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Treatment of Osteoporosis in Postmenopausal Women Who Are At Risk of Fracture

Published Online: June 6th 2011 US Endocrinology, 2006;(2): DOI: http://doi.org/10.17925/USE.2006.00.02.1w
Authors: Adriana Ioachimescu, Angelo Licata
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Osteoporosis consists of decreased bone strength and increased risk of fractures due to decreased mass and abnormal bone microarchitecure. Almost 20% of postmenopausal women have osteoporosis as defined by World Health Organization (WHO) criteria (T-score <- 2.5). Besides the bone mineral density (BMD) expressed by T-score, advancing age, premature menopause, low body weight (≤120lbs), maternal history of hip fracture, previous fracture, loss of height (≥3 inches) and the use of glucocorticosteroids are risk factors for bone fractures. Identifying the postmenopausal women at risk include both an evaluation for risk factors (including secondary causes of osteoporosis) and measurement of bone mass density (BMD) by dual X-ray absorbtiometry (DXA).

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All postmenopausal women should be advised to avoid smoking and excessive alcohol intake, exercise regularly, and take calcium (1,200–1,500mg daily from food and supplements) and vitamin D (800–1,200 international units (IU) daily). The guidelines for pharmacologic treatment of postmenopausal osteoporosis are not uniform among medical organizations. The pharmacologic options fall into two main categories: antiresorptive and anabolic agents.

All postmenopausal women should be advised to avoid smoking and excessive alcohol intake, exercise regularly, and take calcium (1,200–1,500mg daily from food and supplements) and vitamin D (800–1,200 international units (IU) daily). The guidelines for pharmacologic treatment of postmenopausal osteoporosis are not uniform among medical organizations. The pharmacologic options fall into two main categories: antiresorptive and anabolic agents. An overview of the medications current approved by US Food and Drug Administration (FDA) for prevention and treatment of postmenopausal osteoporosis is presented in Table 1.

Postmenopausal Hormone Replacement Therapy
Postmenopausal hormone replacement therapy was the primary therapy for management of postmenopausal osteoporosis. Estrogen slows bone resorption by blocking cytokine signaling to the osteoclasts. Conjugated estrogens were approved by prevention and treatment of osteoporosis in the early 1990s based on positive results of small studies. The Women’s Health Initiative (WHI) study was the first large randomized placebo-controlled study that proved that estrogen has a favorable effect on bone fractures. In this study, conjugated equine estrogen in a dose of 0.625mg daily decreased vertebral fractures by 48% and hip fractures by 33%. Discontinuation of estrogen resulted in bone loss within the next six months. Low-dose conjugated estrogens (0.3 and 0.45mg/day) or estradiol also increase BMD, but have no antifracture data. The nonskeletal risks associated with postmenopausal hormone replacement therapy and the availability of other medications which effectively treat postmenopausal osteoporosis led to a marked decrease in its use after 2000. Currently, estrogen is approved by the FDA for prevention (not treatment) of postmenopausal osteoporosis “for women with significant risk of osteoporosis that outweighs the risks of the drug”.The ‘black-box’ estrogen warning includes the increased risk of thromboembolic disease, coronary artery disease, stroke, and breast cancer. Since estrogens are metabolized by the cytochrome P450(CYP)3A4 isozyme, CYP3A4 inducers (St. John’s wort, phenobarbital, carbamazepine, and rifampin) decrease their effect, while CYP3A4 inhibitors (grapefruit juice, erythromycin, clarithromycin, ketoconazole, and ritonavir) increase it.

Selective Estrogen – receptor Modulators
Raloxifene acts as an estrogen agonist on bone and lipid metabolism and as an estrogen antagonist in the breast and endometrium. Raloxifene is approved for prevention and treatment of postmenopausal osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) study enrolled postmenopausal women with a spine or hip T-score ≤-2.5 or existing morphometric vertebral fracture. The 60mg dose increased the spine BMD and decreased the risk of vertebral fracture by 40% compared with placebo.The study was not powered to detect a decrease in the risk of nonvertebral fracture. The risk of breast cancer is reduced with long-term use of raloxifene but the drug does not have US Food and Drug Administration (FDA) approval for this indication. Side effects include hot flashes, nausea, leg cramps, and increased risk for venous thromboembolic events. Bisphosphonates
The bisphosphonates currently are the most widely used agents for prevention and treatment of postmenopausal osteoporosis. They inhibit resorption by blocking the osteoclasts’ recruitment, differentiation and attachment to bone matrix, and augmentation of osteoclast apoptosis. N-bisphosphonates (alendronate, risedronate and ibandronate) inhibit the mevalonate pathway, which is critical for production of cholesterol.

Alendronate was approved for prevention and treatment of osteoporosis in 1995.The Fracture Intervention Trial (FIT) enrolled postmenopausal women with hip T-score ≤-2.1, with or without previous history of fracture. At three years, daily alendronate decreased the incidence of fractures by 47% for the spine, 51% for the hip, and 20% for the nonvertebral fractures compared with placebo. The BMD and bone turnover makers improved significantly. The optimal duration of treatment with alendronate remains uncertain. Ten-year follow-up of patients included in initial phase III trial showed that BMD continued to increase in women still taking alendronate and tended to decrease in the ones who stopped it. FIT extension study (FLEX) also showed that BMD continued to increase in patients taking alendronate and decreased in the patients who received placebo after five years of alendronate therapy. Biochemical markers of bone resorption remained suppressed in both groups and the incidence of vertebral and nonvertebral fractures was not different in between the two groups. Bone biopsies studies from women who received alendronate for 10 years showed suppressed bone remodeling and no mineralization defect.

Risedronate was approved for prevention and treatment of postmenopausal osteoporosis in 1998.The Risedronate Vertebral Fracture Study enrolled postmenopausal women with spine T-score ≤-2.0 and a previous vertebral fracture or women with two or more vertebral fracture regardless of the BMD. At three years, daily risedronate decreased the risk of vertebral fracture by 41% and nonvertebral fracture by 39% compared with placebo. BMD and bone turnover markers significantly improved. The Hip Intervention Trial (HIP) was the first prospective study to investigate effect of a medication on hip fractures as primary end-point.The study enrolled postmenopausal women age 70–79 with hip T-score ≤-3.0 and women 80 years or older with unknown BMD but at risk for falls.At three years, the risedronate group aged 70–79 had a reduction in hip fractures by 40% compared with placebo, while women older than 80 did not have significantly less hip fractures compared with placebo.Both alendronate and risedronate have been approved for weekly oral administration based on pharmacokinetics, preclinical studies, and two-year non-inferiority trials that showed similar improvement of the BMD and bone resorption markers as the daily administration.The risk of fractures was not examined for weekly administered alendronate or risedronate. Ibandronate was approved for prevention and treatment of postmenopausal osteoporosis in 2003. A placebo-controlled randomized trial in postmenopausal women with spine T-score ≤-2.0 showed that daily administered ibandronate in a dose of 2.5mg daily resulted in a significant increase of spine and hip BMD.The BONE trial enrolled postmenopausal women with a single vertebra T-score ≤-2.0 randomized to oral ibandronate (2.5mg daily and 20mg every other day for 12 doses every three months) or placebo.To date this is the only bisphosphonate trial showing a significant decrease of the vertebral fracture risk as a result of intermittent administration of bisphosphonates (48%). However, unlike alendronate and risedronate, ibandronate does not have supporting evidence of decreased risk for hip fractures. In 2006 intravenous ibandronate administered once every three months became the first intravenous bisphosphonate FDA approved for treatment of postmenopausal osteoporosis. Intravenous pamidronate and zoledronate have been used off-label for treatment of osteoporosis in women who cannot tolerate oral bisphosphonates. There have been no randomized, placebo-controlled trials showing a decrease of incidence of fractures with pamidronate. Zoledronate was shown to increase spine and hip BMD and decrease bone turnover makers in a phase II trial of post-menopausal women with T-score ≤-2.0. Small uncontrolled studies have suggested that zoledronate has antifracture efficacy.These findings were confirmed by an interim analysis (99% data) of Horizon trial presented in 2006. Postmenopausal women with osteoporosis who received intravenous zoledronate 5mg once-yearly experienced a 70% risk reduction of new spine fractures and a 40% risk reduction of hip fractures compared with placebo.

Side effects of oral bisphosphonates include diarrhea, esophagitis, and myalgias. Intravenous bisphosphonates may cause acute-phase reactions (flu-like syndrome and myalgias) in 20% of patients with initial administration, but tend to be mild and decrease in frequency and severity with repeated dosing. Zoledronate carries a risk of hypocalcemia if used with loop diuretics and a risk of deterioration of renal function if used with other nephrotoxic drugs such as aminoglycosides. The ‘black box’ warning for all bisphosphonates points indicates a risk of osteonecrosis of the jaw. Most of the cases were reported in patients treated for multiple myeloma or hypercalcemia of malignancy with high doses of intravenous zolendronate and pamidronate. However, some cases were described in postmenopausal women treated with oral alendronate and risedronate for osteoporosis.Salmon Calcitonin
Salmon calcitonin was approved for nasal treatment of postmenopausal osteoporosis in 1995.This hypocalcemic hormone partially inhibits the osteoclast activity and increases the mineral stores in bone.The PROOF study enrolled postmenopausal women with history of vertebral fractures or lumbar T-score ≤-2.5 who were randomized to either placebo or nasal calcitonin.At five years, 200 IU calcitonin reduced the incidence of vertebral fractures by 33% in women with low BMD and 36% in women with previous vertebral fractures compared with placebo.The BMD did not significantly differ between calcitonin and placebo groups. Calcitonin also reduced the pain associated with new spine fractures. Side effects of nasal administration include rhinitis, epistaxis, and nausea.

Teriparatide
Teriparatide (recombinant parathyroid hormone) is the only anabolic agent approved by the FDA for treatment of postmenopausal osteoporosis (2002). The mechanism of action consists of stimulation of bone formation by promoting cell proliferation and differentiation of osteoblasts. Recent bone biopsy studies have brought direct evidence that 12–24 months of teriparatide treatment induced greater bone formation than remodeling. The Fracture Prevention Trial enrolled postmenopausal women with prior vertebral fractures.At one year, 20μg teriparatide administered subcutaneously reduced vertebral fractures by 65% and nonvertebral fractures by 53% compared with placebo.The study was terminated after 20 months due to concerns regarding development of osteosarcoma in rats. Although a ‘blackbox’ warning was added to the teriparatide label, no causes of osteosarcomas were reported in humans treated with teriparatide. The use of teriparatide is indicated in patients with moderate-to-severe osteoporosis who did not respond or cannot tolerate the bisphosphonates.The duration of the treatment should be two years or less. Side effects include mild hypercalcemia and hypercalciuria, nausea, leg cramps, and serum uric acid elevation.

Despite the availability of multiple FDA-approved agents, osteoporosis remains a significant problem. No existing therapy can completely eliminate fracture risk. Therefore, research continues and new agents are being tested in clinical trials: strontium ranelate, cathepsin K inhibitors, nitrosylated non-steroidial antiinflammatory drugs, RANKL inhibitors, recombinant complex of insulin-like growth factor-I and insulin-like growh factor binding protein-3, integrin receptor antagonists, and tyrosine kinase Src inhibitors. Summary and Recommendations
All postmenopausal women should be evaluated with a careful history, physical examination and baseline BMD measurement in order to determine the risk for osteoporosis. Daily calcium and vitamin D supplementation, as well as weight-bearing exercise, should be recommended.Women identified at risk of osteoporosis should receive pharmacologic therapy which effects should be evaluated at 1–2 years with a second BMD measurement.We also recommend measurement of bone turnover markers prior to the onset the therapy and at 3–6 months afterwards.A significant decrease of the bone turnover markers (i.e. 50% for urine N-telopeptide) is evidence that the antiresorptive drug has the expected effect. On the other hand, an increase of >10μg/l in N-terminal propeptide of type I procollagen (PINP) at 1–3 months during treatment with teriparatide indicate an anabolic response. Bone-specific alkaline phosphatase and urinary deoxypyridinoline have also been used to monitor response to teriparatide. The first line in prevention and treatment of postmenopausal osteoporosis in 2006 are the bisphosphonates, which may be administered daily or intermittently. Oral administration is preferred, if tolerated. For early postmenopausal women with significant estrogen deprivation symptoms, hormone replacement therapy should be considered for two years or less at the lowest dose that alleviates the symptoms. For women with severe osteoporosis, who did not respond to or could not tolerate bisphosphonates, teriparatide treatment should be prescribed for a maximum of two years.We recommend administration of a bisphosphonate after teriparatide course finished. SERMs should be considered for women at risk for both osteoporosis and breast cancer. Calcitonin is rarely recommended due to its weak effect compared with the other available agents. At the present time, simultaneous administration of more than one pharmacologic therapy has not been shown to be superior to their single use.

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