Abstract
The Santa Fe Bone Symposium is an annual forum for the exchange of scientific, social and economic information on osteoporosis, bone densitometry and metabolic bone disease. Sponsored by the Osteoporosis Foundation of New Mexico in cooperation with the International Society for Clinical Densitometry, this is an open meeting with registration limited to 200 healthcare professionals with a special interest in bone disease. Santa Fe was established as the permanent location for the symposium due to its historical significance, multicultural legacy and worldwide recognition as a venue of creativity for many disciplines in the arts and sciences. Each year, new topics for the symposium are selected based on clinical relevance, recent developments or controversy. Faculty members are internationally recognized for their expertise in the basic science of bone physiology or applications of clinical research to patient care. Nonfaculty participants represent a broad range of medical specialties, scientists, clinical research coordinators, ancillary healthcare providers, and dual-energy x-ray absorptiometry (DXA) technologists. The Seventh Annual Santa Fe Bone Symposium was held on August 11–12, 2006, in Santa Fe, NM, USA, followed by the ISCD Bone Densitometry Course on August 13–14, 2006. Highlights of interactive presentations and panel discussions at the symposium are presented here.
Key presentations
Faculty and the topics addressed at the Seventh Annual Santa Fe Bone Symposium were Felicia Cosman (anabolic therapy for osteoporosis, selective estrogen receptor modulators); Nancy E Lane (treatment-induced osteoporosis, stress fractures); Michael Kleerekoper (parathyroid disorders and skeletal health, bone turnover markers to monitor osteoporosis therapy); Neil Binkley (osteoporosis in men, update on bisphosphonate therapy for osteoporosis); Paul D Miller (new treatments for Paget's disease), Michael R McClung (receptor activator of nuclear factor κB [RANK] ligand inhibition and skeletal health); and Mone Zaidi (nonvertebral fractures); with E Michael Lewiecki as moderator.
Osteoporosis is a disease characterized by bone fragility and high risk of fracture. It is a common disease that has been identified as a major public health concern by the WHO and the US Surgeon General. Approximately two-thirds of osteoporotic fractures occur at the spine or hip, with serious consequences in terms of morbidity and a 20% increase in mortality. The number of hip fractures worldwide due to osteoporosis is expected to rise three-fold by the middle of the next century, from 1.7 million in 1990 to 6.3 million by 2050. Osteoporosis is underdiagnosed and undertreated, particularly in men, even in patients with previous fractures who are at very high risk for future fractures. Most professional societies with guidelines for bone density testing recommend that women aged 65 and older, and younger postmenopausal women with clinical risk factors for fracture, be considered for bone density testing. The International Society for Clinical Densitometry also suggests that men aged 70 years and older have bone density testing. When patients are treated for osteoporosis, adherence to therapy is poor. Studies have typically shown that less than 50% of patients who begin therapy are still taking it 12 months later. Of those who are taking bisphosphonates, the most commonly prescribed treatment for osteoporosis, many are taking it incorrectly. Less complex dosing regimens, less frequent dosing and parenteral therapy offer hope for improved adherence and improved outcomes (reduced fracture risk).
Osteoporosis is diagnosed by bone mineral density (BMD) testing with DXA according to established criteria. A clinical diagnosis of osteoporosis may be made in the presence of a fragility fracture in an adult, independently of BMD, provided other causes of fracture have been ruled out. Bone density measurement by DXA and other technologies (e.g., quantitative ultrasound [QUS]) may be used to predict fracture risk. Bone turnover markers (BTMs) provide a dynamic assessment of bone metabolism that has been useful in understanding the pathogenesis of osteoporosis and metabolic bone diseases, and has enhanced our understanding of the mechanisms of action of therapeutic interventions. DXA of central skeletal sites, especially the lumbar spine, is useful in monitoring response to therapy. In patients with structural abnormalities of the spine, such as osteoarthritis, the total hip is used to monitor therapy. QUS of peripheral skeletal sites cannot be used to monitor response to therapy because the changes at the measured sites are too small and occur too slowly to be practical in managing patients. In the care of individual patients, BTMs may be considered a clinical tool that is complementary to, but not a substitute for, BMD testing. BTMs cannot be used to diagnose osteoporosis, but may be helpful in assessing the response to therapy and motivating patients to continue therapy. Serum levels of bone resorption markers have been shown to be less variable the urine levels, suggesting that they may have greater clinical utility for patient care.
Normal adult bone is continually renewed in a process called remodeling, whereby bone resorbing cells (osteoclasts) remove bone in discreet packets from the surface of trabecular bone or within Haversian systems in cortical bone, followed by bone-forming cells (osteoblasts) depositing collagen that subsequently becomes mineralized. With normal bone remodeling (bone formation = bone resorption), bone mass remains stable. If resorption exceeds formation, there is a net loss of bone that may eventually result in osteoporosis. In some common skeletal disorders, such as postmenopausal osteoporosis, there is high bone turnover with increased activity of both osteoclasts and osteoblasts, where bone resorption exceeds formation. In other disorders, such as osteoporosis of aging, bone turnover may be normal or low, but osteoblast activity is insufficient to keep up with the demands of bone resorption. In the physiological state, there is ‘coupling’ of osteoclast and osteoblast activity due to local factors, so that as the activity of the two cell types typically rises and falls in the same direction, although not always to the same magnitude.
The principal final regulator of osteoclastic bone resorption is RANK ligand (RANKL), a cytokine member of the tumor necrosis factor family that is expressed by osteoblasts and other cells. When RANKL binds to its receptor (RANK) on the surface of pre-osteoclasts and osteoclasts, it stimulates osteoclast differentiation, activity and survival, resulting in increased bone resorption. Osteoprotegerin (OPG) is a naturally occurring soluble ‘decoy receptor’ produced by osteoblasts that binds to RANKL, thereby preventing its interaction with RANK and resulting in reduced bone resorption. An imbalance in the ratio of RANKL to OPG has been implicated in the pathogenesis of postmenopausal osteoporosis, osteoporosis in men, treatment-induced osteoporosis, rheumatoid arthritis and skeletal complications of malignancy. Strategies to modulate the RANKL/RANK/OPG pathway offer intriguing possibilities for the treatment of osteoporosis and other skeletal diseases. Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for RANKL. By inhibiting the action of RANKL, denosumab reduces the differentiation, activity and survival of osteoclasts, thereby slowing the rate of bone resorption. A Phase II clinical trial with denosumab showed that it increased BMD in postmenopausal women with low BMD, with a rapid, sustained and reversible suppression of bone resorption. Treatment was well tolerated with no observed increase in the incidence of infection or malignancy. Long-term efficacy (fracture risk reduction) and safety is now being evaluated in a Phase III clinical trial using a dose of 60 mg of denosumab administered by subcutaneous injection every 6 months. RANKL inhibition with denosumab has potential clinical application in the management of other skeletal disorders, including Paget's disease of bone, treatment-induced osteoporosis, hypercalcemia of malignancy, multiple myeloma, metastatic bone disease and bone loss associated with inflammatory diseases such as rheumatoid arthritis.
The bisphosphonates alendronate, risedronate and ibandronate are used extensively for the management of osteoporosis. These drugs have been shown to reduce fracture risk and be remarkably safe with long-term use. Intravenous ibandronate has recently been approved for the treatment of postmenopausal osteoporosis. Intravenous zoledronate has been shown to increase BMD and suppress bone turnover for at least 12 months in postmenopausal women with low BMD. Results of Phase III zoledronate studies evaluating fracture risk are expected soon. Bisphosphonates and other agents that are approved for the treatment of osteoporosis have all been shown to reduce the risk of vertebral fractures in women with postmenopausal osteoporosis. Nonvertebral fracture risk reduction, a secondary outcome measure in most clinical trials, has been proven for some but not all of these agents. Attempts to compare the efficacy of different drugs in reducing nonvertebral fracture risk are confounded by factors that include differences in populations studied (e.g., fall risk and number of fractures in placebo group) and differences in clinical trial design (e.g., skeletal sites included for nonvertebral fractures, observation period). Clinical trials designed to examine nonvertebral fracture as a well-defined primary outcome measure are thus required to examine the effects of bisphosphonates more rigorously.
Recent reports regarding osteonecrosis of the jaw (ONJ), predominately observed in cancer patients being treated with large doses of intravenous bisphosphonates, have raised concern that osteoporosis patients treated with lower doses of bisphosphonates may also be at risk for ONJ. It has been difficult to obtain data on this condition because there is no consensus definition, no clear diagnostic criteria and poor understanding of its pathogenesis, natural history and baseline prevalence in the community. It most often presents as a persistent open wound in the jaw with exposed bone after a tooth extraction or other dental surgery, but may occur spontaneously. While it may occur in as many as 5–10% of cancer patients receiving long-term, extremely high-dose intravenous bisphosphonates, the risk of ONJ in osteoporosis patients treated with lower doses of bisphosphonates appears to be extremely low, estimated at approximately 0.7/100,000 cases/patient-year of treatment. Despite the low risk of ONJ in comparison with the high risk of fracture if osteoporosis is untreated (approximately 50% lifetime risk of fragility fracture), widespread descriptions of ONJ in the lay press have lead some patients to stop taking their bisphosphonate treatment. Continued study is necessary to have a better understanding of ONJ. Physicians must be prepared to discuss the benefits and potential risks of any medication in order for patients to make an informed decision about their care. In the case of patients with osteoporosis, the risks of fracture appear to far outweigh the rare occurrence of ONJ. Routine dental care is suggested for all patients, including those with osteoporosis. In addition, if dental surgery is anticipated, it would be prudent to complete this and assure adequate healing before starting bisphosphonate therapy. For patients already receiving a bisphosphonate who must have oral surgery, it has been proposed that the bisphosphonate be withheld for several weeks or months before the procedure, and not restarted until the bone is healed. There are no data to support this recommendation. If ONJ is suspected or diagnosed, referral to an oral surgeon familiar with this condition is suggested.
The selective estrogen receptor modulators (SERMs) are a group of drugs that act as estrogen agonists in some tissues and antagonists in others. Raloxifene is an agent for the treatment of postmenopausal osteoporosis that has be shown to reduce the risk of vertebral fractures. It was recently reported that it reduces the risk of invasive breast cancer as effectively as tamoxifen, but provides no reduction in the risk of coronary artery disease, despite beneficial effects on lipid metabolism. Potential side effects include increased risk of thromboembolic disease, hot flashes, cataracts and fatal stroke. The ideal patient for the use of raloxifene may be an early postmenopausal woman without severe hot flashes who is at high risk for breast cancer and low risk for cardiovascular disease and thromboembolic disease.
Parathyroid hormone (PTH) administered as a daily subcutaneous injection, is a potent bone forming agent that causes large increases in BMD and reduction in fracture risk. Teriparatide (recombinant human PTH[1–34]) is approved for the treatment of postmenopausal women with osteoporosis and for men with primary or hypogonadal osteoporosis who are at high risk for fracture. It is given as a daily 20 μg subcutaneous injection for no more than 18–24 months. While carcinogenicity studies in rats showed an increased risk of osteosarcoma that was dependent on the dose and duration of therapy, the risk of osteosarcoma in patients treated with teriparatide appears to be no different than expected in the community. PTH therapy seems to be effective in patients previously treated with antiresorptive agents, although the increase in BMD may be delayed or attenuated in those previously treated with alendronate. There is no proven added benefit with simultaneous use of teriparatide and bisphosphonates in patients on no prior therapy, but there may be an additive effect on BMD in those simultaneously taking PTH with estrogen or raloxifene. Most experts suggest using PTH as monotherapy regardless of previous antiresorptive therapy, with administration of an antiresorptive agent after completion of a course of PTH to avoid bone loss that might otherwise occur. Novel PTH dosing regimens, such as cyclical administration (3 months on alternating with 3 months off) in patients continuing alendronate, are being studied.
Treatment-induced osteoporosis is associated with drugs that include long-term glucocorticoids, aromatase inhibitor therapy and androgen deprivation therapy. Unfortunately, it is often not appreciated that patients treated with these drugs are at increased risk for fractures and their consequences. Patients receiving medications associated with bone loss should have a comprehensive assessment of skeletal health with laboratory studies and periodic BMD testing. Nonpharmacological management with good nutrition, particular attention to sufficiency of calcium and vitamin D and regular weight-bearing exercise are appropriate for all patients. All patients starting these drugs and those already taking them who have low BMD should be considered as potential candidates for pharmacological agents. Bisphosphonates are the class of drugs most often used in these patients when drug therapy is used.
The role of vitamin D in maintenance of skeletal and nonskeletal health continues to be a focus of considerable interest. Adequacy of vitamin D is necessary to optimize intestinal absorption of calcium, suppress PTH secretion, and reduce bone turnover. Low vitamin D is associated with poor balance, muscle weakness, and increased risk of falling. Evidence is accumulating that low vitamin D is correlated with increased risk of some malignancies. There is emerging consensus that a serum 25OHD concentration of 30 ng/ml (75 nmol/l) or greater be used to define optimal vitamin D status. Using this definition, most experts agree that vitamin D deficiency and insufficiency is very common, even in areas with abundant sun exposure, and that current recommendations for vitamin D supplementation are too low. Very recent observations suggest that the accuracy of clinical 25OHD determination has improved. A daily intake of vitamin D3 (cholecalciferol) of at least 800–1200 IU is probably necessary.
Future perspective
As our knowledge of the molecular biology and genetic origins of osteoporosis and metabolic bone diseases expands, so do opportunities to develop highly specific pharmacological interventions for treating these diseases. It is likely that a selection of fully human monoclonal antibodies and other novel compounds will emerge as options to complement our current therapeutic choices, perhaps used sequentially or in combination with them. Less frequent dosing of long-acting agents offers the hope for improved adherence to therapy. New and better methods for evaluation of bone microarchitecture and bone turnover in clinical practice will enhance our ability to manage patients at risk for fracture.
Information resources
To learn more about the Santa Fe Bone Symposium, osteoporosis, and metabolic bone disease:
The Eighth Annual Santa Fe Bone Symposium will be held August 3–4, 2007, followed by the ISCD Bone Densitometry Course on August 5–6, 2007, at the Eldorado Hotel in Santa Fe, NM, USA. Information and links to online registration for both events will be available after January 1, 2007, on the website of the Osteoporosis Foundation of New Mexico [1]. Handouts from presentations for the 2006 Santa Fe Bone Symposium are available on the same website. Clinical information about the Santa Fe Bone Symposium is available by contacting the author of this review.
For information on the prevalence of osteoporosis and its consequences, visit the website of the National Osteoporosis Foundation [2] or the International Osteoporosis Foundation [3].
The website of the International Society for Clinical Densitometry (ISCD) at [4] provides information regarding scheduled courses in bone densitometry and the Official Positions of the ISCD.
The Surgeon General's Report on Bone Health and Osteoporosis, a comprehensive source of information about many aspects of osteoporosis, can be obtained through a link [5].
Information on Paget's disease of bone and related disorders may be found on the website for The Paget Foundation [6].
Highlights
Receptor activator of nuclear factor-κb (RANK) ligand inhibition with a fully human monoclonal antibody, denosumab, causes rapid, sustained and reversible reduction in bone turnover, increased bone mineral density (BMD), and a good safety profile in postmenopausal women with low BMD. Further studies are underway to evaluate efficacy and long-term safety in women with postmenopausal osteporosis (PMO) and patients with other skeletal disorders associated with bone loss.
Parathyroid hormone (PTH) given as a daily subcutaneous injection causes large increases in BMD in treatment-naïve patients or those taking mild antiresportive medications (estrogen and raloxifene), but has delayed or attenuated effect on those previously treated with a potent bisphosphonate, such as alendronate. A course of therapy with teriparatide should be followed by treatment with an antiresportive agent to avoid a subsequent loss of BMD.
Long-term use of bisphosphonates is safe and effective compared with other commonly used drugs. Osteonecrosis of the jaw (ONJ) has been associated with the use of high-dose parenteral bisphosphonates in cancer patients, and rarely in patients with osteoporosis treated with oral bisphosphonates. The risk of fracture in untreated osteoporosis patients appears to be at least 1000-fold greater than the risk of ONJ in those treated with bisphosphonates.
Raloxifene reduces vertebral fracture risk in patients with PMO and reduces the risk of invasive breast cancer. In women at high risk for cardiovascular disease, it does not reduce the risk of cardiovascular end points and is associated with a slight increase in the risk of fatal stroke. Appropriate patients for treatment with this drug may be early postmenopausal women with low BMD, high risk for breast cancer, no severe hot flashes and low risk for thromboembolic and cardiovascular disease.
Treatment-induced osteoporosis results in increased fracture risk and morbidity in patients who already suffer from another major disease. Bisphosphonates and other interventions can prevent or attenuate bone loss associated with these drugs.
Vitamin D deficiency and insufficiency are very common, easily detected and associated with osteoporosis, osteomalacia and suboptimal response to osteoporosis therapy, as well as nonskeletal disorders that include poor balance, falling and increased risk of malignancy.