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8 How do we manage specific types of osteoporosis?
8 How do we manage specific types of osteoporosis? Philip
N. S a m b r o o k Professor of Rheumatology
MBBS, FRACP, MD, LLB
Vasi Naganathan MBBS,FRACP Research Fellow
Sydney Umverstty Department of Rheumatology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Austra#a
Osteoporosis in children, adolescents and corticosterold-treated patients represent a particular problem for clinicians In children and adolescents, the main management question is whether any specific interventions can influence attainment of peak bone mass and so decrease the chance of osteoporosls in later adult life. The role of physical activity and calcium in particular are rewewed. In adolescence, osteoporosis is usually due to idiopathic juvenile osteoporosis or secondary to amenorrhoea or anorexia nervosa. These entities, as well as the management of corticosterold-induced osteoporosls at all ages, are discussed
Key words: osteoporosis; adolescence; growth; anorexia nervosa; cort~costeroids; b~sphosphonates; vitamin D; oestrogen.
Management of osteoporosis in children and adolescents Chnicians are increasingly confronted with managing cases of osteoporosis in children and adolescents. In th~s age group osteoporosls may be idiopathic or secondary to other me&cal conditions, however there are wider lmphcat~ons because this period is critical in the attainment of peak bone mass (Matkovlc et al, 1994; Teegarden et al, 1995). Peak bone mass, along with loss of bone later in life, are the two most important determinants of risk of osteoporotic fracture among post-menopausal women and elderly adults. Since therapeutic mtervenuons may potenually influence attainment of peak bone mass in children and juvemles, a number of issues arise in this age group with regard to the diagnosis and management of osteoporos~s. For example, the use of the diagnostic label 'osteoporosls' may be misleading m children and adolescents. In adults, osteoporosis is usually defined in relation to the degree to which bone mineral density Ballhere's ChmcalRheumatology-Vol 11, No 3, August 1997 ISBN 0-7020-2320-5 0950-3579/97/030597 + 16 $12 00/00
597 Copyright © 1997, by Bailh~re Tindall All rights of reproduotaon in any form reserved
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(BMD) is reduced, but it must be remembered that BMD is not a true density but rather, in most cases, an apparent density corrected for length and width (g/cm2). Bone size and structure must also be considered in its interpretation. The increase in BMD during growth also reflects increases in bone size and while peak BMD is the same for men and women, peak bone mass is generally less in women because they have smaller bones. Bone mass and BMD in childhood and adolescence
Skeletal growth revolves bone remodelling and occurs by either endochondral or intramembranous osslficanon. Concomitant with skeletal growth throughout early childhood, bone mass and BMD gradually increase in a linear fashion (Specker et al, 1987; Glastre et al, 1990). During puberty there is rapid accumulation of skeletal mass by linear growth as well as a rapid increase m BMD (De Schepper et al, 1991). The most significant increase is seen m the spine. In a 3-year study of 90 children aged 6-14 years, the increase in lumbar spine BMD was observed to be nearly threefold greater during puberty than before puberty (Slemenda et at, 1994). In children, height and weight are predictors of bone mass and BMD (Lloyd et al, 1992), however during adolescence the degree of sexual maturation begins to have a greater influence (Slemenda et al, 1994). Peak bone mass is generally thought to be attained by late adolescence in both males and females. In a cross-sectional study of 265 pre-menopausal women aged 8-50, peak bone mass and peak BMD at multiple skeletal sites were achmved by late adolescence (Matkovlc et al, 1994). This was parncularly notable for the proximal femur and spine. However in another cross-sectional study, peak BMD did not appear to be reached until the early 20s, whereas bone mass continued to increase slowly unnl the late 20s (Teegarden et al, 1995). There are a number of factors thought to influence bone mass and BMD acquisition in children and adolescenl;s. Studies in twins have shown a strong genetic effect on BMD in the forearm, lumbar spine, and femoral neck with generic factors esnmated to contribute up to 80% of the total population variance in BMD. Slmdarly, family studies have shown that BMD is reduced m the daughters of women with osteoporosis. Enwronmental factors also contribute to the variance in populanon BMD and it is hkely that factors such as d~etary calcium intake and physical activity interact with generic effects in the determination of peak bone mass in any individual. An important quesnon is whether modification of these factors in children and adolescents can influence attainment of peak bone mass and BMD and, as a result, decrease the risk of osteoporotic fractures in adulthood. Effect of habitual dietary calcium on BMD in children
A number of cross-secnonal studies support the influence of dietary calcmm during childhood and adolescence on attainment or maintenance
Management of osteoporosis 599
of peak bone mass. In a study of 139 women aged 30-39, teenage calcium intake was found to be associated w~th hip BMD but not with lumba~ spine or distal forearm BMD (Nieves et al, 1995). In a study of 151 children and adolescents aged 7-15, dietary calcium was shown to be sigmficantly associated with vertebral and femoral BMD m boys when expressed as g/cm2 and in both boys and girls when BMD was expressed as a Z score (Ruiz et al, 1995). When divided according to Tanner stages, dietary calcium only had an effect on spinal BMD before puberty and there was no effect on femoral BMD. A 15-year longitudinal study found daily calcium retake during adolescence and young adulthood (13-28 years) had no effect on the development of BMD at age 27 when the influence of weight-bearing activity and body weight was taken into account (Welten et al, 1994). The inconsistency in results from the above studies dlustrate the difficulty m arriwng at evidence-based recommendanons for dietary calcium intake for children and adolescents. In general, properly designed prospective longitudinal studies provide better evidence than cross-sectional studies and more such studies are required. Currently the recommended daily allowance (RDA) for calcium m North America is 800 mg/day during childhood and 1200mg/day during adolescence (Fassler and Bonjour, 1995). However, surveys of dietary calcium intake in adolescent girls have frequently found consumption of calcmm is significantly less than the recommended RDA (Flemming and Heinbach, 1994). Effect of calcium supplementation on BMD in children
There have been few randomized controlled trials looking at the effect of calcium supplementation in childhood and adolescence. One longitudinal cotwin-controlled study demonstrated that forearm and hip BMD was significantly increased by calcium supplementanon, the response mainly being seen in pre-pubertal children (Johnston et al, 1992). There was no difference between male twins and female twins in response to calcium supplement. This effect was independent of the level of physical activity and the difference between the supplemented and non-supplemented twins was not evident at follow-up several years later. In another trial, 94 girls (mean age 11.9) were randomized to 500 mg of calcium citrate. After 2 years the calcium-treated group were found to have a significant increase in lumbar spine and total body BMD (TBBMD) compared with the placebo group (Lloyd et al, 1993). The groups were re-randomized m a crossover fashion so that 2 and 4 years of calcium supplementanon could be compared with placebo. Five years after commencing the study, there was no significant difference in bone acquislnon between the two groups (Lloyd et al, 1996). This temporary effect of calcmm supplementanon was also seen in a controlled trial in 7-year-old Hong Kong Chinese children (Lee et al, 1996). Thus the currently avadable data do not provide evidence to recommend widespread use of calcium supplementation during childhood or adolescence.
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Physical activity and BMD in children A positive effect of physical activity and, m particular, weight-bearing exerose, has been observed m several cross-sectional studies. Rmz et al (1995) found the duration of weekly sports acuvity to have a greater effect on BMD in girls aged 7-15 than their calcium intake. A study of 90 children aged 6-14 years used a questionnaire administered to both the children and their mothers to esumate physical activity. Physical activity was a sigmficant predictor of BMD of the lumbar spine and femoral neck m the pre-pubertal group (Slemenda et al, 1994). There have been few studies to see if the benefits of physical activity in terms of bone mass and density persist into adulthood. The Amsterdam Growth and Health Study (Welten et al, 1994), which followed up sublects for 15 years and evaluated weight-bearing activity on six occasions during the study period, found weight-bearing activity to be the best predictor of BMD of the lumbar spine at age 27 in males (compared with body weight and calcmm intake). In females, however, no such association was found. In summary, there is evidence that childhood and adolescent physical activity have beneficial effects on attainment of peak bone mass in those age groups. The &fficulties of recalling childhood &ets in adult life makes it difficult to interpret retrospective studies that suggest any benefit has been maintained into adulthood. There is a paucity of controlled longitudinal studies looking at the effects of physical activity during childhood and adolesence.
Idiopathtc juvenile osteoporosis Idiopathic luvemle osteoporosis (IJO) IS an uncommon, self-limiting disease. IJO has been considered to have four cardinal features: (a) onset before puberty; (b) fractures of the vertebrae and long bones; (c) so called neo-osseous osteoporosls radiologlcally, whereby fractures occur at sites of newly formed weight-bearing metaphyseal bone; and (d) spontaneous recovery after skeletal maturity (Bartal and Gage, 1982). In making this diagnosis, ~t is important to exclude other causes of osteoporosls in this age group, such as Cushing's syndrome, malabsorption, leukaemla, and mild forms of osteogenesls ~mperfecta. After the diagnos~s is made, management is mainly &rected at the control of symptoms and minimizing permanent deformities. In a recent review of the case history of 21 patients with IJO, Smith (1995) confirmed that most pauents followed to adolescence had slgmficantly improved. The author concluded that because of the spontaneous ~mprovement, it was difficult to assess the effectweness of any particular treatments gwen. Sex hormones, calcitrlol, bisphosphonates and calc~tomn had all been used in different cases, but it was concluded that no specific treatment for IJO could be recommended.
Management of osteoporosls 601
Growth hormone deficiency in children Growth hormone (GH)-deficlent adults have an approximately 10% lower or 1 SD reduction in BMD. GH treatment given to children with GH deficiency has been shown to increase height velocity, as well as both muscle and bone mass. In an open label study (Saggese et al, 1996), 12 of 26 children had increased BMD in the distal radius to normal values for their age after 12 months of recombinant human GH (0.6 IU/kg weekly, given as subcutaneous injections six times a week). The increase in BMD was generally greater than expected by the increase in height.
Management of osteoporosis in the 'at risk' pre-menopausal woman BMD in elite female athletes and females with eating disorders Young women at risk of hypothalamic amenorrhoea include athletes, dancers, and those with eating disorders. Disruption of the pulsatlle release of gonadotrophic hormones results in low levels of folhcle stimulating hormone (FSH) and luteinizmg hormone (LSH) and therefore low levels of oestrogen and progesterone. This is thought to result in both failure to attain peak bone mass and bone loss. Negative energy balance and low body weight are probably also important factors. In female athletes, the association of anorexia nervosa, amenorrhoea, and osteoporosis is sometimes called the 'female athlete triad.' It has been estimated that between 5-35% of female athletes and dancers have eating disorders (Hergenroeder, 1995). A number of studies have shown amenorrhoeic athletes to have lower BMD particularly of the lumbar spine, where trabecular bone predominates. Rutherford (1993) found that amenorrhoelc athletes had lower lumbar and total spine BMD compared with eumenorrhoeic athletes. Interestingly, there was no difference in TBBMD suggesting the possibility that cortical bone may be relatively protected by athletic activity, despite amenorrhoea. In contrast, a recent study found that not only did amenorrhoelc athletes have lower lumbar BMD, but BMD of all regions of the hip, femoral shaft, and tibia were lower than controls with normal menses (Rencken et al, 1996). The relationship between body weight, body fat, and BMD in athletes remains controversial, except in the cases of athletes with very low body weight (Fruth and Worrell, 1995). In anorexia nervosa, hypothalamlc amenorrhoea also results in a loss of trabecular bone. In a study of 48 anorexic women who were amenorrhoelc, 52% had a baseline lumbar BMD <2 SD of the mean of young normal values (Khbanskl et al, 1995). There was a correlation with the durauon of amenorrhoea. Those who did not recover their menses continued to lose
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trabecular bone. In anorexia nervosa, factors other than hypothalamic amenorrhoea appear to play a role m the pathogenes~s of the osteoporosis. For example, body mass index and weight are related to BMD independent of the duration of amenorrhoea (Bachrach et al, 1990). Moreover, the recovery of BMD m anorexm nervosa can precede spontaneous menstruation, suggesting an independent effect of weight gain on BMD accretion. This suggests that BMD can increase in the absence of oestrogen supplementation (Hergenroeder, 1995). Hypercortisolism may also be revolved in the pathogenesis of the abnormal mineral metabohsm (Abrams et al, 1993).
Prevention and management of osteopenia in athletes and females with eating disorders Early recognmon is the key to minimizing bone mass effects and thereby reducing the risk of osteoporotic fractures in the future. Even with treatment, there is ewdence that the reduction in BMD cannot necessarily be completely reversed (Gulekli et al, 1994). In both female athletes and women with anorexm nervosa, menstrual abnormaliues can go undetected if not sought. Simxlarly, even m cases where there is no obvious weight loss, a good dietary history is mandatory. Other causes for amenorrhoea should also be excluded, for example, hyperprolactinaemia, and primary ovarian failure. In athletes, modification of duration and intensity of exercise should be advised. However, compliance with such advice may be a problem in elite athletes and the duration, intensity, and nature of physical activity do not necessarily correlate with the extent of reducuon m BMD. Female rowers, for example, have been shown to have higher BMD of the lumbar spree compared with controls, even when amenorrhoeic (Natuv et al, 1994). In anorexia nervosa, there is no evidence that regular exercise will have any benefit on bone mineralization. In athletes or in those with anorexia nervosa, low body mass and low body mass index should be corrected by increasing caloric retake where possible, although compliance will again be a problem in many subjects. Gains in BMD can occur with weight gain, even before the return of menstrual function (Bachrach et al, 1991). Oestrogen deficiency may have a detrimental effect on calcmm metabolism, but there is little evidence that calcium supplementation has a role to play in the management of these premenopausal women unless they have a poor daily calcium retake (SnowHatter, 1994). Females who have been amenorrhoeic for more than 6 months should have BMD studies performed. If there is evidence of osteopema, conslderation should be given to hormonal replacement theraphy (HRT). This will be discussed in more detail below. If there is no evidence of osteopenia but menstrual function does not return to normal, then bone density studies should be repeated after 12 months.
Management of osteoporosis 603
HRT
A recent survey of members of the American Medical Society for Sports Medicine, found that 92% of respondents prescribed sex steroids at some stage for amenorrhoeic athletes (Haberland et al, 1995). However there is a relative paucity of prospective data demonstrating the efficacy of HRT m preserving or restoring bone mass in athletes or females with eating dxsorders. There has been one randomized controlled trial looking at oestrogen therapy in anorexic women (Klibanskl et al, 1995) and one randomized trial in women with miscellaneous causes of amenorrhoea (Warren et al, 1994). There have been no controlled trials using either HRT or the oral contraceptive pill (OCP) specifically in amenorrhoeic female athletes. In the only randomized controlled trial specifically of anorexic women, 22 women were randomized to oestrogen therapy (Klibanski et al, 1995). Sixteen received HRT (Premarin 0.625 mg on days 1-5 and Provera 5 mg on days 16-25) and six an OCP (35 ~tg ethinyl oestradiol). Comparisons were made w~th 26 controls after 1.5 years. Patients in the oestrogen group as a whole did not show a significant improvement in lumbar BMD measured by computed tomography. However in women with initial body wexghts less than 70% of ~deal body weight, an increase of 4% m BMD was seen with oestrogen compared with a 20% decrease in the control group. There was no difference in the BMD between those who recewed Premarin plus Provera compared with OCP. The authors concluded that oestrogen therapy may only be beneficial in a subset of anorexic women with markedly reduced body weight. The study by Warren et al (1994) was a randomized controlled trial in amenorrhoeic women treated w~th HRT for 2 years. It grouped together women with a number of different causes for amenorrhoea including anorexic women, athletes, dancers, and women w~th primary ovarian failure and hyperprolactinaemia. No difference was found in change in BMD of the spine, forearm, or foot with treatment compared w~th a placebo group. Weight was suggested as a cofactor mitigating the effects of oestrogen deficiency. In contrast in another longitudinal study of women aged 17-40 years with a past or current history of amenorrhoea from various causes, a significant improvement in lumbar BMD was seen in women treated with all types of oestrogen therapy. The mean time of treatment was 19.6 months (Gulekli et al, 1994). Once again the importance of weight gain m improving BMD was shown. There are, of course, difficulties in conducting truly 'blind' controlled trials wxth HRT or OCP because of withdrawal bleeding and subjects not knowing if they are receiving contraception. Another problem with interpretation of these trials is that many of the women included in the trials have had amenorrhoea for more than 6 months, often for 2-4 years. The longer the duration of amenorrhoea, the less likely it is that bone loss is completely reversible (Bachrach et al, 1991; Gulekh et al, 1994). It is of interest that the study by Khbanski et al (1995) showed a marked improvement in spinal BMD m those patients who spontaneously resumed
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menses. This contrasts with the mimmal benefit that was seen with oestrogen replacement therapy. The authors concluded that progesterone may have been the factor contributing to the differennal effect on BMD between exogenous oestrogen and restored gonadal function. A 1-year randomized trial of physmally active pre-menopausal women (recreational athletes) with amenorrhoea, oligomenorrhoea, anovulation or short luteal phase cycles examined the effects of medroxyprogesterone at 10 mg/day for 10 days per month (Prior et al, 1994). A significant gain m spinal BMD was seen m the groups who received medroxyprogesterone. This compared with no change in the group who received calcium alone and a decrease in BMD in the placebo groups.
Practical management guidehnes of the 'at risk' pre-menopausal women The treatment of athletes or panents w~th an eating &sorder who are at risk of osteopema as a result of hypothalalmic amenorrhoea should first include correction of any primary cause for the amenorrhoea. In anorexic patients and underwmght athletes, correction of the low body weight is the most effective treatment both to restore bone mass and prevent loss. Compliance may be improved by education about the potential complications. In athletes, mo&ficanons should be made to training schedules to try to attain normal menstrual cycles. Again, compliance may be improved by educanon. BMD should be measured if amenorrhoea has been present for more than 6 months. If there is evidence of osteopema, then oestrogen replacement should be commenced. It is important to note that although low-dose HRT has been shown to be effective m post-menopausal women, these doses may not be physiological in young pre-menopausal women. Although yet to be definitely proven in randomized trials, treatment with the higher oestrogen doses usually encountered m formulations of the OCP may be more beneficial. Another theoretical consideration is that in Practice points •
an adequate dietary calcmm intake in childhood and adolescence appears to be an ~mportant determinant of peak bone mass in adulthood; however, there is no evidence for the routine use of calcmm supplementation
•
females who have been amenorrhomc for more than 6 months should have bone mineral density stu&es
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invesngate and correct any primary causes for amenorrhoea
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in amenorrhoem athletes and anorexic women correction of low body wmght is the most effective treatment for reduced bone mass
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If bone density is low after 6 months of amenorrhoea then oestrogen replacement should be commenced
Management of osteoporosis 605
adolescents, who have not reached their maximum height, oestrogen replacement could result ,n early skeletal maturation and accelerated fusion of the epiphyses. The potential loss of height needs to be weighed up against the potennal morbMlty associated with developing osteopenia at this age.
Corticosteroid osteoporosis Corticosteroids are widely used m the treatment of panents w~th chronic inflammatory diseases such as rheumatoid arthritis (RA), connective tissue diseases, inflammatory bowel disease, skin disease, and chronic lung disease. Since the most rapid bone loss occurs m the first 12-24 months in patients commencing h~gh-dose cortlcosterolds, it is important to consMer two different treatment situations: (a) prevention in patients starting corticosteroids who have not yet lost bone; and (b) treatment of patients on chromc corticosterolds who will almost certainly have some significant degree of existing corncosterold-related osteoporosis.
Role of investigations Corticosteroids effects on bone metabohsm are reflected m marked changes in biochemical markers of bone turnover, opening the posslbihty that some markers may be predictive of those patients who lose bone rapidly with corticosteroids. Serum osteocalcm falls within hours of treatment with corticosteroids (Cosman et al, 1994) and levels are sigmficantly related to cortlcosteroid dose. A recent study found tartrate-reslstant acid phosphatase rose following acute corncosteroid administration but there was no change in collagen crosslinks such as pyridinoline (Cosman et al, 1994). However, no studies have shown the degree of change m any markers to be predictive of bone loss, although in a recent clinical trial the serum osteocalcin at 12 months was related to the degree of bone loss, with an inverse relationship such that those who lost the most bone showed the most marked rebound in serum levels (Sambrook et al, 1993). Accordingly at present there is no reliable way of predicting by such biochemical markers, or indeed by clinical risk factors, which patients will lose bone on corticosteroids. However, a bone density measurement is appropriate m patients starting high-dose, long-term corticosteroids as well as a lateral X-ray of the thoracic and lumbar spree. If the spinal X-ray reveals a prior vertebral fracture or the bone density measurement reveals a reduced value, a poorer outcome ~s suggested and intervention becomes more important.
Treatment of cortlcosterold osteoporosis The first principle of treatment of corncosteroid-induced bone loss is to use the lowest dose of corncosterold possible and withdraw corncosterolds
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whenever possible. There ~s evidence that corticosterold osteoporosis may be partially reversible and if the treatment course is less than 6 months, the risk of significant bone loss or fracture is considerably reduced. Numerous therapeuuc approaches have been used for glucocorticoidreduced bone loss, and the evidence supporting these treatments will now be summarized. Calcium
Corticosteroid bone loss results in part from impaired calcmm absorption from the gastrointestinal tract and increased urinary calcium loss. Although the use of calcium supplements has been shown to decrease markers of bone resorption in corticosterold-treated patients, recent randomized controlled trials in patients starting cort~costeroids where calcium was used as the control therapy observed rapid rates of loss (Sambrook et al, 1993; Mulder and Struys, 1994). While an adequate calcium intake should therefore be recommended, calcium alone probably does not have a major role to play in prevention of treatment of corticosteroid bone loss. Vitamin D
The use of calcium with vitamin D as a treatment for corticosteroid bone loss has been suggested following a series of different studies conducted in the 1970s. Hahn and Hahn (1976) examined treatment with calcium 500 mg/day and vitamin D 50 000 units per week in patients on chronic corucosteroids. A slgmficant increase in forearm bone density was observed with treatment but the study was not randomized nor primary prevention in design. Moreover, since bone density was only measured in the radms, whereas bone loss mostly occurs from the spine with corticosterolds, the clinical s~gnlficance of these findings as unclear. In another study, positive results were reported with treatment with 25-hydroxyvltamin D (40 ~tg/day) plus calcium (Hahn et al, 1979) but again this was not a prevention study and only forearm bone mass was monitored, not spinal bone density. Adachi et al (1996) recently reported the results of a prevention study comparing treatment with calcium 1000 mg daily plus vitamin D (50 000 units weekly) against placebo over 3 years. There was no statistically significant difference m bone loss at the lumbar spine between calcium/ vitamin D and placebo. The data were interpreted as suggesting some potentml benefit of calcmm/vitamm D in terms of rates of loss, but the amount of bone loss observed at the spine after 12 months with the calcmm/vltamm D combination (4.9%) was similar to that seen in the calcium-treated control groups in two recent prevention studies (Sambrook et al, 1993; Mulder and Struys, 1994). In contrast, a recent study by Buckley et al (1996) observed an apparent benefit of calcium (1000 mg daily) plus vitamin D3 (500 IU/day) in patients with RA treated with chronic
Management of osteoporosis 607
low-dose corucosteroids, amounting to about a 2% difference compared with placebo. However, the authors noted several caveats: half of the basehne values of spine BMD were esumated from lateral scans; the results were not generalizable to patients commencing high-dose corticosterolds, i.e. prevention; and, as this was a study of chromc low-dose corticosteroid users, the BMD rise may have largely been a 'remodelling transient' whereby the rise m BMD is due to an initial filling of bone spaces undergoing remodelling. Calcitriol
Although the term vitamin D is sometimes used to encompass both the calciferols and calotrlol, this is misleading since calcimol has qmte a &stinct therapeuuc profile. Calcltnol is the active hormonal form of vitamin D, 1,25 dihydroxyvltamin D (1,25(OH2)D3) and two pubhshed studies have examined its use in corticosteroid osteoporosis. In one early study of chronic corucosteroid users, the effect of calcitrlol (0.4 Bg/day) was examined and, although calcium absorption improved, there was no significant benefit of treatment on forearm bone density, w:th both groups showing a small rise in bone mass (Dykman et al, 1984). A more recent study examined the effect of calcitriol as a preventative agent in a much larger randomized double bhnd controlled trial with spine bone density as the primary end point (Sambrook et al, 1993). Patients treated with calcium only lost bone at the lumbar spine (4.3% per year) whereas patients treated with either calcltnol or calcitnol and calc~tomn lost bone at a much reduced rate (1.3% and 0.2% per year, respectively). There was no significant difference between the two calcltriol groups, whereas both groups were significantly different from the calcium group. The mean daily dose of calotrlol at 0.6 ~tg was h:gher than m the earher study and, although similar trends were observed for the distal radius, these were not significant, so these data are actually consistent with the earher Dykman study. A recent study with 1-0~ hydroxyvitamin D (0~-calcidol) appears to confirm that the active vitamin D analogues have efficacy m prevention of bone loss m patients starting corticosteroids (Lakatos et al, 1996). Mild hypercalcaemla was reasonably common in the study by Sambrook et al (1993), probably related to the concomitant admimstration of a calcium supplement. In clinical practice, if dietary calcmm is adequate, supplementation should be avoided but monitoring of plasma calcium every 3-6 months is appropriate when vitamin D metabohtes are used. HRT
Corucosteroid use is assooated with suppression of adrenal androgens, and hypogonadlsm is commonly seen in males and females treated with corticosteroids. In one small open study of post-menopausal women with asthma, the combination of oestrogen and progestogen therapy increased bone mass
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in patients on chromc corticosterolds over 1 year (Lukert et al, 1992). In a subgroup of patients on chronic low-dose cortlcosteroids participating in a randomized controlled trial of the effect of HRT on disease activity and bone loss m RA, some benefit of treatment was seen at the lumbar spine over 2 years (Hall et al, 1994). Based on the results of these studies, it has been recommended that post-menopausal women taking glucocorticolds should received HRT if there are no contra-indications. No randomized trials have been performed in glucocorticoid-treated pre-menopausal women and, in those with normal menstrual cycles, hormone treatment is inappropriate, although in woman with irregular menstrual cycles, use of the OCP may be appropriate. There has also been one study m a small number of males looking at the efficacy of testosterone therapy m chronically-treated glucocomcold asthmatics, which showed a benefit at the spine but not the hip after 12 months of monthly mlecuons (Reid et al, 1996). If serum testosterone levels are low in men, then consideration could be given to use of testosterone therapy m patients established on corticosteroids.
Bisphosphonates Blsphosphonates are analogues of pyrophosphate that bind to hydroxyapatite at sites of bone remodelling. They inhibit bone resorption primarily, and several bisphosphonates are available in various countries including etidronate, pamidronate, alendronate, tiludronate, and residronate. At this time, only etldronate and pamidronate have been studied to any extent m corucosteroid osteoporosis. In a prevention study of 20 woman with temporal arteritis, m which 10 were randomized to cyclical etidronate prevention of bone loss was seen compared with the calcmm-treated group (Mulder and Struys, 1994). Several other open stu&es also suggest efficacy of cyclical etidronate m chronic cort~osteroid users as well. Studies in patients with chronic obstructive airways disease treated with oral pamidronate have also demonstrated significant benefits at the lumbar spine over 2 years (Reid et al, 1988), suggesting anti-fracture efficacy. It is reasonable to assume that other, newer blsphosphonates, will be similarly active in cortlcosteroid osteoporosis, and currently there are several trials ongoing with these new generation bisphosphonates which will address this issue directly. However, because of their long skeletal retention, blsphosphonates are not normally used in the treatment of younger individuals.
Calcitonin Calcltomn has been trialled in patients starting corticosterolds and receiving chronic corticosterolds with varying results. Interpretation of some of these studies is confounded by the calcitonin-treated group having a significantly lower BMD than the control group at baseline (Rizzato et al, 1998; Luengo eta], 1990). One study of chronic corticosteroid users by Montemurro et at
Management of osteoporosls
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(1991) &d show apparent benefit from calcitonin at the spine. In contrast, in two recent prevention studies there was no statistically significant additional benefit of adding calcltonin to calcitriol or cholecalciferol (Sambrook et al, 1993; Healey et al, 1996).
Approach to the patient commencing long-term corticosteroid therapy In patients commencing cortlcosteroids in high doses for the first time, the best predictor of risk of fracture is a bone density measurement. An adequate calcmm intake is recommended and any contributing factors to osteoporosis should be treated where possible. If long-term therapy is envisaged, then treatment with a bisphosphonate or an active vitamin D metabohte (c~-calcidol or calcitriol) is appropriate in patients starting corticosteroids, and the treatment may need to be continued for 1-2 years. In post-menopausal women, concomitant use of oestrogen replacement therapy is probably also appropriate.
Approach to patient already on long-term corticosteroid therapy It is important in a patient on long-term corticosteroid therapy to rewew the need for continuing treatment or the possibility of reducuon in dosage. A bone density measurement will give information about their risk of future osteoporotic fracture and the need for active pharmacological treatment. In post-menopausal women or men w~th a low serum testosterone, H R T with oestrogen or testosterone respectively, is appropriate. Patients requiring long-term cortlcosterold therapy with clinically significantly reduced bone density values should be treated with vitamin D metabolites (including the calciferols) or a bisphosphonate.
Research agenda •
do patlcntq treated wtth coruco~tcro~d~ tracture at chtlerent B M D levels to other types ot osteoporosi~?
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hte,, n3 prcveutmg cortico,,tcrold bone loss? •
~s therc a,lx ad',autage in COl+Ibmtn!.;antn'e,,orpttve agents Per pre~,OlltlOll or t l ' C a l l l l e l l t ()f c()rtlcoster(>id b o l l e Io++?
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do low doses oI Lorll~.osret'old result l]] dnnc:dh" slgnilicant [)Olle
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Summary In children and adolescents there is evidence to suggest that habitual dietary calcium intake m a y influence attainment of peak B M D . However, a longterm benefit of calcium s u p p l e m e n t a t i o n has not been s h o w n in this age group. Cross-sectional studies showing an association between physical activity and B M D also suggest the level of physical activity during c h i l d h o o d and adolescence m a y m o d i f y peak bone mass. O n current evidence, no specific t r e a t m e n t can be r e c o m m e n d e d for cases o f IJO. G H deficiency in children should be treated with r e c o m b i n a n t G H therapy. A m e n o r r h o e l c athletes and y o u n g w o m e n with eating disorders, such as anorexia nervosa, are at risk of u n d e r a t t a i n m e n t of their potential p e a k bone mass or bone loss, and early recognition is important. Bone density m e a s u r e m e n t should be p e r f o r m e d if a m e n o r r h o e a persists for m o r e t h a n 6 months. Correcting b o d y mass deficit is an i m p o r t a n t goal of treatment as well as h o r m o n e t h e r a p y in the f o r m of the OCP. Patients c o m m e n c i n g high-dose long-term corticosteroid therapy should be treated p r o p h y l actically with active vitamin D metabolites (0~-calcldol or calcitnol) or a bisphosphonate. Patients o n chronic corticosteroids m a y improve their B M D with HRT, vitamin D metabolites (including the calcfferols) a n d blsphosphonates.
References Abrams SA, Sllber TJ, Esteban NV et al (1993) Mineral balance and bone turnover m adolescents with anorexia nervosa. Journal of Pedzatrtcs 123(2): 326-331 Adachi J, Bensen W, Blanch1 F et al (1996) Vitamin D and calcmm m the prevennon of corncosterold-mduced osteoporosls a three year follow up study Journal of Rheumatology 23: 995-1000. Bachrach LK, Guido D, Katzman D et al (199~0) Decreased bone density m adolescent girls with anorexia nervosa. Pedzatr~cs86(3): 440-447. Bachrach LK, Katzman DK, Ltt IF et al (1991) Recovery from osteopema m adolescent girls with anorexia nervosa. Journal of Chmcal Endocrinology and Metabohsm 72(3): 602606. Bartal E, & Gage JR (1982) Idiopathic juvemle osteoporosls and scohosls. Journal of Pedlatr~c Orthopedics 2: 295-298. Buckley LM, Lelb ES, Cartularo KS et al (1996) Calcmm and vitamin D3 supplementation prevents bone loss in the spine secondary to low dose cort~costerolds m patients with rheumatoid arthrms. Annals of Internal Medicine 125: 961-968. Cosman F, Nleves J, Herbert J e t al (1994) High-dose glucocorncolds m multiple sclerosis panents exert direct effects on the kidney and skeleton. Journal of Bone and Mineral Research 9: 1097-1105. De Schepper J, Derde MP, Van den Broeck Met al (1991) Normanve data for lumbar spree bone mineral content m children: influence of age, height, weight and pubertal stage. Journal of Nuclear Medzcme 32:216-220. Dykman TR, Haralson KM, Gluck OS et al (1984) Effect of oral 1,25-dlhydroxyvitamm D and calcium on glucocorncold-mduced osteopema m pattents with rheumatic diseases. Arthr~tls and Rheumatzsm 27: 1336-1343. Fassler ALC & Bonjour JP (1995) Osteoporosls as a pedmtnc problem. Pedlatrzc Chmcs of North America 42(4): 811-824
Management of osteoporos~s 611 Flemming KH & Helmbach JT (1994) Consumptton of calcmm m the Umted States: food sources and intake levels. Journal of Nutrztlon 124 (supplement): $1426-$1430. Fruth SJ & Worrell TW (1995) Factors associated with menstrual lrregulanues and decreased bone mineral density in female athletes. Journal of Orthopaedic and Sports Physical Therapy 22(1): 26-38. Glastre C, Bralllon P, David Let al (1990) Measurement of bone mineral content of the lumbar spree by dual energy x-ray absorpt~ometry m normal children: correlauons with growth parameters. Journal of Ckmcal Endocrinology and Metabohsm 70: 1330-1333. Gulekli B, Davies MC & Jacobs HS (1994) Effect of treatment on estabhshed osteoporosls in young women with amenorrhoea. Chmcal Endocrtnology Oxford 41(3): 275-281. Haberland CA, Seddlck D & Marcus R et al (1995) A physician survey of therapy for exerciseassociated amenorrhea: a brief report. CkmcalJournal of Sports Medlclne 5(4): 246-250. Hahn TJ & Hahn BH (1976) Osteopenla m sublects with rheumatic diseases: principles of diagnosis and therapy. Sermnars m Arthrztzs and Rheumatism 6: 165-188. Hahn TJ, Halstead LR, Teltelbaum SL et al (1979) Altered mineral metabohsm m glucocortlcold-mduced osteopema. Effect of 25-hydroxywtamm D administration. Journal of Ckmcal Investlgauon 64: 655-665. Hall GM, Darnels M, & Doyle DV et al (1994) The effect of hormone replacement therapy on bone mass m rheumatoid arthrms treated w~th and without steroids. Arthrztts and Rheumattsrn 37: 1499-1505. Healey J, Paget S, Wilhams-Russo P e t al (1996) Randomlsed trml of salmon calcltomn to prevent bone loss m cortlcosteroid treated temporal arterltlS and polymyalgm rheumat~ca. Calcified Tissue International 58: 73-80. *Hergenroeder AC (1995) Bone mmerahzatlon, hypothalamlc amenorrhea, and sex steroid therapy m female adolescents and young adults. Journal of Pedtatrzcs 126 (5 Pt 1): 683-689. Johnston CC, Miler JZ, Slemenda CW et al (1992) Calcium supplementation and increases m bone mineral density m children. New EnglandJournal of Medicine 327: 82-87. "Klibanski A, Blller BM, Schoenfeld DA et al (1995) The effects of estrogen admmlstranon on trabecular bone loss m young women with anorexm nervosa. Journal of Ckmcal Endocrinology and Metaboksrn 80(3): 898-904. Lakatos P, Kiss L, Horvath C et al (1996) Effect of alphacalcldol on bone m patients treated with glucocorncolds. Journal of Bone and Mineral Research 11 (supplement): $545. Lee WT, Leung SS, Leung DM & Cheng JC (1996) A follow-up study on the effects of calcmm-supplement withdrawal and puberty on bone acqulsmon of children. Arnerwan Journal of Ckmcal Nutrtt~on 64(1): 71-77. Lloyd T, Rolhngs N, Andon MB et al (1992) Determinants of bone density m young women. I. Relationships among pubertal development, total body bone mass, and total body bone density m premenarchal females. Journal of Ckmcal Endocrinology and Metaboksm 75: 383-387. Lloyd T, Andon MB, Rolhngs N e t al (1993) Calcium supplementatmn and bone mineral density m adolescent girls. Journal of the American MedzcalAssoczatton 270(7): 841-844. 'rLloyd T, Rolhngs N, Andon MB et al (1996) Enhanced bone gain m early adolescence due to calcium supplementation does not persist m late adolescence. Journal of Bone and Mineral Research 11 (supplement): $154. Luengo M, Plcado C, Del Rm L e t al (1990) Treatment of stermd-mduced osteopema with calc~tonm m cortlcosterold-dependent asthma. Arnerzcan Rewew of Resplratory Dtsease 142:104-107 Lukert BP, Johnson BE & Robinson RG (1992) Estrogen and progesterone replacement therapy reduces glucocomcmd induced bone loss. Journal of Bone and Mtneral Research 7:1063-1069 *Matkovic V, Jehc T, Wardlaw GM et al (1994) Timing of peak bone mass m Caucasmn females and its implication for the prevention of osteoporosts. Inference from a cross-sectional model. Journal of Ckmcal Investsgatlon 93(2): 799-808. Montemurro L, Schlraldl G, Fraldl P et al (1991) Preventmn of corncostero~d Induced osteoporosls w:th salmon calc:tomn in sarcold patients. Calcified T~ssue International 49: 71-76. ~'Mulder H & Struys A (1994) Intermittent cychcal etldronate m the preventmn of cortlcostermd Induced bone loss. Br~ushJournal of Rheumatology 33:348-350
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Natnv A, Agosnm R, Drinkwater B et al (1994) The female athlete triad The mterrelatedness of disordered eating, amenorrhea, and osteoporosls Chmcs m Sports Medzclne 13(2): 405-418. Nieves JW, Golden AL, Sms-E et al (1995) Teenage and current calcium retake are related to bone mineral density of the hip and forearm m women aged 30-39 years. American Journal of Eptdermology 141(4): 342-351. Prior JC, Vlgna YM, Barr SI et al (1994) Cychc medroxyprogesterone treatment increases bone density: a controlled real m acnve women w~th menstrual cycle disturbances. American Journal of Medicine 96(6): 521-530. Reid IR, King AR, Alexander CJ & Ibbertson HK (1988) Prevention of steroid-reduced osteoporosls with (3-ammo-l-hydroxypropyhdme)-l, 1-blsphosphonate (APD). Lancet 1: 143146. Reid IR, Wattle DJ, Evans MC & Stapleton JP (1996) Testosterone therapy m glucocorncold treated men. Archives of Internal Medlcme 156:1173-1177. Rencken ML, Chesnut CH 3rd & Drinkwater BL (1996) Bone density at multiple skeletal sites m amenorrhelc athletes. Journal of the Amerzcan Medical Assoczatton 276(3): 238-240. Rlzzato G, Tosl G, Schlraldl G e t al (1988) Bone protecnon with salmon calcltomn (sCT) m the long term steroid therapy of chromc sarcoldosls. Sarcotdosls 5: 99-103. *Rulz JC, Mandel C & Garabedmn M (1995) Influence of spontaneous calcmm retake and physical exercise on the vertebral and femoral bone mineral density of children and adolescents. Journal of Bone and Mineral Research 10(5): 675-682. Rutherford OM (1993) Spree and total body bone mineral density m amenorrhelc endurance athletes Journal of Apphed Physiology 74(6): 2904-2908. Saggese G, Baronelh GI, Bertellom S & Barsann S (1996) The effect of long term growth hormone (GH) treatment on bone mineral density m children with GH deficiency. Journal of Ckmeal Endocrinology and Metaboksm 81: 3077-3083. "Sambrook PN, Birmingham J, Kelly PJ et al (1993) Prevennon of corncosteroid osteoporosis; a comparison of calcmm, calcitnol and calcltonm. New England Journal of Medicine 328: 1747-1752. Slemenda CW, Relster TK, Hm SL et al (1994) Influences on skeletal mmerahzanon m chddren and adolescents: evldence for varying effects of sexual maturanon and physical acnwty Journal of Pedtatrtcs 125 (2): 201-207. '-Smith R (1995) Idiopathic luvenfle osteoporosls: experience of twenty-one patients. Br~tzsh Journal of Rheumatology 34: 68-77. Snow-Harter CM (1994) Bone health and prevennon of osteoporosls m active and athlenc women Ckmcs m Sports Medicine 13(2): 389-404. Specker BL, Brazerol W, Tsang RC et al (1987) Bone mineral content m children 1 to 6 years of age. American Journal of Diseases m Children 141: 343-344. '¢Teegarden D, Proulx WR, Martin BR et al (1~95) Peak bone mass m young women. Journal of Bone and Mineral Research 10(5): 711-715. Warren MP, Fox RP, DeRogans et al (1994) Osteopema m hypothalamlc amenorrhea: a 3-year longitudinal study. Abstract. Program of the Endocrine Society Annual Meenng, Anaheim, Cahforma Welten DC, Kemper HC, Post GB et al (1994) Weight-bearing acnvlty during youth Is a more Important factor for peak bone mass than calcium retake. Journal of Bone and Mineral Research 9(7): 1089-1096.
N. S a m b r o o k Professor of Rheumatology
MBBS, FRACP, MD, LLB
Vasi Naganathan MBBS,FRACP Research Fellow
Sydney Umverstty Department of Rheumatology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Austra#a
Osteoporosis in children, adolescents and corticosterold-treated patients represent a particular problem for clinicians In children and adolescents, the main management question is whether any specific interventions can influence attainment of peak bone mass and so decrease the chance of osteoporosls in later adult life. The role of physical activity and calcium in particular are rewewed. In adolescence, osteoporosis is usually due to idiopathic juvenile osteoporosis or secondary to amenorrhoea or anorexia nervosa. These entities, as well as the management of corticosterold-induced osteoporosls at all ages, are discussed
Key words: osteoporosis; adolescence; growth; anorexia nervosa; cort~costeroids; b~sphosphonates; vitamin D; oestrogen.
Management of osteoporosis in children and adolescents Chnicians are increasingly confronted with managing cases of osteoporosis in children and adolescents. In th~s age group osteoporosls may be idiopathic or secondary to other me&cal conditions, however there are wider lmphcat~ons because this period is critical in the attainment of peak bone mass (Matkovlc et al, 1994; Teegarden et al, 1995). Peak bone mass, along with loss of bone later in life, are the two most important determinants of risk of osteoporotic fracture among post-menopausal women and elderly adults. Since therapeutic mtervenuons may potenually influence attainment of peak bone mass in children and juvemles, a number of issues arise in this age group with regard to the diagnosis and management of osteoporos~s. For example, the use of the diagnostic label 'osteoporosls' may be misleading m children and adolescents. In adults, osteoporosis is usually defined in relation to the degree to which bone mineral density Ballhere's ChmcalRheumatology-Vol 11, No 3, August 1997 ISBN 0-7020-2320-5 0950-3579/97/030597 + 16 $12 00/00
597 Copyright © 1997, by Bailh~re Tindall All rights of reproduotaon in any form reserved
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(BMD) is reduced, but it must be remembered that BMD is not a true density but rather, in most cases, an apparent density corrected for length and width (g/cm2). Bone size and structure must also be considered in its interpretation. The increase in BMD during growth also reflects increases in bone size and while peak BMD is the same for men and women, peak bone mass is generally less in women because they have smaller bones. Bone mass and BMD in childhood and adolescence
Skeletal growth revolves bone remodelling and occurs by either endochondral or intramembranous osslficanon. Concomitant with skeletal growth throughout early childhood, bone mass and BMD gradually increase in a linear fashion (Specker et al, 1987; Glastre et al, 1990). During puberty there is rapid accumulation of skeletal mass by linear growth as well as a rapid increase m BMD (De Schepper et al, 1991). The most significant increase is seen m the spine. In a 3-year study of 90 children aged 6-14 years, the increase in lumbar spine BMD was observed to be nearly threefold greater during puberty than before puberty (Slemenda et at, 1994). In children, height and weight are predictors of bone mass and BMD (Lloyd et al, 1992), however during adolescence the degree of sexual maturation begins to have a greater influence (Slemenda et al, 1994). Peak bone mass is generally thought to be attained by late adolescence in both males and females. In a cross-sectional study of 265 pre-menopausal women aged 8-50, peak bone mass and peak BMD at multiple skeletal sites were achmved by late adolescence (Matkovlc et al, 1994). This was parncularly notable for the proximal femur and spine. However in another cross-sectional study, peak BMD did not appear to be reached until the early 20s, whereas bone mass continued to increase slowly unnl the late 20s (Teegarden et al, 1995). There are a number of factors thought to influence bone mass and BMD acquisition in children and adolescenl;s. Studies in twins have shown a strong genetic effect on BMD in the forearm, lumbar spine, and femoral neck with generic factors esnmated to contribute up to 80% of the total population variance in BMD. Slmdarly, family studies have shown that BMD is reduced m the daughters of women with osteoporosis. Enwronmental factors also contribute to the variance in populanon BMD and it is hkely that factors such as d~etary calcium intake and physical activity interact with generic effects in the determination of peak bone mass in any individual. An important quesnon is whether modification of these factors in children and adolescents can influence attainment of peak bone mass and BMD and, as a result, decrease the risk of osteoporotic fractures in adulthood. Effect of habitual dietary calcium on BMD in children
A number of cross-secnonal studies support the influence of dietary calcmm during childhood and adolescence on attainment or maintenance
Management of osteoporosis 599
of peak bone mass. In a study of 139 women aged 30-39, teenage calcium intake was found to be associated w~th hip BMD but not with lumba~ spine or distal forearm BMD (Nieves et al, 1995). In a study of 151 children and adolescents aged 7-15, dietary calcium was shown to be sigmficantly associated with vertebral and femoral BMD m boys when expressed as g/cm2 and in both boys and girls when BMD was expressed as a Z score (Ruiz et al, 1995). When divided according to Tanner stages, dietary calcium only had an effect on spinal BMD before puberty and there was no effect on femoral BMD. A 15-year longitudinal study found daily calcium retake during adolescence and young adulthood (13-28 years) had no effect on the development of BMD at age 27 when the influence of weight-bearing activity and body weight was taken into account (Welten et al, 1994). The inconsistency in results from the above studies dlustrate the difficulty m arriwng at evidence-based recommendanons for dietary calcium intake for children and adolescents. In general, properly designed prospective longitudinal studies provide better evidence than cross-sectional studies and more such studies are required. Currently the recommended daily allowance (RDA) for calcium m North America is 800 mg/day during childhood and 1200mg/day during adolescence (Fassler and Bonjour, 1995). However, surveys of dietary calcium intake in adolescent girls have frequently found consumption of calcmm is significantly less than the recommended RDA (Flemming and Heinbach, 1994). Effect of calcium supplementation on BMD in children
There have been few randomized controlled trials looking at the effect of calcium supplementation in childhood and adolescence. One longitudinal cotwin-controlled study demonstrated that forearm and hip BMD was significantly increased by calcium supplementanon, the response mainly being seen in pre-pubertal children (Johnston et al, 1992). There was no difference between male twins and female twins in response to calcium supplement. This effect was independent of the level of physical activity and the difference between the supplemented and non-supplemented twins was not evident at follow-up several years later. In another trial, 94 girls (mean age 11.9) were randomized to 500 mg of calcium citrate. After 2 years the calcium-treated group were found to have a significant increase in lumbar spine and total body BMD (TBBMD) compared with the placebo group (Lloyd et al, 1993). The groups were re-randomized m a crossover fashion so that 2 and 4 years of calcium supplementanon could be compared with placebo. Five years after commencing the study, there was no significant difference in bone acquislnon between the two groups (Lloyd et al, 1996). This temporary effect of calcmm supplementanon was also seen in a controlled trial in 7-year-old Hong Kong Chinese children (Lee et al, 1996). Thus the currently avadable data do not provide evidence to recommend widespread use of calcium supplementation during childhood or adolescence.
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Physical activity and BMD in children A positive effect of physical activity and, m particular, weight-bearing exerose, has been observed m several cross-sectional studies. Rmz et al (1995) found the duration of weekly sports acuvity to have a greater effect on BMD in girls aged 7-15 than their calcium intake. A study of 90 children aged 6-14 years used a questionnaire administered to both the children and their mothers to esumate physical activity. Physical activity was a sigmficant predictor of BMD of the lumbar spine and femoral neck m the pre-pubertal group (Slemenda et al, 1994). There have been few studies to see if the benefits of physical activity in terms of bone mass and density persist into adulthood. The Amsterdam Growth and Health Study (Welten et al, 1994), which followed up sublects for 15 years and evaluated weight-bearing activity on six occasions during the study period, found weight-bearing activity to be the best predictor of BMD of the lumbar spine at age 27 in males (compared with body weight and calcmm intake). In females, however, no such association was found. In summary, there is evidence that childhood and adolescent physical activity have beneficial effects on attainment of peak bone mass in those age groups. The &fficulties of recalling childhood &ets in adult life makes it difficult to interpret retrospective studies that suggest any benefit has been maintained into adulthood. There is a paucity of controlled longitudinal studies looking at the effects of physical activity during childhood and adolesence.
Idiopathtc juvenile osteoporosis Idiopathic luvemle osteoporosis (IJO) IS an uncommon, self-limiting disease. IJO has been considered to have four cardinal features: (a) onset before puberty; (b) fractures of the vertebrae and long bones; (c) so called neo-osseous osteoporosls radiologlcally, whereby fractures occur at sites of newly formed weight-bearing metaphyseal bone; and (d) spontaneous recovery after skeletal maturity (Bartal and Gage, 1982). In making this diagnosis, ~t is important to exclude other causes of osteoporosls in this age group, such as Cushing's syndrome, malabsorption, leukaemla, and mild forms of osteogenesls ~mperfecta. After the diagnos~s is made, management is mainly &rected at the control of symptoms and minimizing permanent deformities. In a recent review of the case history of 21 patients with IJO, Smith (1995) confirmed that most pauents followed to adolescence had slgmficantly improved. The author concluded that because of the spontaneous ~mprovement, it was difficult to assess the effectweness of any particular treatments gwen. Sex hormones, calcitrlol, bisphosphonates and calc~tomn had all been used in different cases, but it was concluded that no specific treatment for IJO could be recommended.
Management of osteoporosls 601
Growth hormone deficiency in children Growth hormone (GH)-deficlent adults have an approximately 10% lower or 1 SD reduction in BMD. GH treatment given to children with GH deficiency has been shown to increase height velocity, as well as both muscle and bone mass. In an open label study (Saggese et al, 1996), 12 of 26 children had increased BMD in the distal radius to normal values for their age after 12 months of recombinant human GH (0.6 IU/kg weekly, given as subcutaneous injections six times a week). The increase in BMD was generally greater than expected by the increase in height.
Management of osteoporosis in the 'at risk' pre-menopausal woman BMD in elite female athletes and females with eating disorders Young women at risk of hypothalamic amenorrhoea include athletes, dancers, and those with eating disorders. Disruption of the pulsatlle release of gonadotrophic hormones results in low levels of folhcle stimulating hormone (FSH) and luteinizmg hormone (LSH) and therefore low levels of oestrogen and progesterone. This is thought to result in both failure to attain peak bone mass and bone loss. Negative energy balance and low body weight are probably also important factors. In female athletes, the association of anorexia nervosa, amenorrhoea, and osteoporosis is sometimes called the 'female athlete triad.' It has been estimated that between 5-35% of female athletes and dancers have eating disorders (Hergenroeder, 1995). A number of studies have shown amenorrhoeic athletes to have lower BMD particularly of the lumbar spine, where trabecular bone predominates. Rutherford (1993) found that amenorrhoelc athletes had lower lumbar and total spine BMD compared with eumenorrhoeic athletes. Interestingly, there was no difference in TBBMD suggesting the possibility that cortical bone may be relatively protected by athletic activity, despite amenorrhoea. In contrast, a recent study found that not only did amenorrhoelc athletes have lower lumbar BMD, but BMD of all regions of the hip, femoral shaft, and tibia were lower than controls with normal menses (Rencken et al, 1996). The relationship between body weight, body fat, and BMD in athletes remains controversial, except in the cases of athletes with very low body weight (Fruth and Worrell, 1995). In anorexia nervosa, hypothalamlc amenorrhoea also results in a loss of trabecular bone. In a study of 48 anorexic women who were amenorrhoelc, 52% had a baseline lumbar BMD <2 SD of the mean of young normal values (Khbanskl et al, 1995). There was a correlation with the durauon of amenorrhoea. Those who did not recover their menses continued to lose
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trabecular bone. In anorexia nervosa, factors other than hypothalamic amenorrhoea appear to play a role m the pathogenes~s of the osteoporosis. For example, body mass index and weight are related to BMD independent of the duration of amenorrhoea (Bachrach et al, 1990). Moreover, the recovery of BMD m anorexm nervosa can precede spontaneous menstruation, suggesting an independent effect of weight gain on BMD accretion. This suggests that BMD can increase in the absence of oestrogen supplementation (Hergenroeder, 1995). Hypercortisolism may also be revolved in the pathogenesis of the abnormal mineral metabohsm (Abrams et al, 1993).
Prevention and management of osteopenia in athletes and females with eating disorders Early recognmon is the key to minimizing bone mass effects and thereby reducing the risk of osteoporotic fractures in the future. Even with treatment, there is ewdence that the reduction in BMD cannot necessarily be completely reversed (Gulekli et al, 1994). In both female athletes and women with anorexm nervosa, menstrual abnormaliues can go undetected if not sought. Simxlarly, even m cases where there is no obvious weight loss, a good dietary history is mandatory. Other causes for amenorrhoea should also be excluded, for example, hyperprolactinaemia, and primary ovarian failure. In athletes, modification of duration and intensity of exercise should be advised. However, compliance with such advice may be a problem in elite athletes and the duration, intensity, and nature of physical activity do not necessarily correlate with the extent of reducuon m BMD. Female rowers, for example, have been shown to have higher BMD of the lumbar spree compared with controls, even when amenorrhoeic (Natuv et al, 1994). In anorexia nervosa, there is no evidence that regular exercise will have any benefit on bone mineralization. In athletes or in those with anorexia nervosa, low body mass and low body mass index should be corrected by increasing caloric retake where possible, although compliance will again be a problem in many subjects. Gains in BMD can occur with weight gain, even before the return of menstrual function (Bachrach et al, 1991). Oestrogen deficiency may have a detrimental effect on calcmm metabolism, but there is little evidence that calcium supplementation has a role to play in the management of these premenopausal women unless they have a poor daily calcium retake (SnowHatter, 1994). Females who have been amenorrhoeic for more than 6 months should have BMD studies performed. If there is evidence of osteopema, conslderation should be given to hormonal replacement theraphy (HRT). This will be discussed in more detail below. If there is no evidence of osteopenia but menstrual function does not return to normal, then bone density studies should be repeated after 12 months.
Management of osteoporosis 603
HRT
A recent survey of members of the American Medical Society for Sports Medicine, found that 92% of respondents prescribed sex steroids at some stage for amenorrhoeic athletes (Haberland et al, 1995). However there is a relative paucity of prospective data demonstrating the efficacy of HRT m preserving or restoring bone mass in athletes or females with eating dxsorders. There has been one randomized controlled trial looking at oestrogen therapy in anorexic women (Klibanskl et al, 1995) and one randomized trial in women with miscellaneous causes of amenorrhoea (Warren et al, 1994). There have been no controlled trials using either HRT or the oral contraceptive pill (OCP) specifically in amenorrhoeic female athletes. In the only randomized controlled trial specifically of anorexic women, 22 women were randomized to oestrogen therapy (Klibanski et al, 1995). Sixteen received HRT (Premarin 0.625 mg on days 1-5 and Provera 5 mg on days 16-25) and six an OCP (35 ~tg ethinyl oestradiol). Comparisons were made w~th 26 controls after 1.5 years. Patients in the oestrogen group as a whole did not show a significant improvement in lumbar BMD measured by computed tomography. However in women with initial body wexghts less than 70% of ~deal body weight, an increase of 4% m BMD was seen with oestrogen compared with a 20% decrease in the control group. There was no difference in the BMD between those who recewed Premarin plus Provera compared with OCP. The authors concluded that oestrogen therapy may only be beneficial in a subset of anorexic women with markedly reduced body weight. The study by Warren et al (1994) was a randomized controlled trial in amenorrhoeic women treated w~th HRT for 2 years. It grouped together women with a number of different causes for amenorrhoea including anorexic women, athletes, dancers, and women w~th primary ovarian failure and hyperprolactinaemia. No difference was found in change in BMD of the spine, forearm, or foot with treatment compared w~th a placebo group. Weight was suggested as a cofactor mitigating the effects of oestrogen deficiency. In contrast in another longitudinal study of women aged 17-40 years with a past or current history of amenorrhoea from various causes, a significant improvement in lumbar BMD was seen in women treated with all types of oestrogen therapy. The mean time of treatment was 19.6 months (Gulekli et al, 1994). Once again the importance of weight gain m improving BMD was shown. There are, of course, difficulties in conducting truly 'blind' controlled trials wxth HRT or OCP because of withdrawal bleeding and subjects not knowing if they are receiving contraception. Another problem with interpretation of these trials is that many of the women included in the trials have had amenorrhoea for more than 6 months, often for 2-4 years. The longer the duration of amenorrhoea, the less likely it is that bone loss is completely reversible (Bachrach et al, 1991; Gulekh et al, 1994). It is of interest that the study by Khbanski et al (1995) showed a marked improvement in spinal BMD m those patients who spontaneously resumed
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menses. This contrasts with the mimmal benefit that was seen with oestrogen replacement therapy. The authors concluded that progesterone may have been the factor contributing to the differennal effect on BMD between exogenous oestrogen and restored gonadal function. A 1-year randomized trial of physmally active pre-menopausal women (recreational athletes) with amenorrhoea, oligomenorrhoea, anovulation or short luteal phase cycles examined the effects of medroxyprogesterone at 10 mg/day for 10 days per month (Prior et al, 1994). A significant gain m spinal BMD was seen m the groups who received medroxyprogesterone. This compared with no change in the group who received calcium alone and a decrease in BMD in the placebo groups.
Practical management guidehnes of the 'at risk' pre-menopausal women The treatment of athletes or panents w~th an eating &sorder who are at risk of osteopema as a result of hypothalalmic amenorrhoea should first include correction of any primary cause for the amenorrhoea. In anorexic patients and underwmght athletes, correction of the low body weight is the most effective treatment both to restore bone mass and prevent loss. Compliance may be improved by education about the potential complications. In athletes, mo&ficanons should be made to training schedules to try to attain normal menstrual cycles. Again, compliance may be improved by educanon. BMD should be measured if amenorrhoea has been present for more than 6 months. If there is evidence of osteopema, then oestrogen replacement should be commenced. It is important to note that although low-dose HRT has been shown to be effective m post-menopausal women, these doses may not be physiological in young pre-menopausal women. Although yet to be definitely proven in randomized trials, treatment with the higher oestrogen doses usually encountered m formulations of the OCP may be more beneficial. Another theoretical consideration is that in Practice points •
an adequate dietary calcmm intake in childhood and adolescence appears to be an ~mportant determinant of peak bone mass in adulthood; however, there is no evidence for the routine use of calcmm supplementation
•
females who have been amenorrhomc for more than 6 months should have bone mineral density stu&es
•
invesngate and correct any primary causes for amenorrhoea
•
in amenorrhoem athletes and anorexic women correction of low body wmght is the most effective treatment for reduced bone mass
•
If bone density is low after 6 months of amenorrhoea then oestrogen replacement should be commenced
Management of osteoporosis 605
adolescents, who have not reached their maximum height, oestrogen replacement could result ,n early skeletal maturation and accelerated fusion of the epiphyses. The potential loss of height needs to be weighed up against the potennal morbMlty associated with developing osteopenia at this age.
Corticosteroid osteoporosis Corticosteroids are widely used m the treatment of panents w~th chronic inflammatory diseases such as rheumatoid arthritis (RA), connective tissue diseases, inflammatory bowel disease, skin disease, and chronic lung disease. Since the most rapid bone loss occurs m the first 12-24 months in patients commencing h~gh-dose cortlcosterolds, it is important to consMer two different treatment situations: (a) prevention in patients starting corticosteroids who have not yet lost bone; and (b) treatment of patients on chromc corticosterolds who will almost certainly have some significant degree of existing corncosterold-related osteoporosis.
Role of investigations Corticosteroids effects on bone metabohsm are reflected m marked changes in biochemical markers of bone turnover, opening the posslbihty that some markers may be predictive of those patients who lose bone rapidly with corticosteroids. Serum osteocalcm falls within hours of treatment with corticosteroids (Cosman et al, 1994) and levels are sigmficantly related to cortlcosteroid dose. A recent study found tartrate-reslstant acid phosphatase rose following acute corncosteroid administration but there was no change in collagen crosslinks such as pyridinoline (Cosman et al, 1994). However, no studies have shown the degree of change m any markers to be predictive of bone loss, although in a recent clinical trial the serum osteocalcin at 12 months was related to the degree of bone loss, with an inverse relationship such that those who lost the most bone showed the most marked rebound in serum levels (Sambrook et al, 1993). Accordingly at present there is no reliable way of predicting by such biochemical markers, or indeed by clinical risk factors, which patients will lose bone on corticosteroids. However, a bone density measurement is appropriate m patients starting high-dose, long-term corticosteroids as well as a lateral X-ray of the thoracic and lumbar spree. If the spinal X-ray reveals a prior vertebral fracture or the bone density measurement reveals a reduced value, a poorer outcome ~s suggested and intervention becomes more important.
Treatment of cortlcosterold osteoporosis The first principle of treatment of corncosteroid-induced bone loss is to use the lowest dose of corncosterold possible and withdraw corncosterolds
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whenever possible. There ~s evidence that corticosterold osteoporosis may be partially reversible and if the treatment course is less than 6 months, the risk of significant bone loss or fracture is considerably reduced. Numerous therapeuuc approaches have been used for glucocorticoidreduced bone loss, and the evidence supporting these treatments will now be summarized. Calcium
Corticosteroid bone loss results in part from impaired calcmm absorption from the gastrointestinal tract and increased urinary calcium loss. Although the use of calcium supplements has been shown to decrease markers of bone resorption in corticosterold-treated patients, recent randomized controlled trials in patients starting cort~costeroids where calcium was used as the control therapy observed rapid rates of loss (Sambrook et al, 1993; Mulder and Struys, 1994). While an adequate calcium intake should therefore be recommended, calcium alone probably does not have a major role to play in prevention of treatment of corticosteroid bone loss. Vitamin D
The use of calcium with vitamin D as a treatment for corticosteroid bone loss has been suggested following a series of different studies conducted in the 1970s. Hahn and Hahn (1976) examined treatment with calcium 500 mg/day and vitamin D 50 000 units per week in patients on chronic corucosteroids. A slgmficant increase in forearm bone density was observed with treatment but the study was not randomized nor primary prevention in design. Moreover, since bone density was only measured in the radms, whereas bone loss mostly occurs from the spine with corticosterolds, the clinical s~gnlficance of these findings as unclear. In another study, positive results were reported with treatment with 25-hydroxyvltamin D (40 ~tg/day) plus calcium (Hahn et al, 1979) but again this was not a prevention study and only forearm bone mass was monitored, not spinal bone density. Adachi et al (1996) recently reported the results of a prevention study comparing treatment with calcium 1000 mg daily plus vitamin D (50 000 units weekly) against placebo over 3 years. There was no statistically significant difference m bone loss at the lumbar spine between calcium/ vitamin D and placebo. The data were interpreted as suggesting some potentml benefit of calcmm/vitamm D in terms of rates of loss, but the amount of bone loss observed at the spine after 12 months with the calcmm/vltamm D combination (4.9%) was similar to that seen in the calcium-treated control groups in two recent prevention studies (Sambrook et al, 1993; Mulder and Struys, 1994). In contrast, a recent study by Buckley et al (1996) observed an apparent benefit of calcium (1000 mg daily) plus vitamin D3 (500 IU/day) in patients with RA treated with chronic
Management of osteoporosis 607
low-dose corucosteroids, amounting to about a 2% difference compared with placebo. However, the authors noted several caveats: half of the basehne values of spine BMD were esumated from lateral scans; the results were not generalizable to patients commencing high-dose corticosterolds, i.e. prevention; and, as this was a study of chromc low-dose corticosteroid users, the BMD rise may have largely been a 'remodelling transient' whereby the rise m BMD is due to an initial filling of bone spaces undergoing remodelling. Calcitriol
Although the term vitamin D is sometimes used to encompass both the calciferols and calotrlol, this is misleading since calcimol has qmte a &stinct therapeuuc profile. Calcltnol is the active hormonal form of vitamin D, 1,25 dihydroxyvltamin D (1,25(OH2)D3) and two pubhshed studies have examined its use in corticosteroid osteoporosis. In one early study of chronic corucosteroid users, the effect of calcitrlol (0.4 Bg/day) was examined and, although calcium absorption improved, there was no significant benefit of treatment on forearm bone density, w:th both groups showing a small rise in bone mass (Dykman et al, 1984). A more recent study examined the effect of calcitriol as a preventative agent in a much larger randomized double bhnd controlled trial with spine bone density as the primary end point (Sambrook et al, 1993). Patients treated with calcium only lost bone at the lumbar spine (4.3% per year) whereas patients treated with either calcltnol or calcitnol and calc~tomn lost bone at a much reduced rate (1.3% and 0.2% per year, respectively). There was no significant difference between the two calcltriol groups, whereas both groups were significantly different from the calcium group. The mean daily dose of calotrlol at 0.6 ~tg was h:gher than m the earher study and, although similar trends were observed for the distal radius, these were not significant, so these data are actually consistent with the earher Dykman study. A recent study with 1-0~ hydroxyvitamin D (0~-calcidol) appears to confirm that the active vitamin D analogues have efficacy m prevention of bone loss m patients starting corticosteroids (Lakatos et al, 1996). Mild hypercalcaemla was reasonably common in the study by Sambrook et al (1993), probably related to the concomitant admimstration of a calcium supplement. In clinical practice, if dietary calcmm is adequate, supplementation should be avoided but monitoring of plasma calcium every 3-6 months is appropriate when vitamin D metabohtes are used. HRT
Corucosteroid use is assooated with suppression of adrenal androgens, and hypogonadlsm is commonly seen in males and females treated with corticosteroids. In one small open study of post-menopausal women with asthma, the combination of oestrogen and progestogen therapy increased bone mass
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in patients on chromc corticosterolds over 1 year (Lukert et al, 1992). In a subgroup of patients on chronic low-dose cortlcosteroids participating in a randomized controlled trial of the effect of HRT on disease activity and bone loss m RA, some benefit of treatment was seen at the lumbar spine over 2 years (Hall et al, 1994). Based on the results of these studies, it has been recommended that post-menopausal women taking glucocorticolds should received HRT if there are no contra-indications. No randomized trials have been performed in glucocorticoid-treated pre-menopausal women and, in those with normal menstrual cycles, hormone treatment is inappropriate, although in woman with irregular menstrual cycles, use of the OCP may be appropriate. There has also been one study m a small number of males looking at the efficacy of testosterone therapy m chronically-treated glucocomcold asthmatics, which showed a benefit at the spine but not the hip after 12 months of monthly mlecuons (Reid et al, 1996). If serum testosterone levels are low in men, then consideration could be given to use of testosterone therapy m patients established on corticosteroids.
Bisphosphonates Blsphosphonates are analogues of pyrophosphate that bind to hydroxyapatite at sites of bone remodelling. They inhibit bone resorption primarily, and several bisphosphonates are available in various countries including etidronate, pamidronate, alendronate, tiludronate, and residronate. At this time, only etldronate and pamidronate have been studied to any extent m corucosteroid osteoporosis. In a prevention study of 20 woman with temporal arteritis, m which 10 were randomized to cyclical etidronate prevention of bone loss was seen compared with the calcmm-treated group (Mulder and Struys, 1994). Several other open stu&es also suggest efficacy of cyclical etidronate m chronic cort~osteroid users as well. Studies in patients with chronic obstructive airways disease treated with oral pamidronate have also demonstrated significant benefits at the lumbar spine over 2 years (Reid et al, 1988), suggesting anti-fracture efficacy. It is reasonable to assume that other, newer blsphosphonates, will be similarly active in cortlcosteroid osteoporosis, and currently there are several trials ongoing with these new generation bisphosphonates which will address this issue directly. However, because of their long skeletal retention, blsphosphonates are not normally used in the treatment of younger individuals.
Calcitonin Calcltomn has been trialled in patients starting corticosterolds and receiving chronic corticosterolds with varying results. Interpretation of some of these studies is confounded by the calcitonin-treated group having a significantly lower BMD than the control group at baseline (Rizzato et al, 1998; Luengo eta], 1990). One study of chronic corticosteroid users by Montemurro et at
Management of osteoporosls
609
(1991) &d show apparent benefit from calcitonin at the spine. In contrast, in two recent prevention studies there was no statistically significant additional benefit of adding calcltonin to calcitriol or cholecalciferol (Sambrook et al, 1993; Healey et al, 1996).
Approach to the patient commencing long-term corticosteroid therapy In patients commencing cortlcosteroids in high doses for the first time, the best predictor of risk of fracture is a bone density measurement. An adequate calcmm intake is recommended and any contributing factors to osteoporosis should be treated where possible. If long-term therapy is envisaged, then treatment with a bisphosphonate or an active vitamin D metabohte (c~-calcidol or calcitriol) is appropriate in patients starting corticosteroids, and the treatment may need to be continued for 1-2 years. In post-menopausal women, concomitant use of oestrogen replacement therapy is probably also appropriate.
Approach to patient already on long-term corticosteroid therapy It is important in a patient on long-term corticosteroid therapy to rewew the need for continuing treatment or the possibility of reducuon in dosage. A bone density measurement will give information about their risk of future osteoporotic fracture and the need for active pharmacological treatment. In post-menopausal women or men w~th a low serum testosterone, H R T with oestrogen or testosterone respectively, is appropriate. Patients requiring long-term cortlcosterold therapy with clinically significantly reduced bone density values should be treated with vitamin D metabolites (including the calciferols) or a bisphosphonate.
Research agenda •
do patlcntq treated wtth coruco~tcro~d~ tracture at chtlerent B M D levels to other types ot osteoporosi~?
•
d() i'lCl'lVC vIt,llllltl L') ,netabohtcs such as 1.25 ¢hh.+drox.~v~ta,mn D and ~-calcJdol hast .,i,perlor efficacy to orher 'vmun,n I) mei',ff,o-
hte,, n3 prcveutmg cortico,,tcrold bone loss? •
~s therc a,lx ad',autage in COl+Ibmtn!.;antn'e,,orpttve agents Per pre~,OlltlOll or t l ' C a l l l l e l l t ()f c()rtlcoster(>id b o l l e Io++?
•
do low doses oI Lorll~.osret'old result l]] dnnc:dh" slgnilicant [)Olle
Io++? •
tf cortlCOStCl'Otd b o n e 1o.~,, i~, ilnO~,l" talc,el ,n the first "12-1 ,~ IllOnl[1,, el therapx, doe,, prophyla×'l<, need to continue mdcfimteh ?
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Summary In children and adolescents there is evidence to suggest that habitual dietary calcium intake m a y influence attainment of peak B M D . However, a longterm benefit of calcium s u p p l e m e n t a t i o n has not been s h o w n in this age group. Cross-sectional studies showing an association between physical activity and B M D also suggest the level of physical activity during c h i l d h o o d and adolescence m a y m o d i f y peak bone mass. O n current evidence, no specific t r e a t m e n t can be r e c o m m e n d e d for cases o f IJO. G H deficiency in children should be treated with r e c o m b i n a n t G H therapy. A m e n o r r h o e l c athletes and y o u n g w o m e n with eating disorders, such as anorexia nervosa, are at risk of u n d e r a t t a i n m e n t of their potential p e a k bone mass or bone loss, and early recognition is important. Bone density m e a s u r e m e n t should be p e r f o r m e d if a m e n o r r h o e a persists for m o r e t h a n 6 months. Correcting b o d y mass deficit is an i m p o r t a n t goal of treatment as well as h o r m o n e t h e r a p y in the f o r m of the OCP. Patients c o m m e n c i n g high-dose long-term corticosteroid therapy should be treated p r o p h y l actically with active vitamin D metabolites (0~-calcldol or calcitnol) or a bisphosphonate. Patients o n chronic corticosteroids m a y improve their B M D with HRT, vitamin D metabolites (including the calcfferols) a n d blsphosphonates.
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Natnv A, Agosnm R, Drinkwater B et al (1994) The female athlete triad The mterrelatedness of disordered eating, amenorrhea, and osteoporosls Chmcs m Sports Medzclne 13(2): 405-418. Nieves JW, Golden AL, Sms-E et al (1995) Teenage and current calcium retake are related to bone mineral density of the hip and forearm m women aged 30-39 years. American Journal of Eptdermology 141(4): 342-351. Prior JC, Vlgna YM, Barr SI et al (1994) Cychc medroxyprogesterone treatment increases bone density: a controlled real m acnve women w~th menstrual cycle disturbances. American Journal of Medicine 96(6): 521-530. Reid IR, King AR, Alexander CJ & Ibbertson HK (1988) Prevention of steroid-reduced osteoporosls with (3-ammo-l-hydroxypropyhdme)-l, 1-blsphosphonate (APD). Lancet 1: 143146. Reid IR, Wattle DJ, Evans MC & Stapleton JP (1996) Testosterone therapy m glucocorncold treated men. Archives of Internal Medlcme 156:1173-1177. Rencken ML, Chesnut CH 3rd & Drinkwater BL (1996) Bone density at multiple skeletal sites m amenorrhelc athletes. Journal of the Amerzcan Medical Assoczatton 276(3): 238-240. Rlzzato G, Tosl G, Schlraldl G e t al (1988) Bone protecnon with salmon calcltomn (sCT) m the long term steroid therapy of chromc sarcoldosls. Sarcotdosls 5: 99-103. *Rulz JC, Mandel C & Garabedmn M (1995) Influence of spontaneous calcmm retake and physical exercise on the vertebral and femoral bone mineral density of children and adolescents. Journal of Bone and Mineral Research 10(5): 675-682. Rutherford OM (1993) Spree and total body bone mineral density m amenorrhelc endurance athletes Journal of Apphed Physiology 74(6): 2904-2908. Saggese G, Baronelh GI, Bertellom S & Barsann S (1996) The effect of long term growth hormone (GH) treatment on bone mineral density m children with GH deficiency. Journal of Ckmeal Endocrinology and Metaboksm 81: 3077-3083. "Sambrook PN, Birmingham J, Kelly PJ et al (1993) Prevennon of corncosteroid osteoporosis; a comparison of calcmm, calcitnol and calcltonm. New England Journal of Medicine 328: 1747-1752. Slemenda CW, Relster TK, Hm SL et al (1994) Influences on skeletal mmerahzanon m chddren and adolescents: evldence for varying effects of sexual maturanon and physical acnwty Journal of Pedtatrtcs 125 (2): 201-207. '-Smith R (1995) Idiopathic luvenfle osteoporosls: experience of twenty-one patients. Br~tzsh Journal of Rheumatology 34: 68-77. Snow-Harter CM (1994) Bone health and prevennon of osteoporosls m active and athlenc women Ckmcs m Sports Medicine 13(2): 389-404. Specker BL, Brazerol W, Tsang RC et al (1987) Bone mineral content m children 1 to 6 years of age. American Journal of Diseases m Children 141: 343-344. '¢Teegarden D, Proulx WR, Martin BR et al (1~95) Peak bone mass m young women. Journal of Bone and Mineral Research 10(5): 711-715. Warren MP, Fox RP, DeRogans et al (1994) Osteopema m hypothalamlc amenorrhea: a 3-year longitudinal study. Abstract. Program of the Endocrine Society Annual Meenng, Anaheim, Cahforma Welten DC, Kemper HC, Post GB et al (1994) Weight-bearing acnvlty during youth Is a more Important factor for peak bone mass than calcium retake. Journal of Bone and Mineral Research 9(7): 1089-1096.