Osteoporos Int (2015) 26 (Suppl 1):S29–S33 DOI 10.1007/s00198-015-3060-y
World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO 2015): Plenary Lecture Abstracts
# International Osteoporosis Foundation and National Osteoporosis Foundation 2015
PL1 OSTEOPOROSIS OR SARCOPENIA: TWO DISORDERS OR ONE? R. Fielding1 1 Nutrition, Exercise, Physiology, and Sarcopenia Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University, Boston, MA, United States The loss of muscle mass (sarcopenia) and BMD parallel each other throughout the lifespan. Skeletal muscle is required for locomotion, oxygen consumption, whole body energy metabolism, and substrate turnover and storage. Robust skeletal muscle mass is essential for maintaining homeostasis and whole body health. Sarcopenia is associated with declines in physical functioning with advancing age. The underlying causes of sarcopenia are multifactorial and include decreased physical activity, increased cytokine activity, increased irregularity of muscle unit firing, and a decrease in anabolic hormones. There are several parallels with the age-associated declines in BMD and development of osteoporosis that suggest common underlying mechanisms contributing to bone and muscle loss. With the loss of muscle and bone mass and strength, a decrease in physical function and an increased risk of fracture and disability tends to be the result. The final common pathway resulting in fracture sits at the crossroads of bone loss and skeletal muscle dysfunction. Common underlying pathophysiological mechanisms and the large unmet clinical need will necessitate the examination of therapies that target both age-associated muscle and bone loss.
PL2 MANAGEMENT OF OSTEOPOROSIS IN RENAL FAILURE M. H. Lafage-Proust1 1 LBTO Inserm U1059 Université de Lyon, Saint Etienne, France Fractures, together with vascular calcifications constitute the main features of CKD mineral and bone disorders (CKDMBD) [1], a major complication of chronic uraemia, which severely affects patients’ morbidity and mortality [2]. Indeed, fracture risk increases as renal function declines from CKD stages 3 to 5. In dialysed patients, fractures occur roughly 10 years earlier and hip fracture risk is about 4.5 fold compared to that of non-uremic patients. Clinical risk factors for fractures consist of the “classical” ones (age, female gender, low BMI, vascular calcifications, drugs) and those specific to CKD such as dialysis vintage and kidney transplantation or parathyroïdectomy history. The biological mechanisms which underlie the bone histologic lesions (referred to as “renal osteodystrophy”-ROD-) are being progressively unravelled. Overall, ROD involves anomalies of turnover which can be too high (osteitis fibrosa or “mixed uremic lesions”) or too low (adynamic bone disease) and defects in bone primary (osteomalacia or “mixed uremic lesions”) and secondary mineralisation. They result from the severe dysregulation of calcium and phosphate metabolism which occurs as soon as the glomerular filtration rate (GFR) deteriorates [3]. Briefly, at earlier stages, the phosphate retention due to nephronic reduction, stimulates FGF23 secretion which exerts anti-vitamin D (VD) effects [4]. This, together
S30
with the resulting decrease in calcium intestinal absorption, triggers secondary hyperparathyroidism and leads to high bone turnover. Later on, CKD progressively causes the loss of various cell receptors (R). Indeed, parathormone (PTH)-R expression decreases in bone, which leads to skeletal resistance to PTH and may participate to the development of low bone turnover. In parathyroid glands, expression of VDR, calcium sensing R and FGF23 R wanes over time, which promotes gland autonomisation. Many other mechanisms are currently being explored such as the increase in circulating sclerostin and Dkk1, two members of the wnt signalling system, accumulation of SIBLINGs proteins in bone extracellular matrix, chronic inflammation and dysregulation of energetic metabolism. Bone status assessment in CKD may be difficult. BMD measurement by DXA was not recommended by KDIGO (the “Kidney Disease Improving Global Outcome” initiative) in 2009 [5] but recent papers showed that it predicts fractures in both dialysis [6], and predialysis [7,8] populations, as it does in the general population. The hip or the wrist may be the best sites, spine measurements being biased by superposition of aortic vascular calcifications. FRAX does not include CKD as a risk factor and may therefore underestimate the 10year probability of fracture [9]. Interestingly, it was also shown that testing of neuromuscular function may discriminate well among fractured and non-fractured patients with Stage 5 CKD on dialysis [10]. HRpQCT studies showed that cortical bone is affected early, with a reduction in cortical thickness and an increase in cortical porosity, as compared to control populations, which was positively correlated to the time-averaged levels of serum PTH [11]. PTH serum levels have long been a surrogate albeit flawed marker for evaluating bone turnover, due to the more or less marked skeletal resistance to PTH. When associated to serum PTH, Bone Alkaline Phosphatase serum levels, which do not depend on GFR, are better predictors of bone turnover than PTH alone [12]. Because of the lack of specificity of biological markers, iliac crest bone biopsy may be sometimes necessary for histological diagnosis of the ROD type especially when administration of anti-osteoporotic drug is considered. The aim of CKD-induced osteoporosis treatment is triple: 1) to fight against phosphate retention (diet and chelation of dietary phosphate) 2) to prevent secondary hyperparathyroidism via vitamin D (cholecalciferol and also one-alpha Vitamin D derivatives), calcium supplementation or even cinacalcet, a calcium sensing receptor agonist, 3) to treat bone fragility with anti-osteoporotic molecules. While the post- hoc analyses of pivotal studies suggested that bisphosphonates [13], denosumab [14] or teriparatide [15] are rather safe and efficacious in patients at CKD stage 2 and 3 (i.e., GFR >30 ml/min), there is no available information about drug safety or efficacy at stage 4 and 5 and all the more so in dialysed patients. Conclusion: Prospective studies evaluating anti-osteoporotic molecules, especially in patients at the later stages of the
Osteoporos Int (2015) 26 (Suppl 1):S29–S33
disease, are sorely lacking, making difficult if not impossible to rationally take care of CKD- associated osteoporosis. Thus, thorough tracking of secondary hyperparathyroidism and other fracture risk factors in CKD patients at early as possible in order to prevent worsening of bone fragility seems a reasonable recommendation. References: [1] Moe et al., Kidney Int 2006;69:1945 [2] Nair SS et al., Clin J Am Soc Nephrol 2013;8:1336. [3] Mac Way F et al., Joint Bone Spine 2012;79:544. [4] Isakova T et al., Kidney Int 2011;79:1370 [5] Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. Kidney Int Suppl 2009;113:S1-130 [6] Iimori S et al., Nephrol Dial Transplant 2012;27:345. [7] West SL et al., J Bone Miner Res 2014 [Epub ahead of print] [8] Yenchek RH et al., Clin J Am Soc Nephrol 2012;7:1130. [9] Jamal SA et al., Osteoporos Int 2014;25:71. [10] West SL et al., Nephrol Dial Transplant 2012;27:2384. [11] Nickolas TL et al., J Bone Miner Res 2013;28:1811 [12] Sardiwal S et al., Am J Kidney Dis 2013;62:810. [13] Miller PD, Bonekey Rep 2014;3:542. [14] Jamal SA et al., J Bone Miner Res 2011;26:1829 [15] Miller PD et al., Osteoporos Int 2007;18:59. Disclosures: Amgen, Research funding
PL3 BONE ANABOLIC THERAPIES FOR OSTEOPOROSIS S. Papapoulos1 1 Center for Bone Quality, Leiden University Medical Center, Leiden, Netherlands The aim of pharmacological management of osteoporosis is the reduction of the risk of fractures and associated clinical consequences. Most currently available agents inhibit bone resorption and bone turnover to varying degrees and decrease the risk of fractures. However, these agents do not stimulate the formation of new bone that is essential for the management of patients with severe disease and only modestly decrease the risk of nonvertebral fractures, the most frequent osteoporotic fractures that occur predominantly at cortical bone sites. For such patients, agents capable of stimulating new bone formation are required. Teriparatide, the most extensively studied bone forming treatment, stimulates not only bone formation but also bone resorption, acts mainly at bone sites undergoing active remodeling and increases cortical porosity. Studies with teriparatide raised the question whether concurrent inhibition of bone resorption might improve its effect on bone mass, particularly at cortical sites. Combination treatment with teriparatide and
Osteoporos Int (2015) 26 (Suppl 1):S29–S33
denosumab increased BMD at all skeletal sites considerably more than either monotherapy alone after 1 year suggesting that for optimal therapeutic outcome bone formation and bone resorption should be modulated in opposite directions. Human and animal genetics indicated that this aim may be achievable. The recognition of the role of the Wnt signaling pathway in bone formation provided a number of potential targets for the development of new bonebuilding pharmaceuticals. Such targets include sclerostin, Dkk1 and LRP4. For clinical use, however, treatments should not only modify the expression of target molecules but need also to have bone specificity to avoid potential off-target effects. The restricted expression of sclerostin in the skeleton and the lack of abnormalities in organs other that the skeleton in animals and patients with sclerostin deficiency made this protein the most attractive target for the development of new therapeutics. Inhibition of sclerostin in animal models stimulated trabecular and cortical bone formation and increased bone mass and strength. The majority of new bone formation was modeling-based, at quiescent surfaces, a property that differentiates an anabolic from a bone-forming therapy. Increased bone formation by treatment was not associated with an increase in bone resorption. Instead, a decrease of osteoclast surface was observed suggesting a functional uncoupling of bone resorption and formation with treatment. Two humanized antibodies to sclerostin, blosozumab and romosozumab, were investigated in phase I and II clinical studies. These antibodies given by subcutaneous injections every 2 or 4 weeks showed impressive increases in BMD at the spine and the hip after 1 year of treatment which exceeded increases previously observed with any other monotherapy. In addition, these studies provided important insights into the mechanism of action of these inhibitors and confirmed the transient dissociation of bone formation and resorption with treatment. Phase III clinical studies with fracture outcomes are currently underway with romosozumab. Apart from establishing the efficacy of these new molecules in the management of osteoporosis a critical issue for their introduction into clinical practice will be their tolerability and safety profile.
PL4 CAN WE ALTER THE NATURAL HISTORY OF OSTEOARTHRITIS? M. C. Hochberg1 1 Medicine and Epidemiology and Public Health, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine and Director, Medical Care Clinical Center, Veterans Affairs Maryland Health Care System, Baltimore, Maryland, United States
S31
Osteoarthritis (OA) can be defined as “a progressive disease representing the failed repair of joint damage that, in the preponderance of cases, has been triggered by abnormal intraarticular stress.” This presentation will review data from both observational epidemiologic studies and randomized clinical trials that support the use of nonpharmacologic, including surgical, and pharmacologic modalities in the alteration of the progression of OA.
PL5 IS IT TIME TO RESURRECT MENOPAUSE HORMONE THERAPY IN OSTEOPOROSIS? J. C. Stevenson1 1 National Heart & Lung Institute, Imperial College London, Royal Brompton Hospital, London, United Kingdom Objective: Bisphosphonates are a widely used treatment for postmenopausal osteoporosis. However, long term safety issues have become apparent. Material and Methods: An increased incidence of atrial fibrillation has been found in some clinical trials; osteonecrosis of the jaw has been increasingly seen particularly following dental extractions, and inflammatory eye disease has also been reported. These adverse effects, fortunately rare, are found mainly, or exclusively, with intravenous bisphosphonates. There are increasing numbers of reports of fragility fractures of the femur with long-term bisphosphonate use. These are probably due to over-suppression of bone turnover in certain susceptible individuals, and have also been seen with denosumab. Bisphosphonates have an extremely prolonged skeletal retention time, and since unexpected adverse effects could yet arise in the future they should be avoided where possible in women aged below 60 years. Results: Serious side-effects have been noted with strontium ranelate. Even calcium and vitamin D supplements have been shown to have safety issues with increases in renal calculi and possible increased risks for cardiovascular disease. Hormone replacement therapy (HRT) should remain the first-line therapy for primary prevention of osteoporosis, and is an effective and safe therapy providing it is used appropriately. There are no cardiovascular risks, and likely coronary benefits, when HRT is initiated early in the menopause; venous thrombo-embolic events can be avoided with low dose or non-oral HRT, and any possible small increased risk of breast cancer remains controversial and unproven. Newer agents which affect the Wnt-LRP signal to osteoblasts or block the osteoclast-produced cathepsin K protease are under development, but again there are safety issues. Thus newer agents may prove to have very potent bone effects but what will be their adverse effects? Conclusion: For most women, except for the elderly with severe osteoporosis, a step back to HRT seems the best management.
S32
Disclosures: Grants/Research Support: Abbott; Speakers Bureau/Honoraria: Abbott, Amgen, Bayer, Novo Nordisk, Pfizer and Theramex; Consulting Fees: Abbott, Pfizer
PL6 HOW LONG SHOULD WE TREAT OSTEOPOROTIC PATIENTS? M. L. Brandi1 1 Department of Surgery and Translational Medicine, University of Florence, Florence, Italy The agents shown to reduce the risk of fragility fractures include the bisphosphonates alendronate, ibandronate, risedronate and zoledronic acid; raloxifene; strontium ranelate; teriparatide and denosumab. Currently available treatments are all very effective, with several agents safety yielding 40 to 69 % reductions in the risk of fractures. The choice of the drug is based on BMD and clinical risk factors, effectiveness, costs, reimbursement policy and adverse effects. The length of treatment is, however, not defined. Should the patients be treated lifetime? Should the treatment be safe if prolonged over the duration of the controlled clinical trials (a minimum of 3 years)? Do validated surrogate measures exist? Establishing treatment targets, often intended as “treat to target” would simplify clinical decision making. There are not validated surrogate measures in osteoporosis and this is becoming an area of ongoing and much needed research. At the moment reasons for interrupting a therapy include treatment failures, as in patients who lose bone density or fracture on treatment. However, BMD alone cannot be considered an adequate surrogate measure for clinically relevant endpoints: QOL, function, or survival. Similarly, FRAX is not responsive enough to be used as a target for goal-directed treatment. Another factor influencing duration of treatment is the recognition of side effects that emerge in long-term use, as it happened for bisphosphonates and denosumab. Because bisphosphonates accumulate in bone and are released for years after treatment interruption, it make sense to consider the practical question of how long to treat. The indication is that patients at mild risk might interrupt the therapy after 3– 5 years and remain without treatment as long as BMD is stable and no fractures occur. Conversely, high risk patients should be treated even longer and probably be on a nonbisphosphonate treatment during drug holiday. The only drug for which an indication for length of treatment exists is teriparatide, that cannot be administered for more than 2 years. In conclusion, there is considerable controversy regarding the optimal duration of therapy and the length of the holiday, both
Osteoporos Int (2015) 26 (Suppl 1):S29–S33
of which should be based on individual assessment of risk and benefit.
PL7 INFLAMMATION AND BONE FRAGILITY C. Roux1 1 Paris Descartes Université, Paris, France Systemic inflammation as observed in inflammatory rheumatic disorders is associated with increased risk of osteoporosis and fractures. In rheumatoid arthritis, periarticular bone loss, bone erosions, and systemic osteoporosis are observed, with an increased risk of fractures. Determinants of fractures are underlying conditions (as RA has a female preponderance and an increased prevalence with age), severity of the disease, and use of glucocorticoids. However, bone loss can occur even in glucocorticoidnaive patients. Prospective data show that the optimal control of inflammation in RA is associated with decrease in structural damage and bone loss. There is a strong rationale for these clinical observations, as osteoclastogenesis and osteoclasts activity are under the control of RANK L produced by other cells than osteocytes, such as fibroblasts and activated T lymphocytes. Moreover auto antibodies against citrullinated proteins can also activate bone resorption. Finally inflammatory cytokines up regulate sclerostin and thus produce a decrease in bone formation. Thus the consequence of inflammation is an uncoupling bone remodeling. These data must be taken into account in patients with glucocorticoid therapy; their dramatic increased risk of fracture must be assessed in the perspective of the deleterious effect of the underlying inflammation.
PL8 GUIDELINE DIVERSITY IN GLUCOCORTICOIDINDUCED OSTEOPOROSIS C. Cooper1,2 1 MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom, 2 Department of Musculoskeletal Science, University of Oxford, Oxford, United Kingdom Oral glucocorticoids are prescribed for a wide variety of medical disorders, and the prevalence of use has been estimated as 4.6 % among postmenopausal women. Fracture risk increases during the first 6 months of glucocorticoid therapy; decreases following withdrawal; and is strongly associated with dose. Guidelines for GIOP stress the importance of initiating osteoporosis prophylaxis in patients receiving chronic glucocorticoid therapy. The most recent recommendations from the
Osteoporos Int (2015) 26 (Suppl 1):S29–S33
American College of Rheumatology stratify intervention by glucocorticoid dose and fracture risk, based on the FRAX risk assessment tool. Low and medium risk patients (20 %) are treated at a glucocorticoid dose of 5 mg daily. In contrast, the IOF/ECTS guidelines recommend that all post-
S33
menopausal women and men aged 50 years and over who are exposed to 3 months or more of oral glucocorticoids should undergo risk assessment by FRAX, and therapeutic intervention on the basis of fracture history, age and glucocorticoid dose. Intervention thresholds are country-specific. The use of these guidelines will permit the delivery of effective pharmacological interventions for GIOP in a rational and cost effective manner.
World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO 2015): Plenary Lecture Abstracts
# International Osteoporosis Foundation and National Osteoporosis Foundation 2015
PL1 OSTEOPOROSIS OR SARCOPENIA: TWO DISORDERS OR ONE? R. Fielding1 1 Nutrition, Exercise, Physiology, and Sarcopenia Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University, Boston, MA, United States The loss of muscle mass (sarcopenia) and BMD parallel each other throughout the lifespan. Skeletal muscle is required for locomotion, oxygen consumption, whole body energy metabolism, and substrate turnover and storage. Robust skeletal muscle mass is essential for maintaining homeostasis and whole body health. Sarcopenia is associated with declines in physical functioning with advancing age. The underlying causes of sarcopenia are multifactorial and include decreased physical activity, increased cytokine activity, increased irregularity of muscle unit firing, and a decrease in anabolic hormones. There are several parallels with the age-associated declines in BMD and development of osteoporosis that suggest common underlying mechanisms contributing to bone and muscle loss. With the loss of muscle and bone mass and strength, a decrease in physical function and an increased risk of fracture and disability tends to be the result. The final common pathway resulting in fracture sits at the crossroads of bone loss and skeletal muscle dysfunction. Common underlying pathophysiological mechanisms and the large unmet clinical need will necessitate the examination of therapies that target both age-associated muscle and bone loss.
PL2 MANAGEMENT OF OSTEOPOROSIS IN RENAL FAILURE M. H. Lafage-Proust1 1 LBTO Inserm U1059 Université de Lyon, Saint Etienne, France Fractures, together with vascular calcifications constitute the main features of CKD mineral and bone disorders (CKDMBD) [1], a major complication of chronic uraemia, which severely affects patients’ morbidity and mortality [2]. Indeed, fracture risk increases as renal function declines from CKD stages 3 to 5. In dialysed patients, fractures occur roughly 10 years earlier and hip fracture risk is about 4.5 fold compared to that of non-uremic patients. Clinical risk factors for fractures consist of the “classical” ones (age, female gender, low BMI, vascular calcifications, drugs) and those specific to CKD such as dialysis vintage and kidney transplantation or parathyroïdectomy history. The biological mechanisms which underlie the bone histologic lesions (referred to as “renal osteodystrophy”-ROD-) are being progressively unravelled. Overall, ROD involves anomalies of turnover which can be too high (osteitis fibrosa or “mixed uremic lesions”) or too low (adynamic bone disease) and defects in bone primary (osteomalacia or “mixed uremic lesions”) and secondary mineralisation. They result from the severe dysregulation of calcium and phosphate metabolism which occurs as soon as the glomerular filtration rate (GFR) deteriorates [3]. Briefly, at earlier stages, the phosphate retention due to nephronic reduction, stimulates FGF23 secretion which exerts anti-vitamin D (VD) effects [4]. This, together
S30
with the resulting decrease in calcium intestinal absorption, triggers secondary hyperparathyroidism and leads to high bone turnover. Later on, CKD progressively causes the loss of various cell receptors (R). Indeed, parathormone (PTH)-R expression decreases in bone, which leads to skeletal resistance to PTH and may participate to the development of low bone turnover. In parathyroid glands, expression of VDR, calcium sensing R and FGF23 R wanes over time, which promotes gland autonomisation. Many other mechanisms are currently being explored such as the increase in circulating sclerostin and Dkk1, two members of the wnt signalling system, accumulation of SIBLINGs proteins in bone extracellular matrix, chronic inflammation and dysregulation of energetic metabolism. Bone status assessment in CKD may be difficult. BMD measurement by DXA was not recommended by KDIGO (the “Kidney Disease Improving Global Outcome” initiative) in 2009 [5] but recent papers showed that it predicts fractures in both dialysis [6], and predialysis [7,8] populations, as it does in the general population. The hip or the wrist may be the best sites, spine measurements being biased by superposition of aortic vascular calcifications. FRAX does not include CKD as a risk factor and may therefore underestimate the 10year probability of fracture [9]. Interestingly, it was also shown that testing of neuromuscular function may discriminate well among fractured and non-fractured patients with Stage 5 CKD on dialysis [10]. HRpQCT studies showed that cortical bone is affected early, with a reduction in cortical thickness and an increase in cortical porosity, as compared to control populations, which was positively correlated to the time-averaged levels of serum PTH [11]. PTH serum levels have long been a surrogate albeit flawed marker for evaluating bone turnover, due to the more or less marked skeletal resistance to PTH. When associated to serum PTH, Bone Alkaline Phosphatase serum levels, which do not depend on GFR, are better predictors of bone turnover than PTH alone [12]. Because of the lack of specificity of biological markers, iliac crest bone biopsy may be sometimes necessary for histological diagnosis of the ROD type especially when administration of anti-osteoporotic drug is considered. The aim of CKD-induced osteoporosis treatment is triple: 1) to fight against phosphate retention (diet and chelation of dietary phosphate) 2) to prevent secondary hyperparathyroidism via vitamin D (cholecalciferol and also one-alpha Vitamin D derivatives), calcium supplementation or even cinacalcet, a calcium sensing receptor agonist, 3) to treat bone fragility with anti-osteoporotic molecules. While the post- hoc analyses of pivotal studies suggested that bisphosphonates [13], denosumab [14] or teriparatide [15] are rather safe and efficacious in patients at CKD stage 2 and 3 (i.e., GFR >30 ml/min), there is no available information about drug safety or efficacy at stage 4 and 5 and all the more so in dialysed patients. Conclusion: Prospective studies evaluating anti-osteoporotic molecules, especially in patients at the later stages of the
Osteoporos Int (2015) 26 (Suppl 1):S29–S33
disease, are sorely lacking, making difficult if not impossible to rationally take care of CKD- associated osteoporosis. Thus, thorough tracking of secondary hyperparathyroidism and other fracture risk factors in CKD patients at early as possible in order to prevent worsening of bone fragility seems a reasonable recommendation. References: [1] Moe et al., Kidney Int 2006;69:1945 [2] Nair SS et al., Clin J Am Soc Nephrol 2013;8:1336. [3] Mac Way F et al., Joint Bone Spine 2012;79:544. [4] Isakova T et al., Kidney Int 2011;79:1370 [5] Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. Kidney Int Suppl 2009;113:S1-130 [6] Iimori S et al., Nephrol Dial Transplant 2012;27:345. [7] West SL et al., J Bone Miner Res 2014 [Epub ahead of print] [8] Yenchek RH et al., Clin J Am Soc Nephrol 2012;7:1130. [9] Jamal SA et al., Osteoporos Int 2014;25:71. [10] West SL et al., Nephrol Dial Transplant 2012;27:2384. [11] Nickolas TL et al., J Bone Miner Res 2013;28:1811 [12] Sardiwal S et al., Am J Kidney Dis 2013;62:810. [13] Miller PD, Bonekey Rep 2014;3:542. [14] Jamal SA et al., J Bone Miner Res 2011;26:1829 [15] Miller PD et al., Osteoporos Int 2007;18:59. Disclosures: Amgen, Research funding
PL3 BONE ANABOLIC THERAPIES FOR OSTEOPOROSIS S. Papapoulos1 1 Center for Bone Quality, Leiden University Medical Center, Leiden, Netherlands The aim of pharmacological management of osteoporosis is the reduction of the risk of fractures and associated clinical consequences. Most currently available agents inhibit bone resorption and bone turnover to varying degrees and decrease the risk of fractures. However, these agents do not stimulate the formation of new bone that is essential for the management of patients with severe disease and only modestly decrease the risk of nonvertebral fractures, the most frequent osteoporotic fractures that occur predominantly at cortical bone sites. For such patients, agents capable of stimulating new bone formation are required. Teriparatide, the most extensively studied bone forming treatment, stimulates not only bone formation but also bone resorption, acts mainly at bone sites undergoing active remodeling and increases cortical porosity. Studies with teriparatide raised the question whether concurrent inhibition of bone resorption might improve its effect on bone mass, particularly at cortical sites. Combination treatment with teriparatide and
Osteoporos Int (2015) 26 (Suppl 1):S29–S33
denosumab increased BMD at all skeletal sites considerably more than either monotherapy alone after 1 year suggesting that for optimal therapeutic outcome bone formation and bone resorption should be modulated in opposite directions. Human and animal genetics indicated that this aim may be achievable. The recognition of the role of the Wnt signaling pathway in bone formation provided a number of potential targets for the development of new bonebuilding pharmaceuticals. Such targets include sclerostin, Dkk1 and LRP4. For clinical use, however, treatments should not only modify the expression of target molecules but need also to have bone specificity to avoid potential off-target effects. The restricted expression of sclerostin in the skeleton and the lack of abnormalities in organs other that the skeleton in animals and patients with sclerostin deficiency made this protein the most attractive target for the development of new therapeutics. Inhibition of sclerostin in animal models stimulated trabecular and cortical bone formation and increased bone mass and strength. The majority of new bone formation was modeling-based, at quiescent surfaces, a property that differentiates an anabolic from a bone-forming therapy. Increased bone formation by treatment was not associated with an increase in bone resorption. Instead, a decrease of osteoclast surface was observed suggesting a functional uncoupling of bone resorption and formation with treatment. Two humanized antibodies to sclerostin, blosozumab and romosozumab, were investigated in phase I and II clinical studies. These antibodies given by subcutaneous injections every 2 or 4 weeks showed impressive increases in BMD at the spine and the hip after 1 year of treatment which exceeded increases previously observed with any other monotherapy. In addition, these studies provided important insights into the mechanism of action of these inhibitors and confirmed the transient dissociation of bone formation and resorption with treatment. Phase III clinical studies with fracture outcomes are currently underway with romosozumab. Apart from establishing the efficacy of these new molecules in the management of osteoporosis a critical issue for their introduction into clinical practice will be their tolerability and safety profile.
PL4 CAN WE ALTER THE NATURAL HISTORY OF OSTEOARTHRITIS? M. C. Hochberg1 1 Medicine and Epidemiology and Public Health, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine and Director, Medical Care Clinical Center, Veterans Affairs Maryland Health Care System, Baltimore, Maryland, United States
S31
Osteoarthritis (OA) can be defined as “a progressive disease representing the failed repair of joint damage that, in the preponderance of cases, has been triggered by abnormal intraarticular stress.” This presentation will review data from both observational epidemiologic studies and randomized clinical trials that support the use of nonpharmacologic, including surgical, and pharmacologic modalities in the alteration of the progression of OA.
PL5 IS IT TIME TO RESURRECT MENOPAUSE HORMONE THERAPY IN OSTEOPOROSIS? J. C. Stevenson1 1 National Heart & Lung Institute, Imperial College London, Royal Brompton Hospital, London, United Kingdom Objective: Bisphosphonates are a widely used treatment for postmenopausal osteoporosis. However, long term safety issues have become apparent. Material and Methods: An increased incidence of atrial fibrillation has been found in some clinical trials; osteonecrosis of the jaw has been increasingly seen particularly following dental extractions, and inflammatory eye disease has also been reported. These adverse effects, fortunately rare, are found mainly, or exclusively, with intravenous bisphosphonates. There are increasing numbers of reports of fragility fractures of the femur with long-term bisphosphonate use. These are probably due to over-suppression of bone turnover in certain susceptible individuals, and have also been seen with denosumab. Bisphosphonates have an extremely prolonged skeletal retention time, and since unexpected adverse effects could yet arise in the future they should be avoided where possible in women aged below 60 years. Results: Serious side-effects have been noted with strontium ranelate. Even calcium and vitamin D supplements have been shown to have safety issues with increases in renal calculi and possible increased risks for cardiovascular disease. Hormone replacement therapy (HRT) should remain the first-line therapy for primary prevention of osteoporosis, and is an effective and safe therapy providing it is used appropriately. There are no cardiovascular risks, and likely coronary benefits, when HRT is initiated early in the menopause; venous thrombo-embolic events can be avoided with low dose or non-oral HRT, and any possible small increased risk of breast cancer remains controversial and unproven. Newer agents which affect the Wnt-LRP signal to osteoblasts or block the osteoclast-produced cathepsin K protease are under development, but again there are safety issues. Thus newer agents may prove to have very potent bone effects but what will be their adverse effects? Conclusion: For most women, except for the elderly with severe osteoporosis, a step back to HRT seems the best management.
S32
Disclosures: Grants/Research Support: Abbott; Speakers Bureau/Honoraria: Abbott, Amgen, Bayer, Novo Nordisk, Pfizer and Theramex; Consulting Fees: Abbott, Pfizer
PL6 HOW LONG SHOULD WE TREAT OSTEOPOROTIC PATIENTS? M. L. Brandi1 1 Department of Surgery and Translational Medicine, University of Florence, Florence, Italy The agents shown to reduce the risk of fragility fractures include the bisphosphonates alendronate, ibandronate, risedronate and zoledronic acid; raloxifene; strontium ranelate; teriparatide and denosumab. Currently available treatments are all very effective, with several agents safety yielding 40 to 69 % reductions in the risk of fractures. The choice of the drug is based on BMD and clinical risk factors, effectiveness, costs, reimbursement policy and adverse effects. The length of treatment is, however, not defined. Should the patients be treated lifetime? Should the treatment be safe if prolonged over the duration of the controlled clinical trials (a minimum of 3 years)? Do validated surrogate measures exist? Establishing treatment targets, often intended as “treat to target” would simplify clinical decision making. There are not validated surrogate measures in osteoporosis and this is becoming an area of ongoing and much needed research. At the moment reasons for interrupting a therapy include treatment failures, as in patients who lose bone density or fracture on treatment. However, BMD alone cannot be considered an adequate surrogate measure for clinically relevant endpoints: QOL, function, or survival. Similarly, FRAX is not responsive enough to be used as a target for goal-directed treatment. Another factor influencing duration of treatment is the recognition of side effects that emerge in long-term use, as it happened for bisphosphonates and denosumab. Because bisphosphonates accumulate in bone and are released for years after treatment interruption, it make sense to consider the practical question of how long to treat. The indication is that patients at mild risk might interrupt the therapy after 3– 5 years and remain without treatment as long as BMD is stable and no fractures occur. Conversely, high risk patients should be treated even longer and probably be on a nonbisphosphonate treatment during drug holiday. The only drug for which an indication for length of treatment exists is teriparatide, that cannot be administered for more than 2 years. In conclusion, there is considerable controversy regarding the optimal duration of therapy and the length of the holiday, both
Osteoporos Int (2015) 26 (Suppl 1):S29–S33
of which should be based on individual assessment of risk and benefit.
PL7 INFLAMMATION AND BONE FRAGILITY C. Roux1 1 Paris Descartes Université, Paris, France Systemic inflammation as observed in inflammatory rheumatic disorders is associated with increased risk of osteoporosis and fractures. In rheumatoid arthritis, periarticular bone loss, bone erosions, and systemic osteoporosis are observed, with an increased risk of fractures. Determinants of fractures are underlying conditions (as RA has a female preponderance and an increased prevalence with age), severity of the disease, and use of glucocorticoids. However, bone loss can occur even in glucocorticoidnaive patients. Prospective data show that the optimal control of inflammation in RA is associated with decrease in structural damage and bone loss. There is a strong rationale for these clinical observations, as osteoclastogenesis and osteoclasts activity are under the control of RANK L produced by other cells than osteocytes, such as fibroblasts and activated T lymphocytes. Moreover auto antibodies against citrullinated proteins can also activate bone resorption. Finally inflammatory cytokines up regulate sclerostin and thus produce a decrease in bone formation. Thus the consequence of inflammation is an uncoupling bone remodeling. These data must be taken into account in patients with glucocorticoid therapy; their dramatic increased risk of fracture must be assessed in the perspective of the deleterious effect of the underlying inflammation.
PL8 GUIDELINE DIVERSITY IN GLUCOCORTICOIDINDUCED OSTEOPOROSIS C. Cooper1,2 1 MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom, 2 Department of Musculoskeletal Science, University of Oxford, Oxford, United Kingdom Oral glucocorticoids are prescribed for a wide variety of medical disorders, and the prevalence of use has been estimated as 4.6 % among postmenopausal women. Fracture risk increases during the first 6 months of glucocorticoid therapy; decreases following withdrawal; and is strongly associated with dose. Guidelines for GIOP stress the importance of initiating osteoporosis prophylaxis in patients receiving chronic glucocorticoid therapy. The most recent recommendations from the
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American College of Rheumatology stratify intervention by glucocorticoid dose and fracture risk, based on the FRAX risk assessment tool. Low and medium risk patients (20 %) are treated at a glucocorticoid dose of 5 mg daily. In contrast, the IOF/ECTS guidelines recommend that all post-
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menopausal women and men aged 50 years and over who are exposed to 3 months or more of oral glucocorticoids should undergo risk assessment by FRAX, and therapeutic intervention on the basis of fracture history, age and glucocorticoid dose. Intervention thresholds are country-specific. The use of these guidelines will permit the delivery of effective pharmacological interventions for GIOP in a rational and cost effective manner.
