030_0609tfp_bonehealth.indd

Approaches to the Treatment
of Osteoporosis
JoAnn V. Pinkerton, MD; Alan C. Dalkin, MD
3% to 6% during the fi rst year, and any frac- Primary osteoporosis preventive mea-
sures include exercise plus adequate
calcium and vitamin D in the diet or by
Selective Estrogen Receptor
Modulators (SERMS)
supplement. FDA-approved treatment SERMs act as estrogen receptor agonists and/
options for osteoporosis include oral
or antagonists. Raloxifene 60 mg daily as an and intravenous bisphosphonates, ral-
oral dose is approved for the prevention and oxifene, teriparatide, and calcitonin.
treatment of osteoporosis and breast cancer. Three years of raloxifene therapy signifi cantly Estrogen is FDA-approved for preven-
increased bone mineral density (BMD) versus tion of osteoporosis.
placebo by 2.6% at the spine and 2.1% at the femoral neck, and reduced the risk of verte-bral fracture by 55%. No effect was found on PREVENTION AND TREATMENT
the hip or other nonvertebral site.4 Raloxifene PHARMACOLOGIC STRATEGIES
Estrogen Therapy
decrease the risk of estrogen receptor positive Although the primary indication for systemic breast cancer and was comparable to tamoxi- estrogen therapy is the treatment of moderate fen for prevention of invasive breast cancer.5 en’s Health Initiative (WHI) confi rmed the effi cacy of hormone therapy (HT) in prevent- VTEs and fatal stroke in one study, but it does ing vertebral and hip fractures.1 Increased not increase the risk of overall strokes, cata- risks of heart disease, breast cancer, venous racts, gallbladder disease, endometrial hyper- thromboembolism (VTE), dementia, and plasia, or endometrial cancer, or cause vaginal gallstones were found, with fewer fractures bleeding or breast pain. Bone loss resumes and colon cancer. The estrogen-alone arm showed fewer breast cancers at 6.7 years. The women at risk for vertebral fracture with an WHI reanalysis in 2007 revealed decreased elevated risk of breast cancer, raloxifene may mortality for women younger than age 60 and be the appropriate choice of therapy.
within 10 years of menopause.2 Systemic estrogen products are approved for preven- Oral Bisphosphonate Therapy
tion, but not treatment of osteoporosis. Lower- Bisphosphonates block bone resorption by than-standard doses of HT show less bone inhibiting osteoclasts. Numerous studies density increases but may be considered for show these agents increase BMD and reduce prevention of bone loss, recognizing there is the risk of vertebral fractures by 40% to 50%, no fracture effi cacy data available. Discon- as well as reduce the incidence of nonverte- tinuation of HT leads to rapid bone loss of bral fracture, including hip fracture.
Alendronate is available for daily or weekly
JoAnn V. Pinkerton, MD, is Vice Chair for Academic Affairs,
oral dosing for the prevention and treatment Professor of Obstetrics and Gynecology, and Director, Midlife of osteoporosis. In older women with osteo- Health Center, Departments of Obstetrics and Gynecology; porosis, BMD was increased from baseline of and Alan C. Dalkin, MD, is Professor of Medicine and Interim
5% to 10% at the spine and hip in postmeno- Chief, Division of Clinical Rheumatology, both at University of Virginia, Charlottesville.
pausal women with low BMD or established 30 The Female Patient | VOL 34 JUNE 2009
Pinkerton and Dalkin
osteoporosis. In the Fracture Intervention Ibandronate is approved for the prevention
Trial (FIT), daily alendronate therapy for 2.9 and treatment of postmenopausal osteoporo- years signifi cantly reduced the risk of verte- sis in daily and monthly (oral) and every 3 bral fracture by 47% and of hip fracture by In older women (mean 69 FOCUSPOINT
vertebral fracture with a reduction of 59% in Numerous studies
domized to alendronate in FIT were random- show bisphospho-
ized to alendronate or placebo for an BMD compared with placebo nates increase BMD
additional 5 years (FLEX).7 BMD decreased and reduce the risk
2.4% at hip and 3.7% at the spine although ral neck (4.1%) after 3 years. of vertebral and non-
levels remained above pretreatment levels from 10 years earlier. Bone turnover markers reduced vertebral fractures vertebral fractures.
increased after discontinuation but also by 52% over the 3 years, Some reduce the
remained below pretreatment levels. No dif- although no signifi cant effect incidence of hip
ference in morphometric vertebral fractures was seen, although fewer clinically recog- fractures.
nized vertebral fractures were seen. There did not appear to be a negative impact on Intravenous (IV)
bone formation or quality with long-term use Bisphosphonate Therapy:
of alendronate. However, while discontinuing Zolendronic Acid and Ibandronate
alendronate after 5 years may not increase fracture risk, patients at high risk for clinical mented effi cacy of IV zolendronic acid with fractures may benefi t from continuing more reduced bone turnover markers, increased BMD, as well as a reduction in vertebral and Risedronate is approved for the prevention
hip fracture with a regimen of 5 mg given as and treatment of postmenopausal osteoporo- a 15-minute infusion on an annual basis. sis. Daily oral risedronate therapy led to BMD Similarly, a randomized controlled trial increases of 4.3% in the spine and 2.8% in the given within 90 days of surgical repair of a therapy for 7 years, resulting in progressive hip fracture, resulted in a signifi cant increase increases in BMD of 11.5% from baseline.8 in BMD, reduction in subsequent vertebral Vertebral fracture was reduced by 41% to 49% and non-vertebral fractures, and an improved compared with placebo. Within the fi rst year of therapy, the relative risk of vertebral frac-ture was reduced by 61% to 65%. Compared to placebo, continued reduction in vertebral fractures was seen through 7 years of treat-ment.9 In the Hip Intervention Program Study TABLE. Fracture Prevention Efficacy
Group of women aged 70 to 79 years, risedro- Vertebral
Nonvertebral
nate therapy signifi cantly reduced the rela- Therapy Fracture
Fracture
Fracture
tive 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 signifi cantly 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 signifi cant bone loss at both the spine and hip during the fi rst year after The Female Patient | VOL 34 JUNE 2009 31
BONEHEALTH
Approaches to the Treatment of Osteoporosis
In a RCT noninferiority fractures or who have failed other therapy. In FOCUSPOINT
postmenopausal women with prior vertebral fracture, 19 months of teriparatide signifi - cantly increased BMD in the spine by 8.6% and in the femoral neck by 3.5% compared with Choice of
placebo. New vertebral fractures were reduced therapy depends on
by 65% and new nonvertebral fragility frac- individual risk factors,
tures by 53%. A reduced risk of moderate and severe vertebral fractures by 90% was found, tolerability, cost, and
as well as a reduced risk of nonvertebral fragil- effectiveness of
ity fractures by 53%; the study was not pow- the therapy.
ered to examine the effect on hip fractures.18 Adverse effects include muscle cramps and infrequent hypercalcemia, nausea, and dizzi- this complaint appears to ness. Teriparatide caused osteosarcoma in a rat diminish in intensity with sub- model at much higher doses than those used in humans; the signifi cance of this in humans is uncertain. Contraindications include hyper- Potential Concerns with
calcemia; bone metastases; disorders that pre- Bisphosphonate Use
dispose them to bone tumors, such as Paget’s Osteonecrosis of the jaw associated with den- disease; or prior skeletal irradiation. Following toalveolar trauma, such as tooth extraction, discontinuation of parathyroid hormone (PTH) has been reported with oral or IV alendro- therapy, substantial bone loss occurs within nate, primarily in patients with multiple the fi rst year.
myeloma or metastatic breast cancer. Risk for healthy women is estimated as less than 1 in Combination therapy
100,000 treatment years. Dental evaluation is Combining potent antiresorptive agents leads recommended prior to initiation of bisphos- to small additional increments in bone density. phonate therapy. Discontinuation has been BMD improvements in the spine and hip were recommended prior to oral surgery without found when alendronate was combined with data to support this recommendation. Treat- estrogen were signifi cantly greater (8.3%) than ment includes systemic antibiotics and oral results for either agent alone (6.0%). Similar, antibiotic rinses. Hypothesized etiologies although more modest, results have been seen include excessive suppression of bone turn- with combined risedronate and HT. The ana- over, decreased angiogenesis, or dental infec- bolic agent, teriparatide, in combination with estrogen also led to signifi cant increases in For more information, refer to the recent FDA BMD. Combinations of bis-phosphonates with report that updated the agency’s safety recom- estrogen or SERMS have been shown to increase mendations regarding bisphosphonates.15 In BMD more than single agents. Prior or concur- addition, a recent study looked at atypical frac- rent alendronate treatment appears to reduce tures and bisphosphonates.16 Based on reports the anabolic effect of PTH with slowed bone to the FDA of esophageal cancer, avoid prescrib- turnover and decreases in PTH-induced BMD ing oral bisphosphonates for patients with Bar- increases. Alendronate administered after dis- continuation of PTH has been shown to main-tain or increase BMD and prevent loss Parathyroid Hormone
associated with discontinuation of PTH.19 Con- Teriparatide (recombinant human PTH 1-34) cern exists that combining 2 antiresorptive is an anabolic daily subcutaneous injection agents could lead to oversuppression of bone approved for 18 to 24 months for treatment turnover, adversely affect bone quality, or lead of severe postmenopausal osteoporosis. It directly stimulates osteoblastic bone forma-tion, resulting in substantial increases in tra- becular bone density and connectivity. It is Early diagnosis and prevention of osteoporo- currently targeted at women who are at high sis can prevent fractures. Choice of therapy risk for fracture, particularly those with prior depends on individual risk factors, tolerability, 32 The Female Patient | VOL 34 JUNE 2009
Pinkerton and Dalkin
cost, and effectiveness of the therapy (Table). Study of Tamoxifen And Raloxifene (STAR) P-2 Trial. JAMA. 2006;295(23):2727–2741.
Estrogen may be considered fi rst-line therapy 6. Black DM, Cummings SR, Karpf DB, et al. Randomised for the prevention of osteoporosis in prema- trial of effect of alendronate on risk of fracture in women turely menopausal women younger than age with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348(9041):1535–1541.
50, as well as for women younger than age 60 7. Black DM, Schwartz AV, Ensrud KE, et al. Effects of con- and within 10 years of menopause with meno- tinuing or stopping alendronate after 5 years of treatment: pausal symptoms and bone loss. SERM treat- the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296(24): ment with raloxifene has shown vertebral fracture risk reduction and prevention of 8. Mellström DD, Sörensen OH, Goemaere S, Roux C, John- breast cancer. Oral and IV bisphosphonates son TD, Chines AA. Seven years of treatment with risedro-nate in women with postmenopausal osteoporosis. Calcif have RCT data showing risk reductions in Tissue Int. 2004;75(6):462–468.
both vertebral and, in some, non-vertebral 9. Harris ST, Watts NB, Genant HK, et al. Effects of risedro- fractures. Anabolic therapy with PTH shows nate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A random- reduction in vertebral and non-vertebral frac- ized controlled trial. Vertebral Effi cacy With Risedronate ture and is reserved for women at particularly Therapy (VERT) Study Group. JAMA. 1999;282(14): high-risk for future fracture. Nasal calcitonin 10. Watts NB, Chines A, Olszynski WP, et al. Fracture risk shows reductions in vertebral fracture in remains reduced one year after discontinuation of rise- dronate. Osteoporos Int. 2008;19(3):365–372.
Combination therapy is reserved for treat- 11. 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 assured, recognizing lack of fracture effi cacy Miner Res. 2004;19(8):1241–1249.
12. Black DM, Delmas PD, Eastell R, et al. Once-yearly zole- dronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809–1822.
Dr Pinkerton reports she is a consultant to and 13. Delmas PD, Adami S, Strugala C, et al. Intravenous iban- serves on the advisory board for Eli Lilly and dronate injections in postmenopausal women with osteo- Company, Duramed Pharmaceuticals, Inc., porosis: one-year results from the dosing intravenous administration study. Arthritis Rheum. 2006;54(6): Novo Nordisk, Amgen, and Wyeth. She receives research support from Wyeth and Pfizer Inc. 14. Strampel W, Emkey R, Civitelli R. Safety considerations Dr. Dalkin reports no actual or potential con- with bisphosphonates for the treatment of osteoporosis. Drug Saf. 2007;30(9):755–763.
fl icts of interest in relation to this article. 15. U.S. Food and Drug Administration. Update of Safety Review Follow-up to the October 1, 2007 Early Com- REFERENCES
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18. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of para- 4. Ettinger B, Black DM, Mitlak BH, et al. Reduction of verte- thyroid hormone (1-34) on fractures and bone mineral bral fracture risk in postmenopausal women with osteo- density in postmenopausal women with osteoporosis. porosis treated with raloxifene: results from a 3-year N Engl J Med. 2001;344(19):1434–1441.
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5. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of 20. Pinkerton JV, Dalkin AC. Combination therapy for treat- tamoxifen vs raloxifene on the risk of developing invasive ment of osteoporosis: A review. Am J Obstet Gynecol. breast cancer and other disease outcomes: the NSABP The Female Patient | VOL 34 JUNE 2009 33

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