Postmenopausal Osteoporosis RESULTS

Pharmacological treatment recommendations to prevent fractures in women with PMO include:

  • antiresorptive agents: bisphosphonates, selective estrogen receptor modulators (SERMs), and calcitonin.
  • bone anabolic agents: the parathyroid hormone (PTH) therapeutic class.

Until evidence of risks of cardiovascular disease and breast cancer associated with hormone replacement therapy (HRT) was published in 2003, HRT had been recommended for preventing menopause-related bone loss and PMO until evidence of risks of cardiovascular disease and breast cancer associated with HRT was published in 2003. Based on these risks, most guidelines do not broadly recommend HRT for PMO prevention; instead, they suggest that the risks and benefits of HRT be carefully weighed for each patient.

In this article, we discuss products for which an indication has been approved by the Food and Drug Administration (FDA), or when clinical trial data support their use for PMO, and when there is a focus on clinical efficacy, as measured by a reduced risk of fracture. Approved indications, recommended dosages, and side effects are summarized in Table 2. Table 3 presents an overview of clinical trials reporting efficacy for these products.

Multiple products are in clinical development in the U.S. for use in PMO, such as:

  • zoledronic acid (Reclast, Novartis), a bisphosphonate.
  • two SERMs (one agent, bazedoxifene, has received an approvable letter from the FDA).
  • another form of human PTH (1-84), or “full-length” PTH.
  • two PTH intranasal agents.
  • an oral PTH formulation.
  • PTH-related protein (PTHrP).
  • denosumab (AMG-162, Amgen, a fully human monoclonal antibody that neutralizes the receptor activator of nuclear factor-KB ligand (RANKL).
  • cathepsin K inhibitor, which prevents bone loss while allowing bone formation to continue.
  • Strontium ranelate, which is available in Europe and promotes bone formation while decreasing bone resorption.

Published phase 2 and 3 studies with fracture endpoints were available for PTH (1-84) and strontium ranelate, and they are thus discussed in this review.

Antiresorptive Agents

Bisphosphonates

Bisphosphonates are antiresorptive agents that inhibit the bone-resorptive activity of osteoclasts, thereby reducing bone turnover and bone loss. Three bisphosphonates have FDA approval for treating and preventing osteoporosis: alendronate (Merck), risedronate (Procter & Gamble/Sanofi-Aventis), and (Roche). These drugs for PMO are available in oral formulations for daily dosing. Alendronate and risedronate are also available in once-weekly oral formulations, and ibandronate is available in a once-monthly oral formulation. Injectable ibandronate is available for quarterly administration.

Table 2 Indications and Dosing for Products Used

Product Approved Indication PMO Dose* Side Effect Comment
Bisphosphonates
  Prevention and treatment of PMOOsteoporosis in men

Glucocorticoid-induced osteoporosis

Paget’s disease

Prevention: 35 mg q.w.,5 mg q.d. Treatment: 70 mg q.w.,

10 mg q.d.

Dysphagia, esophagitis, esophageal ulcer, gastric ulcer Risk of upper GI adverse events may be greater in women who lie down after taking dose or who do not take with adequate amount of water
Risedronate Prevention and treatment of PMOGlucocorticoid-induced osteoporosis

Osteoporosis in men

Paget’s disease

5 mg q.d., 35 mg q.w. Dysphagia, esophagitis, esophageal ulcer, gastric ulcer Risk of upper GI adverse events may be greater in women who lie down after taking dose or who do not take with adequate amount of water
Ibandronate Prevention and treatment of PMO 2.5 mg q.d.; 150 mg q.m. 3 mg IV, every 3 months Dysphagia, esophagitis, esophageal ulcer, gastric ulcer Risk of upper GI adverse events may be greater in women who lie down after taking dose or who do not take with adequate amount of water
  Paget’s disease 400 mg/day every 3 months Headache, gastritis, leg cramps, arthralgia Approved for use in osteoporosis outside U.S.
Pamidronate Hypercalcemia of malig-nancy,Paget’s disease, osteolytic bone metasta­sis of breast cancer, osteolytic lesions of multiple myeloma 30 mg IV over 3 hours every 3 months Hypertension, headache, musculoskeletal pain, ONJ Dose and infusion times vary byindication See package insert for details Risk of renal adverse events may

be reduced if infused over a

longer time

Zoledronic acid Hypercalcemia of malig-nancy,bone metastasis of solid tumor,Paget’s disease 4 mg IV over 15 minutes for one dose Musculoskeletal pain, nausea, fever, deteriora­tion in renal function,ONJ Incidence of renal adverse effects greater with short infusion time (i.e., 5 minutes)
SERMs
  Prevention and treatment of PMO 60 mg q.d. Hot flashes, leg cramps Associated with increased risk of venous thrombosis
Calcitonin
Calcitonin-salmon Treatment of PMO 200 IU intranasal q.d. 100 IU SQ q.o.d. Rhinitis, back pain Indicated for PMO when HRT is not tolerated or is not acceptable
Parathyroid hormones
Teriparatide Treatment of PMO with previous fracture or multiple risk factors 20 mcg SQ q.d. Leg cramps, dizziness Associated with osteosarcoma in ratsTreatment for more than 2 years not recommended
GI = gastrointestinal; HRT = hormone replacement therapy; IU = International Unit; ONJ = osteonecrosis of the jaw; PMO = postmenopausal osteoporosis; q.d. = daily; q.m. = monthly; q.o.d. = every other day; q.w. = weekly; SERM = selective estrogen receptor modulator; SQ = subcutaneous. * If not approved for PMO, the dose provided is the approved indication. Data from product prescribing information.

Bridging studies were conducted for intermittent oral and in-jectable dosage forms of alendronate mediacation, risedronate, and iban-dronate to establish equivalency to daily dosage formulations based on BMD outcomes. However, because these studies did not include fracture outcomes, they are not discussed in this article.

Etidronate disodium (Didronel canadian, Procter & Gamble) and zol-edronic acid are available in the U.S. Although they show evidence of fracture efficacy in PMO, they are not approved for osteoporosis. Etidronate tablet, indicated for Paget’s disease, is approved for osteoporosis outside the U.S. An injectable agent, zoledronic acid is approved for hypercalcemia of malignancy, bone metastases of solid tumors, and Paget’s disease.

Table 3 Efficacy of Treatment in Fracture Prevention in Postmenopausal Osteoporosis

Product

Dose for Active Arm

Reduction in Fracture Risk

Key/Comment

Bisphosphonates
Alendronate 5 mg q.d. 24 months, then 10 mg/day 5 mg or 10 mg q.d.5 mg or 10 mg q.d. 5 mg, 10 mg q.d. 47% (v) a 44% (v) bNS (nv) c 65% (v) c

48% (v) d

NS (v) e

a.  postmenopausal women with a prior fracture at 3 years51b.  postmenopausal women with no prior fracture at 4 years52

c.  trial extension, between treatment years 6 and 1054

d.  postmenopausal women at 3 years51

e.  trial extension, between treatment years 6 and 1054

  2.5 mg or 5 mg q.d. 2.5 mg or 5 mg q.d.

41% (v) f

40% (h) g

f.  postmenopausal women with a prior fracture at 3 years57g. postmenopausal women with T-scores of -3.0 to -4.0, + one other

risk factor at 3 years58

Ibandronate 2.5 mg q.d. or 20 mg cyclicj

50%-62% (v) h

h. postmenopausal women with T-scores below -2.5 and a prior frac­ture at 3 years60
Etidronate 400 mg days 4-17 of 90-day cycle

NS i

i. prevention trial in postmenopausal women at 3 years61,62
Zoledronic acid 5 mg IV over 15 minutes

25% (nv)j

41% (h)j

70% (v) j

j. postmenopausal women with T-scores below -2.5 or below -1.5 and two prior mild or one moderate vertebral fracture63
SERMs
Raloxifene tablet 60 mg q.d. 40% (v) k 30%%(v)l lNS m k. postmenopausal women with T-scores below -2.5 with no prior frac­ture at 3 years65l. postmenopausal women with T-scores of below -2.5, with a prior

fracture at 3 years65

m. extension trial, years 4 to 867

Calcitonin
Calcitonin-salmon 200 IU intranasal q.d.

33% (v)n

n. postmenopausal women at 5 years68
Parathyroid hormone
Teriparatide 20 mcg

65% (v) o

53% (nv) o

o. postmenopausal women with a prior vertebral fracture at 17 to 19 months70
h = hip; IU = International Units; NS = not significant; nv = nonvertebral; q.d.,= daily; q.m. = monthly; q.w. = weekly; v = vertebral. * All were randomized, placebo-controlled trials of fracture reduction with treatment versus placebo. j Once daily for 12 doses every 3 months.

The most common adverse drug events (ADEs) associated with alendronate, risedronate, and ibandronate are upper gastrointestinal (GI) side effects such as dysphagia, esophagitis, esophageal ulcers, and gastric ulcers. A rare but recently publicized ADE occurring with all bisphosphonates is osteo-necrosis of the jaw (ONJ). This uncommon ADE has been reported most frequently with zoledronic acid and pamidronate (Aredia, Novartis) in cancer patients who have received chemotherapeutic agents or glucocorticoids and who have undergone invasive dental procedures. A few cases have been reported for patients using oral bisphosphonates for PMO or other diagnoses.