Osteoporosis Treatment & Management

Updated: Dec 21, 2022
  • Author: Rachel Elizabeth Whitaker Elam, MD, MSc; Chief Editor: Herbert S Diamond, MD  more...
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Approach Considerations

A clinical practice guideline from the American College of Physicians on treatment to prevent fractures in men and women with low bone density or osteoporosis includes six recommendations: two strong recommendations, based on high- or moderate-quality evidence, and four weak ones, based on low-quality evidence. [144] The two strong recommendations are as follows:

  • Clinicians should offer pharmacologic treatment to women with known osteoporosis to reduce the risk for hip and vertebral fractures; alendronate, risedronate, zoledronic acid, or denosumab may be used.
  • In postmenopausal women, estrogen or estrogen plus progestogen or raloxifene should not be used for the treatment of osteoporosis.

The four weak recommendations are as follows:

  • In women with osteoporosis, pharmacologic treatment should last for 5 years; generic drugs should be used when possible.

  • Monitoring of bone mineral density (BMD) during the 5 years of treatment in women with osteoporosis is not advised, as evidence suggests that fracture risk may be reduced regardless of BMD changes.

  • For women aged 65 and older who have osteopenia and are at high fracture risk, decisions to treat should take into account patient preference, fracture-risk profile, benefits, harms, and price of medications.

  • In men with clinically recognized osteoporosis, clinicians should offer bisphosphonate therapy to reduce the risk of vertebral fracture; evidence is lacking on BMD monitoring in men.

Nonpharmacologic preventive measures include modification of general lifestyle factors, such as increasing weight-bearing and muscle-strengthening exercise, which epidemiologic studies have linked to lower fracture rates, and ensuring optimum calcium and vitamin D intake as adjunct to active antifracture therapy. [11]  In addition, potentially treatable underlying causes of osteoporosis such as hyperparathyroidism and hyperthyroidism should be ruled out or treated if detected.

There may be an increased risk of fractures involving adjacent vertebrae if therapies including vertebroplasty or kyphoplasty were used in the management of painful osteoporotic fractures [145, 146]

A 2008 literature review suggested that the use of "reminders plus education targeted to physicians and patients" can lead to increased BMD testing and greater use of osteoporosis medications. [147] In addition, a physician reminder in conjunction with a patient risk assessment strategy can result in a reduction in patient fractures and an increase in osteoporosis therapy. The authors concluded that multicomponent tools aimed at doctors and patients may support clinical decision making in the management of osteoporosis.

A 2009 study indicated that the use of a case manager for the treatment of patients with hip fractures can lead to more frequent use of appropriate osteoporosis treatment and may result in fewer fractures, increased life expectancy, and significant health-care cost savings. [14]

In patients who have experienced an osteoporotic fracture, the first goal of rehabilitation is to control pain. Spinal compression fractures can be extremely painful and can cause short- and long-term morbidity. Oral analgesics can be implemented. Calcitonin may rarely help acute pain associated with acute osteoporotic vertebral compression fractures. [148] Nonpharmacologic pain-relieving modalities such as moist hot packs and transcutaneous electrical nerve stimulation should also be considered. Patients receiving narcotic analgesics for acute pain control require careful monitoring for adverse effects of these agents: constipation, urinary retention, and respiratory depression. Orthotics may be used to decrease the flexion forces to prevent the worsening of kyphosis and to reduce the pressure on the fracture site in the acute phase of disease. [149, 150]


Pharmacologic Therapy

Currently, no treatment can completely reverse established osteoporosis. Early intervention can prevent osteoporosis in most people. For patients with established osteoporosis, medical intervention can halt its progression. If secondary osteoporosis is present, treatment for the primary disorder should be provided. Therapy should be individualized based on each patient’s clinical scenario, with the risks and benefits of treatment discussed between the clinician and patient. [109, 151]

Patients identified as at risk for osteoporosis (including children and adolescents) should undergo preventive measures, including adequate calcium intake, vitamin D intake, and exercise. Patients should be counseled to avoid tobacco and excessive alcohol use.

Protective measures should be taken in patients who must take glucocorticoids for other medical conditions. These include using the minimum effective dose of glucocorticoid and discontinuing the drug as soon as possible. The American College of Rheumatology provides recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis, which were updated in 2017. Recommendations include optimizing calcium and vitamin D supplementation, lifestyle modifications, and fracture risk stratification for all adults on long-term glucocorticoid treatment (≥2.5 mg/day prednisone for ≥3 months). [12]  Further recommendations regarding pharmacological therapy as dictated by fracture risk stratification for prevention of glucocorticoid-induced osteoporosis (GIOP) are discussed below in Prevention of Osteoporosis.  


Bisphosphonates are the most commonly used agents for osteoporosis. Oral and intravenous options are available.


Alendronate (Fosamax) is approved for the treatment of osteoporosis in men, in postmenopausal women, and in patients with glucocorticoid-induced osteoporosis. It has been shown to increase spine and hip bone mineral density in postmenopausal women. Well-conducted controlled clinical trials indicate that alendronate reduces the rate of fracture at the spine, hip, and wrist by 50% in patients with osteoporosis.

The treatment dose of alendronate is 70 mg/week, to be taken sitting upright with a large glass of water at least 30 minutes before eating in the morning. Alendronate is also available in combination with cholecalciferol (vitamin D3). The combination of alendronate with vitamin D3 (Fosamax Plus D) is indicated for the treatment of osteoporosis in men to increase bone mass.

The oral bioavailability of alendronate is drastically reduced when taken with food, even black coffee or orange juice alone. [152]  In addition, the results of a population-based, national register–based, open cohort study of 38,088 patients suggest that elderly patients who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. [153]


Other oral bisphosphonates include risedronate (Actonel) or risedronate delayed-release (Atelvia), given daily, weekly, or monthly. It is also available as a combination product with calcium as risedronate/calcium carbonate (Actonel with Calcium). Risedronate reduced vertebral fractures by 41% and nonvertebral fractures by 39% over 3 years. [154]


Ibandronate (Boniva) is another bisphosphonate that can be given orally once a month and is also available as an intravenous formulation that is given every 3 months. Intravenous bisphosphonates are excellent choices for patients intolerant of oral bisphosphonates or for those in whom adherence is an issue. However, ibandronate has not shown efficacy in nonvertebral fractures in clinical trials.

Zoledronic Acid

Zoledronic acid (Reclast) is a once-yearly intravenous infusion approved for the treatment of osteoporosis in men, in postmenopausal women, and in patients with glucocorticoid-induced osteoporosis. [155]  Zoledronic acid is the most potent bisphosphonate available. It increases BMD at the spine by 4.3-5.1% and the hip by 3.1-3.5%, as compared with placebo. Over 3 years, it reduces the incidence of spine fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25% in postmenopausal women. A similar effect on vertebral fractures has been shown in men. A randomized, 2-year trial of men with osteoporosis found that once-yearly zoledronic acid infusions significantly decreased the risk of new morphometric vertebral fractures by 67%. [156]

A randomized, placebo-controlled, double-blind trial suggested that a once-yearly 5-mg dose of IV zoledronic acid increases bone mass in men within 90 days of hip fracture repair; similar increases were noted in women. [157]

Bisphosphonates and bone turnover

Over time, bisphosphonate therapy decreases bone turnover and, at very high levels in animals, decreases bone strength and resilience. Some limited reports, including that by Odvina et al, describe patients on long-term bisphosphonate therapy developing transverse stress fractures; biopsy specimens of these individuals have suggested extremely low turnover states in some of them. [158]

Alendronate and risedronate inhibit bone resorption at doses 10-fold lower than those reducing osteoclast number. Thus, suppression of bone resorption with these agents is independent of their effects on apoptosis. [159]

Complications of bisphosphonate therapy, treatment length, and drug holidays

In 2011, the US Food and Drug Administration (FDA) updated the prescribing information for zoledronic acid to provide improved information regarding the risk of kidney failure. Acute kidney injury requiring dialysis and fatal outcomes have been reported to the FDA following the use of zoledronic acid. The drug is contraindicated in patients with moderate to severe renal impairment (ie, creatinine clearance < 35 mL/min) or evidence of acute renal impairment. Risk for acute kidney injury is also increased by the following [160] :

  • Coadministration of zoledronic acid with nephrotoxic or diuretic medications
  • Severe dehydration before or after administration
  • Advanced patient age

In 2012, the FDA made safety labeling changes for bisphosphonates, including zoledronic acid, to advise of the risk for atypical subtrochanteric and diaphyseal femoral fractures in patients who have received bisphosphonate therapy, including zoledronic acid. These fractures occur with minimal or no trauma and may present as groin pain weeks to months after fracture. The FDA also includes a safety warning for bisphosphonates, including zoledronic acid, regarding the risk for osteonecrosis of the jaw (ONJ). [161]  Atypical femur fractures and ONJ are rare events in patients on long- term antiresportive agents, including bisphosphonates or denosumab, when used in the treatment of osteoporosis.

The incidence of ONJ in patients on antiresportive therapy for osteoporosis is estimated to be between 1 in 10,000 and 1 in 100,000 per year of use; this risk is only very minimally, if at all, increased compared with the general population. In contrast, the use of IV bisphosphonates and denosumab in cancer patients to reduce complications of metastatic cancer results in the administration of substantially higher cumulative doses (due to the increased dosage used for these indications); therefore, atypical femoral fractures and ONJ are more commonly seen when IV bisphosphonates or denosumab are used as part of cancer treatment. [162]

In 2012, the FDA made safety labeling changes for zoledronic acid to warn against the following adverse reactions [161] :

  • Acute phase reaction within 3 days of zoledronic acid administration: symptoms include pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, and influenza-like illness; symptoms usually resolve within 3 days of onset but can take 7-14 days to resolve, and some symptoms may persist for longer 

  • Hypersensitivity reactions presenting as bronchospasms; interstitial lung disease (ILD) with positive re-challenge

The limited trial data available regarding long-term treatment with bisphosphonates has raised questions about the optimal length of treatment with these medications. [163] This issue has become more important, given newly recognized complications of bisphosphonate use, including ONJ [164] and atypical (subtrochanteric or femoral shaft) femur fractures.

Some studies have sought to clarify the true risks of complications in patients receiving bisphosphonates. A Canadian study by Park-Willie et al found the estimated absolute risk of a subtrochanteric or femoral shaft fracture to be low in 52,595 women with at least 5 years of bisphosphonate therapy (0.13% during the subsequent year and 0.22% within 2 years). [165]  Longer use of bisphosphonates has been shown to increase risk of atypical femoral fractures. [166]  Overall, a patient’s risk of fracture can be used to help guide length of treatment. Patients at high risk may be continued on bisphosphonates after 5 years; however, in some patients, especially those with a lower risk of fracture, bisphosphonate treatment may be stopped for a period with subsequent reassessment of fracture risk, often termed a "drug holiday." [167]

The AACE recommends that if fracture risk is no longer high or the patient has remained fracture free, clinicians should consider a drug holiday after 5 years of bisphosphonate treatment; treatment should continue up to an additional 5 years if fracture risk remains high. For high fracture risk patients, a drug holiday may be considered after 6-10 years of treatment. For zoledronate, consider a bisphosphonate holiday after 3 years in high-risk patients or until fracture risk is no longer high, and continue for up to 6 years in very-high risk patients. [11]

The ending of a bisphosphonate holiday should be based on individual patient circumstances. BMD and bone turnover markers should be monitored, and treatment should be restarted when the density declines substantially, bone turnover markers increase, or an increase in fracture risk or fracture occurs. [11]

In 2016, the American Society for Bone and Mineral Research published guidelines on long-term bisphosphonate treatment that included the following recommendations [168] :

  • After 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, reassessment of risk should be considered.
  • In women at high risk (eg, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or those who fracture on therapy), continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered.
  • The risk of atypical femoral fracture, but not ONJ, clearly increases with the duration of bisphosphonate therapy, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients.
  • For women not at high fracture risk, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of bisphosphonate treatment.

Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) are considered to provide the beneficial effects of estrogen while mitigating the potentially adverse outcomes.


Raloxifene (Evista) is a SERM indicated for the treatment and prevention of osteoporosis in postmenopausal women. The usual dose is 60 mg given orally daily. It can also be given in combination with calcium and vitamin D. It is the first SERM studied for breast cancer prevention, and it decreases bone resorption through actions on estrogen receptors.

Raloxifene has been shown to prevent bone loss, and data in women with osteoporosis have demonstrated that this agent causes a 35% reduction in the risk of vertebral fractures. It has also been shown to reduce the prevalence of invasive breast cancer. However, raloxifene is not without risk; it has been shown to increase the incidence of deep vein thrombosis, stroke, and hot flashes.

Raloxifene may be most useful in younger postmenopausal women without severe osteoporosis. In 601 postmenopausal women who had daily therapy with raloxifene, BMD was increased, serum concentrations of total low-density lipoprotein cholesterol were lowered, and the endometrium was not stimulated.

Pooled mortality data from large clinical trials of raloxifene (60 mg/day) were analyzed by Grady et al in 2010. When compared with placebo, all-cause mortality was 10% lower in older postmenopausal women receiving raloxifene. The primary reduction was in noncardiovascular, noncancer deaths. [169]  However, in contrast, the FDA has advised a black box warning on raloxifene for increased risk of venous thromboembolism and death from stroke. Increased risk of deep vein thrombosis, pulmonary embolism, and death due to stroke have been seen in trials with raloxifene and this must be weighed against potential benefit to patient for osteoporosis when considering prescribing raloxifene or other SERMs.

Bazedoxifene/conjugated estrogens

The combination product of bazedoxifene, a SERM, and conjugated estrogens (CEs) is approved by the FDA for prevention of osteoporosis and treatment of vasomotor symptoms in postmenopausal women. Combining a SERM with CEs lowers the risk of uterine hyperplasia caused by estrogens. This eliminates the need for a progestin and its associated risks (eg, breast cancer, myocardial infarction, venous thromboembolism).

In clinical trials, this combination decreased bone turnover and bone loss in postmenopausal women at risk for osteoporosis. Bone mineral density increased significantly more with all bazedoxifene/CE doses compared with placebo at the lumbar spine and total hip and with most bazedoxifene/CE doses compared with raloxifene at the lumbar spine. [170]

Parathyroid hormone analogues


Teriparatide (Forteo) is a recombinant human parathyroid hormone (1-34) (PTH [1-34]) that acts as an anabolic agent for the treatment of osteoporosis. It is indicated for the treatment of women with postmenopausal osteoporosis who are at high risk of fracture, who have been intolerant of previous osteoporosis therapy, or in whom osteoporosis treatment has failed to increase bone mass. It is indicated in men with idiopathic or hypogonadal osteoporosis who are at high risk of fracture, who have been intolerant of previous osteoporosis therapy, or in whom osteoporosis therapy has failed. Teriparatide is also approved for the treatment of patients with glucocorticoid-induced osteoporosis.

Before treatment with teriparatide, levels of serum calcium, PTH, and 25(OH)D need to be monitored. Teriparatide cannot be given for more than 2 years total in a lifetime due to concerns for increased risk of osteosarcoma; higher incidence of osteosarcoma was seen with high doses in animal studies. However, evidence to show an increased risk of osteosarcoma in humans receiving therapeutic doses of teriparatide has not been obtained. [171]  Contraindications include the following:

  • Pre-existing hypercalcemia
  • Severe renal impairment
  • Pregnancy
  • Breast-feeding mothers
  • History of bone metastases or skeletal malignancies
  • Increased baseline risk for osteosarcoma, including but not limited to Paget disease, unexplained elevated alkaline phosphatase level, or prior external beam or implant radiation therapy
  • Children and young adults with open epiphyses or prior radiotherapy of the skeleton [172]

When PTH is given continuously, both osteoclastic and osteoblastic turnover increase, leading to a net loss of bone. However, intermittent subcutaneous administration of PTH in a dosage of 20 mcg/day has been demonstrated to induce a very active anabolic phase, with bone mass increasing up to 13% over 2 years in the spine and to a lesser degree in the hip. [174, 175, 176]

Indications for PTH in men and women are a bone density decline while on bisphosphonate therapy, bone density stabilization while on extremely low-level bisphosphonate therapy, a fracture occurring while on bisphosphonate therapy, or a very low initial bone turnover rate for which an anabolic effect is clearly warranted. Teriparatide should be considered in younger and older postmenopausal women with severe osteoporosis.

Most studies with PTH have been performed on women. The medication decreases the risk of vertebral and nonvertebral fractures to the same extent as bisphosphonates. Teriparatide is given for a maximum of 2 years, after which time the gains in BMD achieved with PTH are secure and can even be augmented with bisphosphonate therapy; otherwise, the BMD slowly deteriorates to pretreatment levels. [177]

According to Finkelstein et al, initial studies using a combination of concurrent PTH and bisphosphonate therapy showed decreased benefit compared with therapy with either agent alone; therefore, the general recommendation is that these drugs be given separately and in sequence. [178]

A study by Cosman and colleagues challenged this conclusion by giving 3-month-on, 3-month-off pulses of teriparatide while the patients were on weekly alendronate; BMD in the spine increased above that of the alendronate-only arm. [179] This pulsed regimen appears to take advantage of the 3- to 4-month so-called anabolic window, in which the markers of bone formation rise more quickly than the markers of bone resorption.

Studies in women by Deal et al and Ste-Marie et al have shown that the concurrent use of estrogen or raloxifene can enhance the bone-forming effects of teriparatide. [180, 181] Data on the use of PTH in men are much more limited, but its efficacy appears to be relatively comparable.

In a randomized, controlled trial (DATA), 94 osteoporotic postmenopausal women were randomized to take 24 months of teriparatide or denosumab alone, or teriparatide and denosumab in combination. Those women taking teriparatide and denosumab in combination had increased BMD after 12 months. The 12-month changes in posterior-anterior lumbar spine, femoral neck, and total hip BMD in the combination-therapy group (9.1%, 4.2% and 4.9%, respectively) were greater than those in the groups receiving only teriparatide (6.2%, 0.8% and 0.7%, respectively) or only denosumab (5.5%, 2.1% and 2.5%, respectively). [182]  

As an extension to this study (DATA-Switch), women originally assigned to teriparatide received denosumab after 24 months and those originally assigned to denosumab received teriparatide. Switching from teriparatide to denosumab yielded progressive BMD increases, whereas switching from denosumab to teriparatide resulted in progressive or transient bone loss. [183]  Given those findings, using teriparatide early in the treatment course before instituting other therapies when severe osteoporosis is diagnosed is preferred.

In a retrospective analysis of the data from the Fracture Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation trial, Bouxsein et al found that teriparatide reduced fracture risk to a greater extent than raloxifene in postmenopausal osteoporotic women. Compared with placebo, teriparatide reduced the risk of any new fractures by 72%, new adjacent fractures by 75%, and new nonadjacent vertebral fractures by 70%. Raloxifene reduced the risks by 54%, 54%, and 53%, respectively. [184]

A double-blind, double-dummy trial by Kendler et al found that in postmenopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures was significantly lower in patients receiving teriparatide than in those receiving risedronate. Study subjects had experienced at least two moderate or one severe vertebral fracture and had a BMD T-score of -1.50 or less. They were randomly assigned to receive teriparatide (daily injections of 20 μg) plus oral weekly placebo or risedronate (35 mg orally once weekly) plus daily injections of placebo for 24 months. [185]

At 24 months, new vertebral fractures had occurred in 28 (5.4%) of 680 patients in the teriparatide group and 64 (12.0%) of 680 patients in the risedronate group (hazard ratio [HR] 0.44, 95% confidence index [CI] 0.29-0.68; P < 0·0001). Clinical fractures occurred in 30 (4.8%) of 680 patients in the teriparatide group compared with 61 (9.8%) of 680 in the risedronate group (hazard ratio 0.48, 95% CI 0.32-0.74; P=0.0009). [185]

Use of teriparatide for atypical fractures has not been studied in large randomized controlled trials due to the small numbers of atypical fractures. Gomberg et al reported a case of successful healing of bilateral subtrochanteric stress fractures in a postmenopausal woman who had used a bisphosphonate for 13 years. [186] A small case series showed that teriparatide may have potential in promoting healing of atypical fractures with radiolucent line in an incomplete fracture. [187]

For ONJ, teriparatide may be a useful adjunctive therapy. Three cases have been reported in which teriparatide has been used successfully in patients with bisphosphonate-associated ONJ. [188, 189, 190]


Another PTH analogue, abaloparatide (Tymlos), was approved by the FDA in 2017 for women and in 2022 for men. It is indicated for treatment of postmenopausal women with osteoporosis or to increase bone density in men at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients with failure of or intolerance to other available osteoporosis therapy. Approval in women was based on results at 18 months from the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial [191] and first 6 months of the ACTIVExtend trial. [192]  Approval in men was supported by the Abaloparatide Treatment of Men (ATOM phase 3 study). [193]  

In the ACTIVE trial of more than 2000 women, subcutaneous abaloparatide was associated with significant reductions in the relative risk for new vertebral fractures (86% reduction) and nonvertebral fractures (43% reduction) compared with placebo. The absolute risk reductions were 3.6% and 2.0%, respectively. The benefits were evident regardless of age, years since menopause, presence or absence of prior fracture (vertebral or nonvertebral), and BMD at baseline. [191]

In the ACTIVExtend trial, roughly 1100 patients who had completed 18 months of abaloparatide or placebo in ACTIVE received open-label alendronate for up to 24 additional months. Data from the first 6 months of ACTIVExtend showed improved BMD and reduced fracture risk throughout the skeleton. [192]

A study performed by an Austrian group using PTH 1-84 to treat pelvic fractures in postmenopausal women with osteoporosis demonstrated that this anabolic agent has the ability to both increase the rate of union and enhance the speed of the process. In addition to improved fracture healing, treatment with PTH 1-84 was also associated with a significant decrease of pain and improved function over the placebo arm. This clinical study supports the extensive animal data that predicted a clear role for PTH in fracture repair. [194]  

The ATOM study in men showed an increase from baseline in mineral density at 12 months of 8.5% and 1.2% in the abaloparatide and placebo groups, respectively (p < 0.0001). [193]   

Contraindications to abaloparatide are similar to those for teriparatide. A Black Box warning regarding increased risk of osteosarcoma, based on studies in rats, was removed in December 2021; however, use of abaloparatide should be avoided in patients with increased risk of osteosarcoma, and use of the drug for more than 2 years during a patient’s lifetime is not recommended.


Romosozumab (Evenity) is a monoclonal antibody that binds with and inhibits sclerostin, and thus both increases bone formation and decreases bone resorption. It was approved by the FDA in 2019 for treatment of osteoporosis in postmenopausal women who are at high risk for fracture. It has been shown to reduce vertebral fracture rates in postmenopausal women with osteoporosis. [195, 196, 197]

In the Fracture Study in Postmenopausal Women With Osteoporosis (FRAME), a phase 3 randomized trial in 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck, 1 year of treatment with romosozumab reduced vertebral fracture rates by 73% compared with placebo. A further reduction in vertebral fracture risk occurred in the second year following transition to denosumab. [195, 197]

Romosozumab is also being investigated in men with osteoporosis. In the BRIDGE clinical trial, spine and hip BMD significantly improved following romosozumab for 12 months compared with placebo. [198]

In a randomized, controlled trial of 4093 postmenopausal women with osteoporosis and a fragility fracture, a higher rate of adjudicated serious cardiovascular events (a composite endpoint including cardiac ischemic events, cerebrovascular events, heart failure, death, noncoronary revascularization, and peripheral vascular ischemic event not requiring revascularization) was seen in the romosozumab group (2.5%) compared with the alendronate group (1.9%), although the increased risk only reached statistical significance for cardiac ischemic events (0.8% versus 0.3%; odds ratio 2.65 with 95% CI 1.03 to 6.77). [199]  

Romosozumab carries a black box warning regarding increased risk of myocardial infarction, stroke, and cardiovascualr death. Romosozumab should not be initaited in patients who have had a myocardial infarction or stroke within the preceding year, and cardiovascular risk profile must be considered before initiating romosozumab. In patients who experience a myocardial infarction or stroke during therapy, romosozumab should be discontinued.


Denosumab (Prolia) is a humanized monoclonal antibody directed against the receptor activator of the nuclear factor–kappa B ligand (RANKL), which is a key mediator of the resorptive phase of bone remodeling. [181] Denosumab decreases bone resorption by inhibiting osteoclast activity. Denosumab was approved by the FDA in 2010. It has shown benefit in cancer patients, patients with postmenopausal osteoporosis, and men with low BMD. [200, 201, 202]  The approved dosage is 60 mg given subcutaneously every 6 months.

Denosumab may be considered in certain patients with renal insufficiency, as impaired kidney function does not significantly affect the metabolism or excretion of the drug. [203]

In 2018, denosumab was approved for treatment of glucocorticoid-induced osteoporosis (GIOP) in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who are expected to remain on glucocorticoids for at least 6 months. Patients are considered at high risk of fracture if they have a history of osteoporotic fracture, multiple risk factors for fracture, or failed or cannot tolerate other available osteoporosis therapy.

Approval for use in GIOP was based on an international phase 3 study in which denosumab proved more effective than the bisphosphonate risedronate for increasing BMD at the lumbar spine. In patients who had been on steroids for at least 3 months (n=505), the change from baseline in BMD at 12 months was 4.4% with denosumab versus 2.3% with risedronate (P < 0.0001); in those who had started steroids less than 3 months previously (n=290), the change was 3.8% vs 0.8% (P < 0.0001). [204]

In postmenopausal women with osteoporosis, denosumab reduces the incidence of vertebral, nonvertebral, and hip fractures. [205]  Denosumab also increases bone mass in men at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer, [206]  and in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. 

A meta-analysis of 10 randomized, controlled trials concluded that denosumab improved BMD significantly more than bisphosphonate treatment at the lumbar spine, total hip, and femoral neck at 12 and 24 months. However, only 1 of the 10 studies demonstrated greater osteoporotic fracture reduction with denosumab treatment. [207]

In patients with multiple myeloma or bone metastases from breast cancer, a single subcutaneous dose of denosumab decreases bone turnover markers within 1 day, and this effect is sustained through 84 days at higher doses. [200] Denosumab has been shown to increase BMD and decrease bone resorption in postmenopausal women with osteoporosis over a 12-month period. Because the overactivity of RANKL is a major factor in bone loss in patients with autoimmune and inflammatory disorders, such as ulcerative colitis, denosumab may become first-line therapy for these patients. [208]  Denosumab in combination with teriparatide has been shown to increase BMD more than either drug alone, [209]  although combination therapy with osteoporosis medications is not currently recommended in clinical practice.

Denosumab has uniquely been associated with rebound lumbar vertebral fractures after denosumab discontinuation. These vertebral fractures are often multiple and occur within months of the time that the next dose of denosumab would be due for administration. [210]  For this reason, denosumab should be continued indefinitely or followed by bisphosphonate therapy, if not contraindicated.


Calcitonin salmon (Fortical, Miacalcin) is a hormone that decreases osteoclast activity, thereby impeding postmenopausal bone loss. It is indicated for the treatment of women who are more than 5 years post menopause and have low bone mass relative to healthy premenopausal women. Calcitonin salmon is not considered a first-line therapy for osteoporosis, and should be reserved for patients who refuse or cannot tolerate bisphosphonates or in whom bisphosphonates are contraindicated. It is recommended in conjunction with adequate calcium and vitamin D intake to prevent the progressive loss of bone mass. It is available as an injection and as an intranasal spray. The intranasal spray is delivered as a single daily spray that provides 200 IU of the drug. The drug can be delivered subcutaneously, but this route is rarely used.

Results from a single controlled clinical trial indicate that calcitonin may decrease osteoporotic vertebral fractures by approximately 30%. In the first 2 years, calcitonin has been found to increase spinal bone mineral density (BMD) by approximately 2%. Calcitonin also has  analgesic properties. However, calcitonin lacks data showing a reduction in nonvertebral fracture rates.

In 2013, an FDA post-marketing review was prompted after studies showed increased risk of malignancies in calcitonin-treated patients. In a meta-analysis of 21 randomized, controlled clinical trials with calcitonin salmon (nasal spray or investigational oral formulations), the incidence of malignances in calcitonin-treated patients was 4.1%, versus 2.9% in placebo-treated patients. The data were not sufficient for further analysis by specific malignancies and a definitive causal relationship between calcitonin use and malignancies could not be established. The FDA has recommended that health care professionals assess a patient’s need for osteoporosis therapy as well as benefits and risk of available treatments. [211]

Calcitonin is no longer widely used for treatment of osteoporosis. [144]   Common side effects of nasally administered calcitonin include nasal discomfort, rhinitis, irritation of nasal mucosa, and occasional epistaxis. Nausea, local inflammatory reactions at the injection site, sweating, and flushing are side effects noted with parenteral use.

Hormone replacement therapy

Hormone replacement therapy (HRT) was once considered a first-line therapy for the prevention and treatment of osteoporosis in women. Although HRT is not currently recommended for the treatment of osteoporosis, it is important to mention because many osteoporosis patients in a typical practice still use it for controlling postmenopausal symptoms.

The American College of Physicians concluded that moderate-quality evidence showed that estrogen treatment did not reduce fracture rates in postmenopausal women with established osteoporosis. [144] Data from the Women's Health Initiative indicated that HRT can reduce fractures. [212] However, the results of the Women's Health Initiative were distressing with respect to the adverse outcomes associated with combined estrogen and progesterone therapy (eg, risks for breast cancer, myocardial infarction, stroke, and venous thromboembolic events) and estrogen alone (eg, risks for stroke and venous thromboembolic events).

Other agents

Strontium ranelate is approved for the treatment of osteoporosis in some countries in Europe. It reduces the risk of both spine and nonvertebral fractures. [213, 214] Strontium is not approved for the treatment of osteoporosis in the United States.


Dietary Measures

Adequate calcium and vitamin D intake are important in persons of any age, particularly in childhood as the bones are maturing, and are essential in the prevention and treatment of osteoporosis. Vitamin D is increasingly being recognized as a key element in overall bone health, calcium absorption, balance (eg, reduction in risk of falls), [215] and muscle performance. Patients who ingest inadequate amounts of vitamin D and calcium in their diet should not receive additional oral supplements.

Good dietary sources of calcium include dairy products, sardines, nuts, sunflower seeds, tofu, vegetables such as turnip greens, and fortified food such as orange juice. Good dietary sources of vitamin D include eggs, liver, butter, fatty fish, and fortified food such as milk and orange juice. See the National Osteoporosis Foundation Website for further calcium and vitamin D recommendations.

The goal of the current recommendations for daily calcium intake is to ensure that individuals maintain an adequate calcium balance. Current recommendations from the American Association of Clinical Endocrinologists (AACE) for daily calcium intake are as follows [11] :

  • Age 0-6 months: 200 mg/day
  • Age 6-12 months: 260 mg/day
  • Age 1-3 years: 700 mg/day
  • Age 4-8 years: 1000 mg/day
  • Age 9-18 years: 1300 mg /day
  • Age 19-50 years: 1000 mg/day
  • Females Age 51 years and older: 1200 mg/day
  • Males Age 51-70: 1000 mg/day
  • Males Age 71 and older: 1200 mg/day

The Institute of Medicine (IOM) has issued recommendations for calcium and vitamin D daily intake in older adults. For women older than 50 years, the IOM recommended 1200 mg/day of calcium. The IOM recommended 1000 mg/day of calcium for men 51-70 years of age and 1200 mg/day for men over 70. For both sexes, the recommended upper level was 2000 mg/day. [216]

For both women and men, the recommended daily dietary allowance of vitamin D was 600 IU from age 51-70 and 800 IU for after age 70, with a recommended maximum of 4000 IU. Amid considerable controversy, the IOM also stated that the evidence supported a role for vitamin D and calcium in bone health, but not in other conditions. [216]

The minimum daily requirement of vitamin D in patients with osteoporosis is 800 IU of cholecalciferol. Many patients require higher levels (continuously or for a short period) to be considered vitamin D replete, which is defined as a serum 25-hydroxyvitamin D level of at least 32 ng/mL.

Alcohol and anorexia nervosa can interfere with nutrition. Excessive alcohol intake can interfere with calcium balance by increasing PTH production and by inhibiting the enzymes that convert inactive vitamin D to its active form; in addition, alcohol can result in hormonal deficiencies and can increase the tendency for falls. Poor nutritional states, such as in anorexia nervosa, [217] have been strongly associated with bone loss. Nutritional and endocrine factors contribute to bone loss; in particular, low estrogen states, which result from low body weight, result in significant bone loss.

Calcium and vitamin D supplementation

Commonly used calcium supplements include calcium carbonate and calcium citrate. Calcium carbonate is generally less expensive and is recommended as a first choice option. Calcium carbonate has better absorption with food, as opposed to calcium citrate, which is better absorbed in the fasting state. Also, fewer tablets are needed with calcium carbonate than with calcium citrate.

Vitamin D is available as ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D is metabolized to active metabolites. These metabolites promote the active absorption of calcium and phosphorus by the small intestine, elevating serum calcium and phosphate levels sufficiently to permit bone mineralization. Ergocalciferol, the form mostly used in supplements and fortified foods, is absorbed with similar efficiency to cholecalciferol, the main dietary form, with similar effects on suppression of PTH.

Calcium and vitamin D studies

A meta-analysis suggested that supplementation with a combination of calcium and vitamin D can reduce fracture risk. [218] Another meta-analysis of 12 double-blind, randomized, controlled trials for nonvertebral fractures and eight trials for hip fractures reported that nonvertebral fracture prevention with vitamin D was dose dependent and that a higher dose (> 400 IU/d) reduced fractures by at least 20% for individuals aged 65 years or older. [219] However, a longitudinal and prospective cohort study concluded that gradual increases in dietary calcium intake did not further reduce fracture risk or osteoporosis in women. [220]

Another meta-analysis concluded that vitamin D alone is not effective in preventing fractures, but vitamin D given together with calcium reduced hip fractures and total fractures, and possibly vertebral fractures. [221] The conclusions were based on seven large studies that were randomized with at least one intervention arm in which vitamin D was given and included analysis of fractures as an outcome and at least 1000 participants.

More information is needed regarding risks associated with long-term calcium supplementation. Dietary calcium intake has not been associated with an increased risk of cardiovascular events. [222] Additionally, some [223] but not all [224] studies suggest an increased risk of nephrolithiasis with calcium and vitamin D supplements, but not with calcium ingested in the diet. [225]


Physical and Occupational Therapy

Physical therapy

Physical therapy focuses on improving a patient's strength, flexibility, posture, and balance to prevent falls and maximize physical function. [226, 227] Postural retraining is key in this population. Spinal bone mineral density (BMD) is directly correlated with the strength of the back extensors; therefore, maintaining and strengthening the back extensors should be emphasized. [228] In studies by Sinaki and colleagues, strengthening the back extensor muscles reduced kyphosis and decreased the risk of sustaining vertebral compression fractures. [229, 230]

As soon as the course of therapy allows, weight-bearing exercises should be initiated. Regular weight-bearing exercises are essential for the maintenance of bone mass [65] and should be encouraged in all patients, including children and adolescents (to strengthen the skeleton during the maturation process). Exercise also improves agility and balance, thereby reducing the risk of falls.

Occupational therapy

Training in the performance of activities of daily living (ADLs) and in the proper use of adaptive equipment are essential to the prevention of future falls. [227] Home modification focuses on reducing the risk of falling by installing handrails and grab bars in hallways, stairs, and bathrooms. The use of a shower chair, tub bench, and adaptive bathing devices also can be beneficial. The application of nonskid tape to steps (indoors and outdoors), as well as the removal of throw rugs, may improve home safety.



Aerobic low-impact exercises, such as walking and bicycling, generally are recommended. During these activities, ensure that the patient maintains an upright spinal alignment. Sinaki and Mikkelsen showed that exercises that place flexion forces on the vertebrae tend to cause an increase in the number of vertebral fractures in patients. [228]

Proper therapy for osteoporosis includes 3-5 sessions per week of weight-bearing exercises, such as walking or jogging, with each session lasting 45-60 minutes. The patient should be instructed in a home-exercise program that incorporates the necessary elements for improving posture and overall physical fitness.

In postmenopausal women, impact exercises can increase BMD in the hip and spine. Chien et al examined the efficacy of a 24-week aerobic exercise program consisting of treadmill walking followed by stepping exercises in osteopenic postmenopausal women aged 48-65 years. Women who exercised had increased bone mineral density in L2-L4 and the femoral neck, as well as improved quadriceps strength, muscular endurance, and peak exercise oxygen consumption (VO2 max), whereas values in the control group declined. [231]

Snow et al found increased BMD of the femoral neck, trochanter, and total hip in 18 postmenopausal women (average age, 64 years) who wore weighted vests and participated in jumping exercises 3 times per week for 32 weeks a year for 5 years. [232]

The results of a Cochrane Database of Systematic Reviews study found that exercise may help prevent bone loss and fractures in postmenopausal women. The most effective type of exercise on BMD for the neck of the femur was found to be non–weight-bearing, high-force exercise, such as lower limb resistance strength training; combination exercise programs were most effective for BMD at the spine. [233]

Although swimming is not a weight-bearing exercise that will improve BMD, it does provide chest expansion, spinal extension, and low-impact cardiopulmonary fitness. Isometric exercises should also be used to strengthen abdominal muscles, aiding in the prevention of kyphosis.

The physical therapist must address balance training, because fall prevention is important in reducing the risk of the clinically apparent manifestation of osteoporosis, fracture. Improving one's balance can significantly lower the risk of falling. Balance training incorporates the strengthening of various parts of the body (eg, trunk, legs), proprioception, and vestibular input. Several different exercises have been shown to be beneficial in patients with osteoporosis. [234, 235, 236, 237]

Tai chi chuan and specific physical therapy programs may be effective in improving balance and reducing falls. Wolf et al monitored 200 elderly community dwellers who received tai chi and computerized balance training. After a 15-week intervention, the authors documented decreased fear of falling responses. In addition, tai chi was shown to reduce the risk of multiple falls by 47.5%. [238]

Campbell et al monitored 233 elderly community dwellers randomized to an individually tailored physical therapy program in the home compared with usual care and an equal number of social visits. The authors found that after one year, the mean rate of falls was lower in the exercise group than in the control group (0.87 vs 1.34, respectively). In addition, after 6 months, persons in the exercise group had improved balance.

Other types of exercise training programs may also positively impact balance and strength. Carter et al demonstrated that osteoporotic women aged 65-75 years who underwent a 10-week community-based physical activity intervention program showed a trend toward improved static balance, dynamic balance, and knee extension strength, although the study failed to show a statistically significant reduction in these fall risk factors, likely due to limited power. [239]


Prevention of Osteoporosis

Primary prevention of osteoporosis starts in childhood. Patients require adequate calcium intake, vitamin D intake, and weight-bearing exercise. Beyond this, prevention of osteoporosis has two components: behavior modification and pharmacologic interventions.

The National Osteoporosis Foundation specifies that the following behaviors should be modified to reduce the risk of developing osteoporosis [4] :

  • Cigarette smoking
  • Physical inactivity
  • Intake of alcohol, caffeine, sodium, animal protein, and calcium

Patients should be counseled on smoking cessation and moderation of alcohol intake. Regular weight-bearing exercise and back extensor strengthening help delay bone loss. In a study that found osteopenia in over a quarter of men and women in early middle age, there was a negative correlation between exercise and BMD in the men despite relatively high levels of exercise—but the majority of men in the study reported cycling as their preferred exercise, rather than weight-bearing activities such as walking or running. [76]

Patients who have disorders or take medications that can cause or accelerate bone loss should ensure adequate intakes of calcium and vitamin D  and, in some cases, pharmacologic treatment. [240]  Pharmacologic prevention methods include calcium supplementation and administration of raloxifene or bisphosphonates (alendronate or risedronate). Bisphosphonates should be considered as first-line agents for the prevention of osteoporosis. [241]

In 2017, the American College of Rheumatology published revised recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Recommendations include optimizing calcium and vitamin D supplementation and lifestyle modifications for all adults on long-term glucocorticoid treatment (≥2.5 mg/day prednisone for ≥3 months). Furthermore, categorization of patients by fracture risk (using the FRAX score adjusted for glucocorticoid use) is recommended. First-line pharmacotherapy for patients at moderate-to-high fracture risk is an oral bisphosphonate, which is preferred for safety, cost, and because of lack of evidence of superior antifracture benefits from alternative medications. Other pharmacologic treatments recommended, if oral bisphosphonates are not appropriate, include (in order of preference): IV bisphosphonates, teriparatide, denosumab, and raloxifene. [12]

Estrogen-progestin therapy is no longer considered a first-line approach for the treatment of osteoporosis in postmenopausal women, because it has been linked to an increased risk for breast cancer, stroke, venous thromboembolism, and perhaps coronary disease. Estrogen is now recommended only if patients are also seeking relief of postmenopausal symptoms.

Regular monitoring may be helpful. Periodic bone densitometry helps in diagnosing osteoporosis in the early phase and aids in preventing fractures. According to the National Osteoporosis Foundation, evaluating BMD on a periodic basis is the best way to monitor bone density and future fracture risk. [4] However, there is considerable controversy about how often to repeat BMD measurements, particularly in postmenopausal women with a normal baseline BMD. [242]

Prevention of falls

Environmental measures to prevent falls/fractures include [11] :

  • Remove or anchor rugs and use nonskid mats
  • Minimize clutter
  • Remove loose wires
  • Install handrails in bathrooms, halls, and long stairways
  • Ensure hallways, stairwells, and entrances are well lighted
  • Encourage patient to wear sturdy, low-heeled shoes


For a patient with osteoporosis in the diagnostic and therapeutic phases, the most important consultation is with a rheumatologist or an endocrinologist. These specialists can help obtain the proper laboratory tests and imaging studies needed to rule out causes of secondary osteoporosis. In patients with uncontrolled pain that does not respond to conventional therapies, an invasive pain specialist may be consulted for proper interventional procedures.

A rheumatologist or endocrinologist may also provide useful assistance with management and determination of underlying etiologies in complex cases.

Consultations can include discussions of nonmedical/nonpharmacologic management of osteoporosis. [243, 244] Consult an orthopedist to assist with fracture management. Consultation with a spine surgeon is appropriate for patients with intractable, severe, function-limiting symptomatology from vertebral fractures that has not been relieved by noninterventional techniques. Consultation with a nonsurgical spine specialist is appropriate for a patient who is not a surgical candidate or whose symptoms persist despite surgical fixation.


Long-Term Monitoring

The US Preventive Services Task Force (USPSTF) 2011 recommendations state that evidence is lacking regarding optimal intervals for repeated screening by dual-energy x-ray absorptiometry (DXA) for individuals with osteoporosis, as well as regarding whether a woman with a normal BMD requires repeated screening. The USPSTF noted that, “a minimum of 2 years may be needed to reliably measure a change in BMD; however, longer intervals may be necessary to improve fracture risk prediction.” [109]

According to a study funded by the National Institutes of Health, osteoporosis will develop in fewer than 10% of older, postmenopausal women during the following rescreening intervals [245] :

  • Women with normal BMD or mild osteopenia - Approximately 15 years
  • Women with moderate osteopenia - Approximately 5 years
  • Women with advanced osteopenia - Approximately 1 year