OSTEOPOROSIS
Systematic literature search to December 2000 plus some key references from 20
OSTEOPOROSIS |
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Systematic literature search to December 2000 plus some key references from 20 |
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| 5.1
Corticosteroid Induced Osteoporosis
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| 5.1a. Bisphosphonates are
effective in preventing and treating steroid-induced bone
loss at the lumbar spine and femoral neck (weighted mean difference in
bone mineral density between treatment and placebo groups was 4.3 (95%
CI 2.7-5.9) and 2.1% (95% CI 0.01-3.8)
respectively. Excluding two heterogeneous trials, five primary prevention
trials showed a weighted mean difference at lumbar spine of 4.4% (95%
CI, 3.0-5.8) and six secondary prevention trials showed a weighted
mean difference of 3.2% (95% CI, 2.0-4.5). Efficacy
regarding fracture prevention could not be concluded although bone mineral
density is correlated with fracture risk. They also appear to be
efficacious at preventing or treating corticosteroid induced osteoporosis
at the femoral necki. (Health gain notation - 2 "likely to be beneficial") |
i. Homik J, Cranney A, Shea
B et al. Bisphosphonates for steroid induced osteoporosis. [updated
17 November 1998] Cochrane Database of Systematic Reviews. Cochrane
Library 2001, Issue 4 http://www.update-software.com/ abstracts/ab001347.htm [accessed 29.11.01] (Type I evidence - systematic review and meta-analysis of 13 controlled clinical trials and 842 patients, where the corticosteroid dose was 7.5 mg/day or higher) |
| 5.1b. Bisphosphonates significantly increased BMD in patients at risk for corticosteroid-induced bone-loss. Changes in BMD at the lumbar spine in treatment groups ranged from 0.137% to +4.9%; the control groups ranged from 3.7% to +0.98%. However, there is a sparsity of data concerning the ability of these agents to affect the clinically important outcome of fracture rate reductioni Long-term studies powered to detect fracture risk reduction are needed as well as comparative trials with bisphosphonates and other agents. | i. Blair MM, Carson
DS, Barrington R. Bisphosphonates in the prevention and treatment of
glucocorticoid-induced osteoporosis. Journal of Family Practice 2000;
49(9): 839-848 (Type I evidence systematic review of 13 randomised controlled trials) |
| 5.1c. Alendronate increases bone density in patients receiving glucocorticoid therapy. The mean (±SE) bone density of the lumbar spine increased by 2.1±0.3% and 2.9±0.3%, respectively, in the groups that received 5 and 10 mg alendronate per day (p<0.001) and decreased by 0.4±0.3% in the placebo group. The femoral neck bone density increased by 1.2±0.4% and 1.0±0.4% in the respective alendronate groups (p<0.01) and decreased by 1.2±0.4% in the placebo group (p<0.01). There were proportionally fewer new vertebral fractures in the alendronate groups (overall incidence, 2.3%) than in the placebo group (3.7%) (relative risk, 0.6; 95% CI 0.1-4.4). There were no differences in serious adverse effects among the three groups, but there was a small increase in nonserious upper gastrointestinal effects in the group receiving 10 mg alendronatei. | i. Saag KG, Emkey R,
Schnitzer TJ et al. Alendronate for the prevention and treatment of
glucocortocoid-induced osteoporosis. New England Journal of Medicine 1998;
339(5): 292-299 (Type II evidence Two 48-week randomised controlled trials of 477 women (aged 17-83 years) receiving glucocorticoid therapy. Subjects were allocated 5 or 10 mg/day alendronate or matching placebo. Each patient received 800-1000 mg elemental calcium and 250-500 IU vitamin D daily. 85% of subjects completed the study and an intention-to-treat analysis was used) |
| 5.1d. Risedronate increased BMD and potentially reduced the incidence of vertebral fractures in men and women with corticosteroid-induced osteoporosis. At 12 months BMD was increased by a mean of 2.9±0.49% at the lumbar spine, 1.8±0.46% at the femoral neck and 2.4±0.54% at the trocanter, whereas BMD was only maintained in the control group. (All patients received 1g calcium and 400 IU vitamin D daily). Risedronate was well tolerated, had a good safety profile, and was not associated with gastrointestinal adverse eventsi. | i. Reid DM, Hughes
RA, Laan RF et al. Efficacy and safety of daily risedronate in the
treatment of corticosteroid-induced ostroporosis in men and women: a
randomized trial. Journal of Bone and Mineral Research 2000; 15(6):
1006-1013 (Type II evidence randomised controlled trial of 290 men and women receiving high-dose corticosteroid therapy (prednisone ≥ 7.5 mg/day or equivalent) for 6 or more months. Subjects were randomised to receive placebo, risedronate (2.5 mg/day) or risedronate (5 mg/day) for 12 months. An intention-to-treat analysis was used) |
| 5.1e. The data for bisphosphonate treatment in corticosteroid induced osteoporosis are more compelling than for any other agent, but for patients who continue to lose bone, hormone replacement therapy may be consideredi. HRT should be considered if hypogonadism is presentii. | i. Adachi JD,
Olszynski WP, Hanley DA et al. Management of corticosteroid induced
osteoporosis. Seminars in Arthritis and Rheumatism 2000; 29(4):
228-251 (Type V evidence expert opinion based on a review of the literature) ii. Sambrook P, Lane NE.
Corticosteroid osteoporosis. Baillieres Best Practice Clinical
Rheumatology. 2001; 15(3): 401-413 |
| 5.1f. Testosterone treatment reverses the deleterious effects of glucocorticoid drugs on skeletal and soft tissues in men and may be an effective therapy for steroid-induced osteoporosis in hypogonadal men. In one small cross-over study, bone density in the lumbar spine increased 5.0%±1.4% (p=0.005) during testosterone supplementation but did not change during the control period. Treatment was well tolerated apart from an apparent allergic reaction to the therapy in one subjecti | i. Reid IR, Wattie
DJ, Evans MC, Stapleton JP. Testosterone therapy in glucocorticoid-treated
men. Archives of Internal Medicine 1996; 156: 1173-1177 (Type II evidence randomised controlled cross-over study of 15 asthmatic men receiving long-term glucocorticoid treatment, randomly allocated to receive therapy with testosterone esters (30 mg of proprionate, 60 mg of phenylprionate, 60 mg of isocaproate, and 100 mg of decanoate 250 mg/mo instamuscular depot injection) or to act as control subjects during 12 months. After a washout period for those men who were receiving testosterone, the groups were then crossed over and studied for a further 12 months) |
| 5.1g. A
meta-analysis demonstrated a clinically and statistically significantly prevention
of bone loss at the lumbar spine and forearm with vitamin D and calcium
in corticosteroid treated patients (weighted mean difference between
treated and control groups = 2.6 (95% CI 0.7-4.5)
and 2.5 (95% CI 0.6-4.4) respectively)i. (Health gain notation 2 "likely to be beneficial") |
i. Homik J, Suarez-Almazor
ME, Shea B, Cranney A, Wells G, Tugwell P. Calcium and vitamin D for
corticosteroid-induced osteoporosis [updated 30 November
1997]. Cochrane Database of Systematic Reviews. Cochrane Library
2001, Issue 4 http://www.update-software.com/ abstracts/ab000952.htm [accessed 29.11.01] (Type I evidence - systematic review and meta-analysis of 5 randomised controlled trials, and 274 patients) |
| 5.1h. Vitamin D plus calcium is more effective than no therapy or calcium alone in the management of corticosteroid induced osteoporosisi. There is a moderate beneficial effect of vitamin D plus calcium versus no therapy, or calcium alone, (from 9 trials, effect size = 0.60, 95% CI 0.34-0.85). In a comparison of vitamin D versus other osteoporosis therapies, bisphosphonates were more effective than vitamin D (from 6 trials, effect size = 0.57, 95% CI 0.09-1.05). Calcitonin was similar in efficacy to vitamin D (from 4 trials, effect size = 0.03, 95% CI 0.39 to +0.45). Fluoride was more effective than vitamin D but there were only two trialsi. | i. Amin S, La Valley
MP, Simms RW, Felson DT. The role of vitamin D in corticosteroid-induced
osteoporosis a meta-analytic approach. Arthritis and Rheumatism 1999;
42(8): 1740-1751 (Type I evidence systematic review and meta-analysis of 21 randomised controlled trials of 23 comparison regimens, including 7 abstracts. Reviewed in: Anonymous. Vitamin D plus calcium is more effective than no therapy or calcium alone in corticosteroid-induced osteoporosis. ACP Journal Club 2000; 132(2): 57) |
| 5.1i. Alfacalcidol (a vitamin D type derivative) can prevent corticosteroid-induced bone loss from the lumbar spine. The percentage change in BMD after 12 months was +0.39% (95% CI, -4.28 to +4.81) for alfacalcidol vs 5.67% (95% CI, -8.31to-3.21) for placebo. The difference was statistically significant (6.06%, 95% CI 0.88-11.24%, p=0.02). An intention-to-treat analysis also showed a significant difference between the two groups in alfacalcidols favour (3.81%, 95% CI 0.92-6.70%, p=0.01). No significant adverse effects were noted but the authors recommended that serum calcium should be monitored regularly during treatmenti. | i. Reginster JY,
Kuntz D, Verdickt W et al. Prophylactic use of alfacalcidol in
corticosteroid-induced osteoporosis. Osteoporosis International 1999;
9: 75-81 (Type II evidence randomised controlled trial of 145 patients embarking on long-term treatment with corticosteroids (30 mg/d or more of prednisolone). Patients were randomised to 1microgram/d alfacalcidol or placebo. 71 subjects completed the study. All subjects received a calcium supplement of 405 mg/day.) |
| 5.1j. The efficacy of calcitonin for fracture prevention in steroid-induced osteoporosis remains to be established. Calcitonin appears to preserve bone mass in the first year of glucocorticoid therapy at the lumbar spine by about 3% compared to placebo (weighted mean difference at 12 months = 3.2%, 95% CI, 0.3-6.1), but not at the femoral neck. At 24 months, lumbar spine BMD was not statistically significant between groups. The protective effect may be greater for the treatment of patients who have been taking corticosteroids for more than 3 monthsi. | i. Cranney A, Welch
V, Adachi JD et al. Calcitonin for preventing and treating
corticosteroid-induced osteoporosis [updated 27 October
1999]. Cochrane Database of Systematic Reviews. Cochrane Library,
2001 Issue 4 http://www.update-software.com/ abstracts/ab001983.htm [accessed 29.11.01] (Type I evidence - systematic review and meta-analysis of 9 randomised controlled trials, including 221 patients randomised to calcitonin and 220 to placebo) |
| 5.1k. One small trial found that human parathyroid hormone (PTH) increased bone mass in the lumber spine and hip in postmenopausal women with glucocorticoid-induced osteoporosis who were taking hormone replacement therapy. The major effect, at the lumbar spine after 24 months, as measured by quantitative computed tomography and dual-energy X-ray absorptiometry was 45.9±6.4% and 12.6±2.2% (p<0.001). However, the maximum effect on bone mass at the hip after 12 months of treatment was not achieved until 6-12 months after PTH treatment was discontinuedi. | i. Lane NE, Sanchez
S, Modin GW, Genant HK, Pierini E, Arnaud CD. Bone mass continues to
increase at the hip after parathyoroid hormone treatment is discontinued
in glucocorticoid-induced osteoporosis: Results of a randomized controlled
clinical trial. Journal of Bone and Mineral Research 2000; 15(5):
944-951 (Type II evidence randomised trial of 51 postmenopausal women, mean age, 63 years. Subjects were assigned to human parathyroid hormone 1-34 (hPTH 1-34, 12 months on and 12 months off treatment) plus estrogen, or estrogen alone. Patients remained on their individual hormone replacement regimens. All patients received a daily supplement of 100 mg calcium carbonate and 800 IU vitamin D) |
| 5.1l. Guidelines
are available for the prevention and management of corticosteroid induced
osteoporosisi,ii,iii. (Health gain notation 1 "beneficial")
|
i. National
Osteoporosis Society. Guidance on the Prevention and Management of
Corticosteroid Induced Osteoporosis. London: National Osteoporosis
Society, 1998 (Type V evidence expert consensus guidelines) Available from the National Osteoporosis Society, PO Box 10, Radstock, Bath BA3 3YB (tel. 01761 471771) ii. American College of Rheumatology Ad Hoc Committee on
Glucocorticoid-Induced Osteoporosis. Recommendations for the prevention
and treatment of glucocorticoid-induced osteoporosis. Arthritis and
Rheumatism 2001; 44(7): 1496-1503 iii. Eastell
R, Reid DM, Compston J et al. A UK consensus group on the
management of glucocorticoid induced osteoporosis: an update. Journal
of Internal Medicine 1998; 244 (4): 271-292 |
| 5.2 Low bone density and osteoporosis following transplantation | |
| 5.2a. After
transplantation, regimens to prevent rejection commonly include
high-dose glucocorticoids and calcineurin-calmodulin phosphatase
inhibitors, which are associated with rapid bone loss. The incidence of
fracture ranges from 8% to 65% during the first year after
transplantation. In general, fracture rates are lowest in renal transplant
recipients (7% to 11% in nondiabetic recipients but higher, 45%, in
insulin-dependent diabetics). The prevalence of vertebral fractures in cardiac
transplant recipients ranges from 18% to 50%i. Fracture prevalence in lung transplantation candidates was 29% in patients with chronic obstructive pulmonary disease and 25% in patients with cystic fibrosis. Fracture incidence following liver transplantation is highest in the first six months and ranges from 24% to 65%, the latter in a group of women with primary biliary cirrhosisi. |
i. Rodino MA, Shane
E. Osteoporosis after organ transplantation. American Journal of
Medicine 1998; 104: 459-469 (Type V evidence expert review of the literature, quoting the results of a large number of prospective studies) |
| 5.2b. Bisphosponates show promise in the prevention of transplantation osteoporosisi. Because they are renally excreted, bisphosphonates are not recommended in patients with moderate-to-severe renal insufficiency (serum creatinine >3.0 mg/dL; creatinine clearance <30 mL/min) and alendronate & pamidronate could exacerbate or prolong the resolution of secondary hyperparathyroidism after renal transplantationi. | i. Rodino MA, Shane
E. Osteoporosis after organ transplantation. American Journal of
Medicine 1998; 104: 459-469 (Type V evidence expert review of the literature, citing seven relevant trials) |
| 5.2c. Etidronate is an effective treatment for low bone mass following renal transplantation. Patients selected for treatment had a lower baseline BMD than control subjects, yet still showed a clinically important increase in BMD. Over a one year period, in patients treated with etidronate, lumbar spine BMD increased 4.3±6.1% in the treatment group versus 0.55±5.3% in the controls (p<0.03) and trochanter BMD increased 10.3±11.9% and 2.2±5.7% respectively in the treatment and control groups (p<0.02)i. | i. Arlen D, Lambert
K, Ioannidis G, Adachi JD. Treatment of established bone loss after renal
transplantation with etidronate. Transplantation 2001; 71(5):
669-673 (Type III evidence controlled trial of 25 renal transplantation patients treated with intermittent cyclic etidronate (400 mg etidronate disodium orally for two weeks out of every 12 weeks). The control group consisted of patients identified as not requiring intervention by their treating physician, although a small number of patients may have declined treatment. Treatment was initiated 10 months after transplantation). |
| 5.2d. One small trial suggested that the rapid early bone loss that occurs in men during the first 12 months after renal transplantation can be prevented by two intravenous doses of pamidronate given at transplantation and one month later. Twelve months after transplantation the mean (±SEM) BMD of the lumbar spine and femoral neck in placebo treated patients had reduced by 6.4% (p<0.05) and 9% (p<0.005) respectively. In contrast, there was no significant reduction at either site in the pamidronate group. Apart from transient hypocalcemia in two patients, no significant adverse effects of pamidronate were notedi. | i. Fan SL-S, Almond
MK, Ball E, Evans K, Cunningham J. Pamidronate therapy as prevention of
bone loss following renal transplantation. Kidney International 2000;
57: 684-690 (Type II evidence randomised controlled trial of 26 male renal transplantation patients. Subjects were randomised to receive either placebo or intravenous pamidronate (0.5 mg/kg) at the time of transplantation and again one month later. Analyses were carried out on the 25 patients completing the twelve month study.) |
| 5.2e. Patients who undergo lung transplantation are at increased risk for osteoporosis both before and after surgery. A significant proportion of patients awaiting lung transplantation were osteoporotic (29%) or osteopenic (55%). Antiresorptive therapy (pamidronate or hormone-replacement therapy) prevented accelerated lumbar spine bone loss after graft. One out of twenty patients experienced clinically evident fractures during antiresorptive therapy, and 3 out of 12 in the calcium-vitamin D group. Lumbar spine BMD was significantly increased after one year with changes in Z score of 0.2±0/1 in the antiresorptive group versus 0.04±0.1 for the calcium-vitamin D group. Adverse events were not consideredi. | i. Trombetti A,
Gerbase MW, Spiliopoulos A, Slosman DO, Nicod LP, Rizzoli R. Bone mineral
density in lung-transplant recipients before and after graft: prevention
of lumbar spine post-transplantation-accelerated bone loss by pamidronate.
Journal of Heart & Lung Transplantation 2000; 19(8):
736-743 (Type IV evidence measurement of areal BMD in 42 patients awaiting lung transplantation and at 6 (n=29) and 12 (n=20) months after surgery. 19 patients received antiresorptive therapy (30 mg pamidronate IV every 3 months (n=14) or hormonal replacement therapy (n=5). This was given as standard treatment after May 1995), plus calcium and vitamin D supplements. 10 patients, treated pre-May 1995, received calcium and vitamin D supplements only) |
| 5.2f. Pamidronate was more effective than calcium + vitamin D alone in improving bone density after lung transplantation in patients with cystic fibrosis. The pamidronate treated group gained (± SD) 8.8±2.5% and 8.2±3.8% in spine and femur BMD after two years in comparison to control subjects who gained, on average, 2.6±3.2% and 0.3±2.2% respectively (p £ 0.015 for both). Seven and six fractures occurred in the control and pamidronate groups respectively (p>0.2). No one dropped out of the study due to adverse drug effectsi. | i. Aris RM, Lester
GE, Renner JB et al. Efficacy of pamidronate for osteoporosis in
patients with cystic fibrosis following lung transplantation. American
Journal of Respiratory and Critical Care Medicine 2000; 162:
941-946 (Type II evidence two year randomised controlled trial of pamidronate (30 mg intravenously every three months) + vitamin D (800 IU/d) + calcium (1g/d) (n=16) compared with vitamin D + calcium alone (n=18). Patients were recruited 1-12 months post-transplant and were stratified by sex and severity of osteopenia before randomisation) |
| 5.2g. Calcitriol
(1,25-dihydroxyvitamin D3) has a role in reducing proximal
femur bone loss after cardiac or lung transplantation but treatment
needs to be continued beyond one yeari. Bone loss at this site
was marginally significantly reduced or prevented by treatment with
calcitriol for two years compared with calcium alone. The difference
between the calcitriol plus calcium and calcium alone (placebo) groups at
two years was 0.038 g/cm2 (95% CI, 0.001-0.075
g/cm2). Mild hypercalcemia was common with calcitriol
therapy, as was mild hypercalcuria (59% in the treated vs 10% in the
control group), but there was no significant differences in groups between
serum creatine after two years. Over the two year period, 22 new vertebral
fractures/deformities occurred in four patients treated with calcium alone
compared to one vertebral fracture in one patient treated with calcitriol
but the sample was too low to provide a reliable interpretation of
fracture ratei. Caveat: 22 patients in the trial were also concurrently enrolled into a mycophendale mofelil vs azothioprine trial. |
i. Sambrook P,
Henderson NK, Keogh A et al. Effect of calcitriol on bone loss
after cardiac or lung transplantation. Journal of Bone and Mineral
Research 2000; 15(9): 1818-1824 (Type II evidence 2 year double-blind stratified study of 65 patients undergoing cardiac or single lung transplantation randomly allocated to calcitriol (0.5-0.75 μg/day) or placebo in a 2:1 ratio. All patients received 600 mg calcium/day. After 12 months, half the calcitriol patients switched to placebo while the remainder continued calcitriol for two years. The analysis was intention-to-treat) |
| 5.2h. During
a two-year evaluation, heart transplant cases lost considerably more bone
immediately after transplantation than liver and lung transplant
recipients. A positive effect of two years alfacalcidol treatment
was observed in all treated groups. Alfacalcidol was particularly
effective against trabecular bone loss at the spine in rheumatoid
arthritis patients and transplant recipients. Liver and lung transplant
recipients responded better to therapy than cardiac recipientsi. Caveat: The randomisation process was unclear. The details of calcium supplementation to control patients are not given. The details of treated and outcomes for the patients with rheumatoid arthritis are not clear. |
i. Dequeker J, Borghs
H, Van Cleemput J, Nevens F, Verleden G, Nijs J. Transplantation
osteoporosis and corticosteroid-induced osteoporosis in autoimmune
diseases: experience with alfacalcidol. Zeitschrift fűr
Rheumatologie 2000; 59(suppl.1): 53-57 (Type III evidence 2 year evaluation of BMD in 112 transplant recipients [(59 heart, 26 liver and 27 lung) treated with 0.5-1 microgram/day alfacalcidol; 45 transplant cases served as control (included in a randomised way to placebo group)] and in 42 rheumatoid arthritis cases. All patients received calcium) |
Health Evidence Bulletins: Wales, Duthie Library, UWCM, Cardiff CF14 4XN. e-mail: weightmanal@cardiff.ac.uk