Treatment options

Following the 2004 release of data from the Women’s Health Initiative, women in the 50- to 60-year-old age group switched en masse to bisphosphonates. But reassessment of the cardiac data showed that the higher mortality risk was predominantly in women over age 60, and younger women are now swinging back to HRT. Excess menopausal symptomatology off HRT, including autonomic imbalance and sleep loss, has hastened the return to estrogen usage. Hip-fracture prevention with estrogen is at least 34% better than without HRT, but a 50% risk reduction is possible with bisphosphonates.

The bisphosphonates achieved their prominent position as the best choice for alleviating postmenopausal osteoporosis and glucocorticoid-induced osteoporosis by virtue of their potent antiresorptive effects. More than 200 million prescriptions have been written for these agents worldwide. The increased rate of bone remodeling and turnover in postmenopausal women leads to rapid bone loss, especially in the first three years, with slowing of loss thereafter to about 1%-2% per year. The bisphosphonates are synthetic analogs of pyrophosphonate, which binds to hydroxyapatite in the mineral bone matrix. Prolonged binding at this site allows the inhibition of osteoclast-mediated bone resorption and establishes a new steady state of turnover, similar to that in healthy premenopausal women.

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Alendronate. In 10-year studies, the antiresorptive effect of alendronate persists over the entire study period, but gains in BMD tend to peak in the first three to five years after initiation of therapy.1 The gains remain level thereafter, resulting in 10% increments at the hip trochanter and 5% at the femoral neck. Lumbar BMD levels increase up to 14% at 10 years, but these likely reflect the sclerotic effects of osteoarthritis combined with the typical osteoporotic gains seen at other sites. Reductions of 70% in urinary N-telopeptide (uNTx), the most commonly used biochemical marker for bone resorption, occur by three to six months and remain stable over the entire 10-year period. The mean premenopausal level of this marker (26 nanomoles bone collagen equivalent/millimole creatinine) is achieved and maintained.

When dosing is halted at five years for a drug holiday, residual bone alendronate maintains the premenopausal turnover effect for one year or even longer. Many patients can be managed with restart of alendronate if the uNTx rises on sequential tests. In 2008, alendronate will achieve generic status, and its lower cost will likely lead to increased usage of bisphosphonates in older individuals on fixed incomes.

Risedronate. The second bisphosphonate to be released, risedronate touted itself as quicker than alendronate in achieving fracture reduction. However, risedronate is likely the less potent antiresorptive agent, as indicated by the Fosamax Actonel Comparison Trial (FACT), in which alendronate yielded significantly greater reductions in biochemical markers at three months compared with risedronate.2 Greater BMD gains occurred with alendronate as well, but fractures occurred at a similar incidence in both treatment groups.

Loss of market share to ibandronate, by virtue of its monthly dosing convenience, led to the recent release of risedronate 75 mg, dosed on two successive days each month. However, biochemical marker suppression is only 34% on this schedule. Monthly risedronate dosing is expected soon.

Ibandronate. Like alendronate, ibandronate reduces uNTx by 60%-70% and clinical vertebral fractures (Figure 2) by 50% with the present dosing schedule of 150 mg/month. Compared with weekly dosing schedules of alendronate and risedronate, compliance with ibandronate is improved, by patient report, with data at one year revealing that only 50% of patients continued to use the other two bisphosphonates. Medication costs and the asymptomatic nature of osteoporosis are blamed for this poor usage of weekly agents.

Zoledronic acid. The newest competitor for the bisphosphonate market is zoledronic acid, an agent previously approved for Paget’s disease of the bone in men and women and now approved for once-yearly administration to treat osteoporosis. Zoledronic acid was previously used for malignancy-induced hypercalcemia. The dosage will be a single 5-mg IV administration, given over 15 minutes, probably on an annual basis for osteoporotic patients. Paget’s disease patients will likely relapse, and shorter intervals between dosings will be needed. Osteopenic patients may eventually qualify as well.

During the first three days post IV treatment, about 10% of patients experience mild-to-moderate influenzalike symptoms. These include fevers, chills, arthralgias and myalgias, and bone pains. Nausea and dizziness occur in about 10% of recipients as well. These symptoms resolve by day 4 but often require analgesics or antipyretics. In one osteoporosis trial, atrial fibrillation occurred more often in the zoledronic-acid group, but this finding has not been noted in other clinical studies or in the Novartis postmarketing data.

Hypocalcemia can occur and requires ongoing calcium and vitamin D dosing. Baseline calcium and creatinine measurements are suggested, since treatment is not recommended if creatinine clearance is <35 mL/min. In the Paget’s disease trials, 21% of patients developed serum calcium levels <8.4 mg/dL 10 days after zoledronic-acid administration.

Most patients prefer the yearly option of a bisphosphonate over weekly or monthly dosing. However, they may be less enthusiastic when informed of the risk of osteonecrosis of the jaw (ONJ), exposed alveolar or palatal bone, which has occurred in patients with malignancy who have received multiple infusions of zoledronic acid. Clinicians administering the agent may also be less apt to recommend it if reimbursement hassles surface as they have with IV ibandronate. Monitoring for re-treatment in osteoporosis will likely be done via biochemical markers, so pretreatment uNTx assessment will be needed, followed by a recheck every 6-12 months.

Keeping tabs on therapy

Monitoring of therapy with a bisphosphonate (or any antiresorptive agent) has typically been by BMD measurement every one to two years, but one does not need to document gains in BMD to show success. Continuing loss suggests poor compliance or an ongoing secondary cause, such as malabsorption, hyperparathyroidism, or vitamin D deficiency. If patients are required by their insurer to utilize a DEXA machine other than the one used at baseline, small changes in BMD will be difficult to interpret, with precision errors adding to the difficulty. The increasing accuracy of biochemical-marker measurements now allows more rapid patient assessment, with three- to six-month values likely predictive of future BMD change.

High pretreatment levels of uNTx, i.e., >100, suggest the need for alendronate or ibandronate, while lower levels might respond adequately to risedronate or even the selective estrogen-receptor modulator raloxifene, which can reduce biochemical markers by 25%. Raloxifene may soon be approved for breast cancer reduction, which will increase its usage. A second voided morning urine specimen is the best way to monitor uNTx. A serum assay becoming available in many areas of the country determines C-telopeptide levels, which may be a better marker.