Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

30th Annual Meeting of the American Society for Bone and Mineral Research

Montreal, Quebec / September 12-16, 2008

In a healthy young skeleton, a continuous cycle of bone remodelling affects 10% to 20% of bone surface at any point in time. “Bone remodelling involves the removal of a quantum of bone by osteoclasts, followed by [new bone] formation in the cavity formed by the osteoclasts… The amounts of bone resorbed and formed in the young adult skeleton are quantitatively similar, maintaining bone mass,” stated Dr. Juliet Compston, Professor of Bone Medicine, Cambridge University School of Clinical Medicine, UK.

Biology of Aging Bone

In her comprehensive review of bone biology, Dr. Compston described various interrelated factors that contribute to age-related bone loss and frailty. Two key mechanisms produce bone loss: an increase in the number and activity of osteoclasts and a reduction in the activity of osteoblasts at the cellular level of the bone remodelling unit. Quantitatively the most important is that the rate of bone resorption outpaces that of bone formation. At the same time, the amount of new bone formed may be inadequate to fill the cavities left by bone resorption processes. “In postmenopausal bone loss, both these mechanisms operate. So you get an increased remodelling rate, increased numbers of resorption cavities along the trabecular surface, and these only get partially filled in,” she summarized.

Age-related changes to the remodelling balance are influenced by genetic factors, such as bone mass acquired during skeletal development, environmental factors including reduced physical activity and vitamin D (vit D) deficiency, and systemic hormonal alterations, chiefly estrogen deficiency and reduced production of growth factors. “All these factors, via multiple pathways... increase osteoclast generation and activity, and reduce the activity of osteoblasts to result in an increase in bone remodelling rates and decreased bone formation,” Dr. Compston noted.

Osteoporotic bone loss is accompanied by age-related qualitative changes that also contribute to bone frailty and fracture. These are not necessarily captured by measurements of bone mass and many require further elucidation, she commented. Among them are alterations in the degree and distribution of mineralization, changes to bone microarchitecture, fatigue damage such as microcracks resulting from reduced bone turnover, modifications to the matrix mineral composition, and loss of osteocyte viability.

Other Factors Influence Therapy

According to Dr. John Bilezikian, Professor of Medicine and Pharmacology and Chief, Division of Endocrinology, Columbia University Medical Center, New York, convenience is an important characteristic for any long-term therapy. Numerous advances have been made in this area, including once-monthly and even once-yearly administration of current therapies. Moreover, costs and tolerability are factors in patients’ adherence to treatment. Generic alendronate is now the most affordable of the osteoporosis agents available, he noted. However, a single-clinic chart review presented here by Canadian investigators found that a substantial number of women with osteoporosis who had previously tolerated branded alendronate experienced gastrointestinal (GI) adverse events with the generic version (Grima et al. Abstract SA414). In this report, 53 of 181 women (29%) who had taken alendronate since before July 2005 (date of the generic’s introduction) discontinued therapy after this date. About half of the discontinuations were due to GI adverse events and another half to declining BMD. These findings have both health and economic implications, stated Dr. Rick Adachi, Head, Division of Rheumatology, Professor of Medicine, McMaster University, Hamilton, Ontario, one of the authors. “If you have a side effect with [branded alendronate] you usually have it within the first two to three months. These patients had been on it for longer and had been doing quite well before they started having problems. That has... consequences. You may be taking a drug that is not working or you may be stopping the drug and have a bad outcome.” The difference in tolerability might relate to the dissolution profile of the generic agent, the investigators suggested.

The safety of treatment for osteoporosis has been a subject of discussion in medical and lay publications. Incomplete information for patients and physicians alike may lead to poor adherence. Dr. Bilezikian stressed that osteonecrosis of the jaw (ONJ) is extremely rare in patients given bisphosphonates for osteoporosis. According to a report by an ASBMR task force, the risk of ONJ is about 0.7 per 100,000 patients treated. Oversuppression syndrome, in which patients treated with bisphosphonates develop chalkstick fractures, is also exceedingly rare, he stated. “It seems to be associated with long-term use. There may be a prodrome of localized bone pain. There may be a radiologically evident reaction at the cortex and there may be low turnover. These [points] are all very indefinite and there is a lot to learn about this syndrome, if indeed it is related to bisphosphonates.”

Similarly, while teriparatide carries a “black box” warning in the US due to an apparent risk of osteosarcoma, only one case has been reported among more than 750,000 individuals treated with the agent since 2002. Given that the incidence of osteosarcoma in adults is about one in 250,000, the association may be questioned, he suggested. Atrial fibrillation was cited as a serious adverse event in the pivotal trials of zoledronic acid for osteoporosis; however, it has not been detected in other studies of this agent, nor with other bisphosphonates. Zoledronic acid is associated with an acute-phase reaction (chiefly with the first dose) that can be managed by pretreatment with acetaminophen.

Recognizing the Role of Vitamin D

Vit D plays a role in bone health by increasing calcium and phosphorus absorption from the gut, and also appears to have a role in bone formation. Various presentations here examined the role of Vit D in osteoporosis prevention and treatment. Dr. Michael Holick, Professor of Medicine, Physiology and Biophysics and Director, Bone Health Care Clinic, Boston University Medical Center, Massachusetts, stressed the fundamental role of Vit D deficiency (25 hydroxy-vitamin D <20 ng/mL or <50 nmol/L) in general health, low bone mineralization and osteoporosis pathogenesis. Deficiency becomes increasingly common with age and is often observed among patients with osteoporotic fractures. This has multiple potential causes including poor diet and physical restrictions and social isolation that cut outdoor activity. Even subclinical deficiency can precipitate and exacerbate osteoporosis, Dr. Holick indicated. “Bisphosphonates are the mainstay of treatment but Vit D deficiency is very important to correct, no matter what osteoporotic medication you are on,” he added. A recent study determined that among women receiving osteoporosis therapy, 52% had a mean serum concentration of 25(OH)D below that considered optimal (Holick et al. J Clin Endocrinol Metab 2005;90(6):3215-24).

Adequate Vit D has been shown to enhance lower extremity strength and improve the risk of falling in older individuals, although the mechanisms for this effect are not clear. High levels of 25(OH)D have also been associated with improved bone density. Additional research presented at this meeting supports the notion that adequate Vit D has health benefits for older individuals. One study determined that men with 25(OH)D deficiency had higher rates of hip bone loss than those with normal levels or Vit D insufficiency (Enrud et al. Abstract F367). A meta-analysis of trials evaluating Vit D for fall prevention in the elderly showed that high therapeutic doses of supplemental Vit D (at least 700 IU/day) were required to reduce the risk by at least 19%. Lower doses or doses resulting in serum 25(OH)D of <60 nmol/L were less likely to reduce the risk of falls (Henschkowski et al. Abstract SU423). A small study found that individuals with 25(OH)D deficiency have lower than average quality of life, independent of the impact of osteoporotic bone loss (Camacho et al. Abstract SU424).

Sun and Other Sources

Current guidelines by Osteoporosis Canada recommend a daily Vit D intake of 800 IU/day for adults aged >50 years, along with 1500 mg/day of calcium. Dr. Holick added that an adequate intake should produce a serum 25(OH)D level of 40 to 60 ng/mL. Vit D intoxication almost never occurs as it requires a serum level over 150 ng/mL.

The most effective source of Vit D remains sunshine. In northern regions, few people receive adequate exposure during the sunnier seasons and the weaker sun in winter makes it nearly impossible to make enough Vit D. “You have to live [south of] Atlanta, Georgia, in wintertime to be able to make Vit D. You essentially make none if you live [in a more northern location],” he remarked. When climate permits, he advised, healthy individuals can get adequate Vit D by exposing their arms and legs to the sun for five to 15 minutes two to three times per week, applying sunscreen after that time. Dark-skinned individuals require substantially longer exposure.

Vit D tablets may be used for supplementation. Standard multivitamins contain 400 IU, but should not be doubled up due to the risk of Vit A excess. While some physicians recommend eating oily fish to increase Vit D intake, the content in one serving of fish (500 to 1000 IU) means daily consumption would be required, observed Dr. Holick. For individuals who are truly Vit D-deficient, he stated, a course of high-dose injections may be preferable. “In patients whose Vit D tank is on empty, I typically treat with 50,000 IU once a week for eight weeks, followed by dosing every two weeks.” His research group reported here that 50,000 IU administered twice a month is also effective in preventing recurrence of deficiency (Pietras et al. Abstract SU426).

The range of findings reported at ASBMR 2008 confirms that there is more to be discovered in the ideal management of osteoporosis. Researchers here agreed that no single therapy or regimen will suit every patient and that the final aim is to be able to tailor treatment to the needs of the individual.