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.

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).

View the Comparison Table: Some Drugs for Postmenopausal Osteoporosis

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.

View the Comparison Table: Drugs for Postmenopausal Osteoporosis

Treatment of epilepsy should begin with a single antiepileptic drug (AED), increasing its dosage gradually until seizures are controlled or adverse effects become intolerable. If seizures persist, specialists generally recommend trying at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs concurrently. When used for the appropriate seizure type, AEDs are roughly equivalent in efficacy. Drug choice is usually based on factors such as ease of use, adverse effects, drug interactions, presence of comorbidities, and cost.

View the Comparison Table: Drugs for Postmenopausal Osteoporosis

The FDA has approved abaloparatide (Tymlos – Radius Health), a synthetic analog of human parathyroid hormone related peptide, for treatment of postmenopausal women with osteoporosis who are at high risk for fracture. Abaloparatide is the second parathyroid hormone receptor agonist to be approved for this indication; teriparatide (Forteo – Lilly), a recombinant parathyroid hormone analog, was the first. They are the only drugs approved for treatment of osteoporosis that stimulate bone formation. Other drugs used for this indication inhibit bone resorption.

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.

Many different drugs are used for treatment of osteoarthritis pain, but none of them prevent progression of the disease. Many nonpharmacologic approaches are available as well, including weight management, exercise, physical therapy, assistive devices, and total joint arthroplasty. New guidelines for the management of osteoarthritis have recently been published.

The FDA has approved Duavee (Pfizer), a fixed-dose combination of conjugated estrogens and the new selective estrogen receptor modulator (SERM) bazedoxifene, for treatment of moderate to severe vasomotor symptoms and for prevention of osteoporosis in postmenopausal women with an intact uterus. Bazedoxifene is an estrogen agonist/antagonist with estrogen-like effects on bone and antiestrogen effects on the uterus. It is the second SERM to be approved for prevention of osteoporosis; raloxifene (Evista, and generics) has been available as a single agent for this indication since 1997.

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?

The US Preventive Services Task Force (USPSTF) has issued a Draft Recommendation Statement saying, in effect, that community-dwelling women and men should not take calcium and vitamin D supplements for primary prevention of osteoporotic fractures because the evidence that they are helpful is insufficient and they increase the risk of kidney stones. The Medical Letter has said previously that there is no evidence that patients with an adequate intake of calcium (1000-1200 mg/day) and vitamin D (600-800 IU/day) will benefit from taking supplements.1

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

Download complete U.S. English article

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

The FDA, which had previously approved intravenous (IV) administration of 5 mg of zoledronic acid (Reclast – Novartis) once a year for treatment of postmenopausal osteoporosis (Med Lett Drugs Ther 2007; 49:89), has now approved the same dose for use once every 2 years to prevent osteoporosis in postmenopausal women with osteopenia.

Clinical Studies – In an unpublished study summarized in the package insert, 224 women with osteopenia ≤5 years after menopause were given an IV infusion of zoledronic acid 5 mg or placebo; 2 years later, total hip bone mineral density (BMD) had increased by 2.6% with the drug and decreased by 2.1% with placebo. Among 357 osteopenic women >5 years after menopause, hip BMD 2 years after one IV dose of zoledronic acid increased by 2.1% and decreased by 1.0% with placebo. Both of these differences from placebo were statistically significant. Similarly significant increases occurred in vertebral BMD. No data are available on the incidence of hip or vertebral fractures in these women, but zoledronic acid once a year for treatment of osteoporosis has been shown to decrease the incidence of such fractures.

Adverse Effects — An acute-phase reaction including fever, flu-like symptoms, headache, arthralgia and myalgia can occur with IV administration of zoledronic acid; symptoms usually subside within a few days. Renal damage can occur after a single dose, especially with concomitant use of other nephrotoxic drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs). Jaw osteonecrosis has occurred rarely. Whether long-term use of bisphosphonates, which interfere with bone remodeling, could increase the incidence of long-bone fractures remains to be established. None of these events, except for acutephase reactions, occurred during the clinical trial, according to the manufacturer.

Cost – The cost of one 5-mg injection of Reclast is about $1200 for the drug alone.

Download: U.S. English

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.

The bisphosphonate risedronate (Actonel - Procter & Gamble) was recently approved by the FDA in a 150- mg once-monthly oral tablet for prevention and treatment of postmenopausal osteoporosis. The drug is also available for the same indication in 5-mg daily, 35-mg weekly and 75-mg twice-monthly tablets.

Some recently published studies suggest that taking selective serotonin reuptake inhibitors (SSRIs) may increase the risk of developing osteoporosis. A relationship between SSRIs and osteoporosis is biologically plausible because bone has serotonin receptors, and SSRI-treated mice have reduced bone mass.

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.

The results of a randomized, placebo-controlled trial of calcium and vitamin D supplements in more than 36,000 postmenopausal women, conducted as part of the Women’s Health Initiative (RD Jackson et al. N Engl J Med 2006; 354:669), have been misinterpreted by some patients to mean that they should stop taking such supplements.

At the time of recruitment, the participants in this study had an average daily calcium intake of 1100-1200 mg. They were randomized to take either 1000 mg of calcium carbonate plus 400 IU of vitamin D₃ or a placebo for an average of 7 years. Both groups were permitted to take calcium and vitamin D supplements on their own as well. In the intention-to-treat population, the study supplements increased hip bone density but did not decrease the incidence of hip fractures. The subgroup of women who adhered to the protocol and actually took the study supplements showed a significant reduction in hip fractures compared to the control group.

Men and women over age 50 should have a total calcium intake of about 1200 mg per day (Treat Guidel Med Lett 2005; 3:69). If they need a supplement to achieve that, calcium citrate is more expensive, but it offers some advantages over calcium carbonate: it can be taken without food, causes less GI disturbance and may be less likely to cause kidney stones.

With any calcium salt, vitamin D is necessary for optimal absorption. The recommended minimum daily requirement of vitamin D (vitamin D₃ is preferred) is 400 IU for people 50-70 years old and 600 IU for those over 70. But those infrequently exposed to the sun may need 800- 1000 IU of vitamin D daily, and many experts recommend 800 IU or more for all postmenopausal women.

Download U.S. English

Preliminary results from a new study, unpublished but reported in a press release from the National Cancer Institute and widely disseminated in the public press, suggest that raloxifene (Evista) might be a better choice than tamoxifen (Nolvadex, and others) for prevention of breast cancer in high-risk postmenopausal women.

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.

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

Claims for the superiority of various calcium supplements are now appearing on television and in the print media. A high calcium intake combined with vitamin D can increase bone density and reduce the incidence of fractures in older women and probably also in men.

A new synthetic conjugated estrogen product (Cenestin - Duramed) was recently approved by the US Food and Drug Administration for treatment of vasomotor symptoms due to estrogen deficiency.

Many different calcium supplements are promoted for prevention of postmenopausal osteoporosis. Whether a lifelong increase in calcium intake decreases the risk of osteoporosis is unclear, but the results of some clinical trials suggest that it might. Calcium supplementation increased bone mineral density in children and adolescents and, started a few years after menopause, decreased bone loss in postmenopausal women (CC Johnston, Jr et al, N Engl J Med, 327:82, 1992; T Lloyd et al, JAMA, 270:841, 1993; IR Reid et al, AM J Med, 98:331, 1995). Elderly women who took calcium and vitamin D supplements had a lower incidence of hip fractures than those who took placebo (MC Chapuy et al. N Engl J Med, 327:1637, 1992)

Use of alendronate (Fosamax), estrogen and other drugs for prevention and treatment of osteoporosis (Medical Letter, 38:1, 1996) has been accompanied by widespread availability of bone density screening tests, not only in doctors offices and hospitals, but even in retail stores. Bone densitometry provides a quantitative measurement of bone mineralization that can be used to predict the risk of osteoporotic fractures.

Two new drugs alendronate (Fosamax - Merck) and salmon calcitonin nasalspray (Miacalcin - Sandoz) are now available in the USA for treatment of postmenopausalosteoporosis. A third drug for treatment of osteoporosis, a slow-release fluoridepreparation (Slow Fluoride -Mission Pharmacal), has been recommended for approvalby an advisory committee of the US Food and Drug Administration (FDA). Various formulationsof fluoride have been available in Europe for this indication for many years.

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.

Whether a lifelong increase in calcium intake can prevent osteoporosis remains controversial, but many women are now taking calcium supplements on the chance that it might. The typical diet of women in the USA includes less than 600 mg of calcium per day. The National Research Council (NRC) recommends a calcium intake of 1200 mg daily from adolescence through age 24, and 800 mg daily thereafter (Food and Nutrition Board, NRC, Recommended Dietary Allowances, 10th ed, Washington, DC:National Academy Press, 1989, p 174). For mature women, some Medical Letter consultants recommend daily calcium intakes of 1000 mg before menopause and 1500 mg afterward. The effectiveness of estrogen replacement at menopause in preventing postmenopausal bone loss is no longer controversial, and the results of one study suggested that calcium supplementation can lower the effective dosage of estrogen (Committee on Diet and Health, NRC, Diet and Health, Washington, DC:National Academy Press, 1989, p 347).