Background

Osteoporosis is characterized by a decrease in bone mass and density, resulting in a predisposition to fractures, typically in vertebrae, hips, or wrists. It is particularly common in postmenopausal women, and its prevalence increases with age, hence the two key forms of the disease, i.e., postmenopausal (also called Type I) and age-related (also called Type II or senile) osteoporosis. Drugs for osteoporosis are aimed at preventing fractures due to reduced bone mass.

While the adult skeleton may appear static, an estimated 10% of the skeleton is replaced annually through a tightly regulated remodeling process, representing a balance between net bone formation and resorption, and modulated by numerous systemic factors (1). Peak bone mass is achieved during young adulthood, but once reached, there is a gradual age-related bone loss, which may average about 0.7% per year. In postmenopausal women, there is an accelerated phase of bone loss superimposed on this pattern. Radiographically, bone loss of more than 2.5 standard deviations below mean peak bone mineral density (BMD) in young adults is considered osteoporosis, whereas bone loss of 1 to 2.5 standard deviations below that mean is considered osteopenia. Since osteoporosis cannot be reliably detected in plain radiographs until 30% to 40% of the bone mass is lost, it is difficult to screen for osteoporosis in asymptomatic individuals. Best diagnostic tests of bone mineral density involve specialized radiographic imaging techniques, such as dual-energy x-ray absorptiometry or bone densitometry, also called DXA or DEXA, which measures an individual’s spine, hip or total body bone density to help gauge fracture risk, and quantitative computed tomography.

Drug Approvals

Since 1984, a total of 9 new drug molecules have been approved for osteoporosis, in 5 pharmacologic classes. Before that time, drugs for this therapeutic class had mainly involved estrogens, with or without progestins, and calcium and vitamin D. The 1995 approval of Fosamax (alendronate), the first of 4 approved biphosphonates, represented an important milestone for this therapeutic class; this pharmacologic class has since remained the dominant class. The other 4 pharmacologic classes involve the SERM’s (Selective Estrogen Receptor Modulators), calcitonins, parathyroid analogs, and the RANK ligands (Receptor Activator of Nuclear factor Kappa-B Ligand).

For new drug molecule approvals for osteoporosis, refer to the accompanying chart below (click here for a larger graph). In keeping with our convention, new formulations of previously approved drugs are not included.

The new drug molecule approvals are listed below:

• Calcitonins: 1 new molecule; Calcimar (calcitonin salmon, 1984, discontinued). More recent formulations are Miacalcin (1986) and Fortical (recombinant, 2005).
• Biphosphonates: 4 new molecules; Fosamax (alendronate, 1995); Actonel (risedronate, 2000); Boniva (ibandronate, 2003); and Reclast (zoledronic acid, 2008). Registration interest spans 12 years and 8 months, from 1995 to 2008.
• SERM’s: 2 new molecules; Evista (raloxifene, 1997); and Duavee (bazedoxifene and conjugated estrogens, 2013). Registration interest spans 15 years and 10 months, between 1997 and 2013.
• Parathyroid Analogs: 1 new molecule; Forteo (teriparatide, 2002).
• RANK Ligands: 1 new molecule; Prolia (denosumab, 2010).

Comments

Osteoporosis is an important public health issue, with its clinical consequences being fractures; signs and symptoms of hip fractures include pain, reduced mobility and disability, whereas those of vertebral fractures include back pain, loss of height and deformity. The treatment benefits of agents directed against osteoporosis thus involve assessments of the reduction in fractures compared with placebo, in addition to biomarker and radiographic measurements. In general, these effects have been considered relatively modest. Of note is that drugs within a given pharmacologic class have their separate benefit-risk considerations, including adverse effect profiles. A few general comments on the current status of modern osteoporosis therapeutics are as follows:

• No new drug mechanism of action introduced since 2010, since the apporval of the RANK ligand Prolia (denosumab).
• There are concerns about bone quality and the effects current osteoporosis drugs may have on bone quality. Although bone quality is a somewhat vague term, it generally refers to the effects of skeletal factors that contribute to bone strength, but are not accounted for by measures of bone mass or quantity (2).
• Official FDA guidelines for the clinical evaluation of drugs used for the treatment of osteoporosis have continued to evolve over time (3). In general, these guidelines have involved evolving emphasis on prevention of fractures vs. radiographic measurements. It has also become apparent that our understanding of the relationship beteeen bone mass measures and risk of fractures is incomplete, and that a better scientific understanding of these relationships is needed.
• A recent draft guidance from FDA (4) calls for additional long-term nonclinical pharmacology studies (bone quality studies) to support new osteoporosis drug development, due to concerns about long-term adverse effects of pharmacologic intervention on bone quality.

References

1. Horvai A: Bones, Joints, and Soft Tissue Tumors, Chapter 26, in: Kumar V, Abbas AK, Aster JC, Robbins and Cotran Pathologic Basis of Disease, Ninth Edition, Elsevier, Philadelphia, 2015, pp. 1179-1227.
2. Hernandez CJ, Keaveny TM: A biomechanical perspective on bone quality. Bone, 39:1173-1181, 2006.
3. Colman EG: The Food and Drug Administration’s osteoporosis guidance document: past, present, and future. Bone Miner. Res., 18:1125-1128, 2003.
4. FDA Draft Guidance: Osteoporosis: Nonclinical Evaluation of Drugs Intended for Treatment. Guidance for Industry. June 2016. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm506366.pdf

Refer to page 25 of Progression of Modern Therapeutics (2015 Report) available under Reports on this website; this report also includes the methodology used.