Pharmaceutical Agents for the Treatment of Osteoporosis

Thomas A. Einhorn, M.D.
Professor and Chairman
Department of Orthopaedic Surgery
Boston University School of Medicine
Boston, MA

Osteoporosis is a chronic, progressive disease characterized by low bone mass, microarchitectural deterioration, decreased bone strength, and a consequent increase in fracture risk. In the United States alone, the number of people aged 50 and older estimated to be at risk for osteoporosis is 44 million and this represents 55% of the US population in this age group1. In North America, osteoporosis is the most prevalent musculoskeletal condition associated with an increase in mortality; due to its association with hip fractures. Over the course of the past two decades, substantial advances have been made in the diagnosis and treatment of this disease and there now exist several new pharmaceutical agents that have been shown to improve the ability to treat osteoporosis and reduce the incidence of fractures. This article will provide a brief background on the cellular processes that are targets of these pharmaceutical interventions and provide a review of pharmacological strategies currently available for osteoporosis treatment.

Cellular Biology of Bone
The ability of bone to be formed, remodeled and support mechanical loads depends on two stem cells populations: 1) mesenchymal stem cells, which give rise to osteoblasts and bone lining cells; and 2) hematopoietic stem cells, which give rise to osteoclasts. Osteoblasts secrete osteoid, a composite of proteins that include the major structural protein of bone, type I collagen, as well as cellular attachment proteins, growth factors, and other signaling molecules that regulate bone homeostasis. Bone lining cells primarily secrete metalloproteinases which are involved in the initial resorption of bone. Osteoclasts are the primary cells responsible for the resorption of bone and are derived from mononuclear precursor cells2. The bone remodeling cycle begins with the action of osteoclasts that attach to bone and begin their resorptive activities. Through a coupling mechanism, osteoblasts sense the need to form bone in response to osteoclasts in order to maintain bone homeostasis (Figure 1). When there is a failure of coupling such that bone resorption exceeds bone formation the result is osteoporosis. Thus, current pharmaceutical strategies focus on a down-regulation of osteoclastic activity and an up-regulation of osteoblastic bone formation3.

einhorn_fig1.jpg

Figure 1
Bone remodeling cycle. Bone resorption is a two-step process involving the secretion of neutral metalloproteinases by bone lining cells and acid hydrolases by osteoclasts. Osteoclasts are formed by the fusion of hematopoietic mononuclear progenitor cells that have differentiated to become pre-osteoclasts. Bone formation occurs by osteoblastic protein synthesis. Osteoblasts are derived from osteoprogenitor cells in the mesenchymal stem cell pool.

Current Osteoporosis Treatments
Treatment of osteoporosis is aimed at preventing bone loss by maintaining adequate calcium intake and inhibiting osteoclastic activity. Agents with the capacity to inhibit osteoclasts include bisphosphonates, estrogen, selective estrogen receptor modulators (SERMs), and calcitonin. Present recommendations on the use of estrogen emphasize caution due to potential serious adverse side effects such as breast cancer, stroke, coronary heart disease and pulmonary embolism4. SERMs have been shown to improve bone mass by reducing bone resportion but their effects are not as profound as those of estrogen or bisphosphonates5. Calcitonin inhibits osteoclastic activity by direct cytotoxic action on the cell, however, calcitonin is a protein and patients typically mount an antibody response to it within in about 24-36 months. Thus, its efficacy seems to diminish over time6.

The only agent currently recommended for the enhancement of bone formation is the 1-34 amino acid fragment of parathyroid hormone (PTH) known as teriparatide7. Although data have shown that continuous exposure to PTH induces bone resorption, pulsatile exposure (as in once per day administration) is known to directly stimulate osteoblasts. Sodium fluoride, a drug that has been shown in the past to stimulate bone formation, produces abnormal bone and has not been associated with a reduction in fracture incidence8 (Table I).

Table I
Current Osteoporosis Treatment*

Anti-resorptive
Formation-stimulating

 

 

  • Bisphosphonates
  • Parathyroid hormone
  • SERMS
  • Sodium fluoride
  • Calcitonin

 

  • Estrogen

 

*All patients receive: 1.5g elemental Ca and 400u Vit. D daily
If hypercalciuric, use thiazide diuretic

Current osteoporosis treatments divided into anti-resorptive and formation-stimulating therapies. Because of potential adverse side effects, estrogen is only recommended in unusual circumstances where other osteoporosis treatments are not likely to be effective or patients are unable to use them. Sodium fluoride is not recommended as current data suggest that the bone that is formed is abnormal and does not lead to a decrease in fracture incidence.

Of the osteoporosis treatment regimens named above, the bisphosphonates and parathyroid hormone are currently the most widely prescribed. These classes of compounds have the potential for future more powerful therapeutic action. Bisphosphonates are analogs of pyrophosphate that bind to the surface of bone. When osteoclasts begin to acidify their microenvironment in preparation for bone resportion, bisphosphonates are released and a rise in their concentration inhibits the ability of the cell to express a ruffled border and induces apoptosis. Because the osteoclast must polarize in order to attach to the surface of bone and elaborate acid hydrolases across its ruffled border, this type of inhibition substantially reduces the ability of the osteoclast to resorb bone. There are two types of bisphosphonates, nitrogen-containing and non-nitrogen containing. It is the nitrogen-containing compounds that are most effective in the treatment of osteoporosis. These include alendronate, risedronate, zoledronate, pamidronate and ibandronate (Table II). These drugs can be administered daily, weekly, monthly or even yearly depending on the drug and how it is prepared. Clinical trials have shown up to a 51% decrease in the risk of hip fracture, 44% decrease in the risk of wrist fracture, and 46% decrease in the risk of vertebral fracture within the first two years of treatment9,10.

TABLE II
Commonly Used Bisphosphonates for the Treatment of Osteoporosis

Generic Name

Proprietary Name

Route of Administration

Relative Potency

Etidronate

Didronel

Oral

-

Alendronate

Fosamax

Oral

150

Risedronate

Actonel, Optinate

Oral

700

Ibrandronate

Bondronat, Boniva

Intravenous, oral

860

Zoledronic acid

Zometa

Intravenous

>10,000

Names and relative potencies of currently available bisphosphonate treatments for osteoporosis. Other bisphosphonates are available for the treatment of skeletal conditions but are not used in the management of osteoporosis.

Parathyroid hormone is the first drug to be shown safe and effective for the stimulation of bone formation in patients with osteoporosis. In a randomized placebo-controlled trial in over 1,500 post-menopausal women, daily subcutaneous injection of 20 mg PTH led to a significant decrease in the risk of vertebral and non-vertebral fractures and an increase in vertebral, non-vertebral and total body bone mineral density. Although currently formulated as a subcutaneous injection, several pharmaceutical companies are now developing oral preparations of this drug and preparing to test them in clinical trials7.

Special Orthopaedic Considerations for Osteoporosis Treatment Drugs
Recent investigations on the use of certain osteoporosis treatment drugs have raised some concerns but also have pointed to potential opportunities in orthopaedic patients. Anecdotal reports have suggested that potential over-suppression of bone turnover during long-term bisphosphonate use leads to an increase in the incidence of stress fractures. Odvina et al.11 reported on nine patients who sustained spontaneous non-spinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for three months to two years during therapy.

Because patients with osteoporosis are typically older and may heal fractures more slowly, the development of a drug that could enhance fracture healing would be attractive. Recent evidence in animal studies suggests that PTH may have this effect. Two independent reports have recently shown that doses of PTH (1-34) similar to those used in patients can enhance and accelerate the healing of fractures12,13. Presently, a randomized controlled clinical trial is underway to test the hypothesis that a daily subcutaneous injection of PTH (1-34) enhances the healing of distal radius fractures in post menopausal women.

Future Directions
With the introduction of nitrogen-containing bisphosphonates and PTH, substantial progress has been made in the treatment of patients with osteoporosis. Future directions for new therapies include the development of drugs that specifically target the cellular mechanisms related to excessive osteoclastic resorption and oral preparations of PTH, a drug that may potentially restore the bone lost as a consequence of this disease. As these new treatments become available it is likely that they will also be applied to other orthopaedic conditions and thus enhance overall skeletal health.

References

  1. www.nof.org. Americas Bone Health: The state of osteoporosis and low bone mass in our nation. National Osteoporosis Foundation. Accessed July 23, 2002.
  2. 2. Baron, R.: General Principles of Bone Biology. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Fifth Edition, Edited by MJ Flavus, Philadelphia, Am. Soc. Bone Miner. Res., 2003, pp.1-8.
  3. Teitelbaum S.L.: Bone resorption by osteoclasts. Science 289:1504-1508, 2000.
  4. Writing Group for the Womens Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Womens Health Initiative Randomized Controlled Trial. JAMA;288:321-333, 2002.
  5. Delmas P.D., Bjarnason N.H., Mitlak, B.H., Ravoux A.C., Shah A.S., Huster W.J., Draper M., Christiansen C.: Effects of raloxifen on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641-1647, 1997.
  6. Silverman S.L., Chestnut C., Baylink D., Gimona A., Adriano K., Mindeholm L. 2001. Salmon calcitonin nasal spray (SCNS) is effective and safe in older osteoporotic women-results from the PROOF study. J Bone Miner Res 16:S1;S530, 2001.
  7. Neer R.M., Arnaud C.D., Zanchetta P.R., Prince R., Gaich G.A., Reginster J.Y., Hodsman A.B., Eriksen F.F., Ish-Shalom S., Genant H.K., Wang O., Mitlak B.H.: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoperosis. N Engl Med;344:1434-14, 2001.
  8. Riggs B.L., Hodgson S.R., OFallon W.M., Chao E.Y., Wahner H.W., Muhs J.M., Cedel S.L., Melton L.J. 3rd: Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoperosis. N Engl J Med;322:802-809, 1990.
  9. Morris C.D., Einhorn T.A.: Current Concepts Review: Bisphosphonates in Orthopaedic Surgery. J Bone Joint Surg., 87:1609-1618,2005.
  10. Black D.M., Cummings S.R., Karpf D.B., Cauley J.A,. Thompson D.E., Nevitt M.C., Bauer D.C., Genant H.K., Haskell W.L., Marcus R., Ott S.M., Torner J.C., Quandt S.A., Reiss T.F., Ensrud K.E.: Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet;348:1535-1541, 1996.
  11. Odvina C.V., Zerwekh J.E., Rao D.S., Maalouf N., Gottschalk F.A., Pak C.Y.: Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab;90:1294-1301, 2005.
  12. Alkhiary Y.M., Gerstenfeld L.C., Krall E., Westmore M., Sato M., Mitlak B.H., and Einhorn T.A.: Enhancement of experimental fracture healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg., 87:731-741, 2005.
  13. Nakazawa T., Nakajima A., Shiomi K., Moriya H., Einhorn T.A., and Yamazaki M.: Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing. Bone, 37:711-719, 2005.

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