Proceedings of the 2011 Santa Fe Bone Symposium

Article Outline

• Abstract
• Introduction
• New and Emerging Therapies for Osteoporosis
  • New Therapies
  • Emerging Therapies
  • Future Therapeutic Approaches
  • Combination and Sequential Administration
  • The Wnt Signaling Pathway
  • Serotonin
• Update on Bone Densitometry
  • Introduction
  • Is STP Assessment Still Useful?
  • Instrument Quality Control
• FRAX Update and the Background to the 2010 ISCD/IOF FRAX Initiative and ISCD Position Development Conference
  • CRFs Currently Used in FRAX
• Balancing the Benefits and Risks of Bisphosphonate Therapy
  • Osteonecrosis of the Jaw
  • Atypical Femur Fractures
  • Atrial Fibrillation
  • Esophageal Cancer
  • Renal Effects
  • Conclusions
• Controversies in Nutritional Therapy for Osteoporosis
  • The IOM Recommendations on Vitamin D
  • Calcium Supplementation and Cardiovascular Disease
  • The Calcium Supplement Wars
  • Calcium and Kidney Stones
• Predictors of Osteoporotic Fracture Risk in Men
  • Risk Factors for Fracture in Men
  • Body Mass Index
  • The Rate of Bone Loss
• PTH for the Assessment and Treatment of Skeletal Disease
• Summary
• Appendix. Summary of 2011 Santa Fe Bone Symposium
• References
• Copyright

Abstract 

The 11th Santa Fe Bone Symposium was held in Santa Fe, NM, USA, on August 6–7, 2010. This annual event addresses the clinical relevance of recent scientific advances in the fields of osteoporosis and metabolic bone disease. The symposium format included plenary presentations, oral abstracts, and interactive panel discussions, with participation of clinicians, researchers, and bone densitometry technologists. Among the many topics included in the symposium were new developments in nutritional therapy for osteoporosis, parathyroid hormone for the assessment and treatment of skeletal disease, osteoporosis in men, new and emerging concepts in osteoporosis therapy, report on the 2010 International Society for Clinical Densitometry (ISCD)—International Osteoporosis Foundation FRAX Initiative and the ISCD Position Development Conference, balancing benefits and risks of bisphosphonate therapy, and an advanced bone densitometry workshop for clinicians and technologists.

Key Words: Denosumab, emerging, FRAX, new, osteoporosis, safety, treatment

Back to Article Outline

Introduction 

The Santa Fe Bone Symposium, sponsored annually by the Osteoporosis Foundation of New Mexico, is devoted to new and emerging scientific, social, political, and economic issues that are relevant to the care of patients with osteoporosis and metabolic bone disease. Faculty are selected from leading researchers and scientists who are charged with presenting the most current data in their areas of interest and providing participants with clinical concepts having potential applications for patient care. There were 231 attendees at the 11th Annual Santa Fe Bone Symposium, held in August 6–7, 2011, in Santa Fe, NM, USA. The topics for the bone symposium were selected with consideration of evaluations from previous programs, recent publications, presentations and abstracts at scientific congresses, clinical importance, and the expertise of the faculty. Areas of particular interest included nutritional therapy for osteoporosis, new and emerging treatments for osteoporosis, safety concerns with bisphosphonate therapy, issues regarding quality bone density testing, the role of parathyroid hormone (PTH) for assessment and treatment of skeletal disease, osteoporosis in men, and new information on the World Health Organization (WHO) fracture risk assessment tool (FRAX).

Highlights from previous Santa Fe Bone Symposia have been published in peer-reviewed journals 1, 2, 3, 4, 5. Enduring medical educational materials with opportunities for continuing medical education credits from these events have been made available through newsletters in print and electronic form 6, 7 and as slides with transcriptions and audio recordings accessible online 8, 9. These proceedings of the 2011 Santa Fe Bone Symposium are composed of material submitted by each faculty member based on the current best medical evidence, expert opinion regarding potential clinical applications of evidence that is often limited, and discussions with participants at the symposium. The organizers of the Santa Fe Bone Symposium, sponsors, faculty members, and titles of presentations are listed in the Appendix.

Back to Article Outline

New and Emerging Therapies for Osteoporosis 

John P. Bilezikian, MD

New Therapies 

The most recent osteoporosis therapy approved by the US Food and Drug Administration (FDA) is denosumab, an inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL) that is critical for intercellular bone signaling. RANKL is expressed by osteoblasts and osteocytes and binds to its cognate receptor (RANK) on the surface of osteoclasts and osteoclast progenitor cells. By activating RANK, RANKL is a powerful stimulator of osteoclastogenesis and osteoclast action (10). Osteoprotegerin (OPG) functions as an important regulator of this system by acting as a decoy receptor for RANKL, making RANKL unavailable for binding to RANK (11). The balance between RANKL and OPG may well be a critical element in the mechanism by which bone remodeling is controlled. Denosumab, a fully human IgG immunoglobulin monoclonal antibody to RANKL, acts in much the same way as OPG, binding to RANKL and preventing it from binding to RANK, thereby reducing the activation and development of osteoclasts. Phase II trials of denosumab demonstrated substantial and sustained increases in bone mineral density (BMD) in the spine, hip, and distal one-third radius 12, 13. The extension of the phase II trial, now well beyond 6yr, documents continuing linear accrual of BMD (14), a result that is distinctly different from the bisphosphonates in which the major increment in BMD occurs within the first 3yr of treatment (15). The phase II trial has also given insight into the reversibility of denosumab (16). When denosumab is discontinued, bone turnover markers, which are markedly suppressed during the treatment period, rapidly increase. This increase even overshoots baseline pretreatment bone turnover maker levels. Thereafter, they return to baseline. BMD also falls when denosumab is discontinued. The rapid reversibility of denosumab is another feature that distinguishes this drug from the bisphosphonates. Although this can be viewed as a positive feature, it is also a negative one, in that faithful compliance would appear to be a key to the ultimate therapeutic potential of this drug.

Use of denosumab is associated with substantial, but transient, increases in intact PTH levels, which persist for approximately 3mo of the 6-mo treatment cycle (13). From this observation arises the paradox that primary hyperparathyroidism, a disorder of excessive PTH, is associated with a decrease in cortical BMD, whereas denosumab treatment is associated with increases in cortical BMD, despite the increase in endogenous PTH. To explain this paradox, the hypothesis has arisen that denosumab shifts the action of endogenous PTH from primarily catabolic at cortical sites to an anabolic one, which may involve favoring the inhibition of sclerostin by PTH. Recently, high-resolution studies of cortical bone, under these conditions, reveal a reduction in cortical porosity, an observation consistent with the anabolic actions of PTH (17). The pivotal trial of denosumab, Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6Mo (FREEDOM), enrolled 7808 postmenopausal women with osteoporosis who were randomized to receive denosumab (60mg) or placebo subcutaneously every 6mo for 36mo (18). The results demonstrated a significantly lower risk of vertebral fractures in the denosumab arm compared with the placebo arm (2.3% vs 7.2%; risk ratio 0.32; 95% confidence interval [CI]: 0.26–0.41%; p<0.001). Patients in the denosumab arm also experienced significantly lower rates of hip fracture (0.7% vs 1.2%; hazard ratio [HR] 0.60; 95% CI: 0.37–0.97; p=0.04) and nonvertebral fracture (6.5% vs 8.0%; HR 0.80; 95% CI: 0.67–0.95; p=0.01).

The approval of denosumab by the FDA came with several cautionary notes. One relates to an association with skin infections (cellulitis) or skin conditions (eczema). The extension of the FREEDOM trial to years 4 and 5 is not supporting the increase in these skin conditions that was seen in the pivotal trial (19). Another concern of the FDA is the possibility of “oversuppression” of bone turnover, a concept that is not clearly defined or understood for any osteoporosis treatment. Nevertheless, bone biopsies from the pivotal clinical trial did show marked suppression of bone turnover and a paucity of osteoclasts (20). Bone biopsy data are now available from subjects who discontinued denosumab (21). Consistent with the rapid reversibility of bone turnover, posttreatment biopsies show rapid return of indices of bone remodeling.

Denosumab can be administered to patients whose renal function is impaired.

Emerging Therapies 

Cathepsin K, an enzyme that is expressed in abundance in osteoclasts, is secreted during the process of bone resorption. It helps to excavate the resorption pits that become bone remodeling units (22). Inhibition of cathepsin K or deletion of the cathepsin K gene leads to shallower resorption pits and greater bone mass in animal models; although osteoclasts remain present and functional in other capacities, including osteoblast signaling (23). Results of a phase II trial of odanacatib are consistent with observations from animal models, indicating that odanacatib inhibits bone resorption in a dose-dependent manner (24). Furthermore, bone resorption is inhibited to a much greater degree than bone formation, a feature that differentiates it from the bisphosphonates and denosumab 24, 25. Although several cathepsin K inhibitors have been in development, only odanacatib has advanced to the stage of a major pivotal clinical trial. Another cathepsin K inhibitor, ONO-5334, is being developed (26).

Future Therapeutic Approaches 

An ideal osteoporosis treatment will have the capability to restore the microarchitectural deficits that are characteristic of osteoporotic bone. The class of drugs that shows potential in this regard is described as osteoanabolic. The 2 drugs that belong to this class are PTH(1-84) and its foreshortened amino-terminal fragment, PTH(1-34), known as teriparatide. When PTH(1-84) or teriparatide is administered in low doses and intermittently (once daily, which leads to a pulsatile delivery of drug), anabolic properties of PTH surface (27). Indeed, several clinical trials using either teriparatide or PTH(1-84) have shown that beneficial effects to reduce vertebral and nonvertebral fractures are associated with improved skeletal microstructure 28, 29, 30, 31. Drawbacks to the use of teriparatide or PTH(1-84) include the need for daily use by subcutaneous injection and expense. In some quarters, there are still concerns about the animal studies that demonstrated a risk of osteosarcoma. After almost a decade of clinical experience with teriparatide, however, this risk of osteosarcoma does not appear to have been substantiated (31). Several approaches are being pursued in an attempt to improve the delivery of PTH or to take advantage of endogenous PTH secretory mechanisms. One approach relies on the use of calcilytics, which are inhibitors of the calcium-sensing receptor. One such agent, ronacaleret, appeared to have promise by being associated with increases in endogenous PTH and concomitant increases in bone turnover markers. However, further experience with ronacaleret has not fulfilled the promise that it would be associated with increases in BMD (32). Another approach to improve PTH-based therapy is the use of an amino-terminal fragment of PTH-related protein (PTHrP). PTHrP is an endogenous protein with sequence homology to PTH at the amino-terminal end of the molecule. It is produced by numerous tissues in the body, including some cancers, and is implicated in hypercalcemia associated with malignancy (33). Studying the therapeutic potential of PTHrP(1-36), studies by Horwitz et al (34) found it to be associated with increases in bone formation markers with little or no change in bone resorption markers in postmenopausal women with osteoporosis. Using PTHrP molecule engineered differently from the molecule studied by Horwitz et al, O’Dea (35) showed that bone resorption markers do eventually increase. In this regard, PTHrP-derived molecules do not appear to be different from PTH-derived molecules. Another approach is one that has focused on improving delivery of PTH by using a transdermal patch. This approach was studied in a phase II trial of 165 postmenopausal women with osteoporosis (36). The study found that transdermal administration of teriparatide significantly increases lumbar spine and total hip BMD to a greater extent than either placebo or subcutaneous teriparatide at 6mo. Importantly, the rapid pharmacokinetics (PKs) of transdermal teriparatide appear to be more favorable than those of subcutaneously administered drug (36).

Combination and Sequential Administration 

From advances in our understanding of PTH as an anabolic agent, a kinetic model has arisen suggesting an “anabolic window,” during which time PTH increases bone formation markers without significantly increasing bone resorption markers. Eventually, bone resorption markers also increase. The increase in bone resorption markers signals a switch from a modeling-based to a remodeling-based mechanism of PTH action. It is currently thought that the osteoanabolic actions of PTH are 30% modeling based and 70% remodeling based. During the remodeling phase, bone formation exceeds bone resorption for the duration of the efficacy period of PTH action. The anabolic window concept has led to various strategies to combine bisphosphonates with PTH-based therapies, administering the drugs either concurrently or sequentially. Many patients who are given PTH(1-84) or teriparatide have been treated previously with a bisphosphonate. In some cases, there is a delay of up to 6mo before the anabolic actions are appreciated. Eventually however, despite the delay, subjects invariably respond. After anabolic treatment for the recommended 2-yr period is completed, it is important to follow with an antiresorptive drug so that the gains with anabolic therapy can be maintained. What has provoked the most interest and controversy are the potential advantages of simultaneous combination therapy with other antiresorptive and anabolic drugs. The rationale for these attempts is clear because simultaneous combination therapy takes advantages of different therapeutic mechanisms that at least theoretically could be advantageous. While of interest, it is still not certain whether these approaches will lead to greater efficacy than using the anabolic or antiresorptive agent alone (37).

The Wnt Signaling Pathway 

The Wnt signaling pathway, a complex and ubiquitous system, is involved in numerous physiological processes, and embryogenesis, neurogenesis, and cancer. It is also a key pathway regulating the differentiation and activity of osteoblasts (38). Activities of the Wnt pathway and hence, bone formation, are controlled by sclerostin, an osteocyte product (38). In this manner, sclerostin is thought to serve as an endogenous brake on bone formation (39). Indeed, studies of osteoporosis in animal models have shown that an antibody against sclerostin increases bone formation and bone mass (40). Drugs targeting other components of the Wnt pathway may also be attractive agents for development for the treatment of osteoporosis.

Serotonin 

Serotonin is produced in the brain and the gastrointestinal tract. There is evidence that excess free serotonin in peripheral tissues, mostly derived from the gastrointestinal tract, reduces bone mass (41). In 2008, Yadav et al (42) presented results from genetic studies suggesting that inhibition of gastrointestinal production of serotonin can promote activity of osteoblasts, leading to bone formation. These findings have led to studies of LP533401, an inhibitor of tryptophan hydroxylase 1, the enzyme responsible for serotonin synthesis in the gastrointestinal tract (but not brain). In a proof-of-principle study in ovariectomized mice, LP533401 prevented and reversed osteoporosis and improved bone quality 43, 44. These results have been questioned in more recent studies 45, 46.

In summary, the future looks bright for the treatment and prevention of osteoporosis with many new pharmacological candidates, including several targeting novel mechanisms or signaling pathways. Many challenges remain, however, in demonstrating efficacy and maintaining safety and bone specificity of these potential new therapies.

Back to Article Outline

Update on Bone Densitometry 

Lawrence G. Jankowski, CBDT

Introduction 

Dual-energy X-ray absoptiometry (DXA) is the “gold standard” for bone mass measurement, replacing single-photon and dual photon absorptiometry, because of short acquisition times, low radiation dose, suitable accuracy, excellent precision, and proven ability to predict fracture risk 47, 48, 49, 50, 51, 52, 53, 54, 55, 56. New fan-beam and cone-beam DXA systems are replacing pencil beam DXA because of improved resolution, better precision, and shorter scan times, with only slightly higher radiation doses 57, 58, 59. Most importantly, DXA offers excellent in vivo short-term precision (STP) at common measurement sites (proximal femur, lumbar spine, and forearm), making it possible to monitor changes in BMD longitudinally in menopause, skeletal unloading (disuse), glucocorticoid use, and response to antiresorptive and anabolic osteoporosis therapies. Unfortunately, many DXA examinations are poorly acquired and/or incorrectly interpreted, questioning whether theoretically excellent precision is routinely being achieved in clinical practice 60, 61.

Methods for the calculation of STP and least significant change (LSC) are well established 62, 63. However, assessment of in vivo STP is not without its shortcomings, and several alternative methods for calculating precision and LSC have been proposed 64, 65, 66. Although it is likely that STP underestimates real long-term precision (LTP) for a variety of reasons, to date there remains no reasonable method to measure LTP in clinical practice.

Is STP Assessment Still Useful? 

Precision error is assumed to be random, with most of that error thought to be due to difficulties in repositioning patients consistently. In vitro (machine-related) precision error using spine phantoms is not subject to such error, and indeed is consistently smaller in phantoms than in patients. Because DXA measures area BMD (in g/cm²), even slight changes in the projected image size or path of the X-ray beam passing through bone alter the calculated area (cm²) independently of bone mineral content (BMC). Therefore, differences in positioning confound the comparison of serial BMD measurements by DXA. Other changes not captured in STP include changes in body fat distribution, such as the presence of a fat panniculus overlying the hip and changes in bowel gas patterns and distribution between spine scans (Fig. 1) 67, 68. Finally, knowledge that a DXA measurement is performed for the purpose of precision assessment may influence a technologist to take more care than with a routine DXA in the clinical setting.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 1 

  Single-energy images from a Hologic DiscoveryA scanner. Upper panel (A, B) show baseline (right) and follow-up (left) spine scans done several years apart, demonstrating changes in bowel gas distribution that cannot be controlled for in a short-term precision study. Lower panel (C, D) demonstrating the presence of a fat panniculus (arrows) before (D) and after retraction (C).

Despite these limitations, STP assessments still have value. First, as an educational tool: new scan operators, by finding different results on duplicate scans, learn how difficult it is to obtain precise measurements. Secondly, it may lead to greater appreciation that seemingly slight errors in scanning can change diagnostic classification, assessment of fracture risk, or evaluation of treatment effect, thereby influencing patient management. Thirdly, precision assessments serve as a meaningful yardstick of operator, equipment, and software performance that cannot be ascertained with phantoms. Clinically, STP also has relevance. For example, the International Society for Clinical Densitometry (ISCD) Official Positions recommend short-term LSC be calculated for a 95% level of confidence, whereas clinical decisions are often made with lesser levels of confidence (69). The larger required change in BMD needed for a short-term LSC with a 95% CI, is perhaps similar to using a poorer long-term LSC at 80% CI, suggesting that the ISCD recommendation of 95% CI for STP is a suitable compromise for true LTP, which is not directly measurable in clinical practice.

Instrument Quality Control 

A source of LTP error that is often unappreciated and not captured with STP assessment is a change in instrument calibration. Although scanners have made tremendous advances in technology over the past 25yr, with much faster scan times and images approaching radiographic quality, quality assurance standards have become less stringent and certainly are more relaxed than those applied in clinical trials. For example, in most clinical trials, spine phantom scanning is required every day a subject is scanned and a minimum of 3 times per week, even when no subjects are scanned. Upper and lower control limits in these trials are set to ±1.5% of an established mean value, with several statistical checks being used to detect changes in calibration 70, 71. The ISCD 2007 Official Positions recommend that phantom scans to be done only once weekly, with more frequent scanning after service and software or hardware changes (69).

Hologic and Norland DXA scanners still require daily spine phantom scans before scanning patients, and use similar control limits of 1.5% of the mean for BMD, BMC, and area of a spine phantom provided by their respective manufacturers 72, 73. In addition, they specify that the percent co-efficient of variation (%CV) over time should be <0.5. GE-Healthcare Lunar densitometers no longer recommend separate spine phantom scanning, stating that scanning a calibration block daily is sufficient, but there may be cases where this does not detect significant long-term drifts in calibration (Fig. 2). Although not requiring phantom scanning, this manufacturer still provides an aluminum bar phantom (now described in its operator’s manual as a “service tool”) with each instrument. The phantom has established upper and lower control limits of either ±2% or ±3% of the factory calibration, depending on model, and software version. GE-Healthcare provides no values for acceptable precision in %CV with the phantom 74, 75. Given the rapid scan times now possible with modern fan-beam systems, there is no reason that spine phantom scanning should not be a part of daily quality assurance testing. It provides an independent test of the health of the entire system from X-ray generation through final BMD results, using patient scan modes and analysis software, rather than special calibration block scan modes and software, and insures that the daily calibration process itself is successful.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 2 

  Software plots of the bone mineral density of low-, medium-, and high-density reference materials of the calibration block of a GE-Prodigy Advance bone densitometer (left), and the image and trending graph of the aluminum bar/water bath spine phantom over the same period (right).

DXA manufacturers now store patient scan data, including spine phantom scan results, in universally accepted relational databases. This allows the user to export spine phantom data and to easily apply many of the same quality assurance methods used in clinical trials, using simple spreadsheet calculations (Fig. 3).

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 3 

  Sample graph generated from a database query showing a system with excellent long-term stability over an entire year, with a slight increase in the variation about the mean occurring mid-year after a service call (solid arrow).

Back to Article Outline

FRAX Update and the Background to the 2010 ISCD/IOF FRAX Initiative and ISCD Position Development Conference 

Eugene McCloskey, MD

The introduction of FRAX has facilitated the assessment of fracture risk on the basis of fracture probability. FRAX integrates the influence of several well-validated risk factors for fracture with or without the use of BMD. Its use in fracture risk prediction has strengths, but also limitations of which the clinician should be aware. The International Osteoporosis Foundation (IOF) and the ISCD appointed a joint Task Force to develop resource documents to make recommendations on how to improve FRAX and better inform clinicians who use FRAX. The Task Force met for 3d in Bucharest, Romania, in November, 2010, to discuss these topics which form the focus of this review.

FRAX is a computer-based algorithm (http://www.shef.ac.uk/FRAX) developed by the WHO Collaborating Center for Metabolic Bone Diseases and first released in 2008. The algorithm, intended for primary care, calculates fracture probability from easily obtained clinical risk factors (CRFs) in men and women. The output of FRAX is the 10-yr probability of a major osteoporotic fracture (hip, clinical spine, humerus, or wrist fracture) and the 10-yr probability of hip fracture.

The relationships between risk factors and fracture probability have been constructed using information derived from the primary data of 9 population-based cohorts from around the world, including centers from North America, Europe, Asia, and Australia, based on a series of meta-analyses to identify CRFs for fracture that provide independent information on fracture risk. It has been validated in 11 independent cohorts with a similar geographic distribution with >1 million patient-years. The use of primary data for the model construct permits the determination of the predictive importance in a multivariable context of each of the risk factors and interactions between risk factors, and thereby optimizes the accuracy by which fracture probability can be computed. Fracture probability varies markedly in different regions of the world. Thus, the FRAX models need to be calibrated to those countries where the epidemiology of fracture and death is known.

The obvious application of FRAX is in the assessment of individuals to identify those who would be candidates for pharmacological intervention. Other uses of FRAX, for guideline development, drug registration, and health economic applications are reviewed elsewhere. It has been widely used for the assessment of patients since the launch of the Web site in 2008, and currently receives about 200,000 hits per working day. Following regulatory review by the FDA, FRAX has been incorporated into DXA scanners to provide FRAX probabilities at the time of scanning. For those without Internet access, hand-held calculators and an application for the iPhone and iPad have been developed by the IOF (http://itunes.apple.com/us/app/frax/id370146412?mt=8). The FRAX pad allows patients to input risk variables before medical consultation and is available in several languages.

CRFs Currently Used in FRAX 

Risk factors included in FRAX were chosen carefully to limit the number and complexity, for ease of input, and to include only well-recognized, independent contributors to fracture risk. In addition, it was important that the factors used identified a risk that was amenable to an intervention. The FRAX tool has been appreciated for its simplicity of use in primary care, but criticized for the same reason because it takes no account of exposure response. For example, the risk of fracture increases with exposure to glucocorticoids, but FRAX only accommodates a yes/no response to the relevant question. Other well-researched examples of “dose response” include the number of prior fractures and the consumption of alcohol. If FRAX is to be made more accurate by the inclusion of different degrees of exposure, then information is required not only on the fracture risk associated with these exposures but also on their dependence on the other risk variables in FRAX and their independent effect on the death hazard. This demands the collection of new population cohorts that include such information and the other FRAX variables in sufficient numbers and with wide geographical representation. At the present time, FRAX remains a clinical tool with dichotomous (yes or no) input for CRFs associated with a range of risk; as FRAX continues to evolve, the addition of other CRFs and other methods of understanding risk will be considered. In the meanwhile, the available research information can inform the clinician how to temper clinical judgment on the existing output of the FRAX models.

FRAX represents a significant advance in the assessment of both women and men at risk for osteoporosis and allows the tailoring of pharmacologic interventions to high-risk subjects. Although FRAX does not define intervention thresholds, which depend on country-specific considerations, it provides a platform to assess fracture probability that is needed to make rational treatment decisions by clinicians and public health agencies. The tool is, however, far from perfect, but better than BMD or CRFs alone. The widespread use of and interest in FRAX, and its adoption into management guidelines, has fueled interest as to how models can be improved, extended to other countries and in particular, how the limitations of FRAX should temper clinical judgment.

The wish list of clinicians for the modulation of FRAX is large, but in many instances these wishes cannot presently be fulfilled. An explanation and understanding of the reasons is perhaps helpful in translating the information provided by FRAX into clinical practice.

Back to Article Outline

Balancing the Benefits and Risks of Bisphosphonate Therapy 

Paul D. Miller, MD

In 2011, bisphosphonates celebrated their 40th year anniversary since their discovery (1). The original work on endogenously produced pyrophosphates by Dr Bill Neuman and Professor Herbert Fleisch at The University of Rochester, Rochester, NY, led to continuation of the study of pyrophosphates by Professors Graham Russell and Herbert Fleisch, in collaboration with Dr David Francis at Proctor and Gamble Pharmaceuticals (76). These scientists discovered that the substitution of a carbon atom for the oxygen atom into the backbone of pyrophosphates rendered this new compound (P-C-P, initially termed a disphosphonate and later a bisphosphonate) nonmetabolizable by the ubiquitous present pyrophosphatases. In studying the effects of the bisphosphonate etidronate in a rat model, Dr Francis observed that at higher doses it could inhibit mineralization of soft tissue and in lower doses inhibit bone resorption. In 1969, an endocrinologist at Columbia University College of Physicians and Surgeons, New York, NY, Dr Samuel Bassett, collaborated with Dr Francis to gain an FDA compassionate approval for use of etidronate in a child with myositis ossificans (77). This first clinical use of a bisphosphonate was successful to prevent this child’s progressive soft tissue calcification. In later years, bisphosphonates were then registered to treat a wide variety of skeletal-related diseases: Paget’s disease of bone, hypercalcemia of malignancy, metastatic cancer in bone and multiple myeloma, postmenopausal, male and glucocorticoid-induced osteoporosis. In addition, bisphosphonates have been used off-label for the management of hypercalcemia in primary hyperparathyroidism, drug-induced and post-solid organ transplantation bone loss, heterotopic ossification, and avascular necrosis of bone. The amino-bisphosphonates that are currently used for the treatment of osteoporosis are not associated with impairment of bone mineralization that has been reported with high doses of etidronate.

Despite the consistent beneficial effects of bisphosphonates observed in multiple clinical trials, in database claim records, and in postmarketing data, there have been a few safety concerns that have received great attention, especially from the news media and litigation advertisements. Although all physicians need to keep the safety of treating their patients at the highest level of priority, we also need to continue to obtain robust data on the benefit to risk relationships of all pharmacological therapies. Only by doing so can we constantly assess benefit/risk ratios to select those patients at great enough risk for a benefit that exceeds a potential negative health outcome.

The potential risks that have created the largest concerns in association with bisphosphonate exposure are osteonecrosis of the jaw (ONJ), atypical femur fractures, atrial fibrillation (AF), esophageal cancer, and renal failure. This review will examine each of these issues and consider the perceptions of risks in the light of the reality of the evidence.

Osteonecrosis of the Jaw 

Osteonecrosis of the jaw in association with bisphosphonate use was first described in a small and uncontrolled number of cases by Marx (78) in a letter to the editor of the Journal of Oral and Maxillofacial Surgery in 2003. The following year, a second series of cases was reported by Ruggiero et al (79). These cases caught the attention predominately of the dental community, leading to 4 perceptions:

None of the perceptions are supported by scientific evidence.

It was suggested by Marx et al, based on an uncontrolled observation by measuring CTX in 30 patients with ONJ, that a serum CTX below 150pg/mL represented a moderate-risk group and below 100pg/mL a high-risk group for developing ONJ (80). This hypothesis propelled the concept that there was causality between the magnitude of bisphosphonate-related reduction in bone turnover and induction of ONJ. The reality is that this theory has never been validated (81). In fact, in the largest normative reference ranges for serum CTX in the premenopausal healthy population, the lower end of this range was 114pg/mL (82). In addition, in the Fracture Intervention Trial Long-term Extension trial, the baseline CTX in patients having received an initial 5yr of alendronate 10mg/d was a mean 120pg/mL, with the mean CTX for the placebo group being 110pg/mL (83). In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, the percentage of patients in the treatment arm receiving 5mg/yr of zoledronic acid who had a serum CTX below 150pg/mL was 78.5% at 6mo, 53.2% at 12mo, 47.1% at 24mo, and 39.1% at 36mo (84). None of the HORIZON clinical trial patients who had a serum CTX<150pg/mL developed ONJ. The American Society for Bone and Mineral Research (ASBMR) and the American Association of Maxillofacial Surgeons position papers have stated that bisphosphonate exposure is one of many risk factors for developing ONJ, nothing more 85, 86. These societies also stated that there is no established causality between bisphosphonates and ONJ, and that there is no predictive value for measuring serum CTX for the intent of predicting ONJ. The number of adjudicated ONJ cases associated with bisphosphonate use in the postmenopausal population is exceedingly small, with a calculated attributable risk of about 0.7 cases/100,000 patient-year exposure (87). In contrast, the risk of ONJ appearing in cancer patients who receive the oncology doses of bisphosphonates (48mg/yr for zoledronic acid) is far greater than reported with using the lower doses for postmenopausal osteoporosis (PMO, 5mg/yr of zoledronic acid). Depending on the reported case series, the risk for ONJ developing in the cancer population ranges from 0.5%/yr to ∼5%/yr (88). However, one has to keep in mind that the cancer population is also a group with much comorbidity, including immunosuppression and/or glucocorticoids, which are also independent recognized risk factors for ONJ.

The skeletal health care community strives to better understand the mechanism(s) behind the development of ONJ in association with bisphosphonate use. In the clinical management of patients receiving bisphosphonates, patients should be advised to maintain good oral care and report any dental issues to their physician so that proper care can be provided. Although there is no evidence that withholding bisphosphonate before and during invasive dental procedures can alter the risk for developing ONJ, the FDA recommends discussing this approach with the patient and dental professional on an individual case basis.

Atypical Femur Fractures 

The first suggestion that there could be a link between bisphosphonate exposure and an increase in risk for fractures came from an uncontrolled study by Odvina et al (89). In this study, quantitative bone histomorphometry of the iliac crest was performed on 9 patients on alendronate who had nonspinal low-trauma fractures. Histomorphometry showed that most had evidence of low bone formation. This study launched the search for other low-trauma fractures in patients on bisphosphonates. A specific form of low-trauma fracture has been observed that appears to be related more to bisphosphonate exposure than not. These have been called atypical subtrochanteric femoral fractures to distinguish them from typical femur fractures occurring above the lesser trochanter femur (90). A major difficulty in characterizing these fractures has been the lack of a consensus among the international metabolic bone and orthopedic communities in exactly what constitutes an atypical fracture; the lack of an ICD-9 (international classification of disease) code for examining claim databases for assessing fracture types in patients on or not on bisphosphonates; and the presence or absence of radiological characterization of the fracture. Some orthopedic communities lump all subtrochanteric femur fractures (both typical and atypical) into a single category termed distal femoral shaft fractures (91). What appear to be the criteria for “atypical” include the occurrence without trauma and the transverse or oblique configuration involving at least the lateral cortex. The ASBMR Task Force on atypical femur fractures has provided a provisional case definition as a starting platform for unanimity in definition (Table 1) (90). An important point to make relative to the ASBMR Task Force criteria is the requirement for radiological definition because misreporting and misclassification could lead to ascertainment bias relative to the fractures that might be associated with bisphosphonate exposure, as opposed to subtrochanteric fractures that are not associated with bisphosphonate exposure. Many of the subsequent epidemiological and/or clinical trial analyses examining these relationships without radiological characterization would fail to fulfill the ASBMR’s criteria (92). Three recently published database studies that have had radiographic data have suggested the following 93, 94, 95:

Table 1. The ASBMR Working Group on Atypical Femur Fractures Provisional Case Definition (90)

Note: Requires radiological confirmation; cannot be made on any ICD-9 coding.

Abbr: ASBMR, American Society of Bone and Mineral Research; ICD-9, international classification of disease.

Clinical data obtained from these reports would suggest that the risk for fracture may decline upon discontinuation of bisphosphonate and that there may be a prolonged prodrome of deep anterior thigh pain that is not altered by body position that may precede the low-trauma midshaft femur fracture for weeks to months. Hence, the FDA has developed the following clinical management recommendations based on the currently available and incomplete data relative to causality and pathophysiology (96):

6.Consider periodic reevaluation of the need for continued bisphosphonate therapy, particularly in patients who have been treated for more than 5yr.

An FDA advisory panel met on September 9, 2011, to consider safety issues with long-term bisphosphonate use in the context of reports of ONJ and bisphosphonate-associated atypical femur fractures (97). The panel voted 17 to 6 for a change in the bisphosphonate product label to reflect the limitations of the data on long-term efficacy and safety, but did not recommend a specific limit for duration of treatment. The FDA is not required to follow the recommendations of the panel, and at the time of this writing, has not published a final ruling on a labeling change.

Although atypical and spontaneous femur fractures are of concern and in need of better understanding for their causality and pathophysiology, it is important to point out some summary points recently made from the most recent claims database report of Schilcher et al (95) and from the US national health and discharge summary (1996–2006), and the European Committee for Medicinal Products for Human Use report of 2011 97, 98:

1.Number needed to harm: If 417 patients were treated with bisphosphonates for 3yr, for each atypical femoral shaft fracture that occurred about 30 vertebral fractures and 5 hip fractures would be prevented.

Finally, a recent systematic analysis from The European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the IOF working group concluded that while there is an association between bisphosphonate use and subtrochanteric femur fractures, there may be no greater risk in persons on bisphosphonates compared with those who are not, with more investigations needed to better risk and causality (99). Thus, the benefit of bisphosphonate use in the correct at-risk population far outweighs the risk for atypical femur fractures.

Atrial Fibrillation 

Atrial fibrillation was observed in a subgroup of the zoledronic acid HORIZON Pivotal Fracture Trial (100). The AF was seen in the study population who had severe adverse events (SAEs) during the 3-yr clinical trial. It is important to understand what constitutes a SAE in clinical trials. SAEs are events that occur during the conduct of the trial that in the opinion of the investigator could be life threatening or require hospitalization. The SAE may or may not be caused by the investigative drug. It was in this population where the AF was seen, not in the overall study population. The FDA subsequently required all industries with a registered bisphosphonate to examine their databases for AF events during the clinical trials. No AF was seen that was statistically significantly greater than placebo in any other bisphosphonate clinical trials and in the 6-yr extension of the original zoledronic acid clinical trial, there was no increase in AF events from the initial trial data (101). The FDA concluded that “After our review, based on the data available at this time, health care professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication (102).”

Esophageal Cancer 

In 2009, in a letter to the editor from the FDA in the New England Journal of Medicine, Wysowski (103) reported on anecdotal uncontrolled observations of 23 patients who developed esophageal cancer in association with oral bisphosphonate use. After examining available data, the FDA announced the following with regard to a potential relationship between bisphosphonates and esophageal cancer 104, 105:

Renal Effects 

The concern surrounding any potential renal effects of bisphosphonates stems from 3 basic observations: that bisphosphonates are cleared by the kidney; have been associated with renal failure and abnormal renal histology in rats given high doses of intravenous (IV) bisphosphonates; and the uncontrolled observations of glomerulosclerosis and acute renal failure in early case reports of IV clodronate, etidronate, and pamidronate (109). Because of these observations, the FDA restricted participation in clinical trials for bisphosphonate PMO registration according to renal function, first based on a serum creatinine concentration cut-off (<2.0mg/dL for alendronate, risedronate, and ibandronate) and later based on an estimated glomerular filtration rate (eGFR) greater than 30mL/min (zoledronic acid). No oral bisphosphonate in the clinical trials affected renal function in these randomized populations. In the IV zoledronic acid PMO population, there were no changes in eGFR that differed from placebo either over the 3-yr registration trial, or in the 6-yr extension data 100, 101. However, in a small subset of the zoledronic acid registration study there was a transient but significant increase in the serum creatinine concentration (>0.5mg/dL increase from baseline) measured 9–11d after the 5-mg infusion over 15-min infusion (21 with zoledronic acid vs 9 placebo-treated subjects, p<0.001) following the second infusion only (110). All of these patients had a return of serum creatinine concentration to baseline before the third IV infusion. When infused appropriately in well-hydrated patients with eGFR >35mL/min at baseline, zoledronic acid is not nephrotoxic. The FDA label contraindicating the use of zoledronic acid in patients with “creatinine clearance” <35mL/min is based more on the lack of data than known renal toxicity, although some cases of renal toxicity have been reported with postmarketing use. It does appear that higher doses (4–8mg/mo) given rapidly (5-min infusion rate) in oncology patients can induce acute renal failure; this risk is reduced when the infusion rate is reduced to 15min, suggesting that any negative renal effects may be due to the C_max of the PK profile vs the area under the curve (AUC) 111, 112.

In 2 post hoc analysis examining the effects of oral alendronate and risedronate on changes in renal function and incident fracture rates in registration PMO clinical trials, there were no changes in serum creatinine concentrations, whereas comparable effects on reduction in incident vertebral fracture rates were observed across tertiles of baseline eGFR, even as low as 15mL/min 113, 114. These data suggest that oral bisphosphonates are safe and effective for at least a 3-yr period of treatment duration in patients classified by the National Kidney Foundation (NKF) as having stage 4 chronic kidney diseases (CKDs) with eGFR 30-15mL/min 115, 116. The NKF classification of CKD does not require evidence of proteinuria or microscopic hematuria to classify patients with CKD in stages 3–5 (eGFR<60mL/min) as it does for classifying patients with stages 1–2 CKD (eGFR<110mL/min). Thus, the clinical trials for PMO bisphosphonate registration included patients with NKF criteria for stage 4 CKD. These data, however, need to be interpreted with caution before one can make the definitive conclusion that the patients in the PMO bisphosphonate registration clinical trials had what the nephrology community embraces as stage 4 CKD. This is because in subjects with eGFR as low as 15mL/min in the PMO trials who had PTH levels measured, none had secondary hyperparathyroidism, a common occurrence in clinical practice patients at this level of renal function 117, 118. Hence, there may be undefined differences in response to therapies for osteoporosis in patients with age-related reductions in GFR as opposed to reductions in eGFR associated with intrinsic kidney disease.

Conclusions 

Bisphosphonates have had a 40-yr track record of being safe and effective therapies for a wide variety of metabolic bone diseases. They are not metabolized, do not induce toxicity to any organ tissue, and have no PK interaction with other pharmacological agents, including anticoagulants. They are retained in bone and are recycled back into the systemic circulation, offering the opportunity for prolonged suppression of bone turnover after discontinuation. Despite these very good features of bisphosphonate pharmacodynamics, there have been concerns raised by the associations of bisphosphonates for very rare yet dramatic events for which no causality has been established—ONJ and atypical femur fractures. There has not been any valid association between bisphosphonates and AF or esophageal cancer. Bisphosphonates are not nephrotoxic in the doses used in the proper formulation and dosing instructions for osteoporosis.

Although we need ensure safety for our patients, the benefit to risk relationships for bisphosphonate usage by far favors benefits when used in the right at-risk populations. We certainly need to better understand mechanism(s) that might be associated with the associations between bisphosphonate dose/duration of use and ONJ or atypical femur fractures. These rare events should not dissuade treatment with these long-standing effective agents in the higher risk postmenopausal population where the consequences of all fractures are substantial both with respect to mortality/morbidity and financial costs to society. It is important to convey these facts to colleagues, patients, and payers.

Back to Article Outline

Controversies in Nutritional Therapy for Osteoporosis 

Sarah L Morgan, MD, RD

Calcium and vitamin D supplementation are considered the foundations upon which pharmacological therapies for osteoporosis are added. Recently, there have been numerous controversies related to calcium and vitamin D supplementation. This update will focus on the following: (1) Institute of Medicine (IOM) Report/vitamin D adequacy; (2) calcium and cardiovascular disease; (3) the calcium supplement “wars;” and (4) calcium and kidney stones.

The IOM Recommendations on Vitamin D 

The 2010 IOM panel, using evidence from randomized controlled trials, made recommendations for optimal calcium and vitamin D intakes and optimal vitamin D status as measured by a serum 25-OH vitamin D level 119, 120. The panel recommended that a target level of 20ng/mL (50nmol/L) would cover the requirements of at least 95% of the population. This recommendation for adults has been controversial and concern has been raised about the distinction between recommendations for healthy individuals vs those with metabolic bone disease (121). Priemel et al (122) completed postmortem histomorphometric evaluations on iliac crest biopsies of 675 males and females after secondary causes for metabolic bone disease had been excluded. Using an osteoid volume of >2% to define osteomalacia, they found that there was not a pathologic accumulation of osteoid in any patient with a circulating 25-OH vitamin D level >75nmol/L (122), suggesting that a target 50nmol/L may not be adequate to exclude findings of osteomalacia.

The panel recommendation that the Recommended Dietary Allowance (RDA, the daily intake that meets the needs of 97.5% of the population) of vitamin D is 600IU/d for adults has also been controversial. Heaney et al (123) gave doses of cholecalciferol (0, 1000, 5000, and 10,000IU/d) to 67 men for 20wk during the winter months in Omaha, NE, USA. The blood levels of 25-OH vitamin D levels were flat with an intake of 1000IU/d, thereby raising concern that an intake of 600IU/d would be inadequate to maintain optimal vitamin D status. In a meta-analysis of double-blind randomized-controlled fracture trials compared vitamin D with or without calcium supplementation to calcium plus placebo, it was found that doses of vitamin D of 700–800IU/d were necessary to reduce the risk of nonvertebral and hip fractures in individuals ≥60yr of age (124). It has recently been suggested that dietary/supplement intake to reach a 25-OH vitamin D target level of 40ng/mL (100nmol/L) is reasonable taking into account safety, physiologically achievable levels, seasonal variability in vitamin D levels, and variations in 25-OH vitamin D assays (125). Recent recommendations of The Endocrine Society related to vitamin D are concordant with these recommendations (126).

Calcium Supplementation and Cardiovascular Disease 

The IOMs recommendation for the RDA for calcium intake is 1000–1200mg/d for individuals >19yr of age. Recent estimations of dietary and supplementary calcium intake from the National Health and Nutrition Examination Survey 2003–2006 have generally shown that dietary intakes for adults are inadequate and that the use of calcium supplements increases with age in both men and women 127, 128. Although there are many hypotheses suggesting that calcium intake might be beneficial related to vascular disease, recent data, widely disseminated to the public, has suggested that calcium supplements have detrimental cardiovascular effects. Bolland et al (129) performed a secondary analysis of a calcium supplementation trial in 1471 postmenopausal women with mean age 74yr. There was a significant increased risk of adjudicated myocardial infarction (relative risk [RR] 2.12, 95% CI: 1.01–4.47) but not for the adjudicated composite endpoint of myocardial infarction, stroke, or sudden death (RR 1.47, 95% CI: 0.97–2.23) in the calcium supplementation group compared with the placebo group. However, evaluation of data from the Women’s Health Trial, after 7yr of follow-up, found no difference in HRs for myocardial infarction (HR 1.04, 95% CI: 0.92–1.18) and stroke (HR 0.94, 95% CI: 0.82–1.10) (130). Two separate research groups completed meta-analyses of cardiovascular outcomes from the same clinical trials of calcium supplementation (>500mg/d). Reports of cardiovascular outcomes were obtained from self-reports, hospital admissions, and death certificates 131, 132, 133. Bolland et al (131) found a significant increase of myocardial infarction (3.47% vs 5.5%), stroke (3.47% vs 3.27%), and the composite of stroke and myocardial infarction (5.85% vs 5.5%) for calcium supplements vs placebo, respectively. However, Wang et al (133), evaluating the same studies, concluded that there was not an excess risk of cardiovascular events with calcium supplementation.

A 5-yr randomized controlled trial, with a 4.5-yr follow-up, evaluated the effect 1200mg of carbonate vs placebo on atherosclerotic vascular hospitalizations and mortality data in 1460 women in Australia using an intention-to-treat study design (134). There was no difference between groups related to death rate or initial hospitalization for atherosclerotic vascular disease. Further analysis suggested that calcium supplementation may lower hospitalizations and mortality in individuals with preexisting cardiovascular disease.

The effect of calcium supplements on aortic valve calcification and calcification of coronary arteries was evaluated in the Epidemiology of Coronary Artery Calcification Study (135) and on coronary artery calcification in the Women’s Health Initiative (136). In the Coronary Artery Calcification study, a community-based observational study, there was no difference in progression of aortic valve calcification or coronary artery calcification between users or nonusers of calcium supplements (135). In the Women’s Health Initiative, women were randomized to either 1000mg of elemental calcium per day and 400IU of vitamin D or placebo. Coronary artery calcification was measured with cardiac computerized tomography and calcium supplements did not affect coronary artery calcification over a mean of 7yr of treatment (136).

A recent ASBMR Web Editor Blog from 06/09/11 concluded that “Based on these criteria, the weight of evidence is insufficient to conclude that calcium supplements cause adverse cardiovascular events” (137). Therefore, it is premature to stop calcium supplements related to concerns about atherosclerotic vascular disease.

The Calcium Supplement Wars 

Among calcium supplements, there is controversy about which supplement is best, calcium carbonate or calcium citrate. Two studies of Heller et al 138, 139 concluded that the AUC for serum calcium after ingesting calcium citrate was greater than for similar doses of calcium carbonate. A randomized 3-way cross-over study comparing single doses of Oscal (GlaxoSmithKline, Philadelphia, PA), calcium carbonate, calcium citrate, or placebo evaluated AUC for serum calcium and PTH levels (140). All supplements had equal bioavailability and equal absorption. A study by Heaney et al (141) compared 300 and 1000mg doses of calcium citrate and calcium carbonate with a light breakfast. Calcium absorption was measured by a doubly labeled stable isotope method. There was no difference in absorption of calcium carbonate vs calcium citrate by this methodology. These authors concluded that the variability in conclusions between calcium citrate and calcium carbonate absorption in other studies is likely related to the methodology to evaluate calcium bioavailability, with a stable isotope tracer method being more sensitive than AUCs for serum or urinary calcium.

The effect of a proton pump inhibitor (20mg of omeprazole for 1wk) on calcium absorption was studied in a double-blind study using ⁴⁵Ca-labeled calcium carbonate (142). The fractional calcium absorption was 9.1% on placebo and 3.5% on omeprazole, with an average decrease of 41%. Recker (143) evaluated calcium absorption in fasting patients with achlorhydria using a double-isotope method. Calcium carbonate absorption was significantly lower than calcium citrate absorption; however, the administration of calcium carbonate as part of a breakfast meal resulted in normal calcium absorption in the subjects with achlorhydria. These data suggest that both calcium carbonate and calcium citrate, when taken with meals, have equal bioavailability. Given the lower cost of calcium carbonate, calcium carbonate is likely the best calcium supplement to recommend, provided the calcium supplements are taken with meals (140).

Calcium and Kidney Stones 

There has been concern about an increased risk of kidney stones in individuals who regularly consuming calcium supplements or relatively high levels of calcium in the diet. The incidence of kidney stones is said to be rising and a majority of kidney stones contain calcium, raising the issue that calcium restriction should be considered in calcium stone formers (144). In the Women’s Health Initiative, there was an increased risk of kidney stone formation, recorded as an adverse event, in the calcium supplementation group (145). In the Nurse’s Health Study, higher dietary calcium intake lowered kidney stone formation and calcium supplementation did not increase kidney stone risk (146).

A prospective study of dietary calcium intake on kidney stones evaluated the risk of kidney stones in 45,619 men, aged 40–75yr (147). Dietary calcium was evaluated by food frequency questionnaires. After adjustment for age, calcium intake was inversely associated with the risk of having a kidney stone. The RR of kidney stones for men in the highest when compared with the lowest quintile of calcium intake was 0.56 (95% CI: 0.43–0.73, p for trend=0.001). Intake of animal protein was associated with the risk of stone formation, whereas potassium and fluid intake were inversely related to stone formation.

Borghi et al (148) completed a 5-yr randomized, controlled clinical trial of 400mg of calcium per day vs 1200mg of calcium per day with low amounts of animal protein and sodium in 120 men who had recurrent calcium oxalate stones and hypercalciuria. The low calcium diet group also avoided sources of oxalate and both groups consumed 2–3L of fluid per day. At 5yr, 20% of men on the normal calcium, low protein, and low salt diet developed kidney stones and 38.3% of men on the low calcium diet developed recurrent kidney stones. The authors concluded that the reduced risk of calcium oxalate stone is likely due to the binding of oxalate in the gut by calcium.

Most of the clinical trials show either no increased risk or an inverse relationship between calcium intake and kidney stones (149). Therefore, it seems unnecessary to restrict calcium in individuals with calcium-containing stones.

In conclusion, it seems reasonable to recommend dietary and supplemental intakes of vitamin D that would maintain a serum 25-OH vitamin D level of approximately 40ng/mL. Moderate calcium intakes in the form of food and supplements do not predispose to atherosclerotic vascular disease or kidney stone risk. In addition, calcium carbonate supplements, if taken with meals, will be adequately absorbed and are generally less expensive than calcium citrate supplements.

Back to Article Outline

Predictors of Osteoporotic Fracture Risk in Men 

Eric Orwoll, MD

Osteoporosis fractures in older men are an important public health problem. Although the incidence of fractures may be gradually declining, the population of older men is expected to expand quickly and the numbers of fractures will likely increase (150). Nonetheless, current efforts to detect men at risk are probably inadequate and men at risk of fracture are commonly untreated (151).

Risk Factors for Fracture in Men 

To facilitate effective case finding, predictors of fracture in men must be better understood and incorporated into clinical practice. Well-conducted observational studies of older men have identified a variety of factors that are associated with an increased likelihood of fracture, including higher age, previous fracture, low BMD, falls, and others 152, 153. As in postmenopausal women, men with multiple risk factors have a particularly elevated fracture incidence. Further refining the understanding of risk factors and how they can be used to reduce the population burden of fracture remains an important goal. Here, 2 issues that modify fracture risk in interesting ways are considered.

Body Mass Index 

From previous research, it is clear that low body mass index (BMI) increases the chance of fracture in the elderly, particularly hip fracture (154). Underweight men and women experience hip fracture much more commonly than those with normal BMI. It also appears that overweight and obese women are protected from hip fracture. In part, this protective effect is because obese women have somewhat higher levels of BMD. In addition, some data suggest that obesity in women is accompanied by an increased trochanteric tissue thickness that reduces fracture by lowering the forces experienced by the proximal femur in a fall (155). In addition, obese men seem to be at somewhat higher risk of hip fracture than normal weight men despite the fact that they also have higher BMD (156). Moreover, when adjusted for BMD, obese men are at markedly increased risk of hip fracture, suggesting that obesity itself imparts harm. The reasons for this finding are incompletely understood, but tissue thickness is not associated with a reduction in hip fracture risk in men, and trochanteric tissue is generally much thinner in men than in women (157). As a result, obese men are subject to increased forces on the hip in a fall (by virtue of their increased body mass) but are not protected by tissue padding. In addition, Nielson et al (156) reported that adjusting for physical performance measures reduces the RR of hip fracture in obese men, suggesting that obese men may be at greater risk of falls and, hence, fracture.

Of critical importance, most of the US population is either overweight or obese. Although the incidence of hip fracture is higher in underweight men and women, there are relatively few of them. As a result, a high proportion of hip fractures in the United States appear to occur in the overweight and obese. In men, most of the hip fractures occur in that group (156).

In sum, most fractures in older men in the United States occur in the overweight and obese. Whereas obese women are somewhat protected from hip fracture, obese men are at higher risk than normal weight men, especially when BMD is taken into account. These data make it clear that the possibility of fracture in overweight and obese men cannot be ignored in clinical situations. Because the population burden of fracture is greatest in those men, strategies must be developed to identify those at highest risk so appropriate diagnostic and treatment decisions can be made. Fall risk may be of special relevance.

The Rate of Bone Loss 

Bone loss is common in older men and presumably is an important contributor to osteoporosis and fracture. Although not commonly appreciated, the rate of bone loss accelerates with age, such that the mean rate of bone loss in 85-yr-old men is 3 times greater than in 65-yr-old men (158). Remarkably, men with lower bone mass were found to be losing at the most rapid rate. This age-related acceleration in bone loss, especially in those with the lowest BMD, probably contributes to the exponential increase in fracture rates that occurs with age. Recently, Cawthon et al (159) examined the independent contribution of the rate of bone loss to the risk of fracture, over and above baseline BMD. They found that those losing the most bone, regardless of the initial BMD, were at considerably higher risk of fracture, particularly hip fracture.

The causation of this age-related acceleration of bone loss is undoubtedly complex, and it is important that we better understand the process so it can be prevented. Some of the factors that may contribute to bone loss have been identified in other studies, such as lower levels of vitamin D and estradiol, weight loss, and smoking 152, 160, 161, 162. Similarly, the histomorphometric basis for accelerated loss, and the structural and biomechanical implications, are uncertain. Is accelerated loss a phenomenon that affects all skeletal elements equally (e.g., trabecular structure, cortical thickness, cortical porosity) or does it preferentially affect some compartments?

The fact that the rate of bone loss appears to be a potent risk factor for fracture over and above a baseline measure of BMD raises several issues that should be resolved. Should some men have serial BMD measures to establish a rate of loss as a means of aiding in the identification of those who may benefit from therapy; for instance, those in whom estimated fracture risk approaches, but does not yet exceed, the threshold for therapeutic intervention? Does accelerated bone loss represent an indication for earlier therapy?

Back to Article Outline

PTH for the Assessment and Treatment of Skeletal Disease 

John T. Potts, Jr. MD

Excess PTH was known for years to cause severe bone loss, although in the modern era the disease is seen in a much milder form and is not always, in the opinion of some physicians, a disorder that need be surgically corrected (163); however, the momentum is moving in the direction of surgery for all. Paradoxically, in work over 30yr ago, PTH was shown to increase BMD if given intermittently. This is quite surprising, given the history of parathyroid disease. The mechanism of this beneficial or anabolic effect on bone is still incompletely understood. It is clear that the therapeutic effectiveness of PTH might be greatly improved by combining it with other therapies, by designing better forms of the drug, or by developing better systems for delivery, the latter perhaps affecting efficacy and convenience 36, 164.

A historic review of our understanding of PTH helps to place some of these issues in context and allows us to predict new directions in the diagnosis and management of osteoporosis 165, 166. A recent and surprising issue is the so-called normocalcemic hyperparathyroidism, in which, without other known secondary causes, PTH is elevated despite persistently normal calcium consistently present in patients with osteoporosis (167). This poses new challenges for the clinician and suggests that PTH measurements could be useful in the workup of patients with osteoporosis.

The mechanism of action of PTH at the receptor in target cells is radically different than that which had been previously suspected (168). The PTH receptor (PTHR1) is a member of the secretin family of G protein–coupled receptors. Their mode of activation has traditionally been thought to involve actions at the surface of the cell, with quickly reversible binding by the ligand, in this case PTH. Each binding event leads to activation of the G proteins and generation of the signal within the cell, which in the case of PTH is principally, but not exclusively, cyclic adenosine monophosphate. Fundamental research has led to an understanding of variations of this mechanism that may contribute to improvements in the design of PTH analogues optimized for treatment of osteoporosis or hypoparathyroidism 169, 170. PTH and PTHrP can be traced back in evolutionary time to fish and even earlier. There may be benefits of PTH action in hypoparathyroidism beyond simply calcium and phosphate regulation because the hormone evolved in an era when calcium availability was assured due to its high concentration in seawater. Only after terrestrial existence developed during evolution do parathyroid glands appear (in amphibians and above) as a source of PTH secretion.

Back to Article Outline

Summary 

E. Michael Lewiecki, MD

The topics presented at the 2011 Santa Fe Bone Symposium represented major advances in the science of skeletal health and disease. Discussions of the data and new guidelines, however, often focused on pragmatic clinical decisions that must be made in the setting of uncertainty and insufficient information. This is consistent with the practice of evidence-based medicine, which has been defined as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients (171),” recognizing that evidence alone “is never sufficient to make clinical decisions (172).” The concept of applying good clinical judgment in the interpretation of the best medical evidence has been well described (173) and is reflected in these writings, which are sprinkled with expert opinion and data.

FRAX is a helpful clinical tool that can assist clinicians in deciding who is most likely to benefit from therapy. The new ISCD-IOF Official Positions on the use of FRAX in clinical practice will help us all to use this tool wisely. Men are particularly underrepresented in the diagnosis and treatment of osteoporosis. Better understanding of osteoporosis in men through studies such as Osteoporotic Fractures in Men will hopefully pay off in improvement of skeletal health care in men. Controversies in the nutritional care of osteoporosis have generated great anxiety. The age-old principle of moderation in the use of calcium and vitamin D is probably most appropriate. When drug treatment is prescribed, the effect of treatment is commonly monitored with DXA, yet the quality of DXA studies is often less than optimal. Education and training in bone densitometry though organizations such as the ISCD, and attention to performing precision assessment and calculating the LSC, are important ways to make the best use of DXA.

Among the most perplexing of clinical issues is the decision on how long to treat, which requires an understanding of the balance between long-term benefits and risks of therapy. Because randomized placebo-controlled registration trials of drugs for the treatment of women with PMO are typically of 3-yr duration, data on efficacy and safety beyond this time are limited. Treatment decisions should be individualized using effective risk communication and shared decision making. These data suggest that in most patients at high risk for fracture, the benefits of treatment far outweigh the risks.

As knowledge of the fundamental regulators and mediators of bone remodeling expands, new potential targets for therapeutic intervention are being identified. Denosumab, a fully human monoclonal antibody to RANKL, is a welcome addition to our options for treating osteoporosis. Other compounds with novel mechanisms of action are sure to follow. Odanacatib, a cathepsin K inhibitor that may partially uncouple bone resorption and formation, is a promising agent that is now in phase III clinical trials. Better use of PTH as a therapeutic agent, perhaps through novel delivery systems or combinations with antiresorptive drugs, continues to be an area of investigation. Perhaps most exciting for those who dream of a “cure” for osteoporosis are osteoanabolic agents, such as inhibitors of sclerostin, that stimulate bone formation while inhibiting bone resorption. These and many other new compounds of great interest are currently in development.

Back to Article Outline

Appendix. Summary of 2011 Santa Fe Bone Symposium 

Sponsor: Osteoporosis Foundation of New Mexico

Supporters: Amgen, Lilly, Merck, Pfizer, Roche Diagnostics, Warner Chilcott

Director: E. Michael Lewiecki, MDProgram Committee:

Back to Article Outline

References 

1. Lewiecki EM, Baim S, Bilezikian JP, et al. 2008 Santa Fe bone symposium: update on osteoporosis. J Clin Densitom. 2009;12(2):135–157
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (454 KB)
   • CrossRef
2. Lewiecki EM, Bilezikian JP, Cooper C, et al. Proceedings of the Eighth Annual Santa Fe bone symposium, August 3-4, 2007. J Clin Densitom. 2008;11(2):313–324
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (325 KB)
   • CrossRef
3. Lewiecki EM. Proceedings of the Santa Fe bone symposium 2006. Womens Health. 2006;2(6):825–828
   • View In Article
4. Lewiecki EM, Bilezikian JP, Laster AJ, et al. 2009 Santa Fe bone symposium. J Clin Densitom. 2010;13(1):1–9
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (130 KB)
   • CrossRef
5. Lewiecki EM, Bilezikian JP, Khosla S, et al. Osteoporosis update from the 2010 Santa Fe bone symposium. J Clin Densitom. 2010;14(1):1–21
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (1261 KB)
   • CrossRef
6. Lewiecki EM, Bilezikian JP, Miller PD, et al. Highlights from the 2009 Santa Fe bone symposium. Osteoporosis Foundation of New Mexico; 2009;Available at: http://www.2009santafebonesymposium.com/downloads/2009-Santa-Fe-Bone-Newsletter.pdfAccessed August 25, 2011
   • View In Article
7. Lewiecki EM, Bilezikian JP, Khosla S, et al. Highlights from the 2010 Santa Fe bone symposium. Osteoporosis Foundation of New Mexico; 2010;Available at: http://santafebonesymposium.squarespace.com/storage/assets/2010_Santa_Fe_Bone.pdfAccessed August 25, 2011
   • View In Article
8. Lewiecki EM, Bilezikian JP, Khosla S, et al. 2010 Santa Fe bone symposium. Osteoporosis Foundation of New Mexico; 2010;Available at: http://www.2010santafebonesymposium.com/Accessed August 25, 2011
   • View In Article
9. Lewiecki EM, Bilezikian JP, Miller PD, et al. Santa Fe bone symposium. Osteoporosis Foundation of New Mexico; 2009;Available at: http://www.2009santafebonesymposium.com/Accessed August 25, 2011
   • View In Article
10. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–342
    • View In Article
    • MEDLINE
    • CrossRef
11. Vega D, Maalouf NM, Sakhaee K. The role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab. 2007;92(12):4514–4521
    • View In Article
    • CrossRef
12. Lewiecki EM, Miller PD, McClung MR, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density. J Bone Miner Res. 2007;22:1832–1841
    • View In Article
    • CrossRef
13. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821–831
    • View In Article
    • CrossRef
14. Miller PD, Wagman RB, Peacock M, et al. Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial. J Clin Endocrinol Metab. 2011;96(2):394–402
    • View In Article
    • CrossRef
15. Bilezikian JP. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med. 2009;122(2 Suppl):S14–S21
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (574 KB)
    • CrossRef
16. Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008;43(2):222–229
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1099 KB)
    • CrossRef
17. Seeman E, Libanati C, Austin M, et al. The transitory increase in PTH following denosumab administration is associated with reduced intracortical porosity: a distinctive attribute of denosumab therapy. J Bone Miner Res. 2011;26:
    • View In Article
18. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765
    • View In Article
    • CrossRef
19. Bone HG, Chapurlat R, Libanati C, et al. Safety observations from denosumab long-term extension and cross-over studies in postmenopausal women with osteoporosis. J Bone Miner Res. 2011;26(Suppl 1):S22
    • View In Article
20. Reid IR, Miller PD, Brown JP, et al. Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies. J Bone Miner Res. 2010;25(10):2256–2265
    • View In Article
    • CrossRef
21. Brown JP, Dempster DW, Ding B, et al. Bone remodeling in postmenopausal women who discontinued denosumab treatment: off-treatment biopsy study. J Bone Miner Res. 2011;26(11):2737–2744
    • View In Article
    • CrossRef
22. Stoch SA, Wagner JA. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther. 2008;83(1):172–176
    • View In Article
    • CrossRef
23. Pennypacker B, Shea M, Liu Q, et al. Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone. 2009;44(2):199–207
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1075 KB)
    • CrossRef
24. Bone HG, McClung MR, Roux C, et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res. 2010;25(5):937–947
    • View In Article
25. Costa AG, Cusano NE, Silva BC, et al. Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis. Nat Rev Rheumatol. 2011;7(8):447–456
    • View In Article
    • CrossRef
26. Eastell R, Nagase S, Ohyama M, et al. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study. J Bone Miner Res. 2011;26(6):1303–1312
    • View In Article
    • CrossRef
27. Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology. 1997;138(11):4607–4612
    • View In Article
    • MEDLINE
    • CrossRef
28. Gallagher JC, Genant HK, Crans GG, et al. Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures. J Clin Endocrinol Metab. 2005;90(3):1583–1587
    • View In Article
    • CrossRef
29. McClung MR, San MJ, Miller PD, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med. 2005;165(15):1762–1768
    • View In Article
    • MEDLINE
    • CrossRef
30. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med. 2007;146(5):326–339
    • View In Article
31. Bilezikian JP. Treatment with parathyroid hormone (PTH) for osteoporosis: novel methods and benefits. JCRMM. 2011;2(1):6–13
    • View In Article
32. Fitzpatrick LA, Dabrowski CE, Cicconetti G, et al. The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab. 2011;96(8):2441–2449
    • View In Article
    • CrossRef
33. Rankin W, Grill V, Martin TJ. Parathyroid hormone-related protein and hypercalcemia. Cancer. 1997;80(8 Suppl):1564–1571
    • View In Article
    • CrossRef
34. Horwitz MJ, Tedesco MB, Garcia-Ocana A, et al. Parathyroid hormone-related protein for the treatment of postmenopausal osteoporosis: defining the maximal tolerable dose. J Clin Endocrinol Metab. 2010;95(3):1279–1287
    • View In Article
    • CrossRef
35. O’Dea L. 2010 BA058, a novel analog of human parathyroid hormone-related peptide (PTHrP), induces a dose-dependent increase in BMD without the dose-limiting hypercalcemia of teriparatide: results of a randomized, placebo-controlled Phase 2 study. 14th International Congress of Endocrinology, Kyoto, Japan. Abstract No. O4–2.
    • View In Article
36. Cosman F, Lane NE, Bolognese MA, et al. Effect of transdermal teriparatide administration on bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 2010;95(1):151–158
    • View In Article
    • CrossRef
37. Cusano NE, Bilezikian JP. Combination antiresorptive and osteoanabolic therapy for osteoporosis: we are not there yet. Curr Med Res Opin. 2011;27(9):1705–1707
    • View In Article
    • CrossRef
38. Kubota T, Michigami T, Ozono K. Wnt signaling in bone metabolism. J Bone Miner Metab. 2009;27(3):265–271
    • View In Article
    • CrossRef
39. Hoeppner LH, Secreto FJ, Westendorf JJ. Wnt signaling as a therapeutic target for bone diseases. Expert Opin Ther Targets. 2009;13(4):485–496
    • View In Article
    • CrossRef
40. Li X, Ominsky MS, Warmington KS, et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res. 2009;24(4):578–588
    • View In Article
    • CrossRef
41. Richards JB, Papaioannou A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188–194
    • View In Article
    • MEDLINE
    • CrossRef
42. Yadav VK, Ryu JH, Suda N, et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 2008;135(5):825–837
    • View In Article
    • CrossRef
43. Yadav VK, Balaji S, Suresh PS, et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat Med. 2010;16(3):308–312
    • View In Article
    • CrossRef
44. Ducy P. 5-HT and bone biology. Curr Opin Pharmacol. 2011;11(1):34–38
    • View In Article
    • CrossRef
45. Goltzman D. LRP5, serotonin, and bone: complexity, contradictions, and conundrums. J Bone Miner Res. 2011;26(9):1997–2001
    • View In Article
    • CrossRef
46. Cui Y, Niziolek PJ, MacDonald BT, et al. Lrp5 functions in bone to regulate bone mass. Nat Med. 2011;17(6):684–691
    • View In Article
    • CrossRef
47. Wahner HW, Dunn WL, Brown ML, et al. Comparison of dual-energy X-ray absorptiometry and dual photon absorptiometry for bone mineral measurements of the lumbar spine. Mayo Clin Proc. 1988;63:1075–1084
    • View In Article
    • MEDLINE
48. Cullum ID, Ell PJ, Ryder JP. X-ray dual-photon absorptiometry: a new method for the measurement of bone density. Br J Radiol. 1989;62(739):587–592
    • View In Article
    • MEDLINE
    • CrossRef
49. Lees B, Stevenson JC. An evaluation of dual-energy X-ray absorptiometry and comparison with dual-photon absorptiometry. Osteoporos Int. 1992;2(3):146–152
    • View In Article
    • CrossRef
50. Kalender WA. Effective dose values in bone mineral measurements by photon absorptiometry and computed tomography. Osteoporos Int. 1992;2(2):82–87
    • View In Article
    • CrossRef
51. Blake GM, Naeem M, Boutros M. Comparison of effective dose to children and adults from dual X-ray absorptiometry examinations. Bone. 2006;38(6):935–942
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (317 KB)
    • CrossRef
52. Svendsen OL, Hassager C, Skodt V, Christiansen C. Impact of soft tissue on in vivo accuracy of bone mineral measurements in the spine, hip, and forearm: a human cadaver study. J Bone Miner Res. 1995;10(6):868–873
    • View In Article
53. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312(7041):1254–1259
    • View In Article
    • MEDLINE
    • CrossRef
54. Cummings SR, Black DM, Nevitt MC, et al. Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet. 1993;341(8837):72–75
    • View In Article
    • Abstract
    • CrossRef
55. Lotz JC, Cheal EJ, Hayes WC. Fracture prediction for the proximal femur using finite element models: part I—linear analysis. J Biomech Eng. 1991;113:353–360
    • View In Article
    • MEDLINE
    • CrossRef
56. McCloskey EV, Johansson H, Oden A, Kanis JA. From relative risk to absolute fracture risk calculation: the FRAX algorithm. Curr Osteoporos Rep. 2009;7(3):77–83
    • View In Article
    • CrossRef
57. Hind K, Oldroyd B, Truscott JG. In vivo precision of the GE Lunar iDXA densitometer for the measurement of total-body, lumbar spine, and femoral bone mineral density in adults. J Clin Densitom. 2010;13(4):413–417
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (73 KB)
    • CrossRef
58. Shepherd JA, Fan B, Lu Y, et al. Comparison of BMD precision for Prodigy and Delphi spine and femur scans. Osteoporos Int. 2006;17(9):1303–1308
    • View In Article
    • CrossRef
59. Blake GM, Knapp KM, Fogelman I. Dual X-ray absorptiometry: clinical evaluation of a new cone-beam system. Calcif Tissue Int. 2005;76(2):113–120
    • View In Article
    • CrossRef
60. Watts NB. Fundamentals and pitfalls of bone densitometry using dual-energy X-ray absorptiometry (DXA). Osteoporos Int. 2004;15(11):847–854
    • View In Article
    • CrossRef
61. Lewiecki EM, Binkley N, Petak SM. DXA quality matters. J Clin Densitom. 2006;9(4):388–392
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (158 KB)
    • CrossRef
62. Glüer CC, Blake G, Lu Y, et al. Accurate assessment of precision errors: how to measure the reproducibility of bone densitometry techniques. Osteoporos Int. 1995;5:262–270
    • View In Article
    • CrossRef
63. Shepherd JA, Lu Y, Wilson K, et al. Cross-calibration and minimum precision standards for dual-energy X-ray absorptiometry: the 2005 ISCD Official Positions. J Clin Densitom. 2006;9(1):31–36
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (104 KB)
    • CrossRef
64. Hangartner TN. A study of the long-term precision of dual-energy X-ray absorptiometry bone densitometers and implications for the validity of the least-significant-change calculation. Osteoporos Int. 2007;18(4):513–523
    • View In Article
    • CrossRef
65. Leslie WD. Factors affecting short-term bone density precision assessment and the effect on patient monitoring. J Bone Miner Res. 2008;23(2):199–204
    • View In Article
    • CrossRef
66. Leslie WD, Moayyeri A. Minimum sample size requirements for bone density precision assessment produce inconsistency in clinical monitoring. Osteoporos Int. 2006;17(11):1673–1680
    • View In Article
    • CrossRef
67. Frimeth J, Galiano E, Webster D. Some physical and clinical factors influencing the measurement of precision error, least significant change, and bone mineral density in dual-energy X-ray absorptiometry. J Clin Densitom. 2010;13(1):29–35
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (159 KB)
    • CrossRef
68. Binkley N, Krueger D, Vallarta-Ast N. An overlying fat panniculus affects femur bone mass measurement. J Clin Densitom. 2003;6:199–204
    • View In Article
    • Abstract
    • Full-Text PDF (1954 KB)
    • CrossRef
69. Baim S, Binkley N, Bilezikian JP, et al. Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom. 2008;11(1):75–91
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (261 KB)
    • CrossRef
70. Pearson D, Cawte SA. Long-term quality control of DXA: a comparison of Shewhart rules and Cusum charts. Osteoporos Int. 1997;7(4):338–343
    • View In Article
    • CrossRef
71. Lu Y, Mathur AK, Blunt BA, et al. Dual X-ray absorptiometry quality control: comparison of visual examination and process-control charts. J Bone Miner Res. 1996;11(5):626–637
    • View In Article
    • MEDLINE
    • CrossRef
72. Hologic Inc. . Hologic Discovery Operator’s Manual. New Bedford, MA: Hologic Inc; 2011;
    • View In Article
73. CooperSurgical Inc. . XR-600 Operator’s Manual. Fort Atkinson, WI: USA, CooperSurgical Inc; 2011;
    • View In Article
74. GE Healthcare Lunar . enCORE DXA Operator’s Manual. Madison, WI: GE Healthcare Lunar; 2011;
    • View In Article
75. GE Healthcare Lunar . DXA On-site PM Quality Record Checklist. Madison, WI: GE Healthcare Lunar; 2011;
    • View In Article
76. Fleisch H, Russell RG, Francis MD. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science. 1969;165:1262–1264
    • View In Article
    • MEDLINE
77. Bassett CA, Donath A, Macagno F, et al. Diphosphonates in the treatment of myositis ossificans. Lancet. 1969;2(7625):845
    • View In Article
    • MEDLINE
78. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61(9):1115–1117
    • View In Article
    • Full Text
    • Full-Text PDF (117 KB)
    • CrossRef
79. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004;62(5):527–534
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (234 KB)
    • CrossRef
80. Marx RE, Cillo JE, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg. 2007;65(12):2397–2410
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1431 KB)
    • CrossRef
81. Baim S, Miller PD. Assessing the clinical utility of serum CTX in postmenopausal osteoporosis and its use in predicting risk of osteonecrosis of the jaw. J Bone Miner Res. 2009;24(4):561–574
    • View In Article
    • CrossRef
82. Glover SJ, Gall M, Schoenborn-Kellenberger O, et al. Establishing a reference interval for bone turnover markers in 637 healthy, young, premenopausal women from the United Kingdom, France, Belgium, and the United States. J Bone Miner Res. 2009;24(3):389–397
    • View In Article
    • CrossRef
83. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296(24):2927–2938
    • View In Article
    • CrossRef
84. Grbic JT, Black DM, Lyles KW, et al. The incidence of osteonecrosis of the jaw in patients receiving 5 milligrams of zoledronic acid: data from the health outcomes and reduced incidence with zoledronic acid once yearly clinical trials program. J Am Dent Assoc. 2010;141(11):1365–1370
    • View In Article
85. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22(10):1479–1489
    • View In Article
    • CrossRef
86. Ruggiero SL, Dodson TB, Assael LA, et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg. 2009;67(5 Suppl):2–12
    • View In Article
    • Full Text
    • Full-Text PDF (2747 KB)
    • CrossRef
87. American Dental Association Council on Scientific Affairs . Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc. 2006;137(8):1144–1150
    • View In Article
    • MEDLINE
88. Coleman RE, Woodward EJ, Brown JE, et al. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvent therapy in a randomized phase III trial for women with stage II/III breast cancer. Breast Cancer Res Treat. 2011;127(2):429–438
    • View In Article
    • CrossRef
89. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90(3):1294–1301
    • View In Article
    • CrossRef
90. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25(11):2267–2294
    • View In Article
    • CrossRef
91. AO Foundation . Muller AO Classification of Fractures-Long Bones. AO Foundation; 2007;Available at: http://www2.aofoundation.org/AOFileServer/PortalFiles?FilePath=/Extranet/en/_att/wor/act/fracture_classif/mueller_ao_class.pdfAccessed September 4, 2011
    • View In Article
92. Nieves JW, Cosman F. Atypical subtrochanteric and femoral shaft fractures and possible association with bisphosphonates. Curr Osteoporos Rep. 2010;8(1):34–39
    • View In Article
    • CrossRef
93. Giusti A, Hamdy NA, Dekkers OM, et al. Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone. 2011;48(5):966–971
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (376 KB)
    • CrossRef
94. Puah KL, Tan MH. Bisphosphonate-associated atypical fracture of the femur: spontaneous healing with drug holiday and re-appearance after resumed drug therapy with bilateral simultaneous displaced fractures—a case report. Acta Orthop. 2011;82(3):380–382
    • View In Article
    • CrossRef
95. Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728–1737
    • View In Article
    • CrossRef
96. US Food and Drug Administration . FDA Drug Safety Communication: ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures. US Food and Drug Administration; 2010;Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203891.htmAccessed January 21, 2011
    • View In Article
97. Nieves JW, Bilezikian JP, Lane JM, et al. Fragility fractures of the hip and femur: incidence and patient characteristics. Osteoporos Int. 2010;21(3):399–408
    • View In Article
    • CrossRef
98. European Medicines Agency . European Medicines Agency concludes class review of bisphosphonates and atypical fractures. European Medicines Agency; 2011;Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2011/04/WC500105281.pdfAccessed September 4, 2011
    • View In Article
99. Rizzoli R, Akesson K, Bouxsein M, et al. Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report. Osteoporos Int. 2011;22(2):373–390
    • View In Article
100. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809–1822
     • View In Article
     • CrossRef
101. Black DM, Reid IR, Boonen S, et al. 2011 The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. In press.
     • View In Article
102. US Food and Drug Administration . Update of safety review follow-up to the October 1, 2007. Early communication about the ongoing safety review of bisphosphonates. U.S. Food and Drug Administration; 2008;Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136201.htmAccessed August 11, 2011
     • View In Article
103. Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med. 2009;360(1):89–90
     • View In Article
     • CrossRef
104. US Food and Drug Administration . Oral Osteoporosis Drugs (bisphosphonates): Drug Safety Communication—Potential Increased Risk of Esophageal Cancer. US Department of Health and Human Services; 2011;Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm264087.htmAccessed September 10, 2011
     • View In Article
105. US Food and Drug Administration . FDA Drug Safety Communication: ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer. US Department of Health and Human Services; 2011;Available at: http://www.fda.gov/Drugs/DrugSafety/ucm263320.htmAccessed September 10, 2011
     • View In Article
106. Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA. 2010;304(6):657–663
     • View In Article
     • CrossRef
107. Green J, Czanner G, Reeves G, et al. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ. 2010;341:c4444
     • View In Article
     • CrossRef
108. Pazianas M, Abrahamsen B. Safety of bisphosphonates. Bone. 2011;49(1):103–110
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (426 KB)
     • CrossRef
109. Kanis JA, Preston CJ, Yates AJ, et al. Effects of intravenous diphosphonates on renal function. Lancet. 1983;1(8337):1328
     • View In Article
     • MEDLINE
110. Boonen S, Sellmeyer DE, Lippuner K, et al. Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women. Kidney Int. 2008;74(5):641–648
     • View In Article
     • CrossRef
111. Novartis Pharmaceuticals Corporation . Zometa (zoledronic acid) Injection Prescribing Information. Novartis Pharmaceuticals Corporation; 2011;Available at: http://www.pharma.us.novartis.com/product/pi/pdf/Zometa.pdfAccessed September 10, 2011
     • View In Article
112. Miller PD. Intravenous bisphosphonate safety: the realities. Bone. 2007;41(5):S42–S43
     • View In Article
     • Full-Text PDF (63 KB)
     • CrossRef
113. Jamal SA, Bauer DC, Ensrud KE, et al. Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Miner Res. 2007;22(4):503–508
     • View In Article
     • MEDLINE
     • CrossRef
114. Miller PD, Roux C, Boonen S, et al. Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res. 2005;20(12):2105–2115
     • View In Article
     • MEDLINE
     • CrossRef
115. Miller PD. Fragility fractures in chronic kidney disease: an opinion-based approach. Cleve Clin J Med. 2009;76(12):715–723
     • View In Article
     • CrossRef
116. Miller PD. The kidney and bisphosphonates. Bone. 2011;49(1):77–81
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (452 KB)
     • CrossRef
117. Miller PD. Is there a role for bisphosphonates in chronic kidney disease?. Semin Dial. 2007;20(3):186–190
     • View In Article
     • MEDLINE
     • CrossRef
118. Miller PD. Diagnosis and treatment of osteoporosis in chronic renal disease. Semin Nephrol. 2009;29(2):144–155
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (1889 KB)
     • CrossRef
119. Institute of Medicine . Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011;
     • View In Article
120. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–58
     • View In Article
121. Rosen CJ, Gallagher JC. The 2011 IOM report on vitamin D and calcium requirements for North America: clinical implications for providers treating patients with low bone mineral density. J Clin Densitom. 2011;14(2):79–84
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (207 KB)
     • CrossRef
122. Priemel M, von DC, Klatte TO, et al. Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res. 2010;25(2):305–312
     • View In Article
     • CrossRef
123. Heaney RP, Davies KM, Chen TC, et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77(1):204–210
     • View In Article
     • MEDLINE
124. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293(18):2257–2264
     • View In Article
     • CrossRef
125. Binkley N, Lewiecki EM. Vitamin D and common sense. J Clin Densitom. 2011;14(2):95–99
     • View In Article
     • Full Text
     • Full-Text PDF (243 KB)
     • CrossRef
126. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–1930
     • View In Article
     • CrossRef
127. Mangano KM, Walsh SJ, Insogna KL, et al. Calcium intake in the United States from dietary and supplemental sources across adult age groups: new estimates from the National Health and Nutrition Examination Survey 2003-2006. J Am Diet Assoc. 2011;111(5):687–695
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (566 KB)
     • CrossRef
128. Bailey RL, Dodd KW, Goldman JA, et al. Estimation of total usual calcium and vitamin D intakes in the United States. J Nutr. 2010;140(4):817–822
     • View In Article
     • CrossRef
129. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ. 2008;336(7638):262–266
     • View In Article
     • CrossRef
130. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation. 2007;115(7):846–854
     • View In Article
     • CrossRef
131. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691
     • View In Article
     • CrossRef
132. Bolland MJ, Grey AB, Gamble GD, Reid IR. Effect of osteoporosis treatment on mortality: a meta-analysis. J Clin Endocrinol Metab. 2010;95(3):1174–1181
     • View In Article
     • CrossRef
133. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152(5):315–323
     • View In Article
134. Lewis JR, Calver J, Zhu K, et al. Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5-year follow-up. J Bone Miner Res. 2011;26(1):35–41
     • View In Article
135. Bhakta M, Bruce C, Messika-Zeitoun D, et al. Oral calcium supplements do not affect the progression of aortic valve calcification or coronary artery calcification. J Am Board Fam Med. 2009;22(6):610–616
     • View In Article
     • CrossRef
136. Manson JE, Allison MA, Carr JJ, et al. Calcium/vitamin D supplementation and coronary artery calcification in the Women’s Health Initiative. Menopause. 2010;17(4):683–691
     • View In Article
137. Bockman RS, Zapalowski C, Kiel DP, Adler RA. The challenges of the single micronutrient study: commentary on calcium supplements and cardiovascular events. American Society for Bone and Mineral Research; 2011;Available at: http://www.asbmr.org/About/detail.aspx?cid=3c1575bc-86cb-49bf-b397-2c748fe86581Accessed June 9, 2011
     • View In Article
138. Heller HJ, Greer LG, Haynes SD, et al. Pharmacokinetic and pharmacodynamic comparison of two calcium supplements in postmenopausal women. J Clin Pharmacol. 2000;40(11):1237–1244
     • View In Article
     • MEDLINE
139. Heller HJ, Stewart A, Haynes S, Pak CY. Pharmacokinetics of calcium absorption from two commercial calcium supplements. J Clin Pharmacol. 1999;39(11):1151–1154
     • View In Article
     • MEDLINE
140. Heaney RP, Dowell MS, Bierman J, et al. Absorbability and cost effectiveness in calcium supplementation. J Am Coll Nutr. 2001;20(3):239–246
     • View In Article
     • MEDLINE
141. Heaney RP, Dowell MS, Barger-Lux MJ. Absorption of calcium as the carbonate and citrate salts, with some observations on method. Osteoporos Int. 1999;9(1):19–23
     • View In Article
     • CrossRef
142. O’Connell MB, Madden DM, Murray AM, et al. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med. 2005;118(7):778–781
     • View In Article
     • Full Text
     • Full-Text PDF (95 KB)
     • CrossRef
143. Recker RR. Calcium absorption and achlorhydria. N Engl J Med. 1985;313(2):70–73
     • View In Article
     • MEDLINE
     • CrossRef
144. Brener ZZ, Winchester JF, Salman H, Bergman M. Nephrolithiasis: evaluation and management. South Med J. 2011;104(2):133–139
     • View In Article
     • CrossRef
145. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669–683
     • View In Article
     • CrossRef
146. Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women: Nurses’ Health Study II. Arch Intern Med. 2004;164(8):885–891
     • View In Article
     • MEDLINE
     • CrossRef
147. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993;328(12):833–838
     • View In Article
     • MEDLINE
     • CrossRef
148. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346(2):77–84
     • View In Article
     • CrossRef
149. Heaney RP. Calcium supplementation and incident kidney stone risk: a systematic review. J Am Coll Nutr. 2008;27(5):519–527
     • View In Article
150. Hopkins RB, Pullenayegum E, Goeree R, et al. 2011 Estimation of the lifetime risk of hip fracture for women and men in Canada. Osteoporos Int. In press.
     • View In Article
151. Feldstein AC, Nichols G, Orwoll E, et al. The near absence of osteoporosis treatment in older men with fractures. Osteoporos Int. 2005;16(8):953–962
     • View In Article
     • CrossRef
152. Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev. 2008;29(4):441–464
     • View In Article
     • CrossRef
153. Lewis CE, Ewing SK, Taylor BC, et al. Predictors of non-spine fracture in elderly men: the MrOS study. J Bone Miner Res. 2007;22(2):211–219
     • View In Article
     • MEDLINE
     • CrossRef
154. De Laet C, Kanis JA, Oden A, et al. Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int. 2005;16(11):1330–1338
     • View In Article
     • CrossRef
155. Bouxsein ML, Szulc P, Munoz F, et al. Contribution of trochanteric soft tissues to fall force estimates, the factor of risk, and prediction of hip fracture risk. J Bone Miner Res. 2007;22(6):825–831
     • View In Article
     • MEDLINE
     • CrossRef
156. Nielson CM, Marshall LM, Adams AL, et al. BMI and fracture risk in older men: the osteoporotic fractures in men study (MrOS). J Bone Miner Res. 2011;26(3):496–502
     • View In Article
     • CrossRef
157. Nielson CM, Bouxsein ML, Freitas SS, et al. Trochanteric soft tissue thickness and hip fracture in older men. J Clin Endocrinol Metab. 2009;94(2):491–496
     • View In Article
158. Cawthon PM, Ewing SK, McCulloch CE, et al. Loss of hip BMD in older men: the osteoporotic fractures in men (MrOS) study. J Bone Miner Res. 2009;24(10):1728–1735
     • View In Article
     • CrossRef
159. Cawthon P, Ewing S, Mackey D, et al. Change in hip bone mineral density (BMD) and risk of fractures in older men. (Abstract #SU0314) J Bone Miner Res. 2010;25(Suppl 1):S314
     • View In Article
160. Ensrud KE, Taylor BC, Paudel ML, et al. Serum 25-hydroxyvitamin D levels and rate of hip bone loss in older men. J Clin Endocrinol Metab. 2009;94(8):2773–2780
     • View In Article
     • CrossRef
161. Cauley JA, Ewing SK, Taylor BC, et al. Sex steroid hormones in older men: longitudinal associations with 4.5-year change in hip bone mineral density—the osteoporotic fractures in men study. J Clin Endocrinol Metab. 2010;95(9):4314–4323
     • View In Article
     • CrossRef
162. Jutberger H, Lorentzon M, Barrett-Connor E, et al. Smoking predicts incident fractures in elderly men: Mr OS Sweden. J Bone Miner Res. 2010;25(5):1010–1016
     • View In Article
163. Bilezikian JP, Khan AA, Potts JT. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94(2):335–339
     • View In Article
164. Kawai M, Modder UI, Khosla S, Rosen CJ. Emerging therapeutic opportunities for skeletal restoration. Nat Rev Drug Discov. 2011;10(2):141–156
     • View In Article
     • CrossRef
165. Albright F, Ellsworth R. Uncharted seas. Portland, OR: Kalmia Press; 1990;
     • View In Article
166. Potts JT. Parathyroid hormone: past and present. J Endocrinol. 2005;187(3):311–325
     • View In Article
     • MEDLINE
     • CrossRef
167. Lowe H, McMahon DJ, Rubin MR, et al. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab. 2007;92(8):3001–3005
     • View In Article
     • CrossRef
168. Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N Engl J Med. 2007;357(9):905–916
     • View In Article
     • CrossRef
169. Ferrandon S, Feinstein TN, Castro M, et al. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat Chem Biol. 2009;5(10):734–742
     • View In Article
     • CrossRef
170. Okazaki M, Ferrandon S, Vilardaga JP, et al. Prolonged signaling at the parathyroid hormone receptor by peptide ligands targeted to a specific receptor conformation. Proc Natl Acad Sci U S A. 2008;105(43):16525–16530
     • View In Article
     • CrossRef
171. Sackett DL, Rosenberg WM, Gray JA, et al. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312(7023):71–72
     • View In Article
     • MEDLINE
     • CrossRef
172. Swiglo BA, Murad MH, Schunemann HJ, et al. A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab. 2008;93(3):666–673
     • View In Article
     • CrossRef
173. Lewiecki EM, Binkley N. Evidence-based medicine, clinical practice guidelines, and common sense in the management of osteoporosis. Endocr Pract. 2009;24(10):1643–1646
     • View In Article