Although they have different mechanisms of action, both agents are important interventions in managing osteoporosis
An estimated 44 million Americans—55 percent of those 50 years of age and older—are at risk of osteoporosis, according to the National Osteoporosis Foundation. Approximately half of all women and one quarter of all men older than age 50 will have an osteoporosis-related fracture in her or his remaining lifetime. That adds up to more than 1.5 million fractures annually, including more than 300,000 hip fractures.
Although orthopaedic surgeons may see themselves only becoming involved when the fracture occurs, this role may change as insurers and the federal government increase the emphasis on prevention. Under the Physicians’ Quality Reporting Initiative, which went into effect this past July 1, half of the 10 measures that apply to orthopaedics relate to management of osteoporosis, including prescribing pharmacologic therapy for patients who have fractures of the hip, spine, or distal radius.
The role of bisphosphonates and parathyroid hormone (PTH) in treating bone disorders such as osteoporosis is evolving as our understanding of the specific actions of these compounds increases. Bisphosphonates are antiresorptive agents that act by inhibiting osteoclastic bone destruction and slowing down bone turnover. PTH, on the other hand, is an anabolic agent that promotes bone formation and improvement in bone micro-architecture and strength.
Osteoporosis is a metabolic bone disorder characterized by decreased bone mass that results from an imbalance between bone formation and bone resorption. The current standard for diagnosis is based on measurement of bone mineral density (BMD) at the spine and hip through dual energy X-ray absorptiometry (DEXA) scanning. Values are reported as t scores, which reflect the difference of the patient’s BMD from those of young adult women.
A t score of -2.5 denotes a BMD that is 2.5 standard deviations below the average peak bone mass of young adult women and defines osteoporosis.
Treating osteoporosis with bisphosphonates
Bisphosphonates are metabolically stable synthetic analogs of pyrophosphate. The phosphorus-carbon-phosphorus (P-C-P) bond replaces the phosphorus-oxygen-phosphorus (P-O-P) bond and imparts resistance to enzymatic degradation. Different bisphosphonate molecules have unique pharmacologic profiles, depending on the side-chains attached to the carbon atom.
The two main classes of bisphosphonates, based on their side-chain groups, are simple or non–nitrogen-containing, and nitrogen-containing or amino-bisphosphonates. Simple bisphosphonates include clodronate (Bonefos®), etidronate (Didronel®), and tiludronate (Skelid®). The more potent nitrogen-containing bisphosphonates include pamidronate (Aredia®), alendronate (Fosamax®), risedronate (Actonel®), and zoledronic acid (Zometa®).
Normal osteoclastic bone resorption renders the local environment acidic and exposes hydroxyapatite. The phosphate groups in bisphosphonates are attracted to the hydroxyapatite calcium ions and bind to them irreversibly through surface charge, thus accumulating on the bone surface.
At this point, the mechanisms of action of the two bisphosphonate classes diverge. When internalized by mammalian cells, simple bisphosphonates are metabolized into methylene-containing analogues of adenosine triphosphate (ATP), which then builds up in the cytosol. The accumulation of these toxic, nonhydrolyzable analogues inhibits ATP-dependent enzymes, leading to osteoclast apoptosis.1 The nitrogen-containing bisphosphonates, on the other hand, inhibit the enzyme farnesyl diphosphate (FPP) synthase. This enzyme plays a central role in the mevalonate pathway that produces cholesterol and isoprenoid lipids, important metabolites for the prenylation (post-translational modification) of membrane-surface proteins such as GTPases, which regulate vital cellular processes.
Alendronate and risedronate are commonly used for treating postmenopausal osteoporosis. The landmark Fracture Intervention Trial studied the effects of alendronate on women who had vertebral fractures at baseline. In postmenopausal women with low bone mass, the use of alendronate increased BMD at the hip by 4.7 percent over a 3-year follow-up. It also reduced the risk for new radiographic vertebral fractures by 47 percent and reduced the risk for new clinical vertebral fractures by 55 percent.2 In another study, treatment with alendronate resulted in a 48 percent lower risk of new vertebral fractures after 3 years.3
BMD increases at the lumbar spine, hip, forearm, and total body were maintained over 10 years, according to a follow-up study on the same patients.4 Risedronate, a second-generation bisphosphonate, has also been shown to increase BMD in women with osteoporosis or osteopenia, and to decrease fracture risk by 30 percent to 50 percent.5 Transiliac bone biopsies after 5 years of risedronate therapy showed preservation of trabecular bone architecture and normal bone mineralization.6 The major adverse effects associated with oral bisphosphonates are dyspepsia, nausea, acid reflux, gastritis, and gastric ulcers.2,3
PTH use in osteoporosis treatment
PTH is a key regulator of calcium metabolism that is secreted as an 84-amino acid protein [hPTH (1-84)] in response to changes in extracellular calcium concentrations. Biologic activity resides in a 34-amino acid portion [hPTH (1-34)] that binds to the same PTH cell-surface receptors in the kidneys and bone. hPTH(1-34) has been synthesized through recombinant DNA and is marketed as teriparatide (Forteo®).
Normally, bone formation is preceded by bone resorption. PTH temporarily uncouples bone formation from resorption and stimulates osteoblastic activity without requiring prior resorption.7 Although the exact mechanisms are still unclear, researchers have observed that daily intermittent injections of PTH temporarily increase levels above normal8 and are followed by a fall to below-normal levels. This results in increased trabecular bone volume9 as well as increased cortical bone thickness.10 PTH therefore represents a bone anabolic therapy, in contrast to the anticatabolic action of bisphosphonates.
In one clinical trial, 1,637 postmenopausal women with prior vertebral fractures were randomized to receive daily subcutaneous self-injections of 20 µg of teriparatide, 40 µg of teriparatide, or placebo. At a median of 21 months, the teriparatide groups had significant increases in spine, hip, and total body BMD. The 40 µg-dose group experienced greater increases in BMD than the 20 µg-dose group, but both groups had similar reductions in risk for both new vertebral and nonvertebral fractures.11 Headaches, nausea, and hypercalcemia occurred more often with the 40 µg-dose. Dizziness and leg cramps were the other reported adverse events; serum creatinine and creatinine clearance were not affected by teriparatide treatment.
In a follow-up study, more than 90 percent of the patients returned for safety surveillance and spine radiographs 18 months after the randomized trial closed. Patients were receiving osteoporosis treatment at the discretion of their private physicians. Although more patients in the original placebo group were now taking osteoporosis drugs, the two teriparatide groups continued to have lower relative risk for new vertebral fractures—41 percent lower in the 20 µg-dose group and 45 percent lower in the 40 µg-dose group.12
Combination or sequential therapy?
If antiresorptive therapy with bisphosphonates and anabolic therapy with PTH are individually effective in increasing BMD and reducing fracture risk, would combination therapy with these agents have additive or synergistic effects?
To answer this question, 238 postmenopausal women with low BMD at the spine or hip were randomly assigned to treatment with 100 µg of hPTH(1-84) daily, 10 mg of alendronate daily, or both.13 After 12 months, spine BMD increased in all treatment groups, but the combination therapy did not show any significant advantage. The volumetric density of trabecular bone at the spine also increased in all groups; the hPTH group experienced a two-fold increase compared to either of the other groups. This short-term study suggests that alendronate reduces, rather than potentiates, the anabolic effect of PTH when they are given together.
In the continuation of this study, the hPTH-treated women were randomly assigned to receive one year of alendronate or placebo.14 Those who received follow-up alendronate therapy had significant increase in BMD; those who received placebo had a substantial loss of BMD, implying that alendronate therapy may be beneficial in sustaining gains in BMD from PTH treatment.
In another study, 126 women with osteoporosis who were already on alendronate therapy were randomized to three groups: a) continued alendronate therapy at 70 mg weekly; b) 25 µg of hPTH(1-34) daily plus alendronate therapy; or c) cyclic hPTH(1-34) therapy plus alendronate therapy(3 months on/3 months off).15 Lumbar spine BMD did not increase significantly in the alendronate group but did increase significantly in both the daily and cyclic hPTH(1-34) groups, suggesting that parathyroid hormone therapy may be beneficial for patients who have not responded to prior alendronate therapy.
The Endocrine Society’s guidelines for clinical practice16 state that candidates for teriparatide therapy include patients with preexisting osteoporotic fractures, patients with very low BMD, and patients with an unsatisfactory response to antiresorptive therapy. Most randomized trials on the use of PTH for postmenopausal osteoporosis have short-term (12 to 36 months) follow-up; teriparatide [hPTH(1-34)] is FDA-approved while intact PTH [hPTH(1-84)] is not.
In contrast, there are 10-year follow-up studies on bisphosphonate use for postmenopausal osteoporosis. Although clinical trials have proven the efficacy of long-term (5 years or more) bisphosphonate therapy, the safety of such regimens should be monitored closely. One recently published case series has identified low-energy subtrochanteric fractures in nine women who had been on alendronate therapy for more than 2.5 years.17 Whether these represent insufficiency fractures caused by chronic, bisphosphonate-induced suppression of bone remodeling is still unknown. At present, long-term bisphosphonate therapy for osteoporotic women is supported by high-level studies.
The important features of the bisphosphonates and PTH are summarized in Table 1. Although these two drug groups feature prominently in osteoporosis management, risk factor modification as well as vitamin D and calcium intake should also be addressed under established guidelines. Lastly, although these drugs have been presented in the context of women’s health, they are also clinically useful for men who have osteoporosis.
Benjamin E. Tuy, MD, is a fellow in musculoskeletal oncology, and Joseph Benevenia, MD, is the director of musculoskeletal oncology and professor of orthopaedics at the University of Medicine and Dentistry-New Jersey Medical School in Newark, N.J. Dr. Benevenia is also a member of the AAOS Biological Implants Committee and can be reached at firstname.lastname@example.org
- Roelofs AJ, et al., Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res, 2006. 12(20 Pt 2): p. 6222s-6230s.
- Black DM, et al., Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet, 1996. 348(9041): p. 1535-41.
- Liberman UA, et al., Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med, 1995. 333(22): p. 1437-43.
- Bone HG, et al., Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med, 2004. 350(12): p. 1189-99.
- Sorensen OH, et al., Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone, 2003. 32(2): p. 120-6.
- Borah B, et al., Long-term risedronate treatment normalizes mineralization and continues to preserve trabecular architecture: sequential triple biopsy studies with micro-computed tomography. Bone, 2006. 39(2): p. 345-52.
- Hodsman AB and Steer BM, Early histomorphometric changes in response to parathyroid hormone therapy in osteoporosis: evidence for de novo bone formation on quiescent cancellous surfaces. Bone, 1993. 14(3): p. 523-7.
- Hock JM and Gera I, Effects of continuous and intermittent administration and inhibition of resorption on the anabolic response of bone to parathyroid hormone. J Bone Miner Res, 1992. 7(1): p. 65-72.
- Reeve J, et al., Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. Br Med J, 1980. 280(6228): p. 1340-4.
- Dempster, DW, et al., Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res, 2001. 16(10): p. 1846-53.
- Neer RM, et al., Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med, 2001. 344(19): p. 1434-41.
- Lindsay R, et al., Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis. Arch Intern Med, 2004. 164(18): p. 2024-30.
- Black DM, et al., The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med, 2003. 349(13): p. 1207-15.
- Black DM, et al., One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med, 2005. 353(6): p. 555-65.
- Cosman F, et al., Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med, 2005. 353(6): p. 566-75.
- Hodsman AB, et al., Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev, 2005. 26(5): p. 688-703.
- Goh S-K, et al., Subtrochanteric insufficiency fractures in patients on alendronate therapy. A Caution. J Bone Joint Surg, 2007. 89-B(3): p. 349-353.