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BONE
HEALTH
Approaches to the Treatment of Osteoporosis
JoAnn V. Pinkerton, MD; Alan C. Dalkin,
MD
Primary osteoporosis preventive measures include exercise plus
adequate calcium and vitamin D in the diet or by supplement.
FDA-approved treatment options for osteoporosis include oral and intravenous
bisphosphonates,
raloxifene, teriparatide, and calcitonin. Estrogen is FDA-approved
for prevention of osteoporosis.
Prevention and Treatment Pharmacologic Strategies
Estrogen Therapy
Although the primary indication for systemic estrogen therapy is
the treatment of moderate to severe menopausal symptoms, the Women’s
Health Initiative (WHI) confirmed the efficacy of hormone therapy
(HT) in preventing vertebral and hip fractures.1 Increased
risks of heart disease, breast cancer, venous thromboembolism (VTE),
dementia,
and gallstones were found, with fewer fractures and colon cancer.
The estrogen-alone arm showed fewer breast cancers at 6.7 years.
The WHI reanalysis in 2007 revealed decreased mortality for women
younger
than age 60 and within 10 years of menopause.2 Systemic
estrogen products are approved for prevention, but not treatment of
osteoporosis. Lower-than-standard
doses of HT show less bone density increases but may be considered
for prevention of bone loss, recognizing there is no fracture efficacy
data available. Discontinuation of HT leads to rapid bone loss
of 3% to 6% during the first year, and any fracture protection declines
as well.3
Selective Estrogen Receptor
Modulators (SERMS)
SERMs act as estrogen receptor agonists and/or antagonists. Raloxifene 60
mg daily as an oral dose is approved for the prevention and treatment of osteoporosis
and breast cancer. Three years of raloxifene therapy significantly increased
bone mineral density (BMD) versus placebo by 2.6% at the spine and 2.1% at
the femoral neck, and reduced the risk of vertebral fracture by 55%. No effect
was found on the hip or other nonvertebral site.4 Raloxifene
has been shown in multiple studies to decrease the risk of estrogen receptor
positive breast
cancer and was comparable to tamoxifen for prevention of invasive breast cancer.5
Raloxifene therapy has been associated with an increase in vasomotor symptoms,
VTEs and fatal stroke in one study, but it does not increase the risk of overall
strokes, cataracts, gallbladder disease, endometrial hyperplasia, or endometrial
cancer, or cause vaginal bleeding or breast pain. Bone loss resumes when raloxifene
therapy is stopped. For women at risk for vertebral fracture with an elevated
risk of breast cancer, raloxifene may be the appropriate choice of therapy.
Oral Bisphosphonate Therapy
Bisphosphonates block bone resorption by inhibiting osteoclasts. Numerous
studies show these agents increase BMD and reduce the risk of vertebral fractures
by 40% to 50%, as well as reduce the incidence of nonvertebral fracture, including
hip fracture.
Alendronate is available for daily or weekly oral dosing for
the prevention and treatment of osteoporosis. In older women with osteoporosis,
BMD was increased
from baseline of 5% to 10% at the spine and hip in postmenopausal women with
low BMD or established osteoporosis. In the Fracture Intervention Trial (FIT),
daily alendronate therapy for 2.9 years significantly reduced the risk of vertebral
fracture by 47% and of hip fracture by 51% in women with low BMD and previous
vertebral fracture with a reduction of 59% in clinical vertebral fractures.6
A group of 1,099 women previously randomized to alendronate in FIT were randomized
to alendronate or placebo for an additional 5 years (FLEX).7 BMD decreased
2.4% at hip and 3.7% at the spine although levels remained above pretreatment
levels from 10 years earlier. Bone turnover markers increased after discontinuation
but also remained below pretreatment levels. No difference in morphometric
vertebral fractures was seen, although fewer clinically recognized vertebral
fractures were seen. There did not appear to be a negative impact on bone formation
or quality with long-term use of alendronate. However, while discontinuing
alendronate after 5 years may not increase fracture risk, patients at high
risk for clinical fractures may benefit from continuing more than 5 years.7
Risedronate is approved for the prevention and treatment of
postmenopausal osteoporosis. Daily oral risedronate therapy led to BMD increases
of 4.3% in
the spine and 2.8% in the femoral neck compared with placebo with therapy for
7 years, resulting in progressive increases in BMD of 11.5% from baseline.8 Vertebral
fracture was reduced by 41% to 49% compared with placebo. Within the first
year of therapy, the relative risk of vertebral fracture was reduced
by 61% to 65%. Compared to placebo, continued reduction in vertebral fractures
was seen through 7 years of treatment.9 In
the Hip Intervention Program Study Group of women aged 70 to 79 years, risedronate
therapy significantly reduced
the relative risk for hip fracture by 40% in the subanalysis of women with
osteoporotic BMD values. In those with prior vertebral fracture, there was
a 60% reduced risk of hip fracture. However, therapy did not significantly
lower the hip fracture risk in women aged 80 years and older who had risk factors
for falling but did not have BMD testing. Discontinuation of risedronate therapy
after 2 years in young postmenopausal women (mean age, 51 to 52 years) resulted
in significant bone loss at both the spine and hip during the first year after
treatment was stopped.10
Ibandronate is approved for the prevention and treatment of postmenopausal
osteoporosis in daily and monthly (oral) and every 3 months intravenously.
In older women (mean 69 years) with low spinal BMD and prevalent vertebral
fractures, ibandronate at 2.5 mg/day significantly increased BMD compared with
placebo in the spine (5.2%) and femoral neck (4.1%) after 3 years. Daily ibandronate
therapy reduced vertebral fractures by 52% over the 3 years, although no significant
effect was found for nonvertebral fracture risk.11
Intravenous (IV) Bisphosphonate Therapy: Zolendronic Acid and Ibandronate
The 3-year pivotal HORIZON trial documented efficacy of IV zolendronic
acid with reduced bone turnover markers, increased BMD, as well
as a reduction in vertebral and hip fracture with a regimen of 5 mg given
as a 15-minute
infusion on an annual basis. Similarly, a randomized controlled
trial (RCT) of annual zolendronic acid (5 mg) given within 90 days of surgical
repair
of a hip fracture, resulted in a significant increase in BMD, reduction
in subsequent vertebral and non-vertebral fractures, and an improved
rate of survival.12
In a RCT noninferiority study comparing oral and IV ibandronate,
both regimens of IV ibandronate (2 mg every 2 months and 3 mg every 3 months)
resulted in greater increases in BMD at both the hip and spine than with
oral dosing.6,13
The primary side effect of these IV medications appears to be flu-like
symptoms occurring within the first few days after dosing. The incidence
of this complaint appears to diminish in intensity with subsequent infusions.
Potential Concerns with
Bisphosphonate Use
Osteonecrosis of the jaw associated with dentoalveolar trauma, such as
tooth extraction, has been reported with oral or IV alendronate,
primarily in patients with multiple myeloma or metastatic breast cancer.
Risk for
healthy women is estimated as less than 1 in 100,000 treatment
years. Dental evaluation is recommended prior to initiation of bisphosphonate
therapy.
Discontinuation has been recommended prior to oral surgery without
data to support this recommendation. Treatment includes systemic antibiotics
and oral antibiotic rinses. Hypothesized etiologies include excessive
suppression
of bone turnover, decreased angiogenesis, or dental infection or
trauma.14
For more information, refer to the recent FDA report that updated
the agency’s safety recommendations regarding bisphosphonates.15 In
addition, a recent study looked at atypical fractures and bisphosphonates.16 Based
on reports to the FDA of esophageal cancer, avoid prescribing oral
bisphosphonates for patients with Barrett’s esophagus.17
Parathyroid Hormone
Teriparatide (recombinant human PTH 1-34) is an anabolic daily subcutaneous
injection approved for 18 to 24 months for treatment of severe
postmenopausal osteoporosis. It directly stimulates osteoblastic bone formation,
resulting
in substantial increases in trabecular bone density and connectivity.
It is currently targeted at women who are at high risk for fracture, particularly
those with prior fractures or who have failed other therapy. In
postmenopausal
women with prior vertebral fracture, 19 months of teriparatide
significantly increased BMD in the spine by 8.6% and in the femoral neck
by 3.5% compared
with placebo. New vertebral fractures were reduced by 65% and new
nonvertebral fragility fractures by 53%. A reduced risk of moderate and
severe vertebral
fractures by 90% was found, as well as a reduced risk of nonvertebral
fragility fractures by 53%; the study was not powered to examine the effect
on hip
fractures.18
Adverse effects include muscle cramps and infrequent hypercalcemia,
nausea, and dizziness. Teriparatide caused osteosarcoma in a rat model at
much higher doses than those used in humans; the significance of this in
humans is uncertain. Contraindications include hypercalcemia; bone metastases;
disorders that predispose them to bone tumors, such as Paget’s disease;
or prior skeletal irradiation. Following discontinuation of parathyroid
hormone (PTH) therapy, substantial bone loss occurs within the first year.
Combination therapy
Combining potent antiresorptive agents leads to small additional increments
in bone density. BMD improvements in the spine and hip were found
when alendronate was combined with estrogen were significantly
greater (8.3%) than results
for either agent alone (6.0%). Similar, although more modest, results
have been seen with combined risedronate and HT. The anabolic agent,
teriparatide, in combination with estrogen also led to significant increases
in BMD. Combinations
of bis-phosphonates with estrogen or SERMS have been shown to increase
BMD more than single agents. Prior or concurrent alendronate treatment
appears
to reduce the anabolic effect of PTH with slowed bone turnover
and decreases
in PTH-induced BMD increases. Alendronate administered after discontinuation
of PTH has been shown to maintain or increase BMD and prevent loss
associated with discontinuation of PTH.19 Concern
exists that combining 2 antiresorptive agents could lead to oversuppression
of bone turnover, adversely affect bone quality, or lead to increased
fracture risk.20
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Summary
Early diagnosis and prevention of osteoporosis can prevent fractures.
Choice of therapy depends on individual risk factors, tolerability, cost,
and effectiveness of the therapy (Table). Estrogen may be considered first-line
therapy for the prevention of osteoporosis in prematurely menopausal women
younger than age 50, as well as for women younger than age 60 and within
10 years of menopause with menopausal symptoms and bone loss. SERM treatment
with raloxifene has shown vertebral fracture risk reduction and prevention
of breast cancer. Oral and IV bisphosphonates have RCT data showing risk
reductions in both vertebral and, in some, non-vertebral fractures. Anabolic
therapy with PTH shows reduction in vertebral and non-vertebral fracture
and is reserved for women at particularly high-risk for future fracture.
Nasal calcitonin shows reductions in vertebral fracture in women more than
5 years postmenopause. Combination therapy is reserved for treatment failures
when compliance has been assured, recognizing lack of fracture efficacy
or long-term safety data.
Dr Pinkerton reports she is a consultant to and serves on the
advisory board for Eli Lilly and Company, Duramed Pharmaceuticals,
Inc., Novo Nordisk,
Amgen, and Wyeth. She receives research support from Wyeth and
Pfizer Inc. Dr. Dalkin reports no actual or potential conflicts of
interest in relation
to this article.
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JoAnn V.
Pinkerton, MD, is Vice Chair for Academic Affairs, Professor
of Obstetrics and Gynecology, and Director, Midlife Health Center, Departments
of Obstetrics
and Gynecology; and Alan C. Dalkin, MD, is Professor of Medicine
and Interim Chief, Division of Clinical Rheumatology, both at University
of Virginia,
Charlottesville.
References
- Lindsay R. Hormones and bone health in postmenopausal
women. Endocrine. 2004;24(3):223–230.
- Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy
and risk of cardiovascular disease by age and years since menopause. JAMA.
2007; 297(13):1465–1477.
- Wasnich RD, Bagger YZ, Hosking DJ, et al. Changes in bone density and turnover
after alendronate or estrogen withdrawal. Menopause. 2004;11(6 Pt 1):622–630.
- Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk
in postmenopausal women with osteoporosis treated with raloxifene: results froma 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation
(MORE) investigators. JAMA. 1999; 282(7):637–645.
- Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene
on the risk of developing invasive breast cancer and other disease outcomes:
the NSABP Study of Tamoxifen And Raloxifene (STAR) P-2 Trial. JAMA. 2006;295(23):2727–2741.
- Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate
on risk of fracture in women with existing vertebral fractures. Fracture Intervention
Trial Research Group. Lancet. 1996;348(9041):1535–1541.
- Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping
alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term
Extension (FLEX): a randomized trial. JAMA. 2006;296(24): 2927–2938.
- Mellström DD, Sörensen OH, Goemaere S, Roux C, Johnson TD, Chines
AA. Seven years of treatment with risedronate in women with postmenopausal osteoporosis.
Calcif Tissue Int. 2004;75(6):462–468.
- Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on
vertebral and nonvertebral fractures in women with postmenopausal osteoporosis:
A randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT)
Study Group. JAMA. 1999;282(14): 1344–1352.
- Watts NB, Chines A, Olszynski WP, et al. Fracture risk remains reduced one
year after discontinuation of risedronate. Osteoporos Int. 2008;19(3):365–372.
- Chesnut III CH, Skag A, Christiansen C, et al. Effects of oral ibandronate
administered daily or intermittently on fracture risk in postmenopausal osteoporosis.
J Bone Miner Res. 2004;19(8):1241–1249.
- Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment
of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809–1822.
- Delmas PD, Adami S, Strugala C, et al. Intravenous ibandronate injections
in postmenopausal women with osteoporosis: one-year results from the dosing intravenous
administration study. Arthritis Rheum. 2006;54(6): 1838–1846.
- Strampel W, Emkey R, Civitelli R. Safety considerations with bisphosphonates
for the treatment of osteoporosis. Drug Saf. 2007;30(9):755–763.
- U.S. Food and Drug Administration. Update of Safety Review Follow-up to
the October 1, 2007 Early Communication about the Ongoing Safety Review of Bisphosphonates.
www.fda.gov/CDER/drug/early_com/bisphosphonates_update_200811.htm. Published
November 12, 2008. Accessed May 13, 2009.
- Kwek EB, Koh JS, Howe TS. More on atypical fractures of the femoral diaphysis. N
Engl J Med. 2008;359(3): 316–317.
- Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use.
N Engl J Med. 2009;360(1):89–90.
- Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34)
on fractures and bone mineral density in postmenopausal women with osteoporosis.
N Engl J Med. 2001;344(19):1434–1441.
- Black DM, Bilezikian JP, Ensrud KE, et al. One year of alendronate after
one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med. 2005;353(6):555–565.
- Pinkerton JV, Dalkin AC. Combination therapy for treatment of osteoporosis:
A review. Am J Obstet Gynecol. 2007;197(6):559–565.
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