Clinical Review

New options in osteoporosis therapy: Combination and sequential treatment

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Perhaps the biggest medical question to emerge from the WHI study is how to best treat postmenopausal osteoporotic women. Could the answer lie in combining 2 current monotherapies?



  • Combination or sequential therapy may benefit the approximately 15% of osteoporosis patients who continue to lose bone on monotherapy.
  • Greater bone-density increases result from bisphosphonate plus either estrogen or raloxifene than from single-agent therapy.
  • The introduction of parathyroid hormone (PTH) (1-34), a therapy that stimulates bone formation, will likely result in development of combination or sequential regimens of PTH plus an antiresorptive agent.
  • Estrogen may be indicated early in the transition to menopause, but many authorities recommend switching to a bisphosphonate in late postmenopause.
  • For menopausal women with a recent osteoporotic fracture, 1 month of calcitonin treatment may help increase bone density and reduce fracture pain. After the pain has resolved, a bisphosphonate, raloxifene, or PTH can be started.
While the headline-grabbing Women’s Health Initiative (WHI) study has been alerting clinicians and patients alike to the risks and benefits associated with hormone replacement therapy (HRT), a series of lower-profile investigations offers new hope to osteoporotic women.

Numerous clinical trials have demonstrated that approximately 15% of women with osteoporosis who are treated with a single drug continue to lose bone mass1,2; particularly resistant are cigarette smokers and women with a body weight below 130 lb.3

But recent studies suggest that combination therapy or sequential treatment may be effective for women:

  • with severe osteoporosis,
  • who continue to lose bone mass while taking a single pharmacologic agent, or
  • who suffer a new fracture while on monotherapy.

No trials to date have shown that combination therapy definitively decreases the fracture rate compared to monotherapy; however, since BMD increases correlate closely with protection against fracture risk, it is likely that a study with adequate power will show a direct correlation.

Here, I review the most promising options.

Combination therapy

The results of the WHI study indicate that estrogen has a complex pattern of risks and benefits in postmenopausal women.4 Clinicians must therefore carefully assess the value of adding estrogen to another pharmacologic osteoporosis treatment for each individual woman.

Patients with menopausal symptoms—such as vasomotor symptoms or urogenital atrophy—are probably the best candidates for combination treatment with estrogen and another antiresorptive agent.

Estrogen plus alendronate. The combination of these 2 agents is probably more effective in increasing BMD than either agent alone.

  • Bone et al.5 For example, in 1 clinical trial, 425 postmenopausal women with osteoporosis were randomized to 1 of 4 treatment groups: conjugated equine estrogens (CEE) alone (0.625 mg daily), alendronate alone (10 mg daily), a combination of the two at the same doses, or placebo. All subjects received daily calcium supplementation (500 mg). After 2 years of treatment, women in the placebo group demonstrated a 0.6% loss in lumbar spine BMD, while patients treated with alendronate or CEE alone showed increases of 6%.
Those taking alendronate plus CEE, however, demonstrated a lumbar-spine BMD gain of 8.3%—an increase significantly greater than that of either monotherapy group (P<.022 in addition women the placebo group showed a increase bmd of proximal femur versus for those taking alendronate given cee and plus cee. all active treatments were well tolerated by participants.>

The authors concluded that the combined use of alendronate and estrogen produced “somewhat larger increases in BMD than either agent alone.”

Fundamentals of osteoporosis prevention and treatment


An optimal daily diet for preventing and treating osteoporosis includes:

  • 1,000 mg to 1,500 mg of elemental calcium in divided doses with meals1
  • Vitamin D 800 IU
  • Sufficient calories to avoid malnutrition
  • Adequate protein

In 1 clinical trial, protein supplementation of 20 g per day was associated with better bone-density preservation and faster rehabilitation after hip fracture than an isocaloric, nonprotein supplement.2


The US Food and Drug Administration (FDA) has approved:

  • Alendronate and risedronate (bisphosphonates) and raloxifene (selective estrogen receptor modulator) for prevention and treatment of osteoporosis (see TABLE 1).
  • Calcitonin and parathyroid hormone (PTH) (1-34) for treatment only.
  • Estrogen for preventing osteoporosis. (Although also effective for treating the disease, it is not specifically approved for this by the FDA.)


FDA-approved treatments*

Alendronate70 mg once per week, orally
Risedronate35 mg once per week, orally
Raloxifene60 mg daily, orally
Calcitonin200 IU daily, by intranasal insufflation
Parathyroid hormone20 μg daily, by subcutaneous injection
*Cost of all agents is approximately $65 per month, except parathyroid hormone, which costs approximately $450 per month.


1. Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med. 1998;338:736.-

2. Schurch MA, Rizzoli R, Slosman D, Vadas L, Vergnaud P, Bonjour JP. Protein supplements increase serum insulin-like growth factor I levels and attenuate proximal femur bone loss in patients with recent hip fracture. Ann Int Med. 1998;128:801-809.

  • Palumba et al.6 In another clinical trial, 150 surgically postmenopausal women with osteoporosis were randomized to 2 years of therapy with 2 mg per day of micronized estradiol plus either placebo, standard-dose alendronate (10 mg daily), or low-dose alendronate (5 mg daily). Micronized estradiol plus alendronate at either the standard or low dose was associated with significantly greater increases in BMD than estradiol plus placebo.
  • Lindsay et al.7 A third clinical trial looked at 428 postmenopausal women with osteoporosis who were already being treated with estrogen for at least 1 year. Subjects were continued on estrogen and randomized to receive alendronate (10 mg daily) or a placebo. After 1 year of treatment, the women taking alendronate showed a significantly greater increase in lumbar-spine BMD (3.6% versus 1%, P<.001 and hip trochanter bmd versus>P<.001 than women taking placebo.>

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