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Keywords:

  • CCFA Guidelines

Abstract

  1. Top of page
  2. Abstract
  3. OSTEOPOROSIS IN IBD
  4. BMD MEASUREMENTS AND TOOLS
  5. PREVENTION AND TREATMENT OF OSTEOPENIA AND OSTEOPOROSIS
  6. PHARMACOLOGICAL THERAPIES
  7. CONCLUSIONS
  8. References

The following are guidelines for evaluation and consideration for treatment of patients with inflammatory bone disease (IBD) after bone mineral density (BMD) measurements. The Crohn's & Colitis Foundation of America (CCFA) has indicated that its recommendations are intended to serve as reference points for clinical decision-making, not as rigid standards, limits, or rules. They should not be interpreted as quality standards.

Bone disease, most commonly reported as osteoporosis and less frequently as osteomalacia (vitamin D deficiency) or hyperparathyroidism, is an extraintestinal complication of inflammatory bowel disease (IBD).1 Osteoporosis is defined by the World Health Organization (WHO) as “a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone, with a consequent increase in bone fragility and susceptibility to fracture.2,3 The literal translation of the term osteoporosis means “porous bone.”

The skeleton is under reconstruction continuously, and it is this process that determines the strength of the bones and their durability.4 Indeed, as long as the bone-forming cell, the osteoblast, sustains its ability to produce adequate amounts of new bone, there is no loss of bone mass over time. However, if the number and activity of the bone-resorbing cells, the osteoclasts, increase beyond the capacity of the osteoblast to fully respond to the new demands, as in menopause, a chronic deficit will develop, leading to bone mass reduction and eventually permanent destruction of its architecture. Furthermore, this same capacity of the osteoblast is reduced by aging. Therefore, osteoporosis often is thought of as an older person's disease. However, it can strike at any age.5 One out of 2 women and 1 in 8 men over age 50 will have an osteoporosis-related fracture in their lifetime. It has been estimated that in the United States, the remaining lifetime fracture risk at the age of 50 is 40% for white women and 13% for white men, the major fracture sites being spine, forearm, and hip.6

Fractures result in significant costs, including acute hospital care and long-term care in the home or nursing facility. Indeed, osteoporosis represents a major public health problem,7 accounting for >1.5 million bone fractures in the United States each year, including 700,000 vertebral fractures, 300,000 hip fractures, 250,000 wrist fractures, and 300,000 fractures at other sites.8 The national direct expenditures (hospitals and nursing facilities) for osteoporosis-associated hip fractures were estimated at $18 billion in 2002, and the cost is rising.8 Furthermore, an average of 24% of hip fracture patients 50 years of age and older die within the year following their fracture.

OSTEOPOROSIS IN IBD

  1. Top of page
  2. Abstract
  3. OSTEOPOROSIS IN IBD
  4. BMD MEASUREMENTS AND TOOLS
  5. PREVENTION AND TREATMENT OF OSTEOPENIA AND OSTEOPOROSIS
  6. PHARMACOLOGICAL THERAPIES
  7. CONCLUSIONS
  8. References

Prevalence

Several reports on the bone mineral density (BMD) of adults with IBD have been published. In the vast majority, the investigators used dual-energy x-ray absorptiometry (DXA), the current gold standard for evaluating BMD, but the number of patients included in each study was rather small. Both controlled9-19 and uncontrolled1,20–31 cross-sectional studies in IBD or in patients with Crohn's disease (CD) only32–41 produced a wide variation in prevalence rates. The prevalence of significantly low BMD, defined by a T score of less than −2.5 or a z score of less than −2.0, has been reported to be as high as 59%.42 However, the overall prevalence of osteoporosis is estimated at ≈15% and is strongly affected by age. Therefore, the effects of IBD on BMD are considered modest. In newly diagnosed IBD patients, the prevalence of reduced BMD is low,17,19,22,29 and longitudinal BMD changes are not excessive.15,22,25,32,35,43–46

BMD is affected to the same extent in both male and female IBD patients, and between them, females exhibit slightly higher T and z scores.1,4,13-15,18,20,22,24-27,29,32,42 There is no consistent pattern of low BMD found exclusively in the spine or in the hip. However, a number of studies reported that the hip could be affected more frequently than the spine.9,14,16,26,28,32,34,36 Generally, in some studies, both osteopenia and osteoporosis (as determined by the T score) have been observed with similar frequencies in CD and ulcerative colitis (UC); 9,16,17,25,26,28,43 other studies suggested that BMD may be lower in CD.10,13,15,22,24 Disease duration has not been established as a significant risk factor for low BMD because some of the studies reported no effects,9,14,15,18,32,35,46,47 other indicated a positive relationship between longer disease duration and lower BMD,13,16,17,27,28,42 and 1 study showed a markedly shorter duration in female patients with sacroiliac involvement.41 In addition, disease activity had no effect on BMD according to findings from some studies,16,22,33 but a study in 137 patients (64 with UC, 73 with CD) reported that age-matched (Z score) BMD was higher with increasing duration of disease remission.48 Furthermore, in 47% of 34 patients with a history of active IBD, biochemical bone markers suggested increased bone degradation.27 Disease site may contribute to low BMD because there is a report of lower BMD in CD patients with jejunal disease,33 although other studies failed to show such effects.9,10,14,15,22,36,43 Previous small bowel surgery, even after taking into account the length of the resection, is not considered a significant risk factor, according to most of the published studies.9,10,14,16,21,23,26,32 However, 2 studies assessing patients who underwent ileal resection,42,49 a cross-sectional analysis of 117 patients with CD and partial small bowel resection,33 and 2 more studies1,49 suggested otherwise. Actually, van Hogezand et al49 reported that ileum resection is the most predictive factor for osteoporosis in patients with CD. Interestingly, colectomy has been reported to stabilize or improve BMD.21,25,51,52 Young age of onset of IBD initially had been reported to be associated with lower BMD,34 but a subsequent study failed to confirm this claim.30

Fracture Risk

Hip fractures are documented more reliably than spinal fractures, the vast majority of which are not clinically evident. In small case series, the reported incidence of new fractures varies considerably, from no difference up to 27% greater in IBD patients compared with the general population.1,10,23,34,46 However, findings of 3 North American population-based studies,53–55 coupled with 2 Danish studies with a respectable number of patients, failed to establish that the risk of fracture in IBD patients is increased.56,57

In more detail, the largest study was conducted in the Canadian province of Manitoba, where comprehensive healthcare coverage is provided for all residents.53 Analysis of data from 6027 IBD patients and an age-, gender-, and geographic residence-matched control group of 60,270 individuals showed a small increased risk of fractures (relative risk [RR] 1.41; and 95% CI 1.27–1.56). These results were confirmed by 2 population-based studies that are smaller (243 CD patients, 273 UC patients)54,55 but involve a relatively homogeneous population from the Olmsted County (Minn) database. In addition, these North American population-based studies confirmed once again that age is an independent risk factor for fractures.

In a nationwide follow-up study of 16,416 patients in Denmark that included patients with CD, UC, and celiac disease,56 CD was associated with a minor increase in overall fracture risk compared with UC and the general population. The second Danish study was based on a survey mailed to members of the Danish Crohn's/Colitis Association.57 The overall fracture rate in UC was similar to that of control subjects, but the RR for CD patients was increased at 1.7 (95% CI 1.7–2.3), with female patients at slightly higher risk (RR 2.5). Vertebral fractures were more common in CD patients (RR 6.7; 95% CI 2.1–21.7), and a similar trend was identified in UC patients (RR 2.4; 95% CI 0.5–11.9). Furthermore, the risk of femur fractures was similar to that of the control subjects. However, these findings should be interpreted with caution because poor matching of control subjects and failure to take corticosteroid use into account may have biased the results.

In the most recently published population-based cohort study,58 subjects within the General Practice Research Database in the United Kingdom with a diagnosis of IBD were matched with up to 5 control subjects for each patient. Seventy-two hip fractures were recorded in 16,550 IBD cases and 223 in 82,917 control subjects, with the rate of hip fracture being increased ≈60% in IBD patients. The risk was 1.5-fold higher in CD compared with UC patients. After the IBD cases were subdivided by disease and after correction for confounding (age, sex, corticosteroid use [both current and cumulative], and opioid use), the hazard ratio remained greater for CD at 1.68 (95% CI 1.01–2.78) than for UC (1.41; 95% CI 0.94–2.11). Therefore, the authors concluded that most hip fracture risk in IBD (>50% in CD and >80% in UC) patients cannot be attributed to steroid use.

Using data from the same database, another group of investigators published a case-control study.59 A total of 2130 IBD patients were among 231,778 case patients with a history of fracture plus an equal number of age- and sex-matched control subjects without recorded fractures. A total of 1134 of the patients with a history of fracture had a diagnosis of IBD compared with 896 IBD patients of the control group (no history of fracture). Furthermore, the risk of hip fracture was increased by 86% in patients with CD and by 40% in patients with UC. The adjusted odds ratio (OR) for fractures at all sites was estimated at 1.21 (95% CI 1.10–1.32). This increased risk was attributed to a combination of disease activity and use of oral corticosteroids.

In summary, the current understanding is that the overall risk of fracture may be slightly increased in IBD patients. Furthermore, risks for fracture are comparable among patients with CD and UC and among male and female IBD patients.

Risk Factors

In general, bone mass in adults >30 years old reflects the bone mass accumulated during growth minus any bone mass lost since the adult peak was attained. In the general and the IBD populations, the risk factors for developing low bone mass, characterized either as osteoporosis or osteopenia, for both men and women can be separated into 2 groups: those that are measurable and those that are modifiable. Measurable risk factors include BMD, serological markers and urinary markers of bone formation and resorption, age, and genotype. Modifiable factors include glucocorticoid therapy, treatment with drugs that could affect bone metabolism, sex hormone and vitamin D status, exercise status, nutritional status, including dietary calcium intake, weight, smoking status, and risks for trauma/fall. The following details the disease states and conditions associated with low bone mineral mass:

  1. Hormone excess:

  2. Parathyroid hormone excess

  3. Primary and secondary thyroxin excess, endogenous and exogenous

  4. Cortisol excess, endogenous and exogenous

  5. Hormone deficiency:

  6. Estrogen deficiency (premenopausal state may be linked with anorexia, bulimia, athletic amenorrhea, premature menopause, prolactinoma, or hypopituitarism)

  7. Estrogen deficiency, postmenopausal

  8. Testosterone deficiency, primary and secondary testicular failure

  9. Vitamin D metabolite deficiency, inadequate intake, or malabsorption

  10. Miscellaneous (not necessarily mediated by hormonal abnormalities):

  11. Medical conditions, including postgastrectomy states, idiopathic hypercalciurie, systemic mastocytosis, and prolonged immobilization (paraplegia and quadriplegia)

  12. Lifestyle factors, including cigarette smoking, excessive ingestion of caffeine, and excessive sodium intake (promotes hypercalciuria)

  13. Medications:

  14. Heparin

  15. Warfarin

  16. Cyclosporin A

  17. Methotrexate

  18. Tacrolimus

Most of these conditions/states associated with low bone mass are not influenced by changes in diet or lifestyle. Each of the circumstances listed could have an impact on the skeleton at any time in life. The effect is aggravated if it occurs in conjunction with low estrogen levels after menopause. Furthermore, as with low BMD, risk factors for fracture may be considered modifiable or nonmodifiable, as follows:

  1. Modifiable risk factors:

  2. Current tobacco smoking

  3. Below-normal body weight (especially those with low body weight <127 lb)

  4. Deficiency of estrogen

  5. Menopause before age 45

  6. Bilateral ovariectomy

  7. Premenopausal amenorrhea for >1 year

  8. Lifelong low intake of calcium

  9. Excessive consumption of ethanol

  10. Visual impairment despite adequate correction (may increase risk of falling)

  11. Repeated falls

  12. Inadequate physical activity

  13. Frailty or poor overall physical condition

  14. Nonmodifiable risk factors:

  15. History of fracture as an adult

  16. Family history of fractures, especially among first-degree relatives

  17. White

  18. Female sex

  19. Dementia

  20. Elderly

  21. Frailty or poor overall physical condition

A strong genetic component is apparent in peak bone mass.60–62 In addition, diet (calcium and protein intake) and exercise contribute to maximum bone mass. Children and adolescents with disease states or conditions that interfere with growth (including sexual maturation), nutrition, and exercise typically have suboptimal bone mass. In women, BMD is stable from the mid 20s to the earlier stages of climacteric and then declines, initially sharply, as estrogen production falls. In men, there is a steady slow decline probably after age 50. Although the priming and mechanism of bone loss are not as extensively studied in men as in women, it is known that estrogen also plays an important role in bone regulation and maturation in males.63

Different risk for bone loss has been reported in people of different ethnic backgrounds. White women have been identified as the racial group with the highest risk. Black women have higher BMD than white non-Hispanic women throughout life and experience lower hip fracture rates. Japanese women have lower peak BMD than white non-Hispanic women but have a lower hip fracture rate, the reasons for which are not fully understood. Mexican American women have bone densities intermediate between those of white non-Hispanic women and black women. Limited available information on Native American women suggests that they have lower BMD than white non-Hispanic women.3

Low bone mass is the most important measurable predictor of fragility fractures. In animal models, ≈80% of the variance in bone strength and resistance to fracture could be explained by bone mineral content per cubic centimeter. However, population-attributable risk for osteoporosis and fracture among older women is modest, ranging from ≈15% for all types of fractures to <10% to 44% for specific types of fractures.64

A meta-analysis of large, well-designed prospective studies confirmed the relationship between BMD and fracture risk in which a decrease in BMD is associated with an increased risk of fracture65 Site-specific BMD measurements could more accurately predict fracture risk because the proportion of trabecular versus cortical bone varies in the different parts of the skeleton. Therefore, it is not surprising that the correlation between femoral neck and lumbar spine BMD ranges between 0.5 and 0.7. It is now known that postmenopausal women in the lowest quartile of bone mass at the femoral neck have the highest incidence of hip fractures. Furthermore, the higher bone mass is related to a lower risk of fracture. These effects were less obvious at sites other than the hip. The same data have historically been extrapolated to the setting of IBD because only limited information is available in patients with CD or UC.

The overall risk of osteoporosis-related fractures in IBD, as in otherwise healthy postmenopausal women, is not entirely reflected by BMD measurements alone. Patients with IBD and normal BMD still may be at increased risk for fractures on the basis of other risk factors.

BMD is determined by genetic and environmental factors. Genetic factors are known to play a role in the pathogenesis of osteoporosis.60 Epidemiological and twin studies suggest that heritable factors account for 65% to 92% of the variability in BMD. Several candidate genes thought to play a role in determining BMD include tumor necrosis factor (TNF) receptor, the interleukin (IL)-1 receptor antagonist gene, and more recently the IL-6 gene.66 It is well established that IL-1 and IL-6 have a central role in the paracrine stimulation of osteoclast development and regulation and the process of bone resorption.67 Enhanced expression of these cytokines in immune-mediated diseases such as IBD may be important. A recent study identified the lack of a 240-bp allele of the IL-1 receptor antagonist gene and the presence of a 130-bp allele of IL-6 as independent variables associated with bone loss in IBD patients.66 However, there is no consistent association between all of these reported polymorphisms and phenotypes of bone mass across studies. The most convincing finding so far is the identification in normal healthy individuals of a gain of function mutation in the LDL receptor-related protein 5 (LRP5) gene that results in the autosomal dominant high-bone-mass trait68 and a loss-of-function mutation that maps to the same genomic region that contains LRP5 and causes the osteoporosis pseudoglioma syndrome.69 Therefore, Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Inflammation has now moved to the center of the pathophysiological mechanisms involved in the process of bone loss in IBD. Transmural inflammation limited to the large intestine of an experimental model of IBD caused rapid and substantial (33% compared with age-matched, pair-fed control animals) cancellous bone loss by reducing the formation rate to <30% of that in control animals. Furthermore, the bone volume returned to control levels after the colitis healed.70 In a bone organ culture system, serum from children with active UC reduced the noncollagen protein synthesis.71 In the same system, serum from untreated children with CD caused disorganization of mineral and osteoid and morphologically abnormal osteoblasts; it also decreased bone dry weight and calcium content.72

Cytokine profiles specific to IBD have been well identified. In CD, the principal cytokines released by the inflammatory cells of the intestine are TNF-α, interferon-γ (IFN-γ), and IL-6.73 These cytokines, particularly TNF-α and IL-6, stimulate osteoclast activity, leading to increased bone resorption and resulting in net bone loss. Recent studies reported improvement of bone turnover markers74,75 and BMD76,77 in CD patients treated with infliximab, an anti-TNF-α antibody. In contrast, the predominant cytokines in UC include IL-4 and IL-10. These are not known to be significantly involved in bone remodeling. In the colon, however, there is an obligatory loss of calcium into the lumen, which is why “net calcium balance” is used in relation to the intestine: balance = absorption − colonic loss.78 This loss could be exaggerated in the inflamed colon and prevented in cases of colectomy. This could explain the positive effects of ileoanal anastomosis on BMD.51

Accumulating evidence suggests that TNF and TNF receptor-related superfamily proteins mediate basic immunological and bone remodeling functions by directly participating in signaling pathways for cell proliferation, differentiation, and survival.79,80 Some of the receptors and ligands of this superfamily are upregulated in IBD.81–83 Activated T cells produce receptor activator of nuclear factor-kB ligand (RANKL), which, through RANK, its receptor, plays an integral role in osteoclast differentiation and activation.84 Osteoprotegerin (OPG), a soluble RANKL decoy receptor, counteracts these effects.85 Indeed, treatment with recombinant human OPG prevented or reversed bone loss in a mouse IBD model.86

Glucocorticoid use, a known cause of bone loss, remains commonplace in the treatment of IBD, but the true incidence of osteoporosis in corticosteroid-treated IBD patients is unknown. It is estimated that one fourth to one half of patients on long-term glucocorticoids will experience bone fractures.87 Glucocorticoids are known mainly to reduce bone formation and, to a lesser extent, enhance bone resorption by means of several mechanisms.88,89 They may inhibit osteoblast maturation and osteoblast bone-forming ability. They may decrease gonadotropin-releasing hormone, leading to decreased estrogen and androgen concentrations. Glucocorticoids also are known to suppress circulating estrogen, thus reducing its role in inhibiting IL-6, a stimulator of osteoclast activity. In men, glucocorticoids have been reported to suppress serum testosterone concentrations, leading to a similar effect on bone. Glucocorticoids also could inhibit intestinal absorption of calcium and increase urinary calcium losses. Together, these effects may lead to negative calcium balance and secondary hyperparathyroidism.

When corticosteroids are used, trabecular bone loss occurs early in the course of therapy; however, both trabecular loss and cortical loss occur over time. The rate of bone loss is greatest during the first 6 months of therapy, and bone loss could be identifiable by 6 months by a DXA scan; up to 15% of bone mass could be lost within the first year of therapy. Furthermore, the increase in fracture risk after oral corticosteroid therapy is begun could be rapid, with significant increases in risk of nonvertebral fractures becoming apparent within the first 3 months.90 During the second year of treatment, bone loss continues, but at a slower rate. Recovery after discontinuation of corticosteroids may occur, although it seems to be related to the dose of corticosteroid used and the duration of treatment.88,89

Cumulative glucocorticoid dose has been demonstrated to be inversely associated with BMD based on data from a number of studies,1,9,10,15,16,18,21,23,24,27,33,35,36,43,45 whereas only a few studies have reported no effect on BMD.22,26,28,32 Significant bone loss has been thought to occur when the daily dose of prednisolone exceeds 7.5 mg. When normal individuals are given a high dose of prednisolone (40 mg/d) for 1 week, significant increases in urinary hydroxyproline and calcium excretion could occur, suggesting an increase in bone resorption.91 Furthermore, daily administration of relatively low-dose glucocorticoid (10 mg prednisone) could have significant negative skeletal effects. Indeed, after 7 months of treatment, iliac crest bone biopsies performed in 10 healthy volunteers (5 male, 5 female) demonstrated a 34.3% reduction in trabecular bone volume from baseline values.92 In a recent large retrospective study involving 244,235 oral corticosteroid users and 244,235 control patients, an assessment of fracture risk for dose of corticosteroid use was attempted.93 There was an increased risk of fractures during oral corticosteroid treatment, with greater effects on the vertebral body (RR 2.60) and hip (RR 1.61) than on the forearm (RR 1.09). A dose dependence of fracture risk was observed. With a daily dose of prednisolone <2.5 mg, the RR for hip fracture was 0.99, with an RR of 1.77 at 2.5 to 7.5 mg, and of 2.27 for doses >7.5 mg daily. For the vertebral fractures, the RR was 1.55 for <2.5 mg/d, 2.59 for 2.5 to 7.5 mg/d, and 5.18 for >7.5 mg/d prednisolone. The fracture risks decreased toward baseline once corticosteroids were stopped.93 In addition, the relationship between use of corticosteroids and fracture risk was estimated in a meta-analysis of data from 7 cohort studies of ≈42,000 men and women. The authors concluded that prior and current exposure to corticosteroids confers an increased risk of fracture that is of substantial importance beyond that explained by the measurement of BMD.94 Finally, a case-control (3 controls for each case), large, community-based study in Denmark assessed all subjects with any fracture sustained during the year 2000 (n = 124,655) and concluded that >2.5 mg/d oral prednisolone (or equivalent) is associated with an increase in fracture risk.95

Vitamin D deficiency has been estimated to occur in 30% to 60% of patients with CD.27,31,40,50,96–99 Factors associated with the development of such deficiency include decreased dairy product intake (supplemented with vitamin D), malabsorption of vitamin D as a result of small bowel disease or short gut syndrome, and bacterial overgrowth, or use of cholestyramine with subsequent steatorrhea. A small cross-sectional study (152 unselected IBD patients, 73 healthy controls) concluded that in IBD patients the calcium intake is not associated with BMD.

BMD MEASUREMENTS AND TOOLS

  1. Top of page
  2. Abstract
  3. OSTEOPOROSIS IN IBD
  4. BMD MEASUREMENTS AND TOOLS
  5. PREVENTION AND TREATMENT OF OSTEOPENIA AND OSTEOPOROSIS
  6. PHARMACOLOGICAL THERAPIES
  7. CONCLUSIONS
  8. References

Background

Bone measurement techniques now available depend on the ability of bone to block the transmission of energy. The types of energy used to evaluate bone density include x-rays and sound (emitted from an ultrasound transducer). Currently available methods to measure BMD include single-energy x-ray absorptiometry or DXA, quantitative computed tomography (QCT), radiographic absorptiometry, and ultrasound. An ideal test of BMD should be rapidly performed, inexpensive, reproducible, highly accurate, painless, and safe (with little or no ionizing radiation). DXA is the establish method of BMD measurements. Routinely, BMD is measured in the hip and the lumbar spine.

The WHO proposed the use of the T score, defined as the number of standard deviations (SD) by which a given BMD measurement exceeds or falls below the normal mean BMD of healthy 30-year-old individuals (peak bone mass), as the strongest determinant of fracture risk. If the BMD is up to 1 SD below the peak bone mass, the subject is considered to have normal bone. If the BMD is 1 to 2.49 SD below peak BMD at either the hip or spine, the subject is considered to be osteopenic and to have mild to moderate bone deficiency. BMD values ≥2.5 SD below the peak BMD are labeled osteoporotic, and these individuals have marked bone deficiency. Finally, those individuals who have a fracture as a result of bone fragility are considered to have severe osteoporosis.

Measurements of bone density by DXA scan also can be reported as a z score. The z score is the number of SDs by which a given BMD measurement exceeds or falls below the mean BMD of healthy individuals of the same age group. z scores, not T scores, are preferred, and the WHO classification should not be applied in women before menopause and in men younger than age 50 according to the official position of the International Society for Clinical Densitometry (ISCD).100 According to the same recommendations, a z score of less than or equal to −2.0 is defined as “below the expected range for age,” and a z score higher than −2.0 is “within the expected range for age.” In serial BMD testing, neither T scores nor z scores should be compared. Instead, only BMD (in g/cm2) should be used.100

It has previously been established that most bone strength (up to 80%) is determined by the amount of bone present,101 and it is generally accepted that BMD is the single best available predictor of in vitro skeletal strength and fracture risk. Furthermore, BMD measurement at a given site best predicts the fracture rate at that site. For example, measuring BMD in the proximal femur is the best site for predicting hip fracture risk. Therefore, the T score from different anatomical sites may not be used interchangeably.102 Total body measurements also can be performed.103,104 DXA is now considered to be the clinical gold standard for bone mineral measurement. However, none of the absorptiometric techniques measures true bone density, partly because of the 2-dimensional configuration of the devices.105

The WHO developed the definition of osteopenia and osteoporosis to facilitate demographic and epidemiological studies. These definitions were not intended to serve as thresholds for therapeutic intervention because diagnostic thresholds are not equivalent to intervention thresholds since the range of risk varies so markedly at any given BMD. Accordingly, the relationship between fracture risk and BMD is best described as a gradient rather than threshold.

DXA Scan

The measurement of bone density by DXA has become the standard of practice as a consequence of several important facts. It serves as a valid predictor of fracture risk; it is reproducible with small variability; and it is a rapid test (usually requiring <5 min). Additional attractive features include exposure to very low doses of radiation (about one sixth that of a chest radiograph) and its relatively low cost (≈$150).

The accuracy of DXA scan assessment of BMD as determined by comparison with dry weight of bone samples is quite good. There is an error of measurement ranging from 5% to 6%.106 This represents a small number relative to the range of values in the general population, thus establishing this as a good technique to assist in the diagnosis of osteoporosis and to assess fracture risk. BMD may be overestimated when bone density is measured in the anteroposterior position compared with the lateral measurement position. This may be caused, especially in individuals older than 60, by the presence of various factors such as osteophytes, degenerative sclerosis, calcification of the abdominal aorta, or other findings that become superimposed. It would thus seem logical to perform lateral spine DXA measurements; however, there are limitations resulting from other factors. The lateral spine DXA management is less prone to these artifacts but can potentially be complicated by the presence of overlying ribs or an overlying iliac crest, thus minimizing the number of available vertebrae for assessment. The current official position of the ISCD100 is that lateral spine should not be used for diagnosis, although it could be useful in monitoring the effectiveness of treatment. The DXA scan measurements over the hip are less prone to be affected by degenerative changes, but the presence of buttressing (defined as thickening of the medial cortex of the neck of the femur) could change the readings, and the hip is more susceptible to patient positioning and degree of hip rotation. The hip also has been recommended to be the preferred site for measuring in the presence of vertebral fractures. If an individual has had a fracture or bony damage on their nondominant hip, then the contralateral hip should be used for DXA scanning. The mean hip BMD can be used for monitoring, with total hip being preferred.100

DXA measurements should be interpreted with caution because a DXA scan cannot differentiate low BMD labeled as osteopenia or osteoporosis from osteomalacia or other metabolic bone diseases. Thus, if a patient is found to have low BMD, it is important to rule out other bone pathologies because osteoporosis is a diagnosis by exclusion.

The ability to reassess BMD over time is a benefit of the reproducibility of the DXA scan. Unfortunately, the variability of DXA scans is similar to the average annual change in bone density; hence, it may be hard to assess whether a small change in bone mass is due to precision error or to a true change in BMD. Reproducibility of the DXA scan is influenced by the instrument being used, the ability of the operator to perform the test, and factors related to the patient (e.g., positioning, previous disease such as Paget's disease). Hip measurements usually are less reproducible than measurements of the spine (mostly because of difficulty in obtaining consistent positioning). The minimal change that can be present before the conclusion that the change is not due to measurement error can be reached is 2.77 times the SD; in other words, a change of at least 3% to 5% is required at the lumbar spine and 4% to 6% is mandated at the total hip before it can be stated that a real change has occurred within a 95% CI.107,108 BMD measurements have been used to assess the risk of fracture. For example, in postmenopausal women, a decrease in BMD of 1 SD yields a 2-fold increase in fracture risk.109

Portable DXA devices also are used.110 They are convenient screening tools because of their small size and low cost. Most of the limitations are common to ultrasound devices and include relatively poor correlation with spine and hip BMD, lack of prospective data that BMD from a peripheral device can predict antifracture efficacy or monitor response to therapy, and probably most important of all, lack of information about how best to interpret the readings. Patel et al111 recently concluded that the use of forearm BMD alone with a modified T score threshold of −2.1 (instead of −2.5) would save the need for spine and hip DXA scans and identify only slightly fewer fracture cases for treatment.

Conventional Radiography

Conventional radiographs are insensitive measures of osteoporosis and osteopenia. The presence of osteoporosis can be reliably identified only after there is a 30% to 50% decrease in bone mass.112 Identifying osteoporosis at this late stage may preclude effective intervention. In addition, overpenetrated films can suggest the appearance of osteoporosis in a person with a normal BMD.

Radiographic absorptiometry compares the density of the proximal phalanges to that of wedge aluminum with known densities placed alongside the hand.113 Studies on its ability to predict fractures are limited.

Ultrasound

Quantitative ultrasound (QUS) is another device that measures BMD of the calcaneus or other sites such as phalanges, tibia, or patella. QUS measurements include speed of sound (SOS), broad-beam ultrasound attenuation (BUA), velocity, and stiffness. Initial expectations that QUS could provide information about bone structure have not been met.114 In the general patient population, QUS predicts the risk of fractures, and it could be used in cases when a DXA densitometer is not accessible because it has not been established that QUS can replace DXA measurements of BMD or improve information already provided by a DXA scan. Furthermore, the use of QUS is not recommended in monitoring progress of disease or treatment.

To date, a small number of studies have been performed comparing calcaneal QUS to a DXA scan in IBD patients. In a small study evaluating 22 patients with CD and 11 patients with UC using DXA scan, r = 0.67 compared with BUA and r = 0.61 compared with SOS.115 Another study with 110 patients suggested that there was a poor correlation between DXA and calcaneal QUS.116 More specifically, the authors reported that CD patients' z scores for both BUA and SOS were significantly <0, and the z score for SOS was significantly lower than that for UC patients. z scores for BMD measured with DXA were significantly lower at all measurements in patients with UC. It is interesting that although QUS and DXA measurements were significantly correlated, the agreement between the measurements in each individual patient was poor. Body mass index was a major determinant for both BUA and SOS. In CD patients, low QUS results were associated with glucocorticoid therapy, and both CD and UC patients with previous fractures had low SOS values. The authors thus concluded that QUS and DXA are not interchangeable methods for estimating bone status. Similar results were obtained in another study involving 100 patients with CD and 52 control subjects. Calcaneal BUA was significantly associated with BMD at the hip and spine, but the authors thought that the correlation was inadequate to recommend this test as a screening tool for performing DXA scans in patients with IBD.117 Schwartz et al118 performed DXA and QUS scans in 50 IBD patients at high risk for significant metabolic bone disease. The heel BMD (T score) correlated poorly with the DXA T score at either hip or spine. Furthermore, no association in osteopenia or osteoporosis was seen between variables such as sex, disease type (UC or CD), smoking, and prior intestinal resection. Finally, von Tirpitz et al119 reported that QUS of the proximal phalanges cannot detect manifest osteoporosis in CD patients.

Therefore, QUS may not (at their present state) be recommended as a first-choice screening test for low BMD in IBD patients.

Computed Tomography Assessment of Bone Density

QCT is a useful research tool for the true volumetric density (in mg/cm3) of vertebral trabecular bone (mainly) or cortical bone at any skeletal site.120 The reported error of precision (reproducibility; i.e., the ability to obtain the same result in the same individual) of 2% to 4% and the reported error of accuracy (how close a measurement approximates the true value) of 5% to 15% documented in vivo for spinal QCT are higher than those observed for posteroanterior DXA scanning of the spine and are comparable to those of lateral DXA. Overall, QCT provides a volumetric measure of bone density, as opposed to DXA, which gives an area measurement. However, QCT is expensive, involves more radiation, and is less precise than DXA except in the most experienced hands. Peripheral QCT systems have had widespread use in Europe, but they have been limited primarily to research use in the United States

Assessment of the Rate of Bone Turnover

The current use of DXA scans and other similar instruments can ascertain the bone mass of a patient; however, a single examination is unable to determine whether the mass is stable, increasing, or decreasing. Recent advances in biochemical markers can help provide additional data to help determine dynamic effects on bone mass and to estimate the rate of bone turnover.121

The individual's bone-forming activity can be assessed by measuring parts of type I collagen that is manufactured by of the osteoblast-the bone-forming cell-and proteins not containing collagen (osteocalcin, bone Gla protein [BGP]) or level of activity of enzymes such as bone-specific serum alkaline phosphatase (BSAP). Thus, during the formation of the procollagen molecule, peptides are cleaved from the carboxy-terminus or amino-terminus of the procollagen molecule, releasing carboxy-terminal propeptide of type I collagen and amino-terminal propeptide of type I collagen as indexes of type I collagen synthesis measurable in the serum. These are not as specific for bone formation as BGP or BSAP.121

As a measure of the breakdown of bone, the osteoclast releases covalent cross-linked molecules during the digestion of bone matrix. These compounds, which include pyridinoline, deoxypyridinoline, N-telopeptide, and C-telopeptide, are excreted in the urine and could be used as markers of bone resorption. As with any urinary marker, they depend on glomerular filtration. To correct for this variable, they are normalized to creatinine excretion. However, this assessment may not be valid when a patient experiences significant alterations in muscle mass or there is a degree of renal impairment. In addition, it is important to realize that there is substantial diurnal variation in these urinary markers. The values tend to peak between 4 and 8 am. As a consequence of this diurnal variation, it is important to standardize the time of day that the sample is collected. Alternatively, the bone-forming activity marker BSAP has a significantly long half-life that shows little circadian variability.

These markers of bone production and degradation reflect bone turnover and do not serve as predictors of BMD. It has been reported that those individuals with elevated levels of bone destruction markers have a higher risk of fracture that is independent of BMD.122–124 In addition, levels of bone resorption markers can change with therapy. A reduction within weeks of starting antiresorptive therapy suggests that these markers may be helpful in confirming that a patient has achieved a therapeutic effect because a significantly reduced level usually is reached ≈2 to 3 months after treatment initiation.125,126 This observed change occurs more rapidly than a change in serial BMD measurements.

In a recent study, 22 male and premenopausal female subjects with “active” CD (C-reactive protein ≥10 and/or erythrocyte sedimentation rate ≥20) but not on corticosteroid therapy were compared with 21 control subjects with “quiescent” CD (C-reactive protein <10 and erythrocyte sedimentation rate <20).127 Active CD was associated with a higher bone resorption but similar bone formation activity: deoxypyridinoline/creatinine (P = 0.02) and ratio of deoxypyridinoline/creatinine to osteocalcin (P = 0.01) but similar osteocalcin (P = 0.24) in the 2 groups. These findings were not explained by vitamin D status, dietary intake, or nutritional status.

Biochemical markers of bone resorption and formation have been studied in IBD patients. In a cross-sectional study of 149 IBD patients (104 with CD, 45 with UC), bone resorption markers were significantly increased compared with normal controls, whereas bone formation did not show a compensatory response. Bone formation was even more suppressed in the subset of patients on corticosteroid treatment.13 Other investigators reported similar findings in IBD patients,12,19,26,27 including low osteocalcin,23,27 and according to the authors, the use of corticosteroids in 3 of the studies,12,26,27 did not significantly affect their findings. Ardizzone et al16 described increased bone resorption and formation activity in UC but not in CD patients. Furthermore, Schulte et al43 concluded that bone markers measured at baseline could not reliably identify the patients who lost bone after an almost 2-year observation period. Dresner-Pollak et al42 arrived at a different conclusion and suggested that increased N-terminal telopeptide of type I collagen level predicts spinal bone loss in IBD patients. This may be true for the specific patient population of this group in whom the prevalence of osteoporosis has been reported at 42% or 59%.28,42

The role of biochemical markers is not well established in clinical management of patients. However, they may be useful to help categorize patients as those with either low or high bone turnover states. Knowledge of these specific states may help the clinician predict rate of bone loss and an individual's risk of fracture. This also has the potential to help guide the effectiveness of therapy for individual patients. Recently, Dobnig et al128 reported that OPG changes are correlated with BMD changes in bisphosphonate-treated osteoporotic patients. This promising finding could lead to the use of OPG level changes in the prediction of the individual response of patients to bisphosphonate treatment. However, it will be interesting to test the findings of Dobnig et al in IBD patients.

Who Should Have BMD Measurements?

It would be reassuring if all patients with IBD could have a BMD assessment at some point and then have it repeated no earlier than a year later to see if change occurs. Indeed, some investigators129–132 suggest that all individuals with IBD should be screened to avoid the consequences of bone loss because the morbidity associated with this complication has the potential to be quite high. However, current data do not support this notion because the absolute risk of fracture is low. Therefore, a more conservative, cost-effective approach that limits screening to all patients with a preexisting fragility fracture, those older than 65, and those with risk factors that increases the likelihood of detecting low bone mass seems more reasonable.133 A low threshold should be maintained for screening individuals who have used glucocorticoids at any time. It is recommended that one should consider obtaining a DXA scan if one has used glucocorticoids for ≥3 months at a dose of at least 2.5 mg/d prednisone.

How Frequently Should BMD Be Assessed in Individuals with IBD?

The factors that are important in determining the optimal time interval for follow-up are a function of the DXA machine precision and the expected rate of bone loss. The DXA scanner typically has been stated to have a relative sensitivity to change of 2×, a precision error of 1% to 2.5%, and an accuracy error of 5% to 6%. Thus, if a patient has a loss of bone mass of 1% yearly, then it would take 3 years to exceed (with 95% CI) the precision limits of a machine with “ideal” performance (CV = 1%, where CV [coefficient of variation] is defined as 100 × SD/mean) and 6 years for a “usual” machine (CV = 2%). Specific patient-related factors of importance include the average and maximum rate of bone loss annually, which is also site specific. The loss of bone from the spine, mainly trabecular, in early postmenopausal women exceeds the bone loss from the hip in these individuals. Also, a typical average rate of bone loss in untreated early postmenopausal women is ≈2% annually; in older women, the rate is ≈1% annually. It also should be stressed that measurements from different machines are difficult to compare, and whenever possible, follow-up examinations should be performed on the same machine.

The percent change annually in adults with IBD followed up longitudinally has been reported from approximately −7% annually to 0.8% annually. To date, several studies have evaluated the change over time in BMD by using DXA scans in patients with IBD. Overall, the impression is that bone loss is comparable to that described in normal healthy individuals of the same sex and age group.

Symptoms Associated with the Presence of Osteoporosis

It is important to realize that there are no specific symptoms associated with the presence of “thin” bones or an ongoing bone loss. Therefore, the presence of low bone mass is a silent risk factor for future development of a fracture. There may, however, be symptoms or clinical findings that develop later in the disease once fractures of the vertebrae, wrists, or hips have already occurred, including low back pain, bone pain or tenderness, loss of height over time, and stooped posture.

PREVENTION AND TREATMENT OF OSTEOPENIA AND OSTEOPOROSIS

  1. Top of page
  2. Abstract
  3. OSTEOPOROSIS IN IBD
  4. BMD MEASUREMENTS AND TOOLS
  5. PREVENTION AND TREATMENT OF OSTEOPENIA AND OSTEOPOROSIS
  6. PHARMACOLOGICAL THERAPIES
  7. CONCLUSIONS
  8. References

Calcium and Vitamin D

Calcium supplements alone have been shown to have a small positive effect on BMD and a trend toward reducing vertebral fractures,134 whereas a meta-analysis of studies on vitamin D supplementation demonstrated that vitamin D decreases vertebral fractures and may decrease nonvertebral fractures.135 However, a Cochrane review concluded that calcium and vitamin D reduce the risk of fracture in some older people, although the effect of vitamin D or its analogs as the sole treatment in fracture prevention is still unclear.136 Findings from the biggest study ever of calcium (1000 mg of elemental [corrected] calcium or placebo) and vitamin D3 supplements (400 IU or placebo) for older women suggested a small but significant improvement in hip BMD but not a significant reduction in hip fractures.137 This 7-year study of 36,282 women ages 50 to 79 was part of the Women's Health Initiative. However, the way the data were interpreted was challenged because, among others, half the patients in each group were taking estrogen; by the end of the trial, >5000 subjects were taking active treatments for osteoporosis; the dose of vitamin D was only 400 U; in the women older than 60, the RR in the treated group was significant at >0.79; and in those with >80% compliance, the RR also was significant at 0.71 (Table 1).

Table Table 1. Treatment of Patients with Osteoporosis: FDA-Approved Medications
 
AgentPreventionTreatmentPreventionTreatment
  1. HRT indicates hormone replacement therapy; PTH, parathyroid hormone.

AledronateYesYesNoYes
RisedronateYesYesYesYes
IbandronateYesYesNoNo
Estrogen/HRTYesNoNoNo
PTHNoYesNoNo
RaloxifeneYesYesNoNo
CalcitoninNoYesNoNo

It has generally been accepted that calcium and vitamin D are essential, although not sufficient, components to the prevention and treatment of osteoporosis.139 By meeting individual daily calcium intake recommendations, patients could reduce bone loss significantly and help prevent osteoporosis. It is recommended that patients not exceed 2500 mg/d calcium.140 The amount of calcium required daily is dependent on an individual's age and gender. The National Institutes of Health and the National Academy of Sciences Food and Nutrition Board have issued the daily calcium intake recommendations given in Table 2.

Table Table 2. Daily Calcium Intake Recommendations: Age Stratification
Age GroupCalcium, mg
Birth-6 mo210
6 mo-1 yr270
1–3 yr500
4–8 yr800
9–18 yr1300
Women 
25–50 yr1000
>50 yr with estrogen1000
>50 yr without estrogen1500
>65 yr1500
Pregnant and nursing1200
Men 
25–65 yr1000
>65 yr1500

The combination of oral calcium and vitamin D supplements is insufficient to inhibit bone loss in patients who require the use of glucocorticoids, including those with IBD. In a randomized, placebo-controlled trial in patients with IBD who were taking glucocorticoids, vitamin D 250 IU (Oscal) and calcium supplementation (1000 mg/d) conferred no significant benefit regarding bone density at 1 year.141

A randomized trial involving 103 patients compared calcium (1000 mg/d) and calcitriol (1,25-dihydroxyvitamin D3, mean dose 0.6 mg/d) as a method of primary prevention. In the first year of the study, calcitriol reduced but did not prevent spinal bone loss (−1.3% vs −4.3% in the calcium group; P = 0.035).142 So far, calcitriol and other vitamin D analogs have not been established as effective treatment for glucocorticoid-induced or postmenopausal osteoporosis.

PHARMACOLOGICAL THERAPIES

  1. Top of page
  2. Abstract
  3. OSTEOPOROSIS IN IBD
  4. BMD MEASUREMENTS AND TOOLS
  5. PREVENTION AND TREATMENT OF OSTEOPENIA AND OSTEOPOROSIS
  6. PHARMACOLOGICAL THERAPIES
  7. CONCLUSIONS
  8. References

All FDA-approved drugs except for Teriparatide are considered antiresorptive agents. Therefore, their effectiveness is rather limited in the treatment of severe osteoporosis because these agents are not able to restore the damaged bone architecture.143 Teriparatide, a synthetic parathyroid hormone fragment, is a promising anabolic agent that stimulates bone formation.

Bisphosphonates

Bisphosphonates are analogs of pyrophosphate in which the linking oxygen of the pyrophosphate is replaced with a carbon and other side chains.144 They include etidronate (Didronel), pamidronate (Aredia), tiludronate, and the nitrogen-containing bisphosphonates alendronate (Fosamax), risedronate (Actonel), and ibandonate (Boniva). These compounds bind tightly to hydroxyapatite crystals in the bone. Interestingly, the nitrogen-containing bisphosphonates inhibit the mevalonate pathway, the same one affected by statins.144

A systematic review and meta-analysis of randomized placebo-controlled trials evaluating alendronate (Fosamax) and risedronate (Actonel) have revealed that both of these bisphosphonates increase BMD at the spine and hip in a dose-dependent manner. They could reduce the risk of vertebral fractures by 30% to 50%. More specifically, alendronate reduces the incidence of spine, hip, and wrist fractures by 50%. Risedronate reduces spine fractures by 40% and hip and nonspine fractures by 30%. Both agents have been approved for the prevention and treatment of postmenopausal osteoporosis and are available in once-per-week preparations. In 2005, the FDA approved the use of ibandonate (Boniva) monthly, following approval of daily administration in 2003; the reported reduction in new vertebral fractures compared with placebo was 62%. Earlier this year, the intravenous (bolus) administration of 3 mg ibandronate every 3 months became available.

A recent systematic review identified 13 randomized controlled trials that evaluated the efficacy of etidronate. The results show that etidronate increases bone density in the lumbar spine and femoral neck compared with placebo. The combined results of fracture reduction with etidronate suggest a decrease in vertebral fractures, but there is no evidence of effect on nonvertebral fractures.145

A meta-analysis of 11 randomized trials involving a total of 12,855 women reported that alendronate significantly reduced vertebral, hip, forearm, and other nonvertebral fractures.146 In a systematic review, Cranney et al147 found good evidence for the efficacy of risedronate in the reduction of both vertebral and nonvertebral fractures in postmenopausal women. In 2 head-to-head studies, alendronate demonstrated greater antiresorptive effects: spinal and hip BMD increased and markers of bone turnover were reduced more than with residronate.148,149 However, there are no fracture data. Therefore, the clinical significance of this finding could not be established. The tolerability profiles were similar.

There are only a limited number of studies on the effectiveness of the bisphosphonates in IBD patients. Sixty-one ambulatory patients with IBD (31 with CD, 30 with UC) participated in a double-blind placebo-controlled study. All received a 600-mg calcium supplement. After 1 year of risedronate or placebo, the BMD increased by 2% at the spine and 1.9% at the hip, a change described by the authors as significant.150

Thirty-two ambulatory patient with CD in remission but not on glucocorticoids were recruited for a 12-month double-blind, randomized, placebo-controlled study that examined the effect of a 10-mg daily dose of alendronate. At the end of the 1-year period, the BMD of the lumbar spine showed an increase of 4.6% ± 1.2% in the alendronate group compared with a decrease of 0.9% ± 1.0% in patients receiving placebo (P < 0.01). BMD of the hip increased by 3.3% ± 1.5% in the alendronate group compared with a smaller increase of 0.7% ± 1.1% in the placebo group (P < 0.08). Bone markers such as S-osteocalcin, urine pyridinoline, and urine deoxypyridinoline were lower in the treatment group.151

Pamidronate (Aredia) has been used off-label in patients with osteoporosis,152 including glucocorticoid-induced osteoporosis. Seventy-four patients with CD and low BMD received 500 mg calcium with 400 IU vitamin D for 1 year. In addition, half of them (n = 37) received four 3-monthly infusions of 30 mg IV pamidronate. The main outcome measure was the change in BMD at the lumbar spine and hip measured by DXA at baseline and 12 months. The BMD of the pamidronate group increased by 2.6% (95% CI 1.4–3.0) at the spine and by 1.6% (95% CI 0.6–2.5) at the hip. The BMD gains in the vitamin D and calcium supplements alone group were smaller at 1.6% (95% CI 0.1–3.2) for the spine and 0.9% (95% CI 0.4–2.1) for the hip. In a study published recently,153 49 IBD patients with low BMD (40 osteoporotic, 9 osteopenic) received 30 mg IV pamidronate every 3 months. They also were treated with calcium 1000 mg and vitamin D 400 IU daily. After 1 year, the authors reported significantly improved T scores in lumbar spine and hip. However, T-score comparisons are not a reliable test, and the ISCD recommends only the use of BMD changes to calculate results.

The bisphosphonate tiludronate is approved for the treatment of Paget's disease as an orally administered agent. It has not conclusively been demonstrated to be effective in treatment of osteoporosis.

The optimal duration of treatment has not been established. A recent study on 10 years' experience with alendronate for osteoporosis in postmenopausal women suggests that normal bone structure and mineralization are preserved.154 However, studies powered to address these issues are not available. Furthermore, the safety and efficacy of bisphosphonate therapy in children and young adults has not been well evaluated.

Estrogen

It is well documented155 that estrogen reduces the number of osteoclasts in vivo, probably by suppressing osteoclast formation. Estrogen may act through altering cytokines such as IL-1, IL-6, or TNF-α, but there also is evidence for a direct action on osteoblasts to increase OPG production156 and on osteoclasts, perhaps mediated by TGF-β, to enhance osteoclast apoptosis.157 An interesting observation was made recently that estrogen deficiency causes bone loss by lowering thiol antioxidants in osteoclasts.158 This directly sensitizes osteoclasts to osteoclastogenic signals and entrains reactive oxygen species-enhanced expression of cytokines that promote osteoclastic bone resorption.

Estrogen therapy alone or in combination with progestin (hormone replacement therapy [HRT]) has been demonstrated to stop progression of bone loss in postmenopausal women, and long-term therapy actually increases BMD and reduces the risk of spine and hip fractures by 34%.159 The main concern with estrogen is the reported increased risk of breast cancer, coronary heart disease, stroke, and pulmonary embolism. Indeed, the Women's Health Initiative was abandoned early because an overall measure suggested that HRT was causing more harm than good.159 Later in the same year, the Medical Research Council halted a British HRT trial. The FDA followed suit by practically restricting the use of HRT for menopausal symptom relief to the lowest doses possible for the shortest period of time. However, it is important to recognize that when hypogonadism is documented in men, testosterone replacement should be considered.

The use of estrogen is not approved for the prevention of glucocorticoid-induced osteoporosis. To date, no studies have been published illustrating a decreased fracture rate in patients taking estrogen therapy for this indication. Estrogen has been reported to prevent bone loss in glucocorticoid-treated women at 1 year, and the efficacy was comparable to that documented in postmenopausal women receiving estrogen therapy in the absence of glucocorticoids.160 In another study, HRT has been reported to preserve bone mass in patients with rheumatoid arthritis taking low-dose corticosteroids.161 However, in neither study was HRT shown to alter the fracture rate.

Selective estrogen receptor modulators are an alternative to estrogen treatment in women. Raloxifene (Evista) is the first selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal spinal osteoporosis. Raloxifene functions as an estrogen agonist in bone, but at the same time, it is an estrogen antagonist in the breast and uterus. A large prospective trial found that this agent reduced the spinal fracture rate by 35% overall in postmenopausal women but was not effective in the prevention of hip fractures.162 A meta-analysis of 7 clinical studies reported a 40% reduction in the risk for vertebral fractures in patients taking 60 mg/d raloxifene.163 Side effects include hot flashes and deep vein thromboses, although on a positive note, raloxifene appears to reduce the risk of estrogen-dependent breast cancer (Study of Tamoxifen and Raloxifene; initial National Institutes of Health report released in April 2006).

Calcitonin (Miacalcin)

Calcitonin acts directly on osteoclasts to inhibit bone resorption. It is a nonsex, nonsteroid hormone that specifically binds to osteoclasts and decreases their activity and numbers. It has been reported to increase bone mass by 4% to 5% at a parenteral (subcutaneous) dose of 100 IU. Calcitonin is now available as an intranasal spray (200 IU/d) that has been reported to reduce the risk of spine fractures by 21%.164 The medication is approved for use in women who are >5 years past menopause and cannot tolerate estrogen or for whom estrogen is not an option. Calcitonin is not effective in preventing bone loss in the hip or hip fractures. This medication has not received approval for use in glucocorticoid-induced osteoporosis, and there are no published data suggesting it is efficacious for this purpose.165

Teriparatide

Teriparatide is a genetically engineered fragment of human parathyroid hormone, which is the primary regulator of calcium and phosphate metabolism. Teriparatide is the first approved agent for the treatment of osteoporosis that stimulates new bone formation. Daily injections of teriparatide stimulate new bone formation, leading to increased BMD.166 Clinical trials also demonstrated that teriparatide reduced the RR of vertebral (by 65%) and nonvertebral (by 53%) fractures in postmenopausal women (absolute risk reduction, 9.3% and 2.9%, respectively). The FDA has approved teriparatide for treating osteoporosis in postmenopausal women who are at high risk for having a fracture. The drug also is approved to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.167 Hypercalcemia is a possible side effect; infrequently, it could become a reason for discontinuation of the treatment. However, the major limiting factors are cost and the requirement of subcutaneous administration. The recommended period of treatment with teriparatide is up to 24 months because of concerns about the development of osteosarcoma. Although the tumors were reported in rats treated with significantly high doses of teriparatide from infancy through senescence, no such complication has been reported in the >200,000 patients treated with parathyroid hormone so far.

Treatment of Glucocorticoid-Induced Bone Disease in IBD Patients

Glucocorticoid use is the variable most strongly associated with the development of osteoporosis. Therefore, glucocorticoids should be avoided as much as possible in treating patients with IBD. If glucocorticoids cannot be avoided, then use of the lowest possible dose for the shortest duration of time is appropriate. Specific measures to help avoid or reduce glucocorticoids have been well outlined.167–169

Widely used agents that have been proved effective in assisting glucocorticoid reduction in patients with IBD have included budesonide (in CD), mesalamine (only in CD), azathioprine/6-mercaptopurine, methotrexate (in CD), and infliximab (in CD and UC). General guidelines for treatment of patients with IBD include maximizing the dose of mesalamine used to prevent the need for glucocroticoid use. Mesalamine has the advantage over sulfasalazine of higher tolerable doses, leading to improved compliance. Alternate-day therapy with glucocorticoids could be used if possible in an attempt to lessen the overall steroid dose of exposure to the individual patient. Nevertheless, there are no convincing data suggesting that use of alternate-day steroids has lessened bone-related complications. Intestinal surgery also should be contemplated for those patients who require glucocorticoids long-term.

If the use of glucocorticoids cannot be avoided, then preventive measures should be undertaken. It is thought that glucocorticoids not only could affect BMD but also could alter bone quality. Therefore, fractures could occur at a lower BMD than might be expected. The UK Consensus Group recommended the use of a T-score threshold of −1.5 at the spine or hip for intervention in patients taking corticosteroids. The American College of Rheumatology recommended a T-score threshold of −1.0.170 The subject, however, remains controversial. A small retrospective analysis of 82 (63 female) patients receiving corticosteroids showed that despite the fact that significantly more patients on corticosteroids suffered from vertebral fractures than the controls (P = 0.0035), the median T scores were only marginally lower in patients on steroids. Therefore, the authors concluded that the same diagnostic threshold should be used for both corticosteroid-induced and postmenopausal osteoporosis.

Alendronate

In a randomized, double-blind, placebo-controlled, multicenter study, 477 men and women receiving a minimum of 7.5 mg prednisone or its equivalent for pathologies of different origins completed initially a 12-month study171; 166 of them completed another year.172 All patients received 800 to 1000 mg elemental calcium and 250 to 500 IU of vitamin D supplements daily. The primary endpoint was the mean percentage change in BMD from baseline to 24 months; vertebral fracture incidence was included in the secondary outcomes. The participants received treatment at various stages of glucocorticoid therapy. The placebo group lost insignificant amounts of lumbar bone mass, but those treated with alendronate gained 2.8% ± 0.6% if on 5 mg/d, 3.9% ± 0.7% if on 10 mg/d, or 3.7% ± 0.6% if on 2.5 mg/d for the first year and then on 10 mg/d. In the treatment groups, BMD of the femoral neck remained stable. Patients on alendronate suffered fewer fractures compared with controls (0.7% vs 6.8%; P = 0.026).

Risedronate

Oral treatment with 5 mg/d improved BMD in 2 multicenter, randomized, controlled clinical trials.173,174 All patients received calcium and vitamin D supplements daily.

The first trial173 was divided into 2 parallel parts: 228 participants in 23 North American centers who had been treated with corticosteroids for ≤3 months before enrollment formed the prevention group, and 290 participants in 28 European centers who had received moderate- to high-dose corticosteroid therapy for at least 6 months before enrollment formed the treatment group. The primary endpoint was the difference between the placebo and active groups in lumbar spine BMD at 1 year. At the completion of the trial, the difference in BMD between the risedronate 5 mg and placebo groups was significant at all skeletal sites (P < 0.05) except the midshaft radius. In addition, compared with the placebo group, the risedronate 5 mg group showed a significant reduction of 70% in vertebral fracture risk (P < 0.01).

The second trial174 contacted 224 men and women with rheumatic diseases who were initiating long-term corticosteroid treatment in the United States. Fifty-seven participants were in the placebo group, 31 were in the 2.5-mg risedronate group, and 62 were in the 5-mg risedronate group. A total of 150 patients completed the 12 months of the study. Lumbar BMD remained stable in the treatment groups, but the loss in the placebo group was significant at 2.8% ± 0.5% (P < 0.05). The differences between the 5-mg risedronate and placebo groups also were significant (P < 0.001) at the lumbar spine (3.8% ± 0.8%) and femoral neck (4.1% ± 1.0%). There was a trend toward a decrease in the incidence of vertebral fracture in the 5-mg risedronate group compared with the placebo group (5.7% vs 17.3%; P < 0.072).

Ibandronate

In an open-label, single-center, parallel-group, controlled study, participants received 500 mg/d calcium supplements plus either 3-monthly intravenous injections of 2 mg ibandronate or oral 1 mg/d alfacalcidol for 3 years.175 Relative to baseline, the BMD gains in the ibandronate group (13.3% at the lumbar spine, 5.2% at the femoral neck) were much greater than those in the alfacalcidol group (2.6% at the lumbar spine, 1.9% at the femoral neck; P < 0.001). Furthermore, the number of new vertebral fractures was significantly lower in the patients receiving ibandronate relative to those taking alfacalcidol (8.6% vs 22.8%, respectively; P = 0.043).

Etidronate

A meta-analysis176 reported that intermittent cyclical etitronade (400 mg/d for 14 d, followed by 500 mg calcium daily for 76 d) was effective in preventing bone loss in the prevention studies. In the treatment studies, it also prevented bone loss or slightly increased bone mass. Furthermore, there was a reduced incidence of fractures in the prevention studies, but it did not achieve statistical significance (RR 0.50; 95% CI 0.21–1.19).

Bisphosphonates are the most effective of all therapies available today for glucocorticoid-induced osteoporosis. The data also suggest that primary prevention is more efficacious than secondary prevention. The use of both alendronate (Fosamax) and risedronate (Actonel) but not etidronate (Didronel) has been approved for the treatment of corticosteroid-induced osteoporosis; risedronate is the only one with approval for prevention.

A reasonable approach for treatment with bisphosphonates could be to begin bone-protective therapy at the time that glucocorticoids are started in patients 65 years of age or older with a BMD inside the osteopenia range who requiring corticosteroid therapy for ≥3 months. Patients with a prior fragility fracture should start treatment with a bisphosphonate straight away. A combination of calcium and vitamin D, along with bisphosphonates, is the most appropriate regimen, in addition to measures such as weight-bearing exercise regimens, smoking cessation, and reduced alcohol consumption. Treatment with bone-forming agents such as intermittent low-dose parathyroid hormone administration to “antagonize” the effects of corticosteroid on the osteoblasts is producing promising results.177,178 However, additional studies are required to establish an effective role for human parathyroid hormone. Monitoring the skeletal status of patients on corticosteroid treatment is recommended, and bone density should be reassessed on a regular basis, but not earlier than a year.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. OSTEOPOROSIS IN IBD
  4. BMD MEASUREMENTS AND TOOLS
  5. PREVENTION AND TREATMENT OF OSTEOPENIA AND OSTEOPOROSIS
  6. PHARMACOLOGICAL THERAPIES
  7. CONCLUSIONS
  8. References

Osteoporosis is a preventable disorder. BMD could be diminished by IBD itself or by medications used to treat IBD. Glucocorticoid use is the variable most strongly associated with the development of osteoporosis. Bone losses occur soon after initiation of glucocorticoids, often within 2 to 3 months. After 6 months, there is a 50% risk of osteoporosis, and the risk of fracture is as high as 50% in those patients taking glucocorticoids at doses equivalent to prednisone ≥7.5 mg/d (the dose above which significant trabecular bone loss could occur). Although no firm randomized controlled trials have been performed to assess when DXA scans should be performed, it is suggested that a DXA scan be obtained soon after the diagnosis and repeated once 12 to 18 months later. Aggressive efforts to reduce the use of glucocorticoids should be initiated while other effective therapies are maximized.

Avoiding glucocorticoids is coupled with attempts to intervene if necessary with medications such as vitamin D, calcium supplementation, and lifestyle changes (performing weight-bearing exercise programs, smoking cessation, and decreasing ethanol intake). The following general recommendations are advisable:

  1. Ensure adequate calcium intake (level II evidence)

  2. Institute regular exercise (level II evidence)

  3. Assess vitamin D status and correct deficiency with an oral supplement if present (level I evidence)

  4. Avoid excessive ethanol intake (level II evidence)

  5. Avoid smoking (level II evidence)

  6. Limit use of corticosteroids, cyclosporine A, tacrolimus and methotrexate to short term (level I evidence)

Bisphosphonates should be used when indicated. The exact impact of glucocorticoid therapy is of concern for pediatric patients who often receive these compounds before achieving peak bone mass; however, bisphosphonates are not approved for use in children. It is the clinician's role to establish and maintain remission, minimize the use of glucocorticoids, and initiate measures to prevent and treat bone loss. It would be interesting to find out whether the promising effects of cortistatin in mice179 could be repeated in patients with CD and therefore the need for costicosteroids could become a “rare” phenomenon. In addition, the increased levels of proinflammatory cytokines could return to normal concentrations.

References

  1. Top of page
  2. Abstract
  3. OSTEOPOROSIS IN IBD
  4. BMD MEASUREMENTS AND TOOLS
  5. PREVENTION AND TREATMENT OF OSTEOPENIA AND OSTEOPOROSIS
  6. PHARMACOLOGICAL THERAPIES
  7. CONCLUSIONS
  8. References