All patients being considered for treatment of osteoporosis should also be counseled on risk factor reduction including the importance of calcium, vitamin D, and exercise as part of any treatment program for osteoporosis. Prior to initiating treatment, patients should be evaluated for secondary causes of osteoporosis and have BMD measurements by central DXA, when available, and vertebral imaging studies when appropriate. Biochemical marker levels should be obtained if monitoring of treatment effects is planned. An approach to the clinical assessment of individuals with osteoporosis is outlined in Table 10.
The percentage of risk reductions for vertebral and nonvertebral fractures cited below are those cited in the FDA-approved prescribing information. In the absence of head-to-head trials, direct comparisons of risk reduction among drugs should be avoided.
Who should be considered for treatment?
Postmenopausal women and men age 50 and older presenting with the following should be considered for treatment:
A hip or vertebral fracture (clinically apparent or found on vertebral imaging). There are abundant data that patients with spine and hip fractures will have reduced fracture risk if treated with pharmacologic therapy. This is true for fracture patients with BMD in both the low bone mass and osteoporosis range [49–58]. In patients with a hip or spine fracture, the T-score is not as important as the fracture itself in predicting future risk of fracture and antifracture efficacy from treatment.
T-score ≤−2.5 at the femoral neck, total hip, or lumbar spine. There is abundant evidence that the elevated risk of fracture in patients with osteoporosis by BMD is reduced with pharmacotherapy [52, 57, 59–70].
Low bone mass (T-score between −1.0 and −2.5 at the femoral neck or lumbar spine) and a 10-year probability of a hip fracture ≥3 % or a 10-year probability of a major osteoporosis-related fracture ≥20 % based on the US-adapted WHO algorithm [13, 15, 71, 72].
Although FRAX calculated fracture risk prediction has been confirmed in multiple studies, there are relatively few data confirming fracture risk reductions with pharmacotherapy in this group of patients.
US FDA-approved drugs for osteoporosis
Current FDA-approved pharmacologic options for the prevention and/or treatment of postmenopausal osteoporosis include, in alphabetical order: bisphosphonates (alendronate, alendronate plus D, ibandronate, risedronate and zoledronic acid), calcitonin, estrogens (estrogen and/or hormone therapy), estrogen agonist/antagonist (raloxifene), tissue-selective estrogen complex (conjugated estrogens/bazedoxifene), parathyroid hormone (PTH [1–34], teriparatide), and the receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL) inhibitor denosumab. Please see prescribing information for specific details of their use.
The antifracture benefits of FDA-approved drugs have mostly been studied in women with postmenopausal osteoporosis. There are limited fracture data in glucocorticoid-induced osteoporosis and in men. FDA-approved osteoporosis treatments have been shown to decrease fracture risk in patients who have had fragility fractures and/or osteoporosis by DXA. Pharmacotherapy may also reduce vertebral fractures in patients with low bone mass (osteopenia) without fractures, but the evidence supporting overall antifracture benefit is not as strong. Thus, the clinician should assess the potential benefits and risks of therapy in each patient and the effectiveness of a given osteoporosis treatment on reduction of vertebral and nonvertebral fractures.
Note that the intervention thresholds do not take into account the nonskeletal benefits or risks associated with specific drug use. NOF does not advocate the use of drugs not approved by the FDA for prevention and treatment of osteoporosis. Examples of these drugs are listed in Table 11 for information only.
Alendronate, brand name: Fosamax®, Fosamax Plus D, Binosto™, and generic alendronate
Alendronate sodium is approved by the FDA for the prevention (5 mg daily and 35 mg weekly tablets) and treatment (10 mg daily tablet, 70 mg weekly tablet, 70 mg weekly tablet with 2,800 or 5,600 IU of vitamin D3, and 70 mg effervescent tablet) of postmenopausal osteoporosis. Alendronate is also approved for treatment to increase bone mass in men with osteoporosis and for the treatment of osteoporosis in men and women taking glucocorticoids .
Alendronate reduces the incidence of spine and hip fractures by about 50 % over 3 years in patients with a prior vertebral fracture or in patients who have osteoporosis at the hip site [49, 59]. It reduces the incidence of vertebral fractures by 48 % over 3 years in patients without a prior vertebral fracture .
Ibandronate, brand name: Boniva® and generic ibandronate
Ibandronate sodium is approved by the FDA for the treatment (150 mg monthly tablet and 3 mg every 3 months by intravenous injection) of postmenopausal osteoporosis. Ibandronate is available as a generic preparation in the USA. The oral preparations are also approved for the prevention of postmenopausal osteoporosis.
Ibandronate reduces the incidence of vertebral fractures by about 50 % over 3 years, but reduction in risk of nonvertebral fracture with ibandronate has not been documented .
Risedronate, brand name: Actonel®, Atelvia™, and generic risedronate
Risedronate sodium is approved by the FDA for the prevention and treatment (5 mg daily tablet; 35 mg weekly tablet; 35 mg weekly delayed release tablet; 35 mg weekly tablet packaged with six tablets of 500 mg calcium carbonate; 75 mg tablets on two consecutive days every month; and 150 mg monthly tablet) of postmenopausal osteoporosis. Risedronate is also approved for treatment to increase bone mass in men with osteoporosis and for the prevention and treatment of osteoporosis in men and women who are either initiating or taking glucocorticoids .
Risedronate reduces the incidence of vertebral fractures by 41 to 49 % and nonvertebral fractures by 36 % over 3 years, with significant risk reduction occurring within 1 year of treatment in patients with a prior vertebral fracture [51, 52].
Zoledronic acid, brand name: Reclast®
Zoledronic acid is approved by the FDA for the prevention and treatment (5 mg by intravenous infusion over at least 15 min once yearly for treatment and once every 2 years for prevention) of osteoporosis in postmenopausal women. It is also approved to improve bone mass in men with osteoporosis and for the prevention and treatment of osteoporosis in men and women expected to be on glucocorticoid therapy for at least 12 months. Zoledronic acid is also indicated for the prevention of new clinical fractures in patients (both women and men) who have recently had a low-trauma (osteoporosis-related) hip fracture .
Zoledronic acid reduces the incidence of vertebral fractures by 70 % (with significant reduction at 1 year), hip fractures by 41 %, and nonvertebral fractures by 25 % over 3 years in patients with osteoporosis defined by prevalent vertebral fractures and osteoporosis by BMD of the hip .
Alendronate (generic and Fosamax) and risedronate (Actonel) tablets must be taken on an empty stomach, first thing in the morning, with 8 oz of plain water (no other liquid). Binosto must be dissolved in 4 oz of room temperature water taken on an empty stomach, first thing in the morning. Delayed release risedronate (Atelvia) tablets must be taken immediately after breakfast with at least 4 oz of plain water (no other liquid). After taking these medications, patients must wait at least 30 min before eating, drinking, or taking any other medication. Patients should remain upright (sitting or standing) during this interval.
Ibandronate must be taken on an empty stomach, first thing in the morning, with 8 oz of plain water (no other liquid). After taking this medication, patients must remain upright and wait at least 60 min before eating, drinking, or taking any other medication. Ibandronate, 3 mg/3 ml prefilled syringe, is given by intravenous injection over 15 to 30 s, once every 3 months. Serum creatinine should be checked before each injection.
Zoledronic acid, 5 mg in 100 ml, is given once yearly or once every 2 years by intravenous infusion over at least 15 min. Patients should be well hydrated and may be pre-treated with acetaminophen to reduce the risk of an acute phase reaction (arthralgia, headache, myalgia, fever). These symptoms occurred in 32 % of patients after the first dose, 7 % after the second dose, and 3 % after the third dose.
Side effects are similar for all oral bisphosphonate medications and include gastrointestinal problems such as difficulty swallowing and inflammation of the esophagus and stomach.
All bisphosphonates can affect renal function and are contraindicated in patients with estimated GFR below 30–35 ml/min. Zoledronic acid is contraindicated in patients with creatinine clearance less than 35 mL/min or in patients with evidence of acute renal impairment. Healthcare professionals should screen patients prior to administering zoledronic acid in order to identify at-risk patients and should assess renal function by monitoring creatinine clearance prior to each dose of zoledronic acid . Eye inflammation can also occur. Any such complication should be reported to the healthcare provider as soon as possible.
There have been rare reports of osteonecrosis of the jaw (ONJ) with long-term use of bisphosphonates for osteoporosis, though ONJ is much more common following high-dose intravenous bisphosphonate treatment for patients with cancer. The risk of ONJ appears to increase with duration of treatment beyond 5 years .
Although rare, low-trauma atypical femur fractures may be associated with the long-term use of bisphosphonates (e.g., >5 years of use). Pain in the thigh or groin area, which can be bilateral, often precedes these unusual fractures. Patients should be evaluated closely for these unusual fractures, including proactive questioning regarding thigh and groin pain. For patients with thigh and groin pain, a stress fracture in the subtrochanteric region or femoral shaft of the femur may be present. Bilateral X-ray of the femurs should be ordered when an atypical femur fracture is suspected, followed by an MRI or a radionuclide bone scan when clinical suspicion is high enough . Surgical fixation is required in some cases, whereas medical conservative treatment is appropriate in other cases. Bisphosphonates should be stopped if atypical femur fractures have occurred.
Brand name: Miacalcin® or Fortical® and generic calcitonin
Salmon calcitonin is FDA-approved for the treatment of osteoporosis in women who are at least 5 years postmenopausal when alternative treatments are not suitable.
Miacalcin nasal spray has not been shown to increase bone mineral density in early postmenopausal women.
Calcitonin reduces vertebral fracture occurrence by about 30 % in those with prior vertebral fractures but has not been shown to reduce the risk of nonvertebral fractures [54, 79]. Due to the possible association between malignancy and calcitonin-salmon use, the need for continued therapy should be re-evaluated on a periodic basis.
Two hundred international units delivered as a single daily intranasal spray. Subcutaneous administration by injection also is available.
Intranasal calcitonin can cause rhinitis, epistaxis, and allergic reactions, particularly in those with a history of allergy to salmon. The FDA has reviewed long-term post-marketing data concerning calcitonin and the very small increase in the risk of certain cancers. A meta-analysis of 21 randomized, controlled clinical trials with calcitonin-salmon (nasal spray and investigational oral forms) suggests an increased risk of malignancies in calcitonin-salmon-treated patients compared to placebo-treated patients. The overall incidence of malignancies reported in the 21 trials was higher among calcitonin-salmon-treated patients (4.1 %) compared with placebo-treated patients (2.9 %). The data were not sufficient for further analyses by specific type of malignancy. Although a definitive causal relationship between the calcitonin-salmon use and malignancies cannot be established from this meta-analysis, the benefits for the individual patient should be carefully evaluated against all possible risks [80, 81].
Estrogen/hormone therapy (ET/HT)
ET brand names:e.g., Climara®, Estrace®, Estraderm®, Estratab®, Ogen®, Premarin®, Vivelle®; HT brand names: e.g., Activella®, Femhrt®, Premphase®, Prempro®
Estrogen/hormone therapy is approved by the FDA for the prevention of osteoporosis, relief of vasomotor symptoms, and vulvovaginal atrophy associated with menopause. Women who have not had a hysterectomy require HT, which also contains progestin to protect the uterine lining.
The Woman’s Health Initiative (WHI) found that 5 years of HT (Prempro®) reduced the risk of clinical vertebral fractures and hip fractures by 34 % and other osteoporotic fractures by 23 % .
ET/HT is available in a wide variety of oral as well as transdermal preparations including estrogen only, progestin only, and combination estrogen–progestin. ET/HT dosages include cyclic, sequential, and continuous regimens. If and when treatment is stopped, bone loss can be rapid and alternative agents should be considered to maintain BMD.
The WHI reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis during 5 years of treatment with conjugated equine estrogen and medroxyprogesterone acetate (Prempro®) . Subsequent analyses of these data showed no increase in cardiovascular disease in women starting treatment within 10 years of menopause . In the estrogen only arm of WHI, no increase in breast cancer incidence was noted over 7.1 years of treatment. Other doses and combinations of estrogen and progestins were not studied and, in the absence of comparable data, their risks should be assumed to be comparable. Because of the risks, ET/HT should be used in the lowest effective doses for the shortest duration to treat moderately severe menopausal symptoms and should be considered primarily for women within the first few years of menopause. When ET/HT use is considered solely for prevention of osteoporosis, the FDA recommends that approved nonestrogen treatments should first be carefully considered. When ET/HT treatments are stopped, bone loss can be rapid and alternative agents should be considered to maintain BMD.
Estrogen agonist/antagonist (formerly known as SERMs): Raloxifene
Raloxifene, brand name: Evista® and generic raloxifene
Raloxifene is approved by the FDA for both prevention and treatment of osteoporosis in postmenopausal women.
Raloxifene reduces the risk of vertebral fractures by about 30 % in patients with a prior vertebral fracture and by about 55 % in patients without a prior vertebral fracture over 3 years . Reduction in risk of nonvertebral fracture with raloxifene has not been documented. Raloxifene is also indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis [83–86]. Raloxifene does not reduce the risk of coronary heart disease.
Available in a 60-mg tablet form to be taken with or without food.
Raloxifene increases the risk of deep vein thrombosis to a degree similar to that observed with estrogen. It can also increase hot flashes and cause leg cramps.
Tissue-selective estrogen complex: conjugated estrogens/bazedoxifene (conjugated estrogens paired with estrogen agonist/antagonist)
Conjugated estrogens/bazedoxifene, brand name: Duavee®
Conjugated estrogens/bazedoxifene is approved by the FDA for women who suffer from moderate-to-severe hot flashes (vasomotor symptoms) associated with menopause and to prevent osteoporosis after menopause.
The medication combines conjugated estrogen with an estrogen agonist/antagonist (bazedoxifene). The bazedoxifene component reduces the risk of endometrial hyperplasia (excessive growth of the lining of the uterus) that can occur with the estrogen component of the drug. Therefore, progestins do not need to be taken with conjugated estrogens/bazedoxifene.
Use of this combination drug significantly increased mean lumbar spine BMD (treatment difference, 1.51 %), at 12 months compared to placebo in women who had been postmenopausal between 1 and 5 years. Treatment with conjugated estrogens/bazedoxifene also increased total hip BMD. The treatment difference in total hip BMD at 12 months was 1.21 % [87–90].
Available as a tablet containing conjugated estrogens and bazedoxifene 0.45 mg/ 20 mg, to be taken once daily without regard to meals.
Conjugated estrogens/bazedoxifene is intended only for postmenopausal women who still have a uterus. Like other products containing estrogen, it should be used for the shortest duration consistent with treatment goals and risks for the individual woman. When using this drug only for the prevention of osteoporosis, such use should be limited to women who are at significant risk of osteoporosis and only after carefully considering alternatives that do not contain estrogen.
Side effects of conjugated estrogens/bazedoxifene include muscle spasms, nausea, diarrhea, dyspepsia, upper abdominal pain, oropharyngeal pain, dizziness, and neck pain. Because this product contains estrogen, it is approved with the same Boxed Warning and other Warnings and Precautions that have been approved with estrogen products.
Parathyroid hormone: teriparatide
PTH(1-34), teriparatide, brand name: Forteo®
Teriparatide is approved by the FDA for the treatment of osteoporosis in postmenopausal women and men at high risk for fracture. It is also approved for treatment in men and women at high risk of fracture with osteoporosis associated with sustained systemic glucocorticoid therapy . Teriparatide reduces the risk of vertebral fractures by about 65 % and nonvertebral fragility fractures by about 53 % in patients with osteoporosis, after an average of 18 months of therapy .
Teriparatide is an anabolic (bone-building) agent administered by 20 μg daily subcutaneous injection. If and when treatment is stopped, bone loss can be rapid and alternative agents should be considered to maintain BMD. Treatment duration is recommended not to exceed 18 to 24 months.
Side effects of teriparatide include leg cramps, nausea, and dizziness. Because it caused an increase in the incidence of osteosarcoma in rats (high doses, long duration treatment in the rodent), patients with an increased risk of osteosarcoma (e.g., patients with Paget’s disease of bone and those having prior radiation therapy of the skeleton), bone metastases, hypercalcemia, or a history of skeletal malignancy should not receive teriparatide therapy. It is common practice to follow teriparatide treatment with an antiresorptive agent, usually a bisphosphonate, to maintain or further increase BMD.
RANKL/RANKL inhibitor: denosumab
Denosumab, brand name Prolia®
Denosumab is approved by the FDA for the treatment of osteoporosis in postmenopausal women at high risk of fracture. Denosumab reduces the incidence of vertebral fractures by about 68 %, hip fractures by about 40 %, and nonvertebral fractures by about 20 % over 3 years . Denosumab is also indicated to increase bone mass in men at high risk of fracture, treat bone loss in women with breast cancer on aromatase inhibitor therapies, and to treat bone loss in men receiving gonadotropin-reducing hormone treatment for prostate cancer who are at high risk for fracture.
Administered by a health professional, 60 mg every 6 months as a subcutaneous injection.
Denosumab may cause hypocalcemia. Hypocalcemia must be corrected before starting denosumab. Denosumab increased the risk of serious skin infections (cellulitis) and skin rash. Denosumab has been rarely associated with the development of ONJ, both when used to treat osteoporosis and to treat patients with cancer (at much higher doses), although it is much more common in the latter setting. Denosumab has also been associated rarely with the development of atypical femur fractures. If and when denosumab treatment is stopped, bone loss can be rapid and alternative agents should be considered to maintain BMD.
Sequential and combination therapy
When osteoporosis is diagnosed in young individuals, choices of osteoporosis medication may change over time to take advantage of the best benefit to risk ratio at each stage of life (sequential monotherapy). For more severe osteoporosis, sequential treatment with anabolic therapy followed by an antiresorptive agent is generally preferred to concomitant combination therapy. However, combination therapy with teriparatide and an antiresorptive can be considered in a few clinical settings in patients with very severe osteoporosis such as spine and hip fractures. There are few indications for combining two antiresorptive treatments, but such options could be considered in the short term in women who are experiencing active bone loss while on low dose HT for menopausal symptoms or raloxifene for breast cancer prevention.
Duration of treatment
No pharmacologic therapy should be considered indefinite in duration. All nonbisphosphonate medications produce temporary effects that wane upon discontinuation. If these treatments are stopped, benefits rapidly disappear. In contrast, bisphosphonates may allow residual effects even after treatment discontinuation. Therefore, it may be possible to discontinue bisphosphonates and retain residual benefits against fracture at least for several years.
Evidence of efficacy beyond 5 years is limited, whereas rare safety concerns such as ONJ and atypical femur fractures become more common beyond 5 years [67, 92]. Since there is no extensive evidence base to guide treatment duration decisions, duration decisions need to be individualized . After the initial 3- to 5-year treatment period, a comprehensive risk assessment should be performed. This should include interval clinical history, particularly with respect to intercurrent fracture history and new chronic diseases or medications, as well as height measurement, BMD testing, and vertebral imaging if there has been any documented height loss during the treatment period. It is reasonable to discontinue bisphosphonates after 3 to 5 years in people who appear to be at modest risk of fracture after the initial treatment period. In contrast, for those who appear to be at high risk for fracture, continued treatment with a bisphosphonate or an alternative therapy should be considered .
It is important to ask patients whether they are taking their medications and to encourage continued and appropriate compliance with their osteoporosis therapies to reduce fracture risk. It is also important to review their risk factors and encourage appropriate calcium and vitamin D intakes, exercise, fall prevention, and other lifestyle measures. Furthermore, the need for continued medication to treat osteoporosis should be reviewed annually. Duration of treatment must be individualized. Some patients may be able to discontinue treatment temporarily after several years of therapy, particularly after bisphosphonate administration [95, 96]. Other patients will need to continue treatment. If treatment is discontinued, serial monitoring should include clinical assessment for fractures, falling, any interval chronic disease occurrence and consideration of serial BMD testing, use of biochemical markers, and vertebral imaging in some patients.
Accurate yearly height measurement is a critical determination of osteoporosis treatment efficacy. Patients who lose 2 cm (or 0.8 in.) or more in height either acutely or cumulatively should have a repeat vertebral imaging test to determine if new or additional vertebral fractures have occurred since the prior vertebral imaging test.
Serial central DXA testing is an important component of osteoporosis management. Measurements for monitoring patients should be performed in accordance with medical necessity, expected response, and in consideration of local regulatory requirements. NOF recommends that repeat BMD assessments generally agree with Medicare guidelines of every 2 years but recognizes that testing more frequently may be warranted in certain clinical situations.
The following techniques may be used to monitor the effectiveness of treatment:
Central DXA assessment of the hip or lumbar spine is the “gold standard” for serial assessment of BMD. Biological changes in bone density are small compared to the inherent error in the test itself, and interpretation of serial bone density studies depends on appreciation of the smallest change in BMD that is beyond the range of error of the test. This least significant change (LSC) varies with the specific instrument used, patient population being assessed, measurement site, technologist’s skill with patient positioning and test analysis, and the confidence intervals used . Changes in the BMD of less than 3–6 % at the hip and 2–4 % at the spine from test to test may be due to the precision error of the testing itself. Information on how to assess precision and calculate the LSC is available at www.ISCD.org.
Volumetric BMD of the lumbar spine can be used to monitor age-, disease, and treatment-related BMD changes in men and women. Precision of acquisition should be established by phantom data and analysis precision by re-analysis of patient data.
pDXA, pQCT, and QUS
Peripheral skeletal sites do not respond with the same magnitude as the spine and hip to medications and thus are not appropriate for monitoring response to therapy at this time.
Biochemical markers of bone turnover
Suppression of biochemical markers of bone turnover after 3–6 months of treatment and biochemical marker increases after 1–3 months of anabolic therapy have been predictive of greater BMD responses and in some cases fracture risk reduction in large clinical trials. Biochemical marker changes in individuals must exceed the LSC in order to be clinically meaningful. The LSC is specific to the biomarker being utilized, which is calculated by multiplying the “precision error” of the specific biochemical marker (laboratory provided) by 2.77 (95 % confidence level). Biological variability can be reduced by obtaining samples in the early morning after an overnight fast. Serial measurements should be made at the same time of day at the same laboratory.
Once the first vertebral imaging test has been performed to determine prevalent vertebral fractures (indications above), repeat testing should be performed to identify incident vertebral fractures if there is a change in the patient’s status suggestive of new vertebral fracture, including documented prospective height loss, undiagnosed back pain, postural change, or a possible finding of new vertebral deformity on chest X-ray. If patients are being considered for a temporary cessation of drug therapy, vertebral imaging should be repeated to determine that no vertebral fractures have occurred in the interval off treatment. A new vertebral fracture on therapy indicates a need for more intensive or continued treatment rather than treatment cessation .
Implementation of FLS secondary fracture prevention programs
FLS programs have been implemented successfully in a number of closed and open settings over the last 15 years, both in the USA (including the American Orthopedic Association Own the Bone program) as well as abroad. These programs have accomplished a reduction in secondary fracture rates as well as health care cost savings [98, 99]. In the USA, Kaiser Permanente’s Healthy Bones program has reduced the expected hip fracture rate by 38 % since 1998 ; Geisinger Health System achieved $7.8 million in cost savings over 5 years .
A Fracture Liaison Service is a coordinated care system headed by an FLS coordinator (a nurse practitioner, physician’s assistant, nurse, or other health professional) who ensures that individuals who suffer a fracture receive appropriate diagnosis, treatment, and support . The FLS uses established protocols to find and assess fracture patients. The program creates a population database of fracture patients and establishes a process and timeline for patient assessment and follow-up care. An FLS coordinator is frequently based in a hospital and requires support from a qualified physician or physician team.