Bisphosphonate treatment of osteoporosis

https://doi.org/10.1016/S0749-0690(02)00069-1Get rights and content

Section snippets

Mechanism of action

As mentioned above, bisphosphonates are considered “antiresorptive” drugs because they reduce bone resorption. Non-nitrogen-containing bisphosphonates (such as etidronate and clodronate; see Table 1) produce toxic analogs of adenosine triphosphate that lead to cell death [33]. Nitrogen-containing compounds (such as alendronate, risedronate, ibandronate, and zoledronate; see Table 1) appear to have a different mechanism of action; they work by interfering with protein prenylation [34] through

Clinical trials

Alendronate was the first bisphosphonate approved by the FDA (1995) for use in osteoporosis. It is approved for prevention and treatment of postmenopausal osteoporosis and for treatment of corticosteroid-induced osteoporosis in men and women and treatment of osteoporosis in men [38].

Alendronate is a nitrogen-containing bisphosphonate (Table 1) [39]. The pivotal phase III study with alendronate involved almost 1000 postmenopausal women who were recruited because of low bone mineral density

Clinical trials

Risedronate is a nitrogen-containing bisphosphonate, with the nitrogen contained in a pyridinyl ring [64]. It is approved for the prevention and treatment of postmenopausal osteoporosis and for prevention and treatment of glucocorticoid-induced osteoporosis [65]. Its effectiveness for prevention of vertebral fractures was shown in two pivotal studies of over 3600 women with prevalent vertebral fractures [66], [67]. The primary end point in these trials was the reduction of new vertebral

Clinical trials

The first bisphosphonate to be studied in osteoporosis was etidronate. Given continuously, etidronate may impair mineralization of new bone [77], so an intermittent cyclical regimen (400 mg daily for 14 days every 3 months) was used that was safe and appeared effective in small trials [78], [79], [80]. As is true for other bisphosphonates, etidronate must be taken on an empty stomach (with water only). Etidronate can be taken between meals (2 hours before and 2 hours after eating) or during the

Bisphosphonates in development

A number of other compounds, including olpadronate and neridronate, have seen clinical use outside the United States, but are not available in the United States and are not being pursued for general commercial development.

Ibandronate, 1 mg given intravenously every 3 months to women with postmenopausal osteoporosis, increased BMD but did not reduce the risk of fracture [129]; perhaps the dose was too low or the interval was too long. Oral ibandronate has recently been reported to prevent bone

How do different bisphosphonates compare in efficacy?

There are no head-to-head trials that compare one bisphosphonate with another for treatment of osteoporosis, except for using surrogate markers such as changes in BMD or biochemical markers. It is tempting to look at increases in bone density in different trials; however, the changes in bone density using the same agent in different trials can vary by 20% to 30% [66], [132], [133], [134], and changes in BMD correlate only weakly with reduction in fractures [135], [136]. Based on available data,

How do bisphosphonates compare with other agents in efficacy?

Again, there are no head-to-head trials with fracture end points that compare bisphosphonates with other agents. Bisphosphonates are the only currently approved agents that have been shown to reduce the risk of hip and other nonvertebral fractures [42], [44], [66], [70]. For this reason, bisphosphonates are considered by most authorities to be the treatment of choice for patients who are at risk for a variety of fractures.

How do bisphosphonates compare with each other in tolerability?

Although alendronate seemed well tolerated in clinical trials [53], daily dosing with alendronate appeared to cause esophageal problems (eg, heartburn, pain on swallowing, and so forth) in about 10% of patients. Tolerability problems with daily dosing of risedronate appear infrequent [75]. There have been a number of head-to-head trials of alendronate and risedronate that looked at gastric lesions (with conflicting results) [140], [141]. A few unpublished studies have looked at rechallenge,

General side effects and toxicity

There has also been concern that potent bisphosphonates might turn off remodeling completely, leading to “frozen bone.” There is no evidence that this actually occurs in humans. There are studies that show increased microcracks but preserved biomechanical properties in dogs treated with very high doses of bisphosphonates [144], [145]. Fracture healing does not appear to be a problem with low doses of etidronate [146], alendronate [147], or any of the newer bisphosphonates [148].

Combination of bisphosphonates with other agents

Should bisphosphonates be used in combination with other agents? Several classes of agents have proven effectiveness in reducing osteoporotic vertebral fractures. Although all current agents are antiresorptive drugs, mechanisms of action differ, which offers the possibility that combining two agents might produce greater benefit than would a single agent. Combining a bisphosphonate with calcitonin is probably safe, although data on BMD response is lacking. Several studies have shown greater

Summary

Bisphosphonates represent the agents of choice for most patients with osteoporosis. They are the best studied of all agents for the prevention of bone loss and reduction in fractures. They increase BMD, primarily at the lumbar spine, but also at the proximal femur. In patients who have established osteoporosis, bisphosphonates reduce the risk of vertebral fractures, and are the only agents in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures.

First page preview

First page preview
Click to open first page preview

References (158)

  • A.B. Hodsman

    Effects of cyclical therapy for osteoporosis using an oral regimen of inorganic phosphate and sodium etidronate: a clinical and bone histomorphometric study

    Bone Miner

    (1989)
  • R.J.M. Herd et al.

    Prevention of early menopausal bone loss by cyclical etidronate therapy: a 2-year, double-blind, placebo-controlled study

    Am J Med

    (1997)
  • A. Struys et al.

    Cyclical etidronate reverses bone loss of the spine and proximal femur in patients with established corticosteroid-induced osteoporosis

    Am J Med

    (1995)
  • B.F. Boyce et al.

    Focal osteomalacia due to low-dose diphosphonate therapy in Paget's disease

    Lancet

    (1984)
  • P.D. Miller et al.

    Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after 7 years of treatment

    Am J Med

    (1997)
  • P. Filipponi et al.

    Cyclical intravenous clodronate in postmenopausal osteoporosis: results of a long-term clinical trial

    Bone

    (1996)
  • S. Giannini et al.

    Effects of one-year cyclical treatment with clodronate on postmenopausal bone loss

    Bone

    (1993)
  • S. Giannini et al.

    Continuous and cyclical clodronate therapies and bone density in postmenopausal bone loss

    Obstet Gynecol

    (1996)
  • J. Herrala et al.

    Clodronate is effective in preventing corticosteroid-induced bone loss among asthmatic patients

    Bone

    (1998)
  • B. Bar Oz et al.

    Myositis ossificans progressiva: a 10-year follow-up on a patient treated with etidronate disodium

    Acta Paediatr

    (1994)
  • R.D. Chapurlat et al.

    Long-term effects of intravenous pamidronate in fibrous dysplasia of bone

    J Bone Miner Res

    (1997)
  • D.E. Garland et al.

    Diphosphonate treatment for heterotopic ossification in spinal cord injury patients

    Clin Orthop Rel Res

    (1983)
  • S.L. Stover et al.

    Disodium etidronate in the prevention of postoperative recurrence of heterotopic ossification in spinal-cord injury patients

    J Bone Joint Surg

    (1976)
  • F.H. Glorieux

    Bisphosphonate therapy for severe osteogenesis imperfecta

    J Pediatr Endocrinol

    (2000)
  • D.W. Kennedy et al.

    The effects of etidronate disodium on progressive hearing loss from otosclerosis

    Otolaryngol Head Neck Surg

    (1993)
  • R.D. Altman et al.

    Influence of disodium etidronate on clinical and laboratory manifestations of Paget's disease of bone (osteitis deformans)

    N Engl J Med

    (1973)
  • C. Roux et al.

    Treatment of patients with Paget's disease of bone

    Drugs

    (1999)
  • D. Chappard et al.

    Effects of tiludronate on bone loss in paraplegic patients [abstract]

    J Bone Miner Res

    (1995)
  • L.A. Ruml et al.

    Prevention of hypercalciuria and stone-forming propensity during prolonged bedrest by alendronate

    J Bone Miner Res

    (1995)
  • S.H. Ralston

    Pathogenesis and management of cancer associated hypercalcemia

    Cancer Surv

    (1994)
  • C.A. Reasner et al.

    Acute changes in calcium homeostasis during treatment of primary hyperparathyroidism with risedronate

    J Clin Endocrinol Metab

    (1993)
  • M. Rossini et al.

    Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism

    J Bone Miner Res

    (2001)
  • D.C. Lee et al.

    The use of pamidronate for hypercalcemia secondary to acute vitamin D intoxication

    J Toxicol Clin Toxicol

    (1998)
  • A.N. Lteif et al.

    Bisphosphonates for treatment of childhood hypercalcemia

    Pediatrics

    (1998)
  • H.N. Rosen et al.

    Therapy with parenteral pamidronate prevents thyroid hormone-induced bone turnover in humans

    J Clin Endocrinol Metab

    (1993)
  • J.D. Adachi et al.

    Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis

    N Engl J Med

    (1997)
  • S. Cohen et al.

    Risedronate therapy prevents corticosteroid-induced bone loss—a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study

    Arthritis Rheum

    (1999)
  • D.M. Reid et al.

    Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial

    J Bone Miner Res

    (2000)
  • K.G. Saag et al.

    Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis

    N Engl J Med

    (1998)
  • K. Ikeda et al.

    Novel usage of alendronate to prevent profound hypocalcemia immediately after parathyroidectomy in patients with severe secondary hyperparathyroidism

    Nephron

    (1999)
  • S. Guis et al.

    Healing of Charcot's joint by pamidronate infusion

    J Rheumatol

    (1999)
  • P.L. Selby et al.

    Bisphosphonates: a new treatment for diabetic Charcot neuroarthropathy

    Diabet Med

    (1994)
  • J.R. Berenson et al.

    Bisphosphonates in the treatment of malignant bone disease

    Annu Rev Med

    (1999)
  • P.P. Major et al.

    Oral bisphosphonates—a review of clinical use in patients with bone metastases

    Cancer

    (2000)
  • J.R. Berenson et al.

    Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma

    N Engl J Med

    (1996)
  • S.F. Hodgson et al.

    The 2001 AACE medical guidelines for clinical practice for the prevention and management of postmenopausal osteoporosis

    Endocr Pract

    (2001)
  • J.C. Koster et al.

    Diminished effect of etidronate in vitamin D deficient osteopenic postmenopausal women

    Eur J Clin Pharmacol

    (1996)
  • J.C. Frith et al.

    Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′ (beta, gamma-dichloromethylene) triphosphate by mammalian cells in vitro

    J Bone Miner Res

    (1997)
  • S.P. Luckman et al.

    Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenelation of GTP-binding proteins, including Ras

    J Bone Miner Res

    (1998)
  • J.E. Fisher et al.

    Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro

    Proc Natl Acad Sci USA

    (1999)
  • Cited by (84)

    • American Association of Oral and Maxillofacial Surgeons’ Position Paper on Medication-Related Osteonecrosis of the Jaws—2022 Update

      2022, Journal of Oral and Maxillofacial Surgery
      Citation Excerpt :

      While the potential for BPs to improve cancer-specific survival remains controversial, these medications have had a significant positive effect on the quality of life for patients with advanced cancer involving the skeleton and reducing or preventing skeletal-related events. Bisphosphonates also are used for the prevention of osteoporosis-related fractures (fragility fractures) in patients with osteoporosis and osteopenia.14-16 BPs administered orally–including alendronate (Fosamax®), risedronate (Actonel®) or parenterally (zoledronic acid [Reclast®]), and ibandronate (Boniva®)—can result in a significant reduction in vertebral and nonvertebral fractures for patients with osteoporosis.17-20

    • Spatiotemporally controlled calcitonin delivery: Long-term and targeted therapy of skeletal diseases

      2021, Journal of Controlled Release
      Citation Excerpt :

      Therefore, osteoporosis therapy is beneficial to solve a severe worldwide public health threat. Until now, there are two commonly used drugs toward osteoporosis in clinic with approval of Food and Drug Administration (FDA): bisphosphonates (BPs) [164] and sCT [165]. The applications of BPs have already been discussed in other reviews. [166–171]

    • Synthesis of some novel orcinol based coumarin triazole hybrids with capabilities to inhibit RANKL-induced osteoclastogenesis through NF-κB signaling pathway

      2018, Bioorganic Chemistry
      Citation Excerpt :

      In view of this, present treatment to bonelytic diseases mainly focuses on the inhibition of osteoclastogenesis. Bisphosphonates are antiresorptive drugs, which are synthetic analogues of pyrophosphates, most commonly used medication for the treatment of osteoporosis and they act by inhibiting osteoclast activity [7]. In addition to this, bisphosphonate have specific serious adverse effects such as renal toxicity and jaw necrosis [8].

    View all citing articles on Scopus
    View full text