Osteoporosis ('brittle bone disease') research and treatment is in a period of rapid change and advance. Long supposed to be a natural accompaniment of ageing, especially in women, it is now recognised as a distinct pathology that is both treatable and preventable. The costs to society and the individual of ignoring the onset of this disease are very large, with hip or spinal fractures requiring costly hospital or outpatient treatment as a typical outcome, but also with frequent permanent disability or disfigurement and even death (after hip fracture).
Osteoporosis is predominantly a disease of the elderly and affects women more frequently than men. The course of the disease typically accelerates after menopause in women, but it is increasingly understood that men may experience osteoporotic bone loss as well, as they age. A 50-year old woman has a one in six chance of breaking a hip during her lifetime, and the chance increases to one in three by the age of 80. With substantial increases expected in the number of elderly people in many countries around the world, osteoporosis threatens to put great burdens on the healthcare systems of many countries over the next 50 years.
However, considerable progress is being made in diagnosing and managing the disease, with several important new or improved therapeutic agents having been introduced since 1995 and others likely to follow over the next three to five years. This report examines the latest findings about the extent of the disease, methods to diagnose it and new therapeutic possibilities.
In 1994 the World Health Organization (WHO) propagated an operational definition of osteoporosis that had an enormous impact on both the investigation and management of the disease. This definition proposed that the disease should be regarded as being present in all individuals with a bone mass density below a benchmark level defined in young, healthy adults, whether or not they exhibited the fractures which are otherwise the only clinical sign of osteoporosis.
This change of perspective had the consequence of greatly increasing estimates of the number of individuals affected, as well as providing a single diagnostic criterion, and at the same time changed the focus of therapy to that of preventing or reversing bone loss (quantitated as bone mineral density � BMD). This has greatly increased the demand for instrumentation to measure BMD at relevant sites and has provided a yardstick by which the efficacy of therapeutic agents can be judged within a relatively short timescale. Chapter 1 of this report examines the methodology of BMD measurement, which has been greatly refined in recent years with the resolution of a number of problems of standardisation and interpretation, and examines whether BMD is a good predictor of the likelihood of osteoporotic fracture. It also reviews recent data on the incidence and prevalence of hip, spine and other fractures, and the substantial costs they impose on the healthcare system. In the US, the direct medical costs to the health system of osteoporotic fractures has been estimated in a recent study as being almost $14 billion per year; in the European Union (EU), the hospital costs of hip fractures alone have been assessed as being equivalent to about $3.9 billion a year.
Given the enormous impact of osteoporosis, Chapter 2 of the report asks what can be done to prevent and treat bone loss in the light of current knowledge about the factors that cause or aggravate osteoporosis. Effective primary prevention rests on both achieving an optimal peak bone mass in early adult life and making lifestyle choices that will preserve this as far as possible throughout the rest of life. Worryingly, recent surveys indicate that today's adolescents risk not achieving maximal bone health, and are adopting lifestyles that may increase the risk of osteoporosis later in life. Moreover, fears about the possible risks of hormone replacement therapy (HRT) are widespread, so that many women are reluctant to start this preventive treatment in their early post-menopausal years or, having started, soon discontinue. Later still, there is evidence that many elderly people, particularly those who are housebound or in residential care, are deficient in diet-derived calcium and vitamin D, which are vital for the maintenance of bone health.
Against this dismal background, there is much debate as to how scarce funding should be spent to best effect: should osteoporosis treatments be targeted to those at the highest risk, or would a population-based intervention bring greater gains? Should population screening for low BMD be implemented, as has been done for breast cancer screening? What is the right approach for osteoporosis treatment in men, where the extent of the problem is becoming better known, but where clinical data is largely lacking? Should preventive therapy be given automatically to patients put on high-dose corticosteroid treatment, known to cause osteoporosis? These are some of the dilemmas being debated at present; guidelines for primary care physicians are under development in a number of countries to encapsulate 'best practice'.
There are five main drug treatment options for osteoporosis available at present: HRT, calcitonin, bisphosphonates, the newly-introduced selective oestrogen receptor modulator (SERM), raloxifene (Evista, Eli Lilly), and the long-established calcium and vitamin D supplements. Chapter 3 reviews the many products available, paying particular attention to new clinical data reported for these drugs.
The risks and benefits of HRT are particularly controversial. Recent publications suggest both that the much-advertised protective benefits on heart disease and dementia may not be soundly based, and that the risk of developing breast cancer may be increased in long-term users. In view of the impact these assertions might have on the acceptability of this key therapy, the main arguments are summarised and bibliographic references are given so that these reports can be located for further consideration. Chapter 3 also describes the various types of HRT products available and summarises new publications on the efficacy of HRT in preventing osteoporotic fractures.
The remainder of the chapter reviews new clinical data with the other drug classes and highlights the convincing results reported for the bisphosphonate, alendronate (Fosamax, Merck), whose sales have grown rapidly since its introduction in 1995. New clinical results showing the importance of the older calcium supplements are also reviewed, and the chapter concludes with an overview of some new clinical data on the less frequently used agents, tibolone (Livial, Organon), ipriflavone and fluoride.
Chapter 4 of the report considers new agents in late-stage clinical trials that may be introduced within the next three to five years, as well as major trials with existing therapeutic agents that may shed further light on their clinical usefulness. Several very large studies are in progress with HRT products to try to answer some of the doubts raised about their risks and benefits, however these will not give results until the latter part of the next decade.
New treatment options are expected in calcitonins, with the development of oral forms of the drug. Three new bisphosphonates are also in late-stage clinical development and should enter the market in the early years of the next century. Follow-up SERMs are also nearing submission for regulatory approval. Parathyroid hormone (PTH) is also nearing the market; this drug will constitute a new therapeutic category, since it acts to stimulate bone formation rather than inhibit bone resorption.
Much has been learned in recent years about the biology of bone remodelling. Research into factors affecting osteoclast formation and osteoblast activity (the cell types that are responsible for bone breakdown and formation) has suggested a number of new targets for therapeutic intervention in osteoporosis. Molecules involved in these processes, such as interleukins (Ils), growth factors, protease inhibitors and osteoprotegerin are in preclinical research, but will not affect clinical practice for some years.
The osteoporosis market is quite diverse; Chapter 5 discusses the various segments involved, factors affecting market dynamics, and the major products. The impact of demographic change is highlighted, and a model of demand is discussed which indicates that the market can be expected to grow significantly over the coming years. This growth will depend partly on educational efforts at all levels, both to generate support for the increased resources required for this to happen, and to spread information to general practitioners and the public about the therapeutic options available. Finally, Chapter 6 profiles 12 of the leading companies active in the osteoporosis market, detailing their key financial figures, leading products and engagement in the field of osteoporosis.
CONTENTS
LIST OF TABLES
LIST OF FIGURES
EXECUTIVE SUMMARY
E.1 Introduction
E.2 Learning to recognise and measure the challenge
E.3 Active bone care
E.4 Current drug treatments
E.5 Future therapies
E.6 The osteoporosis market
GLOSSARY AND ABBREVIATIONS
SCOPE AND METHODOLOGY
CHAPTER 1 INTRODUCTION
1.1 Osteoporosis definition
1.2 Primary and secondary osteoporosis
1.2.1 Primary osteoporosis
1.2.2 Secondary osteoporosis
1.3 Pathogenesis of osteoporosis
1.3.1 Bone remodelling
1.3.2 Bone turnover in osteoporosis
1.4 Genetic factors in osteoporosis
1.5 BMD and the diagnosis of osteoporosis
1.5.1 Techniques for BMD measurement
1.5.2 Where to measure BMD?
1.5.3 What is normal BMD?
1.5.4 Fracture prediction and BMD
1.5.5 Indications for BMD measurement
1.6 Biochemical markers of bone remodelling
1.7 Incidence of fractures and prevalence of osteoporosis
1.7.1 Hip fracture incidence
1.7.2 Vertebral fracture incidence
1.7.3 Wrist fracture incidence
1.7.4 Fractures at other sites
1.7.5 Prevalence of osteoporosis, or 'what the scanner saw'
1.8 The cost of osteoporotic fractures
CHAPTER 2 OSTEOPOROSIS MANAGEMENT STRATEGIES
2.1 Bone care: a lifelong perspective
2.1.1 Bone formation in adolescence
2.1.2 Bone maintenance in adult life
2.1.3 Peri- and post-menopausal bone loss
2.1.4 Bone health in advanced age
2.2 Population-based prevention versus high-risk targeting
2.3 Population screening
2.4 Treatment adoption and compliance
2.5 Osteoporosis in men
2.6 Osteoporosis and corticosteroid treatment
CHAPTER 3 OSTEOPOROSIS PRODUCTS ON THE MARKET
3.1 HRT products
3.1.1 Unopposed oestrogen products
3.1.2 Combined oestrogen/progestogen products
3.1.3 Benefits and risks of HRT
3.1.4 HRT efficacy in fracture prevention
3.2 Calcitonins
3.2.1 Calcitonin efficacy
3.2.2 Pain relief with calcitonin
3.2.3 Side effects of calcitonin
3.2.4 Role of calcitonin in osteoporosis
3.3 Bisphosphonates
3.3.1 Etidronate
3.3.2 Alendronate
3.4 Selective oestrogen receptor modulators
3.4.1 Raloxifene and BMD
3.4.2 Fracture prevention with raloxifene
3.4.3 Safety and tolerability of raloxifene
3.5 Calcium and vitamin D products
3.6 Other products for osteoporosis
3.6.1 Tibolone
3.6.2 Ipriflavone
3.6.3 Fluoride
CHAPTER 4 OSTEOPOROSIS PRODUCTS IN DEVELOPMENT
4.1 HRT products
4.1.1 Ongoing clinical studies with existing products
4.1.2 New HRT products in clinical trials
4.2 New calcitonins
4.3 New bisphosphonates
4.3.1 Risedronate
4.3.2 Ibandronate
4.3.3 Zoledronate
4.3.4 Other bisphosphonates
4.4 New SERMs for osteoporosis
4.4.1 Idoxifene
4.4.2 Levormeloxifene
4.4.3 Droloxifene
4.4.4 Other SERMs
4.5 Parathyroid hormone and analogues
4.5.1 Recent clinical findings
4.5.2 Product developments
4.6 Strontium ranelate
4.7 Preclinical research in osteoporosis
CHAPTER 5 THE OSTEOPOROSIS MARKET
5.1 Population ageing
5.2 The HRT market
5.3 The calcitonin market
5.4 The market for bisphosphonates
5.5 The market for SERMs
5.6 The market for calcium and vitamin D products
5.7 The market for other treatments
5.8 The demand for osteoporosis therapy
CHAPTER 6 COMPANY PROFILES
6.1 Akzo Nobel NV (Organon)
6.1.1 Financial highlights
6.1.2 Osteoporosis products
6.1.3 Other products
6.1.4 Research and development
6.1.5 Osteoporosis agreements
6.2 American Home Products Corporation (Wyeth-Ayerst)
6.2.1 Financial highlights
6.2.2 Osteoporosis products
6.2.3 Other products
6.2.4 Research and development
6.2.5 Osteoporosis agreements
6.3 Eli Lilly & Company
6.3.1 Financial highlights
6.3.2 Osteoporosis products
6.3.3 Other products
6.3.4 Research and development
6.3.5 Osteoporosis agreements
6.4 Merck & Co Inc
6.4.1 Financial highlights
6.4.2 Osteoporosis products
6.4.3 Other products
6.4.4 Research and development
6.4.5 Osteoporosis agreements
6.5 Merck KGaA (Merck Group)
6.5.1 Financial highlights
6.5.2 Osteoporosis products
6.5.3 Other products
6.5.4 Research and development
6.5.5 Osteoporosis agreements
6.6 Novartis Pharmaceuticals (Novartis Group)
6.6.1 Financial highlights
6.6.2 Osteoporosis products
6.6.3 Other products
6.6.4 Research and development
6.7 Novo Nordisk A/S (Novo Nordisk Group)
6.7.1 Financial highlights
6.7.2 Osteoporosis products
6.7.3 Other products
6.7.4 Research and development
6.7.5 Osteoporosis agreements
6.8 Procter & Gamble
6.8.1 Financial highlights
6.8.2 Osteoporosis products
6.8.3 Other products
6.8.4 Research and development
6.8.5 Osteoporosis agreements
6.9 Roche Pharmaceuticals
6.9.1 Financial highlights
6.9.2 Osteoporosis products
6.9.3 Other products
6.9.4 Research and development
6.9.5 Osteoporosis agreements
6.10 Schering AG
6.10.1 Financial highlights
6.10.2 Osteoporosis products
6.10.3 Other products
6.10.4 Research and development
6.10.5 Osteoporosis agreements
6.11 Solvay SA (Solvay Group)
6.11.1 Financial highlights
6.11.2 Osteoporosis products
6.11.3 Other products
6.11.4 Research and development
6.11.5 Osteoporosis agreements
6.12 Warner-Lambert
6.12.1 Financial highlights
6.12.2 Osteoporosis products
6.12.3 Other products
6.12.4 Research and development
6.12.5 Osteoporosis agreements
CHAPTER 7 COMPANY DIRECTORY
REFERENCES AND FURTHER READING
LIST OF TABLES
Table 1.1 International suppliers of DXA scanners
Table 1.2 Suppliers of ultrasound densitometers
Table 1.3 Clinical indications for bone densitometry
Table 1.4 Suppliers of biochemical marker test kits
Table 1.5 Incidence of hip fracture data from recent publications
Table 2.1 Results of an intervention with a 50% risk reduction (RR=2) and an intervention
cost of SKr 5,000 per year over five years
Table 3.1 Selected unopposed oestrogen HRT products
Table 3.2 Sequential combined oestrogen/progestogen HRT products
Table 3.3 Continuous combined oestrogen/progestogen HRT products
Table 3.4 Adverse reactions occurring in at least 3% of post-menopausal patients treated
chronically with calcitonin salmon nasal spray
Table 4.1 Summary of HRT clinical development projects
Table 5.1 Projected female population aged 50 and above (million)
Table 5.2 Projected female population aged 75 and above (million)
Table 5.3 Age-related osteoporosis prevalences used for model-building
Table 5.4 Women aged 50 and above with osteoporosis 1995-2010 (million)
Table 5.5 Estimate of patients treated with various osteoporosis drugs
Table 5.6 Estimated value of the osteoporosis market in 1996
Table 5.7 Breakdown of osteoporosis sales in 1996 by product
Table 6.1 Akzo Nobel consolidated sales and income 1996-1998 ($ million)
Table 6.2 Akzo Nobel net sales by company segment, 1996-1998 ($ million)
Table 6.3 Akzo Nobel sales by geographical destination ($ million)
Table 6.4 AHP consolidated sales and income 1996-1998 ($ million)
Table 6.5 AHP net sales by industry sector 1996-1998 ($ million)
Table 6.6 AHP financial data by geographic region ($ million)
Table 6.7 Eli Lilly & Co consolidated sales and income 1996-1998 ($ million)
Table 6.8 Eli Lilly sales by therapeutic area 1996 and 1997 ($ million)
Table 6.9 Major product sales, first-half 1998 versus 1997 ($ million)
Table 6.10 Merck & Co consolidated sales and income 1996-1998 ($ million)
Table 6.11 Merck & Co sales by therapeutic area 1996-1998 ($ million)
Table 6.12 Merck & Co financial data by geographic region 1996-1997 ($ million)
Table 6.13 Merck Group consolidated sales and income 1996-1998 ($ million)
Table 6.14 Merck Group financial data by business sector 1996-1997 ($ million)
Table 6.15 Merck Group financial data by geographic region 1996-1997 ($ million)
Table 6.16 Merck Group major ethical pharmaceutical products
Table 6.17 Novartis AG consolidated sales and income 1996-1998 ($ million)
Table 6.18 Novartis net sales by business sector 1996-1998 ($ million)
Table 6.19 Novo Nordisk consolidated sales and income 1996-1998 ($ million)
Table 6.20 Novo Nordisk sales by company segment 1994-1997 ($ million)
Table 6.21 Novo Nordisk sales by geographical area ($ million)
Table 6.22 Procter & Gamble consolidated sales and income 1996-1998 ($ million)
Table 6.23 Procter & Gamble financial data by geographic region 1996-1997 ($ million)
Table 6.24 Roche Group consolidated sales and income 1996-1998 ($ million)
Table 6.25 Roche Group sales by industry sector 1996-1998 ($ million)
Table 6.26 Roche Group financial data by geographic region 1996-1997 ($ million)
Table 6.27 Schering AG consolidated sales and income 1996-1998 ($ million)
Table 6.28 Schering AG sales by industry sector 1996-1998 ($ million)
Table 6.29 Schering AG financial data by geographic region 1996-1997 ($ million)
Table 6.30 Solvay Group consolidated sales and income 1996-1998 ($ million)
Table 6.31 Solvay Group sales by industry sector 1996-1998 ($ million)
Table 6.32 Solvay pharmaceutical sales by geographical area ($ million)
Table 6.33 Warner-Lambert consolidated sales and income 1996-1998 ($ million)
Table 6.34 Warner-Lambert sales by company segment 1996-1998 ($ million)
LIST OF FIGURES
Figure 1.1 Bone remodelling
Figure 1.2 Relative site-specific fracture risk as predicted by BMD measurement
Figure 1.3 Comparison of mean femoral neck BMD measurements for a local reference
population (o) as compared with manufacturers' normal data
Figure 1.4 Markers of bone remodelling
Figure 1.5 Projected hip fracture incidence without and with inclusion of a secular increase
in incidence rate
Figure 1.6 Incidence of hip fracture in men and women (MEDOS study)
Figure 3.1 Structure of alendronate
Figure 3.2 Cumulative proportion of osteoporotic post-menopausal women with new
fractures during three years of treatment with alendronate or placebo
Figure 3.3 Mean annual BMD change in post-menopausal women treated with oestrogen
alone and oestrogen with calcium
Figure 4.1 Chemical structures of new SERMs
Figure 4.2 Factors influencing osteoclast differentiation
Figure 5.1 Changes in age strata, projected female population 1995-2010
Published: October 1998
Ref: BS975E
Pages: 151
Price: £370/$780/¥89,000
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