|
Background
Approximately 10 million Americans (80% of them women) suffer from osteoporosis, which may lead to an increased risk of spine, wrist, and hip fractures. For postmenopausal women, age, personal or family history of fracture, Asian or Hispanic heritage, smoking, and cortisone use have been associated with significantly increased likelihood of osteoporosis; while higher body mass index (BMI), African American heritage, estrogen or diuretic use, and exercise have been associated with significantly decreased likelihood of osteoporosis (Siris et al, 2001). Furthermore, Wu and colleagues (2002) reported that any fracture (unrelated to motor vehicle accidents) sustained between the ages of 20 and 50 years is associated with increased risk of fractures after the age of 50 years in women. Although osteoporosis is usually considered a disease of women, up to 20% of vertebral fractures and 30% of hip fractures occur in men. Risk factors for osteoporotic fractures in men include low BMI, smoking, high alcohol consumption, corticosteroid therapy, physical inactivity, and diseases that predispose to low bone mass (Eastell et al, 1998). However, the exact mechanism of bone loss remains unknown in primary male osteoporosis (Legrand et al, 2001).
Bone mineral density (BMD) is useful in the diagnosis of osteoporosis. It is usually provided as the T score -- the number of standard deviations (SDs) the BMD falls below or above the mean value in a reference population (young, healthy adults). The World Health Organization (WHO) osteoporosis diagnostic classification assessment (1994) defines osteoporosis as a T score of 2.5 or more SDs below the mean (i.e., less than -2.5). Osteopenia is defined as a T score of -1.0 to -2.5 and a T score of -1.0 or higher is considered normal. It should be noted that a male database should be used for diagnosing osteoporosis in men.
Body (2002) stated that although hormone replacement therapy (HRT) is still considered as the mainstay for the prevention and the treatment of post-menopausal osteoporosis, there are several controversies regarding HRT. Recent studies have challenged the assumption that HRT conveys real long-term benefits. Raloxifene or other “selective estrogen receptor modulators” should progressively replace HRT in elderly women. Bisphosphonates have been shown to be effective in the treatment of osteoporosis. Alendronate (Fosamax) and risedronate (Actonel) have been the most extensively studied bisphosphonates under clinical trials conditions. Both drugs can lower the risk of vertebral and hip fractures by 25 to 50%. However, oral bisphosphonates exhibit gastrointestinal toxicity and strict adherence to constraining therapeutic schemes is mandatory. Newer more potent bisphosphonates, such as oral ibandronate and intravenous zoledronic acid (Zometa), which will allow much less frequent administration, are currently being investigated (Reid et al, 2002). Moreover, bone-forming agents (e.g., teriparatide) provide another therapeutic option for the treatment of severe osteoporosis.
Teriparatide (Forteo) is the first approved medication for the treatment of osteoporosis that stimulates new bone formation. It is administered by once-daily subcutaneous injection in the thigh or abdomen. The recommended dosage is 20 mcg/day. Teriparatide is a portion of human parathyroid hormone (PTH 1-34), which is the primary regulator of calcium and phosphate metabolism in bones. Daily injections of teriparatide stimulate new bone formation resulting in increased bone mineral density (BMD). Clinical studies showed that teriparatide lowered the risk of vertebral and non-vertebral fractures in postmenopausal women and increased BMD in men with primary or hypogonadal osteoporosis when compared to patients who received only calcium and vitamin D supplementation.
Rehman et al (2003) examined whether daily treatment with PTH 1-34 for 1 year was associated with a change in vertebral cross-sectional area, or vertebral size in postmenopausal women (n = 51), as measured by serial quantitative computed tomography scans. The authors found that daily treatment with PTH 1-34 for 1 year increased vertebral size as measured by vertebral cross-sectional area and this increase was maintained after PTH 1-34 was discontinued. Furthermore, Marcus et al (2003) reported that teriparatide offers clinical benefit to patients across a broad range of age and disease severity.
Body and co-workers (2002) compared the effects of teriparatide and alendronate on BMD, non-vertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily subcutaneous injections of teriparatide 40 mcg plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate. Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group. Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one-third distal radius decreased, compared with alendronate. Non-vertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group. Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. These investigators concluded that teriparatide, a bone-forming agent, increased BMD at most sites and decreased non-vertebral fractures more than alendronate. However, more comparative studies are needed to validate this finding.
Orwoll et al (2003) studied the effects of teriparatide on bone density in men with osteoporosis: 437 men with spine or hip BMD more than 2 standard deviations below the young adult male mean were randomized to three groups: (i) daily injections of placebo, (ii) teriparatide 20 mcg, or (iii) teriparatide 40 mcg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine BMD was significantly greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 mcg) and 9.0% (40 mcg) above baseline. Femoral neck BMD increased 1.5% (20 mcg) and 2.9% (40 mcg), and whole body bone mineral content increased 0.6% (20 mcg) and 0.9% (40 mcg) above baseline in the teriparatide-treated subjects. There was no change in radial BMD in the teriparatide-treated groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline BMD, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-mcg groups, but more frequent in the 40-mcg group. This study shows that teriparatide treatment results in an increase in BMD and is a potentially useful therapy for osteoporosis in men.
Most adverse events reported in association with teriparatide in clinical trials were mild and included nausea, dizziness, and leg cramps. During the clinical trials, early discontinuation due to adverse events occurred in 5.6 and 7.1% of patients in the control and treatment groups, respectively. Although not observed in human clinical trials, teriparatide is associated with development of osteosarcomas in animal studies.
In a review on the use of intermittent human PTH as a treatment for osteoporosis Deal (2004) explained that patients who have Paget's disease, prior radiation therapy to the skeleton, as well as children and young adults with open epiphyses, are at higher risk for osteosarcoma and should not be given PTH. Patients with hypercalcemia and hyperparathyroidism also should not receive the drug.
Forteo's product labeling carries a “black box” safety warning, which highlights the concern over the association between the drug and osteosarcomas in laboratory rats. Because individuals with growing bones (namely children and adolescents with open epiphyses), persons with unexplained elevations in alkaline phosphatase, patients with prior external beam or implant irradiation of the skeleton, and patients with Paget's disease of the bone have a higher risk for developing osteosarcoma, the black box warning states that it is important that teriparatide not be used in these groups. Furthermore, the product labeling states that individuals with hypercalcemia, women who are pregnant or nursing, or those who have ever been diagnosed with bone cancer or other cancers that have metastasized to the bones, should not use teriparatide. According to the product labeling, because the long-term effectiveness and safety of teriparatide treatment are not known at this time, therapy for more than 2 years is not recommended.
The Canadian Coordinating Office of Health Technology Assessment (Shulka, 2003) reached the following conclusions about teriparatide: "Although placebo-controlled trials show that teriparatide can reduce fractures, there is little information on its efficacy compared to available alternatives. In the United States, the Food and Drug Administration highlighted concerns about teriparatide's carcinogenic effects in rats. Company-sponsored studies have been voluntarily stopped … Because of safety concerns and the lack of efficacy and effectiveness data, it is difficult to define teriparatide's role in the treatment of osteoporosis. This is compounded by the possible long-term antagonizing effect of bisphosphonates on teriparatide's bone-forming properties."
Combination therapy with teriparatide or parathyroid hormone (1-84) and an anti-resorptive agent has not been proven to offer advantages over the use of parathyroid hormone or an anti-resorptive agent alone for osteoporosis. Bilezikian and Rubin (2006) discussed the use of anabolic skeletal therapy for the treatment of post-menopausal and other forms of osteoporosis. The authors stated that the only anabolic skeletal agent currently available is teriparatide. Teriparatide improves bone quality by actions on bone turnover, bone density, bone size, and micro-architecture. In post-menopausal women with osteoporosis, teriparatide reduces the incidence for vertebral and non-vertebral fractures. In individuals who have been treated previously with an anti-resorptive agent (e.g., estrogen and bisphosphonates), the subsequent actions of teriparatide on bone density are delayed transiently if bone turnover is markedly suppressed. The authors argued that combination therapy with teriparatide or PTH (1-84) and an anti-resorptive does not appear, at this time, to offer advantages over the use of PTH or an anti-resorptive alone.
In a randomized, open-labeled clinical study, Matsumoto et al (2006) examined the safety and effectiveness of nasal hPTH(1-34) spray in subjects with osteoporosis. A total of 90 osteoporotic subjects aged 52 to 84 years (mean of 66.5 years) were randomly assigned to receive either 250 microg (PTH250, n = 31), 500 microg (PTH500, n = 30), or 1,000 microg (PTH1000, n = 29) of daily nasal hPTH(1-34) spray for 3 months. All subjects received daily supplements of 300 mg calcium and 200 IU vitamin D(3). Daily nasal hPTH(1-34) spray for 3 months increased lumbar bone mineral density (L-BMD) in a dose-dependent manner, and the PTH1000 group showed a 2.4 % increase in L-BMD from baseline. Only the 1,000-microg dose produced consistent and statistically significant changes in markers of bone turnover; after 3 months, median serum type I procollagen N-propeptide (PINP) and osteocalcin increased 14.8 % and 19.4 % from baseline, while urinary type I collagen N-telopeptide (NTX) decreased 16.4 %. Seven subjects developed transient hypercalcemia at 3 hours after nasal hPTH(1-34) spray, but none of the subjects developed sustained hypercalcemia. The authors concluded that these findings showed that nasal hPTH(1-34) spray is safe and well-tolerated and can rapidly increase L-BMD. They noted that the results warrant further studies to examine its long-term effectiveness on bone mass and fractures.
In a randomized, double-blind, controlled study, Saag and colleagues (2007) compared teriparatide with alendronate in 428 women and men with osteoporosis (aged 22 to 89 years) who had received glucocorticoids for at least 3 months (prednisone equivalent, 5 mg daily or more). A total of 214 patients received 20 microg of teriparatide once-daily, and 214 received 10 mg of alendronate once-daily. The primary outcome was the change in BMD at the lumbar spine. Secondary outcomes included changes in BMD at the total hip and in markers of bone turnover, the time to changes in BMD, the incidence of fractures, and safety. At the last measurement, the mean (+/- SE) BMD at the lumbar spine had increased more in the teriparatide group than in the alendronate group (7.2 +/- 0.7 % versus 3.4 +/- 0.7 %, p < 0.001). A significant difference between the groups was reached by 6 months (p < 0.001). At 12 months, BMD at the total hip had increased more in the teriparatide group. Fewer new vertebral fractures occurred in the teriparatide group than in the alendronate group (0.6 % versus 6.1 %, p = 0.004); the incidence of non-vertebral fractures was similar in the two groups (5.6 % versus 3.7 %, p = 0.36). Significantly more patients in the teriparatide group had at least one elevated measure of serum calcium. The authors concluded that among patients with osteoporosis who were at high risk for fracture, BMD increased more in patients receiving teriparatide than in those receiving alendronate.
Rizzoli (2008) stated that "the trial of Saag et al. provides evidence that the bone-forming agent teriparatide is superior to the current standard of care for glucocorticoid-induced osteoporosis. If these promising initial data are confirmed after completion of the trial, with a positive risk-to-benefit ratio, teriparatide could be considered a novel therapeutic option for patients receiving glucocorticoids and at increased risk of fracture. The various guidelines that recommend systematic bisphosphonates in patients with glucocorticoid-induced osteoporosis might then be revisited".
Rodríguez-Bores et al (2007) stated that inflammatory bowel disease (IBD) has been associated with an increased risk of osteoporosis and osteopenia and epidemiological studies have reported an increased prevalence of low bone mass in patients with IBD. Certainly, genetics play an important role, along with other factors such as systemic inflammation, malnutrition, hypogonadism, glucocorticoid therapy in IBD and other lifestyle factors. At a molecular level the pro-inflammatory cytokines that contribute to the intestinal immune response in IBD are known to enhance bone resorption. There are genes influencing osteoblast function and it is likely that LRP5 may be involved in the skeletal development. Also the identification of vitamin D receptors (VDRs) and some of its polymorphisms have led to consider the possible relationships between them and some autoimmune diseases and may be involved in the pathogenesis through the exertion of its immunomodulatory effects during inflammation. These researchers found that there is increasing evidence for the integration between systemic inflammation and bone loss likely mediated via receptor for activated nuclear factor kappa-B (RANK), RANK-ligand, and osteoprotegerin, proteins that can affect both osteoclastogenesis and T-cell activation. Although glucocorticoids can reduce mucosal and systemic inflammation, they have intrinsic qualities that negatively impact on bone mass. It is still controversial if all IBD patients should be screened, especially in patients with pre-existing risk factors for bone disease. Available methods to measure BMD include single energy x-ray absorptiometry, dual energy x-ray absorptiometry, quantitative computed tomography, radiographical absorptiometry, and ultrasound. Dual energy x-ray absorptiometry is the establish method to determine BMD, and routinely is measured in the hip and the lumbar spine. There are several treatments options that have proven their effectiveness, while new emergent therapies such as calcitonin and teriparatide among others remain to be assessed.
Appendix
According to the FDA-approved labeling, teriparatide (Forteo) is contraindicated in any of the following individuals:
- Children and adolescents with open epiphyses; or
- Individuals with Paget's disease of the bone; or
- Individuals with hypercalcemia; or
- Women who are pregnant or nursing; or
- Individuals who have been diagnosed with bone cancer or other cancers that have metastasized to the bones; or
- Individuals with prior radiation therapy to the skeleton.
|
Close Window
