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PHYSICIAN PERSPECTIVE - Viewpoint Based on presentations from 32nd Annual Meeting of the American Society for Bone and Mineral Research (ASBMR)

Toronto, Ontario / October 15-19, 2010

Reviewed and edited by

David L. Kendler, MD, FRCPC, ABIM

Director, Prohealth Clinical Research Centre, Director, Osteoporosis Program, Providence Health Care, Assistant Professor of Medicine, University of British Columbia, Vancouver, British Columbia

Robert G. Josse, MD, FRCPC

Director, Toronto Canadian Multicentre Osteoporosis Study Division of Endocrinology and Metabolism, St. Michael’s Hospital, Professor of Medicine, University of Toronto, Toronto, Ontario

With an aging population, various health problems may reach epidemic proportions. By the year 2050, hip fractures are expected to increase by two- to threefold. The morbidity and mortality associated with hip fracture is high: 1 in 5 patients die within the first year of sustaining their fracture and half do not return to previously independent living nor walk independently after the fracture.

As discussed here at the ASBMR by Dr. Mary Bouxsein, Harvard Medical School, Boston, Massachusetts, 90% of hip fractures are due to a fall and more specifically due to a fall to the side. While the femur is strong when walking and standing, it 3.5 times weaker in a fall configuration and is rendered weaker still as people sustain bone and muscle loss with age. Sarcopenia or age-related loss of skeletal muscle mass is also increasingly prevalent, especially among aging women. Reduction in muscle mass leads to a corresponding bone loss and subsequent falls and fracture risk escalates. Indeed, women with a history of hip fracture have a high prevalence of sarcopenia, as Dr. William Evans, Duke University, Winston-Salem, North Carolina, pointed out.

Somewhat paradoxically, age-standardized hip fracture rates have fallen in many countries in the West since the mid-1990s. Between 1992 and 2002, for example, hip fracture rates decreased by approximately 23% in a cohort of 80- to 84-year-olds enrolled in the SOF (Study of Osteoporotic Fractures). This may be explained in part by a 3-kg weight gain observed in the same cohort over the same decade, which could reduce hip fracture rates by approximately 10%. Bisphosphonate (BP) use in the SOF cohort also increased over the 10-year interval, as did the use of vitamin D and calcium supplements. But as Dr. Steven Cummings, California Pacific Medical Center Research Institute, San Francisco, argued, increased use of OP treatments could only account for about one-quarter of declining hip fracture rates seen in the SOF cohort. Across the US, OP therapies might explain at most 9% of the 24.5% decrease in hip fracture rates seen among women since the earlier 1990s and very little of the 19% decrease in men.

Nevertheless, there are troubling signs that other types of fractures known as atypical femoral fractures (AFFs) may be increasing, possibly as a result of long-term BP use. In a special task force report on AFFs discussed at the meeting, co-chair Dr. Elizabeth Shane, Columbia University, New York, and colleagues cautioned that AFFs are extremely rare, accounting for less than 1% of all hip and thigh fractures overall. However, in their review of 310 cases of atypical subtrochanteric and diaphyseal femoral fractures, they noted that 94% of patients had been exposed to BPs, most for more than 5 years. Approximately 25% of patients with AFFs have simultaneous or sequential bilateral fractures as well. Prevalence data provided by Dr. Bo Abrahamsen, Copenhagen University Hospital Gentofte, Denmark, confirmed that AFFs are rare. As a high-end estimate, the medical community could expect 5 AFFs to occur for every 1000 women with a fracture risk similar to participants in FIT (Fracture Intervention Trial) treated with a BP for 5 years.

However, BPs prevent far more fractures than they might possibly cause, as physicians could expect to see between 35 and 50 non-vertebral fractures and 50 to 115 vertebral fractures prevented in the same 1000 women.

Based on data provided by a large health maintenance organization (HMO) in California, the incidence of AFFs documented in patients between 2007 and 2009 progressively increased from 2/100,000/year with 2 years of BP use to 78/100,000/year with 8 years of BP use. It is noteworthy that 5 out of the 102 patients with AFF cited in this case series had not been exposed to a BP. Again, speakers emphasized that AFFs were known to occur even before the BP became available.

In the meantime, practitioners should be aware that a patient who presents with either sharp or aching prodromal pain lasting several weeks, usually in the thigh but occasionally in the groin, should be investigated by radiograph, CT, MRI or isotope bone scan.

HORIZON Extension Study

As presented here at the ASBMR by Dr. Dennis Black, Chair, HORIZON Steering Committee, 3 years after randomizing patients to zoledronic acid (ZA) or placebo, women were eligible for the extension study provided they had received all 3 annual infusions of ZA. A total of 1233 women were then randomized to either ZA for another 3 years (Z6 group) or to placebo (Z3P3 group). The primary end point was percentage change in femoral neck bone mineral density (BMD) at year 6 relative to year 3, with secondary end points including other BMD sites.

At the end of the 3-year extension study, mean femoral neck BMD remained constant from the extension baseline in the Z6 group whereas it dropped slightly in the Z3P3 controls, for a between-group difference of 1.04% at year 6 (P=0.009) (however, both groups remained well above pretreatment levels). Comparing femoral neck BMD from the origin of the study 6 years earlier, Z6 patients had a 4.5% increase in femoral neck BMD compared to 3.1% for the Z3P3 group, a between-group difference of 1.4% which was again significant.

Gains in total hip BMD at year 6 were similar to those in the femoral neck at 4.3% for the Z6 group vs. 2.8% for the Z3P3 group; as expected, lumbar spine BMD increased by about 12% from baseline for the Z6 group compared to 10% from baseline in the Z3P3 group, a non-significant difference. Slightly over 6% of the Z3P3 had evidence of morphometric vertebral fracture over the 3-year extension and the use of ZA during that interval approximately halved that rate.

Both hip and clinical vertebral fracture rates were very low. Adverse event (AE) rates were similar in both groups; while there were numerically more serious AEs in the Z6 group, the difference was not significant. No AFFs were observed in either group and only one case of osteonecrosis of the jaw occurred in the Z6 group, which resolved. Thus, after 3 years of ZA treatment, it may be beneficial for some women, particularly those with a high vertebral fracture risk, to continue on annual active therapy, as the authors concluded.

Benefits of Recombinant Parathyroid Hormone in Elderly Women

As presented during the ASBMR scientific sessions under lead author Walsh et al. (Poster SU0374), investigators explored the effect of teriparatide, a recombinant form of parathyroid hormone (PTH), on the incidence of fracture, quality of life and back pain in an elderly subgroup of women enrolled in EFOS (European Forsteo Observation Study). Unlike anti-resorptive agents which stop high bone turnover, teriparatide is an anabolic and creates new bone tissues.

A total of 298 women =75 years old were included in the analysis. Women injected teriparatide daily for up to 18 months, after which it was discontinued, and received either a BP or other OP therapies. During 36 months of follow-up, 14.8% of the cohort sustained at least 1 fracture; out of this group, 21.8% sustained 2 or more fractures.

Nevertheless, the incidence of fracture declined from a baseline rate of 4.4% between 0 and 6 months, to 2.9% between 18 and 24 months and to 0.9% between 30 and 36 months. Indeed, there was an 80% decrease in the odds of women sustaining a fracture between the first 6-month period and months 30 to 36 (P<0.009). As importantly, there was a significant decline in the percentage of patients who reported either daily back pain or severe back pain from study outset to study end point. The percentage of patients who reported daily back pain dropped from 68.8% at baseline to 34.3% at 6 months and to 22.5% at month 36. Similarly, the percentage of patients who reported severe back pain dropped from about half at baseline to approximately 20% at 6 months and approximately 11% at month 18 and month 36.

Health-related quality-of-life scores improved significantly from baseline at all post-baseline visits and changes in all end points were still evident after teriparatide was discontinued at 18 months.

Underlining the severity of the disease and associated back pain treated in this study, some 80% of patients remained adherent to the daily injection regimen.

Role of Vitamin D

Throughout the meeting, considerable attention was given to the role of vitamin D. It appears that fracture risk may increase once 25-hydroxyvitamin D (25 [OH] D) levels drop to below 20 to 25 nmol/L but levels ranging from 25 to 50 nmol/L are still considered insufficient. Most now consider serum 25 (OH) D levels =75 nmol/L as potentially beneficial, according to Dr. David Goltzman, Director, Calcium Research Laboratory, and Professor of Medicine, McGill University, Montreal, Quebec, and for most adults, a vitamin D3 supplement >800 IU is appropriate.

As explained by Dr. Chantal Mathieu, Katholieke Universiteit, Leuven, Belgium, vitamin D is an immune modulator with multiple effects on different cells in the immune system including the macrophages. In addition, 25 (OH) D down-regulates inflammatory cytokines, modifies the behaviour of dendritic cells and has direct effects on T lymphocytes.

Intervention with high doses of 25 (OH) D has been shown to prevent autoimmune disease in animal models. In humans, hard data are not compelling, Dr. Mathieu remarked, and there is still a need to determine interpatient differences in vitamin D needs. Dr. JoAnn Mason, Professor of Medicine, Harvard Medical School, Boston, also suggested that evidence supporting a protective effect of vitamin D in either cancer or cardiovascular disease (CVD) is far from consistent and most studies show no significant association.

Laboratory evidence indicates that vitamin D inhibits cell proliferation, induces apoptosis and causes cell differentiation. It has also been shown to inhibit angiogenesis as well as inflammation. Looking across various cancer trials, however, the best evidence supporting a protective benefit from serum 25 (OH) D appears to be strongest for colorectal cancer. In other cancers, its effects are more modest and in pancreatic cancer, there is some concern that it may increase disease risk.

Vitamin D mechanisms that have the potential to protect patients from CVD have been demonstrated in the laboratory; while encouraging, hard data are scarce in humans. Pooled data from epidemiologic studies suggest that the highest levels of serum 25 (OH) D are protective against CVD compared to the lowest levels in individuals with and without prevalent coronary heart disease (CHD). A large-scale randomized trial, VITAL, is currently underway and aims to study 20,000 men and women who will receive vitamin D3 2000 IU/day or placebo, then either omega-3 fatty acids or placebo. The primary objective of VITAL is to evaluate whether vitamin D3 has any effect on total and site-specific cancer outcomes as well as CV outcomes.

Meta-Analysis of RCTs

In a meta-analysis of 12 randomized controlled trials (RCTs) involving over 31,000 participants =65 years of age, Dr. Heike Bischoff-Ferrari, University of Zurich, Switzerland, and colleagues examined how much vitamin D was required to prevent hip and non-vertebral fractures. The analysis showed that only the highest quartiles of vitamin D ranging from 792 to 2000 IU/day reduce fracture risk, 14% for non-vertebral fractures and 30% for hip fractures.

These and related findings underscore the need for higher 25 (OH) D levels for fracture and fall prevention and lower extremity function (namely, 75 to 100 nmol/L). Dr. Christopher Kovacs, Professor of Medicine, Memorial University, St. John’s, Newfoundland and Labrador, reviewed the literature and concluded that maternal requirements for vitamin D do not change during pregnancy or lactation but that maternal 25 (OH) D levels >50 nmol/L should ensure the fetus has adequate levels.

Whatever benefits vitamin D may bring to human health, it does not apparently abrogate the negative impact of calcium supplementation on myocardial infarction (MI) risk. In a re-analysis of the Women’s Health Initiative, Dr. Ian Reid, University of Auckland, New Zealand, and colleagues calculated that for non-obese women, those randomized to the calcium (1 g) vitamin D (400 IU) supplement had a 28% increased risk for a revascularization procedure and a 24% increased risk for the composite end point of total MI, CHD death and revascularization (obese women did nor share this increased risk). Women not taking their own personal calcium supplements at baseline also had a 16% increase in the combined stroke/MI end point (although if they were taking their own calcium supplement, there was no AE from adding further calcium/vitamin D on top of it). CVD risk was also similar between calcium alone and calcium plus vitamin D. Consequently, investigators felt that the role of calcium supplementation with or without vitamin D in OP prevention and treatment warrants reassessment.

Summary

New insights into the preservation of bone and muscle health offer the potential to reduce fracture risk among the most vulnerable patients, namely the elderly. Certainly, ensuring adequate amounts of vitamin D is key, but fracture prevention through suppression of high bone turnover with BPs is equally vital to preserve bone health. In severe OP or in non-response, anabolic agents such as teriparatide are useful as bone anabolics, creating new bone. With goals of fracture prevention and maintenance of independence in our elderly populations, it is reassuring that there are a number of therapeutic options with which to better manage OP.

Based on scientific presentations from the ASBMR meeting selected by a review committee headed by Dr. Kendler, in keeping with the principles of accreditation. Both Dr. Kendler and Dr. Josse have edited and approved the content and related slides as educational material.

This event is approved for up to 0.5 CME study credits by the Centre for Continuing Health Professional Education (CCHPE). The Centre for CCHPE, Faculty of Medicine, McGill University is fully accredited by the Committee on Accreditation of Canadian Medical Schools (CACMS), and through the CACMS is accredited to award AMA PRA category 1 credits. This program meets the accreditation criteria of the College of Family Physicians of Canada for MAINPRO-M1 credits. Members of the American Academy of Family Physicians are eligible to receive credit hours for attendance at this meeting due to a reciprocal agreement with the College of Family Physicians of Canada.

This event is an accredited group learning activity (Section 1) as defined by the Maintenance of Certification program of the Royal College of Physicians and Surgeons of Canada. Through a reciprocal agreement between the American Medical Association and the Royal College of Physicians and Surgeons of Canada, the Centre for CCHPE, Faculty of Medicine, McGill University designates this activity for AMA PRA Category 1 credit(s) up to the maximum number of credit hours noted above. Each physician should claim only those hours of credit that he/she actually spent at the educational activity.