Effects of once-weekly oral alendronate on bone in children on glucocorticoid treatment

S. Rudge, S. Hailwood, A. Horne1, J. Lucas1, F. Wu1 and T. Cundy1

Paediatric Rheumatology, Starship Hospital, Auckland and 1 Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.

Correspondence to: T. Cundy, Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1, New Zealand. E-mail: t.cundy{at}auckland.ac.nz


    Abstract
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 Abstract
 Introduction
 Subjects
 Methods
 Results
 Discussion
 References
 
Objectives. To determine the effects of once-weekly oral alendronate on indices of bone size, density and resorption in children with chronic illness being treated with glucocorticoids.

Methods. Twenty-two children with chronic illness treated with prednisone were randomized to receive 1 year's treatment with either once-weekly oral placebo or alendronate (1–2 mg/kg body weight) in a double-blind study. The main outcome measures were changes in lumbar spine and femoral shaft size and volumetric density (measured by dual energy X-ray absorptiometry) and N-telopeptide excretion (a marker of bone resorption).

Results. Once-weekly alendronate was well tolerated, and there were no major adverse events. In both groups bone size and bone mineral content increased through growth. Volumetric bone density of the lumbar spine increased significantly in the alendronate group (P = 0.013), but not in the placebo group. There were no differences between the groups in growth in the cortical width of the femoral shaft, but the cross-sectional moment of inertia per unit length—a derived estimate of mechanical strength—increased significantly in the alendronate group (P = 0.014) but not in the placebo group. Urine N-telopeptide excretion was suppressed significantly in the alendronate group (P = 0.007) but not in the placebo group. Height velocity was positively correlated with changes in both lumbar spine area and the total width of the femoral shaft (P = 0.015, P = 0.026, respectively).

Conclusion. Once-weekly oral alendronate is well tolerated, suppresses bone resorption and may improve volumetric bone density at the lumbar spine and mechanical strength of the femoral shaft in children with chronic illness taking glucocorticoids. It does not affect bone growth. Larger controlled studies are needed to determine if these changes translate into reduced fracture incidence or greater peak bone mass. This study highlights the importance of differentiating between changes in bone size and changes in volumetric bone density in assessing bone in children, and also having control subjects in intervention studies.

KEY WORDS: Children, Glucocorticoids, Bone density, Bone size, Alendronate, Bisphosphonates


    Introduction
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 Abstract
 Introduction
 Subjects
 Methods
 Results
 Discussion
 References
 
Glucocorticoid treatment is known to cause osteoporosis in adults through a combination of suppressed bone formation and continued (or increased) bone resorption [1, 2]. In children and adolescents, in whom the skeleton is not yet mature, glucocorticoid use can also cause bone loss or inhibit the normal acquisition of bone mass, and cause fractures [3–6]. Bisphosphonates, whether given intravenously or orally have proven efficacy in slowing bone loss from both the axial and peripheral skeleton in adults taking glucocorticoids [7, 8]. There are, however, few data on the use of bisphosphonates in children on glucocorticoid treatment, although they have been used successfully in other childhood osteopenic conditions, most notably osteogenesis imperfecta [9–11]. The only data published to date in children using glucocorticoids have been from uncontrolled studies that have demonstrated increases in spinal bone density Z scores after intravenous bisphosphonates [12, 13] or daily oral alendronate treatment [14] in children with low bone density and/or fractures.

We have undertaken a randomized, double-blind controlled study of the effects of once-weekly oral alendronate therapy on bone mass in children on glucocorticoid treatment. We selected this regimen reasoning that alendronate therapy (which has to be taken fasting, at least half an hour before breakfast) would be more acceptable to children if taken weekly, rather than daily. We were also interested in the effects on cortical as well as spinal bone mass, since in this age group the majority of fractures occur in long bones [6].


    Subjects
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 Subjects
 Methods
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Twenty-two young people (nine male, 13 female) aged from 4.3 to 17.2 yr who were on long-term prednisone therapy were recruited into the study. The clinical indications for prednisone treatment were: juvenile idiopathic arthritis (seven subjects), systemic lupus (six), dermatomyositis (four), inflammatory bowel disease (two) and renal transplantation, autoimmune haemolytic anaemia and allergic bronchopulmonary aspergillosis with cystic fibrosis (one subject each).

At entry into the study the average daily prednisone dosage ranged from 0.1 to 2.4 mg/kg body weight, and the duration of treatment ranged from 0.3 to 7 yr (median 2.1 yr). Four subjects were taking prednisone on alternate days and one subject (No. 5, Table 1) had repeating 2-week tapering courses of prednisone at monthly intervals throughout the study. Three subjects had sustained fractures previously.


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TABLE 1. Details of subjects at entry to study

 
The patients were randomized to receive either once-weekly oral alendronate, using 40 mg tablets (Fosamax, Merck), in a dose of 1–2 mg/kg body weight, or placebo. Subjects weighing <20 kg took one 40 mg tablet fortnightly, those weighing 20–40 kg took 40 mg weekly, those weighing 41–60 kg took 40 mg and 80 mg on alternate weeks, and those weighing >60 kg took 80 mg weekly. Placebo subjects were instructed to take their tablets similarly, according to body weight. Subjects were instructed to take the tablets with water at least half an hour before breakfast. Calcium supplements were not prescribed, but subjects with a plasma calcidiol concentration of <50 nmol/l were given supplementary vitamin D.

Subjects were seen 3-monthly during the study, which was of 1 year's duration. Adherence to therapy was assessed by counting returned pills. Adverse events and plasma and urine biochemistry were assessed 3-monthly. Bone density measurements were made at 0, 6 and 12 months.


    Methods
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 Methods
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Plasma concentrations of calcium, phosphate and albumin, haematological parameters and the activity of alkaline phosphatase and the liver enzymes gamma glutamyl transferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured in blood samples. Plasma calcidiol and parathyroid hormone were measured by radioimmunoassay. Bone resorption was assessed by the ratio in random urine specimens between N-telopeptide and creatinine concentrations (Osteomark NTx, Ostex International Inc., Seattle, WA, USA). Bone formation was assessed by the plasma total alkaline phosphatase (ALP). The normal adult values in our laboratory are <75 nmol bone collagen equivalents (BCE)/mmol creatinine (NTX), and <120 U/l (ALP), respectively. Values are higher in growing children.

Height was measured on a Harpenden stadiometer, and weight was measured wearing light indoor clothing using an electronic balance. Height and weight measurements were expressed relative to age- and gender-specific normal ranges as standard deviation (Z) scores [15]. Height velocity over the study was calculated by subtracting the height at 12 months from the height at entry to the study and correcting for the time between scans. Height velocity was also expressed relative to age- and gender-specific normal ranges as standard deviation (Z) scores [16].

Bone density measurements were made using dual energy X-ray absorptiometry (Lunar DPX-L, Madison, WI, USA), at both the lumbar spine and the mid-femoral shaft. At the lumbar spine (L2–L4) the results were expressed as bone mineral content (BMC; g), and areal bone density (aBMD, BMC/projectional area; g/cm2). The latter was also expressed as an age- and sex-matched standard deviation (Z) score using normal ranges from the manufacturer's database. The volume of L2–L4 (cm3) was estimated as

From this measurement the volumetric bone density was estimated as BMC/volume (vBMD; g/cm3) [17].

Cortical bone mass was measured by scanning a 4 cm2 area centred on the mid-point of the femoral shaft (defined as half the distance from the superior border of the greater trochanter to the inferior border of the lateral tibial plateau), according to the method of Bradney et al. [18]. The BMC of this area was recorded, and using the ruler function the total width (D) and the medullary width (d) were measured. From these measurements the following derived measures were calculated: combined cortical width (D d; mm); cortical bone area [{pi}/4(D2d2); cm2]; and cortical volumetric bone density {vBMD = BMC/[{pi}/4(D2 d 2)]; g/cm3}. These derived measures assume that at its mid-point the femur is cylindrical and that the bone is entirely cortical. Three biomechanical indices of femoral mid-shaft strength were also derived: cross-sectional moment of inertia {CSMI = {pi} [(D/2)4 – (d/2)4]}, the section modulus = CSMI/(D/2) and the cross-sectional moment of inertia per unit length of bone = (CSMI x vBMD)/2 [19, 20].

Mean values are given with the standard error of the mean (SEM). Mean values were compared using Student's t-test for paired or unpaired samples as appropriate, and median values were compared using the Wilcoxon rank sum test. Correlations were calculated by the method of least squares.

The study was approved by the Auckland Regional Ethics Committee and written informed consent was obtained from all subjects and their parents.


    Results
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 Introduction
 Subjects
 Methods
 Results
 Discussion
 References
 
Details of the 22 subjects enrolled in to the study are given in Table 1. Eleven were randomized to receive placebo and 11 to receive alendronate. At entry the median age of the two groups was similar (8.0 yr placebo; 8.7 yr alendronate). The median daily dose of prednisone was similar in the two groups, but the median duration of treatment was somewhat greater in the alendronate group, 3.0 vs 0.7 yr, although this was not statistically significant (P>0.05, Wilcoxon test). The median height Z score was lower in the alendronate group: –2.0 vs –0.2 (P<0.05, Wilcoxon test). The subjects were generally short (mean Z score –0.9), but were not underweight for age (mean Z score + 0.3). The Z scores for height were significantly lower than those for weight (P<0.001, paired t-test). The mean Z score for areal BMD of the lumbar spine was –0.5 (S.D. 1.4), and was similar in the two groups. Only two subjects were significantly osteoporotic on this measurement (Z score ≤–2.5), but seven others were osteopenic (Z score –1.0 to –2.5). The duration of steroid treatment was negatively correlated with height Z score (r = – 0.502, P = 0.017). The areal BMD Z scores and height Z scores were significantly correlated (r = 0.493, P = 0.023).

Four subjects failed to complete the 1-yr study. Three (from the placebo group) moved away and discontinued participation. One subject from the alendronate group (No. 11, Table 1) died 7 months into the study from pulmonary haemorrhage, complicating systemic lupus, thus 18 subjects (eight placebo, 10 alendronate) completed the 12-month study. At the end of the study the mean prednisone dose was significantly lower than at the beginning (0.30 vs 0.65 mg/kg, P = 0.017): prednisone doses had been reduced in seven subjects from the alendronate group and five from the control group.

Spinal bone density
As expected, both bone size (bone volume) and the bone mineral content of the lumbar spine were correlated with height at baseline (r = 0.966, P<0.0001; r = 0.944, P<0.0001, respectively). In both groups bone area (and thus the derived measure of bone volume) increased through growth during the 12 months. The mean change in bone area and volume was similar in the two groups. Bone mineral content also increased in both groups, as did aBMD (both in absolute values and Z score) but the magnitude of the change was greater (but not statistically significant) in the alendronate group. vBMD increased significantly in the alendronate group (P = 0.013) whereas there was little change in the placebo group (Table 2, Fig. 1). The percentage change in vBMD was not related to either the change in prednisone dosage (r = –0.372, P = 0.129) or the age at entry into the study (r = –0.215, P = 0.393). In the alendronate group those with the lowest initial aBMD Z score had the greatest increment in vBMD with treatment. The mean percentage increment in vBMD in those with initial aBMD Z scores below the median (<–0.6) was 27%, compared with 6% in those with Z scores above the median (P = 0.066).


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TABLE 2. Lumbar spine bone densitometry measurements

 


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FIG. 1. Percentage change in volumetric bone density of the lumbar spine (top) and the cross-sectional moment of inertia per unit length of the mid-femoral shaft at 6 and 12 months. Mean values and SEM are indicated. At the lumbar spine there was a significant increase in vBMD in the alendronate group at 12 months (P = 0.013, compared with baseline), but not in the placebo group (P = 0.156). At the mid-femoral site there was a significant increase in CSMI/unit length in the alendronate group at 12 months (P = 0.014, compared with baseline) but not in the placebo group (P = 0.155).

 
Femoral shaft measurements
As expected, both bone size (total width) and the bone mineral content of the femoral shaft were correlated with height at baseline (r = 0.836, P<0.0001; r = 0.734, P<0.0001, respectively). At the mid-point of the femoral shaft increases in BMC were noted, averaging 3.0% in the placebo group and 4.4% in the alendronate group. In both groups there was significant growth in the femoral total width and narrowing of the medullary cavity, resulting in similar increments in cortical width. In both groups CSMI and sectional modulus increased, but although the changes were more marked in the alendronate group, they did not reach statistical significance. The CSMI per unit length, which reflects both the dimensions and density of cortical bone, did increase significantly in the alendronate group (P = 0.014) whereas the change was less in the placebo group (Table 3, Fig. 1). The percentage change in CSMI/unit length was not related to change in either the prednisone dosage (r = –0.236, P = 0.345) or the age at entry into the study (r = –0.023, P = 0.929).


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TABLE 3. Femoral shaft bone densitometry measurements

 
Growth velocity
The height velocity Z score during the study ranged from –4.9 to +2.0, with a mean of –1.4 (S.D. 2.2), so most subjects were growing slower than average for their age. The mean height velocity was similar in the alendronate group (4.2 cm/yr, Z score –1.4) and in the placebo group (4.5 cm/yr, Z score –1.3). In the subjects as a whole, the height velocity (in cm/yr) was significantly correlated with changes in bone size during the study (lumbar spine bone area r = 0.565, P = 0.015; femoral shaft total width r = 0.522, P = 0.026).

Biochemistry
No significant changes in plasma calcium, phosphate or parathyroid hormone were noted in either group. At baseline the mean plasma alkaline phosphatase activity was similar in the alendronate group and the placebo group (161 vs 139 U/l). At 12 months the mean values were 154 and 176 U/l, respectively (not statistically significant). The mean urine N-telopeptide/creatinine ratio fell from a mean of 299 pre-treatment, to 148 after 12 months in the alendronate group (P = 0.007), but not in the placebo group (303 vs 301).

Tolerance, fractures, adverse events and adherence
The treatment was well tolerated and no subject discontinued alendronate because of side-effects. No changes in haematological indices, renal or hepatic function were noted. Only one subject, from the control group (No. 18, Table 1), sustained a fracture (his forearm) during the study. Adherence, assessed by the number of returned tablets, was between 23 and 100% in the alendronate group (median 79%) and 71 to 100% in the placebo group (median 93%).


    Discussion
 Top
 Abstract
 Introduction
 Subjects
 Methods
 Results
 Discussion
 References
 
This study has shown that once-weekly oral alendronate was well tolerated by children on glucocorticoid treatment. Compared with controls, the major impact on bone was a significant increase in volumetric bone density at the lumbar spine, and an increase in the cross-sectional moment of inertia/unit length at the mid-femoral site. This was associated with a significant reduction in N-telopeptide excretion, indicating that bone resorption was reduced by alendronate therapy.

The study highlights a number of important considerations regarding the assessment of bone mass in children. The ability of a bone to resist fracture is determined by a number of factors including bone size, the quantity and distribution of bony tissue within the periosteal envelope and bone quality. In adults, in whom skeletal dimensions change very slowly, the composite measurement of ‘areal’ bone density captures elements of both bone size and bone quantity. In children, the rapid changes in bone size that characterize growth make the interpretation of this measure problematic. For example, the areal bone density of the lumbar spine increases by approximately 70% between Tanner stages 1 and 5, when assessed by dual energy X-ray absorptiometry scanning. This is largely accounted for by increasing bone size: volumetric bone density, as assessed by quantitative computed tomography, increases by only 10% over the same time [21, 22]. In our subjects, bone area (and volume) and BMC increased through growth in both groups, irrespective of treatment allocation. The increments in BMC, aBMD and vBMD were greater in the alendronate group, but even in the placebo group there was sufficient improvement in aBMD to increase the Z score, in part perhaps because in the majority of the participants it was possible to reduce the dosage of prednisone. This emphasizes the importance of having control subjects in interventional studies of bone mass in children.

Because of the small size of our study there were some imbalances between the two groups in their baseline characteristics. In particular, the children in the alendronate-treated group were shorter and had been on steroid treatment for longer than those in the placebo group. The distribution of underlying diseases also differed somewhat: by chance all the subjects with systemic lupus were in the alendronate group, and all the subjects with dermatomyositis were in the placebo group. These differences are potential confounders to our results.

The aetiology of low bone mass in children with chronic illness is complex. In general it arises from a failure of normal bone acquisition rather than bone loss [23, 24]. Amongst the many interrelated factors of likely relevance are the nature and duration of the underlying disease, nutritional status, mobility, regional osteoporosis, delayed puberty and growth retardation. These factors can make the precise contribution of glucocorticoid treatment difficult to determine [25]. The link between acquisition of bone and growth retardation was evident in our subjects, in whom increments in bone size (at both lumbar spine and femoral shaft sites) were correlated with height velocity. On average, the children in this study had not been taking glucocorticoids for long periods, which may explain in part their relatively well-preserved bone density. A recent study of children (average age 9 yr) with relapsing nephrotic syndrome, who had received several courses of steroids from the age of 3, suggested that glucocorticoids may not greatly affect bone accretion in the lumbar spine, or that the effects on bone are offset by weight gain [26]. This study did not, however, include any formal assessment of cortical bone or assess bone size, outside the lumbar spine [25]. The elegant studies by Leong et al. [27, 28] describing bone mass in identical twin girls aged 15, one of whom had Cushing's disease, do indicate that ‘pure’ glucocorticoid excess (at least at this age) affects both the growth of bone—in all dimensions—and volumetric density, and that these deficits persist into adult life.

A beneficial effect of alendronate on cortical bone in the mid-femoral shaft was detected with the measurement of CSMI/unit length. This index incorporates elements of both mechanical strength (related to the dimensions of bone) and volumetric bone density. This observation needs verification, as concerns have been raised about the reproducibility of the technique we used [29]. In osteogenesis imperfecta, the positive effect on cortical bone is achieved largely through the inhibition of the endocortical bone resorption that takes place during growth [30]. This increases cortical width and thus mechanical strength. The greatest increases in strength, however, come from growth in the total width of bone—something that bisphosphonates are not known to influence directly. Our findings highlight the need for adequately powered, well-controlled studies of cortical bone when evaluating bisphosphonate treatment in children [25, 31].

Several uncontrolled studies in children with more severe osteoporosis on long-term glucocorticoid treatment have indicated that either intravenous or oral bisphosphonates are effective in improving spinal bone density measurements [12–14]. In adults, bisphosphonates are effective both as treatment for glucocorticoid-induced osteoporosis and as prophylaxis against glucocorticoid-induced bone loss [7, 8]. There is, however, no consensus—and little evidence—about the prophylactic use of bisphosphonates in children. Intermittent oral treatment would be the most logical approach to prophylaxis, and our study has demonstrated that this is feasible, well-tolerated and may improve volumetric bone density in the lumbar spine and mechanical strength at the mid-femoral site. Larger controlled studies are needed to determine if these changes translate into reduced fracture incidence or greater peak bone mass. Although bisphosphonate use is generally safe in children, there are a number of issues, such as its use in relation to pregnancy, that remain unresolved.


    Acknowledgments
 
We wish to thank the Maurice and Phyllis Paykel Trust and the Health Research Council of New Zealand for funding. Sarah Hailwood was a Michael Mason Travelling Fellow of the Arthritis Research Campaign, 1999–2000. We also thank Dr Alison Wesley, and our other colleagues at the Starship Children's Hospital, for referring patients to the study.

The authors have declared no conflicts of interest.


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 Abstract
 Introduction
 Subjects
 Methods
 Results
 Discussion
 References
 

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Submitted 24 August 2004; revised version accepted 7 December 2004.