Oral Corticosteroids and Osteoporosis Prophylaxis
Case: Margaret is a 46-year-old woman with undifferentiated connective tissue disease. She was
diagnosed at the age of 44 after having 1 year of polyarticular arthritis, tenosynovitis, and chronic
abdominal pain. She had a negative laboratory work-up except a weakly positive SSA titer that was
negative on repeat testing. She was started on prednisone 20mg a day with good relief of her symptoms.
Over the course of the next year, attempts to wean the prednisone were unsuccessful, despite the addition of
low-dose methotrexate. She presents to establish care with her primary care physician on a prednisone
dose of 10mg po qd.
Margaret, like most patients on long-term oral corticosteroid treatment is at increased risk for osteoporosis.
Bone loss in the lumbar spine on high dose therapies can be as high as 27% in the first year of therapy
(Reid et al, 1990), although bone loss after this slows to approximately 2-3 times normal bone loss.
The pathogenesis of bone loss in corticosteroid-induced osteoporosis is multifactorial. In post-menopausal
women, osteoporosis is primarily secondary to increased bone resorption. However, systemic
corticosteroids can cause loss of bone density via both reduction in bone formation and increase in bone
resorption. Some studies have found that trabecular bone is lost to a greater degree than cortical bone, but
this is still in dispute.
Factors Contributing to Bone Loss
With Corticosteroid Use
Reduced Bone Formation
Inhibition of osteoblasts
Inhibition of IGF-1 production
Inhibition of testosterone production
Increased apoptosis of osteoblasts and osteocytes
Increased Bone Resorption
Decrease in intestinal calcium absorption
Increased urinary calcium excretion
Reduced secretion of sex hormones via inhibition of
gonadotropins
Possible direct effect on PTH secretion
The underlying disease (requiring treatment with corticosteroids) can itself contribute to osteoporosis. For
example, persons with diseases as varied as COPD, RA and inflammatory bowel disease have been shown
to have lower bone density independent of their exposure to corticosteroids. Interestingly, individuals with
RA with well-controlled disease, even those on corticosteroids, will lose less bone than patients with poorly
controlled disease (Verhoeven et al., 1997).
The most serious consequence of corticosteroid-induced osteoporosis is fracture. Vertebral fractures can
cause serious morbidity, including both pain and loss of function. Moreover, hip fractures in postmenopausal women have been associated with significant mortality in the year after fracture. In a
retrospective cohort study, 244,235 patients were followed from the initiation of oral corticosteroid therapy
to 3 months after cessation of treatment or to initial fracture. Their rates of non-vertebral, vertebral and hip
fractures rose along with the daily dose (low dose, <2.5mg a day; medium dose, 2.5-7.5mg a day; high
dose, >7.5mg a day): a 20% percent increased risk for those in the low dose group and a 60% greater risk
in the high dose group was observed compared to the control group. Interestingly, rate of fracture was
much more highly associated with daily dose than cumulative dose of steroids. Also, the rate of fracture
approached baseline within 2 years after cessation of corticosteroid treatment (van Staa et al., 2000).
Additional history reveals that Margaret has had a hysterectomy but not oophorectomy. She has had no
subjective symptoms of menopause to date. She has no family history of osteoporosis. She smokes ½ pack
per day, but does not drink alcohol. Should any further work-up be done?
Osteoporisis and steroids have been much less extensively studied in premenopausal women. It is known
that premenopausal women (and men) lose bone mass while on corticosteroid therapy. In a large study of
risedronate vs. placebo in patients taking greater than 7.5 mg of corticosteroid per day, the premenopausal
placebo group’s T score dropped 1.2 points in 12 months (Wallach et al., 2000). However, studies to date
have not shown fracture in the premenopausal population.
A DEXA scan can help to assess a woman’s baseline bone density prior to long-term corticosteroid
therapy. The American College of Rheumatology (2001) has recommended getting a baseline DEXA scan
in any person in whom corticosteroid treatment duration is anticipated to be greater than 6 months. They
suggest follow-up scans as often as 6-12 months.
WHO criteria define osteopenia as a T score between –1 to –2.5 and osteoporosis as –2.5. A bone mineral
density drop of one standard deviation is generally thought to double the risk of fracture, but this is based
on studies of postmenopausal women not on corticosteroids. A few studies have shown that for a similar
change in bone mineral density, patients on corticosteroids may have a higher risk of fracture (Luengo et
al., 1991, Peel et al., 1995). Thus, the recommended threshold for intervention is also quite low: a T score
of –1.5 at the spine or hip from the UK Consensus Group (Eastell et al., 1998) and an even lower T score of
–1.0 from the American College of Rhematology (2001).
Margaret undergoes a DEXA scan on a Hologic machine. Her bone mineral density at the spine (L1-L4)
was 1.0 grams/cm squared. T score at the spine was –0.43 with a Z score of -0.32 (97% of age matched
controls). The total hip bone mineral density was 0.794 grams/cm squared with a T score of –1.21 with a Z
score of -1.11 (85% of age matched controls). Using the T score at the hip and the Fracture Risk
Calculator (Ott, 2003) her estimated lifetime risk of hip fracture is 1.8 times higher than the average
woman and her risk of osteoporotic fracture in the next 10 years is 5%. However, given her history of
prednisone use and cigarette smoking, her risk increases slightly. She still has a <0.4% chance of a hip
fracture in the next 5 years and <8% chance of a non-vertebral fracture. What is the appropriate
intervention in Margaret?
General measures that reduce risk for osteoporosis or fracture risk include smoking cessation, limiting
alcohol consumption, increasing bone-building exercise and limiting fall risk (Yeap et al, 1992, ACR
2001). While these measures have not been specifically addressed in the corticosteroid population, they are
low-cost and likely to provide additional health benefits.
Calcium is a simple and inexpensive choice for prevention of osteoporosis. There is limited data that
calcium alone can help to prevent bone loss, but the majority of studies have demonsrated that calcium plus
vitamin D is more effective. Many studies of bisphosphonates and corticosteroids have demonstrated that
the “placebo” calcium plus vitamin D maintained bone density (Saag et al., 1998, Reid et al., 2000). A
meta-analysis of randomized control trials of long-term oral corticosteroids and bone loss showed that
lumbar spine mineral density was 2.0% greater in patients treated vitamin D than with calcium alone or no
treatment (Amin et al., 2002). Calcitriol and Vitamin D have both been shown to be effective, but the
former can have the side effect of hypercalcemia.
Calcitonin is an agent that may increase bone density in patients on extended courses of glucocorticoids,
but the evidence is mixed. Some studies have shown little effect on bone density (Sambrook et al, 1993,
Healy et al., 1996), but others have shown increased bone density at the lumbar spine but not at the hip
(Montemurro et al., 1991, Luengo et al, 1994, and Adachi et al., 1997). A meta-analysis showed that
calcitonin increased bone mineral density at the lumbar spine 2.3 percent compared to calcium or therapy
in patients on corticosteroids (Amin et al., 2002). However, it has not yet been shown to decrease vertebral
fracture risk.
Fluoride has been shown to increase bone mineral density in the lumbar spine in persons treated with
chronic steroids, but in at least one study it did not prevent loss at the hip (Guaydier-Souquieres et al.,
1996, Lems et al., 1997). However, there is some evidence that fluoride can actually increase the risk of
fracture in postmenopausal women in spite of the increased bone density (Gutterige et al., 2002). Thus, it
is not currently recommended for osteoporosis prevention.
Parathyroid hormone has been used successfully in the treatment of refractory osteoporosis and
corticosteroid-induced osteoporosis. However, it is extremely expensive, and its role in prophylaxis for
corticosteroid-induced osteoporosis is unclear.
Replacement of sex hormones has recently become much more controversial. The Women’s Health
Initiative Trial showed a significant increase in the risk of stroke, heart disease and breasts cancer in
women on hormone replacement therapy (HRT), specifically with estrogen and progesterone (Rossouw et
al, 2002). The risk of hip fracture in this postmenopausal population was also reduced. The relative risk of
hip fracture was 0.66 (0.45-0.98) and there were 5 fewer hip fractures per 10,000 person years. What is
still unclear is how the risks and benefits of HRT might play out in a patient population with a higher risk
of hip fracture, such as patients on chronic corticosteroids, and whether or not SERM’s might play a role in
older women on steroids. At this point, the best advice is to discuss the risks and benefits with patients. In
pre-menopausal women who have oligomenorrhea or amenorrhea, the ACR (2001) recommended
considering oral contraceptive pills, based on observational studies of bone loss in young women with
menstrual irregularities. In men, hypogonadism can also lead to bone loss, and the ACR (2001) also
recommended checking a testosterone level and initiating replacement therapy for levels <300mg/dl in
men without contraindications.
Bisphosphonates are commonly used in the U.S. for prevention of corticosteroid-induced bone loss. Not
only is there data showing increased bone density (compared to calcium and vitamin D) but there is also
evidence demonstrating reduced rate of fracture, even in short term studies of bisphosphonate use with
corticosteroids. Markers of bone turnover are also consistently lower in the bisphosphonate groups in these
trials. A two-year extension study of alendronate use in patients taking 7.5mg prednisone or greater (in
addition to vitamin D and calcium) showed a 3.9% (+/-0.7%) increase in bone mineral density at the
lumbar spine in the 5mg daily alendronate group. Vertebral fracture rate over the two-year study was only
0.7% in the combined alendronate groups and 6.8% in the calcium plus vitamin D group (p=0.26). There
was no significant difference in the number of non-vertebral fractures between groups. There were no premenopausal fractures (Adachi et al., 2001). .
Similarly, a randomized trial of risedronate vs. calcium and vitamin D in patients taking 7.5 mg of
prednisone or greater showed an increase in vertebral bone density in the risedronate group (1.9 +/- 0.38%)
and a loss of bone density in the calcium/vitamin D group over 12 months. Bone mass in the hip was
maintained on risedronate. Risk of vertebral fracture was reduced by 70% in the patients taking risedronate
5mg (vs. 2.5mg or placebo, p=0.01). In the group of patients who had started on tcorticosteroid herapy less
than 3 months prior to risedronate, there was a trend towards vertebral fracture reduction, 71% (p=0.07).
The overall number of fractures was small though. Subgroup analysis did show a significant reduction in
fracture in post-menopausal women. Again, no pre-menopausal fractures were observed (Wallach et al.,
2000).
Cyclical etidrodate has also been shown to be effective in osteoporosis prophylaxis. In a study of patients
initiating high dose corticosteroids, bone mineral density of the lumbar spine increased only 0.61% ( +/0.54)over 12 months with q 3 month etidronate infusion , but this was compared to a loss of 3.23% (+/0.60) in the placebo group. Vertebral fractures were significantly reduced by 85% in the postmenopausal
subgroup on etidronate (p= 0.5) (Adachi et al., 1997 (2)). A meta-analysis of pooled studies on
bisphosphonates calculated a 4.9% increase in bone density versus no therapy or calcium (Amin et al.,
2002).
Summary of ACR Recommendations for Prevention
of Glucocorticoid-induced Ostoeoporosis
(Duration of corticosteroid therapy >6months, dose >5mg a day)
Smoking cessation
Weight bearing exercise
Reduction of alcohol consumption
Calcium supplementation
Vitamin D supplementation
Sex hormone replacement if deficient
Obtain DEXA scan
If T score is less than one: first-line bisphosponate, second-line calcitonin
If BMD normal, repeat DEXA in 6 months to 1 year.
Adapted from ACR 2001, Table 2 p.1501
A single cost-effectiveness study of corticosteroid-induced osteoporosis has been performed to date.
Comparisons were made between no therapy, calcium and vitamin D, etidronate and alendronate (efficacy
and cost assumed equal to risedronate) for 4 different age cohorts. Alendronate was more efficacious than
etidronate, which was more effective than calcium vitamin D, in reducing fracture number in the 50,60 and
70 year old groups in the 10 year analysis and in the 30,50,60 and 70 year old cohorts in the lifetime
analysis. However, the cost was significant. Costs of treatment were balanced against cost of vertebral
fracture in disability and actual cost. No treatment was most cost effective for the 30-year-old woman with
a T score of 0. Calcium plus vitamin D was most cost-effective in women with T scores of –1 to –2, at a
cost of $115 per fracture avoided. Notably, the cost per fracture avoided with alendronate therapy in 50year-old women with a T score of –1 was $121,125. Etidronate was most cost effective in the 70-year-old
age group with an estimated T score of –2, at a cost of $838 per fracture avoided. The 70-year-old women
treated with alendronate versus etidronate had 5 versus 11 vertebral fractures. However, the cost per
fracture avoided rose to over $7,000 (Buckley et al., 2003).
Margaret acknowledges her risk of osteoporosis. She agrees to continue calcium and vitamin D
supplementation and work on quitting smoking. However, feels she is on a number of medications at
present and does not feel compelled to start taking another medication, especially one that has been understudied in pre-menopausal women. She agrees to return in 6 months to 1 year for a DEXA scan. In
addition, she has no family history of breast cancer or heart disease, and she may consider at least shortterm estrogen replacement if she becomes symptomatic at menopause.
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