The FDA is requiring a boxed warning in the label of denosumab (Prolia – Amgen), a monoclonal antibody that inhibits osteoclasts, about an increased risk of severe hypocalcemia in patients with advanced chronic kidney disease (CKD; eGFR <30 mL/min/1.73 m²), particularly those on dialysis. FDA-approved indications for Prolia are listed in Table 1.

US guidelines recommend pharmacologic therapy for postmenopausal women with a bone density T-score (standard deviation from normal mean values in healthy young women) of -2.5 or below in the lumbar spine, femoral neck, total hip, or distal radius, a T-score between -1.0 and -2.5 and a history of fragility (low-trauma) fracture of the hip or spine, or a T-score between -1.0 and -2.5 and a FRAX 10-year probability of ≥3% for hip fracture or ≥20% for major osteoporotic fracture (hip, clinical spine, humerus, distal radius).

The FDA has approved romosozumab-aqqg (Evenity – Amgen), a sclerostin inhibitor, for once-monthly subcutaneous (SC) treatment of osteoporosis in postmenopausal women who are at high risk for fracture (history of osteoporotic fracture or multiple risk factors for fracture) or who have failed or cannot tolerate other drugs for this indication. Romosozumab is the first sclerostin inhibitor to be approved in the US and the third drug for treatment of postmenopausal osteoporosis that stimulates bone formation; the parathyroid hormone (PTH) receptor agonists abaloparatide (Tymlos) and teriparatide (Forteo) were approved earlier. Other drugs used for treatment of postmenopausal osteoporosis, such as bisphosphonates, inhibit bone resorption and decrease bone turnover.

Diagnosis of osteoporosis is based on the results of bone mineral density (BMD) testing or by the occurrence of a fragility fracture. Bone densitometry results are generally reported in terms of standard deviations (SD) from the mean value for young adults (T-score). The World Health Organization (WHO) defines osteoporosis in women as a T-score of -2.5 or below in the spine, femoral neck, or total hip. A computerized model (FRAX) is available that estimates the 10-year probability of a hip fracture or other major osteoporotic fracture based on clinical risk factors and BMD at the femoral neck.

US guidelines for the treatment of osteoporosis have been published. The diagnosis of osteoporosis has traditionally been established by the occurrence of fragility fractures or by bone densitometry, which is generally reported in terms of standard deviations (SD) from mean values in young adults (T-score). The World Health Organization (WHO) has defined normal bone mineral density (BMD) for women as a value within one SD of the young adult mean. Values 2.5 SD or more below the mean (T-score -2.5 or below) at the spine, femoral neck, or total hip are defined as osteoporosis. The WHO has developed a computerized model (FRAX) that predicts the 10-year probability of a hip fracture or other major osteoporotic fracture based on clinical risk factors and BMD at the femoral neck.

A new effervescent formulation of alendronate (Binosto – Mission) was recently approved by the FDA for treatment of osteoporosis. The new 70-mg effervescent tablet is considered bioequivalent to the usual 70-mg tablet formulations of alendronate (Fosamax, and generics), which are difficult to swallow and can cause esophageal injury.1 No published studies of the new formulation are available.

LABELING — The new strawberry-flavored effervescent tablet should be dissolved over at least 5 minutes in 4 ounces of water (not mineral or flavored water) and stirred for 10 seconds before drinking. As with tablet formulations of alendronate, the labeling of the effervescent solution says it should be taken once each week in the morning upon rising for the day, at least 30 minutes before eating, drinking or taking other medications, and the patient should remain upright during that interval.

COST — A monthly 4-pack of 70-mg Binosto tablets costs $140.2 A monthly supply of 4 generic 70-mg alendronate tablets costs $9.99 at some large discount pharmacies.

CONCLUSION — Binosto is an expensive new effervescent tablet formulation of alendronate that is dissolved in water and taken as a solution. The solution should be easier to swallow than the regular tablets and theoretically might be better tolerated, but no comparative studies are available.

1. Drugs for postmenopausal osteoporosis. Treat Guidel Med Lett 2011; 9:67.

2. Wholesale acquistion cost (WAC). Source: PricePointRx™ October 5, 2012. Reprinted with permission by FDB, Inc. All rights reserved. ©2012. http://www.firstdatabank.com/support/drug-pricing-policy.aspx. Actual retail prices may be higher.

Download complete U.S. English article

Long-term use of bisphosphonates for prevention and treatment of osteoporosis has been associated with osteonecrosis of the jaw, atypical fractures of the femur, and possibly esophageal cancer. So for how long should patients take them?

Osteoporosis is characterized by low bone mass with microarchitectural disruption and skeletal fragility that results in an increased risk of fracture. The diagnosis has traditionally been established by bone densitometry, which is generally reported in terms of standard deviations (SD) from mean values in young adults (T-score). The World Health Organization (WHO) has defined normal bone mineral density (BMD) for women as a value within one SD of the young adult mean. Values 2.5 SD or more below the mean (T score -2.5) are defined as osteoporosis. The WHO has developed a computerized model (FRAX) that predicts the 10-year probability of a hip fracture or any other major osteoporotic fracture based on clinical risk factors and BMD at the femoral neck.

The FDA and two of its advisory committees have been debating whether to recommend limiting the duration of use of bisphosphonates in order to prevent atypical femoral fractures and possibly other side effects of the drugs. The agency produced a 182-page background document on this subject for a joint meeting of the Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committees held on September 9, 2011 (www.fda.gov). The document concluded that there is no clear evidence, with regard to fractures, of benefit or harm in continuing the drugs beyond 3-5 years. The two advisory committees recommended that the labels for these drugs clarify their duration of use; they did not specify what that duration should be. A Treatment Guidelines from The Medical Letter issue on Drugs for Postmenopausal Osteoporosis will be published in November.

Download U.S. English

The In-Brief article on delayed-release risedronate in issue 1360 (Med Lett Drugs Ther 2011; 53:24) included a statement that alendronate is currently the only bisphosphonate available generically. That would have been accurate if we had added "that is FDA-approved for treatment of osteoporosis." Etidronate (Didronel, and others), which was the first bisphosphonate used to treat osteoporosis (Medical Letter 1990; 32:111) but was never approved for such use by the FDA, is also available generically. It is approved for treatment of Paget's disease and for prevention and treatment of heterotropic ossification following hip replacement and in spinal-cord injured patients.

Download U.S. English

A new enteric-coated delayed-release formulation of risedronate (Atelvia – Warner Chilcott) has been approved by the FDA for treatment of postmenopausal osteoporosis. Unlike immediate-release risedronate (Actonel) and all other oral bisphosphonates, which must be taken after an overnight fast and at least 30 minutes before eating breakfast, the new formulation is taken immediately after breakfast with at least 4 ounces of water. Then the patient must remain upright for at least 30 minutes.

CLINICAL TRIAL — Approval of Atelvia was based on a 52-week non-inferiority study in more than 900 postmenopausal women comparing the new 35-mg delayed-release tablet taken once each week to the original immediate-release 5-mg tablet taken daily at least 30 minutes before breakfast. (FDA approval of risedronate was based on studies with the 5-mg tablet taken once daily; now Actonel is usually taken, like Atelvia, as a 35-mg tablet once a week.) Increases in bone mineral density at the lumbar spine and other locations and changes in markers of bone turnover were similar in both groups. Diarrhea and abdominal pain occurred more frequently with the new formulation once weekly after breakfast than with risedronate 5 mg daily (8.8% vs. 4.9% and 5.2% vs. 2.9%, respectively).1

DOSAGE AND COST — Atelvia is available as a 35-mg tablet taken once each week. A month’s supply of the new formulation (four 35-mg tablets) costs $119.99, which is similar to the cost of Actonel once a week ($126.47).2 Alendronate (Fosamax, and others) is currently the only bisphosphonate available generically that is FDA-approved for treatment of osteoporosis; a month’s supply is available at some discount pharmacies for $9.

CONCLUSION — Taking the new enteric-coated delayed-release formulation of risedronate (Atelvia) after breakfast presumably would be more convenient than taking immediate-release risedronate 30 minutes before breakfast, but it may cause more diarrhea. Generic alendronate costs much less than either one.

1. MR McClung et al. BMD response to delayed-release risedronate 35 mg once-a-week formulation taken with or without breakfast. J Clin Densitom 2010; 13:132; Poster number 067.

2. Cost at drugstore.com. Accessed March 14, 2011.

Download U.S. English

The FDA, which recently approved subcutaneous (SC) administration of denosumab (Prolia – Amgen) for treatment of postmenopausal osteoporosis,1 has now approved the same drug with a different brand name (Xgeva – Amgen) and dosage for prevention of skeletal-related events (such as pathologic fracture, spinal cord compression or radiation to bone) in patients with bone metastases from solid tumors. Denosumab is a fully human anti-RANK ligand antibody that inhibits the formation, activation and survival of osteoclasts.2

A prospective, randomized, double-blind trial in 1901 patients with bone metastases from castration-resistant prostate cancer found that denosumab 120 mg injected SC every 4 weeks, compared to the bisphosphonate zoledronic acid (Zometa) 4 mg IV, delayed the time to a first skeletal event by 3.6 months (20.7 vs. 17.1 months).3 In 1776 patients with bone metastases from solid tumors or multiple myeloma, the mean time to a first skeletal event was 20.6 months with SC denosumab and 16.3 months with IV zoledronic acid.4

Denosumab can lower serum calcium concentrations, especially in patients with impaired renal function. Fatigue is the most commonly reported adverse effect. Other adverse effects of both denosumab and zoledronic acid in clinical trials have included nausea, dyspnea and diarrhea. Acute-phase reactions and renal toxicity have been less frequent with denosumab than with zoledronic acid. Osteonecrosis of the jaw, which can occur with bisphosphonates, has also been reported with denosumab.

1. Denosumab (Prolia) for postmenopausal osteoporosis. Med Lett Drugs Ther 2010; 52: 81.

2. A Lipton and C Goessl. Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasis. Bone 2011; 48:96.

3. K Fizazi et al. A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol 2010; 28:18s (abstr LBA4507).

4. D Henry et al. A double-blind, randomized study of denosumab versus zoledronic acid for the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Eur J Cancer Suppl 2009; 7:11 (abstr 20LBA).

Download U.S. English

The FDA has approved use of denosumab (Prolia – Amgen) for treatment of osteoporosis in postmenopausal women at high risk for fracture.

Disease-modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA) to prevent irreversible damage to joints and minimize toxicities associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids.

Osteoporosis is characterized by low bone mass with microarchitectural disruption and skeletal fragility that results in an increased risk of fracture. The diagnosis has traditionally been established by bone densitometry, which is generally reported in terms of standard deviations (SD) from mean values in young adults (T score). The World Health Organization (WHO) has defined normal bone mineral density (BMD) for women as a value within one SD of the young adult mean. Values 2.5 SD (T score -2.5) or more below the mean are defined as osteoporosis. The WHO has developed a computerized model (FRAX) that predicts the 10-year probability of hip fracture based on clinical risk factors and BMD at the femoral neck.

Zoledronic acid (Reclast - Novartis) is the first bisphosphonate approved by the FDA for once-yearly intravenous (IV) treatment of osteoporosis in postmenopausal women. Reclast is also approved for treatment of Paget's disease. Another IV formulation of zoledronic acid (Zometa) is approved for treatment of hypercalcemia of malignancy, multiple myeloma and bone metastases from solid tumors.

Ibandronate (Boniva - Roche) is the first bisphosphonate approved by the FDA for intravenous (IV) treatment of osteoporosis in postmenopausal women. It is given as a bolus injection once every 3 months. Ibandronate is also available as an oral once-a-month 150-mg tablet and as a daily 2.5-mg tablet.

Many drugs are now marketed for treatment of postmenopausal osteoporosis, but questions remain about their use.

A 10-year study of daily oral alendronate (Fosamax) and a 7-year study of daily oral risedronate (Actonel) indicate that both drugs maintained increases in bone mineral density (BMD) and decreases in markers of bone remodeling throughout the study period. Both drugs are now more commonly taken once weekly. Available data are insufficient to compare fracture rates with alendronate and risedronate, and fracture rates are considered the most important endpoint in osteoporosis studies. Recent reports of severe pain and jaw osteonecrosis with these drugs are disturbing.

Ibandronate (Boniva - Roche/GSK), a new oral bisphosphonate, was recently approved by the FDA in a once-monthly formulation for prevention and treatment of postmenopausal osteoporosis. The drug was initially approved in 2003 as a daily tablet, but was not marketed. An intravenous formulation for use once every 3 months is under investigation.

The FDA has approved a new low-dose estrogen patch (Menostar - Berlex) for prevention of osteoporosis in postmenopausal women. Unlike other estrogen patches, it is not approved for treatment of hot flashes or other menopausal symptoms. Promotional material from the manufacturer suggests that this low dose of estrogen could prevent osteoporosis without some of the adverse effects of higher doses.

Teriparatide (ter i par' a tide; Forteo - Lilly), a recombinant segment of human parathyroid hormone, has been approved by the FDA for parenteral treatment of osteoporosis in post-menopausal women, and in men with idiopathic or hypogonadal osteoporosis, who are at high risk for fracture. Teriparatide is the first approved treatment for osteoporosis that stimulates bone formation. Other drugs approved for this indication inhibit bone resorption (Treatment Guidelines from the Medical Letter 2002;1:13).

Many drugs are now marketed for treatment of post-menopausal osteoporosis (PD Delmas, Lancet 2002; 359:2018). Prevention of this disorder has been complicated by the news that hormone replacement therapy (HRT), which many women have been taking to prevent osteoporosis, increases the incidence of coronary heart disease and that of breast cancer, stroke and pulmonary embolism as well (Medical Letter 2002; 44:78).

A once-weekly 35-mg oral formulation of the bisphosphonate risedronate (Actonel) has been approved by the FDA for prevention and treatment of postmenopausal osteoporosis. A once-weekly formulation of alendronate (Fosamax) was approved last year (Medical Letter 2001; 43:26). Bisphosphonates bind to the mineral surface of bone and decrease osteoclast activity, inhibiting the resorption phase of the bone turnover cycle. These drugs are not metabolized and remain bound to bone for several weeks.

Zoledronic acid (Zometa), a new bisphosphonate, has been approved by the FDA for intravenous (IV) treatment of hypercalcemia of malignancy.

Once-a-week formulations of alendronate (Fosamax) in 35- and 70-mg tablets have now been approved by the FDA and are being heavily promoted for prevention and treatment of postmenopausal osteoporosis. A new formulation of risedronate (Actonel) for once-a-week use is under development and may be available next year.

Many drugs are now marketed for prevention and treatment of postmenopausal osteoporosis. All regimens should include an adequate intake of calcium and vitamin D.

Risedronate (Actonel - Procter & Gamble), a pyridinyl bisphosphonate, has been approved by the FDA for oral treatment of Paget's disease of bone. Characterized by excessive bone resorption, bony deformity, disorganized bone remodeling and structural weakness, Paget's disease occurs in up to 3% of people older than 55 in Europe and North America (PD Delmas and PJ Meunier, N Engl J Med, 336:558, 1997).

Tiludronate (Skelid - Sanofi), a chloro-4-phenylthiomethylene bisphosphonate, has been approved by the US Food and Drug Administration (FDA) for treatment of Paget's disease of bone. Characterized by excessive bone resorption and disorganized bone remodeling, Paget's disease occurs in up to 3% of people more than 55 years old in Europe and North America (PD Delmas and PJ Meunier, N Engl J Med, 336:558, Feb 20, 1997).

The bone mass of an average person reaches a maximum at the age of 25 to 30, stays the same for about 15 years, and then progressively declines at a rate of 0.2% to 0.5% per year. At menopause, women go through a period of increased bone resorption (2% per year) for about 10 years and then resume a gradual rate of bone loss. Current strategies for prevention and treatment of Postmenopausal Osteoporosis include increasing calcium intake to maximize peak bone mass, using antiresorptive drugs to decrease postmenopausal resorption, and using other drugs to stimulate bone systhesis (BL Riggs and LJ Melton, III, N Engl J Med, 327:620, Aug 27, 1992).

Disodium pamidronate (Aredia - Ciba-Geigy), an aminohydroxypropilidene bisphosphonate, has been approved by the US Food and Drug Administration for intravenous (IV) treatment of hypercalcemia associated with malignancy, with or without bone metastases. The drug is also being investigated for use in Paget's disease of bone, hyperparathyroidism, and postmenopausal osteoporosis. An oral formulation of pamidronate has been used in Europe, but is not available in the USA.