Denosumab for osteoporosis

INTRODUCTION — Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL), an osteoclast differentiating factor. It inhibits osteoclast formation, decreases bone resorption, increases bone mineral density (BMD), and reduces the risk of fracture.

This topic review will discuss the use of denosumab as a therapy for osteoporosis. Other treatments for osteoporosis are reviewed in detail elsewhere.

●(See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

●(See "Treatment of osteoporosis in men".)

●(See "Bisphosphonate therapy for the treatment of osteoporosis".)

●(See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis".)

MECHANISM OF ACTION — The receptor activator of nuclear factor kappa-B ligand (RANKL) is a member of the tumor necrosis factor (TNF) superfamily of ligands and receptors that is essential for the function of bone-resorbing osteoclasts. RANKL interacts with a receptor (RANK) on both osteoclast precursors and osteoclasts. The RANKL/RANK interaction results in activation, migration, differentiation, and fusion of hematopoietic cells of the osteoclast lineage to begin the process of bone resorption. Denosumab, a fully human monoclonal antibody that specifically binds RANKL, blocks the binding of RANKL to RANK and thereby reduces the formation, function, and survival of osteoclasts, which results in decreased bone resorption and increased bone density. (See "Normal skeletal development and regulation of bone formation and resorption".)

APPROACH TO TREATMENT OF OSTEOPOROSIS WITH DENOSUMAB

Patient selection — Initial therapy for most patients with osteoporosis includes lifestyle measures and oral bisphosphonates. Denosumab is not considered initial therapy for most patients. It is not intended for use in premenopausal women or children, or for osteoporosis prevention.

In the absence of definitive data comparing osteoporosis therapies, treatment decisions should be individualized. The individual's risk for fracture, presence of comorbid conditions, and personal preference are important for weighing the potential benefits and risks of osteoporosis therapies. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy'.)

There is an increased risk of vertebral fracture with discontinuation of denosumab therapy, and transitioning to another drug is complicated. Therefore, denosumab should be initiated only when the treatment plan is to continue denosumab therapy indefinitely. (See 'Increased vertebral fractures' below and 'Sequential osteoporosis therapy' below.)

Postmenopausal women — For most postmenopausal women with osteoporosis, we suggest not using denosumab as initial therapy. We prefer oral bisphosphonates as initial therapy; however, denosumab could be used as initial therapy in certain patients at high risk for fracture, such as older patients who have difficulty with the dosing requirements of oral bisphosphonates, who are intolerant of or unresponsive to other therapies (including intravenous bisphosphonates), or who have markedly impaired kidney function. (See 'Use in chronic kidney disease' below and "Osteoporosis in patients with chronic kidney disease: Management".)

Denosumab improves bone mineral density (BMD) and reduces fracture risk in postmenopausal women with low BMD [1-5]:

●Compared with placebo – In the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial, 7868 postmenopausal women (60 to 90 years of age) with osteoporosis (T-scores between -2.5 and -4.0 at the lumbar spine [LS] or total hip) were randomly assigned to subcutaneous denosumab (60 mg every six months) or placebo [1]. After three years, the following significant benefits were noted with denosumab compared with placebo [6]:

•A lower rate of new vertebral fractures (cumulative incidence 2.3 versus 7.2 percent; relative risk [RR] 0.32, 95% CI 0.26-0.41)

•A lower rate of hip (0.7 versus 1.2 percent) and nonvertebral (6.5 versus 8.5 percent) fractures

•Improvement in BMD of the LS and total hip compared with placebo (9.2 versus 0 percent and 4 versus -2 percent, respectively).

•Reduction in biochemical markers of bone turnover

In the FREEDOM extension trial, 4550 participants (2343 active treatment, 2207 placebo) remained in the trial and received denosumab, 60 mg twice yearly. After five years of follow-up in the extension trial (representing eight years of continuous denosumab treatment for 1546 patients), cumulative increases in BMD at the LS and hip were 18.4 and 8.3 percent, respectively [7]. After a total of 10 years on treatment, the increase in spine BMD was 21.7 percent and at the total hip was 9.2 percent [8]. The yearly incidence of vertebral and nonvertebral fractures remained low in the long-term (eight-year) denosumab group (1.5, 1.3, and 1.3 percent during years 4/5, 6, and 7/8, respectively, for new vertebral fracture) [7]. The cumulative incidence of new vertebral and nonvertebral fracture was 5.5 and 6.6 percent, respectively.

●Compared with alendronate – Another trial compared denosumab with alendronate in 1189 postmenopausal women with low BMD (T-score ≤-2.0 at the LS or hip) [2]. The patients were randomly assigned to denosumab (60 mg subcutaneously every six months) plus oral placebo or to oral alendronate (70 mg weekly) plus subcutaneous placebo injections every six months. After one year, BMD gains at the total hip (3.5 versus 2.6 percent), femoral neck (2.4 versus 1.8 percent), and LS (5.3 versus 4.2 percent) were slightly but significantly greater with denosumab [2]. Denosumab was also associated with significantly greater reductions in biochemical markers of bone turnover than alendronate. The trial was not designed to assess fracture reduction.

There are few studies that directly compare denosumab with a bisphosphonate in reducing fractures. In a population-based study from Denmark of 92,355 individuals (81 percent women) who were new users of denosumab or alendronate, the incidence of fracture within three years was similar in the two groups [9].

●After alendronate – Denosumab is effective in postmenopausal women who previously were treated with bisphosphonates. In one trial, 500 postmenopausal women (T-scores between -2.0 and -4.0) who previously received alendronate were randomly assigned to switch to denosumab (60 mg subcutaneously every six months) or to continue alendronate (70 mg weekly) [10]. After 12 months, there were small but significantly greater gains in BMD in women assigned to denosumab (total hip 1.9 versus 1 percent, LS 3 versus 1.8 percent) [10].

Men — For most men with osteoporosis who are not undergoing androgen deprivation therapy, we suggest not using denosumab as initial therapy (see 'Other indications for denosumab' below). However, denosumab may have a role in men who are intolerant of or unresponsive to other therapies and in those with impaired kidney function. (See 'Use in chronic kidney disease' below.)

There are few trials evaluating denosumab in men with osteoporosis that is unrelated to androgen deprivation therapy. In one such trial, 242 men (mean age 65 years, mean femoral neck T-score -1.9) were randomly assigned to denosumab (60 mg subcutaneously every six months) versus placebo [11]. After 12 months, denosumab improved BMD at all sites compared with placebo (5.7 versus 0.9 percent, 2.4 versus 0.3 percent, and 2.1 versus 0 percent for LS, total hip, and femoral neck, respectively). Biochemical markers of bone turnover were significantly reduced in men taking denosumab. Clinical fractures occurred in two men in the placebo and one man in the denosumab-treated group. In another trial, denosumab reduced the risk of vertebral fractures (a secondary endpoint) in men with prostate cancer treated with androgen deprivation therapy [12]. This trial is reviewed separately. (See "Side effects of androgen deprivation therapy", section on 'Denosumab'.)

Controversies — There is no consensus on the optimal use of denosumab. Some experts believe that denosumab should not be used as initial therapy for postmenopausal women with osteoporosis at high risk for fracture, because of the availability of oral bisphosphonates, for which there are long-term safety and fracture prevention data. In addition, generic alendronate is less expensive, and bisphosphonates are not associated with an increased risk of vertebral fracture with discontinuation of therapy or with missed doses as may occur with denosumab. (See 'Increased fracture risk after stopping' below and 'Duration of therapy' below.)

However, other experts disagree and would use denosumab as initial therapy for women at high risk for fracture who have difficulty with the dosing requirements of oral bisphosphonates or are unwilling to take bisphosphonates. This is particularly reasonable in patients who have a life expectancy less than 10 years since denosumab has safety data for 10 years and transitioning to another drug is complicated. (See 'Increased vertebral fractures' below and 'Sequential osteoporosis therapy' below.)

There are currently no head-to-head trials comparing the anti-fracture efficacy of denosumab with other available osteoporosis therapies (eg, oral and intravenous bisphosphonates, teriparatide). The reduction in vertebral fracture noted with denosumab is similar to the reductions reported for subcutaneous teriparatide and intravenous zoledronic acid and greater than that reported for oral alendronate. However, these data are based upon clinical trials in different patient populations, not head-to-head comparison trials.

Practical management issues

Patient counseling

Increased fracture risk after stopping — There is an increased risk of vertebral fractures, particularly multiple vertebral fractures, after stopping denosumab. Prior to the initiation of denosumab, therefore, clinicians should discuss the need for timely (every six months) administration of denosumab [13]. Patients with a history of poor adherence to medication or appointment schedules may do better with an alternative agent (eg, intravenous zoledronic acid). Discontinuation of denosumab results in bone loss and increased vertebral fracture risk within a relatively short time (unlike discontinuation of bisphosphonates, which does not lead to immediate bone loss). If denosumab is discontinued, administering an alternative therapy (typically a bisphosphonate) to prevent rapid bone loss and vertebral fracture is advised. (See 'Discontinuation or delay of denosumab' below and 'Duration of therapy' below.)

Pretreatment evaluation

●Secondary causes of osteoporosis – The evaluation of patients who may receive denosumab is the same as the evaluation recommended for all patients with osteoporosis (table 1 and table 2). The general evaluation for secondary causes of osteoporosis is reviewed separately. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men".)

●Risk of hypocalcemia

•All patients – Serum calcium and 25-hydroxyvitamin D levels should be measured in all patients prior to denosumab initiation. Patients who have hypocalcemia should not receive denosumab until hypocalcemia is corrected. Patients with vitamin D deficiency should be replaced with vitamin D prior to administering denosumab. In addition, all patients should be adequately supplemented with calcium and vitamin D while taking denosumab.

•Patients with advanced kidney disease – Patients with advanced kidney disease have significant risk of severe hypocalcemia during denosumab treatment, requiring greater caution and increased monitoring [14]. (See 'Monitoring' below and 'Hypocalcemia' below and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Calcium and vitamin D supplementation in osteoporosis".)

●Suppression of bone remodeling – Denosumab suppresses bone remodeling and therefore may contribute to adverse outcomes, such as osteonecrosis of the jaw (ONJ). Pretreatment considerations are the same as those for bisphosphonates, which also suppress bone remodeling and have been associated with an increased risk of ONJ. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw' and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw'.)

Dosing — Denosumab (60 mg) is administered by subcutaneous injection once every six months. It may be administered in the upper arm, thigh, or the abdomen [15]. It is available in a single-use, prefilled syringe or a single-use vial. The vial requires a 27-gauge needle with syringe to withdraw and inject the 1 mL dose. Denosumab should be stored in the refrigerator and brought to room temperature by removing from the refrigerator 15 to 30 minutes before administration.

Denosumab is not renally excreted, and therefore, dose adjustments for chronic kidney disease are not necessary [16].

Monitoring

●Bone mineral density – Monitoring the bone density response to denosumab therapy is similar to the monitoring of other osteoporosis therapies. Frequency of BMD measurements is variable, but most investigators would not consider a follow-up BMD for at least two years. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Monitoring response to initial pharmacotherapy' and 'Duration of therapy' below.)

●Serum calcium – Patients with chronic kidney disease (creatinine clearance <30 mL/min, including patients receiving dialysis) and/or other conditions that predispose to hypocalcemia (eg, malabsorption syndromes) are at higher risk for hypocalcemia following denosumab administration than patients without these conditions. Specifically, patients with advanced kidney disease, particularly those undergoing dialysis, may be at risk for serious outcomes of severe hypocalcemia, including hospitalization and death [14,17]. In such patients, calcium should be measured approximately 10 days after denosumab administration. (See 'Adverse effects' below.)

In addition, if a patient with a condition that predisposes to hypocalcemia becomes ill and cannot take oral calcium after having received denosumab, there is a greater risk of hypocalcemia. Calcium levels should be monitored more frequently in this setting.

Monitoring of serum calcium is not required in patients without risk factors for hypocalcemia.

●Infections and skin reactions – Because serious infections and skin reactions were reported more frequently in the denosumab than in the placebo group, patients should be advised to seek medical attention if they develop signs of an infection or skin reaction. (See 'Adverse effects' below.)

Use in chronic kidney disease — Denosumab, unlike bisphosphonates, is not cleared by the kidney, so its use is not restricted in patients with creatinine clearances below 35 mL/min, for whom bisphosphonates are considered contraindicated [18].

●Effect on fracture risk – In the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial (see 'Postmenopausal women' above), there was no exclusion criterion based upon serum creatinine [1]. However, women were excluded if they had hyperparathyroidism, including secondary hyperparathyroidism due to kidney dysfunction. In a post hoc analysis that stratified FREEDOM trial data based on kidney function, denosumab reduced fracture risk and was not associated with an increase in adverse events, including changes in estimated glomerular filtration rate (eGFR), among women with moderately impaired kidney function (eGFR ≥30 mL/min/1.73 m²) [19].

In the same analysis, only 73 women had an eGFR of 15 to 29 mL/min/1.73 m² (stage 4 chronic kidney disease [CKD]) and no women had an eGFR <15 mL/min/1.73 m² (stage 5 CKD). Within the subgroup with stage 4 CKD, there were too few events (four vertebral and three nonvertebral fractures) to draw any conclusions. Therefore, although denosumab increases BMD in individuals with advanced CKD [20], data are inadequate for fracture prevention efficacy in late-stage kidney disease (stages 4 and 5). (See "Osteoporosis in patients with chronic kidney disease: Management", section on 'Denosumab'.)

●Risks and concerns – Serious outcomes of severe hypocalcemia have been reported in patients undergoing dialysis during denosumab treatment, prompting a boxed warning for brand name denosumab about severe hypocalcemia in patients with advanced CKD [14]. In such patients, more careful monitoring of serum calcium is warranted [14,17]. (See 'Hypocalcemia' below and 'Monitoring' above and "Osteoporosis in patients with chronic kidney disease: Management".)

The lack of published safety data in this population also suggests caution when using denosumab, and use of potent antiresorptive therapy in individuals with late-stage CKD raises concern for oversuppression of bone turnover [21]. The decision to start any osteoporosis pharmacotherapy requires certainty that patients who fracture have osteoporosis and not some form of CKD-related bone disease. (See 'Oversuppression of bone remodeling' below and "Osteoporosis in patients with chronic kidney disease: Management", section on 'Candidates for pharmacologic treatment'.)

Combination therapy — We do not suggest combination therapy with denosumab and teriparatide or any another osteoporosis therapy. Combination therapy with denosumab and teriparatide is reviewed separately. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Combination therapy not recommended'.)

DURATION OF THERAPY — The need for indefinite treatment should be addressed with patients before denosumab is initiated (see 'Patient counseling' above and 'Patient selection' above). In contrast to patients treated with bisphosphonates, patients treated with denosumab should not have a drug holiday after a given treatment period. If denosumab is discontinued for any reason (eg, due to concerns about cost or potential adverse effects), we usually switch to a bisphosphonate. (See 'Discontinuation or delay of denosumab' below.)

There are few data on the ideal duration of denosumab therapy or on sequential therapy with other osteoporosis agents. The FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) extension trial showed maintenance of BMD with continued use for ten years [7,8].

DISCONTINUATION OR DELAY OF DENOSUMAB — There are many circumstances in which patients are unable to receive a dose of denosumab every six months on time. During the COVID-19 pandemic, in particular, patients are often advised to delay medical visits. Discontinuing (or delaying) denosumab results in rapid bone loss and an increase in vertebral fracture as early as seven months after the prior dose, with increasing risk as delays in administration grow longer [22,23] (see 'Increased vertebral fractures' below). Therefore, if denosumab treatment is discontinued or delayed beyond two to three months, we suggest administering a bisphosphonate to prevent rapid bone loss and increased risk of vertebral fractures. This is largely consistent with guidelines from the American Society of Bone and Mineral Research [24,25]. (See 'Sequential osteoporosis therapy' below.)

Bone loss — The effects of denosumab on bone density and bone remodeling are reversible with discontinuation of therapy [26-28], and discontinuation results in bone loss within a relatively short time, whereas discontinuation of bisphosphonates does not lead to immediate bone loss [26].

This was illustrated by the findings of an extension study of a phase II trial in which postmenopausal women were randomly assigned to receive denosumab (variable dosing), open-label alendronate (70 mg weekly), or placebo [3,5,26]. Patients receiving denosumab either continued treatment (60 mg every six months) for an additional 24 months (n = 231), discontinued therapy for 24 months (n = 47), or discontinued therapy for 12 months and then reinitiated denosumab for 12 months (n = 41) [26]. Women (n = 47) assigned to alendronate discontinued therapy and were followed, and the placebo group (n = 46) was continued. Sixty-four percent of the original cohort completed 48 months of treatment.

●Discontinuation of alendronate did not result in immediate bone loss. Markers of bone turnover increased upon discontinuation of alendronate but remained below baseline through month 48.

●Discontinuation of denosumab for 24 months resulted in decreases in lumbar spine (LS; -6.6 percent) and total hip (-5.3 percent) BMD comparable with the gains previously achieved during 24 months of therapy. Markers of bone turnover increased within three to six months after discontinuation of denosumab to values above baseline but were similar to baseline values within 24 months of discontinuing therapy.

●Retreatment with denosumab 12 months after discontinuing therapy resulted in an increase in LS (9 percent) and total hip (3.9 percent) BMD over the 12-month retreatment phase. Retreatment also resulted in a rapid decrease in markers of bone turnover, such that values were similar to those of the continuous treatment group.

●Continuous denosumab treatment (four years) increased BMD at the LS (9.4 to 11.8 percent) and total hip (4 to 6.1 percent).

Increased vertebral fractures — Emerging data have raised concern about increased vertebral fracture risk after discontinuation or delay of denosumab injections [23,29-34].

●In a case series, vertebral fractures occurred in postmenopausal women after denosumab withdrawal [29-31]. Fractures were often multiple and occurred 8 to 16 months after the last dose, raising concerns about a rebound in fracture risk when denosumab wears off.

●In a post hoc analysis of 1471 patients in the FREEDOM trial and its extension (patients who received at least two doses of denosumab or placebo, discontinued treatment, and remained in the study for at least seven months after discontinuation), there was a rapid rise in vertebral fracture rate upon discontinuation of denosumab (from 1.2 to 7.1 per 100 participant-years), similar to those who received and then discontinued placebo [32]. However, patients who discontinued denosumab had a higher rate of multiple vertebral fractures than the placebo group (60.7 versus 38.7 percent [4.2 versus 3.2 per 100 patient-years]). Patients with a prior vertebral fracture were at greatest risk for multiple fractures upon discontinuation. Longer duration (>3 years) of denosumab therapy also may increase the risk of multiple vertebral fractures after denosumab discontinuation [35].

●In a population-based cohort study from the United Kingdom, there was an increased risk of vertebral fractures over six months in patients who delayed denosumab injections by more than 16 weeks compared with patients who received treatment within four weeks of the recommended date (10.1 and 2.2 per 1000, respectively, HR 3.91, 95% CI 1.62-9.45) [23]. The risk of vertebral fracture for patients who delayed denosumab for 4 to 16 weeks was not significant (3.6 versus 2.2 per 1000, HR 1.48, 95% CI 0.58-3.79). There was insufficient evidence to detect an increased risk of fracture at other sites with delay of therapy.

Sequential osteoporosis therapy — If denosumab is discontinued (or delayed beyond two to three months), we suggest administering a bisphosphonate to prevent rapid bone loss and vertebral fracture.

●Oral alendronate has been shown to maintain bone density after discontinuation of denosumab [36]. It can be initiated six months after the last denosumab dose and should be continued for at least one to two years [37,38].

●Intravenous zoledronic acid would also likely be effective and may be more convenient for some patients. However, the optimal timing and frequency of administration are still uncertain. It is preferable to delay zoledronic acid until the effects of denosumab have begun to dissipate, but not delay long enough to increase the risk of rebound vertebral fractures. Therefore, a minimum of six months after the last dose of denosumab is suggested [37].

If a decision has been made to administer zoledronic acid to prevent bone loss after discontinuation of denosumab, we give the infusion (5 mg) six to seven months after the last dose of denosumab and measure a fasting serum C-telopeptide (CTX) three and six months after the infusion [37]. Some patients may require a second infusion of zoledronic acid (5 mg) three to six months after the first infusion (eg, if serum CTX is >350 pg/mL) [39].

The efficacy of zoledronic acid varies among studies, in part due to the variable duration of prior denosumab therapy and the timing of zoledronic acid administration after denosumab discontinuation [37,40-43]. Zoledronic acid appears to be more effective in preventing bone loss when the duration of denosumab treatment is shorter (eg, <2.5 years) [37]. For longer durations (eg, >3 years of denosumab), some bone loss may be expected even after a single dose of zoledronate administered six months post denosumab.

As examples:

•In a trial comparing a single dose of zoledronic acid (administered six months after last denosumab injection) versus two final doses of denosumab in 60 postmenopausal patients who had received denosumab for 2.4 years, lumbar spine bone density measured two years after the last dose of zoledronic acid or denosumab was maintained in the zoledronic acid group, but declined by 4.8 percent in the denosumab group [41]. In a report from a single-arm observational extension, lumbar spine bone density was also maintained during the third year after the zoledronic infusion [44].

•In a trial comparing administration of zoledronic acid at three different time points (six or nine months after last denosumab injection or when bone turnover had increased) in 61 patients (predominantly postmenopausal women) treated with denosumab for a mean 4.6 years, lumbar spine BMD 12 months after zoledronic acid infusion decreased significantly in all groups (4.8, 4.1, and 4.7 percent, respectively) with no significant difference between groups [42].

•In a multicenter prospective study of 47 postmenopausal patients who received a single zoledronic acid infusion six months after the last denosumab injection, lumbar spine bone density at 12 months decreased significantly in the group that received >3 years of denosumab treatment but was maintained in those who had received ≤3 years of denosumab [43].

●We generally avoid sequential treatment with anabolic therapy (eg, teriparatide, romosozumab) if denosumab was administered first, particularly after a long course (eg, >3 to 4 years) of denosumab. Anabolic treatment should precede rather than follow denosumab therapy. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Management after teriparatide'.)

In the rare setting where a patient is unable to take oral or intravenous bisphosphonates after denosumab is discontinued, there are few options and limited data to guide management decisions. Some UpToDate contributors would try teriparatide, although there is no evidence that teriparatide would prevent vertebral fractures in this setting.

One study compared postmenopausal women who received sequential therapy with denosumab followed by teriparatide versus teriparatide followed by denosumab (each therapy for 24 months) [45]. Women who received denosumab followed by teriparatide had transient decreases in LS, femoral neck, and total hip BMD, followed by increases. Women who received teriparatide followed by denosumab had steady increases at all three sites. Compared with women who received teriparatide first, the net gain in BMD after 48 months was lower in women who received denosumab first (LS [14 versus 18.3 percent], total hip [2.8 versus 6.6 percent], and femoral neck [4.9 versus 8.3 percent]) [45]. The trial was not designed to assess fracture outcomes.

ADVERSE EFFECTS — In the osteoporosis clinical trials, denosumab was generally well tolerated, without evidence of symptomatic hypocalcemia, osteonecrosis of the jaw (ONJ), or atrial fibrillation [1-5,18] (see 'Safety information' below). Overall, the most common adverse effects (>5 percent and more common than placebo) were back, extremity, and musculoskeletal pain; hypercholesterolemia; and cystitis [15]. In postmarketing reports, severe bone, joint, and/or muscle pain has been reported from one day to several months after denosumab administration [46].

In the FREEDOM trial, eczema (3 versus 1.7 percent), cellulitis requiring hospitalization (0.3 versus <0.1 percent), and flatulence (2.2 versus 1.4 percent) were significantly more common in women assigned to denosumab than placebo [1].

SAFETY INFORMATION — Serious risks associated with denosumab include hypocalcemia, osteonecrosis of the jaw (ONJ), atypical femur fractures, and serious infections.

Hypocalcemia — Denosumab should not be given to patients with preexisting hypocalcemia until it is corrected. In addition, patients with conditions predisposing to hypocalcemia (eg, chronic kidney disease) should be monitored for hypocalcemia during treatment. (See 'Pretreatment evaluation' above and 'Monitoring' above.)

●Normal kidney function – In the denosumab trials, all women were supplemented with daily calcium (1000 mg) and vitamin D (400 to 800 international units). A small proportion of women in the denosumab trials had a decrease in the serum calcium level to <8.5 mg/dL (2.1 mmol/L; 1.7 versus 0.4 percent in the placebo group) [15]. The decrease was transient, and there were no episodes of symptomatic hypocalcemia that required discontinuation of denosumab. Thus, in patients with normal kidney function adequately supplemented with calcium and vitamin D, hypocalcemia typically is not a concern.

●Impaired kidney function or other risk factors for hypocalcemia – In patients with conditions that predispose to hypocalcemia, such as chronic kidney disease, malabsorption syndromes, or hypoparathyroidism, severe hypocalcemia may occur [47]. The US Food and Drug Administration (FDA) has added a boxed warning about risk of severe hypocalcemia in individuals with advanced kidney disease for brand name denosumab (Prolia) [14]. The nadir in serum calcium occurs approximately 10 days after denosumab administration.

•For example, in a cohort study of 2804 female patients (aged ≥65 years) undergoing dialysis, severe hypocalcemia (serum calcium <7.5 mg/dL [1.9 mmol/L] or hypocalcemia requiring emergency care) occurred in a higher proportion of patients who initiated denosumab compared with those who initiated an oral bisphosphonate (12-week weighted cumulative incidence 41.1 versus 2 percent, respectively) [48]. Denosumab also was associated with a higher incidence of very severe hypocalcemia (serum calcium <6.5 mg/dL [1.6 mmol/L]) compared with oral bisphosphonates (10.9 versus 0.4 percent, respectively).

•In a study of 55 patients with varying degrees of chronic kidney disease, the proportion of patients with serum calcium <7.5 mg/dL (1.9 mmol/L) or symptomatic hypocalcemia was higher, occurring in 10 and 29 percent of patients with creatinine clearance of 50 to 80 and <30 mL/min, respectively [15]. Hypocalcemia also occurred in 29 percent of patients on hemodialysis. Serious outcomes of hypocalcemia, including hospitalization and death, have been reported in patients undergoing dialysis during treatment with denosumab [17].

Oversuppression of bone remodeling — Denosumab suppresses bone remodeling, but there are few data on the long-term consequences with regard to adverse outcomes, such as ONJ, atypical fractures, and delayed fracture healing. ONJ and atypical fractures have been reported in patients taking denosumab for osteoporosis [15,49-51]. In the FREEDOM extension trial described above, there were five cases of ONJ and one case of atypical femur fracture through extension year 5 (after eight years of denosumab treatment in 1546 postmenopausal women) [7]. In the cross-over group (1457 patients receiving five years of denosumab), there were three cases of ONJ and one atypical fracture. Rates of oversuppression complications did not seem to rise after 10 years of treatment [8]. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw'.)

There are few data on the effects of denosumab on fracture healing. In murine studies, denosumab delayed the removal of cartilage and remodeling of the fracture callus, but it improved strength and stiffness of the healing fracture [52]. In a preplanned analysis of the FREEDOM trial described above (see 'Postmenopausal women' above), there were 851 fractures (386 and 465 in the denosumab and placebo groups, respectively). There was no difference in reports of delayed healing (two and five patients in the denosumab and placebo groups, respectively), even when denosumab was administered within six weeks preceding or following the fracture [53].

Effects on immune system — In addition to suppressing osteoclastogenesis, receptor activator of nuclear factor kappa-B ligand (RANKL) functions within the immune system. Therefore, an important issue with denosumab is whether its inhibition of RANKL has potential infectious and neoplastic complications [54]. In the trials described above, the proportion of patients experiencing adverse events was similar among the placebo, denosumab, and alendronate groups. However, in some [1,4,26], but not all [2,3], of the trials, there were a greater number of infections requiring hospitalization (eg, diverticulitis, pneumonia, atypical pneumonia, appendicitis, cellulitis, and labyrinthitis) in the denosumab group. In the FREEDOM trial, eczema (3 versus 1.7 percent) and severe cellulitis requiring hospitalization (0.3 versus <0.1 percent) were significantly more common in women assigned to denosumab versus placebo [1].The rate of infections did not increase over time as might be expected with cumulative drug effects [55,56]. Pancreatitis has also been reported.

Although in some early trials, there was a nonsignificant increased number of cases of breast, pancreatic, gastrointestinal, ovarian, and uterine tumors [3,57], overall rates of adverse events of neoplasm were similar between treatment groups in subsequent trials, including the larger FREEDOM trial [1-4,26].

OTHER INDICATIONS FOR DENOSUMAB

●Men receiving androgen deprivation therapy – Denosumab has also been shown to prevent osteoporosis and vertebral fracture in men with nonmetastatic prostate cancer receiving androgen deprivation therapy. (See "Side effects of androgen deprivation therapy", section on 'Denosumab'.)

●Women undergoing breast cancer treatment – Denosumab increased bone density in postmenopausal osteopenic women receiving adjuvant aromatase inhibitor therapy. (See "Evaluation and management of aromatase inhibitor-induced bone loss", section on 'Denosumab'.)

●Bone metastases – The role of denosumab in the management of bone metastases in women with breast cancer and in men with advanced prostate cancer is reviewed separately. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Efficacy and dosing considerations for individual agents' and "Bone metastases in advanced prostate cancer: Management", section on 'Osteoclast inhibitors'.)

●Treatment of hypercalcemia – There are an increasing number of case reports and case series of denosumab for the management of hypercalcemia of malignancy, particularly in patients with persistent hypercalcemia despite bisphosphonates. (See "Treatment of hypercalcemia", section on 'Bisphosphonate contraindications or refractory hypercalcemia'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)

SUMMARY AND RECOMMENDATIONS

●Mechanism of action – Denosumab inhibits receptor activator of nuclear factor kappa-B ligand (RANKL), a protein involved with osteoclastogenesis. Denosumab inhibits osteoclast formation, decreases bone resorption, increases bone mineral density (BMD), and reduces the risk of fracture. (See 'Mechanism of action' above.)

●Patient selection – In the absence of definitive data comparing osteoporosis therapies, treatment decisions for patients with osteoporosis should be individualized. The individual's risk for fracture, presence of comorbid conditions, and personal preference are important for weighing the potential benefits and risks of osteoporosis therapies. The need for indefinite treatment should be addressed with patients before denosumab is initiated. There is an increased risk of vertebral fracture with discontinuation of denosumab therapy, and transitioning to another drug is complicated. (See 'Patient selection' above and 'Discontinuation or delay of denosumab' above.)

•Postmenopausal women – For most postmenopausal women with osteoporosis, we suggest not using denosumab as initial therapy (Grade 2B). We prefer oral bisphosphonates as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data. However, denosumab could be used as initial therapy in selected patients at high risk for fracture, such as older patients who have difficulty with the dosing requirements of oral bisphosphonates, those with markedly impaired kidney function, or those with very low BMD. Denosumab is an option for patients who are intolerant of or unresponsive to other therapies. (See 'Patient selection' above.)

•Men – In the absence of fracture prevention data, we suggest not using denosumab for the initial treatment of osteoporosis in men who are not receiving androgen deprivation therapy (Grade 2B). We prefer oral bisphosphonates as initial therapy. However, denosumab may have a role in men who are intolerant of or unresponsive to other therapies and in those with impaired kidney function. (See 'Patient selection' above.)

Use of denosumab in men receiving androgen deprivation therapy is discussed separately. (See "Side effects of androgen deprivation therapy", section on 'Denosumab'.)

●Pretreatment evaluation – Serum calcium and 25-hydroxyvitamin D levels should be measured in all patients prior to denosumab initiation. Patients who have hypocalcemia (eg, those with malabsorption syndromes) should not receive denosumab until hypocalcemia is corrected. Patients with vitamin D deficiency should achieve vitamin D sufficiency prior to initiating denosumab. In addition, all patients should be adequately supplemented with calcium and vitamin D while taking denosumab. Patients with advanced kidney disease have significant risk of severe hypocalcemia during denosumab treatment, requiring greater caution and increased monitoring. (See 'Pretreatment evaluation' above and "Calcium and vitamin D supplementation in osteoporosis".)

●Use in patients with chronic kidney disease – Denosumab, unlike bisphosphonates, is not cleared by the kidney, and as a consequence, there is no restriction of its use in patients with creatinine clearances below 35 mL/min. Inadequate data exist regarding fracture prevention efficacy in those with more severe kidney disease (stages 4 and 5) with concurrent secondary hyperparathyroidism. In addition, the lack of published safety data in this population warrants caution with denosumab use in this group. Serious outcomes of severe hypocalcemia have been reported in patients undergoing dialysis during denosumab treatment, prompting a boxed warning about severe hypocalcemia in patients with advanced kidney disease. (See 'Use in chronic kidney disease' above and 'Hypocalcemia' above.)

●Monitoring

•BMD – Monitoring the BMD response to denosumab therapy is similar to the monitoring of other osteoporosis therapies. Frequency of BMD measurements is variable, but most investigators would not consider a follow-up BMD for at least two years. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Monitoring response to initial pharmacotherapy'.)

•Serum calcium – Patients with chronic kidney disease (creatinine clearance <30 mL/min, including patients receiving dialysis) and/or other conditions that predispose to hypocalcemia (malabsorption syndromes) are at higher risk for hypocalcemia following denosumab administration than patients without these conditions. Such patients may be at risk for severe hypocalcemia. Calcium should be measured in such patients approximately 10 days after denosumab administration. Monitoring of serum calcium is not required in patients without risk factors for hypocalcemia. (See 'Monitoring' above and 'Hypocalcemia' above.)

•Infections and skin reactions – Serious infections and skin reactions were reported more frequently with denosumab than with placebo. Patients should be advised to seek medical attention if they develop signs of an infection or skin reaction. (See 'Adverse effects' above.)

●Discontinuation or delay of treatment – If denosumab treatment is discontinued or delayed beyond two to three months, we suggest administering a bisphosphonate (Grade 2C) to prevent rapid bone loss and increased risk of vertebral fractures. (See 'Discontinuation or delay of denosumab' above and 'Sequential osteoporosis therapy' above.)