Types of Osteoporosis Medications

There are two categories of osteoporosis medications: antiresorptive medications that slow bone loss and anabolic drugs that increase the rate of bone formation.

Bone Remodeling Cycle

Bone is living, growing tissue that constantly forms new bone while replacing older bone. Bone continuously renews and changes through a process called remodeling. The bone remodeling cycle consists of two distinct stages: (1) bone resorption (breakdown or removal) and (2) bone formation. During resorption, special cells (osteoclasts) on the bone's surface dissolve bone tissue and create small cavities. During formation, other cells (osteoblasts) fill the cavities with new bone tissue.

Usually, bone resorption and bone formation take place in close sequence and remain balanced. An imbalance in the bone remodeling cycle occurs with menopause and with aging in both genders, and it can occur with other conditions. An imbalance can result in bone loss that eventually leads to osteoporosis and broken bones (also called fractures).

Antiresorptive Medications

Bisphosphonates, calcitonin, denosumab, estrogen and estrogen agonists/antagonists are antiresorptive medicines. They slow the bone loss that occurs in the breakdown part of the remodeling cycle. When people first start taking these medicines, they stop losing bone as quickly as before, but still make new bone at the same pace. Therefore, bone density may increase. The goal of treatment with antiresorptive medicines is to prevent bone loss and lower the risk of breaking bones.

Anabolic Drugs

Teriparatide, a form of parathyroid hormone, increases the rate of bone formation and is in a distinct category of osteoporosis medicines called anabolic drugs. This is currently the only osteoporosis medicine approved by the FDA that rebuilds bone. The goal of treatment with teriparatide is to build bone and lower the risk of breaking bones.

Special Note

Information provided here about the FDA approved osteoporosis medicines is intended solely for general information and should NOT be relied upon for any particular diagnosis, treatment or care. This information does not imply an endorsement by NOF of any particular medicine or manufacturer.

For more detailed information on the actions, administration and possible side effects for each of the following medicines, please consult the package insert, available online and at pharmacies.

Osteoporosis Medications

Alendronate Sodium or Alendronate Sodium plus Vitamin D3 (Fosamax® and Fosamax Plus D)

Alendronate is approved for the prevention and treatment of osteoporosis in postmenopausal women and for the treatment of osteoporosis in men. It also is approved for the treatment of glucocorticoid-induced osteoporosis in men and women as a result of long-term use of steroid medicines (examples are prednisone and cortisone).

Alendronate reduces bone loss, increases bone density and reduces the risk of spine, hip and other broken bones by about 50 percent over two to four years.

For prevention, alendronate is taken daily as a 5 mg tablet or weekly as a 35 mg tablet. For treatment, it is taken daily as a 10 mg tablet or weekly as a 70 mg tablet with or without vitamin D3. The weekly dose with vitamin D3 contains either 2,800 IU or 5,600 IU of vitamin D3.

The alendronate tablet needs to be taken first thing in the morning after waking up and on an empty stomach. It is swallowed whole with 6 to 8 ounces of plain water (no other liquid), at least 30 minutes before having anything to eat or drink. Patients must remain upright (sitting, standing or walking) during this 30-minute period.

Alendronate with either 2,800 IU or 5,600 IU of vitamin D3 provides another option for a source of vitamin D. Weekly alendronate with 2,800 IU of vitamin D3 is the equivalent of taking 400 IU daily, while weekly alendronate with 5,600 IU of vitamin D3 is the equivalent of taking 800 IU daily. Vitamin D3 is also called cholecalciferol.

Ibandronate Sodium (Boniva®)

Ibandronate is approved for the prevention and treatment of osteoporosis in postmenopausal women. Ibandronate reduces the incidence of spine fractures by about 50 percent over three years.

For both prevention and treatment, ibandronate is taken once monthly as a 150 mg tablet. For treatment, it is also available as an intravenous (IV) injection of 3 mg given every three months. Although the FDA has approved a daily dose, it is not available in the U.S.

Oral ibandronate should be taken on the same day each month, first thing in the morning after waking up and on an empty stomach. It is swallowed whole with 6 to 8 ounces of plain water (no other liquid), at least 60 minutes before having anything to eat or drink. Patients must remain upright (sitting, standing or walking) during this 60-minute period.

A healthcare professional administers the IV dose in a doctor’s office or other outpatient setting. It takes less than a minute to inject. Patients need to have a blood test (serum creatinine) to confirm that kidney function is normal prior to each IV injection.

Risedronate Sodium or Risedronate Sodium with Calcium Carbonate
(Actonel®, Actonel® with Calcium and AtelviaTM)

Risedronate (actonel) is approved for the prevention and treatment of osteoporosis in postmenopausal women and for the treatment of osteoporosis in men. It also is approved for the prevention and treatment of glucocorticoid-induced osteoporosis in men and women as a result of long-term use of steroid medicines (examples are prednisone and cortisone). Risedronate (Atelvia) is approved for the treatment of osteoporosis in postmenopausal women.

Risedronate slows bone loss, increases bone density and reduces the risk of spine and non-spine fractures by 35 to 45 percent over three years.

For both prevention and treatment, risedronate is taken daily as a 5 mg tablet, weekly as a 35 mg tablet that is available with or without separate calcium carbonate tablets, twice monthly as a 75 mg tablet (on two consecutive days) or monthly as a 150 mg tablet.

The Actonel tablet needs to be taken first thing in the morning after waking up and on an empty stomach. It is swallowed whole with 6 to 8 ounces of plain water (no other liquid), at least 30 minutes before having anything to eat or drink. The Atelvia tablet needs to be taken immediately after breakfast with at least 4 ounces of plain water (no other liquid). Patients must remain upright (sitting, standing or walking) for at least 30 minutes after taking Actonel or Atelvia.

Weekly risedronate with calcium carbonate offers another way to get calcium. The once weekly risedronate tablet comes with six individual tablets that contain 500 mg of calcium in the form of calcium carbonate. One calcium tablet is taken daily except on the day of the week when risedronate is taken. If calcium is taken with the risedronate tablet, it will prevent the absorption of risedronate and the desired effect will not occur. Calcium carbonate supplements should be taken with food to be well absorbed.

Zoledronic Acid (Reclast®)

Zoledronic acid is approved for the prevention and treatment of osteoporosis in postmenopausal women. It is also approved to increase bone mass in men with osteoporosis and for the prevention of new clinical fractures in patients who have recently had a low-trauma hip fracture. In 2009, it was approved for the prevention and treatment of glucocorticoid-induced osteoporosis in men and women as a result of long-term use of steroid medicines (examples are prednisone and cortisone).

Zoledronic acid is given once a year as an intravenous (IV) infusion to treat osteoporosis. It is also given every two years as an IV infusion to prevent osteoporosis. Although the FDA approved zoledronic acid in 2007 to treat osteoporosis, the medicine was already available under the name Zometa® for use in cancer patients with certain bone conditions. The FDA first approved zoledronic acid as Zometa® in 2001.

Zoledronic acid increases bone density and reduces fractures in the hip, spine and non-spine areas (such as the wrists and arms). In one major study, zoledronic acid reduced the risk of spine fractures by 70 percent and hip fractures by 41 percent. Zoledronic acid also reduces the risk of more broken bones in people who have recently broken a hip.

A healthcare provider gives zoledronic acid as an intravenous (IV) dose of 5 mg in a doctor’s office or other outpatient setting. It takes at least 15 minutes for the yearly infusion. Patients need to have two blood tests prior to each IV dose. One is a test for creatinine to confirm that kidney function is normal. The other is a test for calcium to confirm that the blood calcium level is normal.

Side Effects of Bisphosphonates
(Alendronate, Ibandronate, Risedronate and Zoledronic Acid)

Side effects for all the bisphosphonates (alendronate, ibandronate, risedronate and zoledronic acid) may include bone, joint or muscle pain. Side effects of the oral tablets may include nausea, difficulty swallowing, heartburn, irritation of the esophagus (tube connecting the throat to the stomach) and gastric ulcer.

Side effects that can occur shortly after receiving an IV bisphosphonate include flu-like symptoms, fever, headache and pain in muscles or joints. These generally stop within two to three days and usually do not happen with future infusions.

Inflammation of the eye (called uveitis) is a rare side effect of all bisphosphonates. Bisphosphonates are not recommended for people with severe kidney disease or low blood calcium. People with certain problems of the esophagus may not be able to take the oral tablets.

There have been rare reports of osteonecrosis (death of bone cells or tissue) of the jaw (ONJ) with bisphosphonate medicines. Of the cases reported to date in 2007, nearly 95 percent were in cancer patients receiving an intravenous bisphosphonate, pamidronate (Aredia®) or zoledronate (Zometa®), typically given every three to four weeks in much larger doses than given for osteoporosis. Although quite unusual, patients treated with the bisphosphonate tablets, alendronate (Fosamax®), ibandronate (Boniva®) and risedronate (Actonel®), for osteoporosis prevention or treatment have also been reported to have developed ONJ.

There have also been recent reports of unusual fractures of the upper femur (thigh bone) in people taking bisphosphonate medicines. If you have been taking bisphosphonate medicines for several years or longer and have an unusual ache or pain in your hip or thigh bone, it's important to tell your healthcare provider. There have been reports of people having an ache or pain, sometimes for several weeks or even months, before having an unusual break in the thigh bone.

Patients taking the oral bisphosphonate tablets should stop taking the drug and contact their healthcare provider immediately when experiencing chest pain, new or worsening heartburn, or difficult or painful swallowing. It is important that patients report these or other side effects to their healthcare provider.

Calcitonin-Salmon (Fortical® and Miacalcin®)

Calcitonin is a synthetic hormone for the treatment of osteoporosis in postmenopausal women who are at least five years beyond menopause. The naturally occurring hormone is involved in calcium regulation and bone metabolism.

Calcitonin slows bone loss and increases bone density in the spine. It reduces the risk of spine fractures but has not been shown to decrease the risk of non-spine fractures.

Calcitonin is available as a nasal spray (200 IU daily) or an injection (dosage varies). An oral form of the drug is also being tested in clinical trials.

Side Effects

Common side effects with nasal calcitonin are a runny nose, headache, back pain and nosebleed (epistaxis). Injectable calcitonin may cause an allergic reaction and unpleasant side effects including flushing of the face and hands, urinary frequency, nausea and a skin rash.

Denosumab (Prolia)

Denosumab is approved by the FDA for the treatment of osteoporosis in postmenopausal women at high risk of fracture and to increase bone mass in men with osteoporosis at high risk of fracture. The medicine is also approved to increase bone mass in men at high risk of fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer and treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

Denosumab is a RANK ligand (RANKL) inhibitor/human monoclonal antibody. A healthcare professional gives denosumab by injection every six months. Patients need to have a blood test before each dose to confirm that blood calcium level is normal. As for all people with osteoporosis, it is very important to get enough calcium, vitamin D and exercise everyday.

Denosumab reduces the risk of broken bones in the spine, hip and other bones. In clinical trials, denosumab significantly reduced the incidence of new spine fractures by 68 percent, reduced the incidence of hip fractures by 40 percent and reduced the incidence of all non-spine fractures by 20 percent over three years.

Side Effects

Denosumab may lower the calcium levels in the blood. If blood calcium levels are low before receiving denosumab, the low calcium level must be corrected before giving the medicine or it will get worse. Signs of low calcium levels include spasms, twitches or cramps in the muscles; or numbness and tingling in the fingers, toes or around the mouth. If any of these symptoms are seen while on this medicine, patients should contact their healthcare provider. Most patients with low calcium levels, however, do not show these signs.

People who have weak immune systems or take other medicines that affect the immune system may have an increased chance of having serious infections with denosumab. Even patients who have no immune system problems may be at higher risk of certain infections such as those of the skin. Patients should contact their healthcare provider right away if signs of infection occur. These signs may include fever, chills, red and swollen skin, skin that is hot or sore to the touch, severe pains in the abdomen, or pain or burning when passing urine or passing urine more frequently and in small amounts.

Denosumab may also cause skin rashes. Call your healthcare provider if you notice any abnormal skin-related symptoms. Denosumab has caused osteonecrosis of the jaw (ONJ) when used to treat patients with cancer although at this time, these have not been seen in patients with osteoporosis. Patients should practice good dental care during treatment and should have an examination of the mouth by a doctor or dentist before starting the medicine.

Raloxifene (Evista®)

(Brand name Evista®)

Raloxifene is approved for the prevention and treatment of osteoporosis in postmenopausal women. It is in a class of drugs called estrogen agonists/antagonists that have been developed to provide the beneficial effects of estrogens without their potential disadvantages. It is neither an estrogen nor a hormone. Raloxifene used to be called a selective estrogen receptor modulator (SERM).

Raloxifene increases bone density and reduces the risk of spine fractures. There are no data showing that raloxifene reduces the risk of hip and other non-spine fractures.

For both prevention and treatment, raloxifene is taken daily as a 60 mg tablet with or without meals.

Raloxifene appears to decrease the risk of estrogen-dependent breast cancer by 65 percent over eight years. It is now FDA approved to decrease the risk of breast cancer in women with osteoporosis and even in women without osteoporosis who are at high risk of breast cancer.

Side Effects

While side effects are not common, they include hot flashes, leg cramps and deep vein thrombosis (blood clots). Blood clots are also associated with estrogen therapy. Other side effects include swelling and temporary flu-like symptoms. Raloxifene is not associated with diseases of the uterus or ovaries and does not affect cognitive (mental) function.

Raloxifene should not be given to women at increased risk for stroke. This includes women who have had previous strokes, transient ischemic attacks (TIAs), atrial fibrillation (a type of serious irregular heart beat) or uncontrolled hypertension (high blood pressure).

Teriparatide Parathyroid Hormone (PTH) (1-34) (Forteo®)

Teriparatide, a type of parathyroid hormone, is approved for the treatment of osteoporosis in postmenopausal women and in men who are at high risk of breaking a broken bone. It is also approved for the treatment of osteoporosis in men and women who are at high risk of breaking a bone as a result of taking steroid medicines for a long time. This medicine rebuilds bone and significantly increases bone mineral density, especially in the spine.

In clinical studies of postmenopausal women using teriparatide, fractures were reduced in the spine and throughout the skeleton. In men, bone density increased, but the study was too small and not long enough to determine whether fractures decreased.

Good candidates for teriparatide include those who have had an osteoporosis related fracture and those with very low bone density (T-scores lower than -3.0). Teriparatide is also an option for patients who continue to lose bone density or break a bone during treatment with other osteoporosis medicines.

Teriparatide is self-administered as a daily injection from a pre-loaded pen containing a one month supply of medicine. It can be taken for a maximum of two years. At the end of two years, to retain the benefits of treatment with teriparatide, most experts recommend that patients start an antiresorptive medicine.

Side Effects

Side effects include leg cramps and dizziness. Modest elevations in serum and urine calcium can occur, but there is no documented increase in the risk of kidney stones.

In animal studies, very high doses of teriparatide that were given for a long period of time increased the incidence of rat osteosarcoma, a type of bone cancer. Although common in rats, this type of tumor is extremely rare in adult humans. For this reason, the FDA approved its use for up to two years only. There has been no evidence of increased risk of osteosarcoma in humans taking teriparatide.

People with certain conditions should not take this medicine. This includes people with Paget’s disease, children with growing bone, persons with unexplained serum alkaline phosphatase elevations, and those who have had radiation treatment involving the skeleton. It also should not be given to people with metabolic bone diseases such as hyperparathyroidism and those with cancer that has spread to the bone. Also, people who have certain abnormal blood tests, including increased calcium levels, should not take this medicine.

Estrogen Therapy (ET) and Hormone Therapy (HT) (Multiple brands available)

Estrogen therapy (ET) and estrogen with progesterone hormone therapy (HT) are approved for the prevention of osteoporosis in postmenopausal women. ET and HT reduce bone loss, increase bone density in both the spine and hip, and reduce the risk of hip, spine and other fractures in postmenopausal women. ET and HT also relieve menopausal symptoms.

ET and HT are commonly available as a tablet or skin (transdermal) patch and in other forms. Estrogen and hormone medicines come in a wide variety of doses.

Side Effects

When estrogen is taken alone, it can increase a woman's risk of developing cancer of the uterine lining (endometrial cancer). To reduce this risk, physicians prescribe the hormone progesterone in combination with estrogen (hormone therapy or HT) for those women who have a uterus. Estrogen therapy (ET) is prescribed for women who have had hysterectomies. Side effects may include vaginal bleeding, breast tenderness and gallbladder disease.

The Woman’s Health Initiative (WHI) study confirmed that one type of HT, Prempro® (given to women who on average were more than ten years past menopause), reduced the risk of hip and other fractures, as well as colon cancer. However, it was associated with a slight increase in the risk of breast cancer, strokes, heart attacks, venous blood clots and cognitive (mental) decline. Although ET was associated with a similar increase in the risk of strokes, venous blood clots and cognitive decline, it did not increase the risk of breast cancer or heart attacks.

Women who have early menopause or their ovaries removed in their 30s or early 40s may benefit from low dose ET or HT. The results of the WHI study do not apply to women in this age group. Women who have had breast cancer or have a high risk for breast cancer should not consider ET or HT.

According to the FDA, postmenopausal women should consider other osteoporosis medicines before taking ET or HT to prevent osteoporosis. Because estrogen use has serious risks, women should discuss with their healthcare providers whether the benefits outweigh the risks. Women who decide to take ET or HT should take the lowest possible dose for the shortest period of time to control menopausal symptoms.

Bioidentical Hormones

NOF is aware that some women are interested in taking hormones that are prepared especially for them by a compounding pharmacist. These medicines, called bioidentical hormones, contain the same active ingredients as ET and HT, but are not overseen by the FDA for accuracy of contents or purity like FDA-approved medicines. For this reason, NOF does not recommend the use of bioidentical hormones. It is important to remember that the same precautions be followed with all preparations containing estrogen. Always work with your healthcare provider to determine the best treatment for you.

Response to Treatment

A medicine that is appropriate and effective for one person may not be the best choice for another person. People can respond differently to treatment with the same medicine.

To be effective, an osteoporosis medicine must be taken as prescribed. It is important to stay with the plan on which you and your healthcare provider have agreed. Most people cannot feel their bones getting stronger (or weaker) in response to treatment with a medicine. So if you decide that a particular treatment plan is not right for you, discuss your concerns with your healthcare provider before stopping or interrupting treatment. For your medicine to work, you need to exercise regularly and continue to get enough calcium and vitamin D.

With the antiresorptive medicines (bisphosphonates, calcitonin, estrogen, estrogen agonists/antagonists and denosumab), the goal of treatment is to prevent further bone loss and to reduce the risk of fractures. Fractures can cause deformities, disabilities, and serious, as well as life threatening complications. A patient has a favorable response to treatment when bone mineral density either remains stable or improves and no broken bones occur.

With the one anabolic medicine, teriparatide (Forteo®), the goal of treatment is to rebuild bone, increase bone mass, repair microscopic defects in bone and reduce the risk of fractures. A patient has a favorable response to treatment when both bone quantity and quality improve and there is a substantial increase in bone strength.

Monitoring Treatment

Most healthcare providers repeat the bone density test at least every two years to monitor the effectiveness of treatment with an osteoporosis medicine. Healthcare providers may have some patients repeat a bone density test in one year. Bone density tests and blood and urine tests called bone markers are the most available monitoring tools. At the current time, there is no easy way to measure improvement in bone quality.

How Long to Treat

There are currently no conclusive research findings to suggest how long an osteoporosis drug remains safe and effective, except for teriparatide (Forteo®). Teriparatide can be taken for no more than two years according to the FDA. It is uncertain how long any of the osteoporosis medicines remain effective after they are stopped.

Past Experience and Studies

Past experience with bisphosphonates (Actonel®, Boniva® and Fosamax®) suggests that upon discontinuation of any of these drugs, the benefits may continue for several years or longer. This is because the drugs remain in the bone for a long time. Eventually, however, the beneficial effect begins to lessen, bone remodeling rates increase and bone loss may occur.

One study found that alendronate (Fosamax®) continued to have a beneficial effect on bone mineral density for up to 10 years in postmenopausal women taking the medicine. Biopsies of bone tissue in women on alendronate for 10 years show that bone tissue looks healthy and normal. Other studies show that treating with alendronate for more than five years improves bone strength and reduces fractures of the spine.

Another study suggested that women who discontinued taking alendronate after five years of treatment did not significantly increase their fracture risk for up to an additional five years. Women who stopped alendronate after five years had the same rate of non-spine fractures as women who continued using the drug for 10 years. However, the study found that women at very high risk of spine fractures may benefit by continuing to take alendronate beyond five years.

How Long to Treat

In the absence of clinical studies on duration of treatment, healthcare providers and patients should discuss options to determine the best course of action. NOF encourages all healthcare providers to evaluate a patient on the basis of clinical risk factors, such as the presence or absence of fractures, bone density status, age, weight, smoking and alcohol use. Length of treatment should be individualized and based on the person’s medical and fracture history, as well as the initial and most recent bone mineral density test results.

It is good practice to reevaluate the need to continue your medicines every year with your healthcare provider. After three to five years of taking a bisphosphonate medicine, individuals should discuss whether they should continue taking the medicine, stop taking the medicine or consider switching to a different medicine. Always talk to your healthcare provider first, before making any changes to your treatment plan.

When a patient has a good response to treatment with an osteoporosis medicine, some healthcare providers will consider a drug holiday. This means stopping the medicine for a period of time and continuing to monitor bone mineral density. Some healthcare providers consider a drug holiday after five years when there has been a good response to treatment. Others view it as an option when bone mineral density tests are performed two years apart, and the test results are similar and show a good response to treatment.

Although some healthcare providers give drug holidays, there are few research findings that support (or not support) this practice.

Serious Side Effects

Each individual should talk with their healthcare provider about the risks and benefits of taking or not taking a prescription medicine. While most individuals do not experience any serious side effects, if you have aserious reaction or problem with a drug, either you or your healthcare provider should notify the FDA to report the problem. The toll free number for the FDA is 1 (800) 332-1088. To complete a report online, visit the FDA Web site at www.fda.gov/medwatch. You may want to notify the pharmaceutical manufacturer of the adverse event. Find the phone numbers of the pharmaceutical manufacturers and the date each medicine was approved by the FDA as an osteoporosis medicine here.

Maximizing Your Treatment

Many people have trouble taking their medicines. People with osteoporosis often take one or more medicines for other conditions as well. They may worry about the risks and side effects or find the instructions for taking a medicine confusing or complicated. When you have questions about your medicines, be sure to speak with your healthcare provider or pharmacist.

When you take an osteoporosis medicine, you will not feel your bones getting stronger. This can make it hard to stay on a treatment plan. But it’s important that you take your medicine if you want it to work. You should take it just as your healthcare provider prescribed it, and you must remember to continue to take it. You also need to exercise regularly and get enough calcium and vitamin D.

If you decide that a treatment is not right for you, don’t just stop taking the medicine. First, talk with your healthcare provider about your concerns. When prescriptions are not filled, or if they are forgotten, taken incorrectly or stopped early, your health may not improve or could get worse. Studies show that if you take your osteoporosis medicine half of the time or less, it is the same as if you don’t take it at all.  Healthcare providers may find it difficult to figure out why you are not getting better. They might think the medicine did not work or that another health condition may be present. This can lead to extra tests, prescriptions, costs and broken bones that may have been prevented by taking the medicine as directed.

With antiresorptive medicines, the goal of treatment is to prevent more bone loss and to reduce the risk of breaking bones in the future. Your response to treatment is considered good if your bone density either stays the same or improves and if you don’t break any bones.

With anabolic medicine, the goal of treatment is to build new bone, increase bone density, repair tiny defects in bone and reduce the risk of broken bones. Your response to treatment is considered good if the rate of bone formation increases and your bone density improves and if you don’t break any bones.

To find out how your treatment is working, your healthcare provider will repeat your bone density test every two years. In some cases, healthcare providers will also use special lab tests called bone marker tests or biochemical marker tests to see if patients are losing bone faster than normal. While there is no easy way to measure improvement in bone quality, research in this area is currently underway.

You should be sure to see your healthcare provider regularly and review your medicines at each visit.  This will help to find any side effects of the medicine and make sure you are responding to it as you should.



Related

Managing Your Pain

Recovering from broken bones can be a long and painful process for some people. If you have ongoing pain, talk to your healthcare provider about what you can do to control your pain. 

Low Bone Density

Low bone density is when your bone density is lower than normal, but not low enough to be considered osteoporosis. People with low bone density are more likely to break a bone and may have a greater chance of getting osteoporosis because they have less bone to lose.

Medicines that May Cause Bone Loss

Some medicines can be harmful to your bones, even if you need to take them for another condition. Talk with your healthcare provider about the risks and benefits of any medicines you take and about how they may affect your bones.