Henry G. Bone

Romosozumab in Postmenopausal Women with Low Bone Mineral Density

BACKGROUND Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. METHODS In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 μg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. RESULTS All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. CONCLUSIONS In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).

Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass : A Randomized, Blinded, Phase 3 Trial

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double‐blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty‐nine postmenopausal women with a T‐score ≤ −2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one‐third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12‐mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one‐third radius; p ≤ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab‐ and alendronate‐treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.

Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Randomized Trial

Context Researchers have not previously reported the efficacy and safety of parathyroid hormone (1-84) (PTH) for the primary prevention of osteoporotic fractures. Contributions Among 2532 postmenopausal women with osteoporosis randomly assigned to receive PTH or placebo, PTH decreased new vertebral fractures. The magnitude of the effect depended on assumptions about fractures in the one third of patients who withdrew from the trial prematurely. Adverse effects included hypercalciuria, hypercalcemia, and nausea. Caution Endogenous PTH and vitamin D levels could affect patients response to the drug but were not assessed in the study. Implications Parathyroid hormone (1-84) effectively prevented new vertebral fractures but also increased hypercalciuria, hypercalcemia, and nausea. The Editors Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing patients to an increased risk for fracture (1). Optimal treatment for osteoporosis should improve the amount, density, and quality of bone, thereby reducing skeletal fragility and fractures. Antiresorptive agents, such as bisphosphonates, are commonly used for treating postmenopausal osteoporosis. Although these agents preserve bone architecture, they do not stimulate new bone formation or improve bone architecture. Anabolic or bone-forming agents are an alternative approach to the treatment of osteoporosis. Researchers have shown that parathyroid hormone (PTH) and certain peptide fragments of PTH increase bone mass and improve bone quality (2, 3). Teriparatide, a fragment of human PTH composed of its N-terminal 34 amino acids, has been approved for the treatment of postmenopausal women with osteoporosis who are at high risk for bone fracture. However, researchers have studied this agent only in women with prevalent vertebral fractures (4), and data demonstrating prevention of the first vertebral fracture are lacking. We conducted the Treatment of Osteoporosis with Parathyroid Hormone (TOP) Study to examine the efficacy and safety of PTH (1-84) versus placebo for treating postmenopausal women with osteoporosis. We designed the study to examine the change in incidence of all vertebral fractures between the treatment groups. We also designed the study to examine the efficacy of this new bone-forming agent in preventing a first vertebral fracture in women without a vertebral fracture. Methods Study Participants We included postmenopausal women 45 to 54 years of age if bone mineral density (BMD) was 3.0 SDs or more (T-score 3.0) below the mean peak bone mass of young adult women at the lumbar spine, femoral neck, or total hip with no prevalent vertebral fracture or if BMD T-score was2.5 and they had 1 to 4 vertebral fractures before enrollment. We included postmenopausal women 55 years of age or older if BMD T-score was2.5 and they had no vertebral fractures or if BMD T-score was2.0 and they had 1 to 4 vertebral fractures. We excluded women if baseline serum calcium level was greater than 2.66 mmol/L (>10.7 mg/dL) or if urinary calciumcreatinine ratio was 1.0 or more. We included women with mild hypercalcemia (serum calcium, 2.55 to 2.66 mmol/L [10.2 to 10.7 mg/dL]) and mild hypercalciuria (24-hour urine calcium7.6 mmol [302 mg]) at baseline. We did not measure baseline levels of serum PTH and vitamin D. We excluded women if they had taken bisphosphonates for a total of more than 12 months or for more than 90 days in the 12 months before enrollment. We allowed previous estrogen therapy if it had been discontinued for at least 4 weeks before the screening visit. We excluded women who had received PTH (or a peptide fragment or analogue), PTH-related protein, fluoride, or strontium and those who had a history of metabolic bone disease (other than osteoporosis), nephrolithiasis, or clinically significant hepatic or renal disorders. We also excluded women who were taking medications known to affect bone mineral metabolism. The ethics review committee for each center approved the study. All women provided written informed consent. An independent data and safety monitoring board reviewed the progress and safety of the study. Study Design We conducted a randomized, double-blind, placebo-controlled, parallel-group study in 168 centers in 9 countries. We randomly assigned the study drug to blocks of 4 patients by using a computer-generated algorithm and shipped it in blocks of 4 to each study site. Women at each site were sequentially assigned the uniquely numbered, randomly assigned study drug treatment kits by telephone. Women were stabilized for at least 2 weeks with supplemental calcium, 700 mg/d citrate salt, and vitamin D3, 400 U/d, and then received 100 g of recombinant human PTH or placebo daily by subcutaneous injection for 18 months with continued calcium and vitamin D3 supplementation. Patients were instructed to administer the injection in the morning in the thigh or abdomen by using an injector pen. Study Conduct and Outcome Measures The primary end point was the occurrence of new or worsened vertebral fractures (in all women and in women with and without a prevalent fracture) identified by radiography at baseline, month 18, or the final study visit. Radiologists assessed vertebral fractures in a blinded manner at a central reading organization by using a semiquantitative 4-point grading scale (5). An incident vertebral fracture (new or worsened) was identified by a change in grade of 1 or more from baseline. Secondary outcomes included changes in BMD at lumbar spine, hip, whole body, and forearm (distal one-third radius) that we measured by using dual-energy x-ray absorptiometry with Hologic (Hologic Inc., Bedford, Massachusetts) or Lunar (GE Medical Systems, Madison, Wisconsin) densitometers (reported as percentage change from baseline to standardize instrumental differences in determining absolute BMD) and stadiometric measurements of height. We measured whole body and forearm BMD only in a subset of approximately 300 women from selected sites with appropriate software. We reported nonvertebral clinical fractures and bone loss (>7% at lumbar spine or >9% at total hip or femoral neck) as adverse events. We did not distinguish between traumatic and fragility nonvertebral fractures. We used quantitative computed tomography (6, 7) to evaluate the effects of PTH treatment at month 18 on volumetric cortical and trabecular BMD at lumbar vertebra (L3) and the hip in 122 consenting women from a single center at which the technique was available. We assessed bone turnover markers (serum bone-specific alkaline phosphatase and urinary N-telopeptides of type I collagen) in the first 600 randomly assigned women in the study. We measured bone-specific alkaline phosphatase by using the Tandem R-Ostase immunoradiometric assay (interassay coefficient of variation, 8%) (Hybritech, San Diego, California). We measured N-telopeptides of type I collagen by using Osteomark enzyme-linked immunoabsorbent assay kits (interassay coefficient of variation, 4.0%) (Wampole Laboratories, Princeton, New Jersey) normalized to urine creatinine concentrations. We made safety assessments at months 1, 3, 6, 9, 12, 15, and 18 that included physical examinations, vital signs, electrocardiography (months 1, 12, and 18), adverse-event monitoring and central clinical laboratory assessments consisting of chemistry (including serum total calcium and creatinine), hematology, and urinalysis (including 24-hour urine collections and fasting, morning urinary calciumcreatinine ratios). Adverse events were reported spontaneously by patients, captured in a patients diary, or reported by a patient in response to an open-ended question from clinical study personnel. We used a central laboratory normal range for serum total calcium level of 2.15 to 2.55 mmol/L (8.6 to 10.2 mg/dL). We performed an analysis for antibodies to PTH with a validated electrochemiluminescent immunoassay by using biotinylated recombinant human PTH (range, 26.3 to 2632.5 pmol/L; intra-assay coefficient of variation, 8% to 16%) (Igen International, Inc., Gaithersburg, Maryland). We obtained iliac crest bone biopsy specimens at month 12 or 18 from a subset of 40 consenting women after tetracycline double-labeling (8) that we examined for abnormal bone structure. We anticipated that women might need to discontinue calcium supplementation and reduce the dosing frequency of the study drug to prevent excessive increases in serum calcium level, urinary calcium level, or both. We conservatively predefined hypercalcemia as a single, unconfirmed, predose serum total calcium value greater than 2.66 mmol/L (>10.7 mg/dL) and hypercalciuria as a 24-hour urinary calcium value of 7.6 mmol or more (302 mg) (increased to >9.0 mmol [>360 mg] during the study) or a fasting urinary calciumcreatinine ratio of 1.0 or more. If a woman developed hypercalcemia or hypercalciuria, we discontinued the daily calcium supplementation; if either condition continued, we reduced the dosing frequency of the study drug. Statistical Analysis We estimated the sample size for our study by assuming that 67% of the patients would not have a prevalent fracture; that the 18-month vertebral fracture incidence for patients with and without a prevalent fracture who received placebo would be 10% and 2.5%, respectively; and that 20% of the patients in each group would discontinue the study early without a new or worsened fracture. We expected a sample of 2600 patients (1300 per treatment group) to provide at least 90% power to detect a significant 60% or greater reduction in vertebral fracture incidence in the PTH treatment group compared with the placebo group (2-sided level of 0.05). We analyzed data by using SAS software, version 8.0 (SAS Institute, Inc., Cary, North Carolina). We used descriptive statistics to summarize demographic and other baseline variables. We assessed comparability of the treatment groups at baseline by using t-tests for continuous varia

Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis

Dosing convenience is a key element in the effective management of any chronic disease, and is particularly important in the long-term management of osteoporosis. Less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Animal data support the rationale that once-weekly dosing with alendronate 70 mg (7 times the daily oral treatment dose) could provide similar efficacy to daily dosing with alendronate 10 mg due to its long duration of effect in bone. In addition, dog studies suggest that the potential for esophageal irritation, observed with daily oral bisphosphonates, may be substantially reduced with once-weekly dosing. This dosing regimen would provide patients with increased convenience and would be likely to enhance patient compliance. We compared the efficacy and safety of treatment with oral once-weekly alendronate 70 mg (N=519), twice-weekly alendronate 35 mg (N=369), and daily alendronate 10 mg (N=370) in a one-year, double- blind, multicenter study of postmenopausal women (ages 42 to 95) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak premenopausal mean, or prior vertebral or hip fracture). The primary efficacy endpoint was the comparability of increases in lumbar spine BMD, using strict pre-defined equivalence criteria. Secondary endpoints included changes in BMD at the hip and total body and rate of bone turnover, as assessed by biochemical markers. Both of the new regimens fully satisfied the equivalence criteria relative to daily therapy. Mean increases in lumbar spine BMD at 12 months were: 5.1% (95% CI 4.8, 5.4) in the 70 mg once-weekly group, 5.2% (4.9, 5.6) in the 35 mg twice-weekly group, and 5.4% (5.0, 5.8) in the 10 mg daily treatment group. Increases in BMD at the total hip, femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatment groups similarly reduced biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and bone formation (serum bone-specific alkaline phosphatase) into the middle of the premenopausal reference range. All treatment regimens were well tolerated with a similar incidence of upper GI adverse experiences. There were fewer serious upper GI adverse experiences and a trend toward a lower incidence of esophageal events in the once-weekly dosing group compared to the daily dosing group. These data are consistent with preclinical animal models, and suggest that once-weekly dosing has the potential for improved upper GI tolerability. Clinical fractures, captured as adverse experiences, were similar among the groups. We conclude that the alendronate 70 mg once-weekly dosing regimen will provide patients with a more convenient, therapeutically equivalent alternative to daily dosing, and may enhance compliance and long-term persistence with therapy.

Effects of denosumab on bone mineral density and bone turnover in postmenopausal women.

CONTEXT Denosumab is an investigational fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, a mediator of osteoclastogenesis and osteoclast survival. OBJECTIVE This study evaluated the ability of denosumab to increase bone mineral density (BMD) and decrease bone turnover markers (BTMs) in early and later postmenopausal women with low BMD. DESIGN AND SETTING This 2-yr randomized, double-blind, placebo-controlled study was conducted in North America. PARTICIPANTS Subjects included 332 postmenopausal women with lumbar spine BMD T-scores between -1.0 and -2.5. INTERVENTIONS SUBJECTS were randomly assigned to receive denosumab sc, 60 mg every 6 months, or placebo. Randomization was stratified by time since onset of menopause (< or =5 yr or > 5 yr). MAIN OUTCOME MEASURES The primary end point was the percent change in lumbar spine BMD by dual-energy x-ray absorptiometry at 24 months. Additional end points were percent change in volumetric BMD of the distal radius by quantitative computed tomography; percent change in BMD by dual-energy x-ray absorptiometry for the total hip, one-third radius, and total body; hip structural analysis; percent change in BTMs; and safety. RESULTS Denosumab significantly increased lumbar spine BMD, compared with placebo at 24 months (6.5 vs. -0.6%; P<0.0001) with similar results for both strata. Denosumab also produced significant increases in BMD at the total hip, one-third radius, and total body (P < 0.0001 vs. placebo); increased distal radius volumetric BMD (P < 0.01); improved hip structural analysis parameters; and significantly suppressed serum C-telopeptide, tartrate-resistant acid phosphatase-5b, and intact N-terminal propeptide of type 1 procollagen. The overall incidence of adverse events was similar between both study groups. CONCLUSIONS Twice-yearly denosumab increased BMD and decreased BTMs in early and later postmenopausal women.

Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy

Patients treated with bisphosphonates for osteoporosis may discontinue or require a switch to other therapies. Denosumab binds to RANKL and is a potent inhibitor of bone resorption that has been shown to increase bone mineral density (BMD) and decrease fracture risk in postmenopausal women with osteoporosis. This was a multicenter, international, randomized, double‐blind, double‐dummy study in 504 postmenopausal women ≥ 55 years of age with a BMD T‐score of −2.0 or less and −4.0 or more who had been receiving alendronate therapy for at least 6 months. Subjects received open‐label branded alendronate 70 mg once weekly for 1 month and then were randomly assigned to either continued weekly alendronate therapy or subcutaneous denosumab 60 mg every 6 months and were followed for 12 months. Changes in BMD and biochemical markers of bone turnover were evaluated. In subjects transitioning to denosumab, total hip BMD increased by 1.90% at month 12 compared with a 1.05% increase in subjects continuing on alendronate (p < .0001). Significantly greater BMD gains with denosumab compared with alendronate also were achieved at 12 months at the lumbar spine, femoral neck, and 1/3 radius (all p < .0125). Median serum CTX levels remained near baseline in the alendronate group and were significantly decreased versus alendronate (p < .0001) at all time points with denosumab. Adverse events and serious adverse events were balanced between groups. No clinical hypocalcemic adverse events were reported. Transition to denosumab produced greater increases in BMD at all measured skeletal sites and a greater reduction in bone turnover than did continued alendronate with a similar safety profile in both groups. Copyright

Short-Term Inhibition of Parathyroid Hormone Secretion by a Calcium-Receptor Agonist in Patients with Primary Hyperparathyroidism

BACKGROUND Surgery is the usual therapy for patients with primary hyperparathyroidism. We investigated the ability of a calcimimetic drug that inhibits parathyroid hormone secretion in vitro to decrease serum parathyroid hormone and calcium concentrations in patients with this disorder. METHODS We performed a randomized, placebo-controlled study of single oral doses of 4 to 160 mg of the calcium-receptor agonist drug R-568 in 20 postmenopausal women with mild primary hyperparathyroidism. At base line, the mean (+/-SE) serum calcium concentration was 10.7+/-0.2 mg per deciliter (2.67+/-0.05 mmol per liter). Serum parathyroid hormone and calcium were measured repeatedly after each dose, and safety was assessed. RESULTS Administration of R-568 resulted in a dose-dependent inhibition of parathyroid hormone secretion. The mean serum parathyroid hormone concentration, which was 77+/-11 pg per milliliter (18.8+/-2.7 pmol per liter; normal range, 16 to 65 pg per milliliter [3.9 to 15.9 pmol per liter) at base line, fell by 26+/-8 percent after 20 mg of R-568 (P=0.03), by 42+/-7 percent after 80 mg (P = 0.01), and by 51+/-5 percent after 160 mg (P=0.005). Serum ionized calcium concentrations fell only after the 160-mg dose, with the decrease closely following the decrease in the serum parathyroid hormone concentration. CONCLUSIONS The calcimimetic drug R-568 reduces serum parathyroid hormone and ionized calcium concentrations in postmenopausal women with primary hyperparathyroidism.

Odanacatib, a cathepsin-K inhibitor for osteoporosis: A two-year study in postmenopausal women with low bone density

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1‐year dose‐finding trial with a 1‐year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T‐scores of −2.0 or less but not less than −3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty‐four months of treatment produced progressive dose‐related increases in BMD. With the 50‐mg dose of odanacatib, lumbar spine and total‐hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (−0.2% and −0.9%). Biochemical markers of bone turnover exhibited dose‐related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose‐related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well‐tolerated and increased lumbar spine and total‐hip BMD in a dose‐related manner in postmenopausal women with low BMD.

Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect

The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased bone‐resorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1‐year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T‐scores between −2.0 and −3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n = 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross‐linked N‐telopeptide of type I collagen (NTx) remained suppressed at year 3 (−50.5%), but bone‐specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse‐event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone‐resorption markers remained suppressed, whereas bone‐formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation.

Effects of Denosumab Treatment and Discontinuation on Bone Mineral Density and Bone Turnover Markers in Postmenopausal Women with Low Bone Mass

CONTEXT Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. OBJECTIVE The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. DESIGN We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study. PARTICIPANTS A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of -1.61 at randomization participated in the study. INTERVENTIONS Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. MAIN OUTCOME MEASURES We measured the percentage changes in BMD and BTM, and evaluated safety. RESULTS Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P ≤ 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. CONCLUSIONS In postmenopausal women with low BMD, the effects of 60 mg denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo.