The Role of RANK/RANKL/OPG Pathway in Bone Loss: New Insights

Bone Biology and the Role of RANK/RANKL/OPG Pathway

Speaker: Robert G. Josse, MD, Division of Endocrinology & Metabolism, St. Michael’s Hospital; Professor of Medicine, University of Toronto, Toronto, ON.

Advances in the understanding of bone biology and the role of the RANK/RANKL/OPG pathway have opened new treatment avenues for osteoporosis. To facilitate understanding of the “new biology,” Dr. Robert Josse first reviewed determinants of bone strength.

Trabecular bone, a spongy network of delicate plates of bone known as trabeculae, constitutes 20% of skeletal mass but accounts for ~80% of bone turnover. In contrast, cortical bone constitutes 80% of mass but ~20% of turnover. The interior surface of cortical bone, the endosteum, is the primary site of remodeling and metabolic activities while the exterior surface, the periosteum, is the site of new bone formation.

Remodeling, Dr. Josse noted, takes place continuously: tiny packets of bone throughout the skeleton constantly undergo this process during the life-span. Remodeling optimizes bone structure for mechanical function and repairs microdamage, adding strength where it is needed. Bone is deposited and resorbed in accordance with the stresses placed upon it. Bone is also a source of circulating growth factors, which is important in our understanding of bone biology. Finally, bone acts as a reservoir for calcium and phosphate. A feedback mechanism enables parathyroid hormone (PTH) to stimulate the release of calcium from the skeleton when needed as well as enhance bone resorption to increase the availability of calcium for vital tissues and metabolic functions.

Excessive remodeling contributes to osteoporosis as accelerated bone remodeling results in structural decay and net bone loss. Bone strength and ability to resist fracture depend on both structural integrity and mass, and both tend to deteriorate with age and with menopause in women.

Understanding bone biology involves comprehending the function of the bone cells involved in remodeling. Dr. Josse went on to review the bone remodeling sequence. The first step in remodeling is activation of osteoclasts responsible for resorption. Cells that line bone surfaces retract, allowing the osteoclasts to resorb exposed bone tissue, creating “pits.” Following the reversal stage, osteoblasts lay down new osteoid matrix, which subsequently mineralizes. Osteoclasts are derived from the monocyte macrophage series. They attach to bone, form a tight seal, and start resorbing the bone. Osteoclasts excavate trenches in bone. Osteoblasts are derived from mesenchymal precursors in the marrow responsible finally for differentiating into osteoblasts. These mesenchymal stem cells are the same cells that differentiate into myoblasts and adipoblasts. Thus those stem cells that make bone also make muscle and fat. Age-associated biological processes determine a shift of these stem cells toward fat. This is in part why in older adults there is sarcopenia and the marrow is fat-laden.

Once osteoclasts excavate an area of bone, osteoblasts fill up the bone resorption pit with unmineralised matrix. This hardens when minerals, e.g., calcium, are deposited in it. In healthy young individuals, the amount of resorption is balanced with formation. An imbalance in bone remodeling that favours resorption, such as occurs in osteoporosis, leads to decreased mineral density and microarchitectural deterioration, increasing fragility and fracture susceptibility. Although we have less trabecular versus cortical bone, the effects of an imbalance in bone remodeling will first become apparent in trabecular bone, which is more readily disrupted by excess bone resorption. In states of imbalance and weakened trabecular bone, the bone’s platelike structures convert to rod-like structures, which are mechanically weaker.

Biologists were perplexed for years, Dr. Josse explained, by how osteoclasts resorbed bone. The osteoclast does not possess receptors for the substances (cytokines, hormones, etc.) that activate resorption.

This conundrum was settled when the RANK ligand system was discovered. Receptor activator of nuclear factor-kB ligand (RANKL), a protein that binds to receptor activator of nuclear factor-kB (RANK), is the primary mediator of osteoclast differentiation, activation, and survival (Figure 1). RANK ligand is the primary mediator of bone resorption. Osteoprotegerin (OPG) provides an alternative binding site for RANKL and acts as a decoy receptor by blocking RANK ligand binding to its cellular receptor RANK. Ligand binding activates cellular signalling. Ligand that is bound to a decoy receptor cannot activate cellular signalling.^1-6

 

Osteoprotegerin is the natural key endogenous regulator of the RANKL–RANK pathway. When RANK ligand is bound and neutralized by OPG, osteoclasts cannot form,^2,5 function,² or survive.³ Osteoprotegerin acts as a decoy receptor by binding with RANKL, thereby inhibiting osteoclastogenesis and the survival of pre-existing osteoclasts.^1,4,7,8 By binding to and neutralizing the effects of RANKL, it thereby inhibits bone resorption.^1,4,7,8 More RANKL equates with more bone loss.

Denosumab is an osteoporosis treatment designed to target RANKL. It is a fully human monoclonal antibody (IgG2) that binds to RANKL with high affinity and specificity. It blocks the interaction of RANKL with RANK, mimicking osteoprotegerin.
The clinical use of OPG is impractical, Dr. Josse observed, and researchers saw the need to create other agents to neutralize RANKL, which increases bone resorption and reduces trabecular and cortical bone. It is implicated in osteoporosis and its inhibition increases bone mineral density and maintains bone architecture. Denosumab is now being investigated in treatments other than osteoporosis, including cancer-related bone destruction and bone erosion in the setting of rheumatoid arthritis.

Dr. Josse reiterated that a healthy skeleton depends on a balance between bone resorption and formation; treatments that are able to achieve RANK ligand inhibition and therefore appropriate suppression of bone resorption could offer significant clinical value to patients with bone loss.^1,6

References:

1. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–42.
2. Fuller K, Wong B, Fox S, et al. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 1998;188:997–1001.
3. Lacey DL, Tan HL, Lu J, et al. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol 2000;158:435–48.
4. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165–76.
5. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 1998;95:3597–602.
6. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/ RANK system for bone and vascular diseases. JAMA 2004;292:490–5.
7. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309–19.
8. Bekker PJ, Holloway D, Nakanishi A, et al. The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 2001;16:348–60.

Sponsored by an unrestricted educational grant from Amgen Canada Inc.

Systems Approach to Fracture Prevention: The Ontario Project

Speaker: Earl Bogoch, MD, FRCSC, University of Toronto; St. Michael’s Hospital, Toronto, ON.

Dr. Earl Bogoch’s key message concerned the importance of identifying and treating osteoporosis after a fragility fracture, in order to prevent future fractures, most importantly of the hip.

The care gap for patients after a fragility fracture is well-known and exists internationally. This problem is significant; about 80% of hospitalized fracture patients over the age of 60 have osteoporosis as an underlying cause of their fracture. From the age of 50, half of women and one-fifth of men are likely to experience an osteoporotic fracture. The economic burden has been well documented as well as major personal morbidity—and mortality—in those with hip fractures, with loss of function and independence.

The current method for treating fragility fracture patients may focus only on treating the fracture; the literature shows that only about 20% of cases receive appropriate investigation and management for the underlying osteoporosis.

Dr. Bogoch offered a critique of the traditional care model that relies on the expertise and initiative of a single doctor, which serves osteoporosis care poorly. While surgeons deal with fractures, frequently no one focuses on patients’ bone health. The solution he posed is a system that results in the diagnosis and treatment, rather than a care model relying on a single physician.

Ten years ago, Dr. Bogoch carried out a study in five Ontario hospitals. Patients with wrist, shoulder, vertebral, or hip fractures were provided with a written explanation of the risks of osteoporosis, and a letter was mailed to the family doctor recommending osteoporosis follow-up. Afterward, less than two-thirds saw their family doctor and, of those, 69% had densitometry. Treatment rate went up only slightly, from 17% (historical controls) to 24%. Disappointed with the results, Dr. Bogoch determined that simply informing patients and physicians was insufficient; they needed a coordinator to promote good care.

Other studies in Ontario had similar results; densitometry and treatment rates increased minimally or not at all. The lack of success with these programs led to their decision to focus on the coordinator program (Figure 1).

 

In this program, coordinators screened all orthopedic inpatients as well as outpatients in their fracture clinic, who had low-trauma fractures of the wrist, hip, vertebrae, and humerus. Coordinators assessed the etiology of the osteoporosis and the patient’s fracture risk. They gave patients recommendations, provided educational materials, communicated with their family physicians, and then closely followed every patient.

Three messages were delivered to fragility fracture patients: 1) Your fracture is probably related to underlying weakness of the bone. 2) By having this fracture, you are now at risk of a hip fracture. 3) Treatment is convenient, safe, and effective.

After 1 year, they found that 95% of their patients received appropriate osteoporosis attention. At 6 months and at 1 year, three-quarters of the patients had undergone a BMD as recommended. Three-quarters of those referred to a specialist had attended, and at 1 year, 50% were adherent with medications. Dr. Bogoch noted that more recent data showed closer to 85% adherence.

According to Dr. Bogoch, similar coordinator or fracture liaison service studies have shown a comparable increase in treatment rates. Further, working with a health economist, they found that the coordinator program was cost-effective, with the coordinator’s salary more than recovered. Additionally, in their cohort of 500 patients, predicted hip fractures were reduced, with considerable hospital cost savings.

There were also other benefits to working with a coordinator: orthopedic surgeons were more likely to document information about overall fragility rather than only the fracture; there was an increase in identification of atypical osteoporosis; there was an improvement in patient knowledge and attitudes; and there was an increase in appropriate referrals to osteoporosis specialists.

A commitment for a comprehensive osteoporosis strategy has now been made in Ontario, and $5 million in annual funding has been committed for this project. The program now includes most types of low-trauma fracture, since they now know they are all predictors of a future hip fracture. Nineteen coordinators work in 33 fracture clinics across Ontario.

They began screening patients in early 2007 and results of the first year were reported. The coordinator met with more than 26,000 patients, about 13,000 of whom completed baseline information questionnaires. They educated 12,000 patients and had an intervention with their family doctor; over 10,000 patients were told they should discuss a BMD with their family physician; and 8,700 family doctors received a letter recommending osteoporosis follow-up. These patients will be followed, and their data linked to CIHI and Ontario Health data, for future fracture rates as well as their utilization of osteoporosis medications, in the over-65 group.
Victoria Elliot-Gibson, osteoporosis coordinator at St. Michael’s and program consultant for Osteoporosis Canada, was the original coordinator of the program, and she addressed the symposium. She explained that osteoporosis screening coordinators are hired by Osteoporosis Canada.

All centres follow a protocol to provide uniformity of care. They screen via a variety of methods because coordinators do not have similar access across all sites, using electronic records, paper charts, or ER referrals. The assessment for each patient is done in a private area. Coordinators are also now collecting consent forms so they can use this data for research purposes. Coordinators have a network, with a website, www.OSCnet.ca. It features a forum for questions to Ms. Elliot-Gibson, as well as relevant articles so that coordinators can stay current with the literature.

Susan B. Jaglal, PhD, Toronto Rehabilitation Institute Chair, Associate Professor, Faculty of Medicine, Department of Physical Therapy, University of Toronto, Toronto, ON.

A wrist fracture is associated with an increased risk of another fracture and should prompt investigation for osteoporosis in both men and women. If the fracture was caused by low trauma (a fall from a standing height or less), a bone density test should be ordered. If the T score is <–1.5, pharmacological treatment with a bisphosphonate and calcium (1,500 mg/d) and vitamin D3 (≥800 IU/d) is recommended. Management should also include balance, posture, and muscle-strengthening exercises and walking, as well as a review of fall-prevention strategies.
Key words: wrist fracture, osteoporosis, diagnosis, treatment, exercise, falls.

Simona Abid, MD, FRCP(C), Geriatric Medicine Fellow, McMaster University, Hamilton, ON.
Alexandra Papaioannou, MD, FRCP(C) MSc, Professor, Department of Medicine, Division of Geriatric Medicine, McMaster University, Hamilton, ON.

Vertebral compression fractures (VCF) are the hallmark of osteoporosis, yet two-thirds of all VCF remain undiagnosed and untreated. Both symptomatic and occult VCF are associated with considerable increases in morbidity and mortality, hospitalization rates, admissions to long-term care, and health care-related costs. These fractures increase the risk of future osteoporotic fractures, both vertebral and nonvertebral, independent of bone mineral density. Older adults have lower rates of diagnosis and treatment compared with younger patients, although clinical studies have shown the efficacy and safety of currently available therapies for osteoporosis in older adults are comparable with those in younger individuals.
Key words: vertebral compression fractures, osteoporosis, bone mineral density, antiresorptive therapy, anabolic agents.

Mohammed O. Rahman, BHSc student, McMaster University, Hamilton, ON.
Aliya Khan, MD, FRCPC, FACP, FACE, Professor of Clinical Medicine, McMaster University, Hamilton, ON, Director, Calcium Disorders Clinic, St. Joseph’s Healthcare, Hamilton; Director, Oakville Bone Center, Oakville, ON.

Osteoporosis is a skeletal disease characterized by impaired bone strength and an increased risk of fragility fracture. Effective screening should be aimed at evaluating risk factors for osteoporosis with identification of individuals at risk, allowing for intervention prior to fragility fracture. This article presents an overview of the risk factors for fracture in men and women and the integration of these factors in various models, enabling an assessment of the 10-year fracture risk. Through effective screening, early identification, and early intervention with pharmacological therapy of osteoporosis, significant impact can be made on reducing fragility fracture incidence, thereby alleviating the economic and clinical costs to our health care system.
Key words: osteoporosis, screening, risk factors, diagnosis, FRAX.

Cathy R. Kessenich, DSN, ARNP, Professor of Nursing, University of Tampa, Tampa, FL, USA.
Darlene A. Higgs, RN, BSN, Nurse Practitioner Student, University of Tampa, Tampa, FL, USA.

Osteoporosis is a major cause of health problems in residents of long-term care facilities. It often results in bone fracture, causing poor quality of life and a national financial burden. As the population ages, the incidence of osteoporosis and its consequences increase. It is essential to employ fracture-prevention strategies that have proven most beneficial in long-term care settings and those tailored to promote adherence among older adults. This article reviews osteoporotic treatment appropriate for individuals in long-term care, including treatment through pharmacology, nutritional support, fall prevention, and hip fracture prevention.
Key words: osteoporosis, long-term care, hip protectors, fall prevention, vitamin D.

Since our last issue focusing on osteoporosis, much has changed and yet much stays the same. We have new Canadian guidelines on the detection and management of osteoporosis, several new treatment modalities, and a better understanding of osteoporosis in men. However, many people with osteoporotic fractures are not identified and managed, many people do not stay on effective treatment, and falls prevention programs are rarely available for appropriate older adults. In other words, we have a long way to go before we can say we are dramatically ameliorating the morbidity that osteoporosis causes. Hopefully, this edition of Geriatrics & Aging will do its part to promote the effective diagnosis and management of this important disorder.

Two articles tackle the important issue of diagnosing osteoporosis and determining who is at particular risk for complications. Dr. Angela Juby and Dr. David Hanley review “Diagnostic Tools for Osteoporosis in Older Adults” while Dr. Aliya Khan and Mohammed Rahman discuss one of the key issues in their article “Osteoporosis Screening and Assessment of Fracture Risk.” In our CME article, Dr. Savannah Cardew reviews “New Pharmacotherapy for Osteoporosis.” Our final focus article concentrates on a group at high risk of having osteoporosis and not being treated. Cathy Kessenich and Darlene Higgs review “Osteoporosis Fracture Prevention in Long Term Care.”

We also have our usual collection of key geriatric topics. My colleague, Dr. M. Bachir Tazkarji reviews the important area of “Blood Pressure and Cardiovascular Risk among Older Adults.” Dr. Ekaterina Rogaeva reviews an area of intense research scrutiny in her article on “The Genetic Profile of Alzheimer’s Disease: Updates and Considerations.” Dr. Sophie Robichaud and Dr. Joseph Blondeau address a common problem in their article “Urinary Tract Infections in Older Adults: Current Issues.” Educating students, residents, and even ourselves in proper medical care of the older adult has been a tremendous challenge so any improvements offered via technology are much appreciated. In their article, Drs. Anita Bagri, Bernard Roos, and Jorge Ruiz discuss “Simulation Technology in Geriatric Education.” And our Sexual Health column, written by Drs. Irwin Kuzmarov and Jerald Bain of our partner organization the Canadian Society for the Study of the Aging Male, looks at the important matter of "Sexuality and the Aging Couple, Part I: The Aging Woman."

Enjoy this issue,
Barry Goldlist

Michael Gordon, MD, MSc, FRCPC, FRCP Edin, Medical Program Director, Palliative Care Baycrest Geriatric Health Care System; Professor of Medicine, University of Toronto, Toronto, ON.
Kayi Li, BHSc, medical student, University of Toronto, Toronto, ON.

Osteoporosis is a systemic disease resulting in bone fragility and increased risk of fractures. For optimal prevention, the literature increasingly supports the combined use of education on nutrition, lifestyle, and exercise. Currently, multidisciplinary, multimodal initiatives are rarely implemented in the community. The POWER (Promoting Osteoporosis Wellness through Education, Exercise and Resources) program in Toronto, Ontario, strives to empower individuals with osteoporosis with diverse cultural backgrounds to sustain healthy behaviours for self-management of their condition. This article provides a description of the POWER program philosophy, as well as a preliminary evaluation to assess its benefits and potential for further expansion and adaptation.
Key words: osteoporosis, management program, cultural differences, education, health beliefs.

John T. Schousboe, MD, MS, Park Nicollet Osteoporosis Center, Park Nicollet Health Services, Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis, MN, USA.

Fractures related to osteoporosis are increasingly recognized as a serious public health problem among older men. As in women, bone densitometry has substantial utility to aid in the identification of older men at high risk of fracture and for whom fracture prevention therapies are indicated. This article briefly reviews the epidemiology of osteoporosis and associated fractures in men, the association of bone mineral density with fractures in men, indications for bone densitometry among older men, and the interpretation of bone mineral density test results in men.
Key words: osteoporosis, bone mineral density, densitometry, men, fractures.