroid therapy is an accepted part of the armamentarium against bone loss in the general osteoporotic population, there is no clinical data regarding its efficacy in IBD-related bone loss. Calcitonin inhibits the functions of the bone resorting osteoclasts. Its efficacy was evaluated for preventing corticosteroid induced bone loss in patients with polymyalgia rheumatica [ 83 ] and asthma [ 59 ]. It was approved to treat, but not to prevent osteoporosis until March of , when the FDA advised calcitonin not to be used in osteoporosis, except Paget's disease and for acute bone loss due to sudden immobilization; and also for excess Ca in the blood caused by cancer.
Osteoprotegerin is a member of the tumor necrosis factor a superfamily. It is produced by the osteoblasts, and plays a role in the regulation of osteoclast functions.
Myeloma bone disease: Pathophysiology and management
Its concentration is secondarily elevated in IBD [ 24 ]. Its therapeutic applicability is widely studied in recent years, but there is no data regarding osteoprotegerin treatment in IBD. Treatment for osteoporosis is prescribed for a minimum of 5 years in the general population. After initiating a therapy for proven osteoporosis or because of the existence of a higher risk for fracture, changes of bone density should be controlled with DEXA measurement one year later.
DEXA should be performed every one or two years as further follow up. There are some biochemical parameters which can be measured before and few months after the initiation of the therapy. Osteocalcin is the most widely used marker for bone formation, and C-terminal crosslinking telopeptide of the type 1 collagen is the most important marker of bone resorption.
However these markers are costly, not widely achievable and require justification of the key outcome of fracture reduction. Use of this kind of laboratory marker is not recommended in daily practice. Detailed information on the use of these markers is discussed elsewhere [ 84 ]. Controlling the serum and urine Ca concentrations is more important in IBD patients.
As this population of patients has an increased tendency for formation of kidney stones and nephrocalcinosis, it is important to keep the serum and urinary Ca concentration within a normal range. Serum and urinary Ca levels should be measured every months. IBD is frequently complicated with bone loss. Inflammatory processes, malnutrition, Vitamin D deficiency and drugs can play a role in the enhanced bone loss, and general risk factors like age, postmenopausal state, body mass index have to be taken into consideration, as well.
The actual guidelines regarding IBD-associated bone loss are nearly 10 years old. New results with the old drugshave been published, and some new therapeutic modalities have been marketed in the last decade. However, most of them are approved exclusively to treat postmenopausal bone loss. We aimed to review the recent literature on the novel therapeutic possibilities regarding IBD-related bone loss. First, we have to perceive that diagnostic recommendations are not clear regarding IBD-associated bone loss. As most patients are under the age of peak bone mass at diagnosis, it is reasonable to use the age- and gender-matched Z-score for the diagnosis, instead of the WHO-advised T-score.
Most of the authors still use the T-score, because all of the recommendations are based on the WHO definitions. Moreover, the fracture, as an endpoint of the bone loss has a different relationship to the BMD in IBD compared to the general osteoporotic population. Bone fractures occur without clinical signs more frequently in IBD compared to other populations, and fractures occur in patients with normal BMD more frequently. We need a much more accurate risk assessment system to predict fractures for proper therapy in this young population with a life-long chronic inflammatory disease.
What we can do without causing any harm is to prevent bone loss. Steroid sparing, Ca and Vitamin D supplementation, appropriate sun exposure and mild exercise could be advised to the patients.