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Osteoporosis: new treatments and updates.

Osteoporosis is defined as a skeletal disorder characterized by low bone mass and compromised bone strength, resulting in increased bone fragility and susceptibility to fracture. (1) That definition, proposed 20 years ago, highlights the intimate association between fractures and bone strength and provides a useful framework for reviewing recent developments and advances impacting the diagnosis and management of persons with compromised bone strength. This brief update will focus on several areas of particular current interest: fracture assessment tools and how they aid in treatment decisions, advances in imaging techniques and how they are providing insights into the relationship between bone structure and fracture resistance, newer drugs that will be available in the near and intermediate future, and some unusual problems that have been observed in users of currently available therapeutic agents.

FRAX[TM] and SOF Assessment Tools for Fracture Risks and Treatment Decisions

A recent advance in the management of people with a low bone mass is FRAX[TM], a computer generated algorithm developed by the World Health Organization. FRAX[TM] provides clinicians with a tool to assess absolute, time-specific fracture risk quantitatively. The FRAX[TM] calculator is available online and provides country and ethnic specific 10-year hip and major osteoporotic fracture risks based on information entered into the calculator. The information requested includes age, sex, weight, height, personal and family history of fracture, current smoking usage, alcohol consumption, corticosteroid use, a history of rheumatoid arthritis, and conditions associated with secondary osteoporosis. In the United States, bone density values at the hip are included in the data used to generate the time-specific fracture risk. Subjects who have, either separately or simultaneously, a 3% or more risk of a hip fracture or 20% risk or more of a major osteoporotic fracture (hip, distal forearm, shoulder, vertebral body) are considered candidates for bone strengthening medication. The tool is particularly useful for younger, healthy postmenopausal females with osteopenia, a group of people with a relatively low 10-year fracture risk.

Another fracture assessment tool was developed by the American Study of Osteoporosis Fractures (SOF) Research Group. These investigators used a model based on bone mineral density and age alone and found that their tool predicted the 10-year risk of hip and major osteoporotic fracture as well as the FRAX[TM] tool did in a group of postmenopausal females, 65 years and older. (2) Their findings emphasize the importance of age as a risk factor for fragility fractures. With increasing concerns regarding the potential adverse effects of long-term use of anti-resorptive agents (see below) and the costs of these drugs, there is likely to be increasing emphasis on identifying and treating those individuals who have a significantly increased absolute fracture risk. Fracture assessment tools provide critical quantitative information on fracture risk and may aid in this endeavor. Both the FRAX[TM] and SOF models have demonstrated older people with low bone density and a history of a fragility fracture are at highest risk for sustaining fragility fractures.

Advances in Imaging--Exploring the Structure of Bone

While bone density testing with dual X-ray absorptiometry (DEXA) scanning is the most commonly used technique to estimate fracture risk, it is a modality that provides two-dimensional information about a three-dimensional structure, the human skeleton. In order to better define the microarchitecture of bone and to investigate how bone microarchitecture influences bone strength and fracture resistance, researchers are increasingly using high resolution imaging techniques. Two recent studies that used high-resolution pQTC (peripheral quantitative computed tomography) machines examined the distal radius and distal tibias in groups of young Caucasian and Chinese females. (3,4) The investigators of these papers reported that Asian females had thicker cortical bones and increased trabecular thickness at these sites than did their white counterparts. They postulated that these differences confer greater bone strength and may help explain why Asian females have a lower incidence of hip and distal forearm fractures than white females.

A small study from this institution, utilizing a 7T whole-body MRI scanner, showed microarchitectural differences in the knees of Olympic athletes, compared to healthy male controls matched for age, height, and weight. (5) It is anticipated that with further improvements in scanning resolution, more detailed information about cortical and trabecular bone structure will increase our understanding of why some people fracture and others do not, despite having similar bone mineral density, as measured by DEXA. Two recent studies, using cadaveric specimens and employing both bone density and microCT technology, analyzed the contributions of bone mass and bone microarchitecture to the mechanical behavior of human lumbar vertebrae and femoral bones, respectively, and are examples of the promise that new imaging modalities may hold. (6,7) Such information may ultimately help predict more accurately who is at greatest risk of fracture and identify individuals who will require bone strengthening treatment.

A Look into the Near and Intermediate Future--New Drugs for Osteoporosis

Denosumab

The newest drug to receive U.S. Food and Drug Administration (FDA) approval for the treatment of osteoporosis is denosumab (Prolia[TM], Amgen[R]). This human monoclonal antibody binds to RANK-Ligand (RANK-L), a soluble cytokine produced by osteoblasts and prevents the osteoclast activation induced by the binding of RANK-L to its receptor RANK. The inhibition of osteoclast activity by the activity of denosumab results in decreased bone resorption, increases in bone mineral density, and decreases in vertebral, non-vertebral, and hip fracture rates among postmenopausal females, when compared to matched control groups who were given placebo. (8,9) The drug will be available as a 60-mg subcutaneous injection to be given every 6 months. RANK-L is expressed on immune cells, and concern regarding an increased incidence of serious infections in patients taking denosumab has been raised. However, results of the large clinical trials mentioned above showed only a slight increase in eczema and cellulitis as adverse events among denosumab users, compared to those receiving placebo. This anti-resorptive drug does not bind to bone directly or require renal clearance, as the bisphosphonates do, but the clinical relevance of these characteristics is still unknown. Denosumab has been shown to be a strong inhibitor of bone remodeling in bone biopsy studies and has similar effects on fracture healing in animal models, as other anti-resorptive agents. Denosumab's potent effect on bone remodeling was confirmed in a group of patients with bone metastases, including those who had previous bisphosphonate exposure. (10)

Selective Estrogen Receptor Modulators (SERMs)

SERMs bind to estrogen receptors and have tissue-specific effects that either mimic or antagonize the actions of estrogen. Raloxifene (Evista[R], Eli Lilly) is the only SERM approved by the FDA for the treatment and prevention of osteoporosis. It has been shown to reduce the incidence of vertebral fractures, but has not been proven to reduce the incidence of hip or non-spinal fractures. (11,12) It has also been shown to reduce the incidence of invasive breast cancer in a number of trials, including the STAR (Study of Tamoxifen and Raloxifene) trial, where it was compared to tamoxifen, a drug widely used to prevent recurrence of estrogen receptor-positive breast cancer. (13) The main adverse reactions from the use of raloxifene in a number of large trials included the expected increases in hot flashes, night sweats, leg cramps, and venous thromboembolic events. Lasofoxifene, a SERM approved for use in Europe but not approved by the FDA for use in the U.S., has been shown to reduce the incidence of vertebral and non-vertebral fractures. (14) Lasofoxifene's side effect profile appears similar to raloxifene, with the exception of an increased incidence of vaginal discharge. Another newly developed SERM, bazodoxifene, has been tested in combination with estrogen. The combination has been designated as a tissue selective estrogen complex (TSEC). The theory behind this approach is that the combination agent will be at least as effective and better tolerated than either drug alone. (15) Bazedoxifene alone at doses of 20 mg and 40 mg daily has been compared to placebo and raloxifene at 60 mg daily in a fracture reduction study. Both doses of bazedoxifene and raloxifene were shown to reduce the incidence of vertebral fractures when compared to placebo, but neither drug had a significant effect on non-vertebral fractures. (16) Bazedoxifene is not currently approved for use in the United States.

Promising "Future"Agents for the Treatment of Osteoporosis

A comprehensive review of preclinical drugs that may have utility as bone strengthening agents is beyond the scope of this review, but there are several agents that are representative of new classes of drugs that warrant discussion. Odanacatib (Merck & Co., Inc,) is an investigational cathepsin-K inhibitor that has been tested in a placebo controlled, 1-year dose finding study, with an additional 1-year extension in a group of post menopausal females with low bone density. Cathepsin K is a protease expressed by osteoclasts that degrades type I collagen, the main component of the organic matrix of bone. Odanacatib, an oral agent administered weekly, significantly reduced bone resorption markers and improved bone mineral density at the spine and hip in this 2-year study. The safety and tolerability of this drug were similar to placebo. (17)

One of the most active and exciting areas of discovery in bone biology over the past decade has been the Wnt signaling pathway. Activation of Wnt signaling can stimulate osteoblast differentiation and gain-of-function mutations in this complex pathway that involves the low-density lipoprotein receptor-related protein 5 (LRP5) and has been shown to result in a phenotype of increased bone mass. (18) A recent landmark study by Yadav and colleagues (19) demonstrated that LRP5 inhibited the expression of Tph 1, an enzyme needed for duodenal production of serotonin. Gut-derived serotonin inhibits osteoblast proliferation, and blocking the actions of this form of serotonin may lead to future therapies that increase bone mass. Wnt signaling is modified by substances that bind Wnt itself or prevent its binding to its receptor or co-receptors. Sclerostin, the protein product of the osteocyte gene SOST, competitively binds to LRP5 and blocks Wnt functioning. Monoclonal antibodies to sclerostin have been developed and may prove to be clinically useful as an anabolic agent in the treatment of osteoporosis. (20)

Bisphosphonates and Unusual Adverse Effects

Osteonecrosis of the Jaw

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) was first reported, in 2003, and since that time there have been numerous case reports published worldwide. In order to help more uniformly define this clinical entity and to review the literature on BRONJ, the American Society for Bone and Mineral Research appointed an expert multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to this disorder. (21) A confirmed case was defined as an area of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a health care provider. The patient had to be receiving or had to have been exposed to a bisphosphonate and had not had radiation therapy to the craniofacial region. The task force estimated the risk of BRONJ related to the use of oral bisphosphonates for osteoporosis to be between 1 in 10,000 and less than 1 in 100,000 patient treatment years. The risk of osteonecrosis of the jaw in patients who have cancer treated with intravenous bisphosphonates was estimated to be in the range of 1 to 10 per 100 patients. Patients being treated for metastatic bone disease or hypercalcemia, or both, often receive significantly larger amounts of bisphosphonates than do individuals being treated for osteoporosis. There is some evidence that smoking and obesity may also be risk factors among cancer patients who develop BRONJ in association with IV bisphosphonate use. (22) It appears that patients with low bone mass who are being treated with oral bisphosphonate are at very low risk for BRONJ, and these individuals should continue to receive their normal dental care while being maintained on their bone strengthening medication. (23)

Subtrochanteric Fractures

Subtrochanteric or "atypical" fractures of the femur below the lesser trochanter have recently been described among patients who have been treated with bisphosphonates. (24) Most data linking these fractures with long-term bisphosphonate use have come from case control studies, and over suppression of bone turnover with accumulation of microdamage suggested as a possible pathogenesis for these fractures. (25) Prior to the fractures being recognized, patients may experience thigh pain, often bilaterally. The characteristic radiological pattern reported in these patients includes cortical thickening, a transverse fracture pattern, and medical cortical beaking. (26) Several reviews of large databases and post-hoc analyses of clinical trials involving different bisphosphonates have not confirmed an increase in the frequency of subtrochanteric or femoral shaft fractures in these populations. (27-29) The reviewers, however, did not have access to the radiographic images of the fractures reported in these studies. As more data accumulates, a better understanding of the issue of atypical fractures in bisphosphonate users will surely emerge. In the interim, approaches to modify long-term use of these drugs, with drug "holidays" and intermittent cycles of therapy, are likely to be increasing popular. (30)

Conclusion

With the aging of the population, low bone mass states will be a significant clinical issue for both men and women. Improvements in imaging technologies will augment efforts to identify patients at increased fracture risk. Fracture assessment tools will become important vehicles to help define when individual patients are at increased fracture risk and when bone strengthening medications should be started. Efforts to improve balance and decrease falls will become vital parts of a comprehensive fall-reduction strategy, particularly for the elderly and those with a history of falling. New bone strengthening medications will expand patient choices and allow physicians to choose among novel anabolic and antiresorptive drugs. Finally, as we have recently learned from drugs that have been used to treat osteoporosis for more than a decade, continued observation and surveillance will remain critical to identifying unusual and often delayed, untoward clinical events from the use of pharmacologic agents with significant effects on bone structure and turnover.

Disclosure Statement

The author has no financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.

References

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Stephen Honig, M.D., M.Sc., is Clinical Associate Professor, New York University School of Medicine, within the Division of Rheumatology, Department of Medicine, and Director, Osteoporosis Center, NYU Hospital for Joint Diseases, NYU Langone Medical Center, New York, New York.

Correspondence: Stephen Honig, M.D., 301 East 17th Street, NYU Hospital for Joint Diseases, New York, New York 10003; stephen. honig@nyumc.org.
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Author:Honig, Stephen
Publication:Bulletin of the NYU Hospital for Joint Diseases
Article Type:Report
Geographic Code:1USA
Date:Jul 1, 2010
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