Future Therapies and Clinical Trials 14

14

Future Therapies and Clinical Trials

C

G. M

Second to being right in this world is being totally wrong.

T.H. Huxley

14.1. Introduction

The diagnosis and treatment of osteoporosis is still a relatively young science.

Although Albright first described osteoporosis in 1947,

it is only since the late 1980s and early 1990s that we have had the instruments available for the diagno- sis and then treatment of this disease. As for any medical area in its infancy, we can, therefore, expect a significant number of changes in the coming years, as a result of more comprehensive understanding of bone physiology and elucidation of the genetic factors leading to increased risk factors.

14.2. Future Therapies

When the first edition of this book was written, it was stated that “In the imme- diate future the therapeutic regimens that will be available to the prescribing physician will increase to include several different formulations of hormone replacement therapy (HRT), with several different modes of delivery, three bis- phosphonates available in Europe (two in the USA), nasal calcitonin, and selective estrogen receptor modulators or SERMs.” In the 4 years since the book was writ- ten, the therapeutic landscape has changed dramatically. HRT, which was once the first-line therapy for osteoporosis, is no longer used, because it was shown in the Women’s Health Initiative study (2002) that women taking this drug had an increased risk of developing breast cancer.

In 2002, the first recombinant parathyroid hormone (PTH) drug was intro-

duced onto the market [PTH(1–34); Forteo

(Eli Lilly and Company, Indianapolis,

USA)]. A second PTH [PTH(1–64); Preos

(NPS Pharmaceuticals, Parsipany, NJ,

USA)] is approved in the European Union (EU) and under review by the US Food

and Drug Administration (FDA). Several more versions of PTH are currently in various stages of development, including forms using different methods of deliv- ery, not just subcutaneous injection. There have been some safety issues, which on the whole have been resolved (i.e. osteosarcoma was reported in rats). It is also worth noting that, after a number of years of prescribing, this issue has not been reported in humans.

Modern medicine and treatment of disease is, generally, based on treating each disease specifically and separately. However, several new therapies (including SERMs) have provided the opportunity for prevention and/or treatment of more than one disease at a time. At the time of writing the first edition of this book, one SERM was on the market (raloxifene) and a second drug in this class was in phase III development. This latter compound, lasofoxifene, was rejected by the FDA for the indication of prevention of osteoporosis in 2005.

A novel area that has shown some major promise is the receptor for activation of NF-KB (RANK) ligand inhibitor denosumab. Phase II study results have demonstrated that twice-yearly subcutaneous injections of the compound demon- strated an increase in bone mineral density (BMD) at the lumbar spine of 5.1%

after 24 months.

The other major development is the bisphosphonate zoledronic acid, which has been show to increased BMD over a 12 month period following a single annual injection.

Although bisphosphonates have been well characterized, and are the leading treatment for osteoporosis, this finding will be an interesting development and could potentially be the first therapy, in any field (except for vaccines), for which a single annual injection provides treatment for 1 year.

14.3. Osteoporosis-Related Diseases

Other bone diseases will also appear on the “radar screen”, developing the range of uses for these treatments. Already, we have seen male osteoporosis become a treatable disease, with alendronate (Fosamax

, Merck & Co. Inc., Whitehouse Station, NJ, USA). It was only a few years ago that the general opinion was that osteoporosis was a female disease. This is no longer the case. We are starting to see development in other therapeutic areas. Bone diseases in children have been an area of minimal concern, but with the FDA now promoting studies in children, we can expect to see diseases such as osteogenesis imperfecta being treated with the bisphosphonates. In later adolescence, amenorrhoea caused either by anorexia nervosa and related diseases or by extreme physical activity, for example Olympic female gymnasts, can result in decreased bone accretion in the formative years. If the level of bone deposition in these juveniles can be improved with the use of some of the new therapeutic agents, the incidence of fracture throughout an indi- vidual’s life span can be reduced.

There are a number of other conditions that have a secondary effect of excessive

bone loss that are currently untreated or undertreated. The use of steroids and bone

loss is well documented, but not everyone is treated. Women taking luteinizing

hormone-releasing hormone (LHRH) analogues for endometriosis, bone loss after transplant owing to cisplatin use and other medications, plus subjects on chronic kidney dialysis also have bone-loss problems. As the number of subjects with transplants increases and this field of medicine develops, the effects of bone loss will become a major problem and not a side issue that can be relatively ignored.

14.4. Fixing the Fracture

No preventative treatment is currently efficacious in all subjects. Risk reduction is still the best outcome available, which means a significant number of individuals will still end up having a fracture. Fractures can be subdivided into two types, according to the current treatment and outcome: vertebral fractures and appendic- ular fractures.

14.4.1. Vertebral Fractures

Until recently, there was nothing available to treat a confirmed fracture of the ver- tebra, other than a brace and conservative noninvasive techniques. Vertebroplasty and kyphoplasty have started to come to the fore. At the time of writing, more studies are warranted to assess the long-term safety and efficacy of these techniques. Both techniques offer the solution of repairing fractured vertebrae. Vertebroplasty involves high-pressure infusion of state methyl methacrolate into the collapsed ver- tebra through a small hole drilled in both pedicles. Kyphoplasty is a refinement of this process, using two small angioplasty balloons that are inflated inside the accessed vertebra; the vertebra is, again, accessed through holes in the pedicles while the subject is in the recumbent position. The balloons move the trabecular bone to the cortical shell, providing a void where the cement can be injected under low pressure. The subject remains supine until the cement has hardened and can bear weight. Not only has the subject’s vertebra been repaired and strengthened, but there is also a reduction in pain, which is thought to be caused by the exothermic curing process of the cement, which probably kills off the bone nociceptors.

It should be appreciated that most vertebrae do not undergo a complete col- lapse at one time or fracture in the classical sense of a “break” in the continuous structure of the bone, but rather undergo a series of deformities, producing a reduction in height. This leads to the challenge of diagnosing a mild fracture or deformity. Therefore, this has to be considered carefully when deciding to use this kind of approach.

Vertebroplasty and kyphoplasty only allow treatment of already deformed

vertebrae. The remaining vertebrae are also at high risk of failure and fracture, so

therapy must be initiated. The choice of therapies must be carefully considered to

improve a subject’s bone mass, although this will only be effective over a period of

time, for example 1 year or more, with the current antiresorption therapies. This still

might not prevent further fracture, but merely reduces the probability that more will

occur. In the meantime, statistics have shown that the greatest risk of sustaining a

new fracture of the vertebrae occurs within 12 months of sustaining the first frac- ture. In future, based on the initial data from clinical trials, PTH will be the initial therapy of choice following vertebral collapse, because of its rapid mode of action.

Further studies must be performed to evaluate how severe the deformity must be before intervention of this kind is contemplated. Without this treatment, relatively small deformities would cause pain for a few weeks or months, but then would set- tle down. For many subjects, this would be relatively mild, and in many cases, is just considered a bout of back pain that does not require a visit to the physician. Even if it does, the impact of the fracture at this stage is not of sufficient morbidity for the subject to require surgery. However, it is arguably these kinds of situations in which this new treatment option might have the best outcome, because the immediately adjacent vertebrae are, perhaps, more likely to deform again. Furthermore, the immediately adjacent vertebrae could also then be treated in a preventative manner.

However, at this stage, the immediate use of this methodology must be around treating the most severely deformed vertebra, because of the invasive nature of the treatment. For subjects with multiple deformities, in which the lower rib is resting on the iliac crest, some surgeons will remove the lower ribs to improve the sub- ject’s comfort. If this can be avoided by the use of vertebral strengthening cement, this would be a valuable treatment option for these subjects.

14.4.2. Appendicular Fractures

Appendicular fractures are treated by reduction and fixing, to prevent further movement. For the femur, which is the most prevalent form of osteoporotic frac- ture in the elderly, this involves pinning and plating the fracture with a hemi- arthroplasty or total arthroplasty. Arthroplasty is the most costly outcome not only for the medical community’s budget, but also because of the comorbidity and mortality related to the fracture and treatment. The mortality rate following a frac- ture is 20% at 3 months and up to 35% within 1 year of the fracture.

There is an approximately 20% chance that a subject will go on to fracture the second hip within the next 2 years.

All the other types of appendicular fracture are not as costly, either because they are less prevalent or because they can be treated on an out-patient basis using standard methodologies. However, the bone is weak because of the nature of the disease and, therefore, might not heal rapidly or well.

In both these kinds of fracture, there is a need for bone-healing compounds to be developed. Bone morphogenic proteins (BMPs) were being evaluated a few years ago, but current research does not seem to bear out the initial promise. There are other slurries and cements that are being evaluated, but at the time of writing, nothing new seems to be coming to the forefront as the latest methodology for bone healing.

One novel compound that, at least at the time of writing, could hold some prom-

ise is the analogue of a naturally occurring somatokine. It is being used in subjects

following hip fracture. The drug’s primary role is in the cognitive functionality it

maintains in the elderly, ensuring that far fewer of them suffer from increased

morbidity. The early studies are very promising. What is more, because of the bio- chemical pathway the drug affects, it has a positive effect on bone. It seems too good to be true that we can have a drug that can have a profound effect on subjects at both mental and bone levels, following such a negative event as a hip fracture.

14.5. Male Osteoporosis and Testosterone

Most of the research in the field of osteoporosis has been historically targeted at women. Women have more fractures per 1000 of the population than men. This is, in part, because of the higher bone mass that men have compared with women.

However, when fracture risk per loss of 1 standard deviation (SD) in bone mass is evaluated, men have the same relative risk (RR) of sustaining a fracture as women for the same absolute BMD. Furthermore, the mortality rate among men who sustain a hip fracture is higher than that in women. Male osteoporosis is, therefore, now being approached as a serious medical disease and treatments for men are being identified.

Obviously, female hormone supplements and SERMs are not available to men, but bisphosphonates and calcitonins work as well for men as for women.

Denosumab would be an ideal double therapy for men because it works directly on the RANK ligand pathway; PTH studies in men are also underway. Testosterone is also being evaluated for male osteoporosis because it apparently has a role in bone homeostasis, at least as a breakdown product.

Male osteoporosis will, therefore, become a significant disease in the eyes of the medical profession, in addition to the lay public. Osteoporosis is now a well- recognized disease among women, although there is still relatively little screening carried out for the disease. Male osteoporosis will have to go through the same slow acceptance process as that for women before a great deal of attention is paid at the general practitioner (GP) level.

14.6. Genetic Influence and Genetic Screening

During the course of writing this book, the human genetic code has been fully

evaluated and the first studies have been presented evaluating the genetic profile

of individuals with the disease, with the goal of providing genetic screening for

the identification of individuals at risk of osteoporosis. Currently, there are

studies underway using low BMD as the phenotype, in which the aim is to eval-

uate the possibility to diagnose the level of risk at birth. It is hoped that by know-

ing the genetics of the parents, an individual’s lifetime risk of fracture could be

evaluated. At least theoretically, children in this situation could be encouraged to

exercise more regularly and have the appropriate amounts of calcium and other

vital nutrients essential for bone development. However, this study presupposes

that BMD is the primary cause of osteoporosis. Another study is also investigat-

ing the familial links of osteoporosis using twins. Fracture is the endpoint of this

study, rather than BMD.

As for most therapeutic fields, we are still a long way off identifying genetic markers for osteoporosis. It is highly unlikely that there is only one or two genes that control bone metabolism, because it is such a complex organ. Therefore, it is going to be some time before genetics has a direct role in identifying people at risk of fracture. We might have better opportunity of identifying receptors or mediators that can be genetically switched on or off, at least in the medium term.

14.7. Differentiation Between those who have a Propensity to Fall and those with Low BMD

One area of differentiation that will become more apparent is the different causes of osteoporotic fracture, i.e. subjects who have low BMD versus those who have a propensity to fall and might have a relatively normal BMD. Currently, this dif- ferential diagnosis is not made, but with a variety of treatments and a better understanding of the individual risks, we can expect subjects to be treated very differently.

The currently available strategy for women with a high propensity to fall is to provide them with underwear that has built-in hip protectors. Studies have shown that these are successful in reducing fracture, at least in elderly women in resi- dential care. These protectors, although carefully designed, unfortunately do have to have some bulk in them and, therefore, widen the hips. There are issues with women (or men) at any age having to wear something that is less than flattering.

This ensures that compliance in wearing the underwear is ⬍100%, plus they offer no protection during times of undressing and moving around the bathroom.

Other than the hip protectors, very little is being done to evaluate those women with a high propensity to fall, and the cause of the disease in these subjects. It is apparently a cognitive functionality that is primarily affected, which could be suc- cessfully treated with somatokines, as discussed in Section 14.4.2. As for all the medications for treatment of osteoporosis, it is unlikely to completely prevent frac- ture from occurring, but will reduce the frequency of fracture within the population.

14.8. Monotherapy and Multiple Therapeutic Responses

Because the treatment of osteoporosis is still in its infancy, most studies have only looked at the effect of monotherapy. The first studies evaluating the combination of Fosamax

and PTH have now been completed.

There seems to be an additive effect, which is only to be expected because bone loss has multiple causes.

Therefore, we can expect, in the future, a more rational approach regarding which

therapies should be used for each situation, with the potential of a planned switch-

ing between therapies at different ages or BMD levels and also the use of combi-

nations of therapies. Preliminary data for PTH and bisphosphonates looks very

promising, if PTH is given first, followed by the bisphosphonate (and not the

other way round).

14.9. Summary

In the past 6–10 years or so, there has been a rapid development in the diagnosis and treatment of osteoporosis. Because of the nature of the disease, clinical trials are long and complex, and yet there have been some remarkable strides in this therapeutic field although, as already stated, we are still in the infancy of treating this disease. Therefore, we can eagerly anticipate some further major develop- ments in this field, many of which have been described.

The field of clinical trials in osteoporosis is changing and we have probably seen the last placebo-controlled trials started in this area. This provides a series of challenges in its own right, because the regulatory agencies cannot ethically expect subjects to participate in placebo-controlled trials. Therefore, as we have already started to see, the guidelines are being changed and will continue to evolve. The challenges associated with active comparator trials and the numbers of subject that will need to be enrolled will have to be carefully evaluated.

As for the near future, at least one more bisphosphonate will be developed.

Zometa

(Novartis International AG, Basel, Switzerland) is the most potent of all the bisphosphonates and has recently gained marketing approval for use in bone metastases. As previously stated, it can be administered annually. This regimen would have the potential to maintain good subject contact, with annual visits to the physician’s office by the subject, providing close to 100% compliance.

New administrative routes and formulations for calcitonin are currently being evaluated. Although the calcitonins have not demonstrated efficacy of the same level as the bisphosphonates, the new formulations could hold some advantage in monotherapy or combination therapy.

We can anticipate at least two formulations of PTH to be on the market in the next few years, probably for treatment of osteoporosis. There is one school of thought that PTH will become the therapy of choice for treatment of osteoporosis, and the other therapies discussed will become front-line prevention therapies. However, there is insufficient evidence to support this hypothesis at the time of writing.

One final area of change that might occur is the involvement of the orthopaedic community in the treatment of osteoporosis. Until now, orthopaedic specialists have, generally, not been involved in this disease because it has not required sur- gery. With the advent of vertebroplasty and kyphoplasty, orthopaedic specialists are beginning to consider this bone disease as one in which they should be involved. They might become the high prescribers of the future.

“Future gazing” is always a challenge. It is difficult to know where the next

new development will come from and where it will take us in our understanding

of bone physiology and treatment. Even during the writing of this book, the treat-

ment potentials have changed several times. Hopefully, this chapter has provided

a near-term perspective on the most probable scenarios, but if one consider the

advances in any field within the past 10 years, it becomes very difficult to predict

with any certainty the changes in the next 10 years. However, the quote by Huxley

at the start of this chapter, “Second to being right in this world is being totally

wrong”, certainly proved correct for the authors’ predictions in the first edition.

The field of osteoporosis, owing to its relative infancy, is still a challenging area, but one in which there is still a good deal of work to be completed by the scientist and physician, with some fascinating discoveries to be made.

References

1. Albright, F. (1947). Ann Int Med 27: Osteoporosis. Nutr Rev 1989;47:85–6.

2. Lacey, J.V., Jr, Mink, P.J., Lubin, J.H. et al. (2002). Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288:334–41.

3. Mclung, M.R., Lewiecki, M., Cohen, S.B. et al. (2006). Denosumab in postmenoausal women with low bone mineral density. New Engl J Med 354:821–31.

4. Reid, I.R., Brown, J.P., Burckhardt, P. et al. (2002). Intravenous Zoledronic Acid in Postmenopausal Women with Low Bone Mineral Density. New Engl J Med 346:653–61.

5. Rittmaster, R.S., Bolognese, M. and Ettinger, M.P. (2000). Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab 85:2129–34.