Pharmacologic Therapies for Prevention and Treatment
Primary health care should routinely address bone health. Young adults should be encouraged to achieve normal peak bone mass through:
- adequate dietary calcium (1000 mg daily)
- weight-bearing exercise
- maintenance of normal body weight and reproductive function
- hormone replacement (often in the form of estrogen containing oral contraceptives) in young women who experience prolonged amenorrhea
For newly menopausal women, estrogen replacement was the standard of practice to prevent bone loss. There was evidence to suggest that initiating estrogen therapy in older women may be of benefit to bone mass, although the maximum benefits were achieved through early menopausal hormone replacement and maintenance of estrogen replete state long-term. Womens Health Initiative, a large prospective study to determine the risk-benefit ratio of estrogen use in older postmenopausal women showed reduction is overall fractures with use of estrogen alone and estrogen-progestin combinations. However, their results showed that the benefit of fracture reduction does not outweigh the increased risk of strokes and breast cancer, even in women at higher risk of fracture. Thus, hormone replacement therapy is not currently recommended for either prevention or treatment of osteoporosis in postmenopausal women.
Testosterone replacement for hypogonadal men preserves bone mass. Testosterone replacement for age-related decline in testosterone levels in healthy older men is currently being studied to determine the risk/benefit profile.
Osteoporosis Management(ref 4, 19) is evolving. There is consensus that calcium and vitamin D intake is needed to increase bone mass. Bisphosphonates are corner stone of therapy for prevention and treatment of osteoporosis and have been shown to reduce vertebral and non-vertebral fractures. There are 4 FDA-approved bisphosphonates: Alendronate, Risedronate, Ibandronate, Zoledronic Aid. Calcitonin has also been shown to reduce vertebral fractures. The table below lists the dosing and side effects of these nonhormonal treatment options.
|Calcium Intake||1500 mg daily (through diet and supplements)|
|Vitamin D||800-1000 units daily is needed to increase bone mass|
(a biphosphonate, FDA approved
|Dosage: 10 mg daily to treat osteoporosis and 5 mg daily to prevent bone loss in post-menopausal women. There are data to show that alternative alendronate dosing of 35 mg twice weekly, or 70 mg once weekly results in similar increases in bone density at one year to daily alendronate therapy, but with less gastrointestinal adverse reactions.(ref 21)Efficacy: Alendronate has shown in three year clinical trials to reduce the risk of new vertebral and hip fractures by 50%. Side Effects: Gastrointestinal are most common, especially nausea, acid reflux symptoms, and constipation. To maximize absorption, should be taken on an empty stomach with water only, waiting 30 minutes before eating or drinking. To minimize acid reflux, patients should not recline for one hour after a dose. To optimize treatment response, adequate calcium and vitamin D as described above are essential.|
(a biphosphonate, FDA approved)
|Dosage: The recommended regimen is 5 mg orally daily for the treatment and prevention of postmenopausal osteoporosis and glucocorticoid-induced osteoporosis.|
Efficacy: In clinical trials, administration of risedronate to postmenopausal women resulted in decreases in biochemical markers of bone turnover. Data on bone mineral density increases and reductions in vertebral compression fractures are comparable to alendronate.(ref 24) Side Effects: Gastrointestinal are most common, especially nausea, acid reflux symptoms, and constipation. To maximize absorption, should be taken on an empty stomach with only water, waiting 30 minutes before eating or drinking. To minimize acid reflux, patients should not recline for one hour after a dose. To optimize treatment response, adequate calcium and vitamin D as described above are essential. Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL”min).
(FDA approved for treatment of post menopausal osteoporosis)
|Dosage: 5 mg intravenously once a year to treat or prevent postmenopausal and corticosteroid induced.Efficacy: In a clinical trial, Zoledronic acid has demonstrated 41% relative reduction in the risk of hip fractures in post-menopausal females over a median duration of follow-up of 3 years. Side Effects: The most common adverse reactions (>10%) fever, myalgia, headache, joint pain. Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal disease. Low calcium levels should be adequately treated before using Zolendronic acid.|
|Rare but serious Side Effects of bisphosphonate therapy||Osteonecrosis of the jawresults in damage to the bone of the jaw with poor healing. It is often precipitated by dental work, in particular if the jaw is exposed, such as tooth extraction. Osteonecrosis of the jaw has been reported in patients treated with bisphosphonates. The majority of the initial reported cases are in cancer patients treated with bisphosphonates requiring a dental procedure. Since then increasing evidence suggests that bisphosphonate use for osteoporosis may also be associated with increased risk of jaw necrosis, although direct cause and effect cannot be determined.Atypical sub-trochanteric femur fracturesare fractures in the femur bone just below the hip joint. These fractures are very uncommon and account for less than 1% of all hip and femur fractures overall. These unusual femur fractures have been mostly reported in patients taking bisphosphonates and may be related to long-term bisphosphonate use. Although it is not clearly established whether bisphosphonate use is the cause of these fractures.While these suspected adverse events with bisphosphonate use may be severe, it is important to remember that they occur infrequently.Given the efficacy of bisphosphonates in the reduction of vertebral and nonvertebral fractures, the benefits likely outweigh potential risk over the short term for most patients. The safety of long-term use of these agents, beyond the first 5 years, is an area of growing research interest.If you currently take a bisphosphonate, you should:Continue to take your medication unless you are told to stop by your healthcare professional.
Talk to your health professional if there is anticipated dental extraction or other procedures planned in future.
Talk to your healthcare professional if you develop new hip or thigh pain (commonly described as dull or aching pain), or have any concerns with your medications
(for those who do not tolerate bisphosphonate therapy)(ref 22)
|Dosage: 200 units, or one metered puff daily alternating nostrils|
Efficacy: Calcitonin is shown to reduce the risk of vertebral fractures, but the effects on the hip appear to be less than that of bisphosphonate therapy.
|Forteo (Teriparrtide)||Dosage:This is a daily injection, 20 mcg/day, approved for treament of post-menopausal and glucocorticoid induced osteoporosis. Its mechanism of action is different compared to bisphosphonates as it works by increasing bone formation.Efficacy:Clinical trials show that Forteo lowers the risk of fractures in postmenopausal women with osteoporosis. In a randomized trial of 1,637 postmenopausal women with prior vertebral fractures, women who took Forteo had a 65% lower risk of new vertebral fractures and a 53% lower risk of new nonvertebral fractures, compared with women who received placebo ( ref Neer RM, May 2001)Side Effects: Side effects are usually mild, including dizziness and leg cramps. A possible serious side effect is elevated blood calcium levels (hypercalcemia). Signs of hypercalcemia include confusion, muscle or bone pain, nausea, vomiting, and a slow or irregular heartbeat. In preclinical trials, rats given Forteo at high doses for two years developed osteosarcoma (a rare form of bone cancer). People who are at increased risk for bone cancer, such as history of Pagets disease or bone radiation should not use Forteo.|
|Prolia (Denosumab)||Dosage:60 mg subcutaneous injection every 6 months. Approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.This is a monoclonal antibody that targets osteoclast function and survival. Osteoclasts are bone cells that are important in resorbing bone.Efficacy:In a 3 year trial of post-menopausal women with osteoporosis, denosumab therapy reduced hip fracture by 40% and vertebral fractures by 68%.Side Effects: The most common adverse reactions were back pain, musculoskeletal pain, hypercholesterolemia. Low calcium levels can be seen and serious infections including skin, urinary and abdominal infections were more common in patients using denosumab.|
Weight-bearing exercise has been shown to increase bone mass, strengthen muscle, and reduce the risk of falls. There is a role for exercise prescriptions in osteoporosis management. The National Osteoporosis Foundation offers an exercise program via video cassette that includes safe and effective exercises that can be performed in the home setting.
Is it reasonable to implement an osteoporosis treatment program in the setting of a recent fracture? Our experience to date is yes. At the Rehabilitation Center of the Johns Hopkins Geriatrics Center, the post-fracture admission orders include calcium and vitamin D supplementation. Bisphosphonate therapy in this setting has been difficult due to the high prevalence of gastroesophageal reflux and constipation. We currently defer bisphosponate or calcitonin therapy until the acute and subacute rehabilitation is complete, which is usually one to two months post-fracture.
For those at risk for falls, a fall prevention strategy is warranted to reduce the number of fall-related fractures. A multi-disciplinary approach includes both medical and physical assessments.(ref 30) Medications are reviewed to determine if any are impairing judgment, balance, or postural hemodynamic stability. Orthostatic and postprandial hypotension are considered. Vision and hearing assessment may target appropriate intervention. Gait assessment is performed during physical therapy evaluation. Training with assistive devices and the use of rubber soled shoes often improve fall risk. Physical therapy should include an exercise program for muscle strengthening and physical reconditioning. A home safety evaluation is used to identify dangers from throw rugs, inadequate lighting, and cluttered walkways, and to provide in-home safety equipment such as bathroom grab bars and raised toilet seats.
Estrogen Replacement and Selective Receptor Modulators
The Women’s Health Initiative, a large randomized trial of hormone replacement in post-menopausal women, showed an increased risk of stroke, breast cancer and thrombosis associated with hormone replacement therapy. This finding had significant implications on clinical management of osteoporosis as hormone replacement therapy till then was considered beneficial in prevention and treatment of post-menopausal osteoporosis. This is no longer the case
Selective estrogen receptor modulators such as raloxifene 60 mg daily are also available for treatment and prevention of post-menopausal osteoporosis. The effects of raloxifene on bone and lipids are comparable to estrogen replacement.(ref 37) There appear to be no growth promoting effects on breast or endometrium, thus reducing the risk profile of hormone replacement. The down side to raloxifene is that hot flushes are not improved over Placebo, and the risk of clotting is at least comparable to estrogen.