Drugs for the treatment of metabolic bone diseases

Musculoskeletal conditions comprise more than 150 diagnoses that affect the locomotor system—that is, muscles, bones, joints, and associated tissues such as tendons and ligaments.1 Musculoskeletal conditions are the second largest contributor to disability worldwide. Among them, bone diseases constitute a significant health burden, although often overlooked by care providers and patients alike. Quantitatively, osteoporosis is the most important metabolic bone disease, with roughly 50% of women and 20% of men greater than 50 years of age expected to suffer an osteoporosis‐associated fracture during their remaining lifetime. In Europe, this translates into annualized rates of 574 000 wrist, 810 000 spine, and 620 000 hip fractures. Collectively, these osteoporotic fractures result in substantial numbers of hospitalizations and increases in mortality, ultimately leading to an estimated annual overall cost of 37 Billion Euro.2 Similar numbers have been described for the United States. With fracture incidence on the rise due to aging of the world's population, osteoporosis is rightfully referred to as a silent epidemic. In comparison, rare metabolic bone diseases such as fibrodysplasia ossificans progressiva (or FOP) can also exert significant burdens on our collective public health systems, a result reflecting the skeletal severity of such diseases rather than the number of patients affected. A third category of diseases involving the skeleton are cancer‐associated bone diseases, comprising disorders of both bone loss and bone metastases, which again affect large numbers of patients.

Over the past several decades, new drugs have become available for the treatment of various metabolic bone diseases, including Paget's disease of bone, osteoporosis, and metastatic bone disease. Indeed, 2019 will mark 50 years since the first publications on the biological effects of the bisphosphonates,3, 4 a therapeutic class that has been dominating the treatment of Paget's disease of bone, osteoporosis, cancer‐associated bone disease, and several rare bone diseases such as osteogenesis imperfecta for years. In this themed issue, one of us who has been involved from the very inception of early bisphosphonate research (RGR) discusses the clinical and translational pharmacology of these drugs, as well as their continued development for the treatment of metabolic bone diseases.5 Despite their widespread clinical utility, however, bisphosphonate use has declined over the past decade. Reasons for this decline are several and include patient and provider concern for rare side effects associated with their long‐term use as described by Skjødt et al,6 loss of patent protection, and decreased reimbursement for bone mineral density (BMD) testing by dual‐energy X‐ray absorptiometry (DXA) in the United States. Newer insights into the (patho‐)physiology of bone, however, including the careful study of patients afflicted with bone diseases such as pycnodysostosis have led to the development of newer antiresorptive agents including the cathepsin K inhibitor odanacatib which is described in this issue by Stone et al7 and a humanized monoclonal antibody directed against the receptor‐activator of nuclear factor kappa B ligand (RANKL)‐antibody denosumab which is described by Tsourdi et al.8 Similar to bisphosphonates the newer antiresorptive agents may also be effective in the treatment of osteoporosis, metastatic bone disease, as well as a few rare bone diseases. Whereas denosumab has received regulatory approval for the treatment of osteoporosis and cancer‐treatment associated bone loss, odanacatib was withdrawn from review due to safety concerns that surfaced during the largest phase 3 trial of an osteoporosis drug ever undertaken.

Other drugs developed for the treatment of osteoporosis include the osteoanabolics, a category which includes the parathyroid hormone (PTH) and parathyroid hormone‐related peptide (PTHrP) analogues. Another therapeutic category is described by a drug in development that appears to have a dual mechanism of action, namely, osteoanabolic and antiresorptive. In this regard, Romosozumab is a humanized monoclonal antibody directed against sclerostin. Notably, romosozumab followed careful studies of the rare skeletal disorders of excessive bone growth: Van Buchem's disease and sclerosteosis. Both genetic diseases are characterized by an absence of sclerostin, an important regulator of the canonical Wnt signalling pathway. Unlike all other drugs, romosozumab stimulates bone formation and soon thereafter shows effects of a potent antiresorptive drug. Both the PTH/PTHrP analogues and romosozumab are discussed in this issue by Tabacco et al.9 Interestingly, whereas foreshortened derivatives of PTH and PTHrP, as recently more extensively described in this journal,10 are now used to treat osteoporosis, full‐length PTH (1‐84) has recently gained approval for treatment of hypoparathyroidism, where it has been shown to reduce supplemental calcium and vitamin D requirements and to improve quality of life.

Adequate vitamin D levels are also a crucial component in the management of metabolic bone diseases, including osteoporosis, primary hyperparathyroidism, rickets, and rare bone diseases such as familial hypocalciuric hypercalcaemia. To this end, accurate measurement of vitamin D concentrations can be a challenge.11 The inappropriately excessive use of vitamin D can lead to vitamin D intoxication.12 While many excellent reviews have been written about vitamin D, in this issue, Jones and Kaufmann13 describe both new applications for currently available vitamin D analogues, as well as new vitamin D analogues presently in development for the treatment of metabolic bone diseases and other skeletal and nonskeletal disorders. Another important but nearly universally underserved aspect affecting patients with many different metabolic bone diseases is the potential for bone pain. In this issue, Mantyh14 delineates the pathophysiology of bone pain and describes recent developments for the treatment of this frequently debilitating complication.

The aforementioned drugs form the basis of our current therapeutic armamentarium for many skeletal disorders including osteoporosis, Paget's disease of bone, metastatic bone disease,15, 16 and several rare bone diseases. More recently, however, significant impediments to the development of novel approaches for the treatment of skeletal disorders have arisen. These include several drugs which have either failed to meet endpoints or have been associated with unwanted side effects in phase 3 clinical trials, as well as patent expirations for the highly effective bisphosphonate class of drugs. Collectively, events have introduced a significant hurdle for the further discovery and development of new drugs for osteoporosis and metastatic bone disease, leading many major pharmaceutical companies to scale back research and development efforts in the field. Further, fear on behalf of both patients and some care providers as to potential side effects associated with the long‐term use of existing drugs has led to a decrease in the use of these agents, thus confounding industry enthusiasm for new drug discovery agendas. These events have conspired to a collective under‐treatment of patients who need to be treated, thus posing a major threat to public health. What is needed is a successful effort to treat an expanding number of patients with osteoporotic fractures or complications from bone metastases in our growing at‐risk population.

One potential approach to addressing this looming epidemic is via improved utilization of existing drugs. Accordingly, improved modes of administration and/or dosing regimens may improve the relative balance between clinical efficacy and unwanted side effects. In this context, clinical pharmacologists have played major roles in the development of drugs for the treatment of metabolic bone diseases. However, clinical pharmacologists also have the potential to exert additional influence on the optimal use of existing agents going forward, both through the improved use of clinical and translational pharmacokinetics and pharmacodynamics as described in this issue by Riggs et al,17 as well as via astute implementation of tools derived from our evolving understanding of the role that genetics plays in metabolic bone diseases, as described by Hannan et al18 in this issue.

The improved utilization of bone active drugs is not restricted to the treatment of patients with osteoporosis, but is also important for the treatment of cancer related bone disease. In this issue, Dionisio et al15 provide an excellent overview of current pharmacologic approaches for the prevention and treatment of cancer‐induced bone loss and metastatic bone disease, while Chukir et al16 specifically focus on important aspects of the prevention and treatment of breast cancer‐associated bone disease. Also, in this issue, Bedastova et al19 provide an overview of the bone loss and associated skeletal complications that can occur as unintended consequences of many treatments utilized in the treatment of cancer.

Aberrant genetics play a causal role in many of the more than 400 described rare bone diseases.20 In this issue, Hannan et al18 describe how our increasing understanding of genetics is providing new paradigms for diagnosis and treatment, as well as for the discovery, translation, and clinical development of new drugs targeting these severely debilitating rare skeletal diseases. Similarly, contributions in this issue describe the discovery and clinical developmental efforts for new drugs designed to treat the rare bone diseases fibrous dysplasia,21 osteogenesis imperfecta, fibrodysplasia ossificans progressiva,22 and X‐linked hypophosphatemia.23

The clinical development of drugs for rare bone diseases is associated with significant and often unique challenges. Routine trial designs may not be applicable, sufficient numbers of affected patients appropriate for study may be difficult to identify, and even logistical aspects involving the travel of severely affected patients to study sites may prove difficult. Such challenges are exemplified in this issue by the contribution from the International Clinical Council on FOP.24 While specifically delineating issues associated with clinical trials in FOP, the generalizability of such described challenges can likely serve as a guide to aid others in the development of drugs for rare (bone) diseases.

Despite the high level of expertise inherent in the development of drugs for the treatment of skeletal disorders, clinical pharmacologists are uniquely positioned for the development of drugs for rare bone diseases as a result of their specialist knowledge of biomarkers, genetics, clinical trial study design, and clinical and translational pharmacokinetics and pharmacodynamics. In addition, clinical pharmacologists are very much aware of the importance of regulatory aspects of drug development. In this themed issue, representatives from both the United States Food and Drug Administration (USFDA) and the European Medicines Agency (EMA) describe the various important regulatory aspects that play key roles in the clinical development of drugs for metabolic bone diseases, including those for rare bone diseases.25

Finally, although rare bone diseases are by definition “rare,” precedent exists for rare bone diseases to add to our understanding of fundamental aspects of bone biology and, as such, to suggest novel and heretofore unexplored approaches for the treatment of skeletal disorders. In this way, the discovery and development of drugs for rare bone diseases may also lead to the development of drugs for the treatment of more common metabolic bone diseases, in essence “returning the favour” for the use in rare bone diseases of drugs originally developed for more common bone diseases (ie, bisphosphonates developed for the treatment of postmenopausal osteoporosis repurposed for the treatment of skeletal fragility in the rare bone disorder osteogenesis imperfecta). An important caveat to this potential reciprocity exists, however, in that it is likely that drugs that permit a very wide clinical target profile become less adaptable when developed via a precision medicine approach. The search for better drugs for the treatment of patients with metabolic bone diseases thus continues. The objective of this themed issue is to inform, to raise awareness, and to stimulate interest and further research in this field.

COMPETING INTERESTS

There are no competing interests to declare.

Drake MT, Cremers S, Russell RG, Bilezikian JP. Drugs for the treatment of metabolic bone diseases. Br J Clin Pharmacol. 2019;85:1049–1051. 10.1111/bcp.13857