Vol 34, No. 2, 2012 Medicographia 111 A Servier publication Bone: a story of breakthroughs, a promising future EDITORIAL 135 Fifty years of discoveries in osteoporosis Cinquante ans de découvertes dans l’ostéoporose P. J. Meunier, France THEMEDARTICLES 142 Bone biology: from macrostructure to gene expression J. E. Fonseca, Portugal 149 Bone remodeling: a social network of cells P. J. Marie, France 155 The complexity and heterogeneity of bone material P. Roschger, B. M. Misof, K. Klaushofer, Austria 163 The fragile beauty of bone architecture N. Dion, L. G. Ste-Marie, Canada 170 Bone imaging - the closest thing to art in medicine J. F. Griffith, T. M. Link, H. K. Genant, Hong Kong and USA 178 Light and resistant: is bone the perfect material? P. Ammann, Switzerland 185 An architect’s dream: a self-repairing structure J. M. Féron, France Contents continued on next page Vol 34, No. 2, 2012 Medicographia 111 A Servier publication CONTROVERSIAL QUESTION 191 Is systematic supplementation with calcium/vitamin D necessary to treat postmenopausal osteoporosis? S. Y. Chia, Singapore - A. Gur, Turkey - P. Lakatos, Hungary - O. M. Lesnyak, Russian Federation - R. S. Mason, Australia - J. L. A. Morales-Torres, Mexico - R. Nuti, Italy - R. Sánchez-Borrego, Spain - M. E. Simões, Portugal - T. J. de Villiers, South Africa - S. S. Yeap, Malaysia PROTELOS 203 Comprehensive antifracture efficacy, improvement of bone quality: Protelos, a first-line treatment in osteoporosis M. Hueber, France INTERVIEW 213 Nutrition influence on bone health R. Rizzoli, Switzerland FOCUS 221 Almost invisible, often ignored: periosteum, the living lace of bone D. B. Burr, G. M. Guillot, USA UPDATE 228 The osteocyte: doing the hard work backstage M. Prideaux, L. F. Bonewald, USA A TOUCH OF FRANCE 238 How did Gallo-Roman physicians treat their patients? A look into the earliest pharmacopoeias of France D. Gourevitch, France 250 Lutetia, the Gallo-Roman ancestor of Paris G. Coulon, France EDITORIAL Issues confronting post- menopausal women represent one of the fastest growing areas of bio- medical investigation. In the last 50 ‘‘years basic and clinical research in Fifty years of discoveries osteoporosis has been extremely productive, generating new bone modeling concepts, new defini- in osteoporosis tions combining BMD values with clinical evaluation of fracture risk factors, and effective new tools for prevention and treatment, reduc- ing an average patient’s lifetime number of fractures by one or two.” by P. J. Meunier, France he continuous increase in life expectancy during the last five decades for females and males in developed countries—about 12 years—has made T osteoporosis a major health issue. The age-related increase in fracture risk has had significant medical and economic consequences. These observa- tions and the pessimistic predictions of the epidemiologists could lead us to con- sider fragility fractures of spine, hip, humerus, or wrist as an inevitable price to pay for a longer life. Fortunately, this pessimism is unjustified because the last 50 years have seen ma- jor advances in the diagnosis of osteoporosis, now defined in terms of fracture risk Pierre J. MEUNIER, MD factors that can be detected before a fracture occurs. The first fracture is an irre- Emeritus Professor, Lyon I versible event that also heralds subsequent fractures. University, Honorary Head of Bone and Joint Department Lyon Hospitals Major advances have also been accomplished in understanding normal bone re- FRANCE modeling, the cellular mechanisms of postmenopausal and age-related bone loss, the pathophysiology of most forms of fragile bone disease, and in the discovery of the mechanisms of action of several new drugs offering effective prevention and treatment of fragility fractures. Bone densitometry provides an accurate and reproducible measure of bone miner- al density (BMD) with minimal radiation exposure. It became established in the early 1990s as a tool for diagnosing prefracture osteoporosis. In 1992, a working group of the World Health Organization (WHO) proposed diagnosing osteoporosis in women on the basis of a BMD 2.5 or more standard deviations below the mean values of a young reference population (T-score below 2.5 sd).1 More recently, in 2010, the WHO Fracture Risk Assessment Tool (FRAX) was shown to be more accurate than BMD alone in predicting 10-year fragility fracture risk: in addition to BMD, the FRAX tool incorporates age, sex, body mass index, long-term steroid use, smoking, alco- holism, any fracture after 50 years, and history of parental hip fracture.2 There have been parallel improvements in understanding the cellular events respon- sible for age-related bone loss, bone disease histopathogenesis, and the long-term Address for correspondence: Pierre J. Meunier, Chancelades, effects of new osteotropic agents. These developments include the discovery of the 48130 Aumont-Aubrac, intermediary level of bone organization, new methods of preparing undercalcified France (e-mail: meunier@ recherche.univ-lyon1.fr) bone sections, quantitative and dynamic evaluation of bone formation using in vivo prebiopsy tetracycline double labeling, measurement of microstructure and miner- Medicographia. 2012;34:135-141 alization parameters on bone biopsy microradiographs, and overall improvement in www.medicographia.com the range of bone quality assessment parameters. Fifty years of discoveries in osteoporosis – Meunier MEDICOGRAPHIA, Vol 34, No.2, 2012 135 E DITORIAL In 1964, using rib cortical bone sections, Harold Frost showed remodeling generally. By decreasing bone turnover they de- that the human adult skeleton is in a dynamic state, being crease bone loss and increase the degree of mineralization continually broken down and reformed by the coordinated ac- of bone.13,14 Most extensively studied to date have been the tivities of osteoclasts and osteoblasts on trabecular surfaces aminobisphosphonates (pamidronate, alendronate), followed and the Haversian systems of cortical compact bone.3,4 This by clodronate, risedronate, ibandronate, and zoledronate. The turnover, or remodeling, occurs in focal and discrete pack- first controlled clinical study was performed with the first-gen- ets, or bone multicellular units (BMU), throughout the adult eration bisphosphonate etidronate, launched in France in skeleton. The remodeling of each BMU takes a finite period 1981. It showed a favorable effect on spinal BMD and a mod- of time estimated as 3 to 4 months, and is topographically est decrease in vertebral fracture rate. In contrast, oral alen- and chronologically distinct from the remodeling in neighbor- dronate, daily (10 mg/day) or weekly (70 mg/week), halved ing BMUs. The new bone formed by a BMU is known as a spine, hip, and distal radius fracture rates.12 Oral risedronate bone structure unit (BSU) in trabecular bone and an osteon in (5 mg/day or 35 mg/week) also reduced vertebral and non- cortical bone. BSUs are the end products of osteoblast activ- vertebral fracture rates in postmenopausal osteoporosis. Al- ity occurring exclusively at sites of recent osteoclast resorption. endronate and risedronate products were recently supple- The last five decades have seen marked progress in quan- mented with vitamin D and calcium due to the high incidence titative histology or bone histomorphometry thanks to new of vitamin D insufficiency among the elderly.15 An American epi- methods of preparing undercalcified bone sections. Quan- demiological survey in 460 584 women recently estimated that titative evaluation of bone formation using tetracycline dou- oral bisphosphonates prevented 144 000 fractures from 2001 ble labeling provides a direct measure of the mineral apposi- to 2008 in women aged 45 years or more.16 The post-launch tion rate and mineralizing trabecular surface. Introduction of years have revealed extremely rare side effects from long-term the time dimension into quantitative histological analysis is cru- use, including osteonecrosis of the jaw and intertrochanteric cial to the dynamic evaluation of bone formation and remod- fractures of the femur, each presumed due to oversuppres- eling at the BMU/BSU level. Neither noninvasive BMD meas- sion of bone remodeling. urement nor the specific and sensitive assays for circulating and urinary bone turnover markers developed in the 1980s5,6 Over the last 50 years, several other antiosteoporotic com- can identify abnormal bone remodeling at the BMU/BSU lev- pounds have been launched and/or withdrawn after controlled el because they each reflect events at the whole-skeleton lev- studies of fracture rates as the primary end point. Thus, be- el. Bone turnover markers are clinically useful in following up tween 1980 and 2011, I was directly involved in histological individual patients receiving antiosteoporosis therapy, but not studies on the effects of parathyroid hormone (PTH) and flu- for diagnosing osteoporosis.7 The advances accomplished in oride salts. In 1980 we reported a 70% increase in iliac can- the histomorphometric approach of bone remodeling have cellous bone volume after injections of PTH at an average also included the measurement of histological parameters of dose of 500 U daily for 6 months, with marked extension of microstructure reflecting the connectivity or the thickness of trabecular mineralizing surfaces on unstained sections of bone the trabeculae, the mean wall thickness of the BSUs, and the biopsies examined under fluorescence after tetracycline dou- number of microcracks. ble labeling.17 It was not until