Nutritional Interventions: Calcium Supplements & Vitamin D
Several studies support the ability of calcium and vitamin D supplements alone to prevent fractures in the elderly to a modest extent. This is especially true for individuals whose calcium intake is below recommended allowances. Every fracture trial done in recent years has included calcium—and usually vitamin D supplementation as well—in both the placebo and treatment groups.
Nutritional interventions for osteoporosis should assure that the diet plus supplements provide at least 1200 mg of elemental calcium per day in patients with postmenopausal or glucocorticoid-induced osteoporosis (Tables 58–3 and 58–8). Measurements of 24-hour urinary calcium excretion can be used to assure adequate absorption and to avoid hypercalciuria.
Table 58–8. Management of Postmenopausal, Male and Glucocorticoid-Induced Osteoporosis. ||Download (.pdf)
Table 58–8. Management of Postmenopausal, Male and Glucocorticoid-Induced Osteoporosis.
- Discontinue tobacco
- Discontinue alcohol intake
- Wear hip protector
- Exercise regularly
|Nutritional interventions||Increase calcium intake to 1000 mg elemental calcium per day for prevention of osteoporosis in premenopausal women and to at least 1200 mg elemental calcium per day for postmenopausal women, men, and patients taking glucocorticoids long term; vitamin D intake: 800–1000 international units/d for men and postmenopausal women, and for patients taking glucocorticoids long-term|
- Alendronate 5 mg/d or 35 mg/wk orally for prevention of osteoporosis; 10 mg/d or 70 mg/wk orally for treatment of postmenopausal, male, and glucocorticoid-induced osteoporosis
- Risedronate 5 mg/d, 35 mg/wk, or 150 mg/mo orally for prevention and treatment of postmenopausal and glucocorticoid-induced osteoporosis
- Ibandronate 150 mg/mo orally for prevention and treatment and 3 mg/3 mos for treatment of postmenopausal osteoporosis
- Zoledronic acid 5 mg/year intravenously for prevention and treatment of postmenopausal osteoporosis and for treatment of male and glucocorticoid-induced osteoporosis
- Parathyroid hormone (PTH)
- Teriparatide (PTH 1–34) 20 mcg subcutaneous injection per day for postmenopausal, male and glucocorticoid-induced osteoporosis, especially in patients at high risk for fractures
- Nasal spray calcitonin 200 international units intranasally daily
- RANK-ligand inhibitor
- Denosumab 60 mg by subcutaneous injection every 6 months for treatment of postmenopausal women at high risk for fracture, men receiving androgen deprivation therapy for nonmetastatic prostate cancer, and women at high risk for fracture receiving adjuvant treatment with aromatase inhibitors for breast cancer
Other than nutritional supplements, there are two major sources of vitamin D. In the United States, milk is fortified with vitamin D and is the main dietary source of this vitamin. The second source of vitamin D is dermal synthesis, which is influenced by latitude and exposure to sunlight. For a variety of reasons, elderly patients and those who are chronically ill, including those with rheumatologic disorders, are often deficient in dairy intake and sunlight exposure. That vitamin D insufficiency is a substantial problem is strongly supported by a survey of 1526 postmenopausal women in North America who take prescription drug therapy for osteoporosis. Approximately 50% of these women had 25-hydroxyvitamin D levels below the desired target of 30 ng/mL.
Vitamin D is universally recommended to preserve bone health. The Institute of Medicine of the National Academy of Sciences in their 2011 report recommended a daily allowance of 400–800 international units depending on age, gender, and individual clinical circumstances (see Table 58–9). This level of intake is expected to maintain the serum levels of 25-hydroxyvitamin D at 20 ng/mL or more in ≥97.5% of the healthy population. The NOF recommended slightly more vitamin D per day (800 to 1000 international units, Table 58–3) for individuals at risk for bone loss and with established osteoporosis. The definition of vitamin D sufficiency is controversial. 25-Hydroxyvitamin D is the metabolite made by the liver and stored in fat, is the best indicator of overall vitamin D status in an individual. Estimates of optimal levels of 25-OH vitamin D to achieve skeletal and nonskeletal benefits range from 20–30 ng/mL (50–75 nmol/L) or higher.
Table 58–9. Recommended Calcium and Vitamin D Reference Intakes by Age in Adults from the 2011 Report of the Institute of Medicine. ||Download (.pdf)
Table 58–9. Recommended Calcium and Vitamin D Reference Intakes by Age in Adults from the 2011 Report of the Institute of Medicine.
|Age, gender, circumstances||Calcium, RDA (mg/d)||Calcium, upper limit of safety (mg/d)a||Vitamin D, RDA (international units/d)b||Vitamin D, upper limit of safety (international units/d)a|
|14–18 yrs (M + F)||1300||3000||600||4000|
|19–50 yrs (M + F)||1000||2500||600||4000|
|51–70 yrs (M)||1000||2000||600||4000|
|51–70 yrs (F)||1200||2000||600||4000|
|71 + yrs (M + F)||1200||2000||800||4000|
|Pregnant or lactating (F)|
Drug therapies have been intensively researched in recent years. Agents that are effective for treating osteoporosis and approved in the United States include (1) bisphosphonates, (2) selective estrogen response modulators, (3) calcitonin, and (4) teriparatide (parathyroid hormone [PTH] 1-34). Hormone therapy (HT) (conjugated estrogen with or without progestin) has also been shown to reduce fractures in the Women’s Health Initiative (WHI) trial. This occurred, however, at the expense of increased cardiovascular events and breast cancer risk in the combined HT arm. Both adverse events were considered unacceptable for postmenopausal women. This has profoundly discouraged the use of HT regimens in osteoporosis prevention and treatment. A summary of treatment and prevention strategies is outlined in Table 58–8.
The skeletal status of young women of child-bearing age must be evaluated and managed with circumspection. Bisphosphonates accumulate in the skeleton and may alter fetal skeletal development should pregnancy occur, theoretically even several years after discontinuing bisphosphonate treatment. None of the medications, especially bisphosphonates, are approved for use in pregnant or lactating women.
Four drugs in this class are approved for the prevention and treatment of osteoporosis in the United States: alendronate, risedronate, ibandronate, and zoledronic acid. Alendronate, risedronate, and zoledronic acid are approved for postmenopausal, glucocorticoid-induced, and male osteoporosis. Monthly oral ibandronate and quarterly intravenous ibandronate are approved to treat postmenopausal osteoporosis. Both glucocorticoid-treated men and women experience statistically significant increases in lumbar spine and hip BMD by DXA measurements compared with placebo. Overall, drugs of the bisphosphonate class are the most frequently prescribed medications for the treatment of osteoporosis.
The ability of oral (alendronate, risedronate, and ibandronate) and intravenous (zoledronic acid) bisphosphonates to reduce major morbidity from typical osteoporotic fractures has been well-demonstrated in several large, double-blind, placebo-controlled trials. These trials led to the registration and approval in the United States of all four agents for postmenopausal osteoporosis treatment as well as a variety of other indications (male and glucocorticoid-induced osteoporosis and prevention of postmenopausal bone loss), depending on the agent and the characteristics of the individuals studied in the trials. Dosing and approved indications for these agents are shown in Table 58–8.
Alendronate has been studied extensively in early postmenopausal women, women with established osteoporosis, men with osteoporosis, and patients taking glucocorticoids. It is approved for the treatment of all four groups of patients based on trials showing reductions in spinal, hip, and nonvertebral fractures (patients with established osteoporosis), reductions in spinal fractures (glucocorticoid-treated persons), and significant increases in BMD compared to placebo at spine and hip sites (all groups).
Risedronate, available in three oral formulations (5 mg daily, 35 mg weekly, 150 mg monthly), has been shown to be effective at increasing spinal and hip BMD in women with postmenopausal osteoporosis and in preventing spinal, hip, and nonvertebral fractures in this high-risk population. These observations are based on two large multinational trials with fractures as their end points (VERT and HIP). Risedronate has been studied in patients starting glucocorticoid therapy as well as in those receiving long-term maintenance glucocorticoid therapy. This agent is highly effective at preventing reductions in spinal and hip BMD seen in placebo-treated patients who are treated with glucocorticoids. Risedronate has been studied in men with osteoporosis and is also effective in enhancing BMD at both spinal and hip sites.
Ibandronate is approved for the treatment of postmenopausal osteoporosis as an oral monthly agent (150 mg/mo) and a quarterly intravenous infusion (3 mg/3 mo). The monthly oral preparation is also approved for the prevention of postmenopausal osteoporosis. Ibandronate has been shown to be effective at reducing the risk of vertebral fractures in postmenopausal women with osteoporosis, compared to placebo, but has not demonstrated nonvertebral or hip fracture reduction in the studies thus far conducted.
Zoledronic acid, administered as an annual intravenous infusion (5 mg), has been extensively evaluated in postmenopausal, male, and glucocorticoid-induced osteoporosis. In the latter two populations, zoledronic acid has been compared to active therapy with an oral daily bisphosphonate. Zoledronic acid has also been compared to placebo in patients post-hip fracture. In the placebo-controlled trial that led to the approval of zoledronic acid for the treatment of postmenopausal osteoporosis, there were significant reductions in all the major osteoporotic fractures: hip (41%), nonvertebral (25%), clinical vertebral (77%), and any clinical (33%).
Esophageal, Musculoskeletal, Ocular, Dental, Renal
Much is known about the clinical tolerability of the bisphosphonates as a group. When bisphosphonates are given orally, esophageal irritation, esophagitis, and pain can occur. Some, but not all, of the recent epidemiology analyses have suggested an association between bisphosphonate use and esophageal cancer. The absolute number of cases is very small; the duration of bisphosphonate use before onset of the cancer is short; and data on compliance with drug therapy are lacking. All of these issues lead one to question the association.
Musculoskeletal pains and uveitis are rarely seen. In the doses used to treat osteoporosis, the complication of osteonecrosis of the jaw (painful or painless exposed bone) is very rare, occurring at a frequency of ∼1/10,000–1/100,000. This oral lesion, often but not invariably, presents after a dental procedure, heals slowly, and can progress to infection and fistula formation along with loss of oral function in the most severe cases. An acute-phase reaction characterized by fever, myalgias, arthralgias, and fatigue can also occur (∼10% of patients) particularly after the first intravenous dose of a bisphosphonate. It is essential that patients receiving these agents, especially intravenously, be vitamin D replete prior to therapy to avoid hypocalcemia due to the acute suppression of bone resorption. Renal function should be checked prior to each intravenous dose of a bisphosphonate and periodically during oral therapy with these agents. Product labeling generally recommends against the use of bisphosphonates in patients with estimated glomerular filtration rates less than 30 mL/min or 35 mL/min (depending on the specific agent).
Considerable attention has focused recently on atypical femur fractures seen in association with bisphosphonate treatment of osteoporosis. Atypical in this context refers to the location, which is subtrochanteric (5 cm distal to the lesser trochanter of the femur) or in the shaft of the femur. These fractures are non-comminuted and frequently bilateral and often present with the prodrome of thigh pain for weeks to months before the fracture presents clinically. Whether bisphosphonates play a causal role in these fractures is uncertain, but they typically occur in patients who have been treated for 5 years or longer with these agents.
Raloxifene belongs to the class of drugs called selective estrogen response modulators (SERMs), which differ from estrogen biochemically and structurally but can act as estrogen agonists or antagonists depending on the specific target tissues. Raloxifene was developed with the goal of capitalizing on the benefits of estrogen in bone and eliminating or strongly diminishing the impact of estrogen-like compounds on cardiovascular and breast cancer risks.
The MORE (Multiple Outcomes of Raloxifene Evaluation) study compared the efficacy of raloxifene to placebo in postmenopausal women with osteoporosis. After 3 years of therapy, women treated with raloxifene (60 or 120 mg/d) demonstrated modest (2.1–2.7%) but significant increases in lumbar spine and femoral neck BMD. The occurrence of vertebral fractures was significantly reduced by 30–50% compared with the placebo group. However, the overall incidence of nonvertebral fractures was unchanged by raloxifene, and there was no significant impact on hip fractures.
Raloxifene was not associated with an increased risk of endometrial carcinoma, vaginal bleeding, or mastalgia. Venous thromboembolic events, however, were increased in women receiving raloxifene compared to women receiving placebo (relative risk 3.1; 95% CI [1.5–6.2]). This incidence of venous thromboembolic events was similar in frequency to that of patients receiving hormone replacement therapy or tamoxifen. Additional adverse events that were increased in women taking raloxifene included hot flashes, leg cramps, edema, and a flulike syndrome.
Interestingly, the incidence of breast cancer was reduced in both groups of women treated for 40 months with either dose of raloxifene (relative risk 0.3; 95% CI [0.2–0.6]) in the initial trial. With continued administration of raloxifene, it appears that the risk of breast cancer is significantly reduced with up to 8 years of treatment. In a large trial comparing raloxifene to tamoxifen both agents had similar effects to reduce the risk of invasive breast cancer in high-risk postmenopausal women selected for enrollment based on clinical risk factors for breast cancer.
In summary, raloxifene has modest positive effects on BMD and reduces vertebral, but not nonvertebral, fractures. It is a useful agent for younger postmenopausal women who have less severe osteoporosis and are at lower risk for hip fracture.
Calcitonin, a 32-amino-acid peptide hormone, binds to receptors on osteoclasts, and this interaction inhibits osteoclast-mediated bone resorption. Calcitonin in the form of a nasal spray (200 units/d) is approved for the treatment of postmenopausal osteoporosis.
The PROOF (Prevent Recurrence of Osteoporotic Fractures) trial established the efficacy of nasal spray calcitonin by comparing it to placebo in 1255 postmenopausal women. All patients received 1000 mg elemental calcium and 400 international units vitamin D daily. After 5 years of therapy, nasal spray calcitonin (200 international units/d) induced 1.0–1.5% increases in lumbar spine BMD that were accompanied by a 33% reduction in new spinal fractures compared with placebo. Hip BMD and hip fractures were not significantly affected by therapy with calcitonin. Adverse events included nasal irritation (congestion, discharge, or sneezing). Calcitonin therefore has modest effects on spinal BMD and does not reduce hip fractures but has an excellent tolerability profile.
Teriparatide or parathyroid hormone (PTH) 1-34 is approved for the treatment of osteoporosis in postmenopausal women, men with osteoporosis, and patients with glucocorticoid-induced bone loss, especially those at high risk for fracture. PTH produces anabolic effects on the skeleton (ie, stimulates bone formation) when it is administered intermittently in low doses, while the chronic elevations of PTH, characteristic of primary hyperparathyroidism, are “catabolic” to bone, cause excessive resorption, and eventually increase fracture risk. Thus, PTH as a therapy for osteoporosis targets the narrow window between the anabolic and catabolic effects of PTH. Studies demonstrating the efficacy of PTH (1-34) in increasing BMD and reducing vertebral and nonvertebral fractures in postmenopausal women and the studies in men are described below.
The fracture prevention trial for teriparatide enrolled 1637 postmenopausal women with at least one moderate or two mild nontraumatic vertebral fractures and compared subcutaneous injections of teriparatide (20 mcg/d) with placebo. All participants took daily supplements of calcium (1000 mg) and vitamin D (400–1200 international units). After 21 months, teriparatide induced dramatic increases in spinal BMD (+9.7%) and modest but significant increases in femoral neck BMD (+2.8%).
Teriparatide reduced new vertebral fractures by 65% and all nonvertebral fractures combined (ie, hip, wrist, ankle, humerus, rib, and so forth) by 54%, but the number of hip fractures did not significantly differ in teriparatide- versus placebo-treated patients. New moderate or severe vertebral fractures were substantially reduced 78–90% in teriparatide- versus placebo-treated patients. Adverse events due to teriparatide included dizziness and leg cramps (both in <10% of patients). Hypercalcemia (defined as serum calcium >10.6 mg/dL) developed in 11% of patients receiving teriparatide, compared with 2% of patients in the placebo group. Ninety-five percent of these serum calcium values were <11.2 mg/dL and were managed by reducing calcium intake in most patients.
In a study of teriparatide in men, 437 participants were enrolled with T-scores < –2 in the lumbar spine or hip. Their average age was 59, and approximately 50% had low serum free testosterone levels. Men were treated for 11 months with teriparatide or with placebo, and all patients received 1000 mg elemental calcium and 400–1200 international units vitamin D per day. This trial was prematurely terminated because ongoing toxicology studies in rats found an increased incidence of osteosarcomas (see below). At study termination, teriparatide (at 20 mcg/d subcutaneously) induced significant average increases in spinal BMD of +5.9%, in femoral neck BMD of +1.5%, and in total body BMD of +0.6%. Teriparatide was found to be effective in men regardless of their gonadal status, age, or baseline BMD values. The changes in BMD were impressive, given the short duration of the study, but the short duration and the limited number of participants rendered it underpowered to assess reduction in fractures.
An active comparator study of 428 men and women (aged 22–89) treated with long-term glucocorticoids (≥5 mg prednisone or its equivalent orally per day for 3 months or longer) compared the efficacy and safety of alendronate (10 mg/d orally) and teriparatide (20 mcg/d subcutaneously) in preserving bone mass and preventing fractures in this high-risk population. Approximately 75% of the patients enrolled had a rheumatologic disorder. After 18 months of therapy, teriparatide produced statistically greater increases in lumbar spine BMD [7.2 +/– 0.7% (teriparatide-treated) vs 3.4 +/– 0.7% (alendronate-treated)] and in total hip BMD [3.8 +/– 0.7% (teriparatide-treated vs 2.4 +/– 0.6% (alendronate-treated)] than daily alendronate. There were significantly less vertebral fractures in teriparatide-treated (0. 6%) vs alendronate-treated patients (6.1%). There were no significant differences in nonvertebral fractures in the two treatment arms of the study. There was a greater incidence of hypercalcemia-related adverse events in the study group treated with teriparatide.
Two of the above studies were terminated early due to results from standard carcinogenicity studies in rats showing that lifelong daily injections of high-dose teriparatide induced osteosclerosis and a markedly increased incidence of osteosarcomas (48% of rats treated with teriparatide [75 mcg/kg for 17 months]). The Food and Drug Administration has concluded that these findings do not preclude the use of teriparatide in humans but required a black box warning on the package insert to inform practitioners and patients of this result.
Given the above findings plus the costs and inconvenience of daily subcutaneous injections, teriparatide is recommended to treat bone loss in the following groups: patients with severe osteoporosis (including those taking glucocorticoids), especially accompanied by fractures; patients intolerant of other therapies for osteoporosis; and patients who have not responded to other drugs for osteoporosis as evidenced by significant losses of BMD by DXA or by the development of fractures. Treatment is recommended not to exceed 2 years in duration and is approved for use in men and women. Teriparatide is contraindicated in growing children (with open epiphyses), patients with bone metastases or those who have had skeletal irradiation, and patients with Paget disease or an unexplained elevation in the alkaline phosphatase value.
Despite the above considerations, teriparatide holds promise for both building new bone and increasing the skeleton’s biomechanical strength—outcomes that are highly desired to prevent ongoing osteoporotic fractures in high-risk patients. How should teriparatide be best used to treat osteoporosis? It is anticipated that 2 years of therapy with this agent will be followed by long-term therapy with antiresorptive drugs in an effort to maintain the gains in BMD achieved with this anabolic agent. While this idea is at present intuitively sound, the long-term efficacy of such regimens has been evaluated to only a limited extent as described below (see the section on combination and sequential regimens, below).
HT refers to the combination of estrogen and progestin while estrogen therapy (ET) involves the use of an estrogen preparation exclusively, typically only in patients who have had a hysterectomy. A variety of estrogen preparations have been used for the prevention and treatment of postmenopausal osteoporosis. Perhaps the most popular and best studied has been the combination of conjugated equine estrogens and medroxyprogesterone acetate in varying dosages. Studies like the PEPI (Postmenopausal Estrogen/Progestin Interventions) trial established the efficacy of various HT and ET regimens to prevent postmenopausal bone loss at the spine and hip, based on DXA measurements after 3 years of therapy. This and other trials did not address the antifracture benefit.
HT and ET were thought to reduce the risks of coronary heart disease and its complications, based on epidemiologic studies, and to have little or no effects on breast cancer. This view changed dramatically with the findings from the WHI. The WHI examined the risks and benefits of HT (0.625 mg conjugated equine estrogens and 2.5 mg medroxyprogesterone acetate per day) in 16,608 women in the primary prevention of several postmenopausal health outcomes. In 2002, this study reported a small but significant increased risk of invasive breast cancer in women receiving HT compared with those receiving placebo after 5.2 years (HR [hazard ratio] 1.26; 95% CI [1.00–1.59]) and a similarly small increase in coronary heart disease end points due to HT (HR 1.29; 95% CI [1.02–1.63]). Ironically, this study did show a reduction in hip fractures (HR 0.66; 95% CI [0.45–0.98]) due to HT.
In 2004, the results of the ET study in the WHI were reported. Of 10,739 postmenopausal women with prior hysterectomies, 5310 were randomized to ET (0.625 mg conjugated equine estrogens), and 5410 were treated with placebo for 6.8 years. Major clinical outcomes were an increased risk of stroke (HR 1.39; 95% CI [1.10–1.77]) and reduced risk of hip fractures (HR 0.61; 95% CI [0.41–0.91]). There was no increased risk of coronary heart disease, pulmonary embolism, or breast cancer.
The risk of fracture and changes in BMD were further examined in a subset of women in the HT trial in WHI. Total hip BMD increased by 3.7% after 3 years of therapy compared to 0.14% in the placebo group. The risk of all fractures was significantly reduced in women on HT (HR 0.76; 95% CI [0.69–0.83]) as were the risks of vertebral and lower arm/wrist fractures.
Despite the positive effects of HT on reducing fractures, the negative nonskeletal outcomes (cancer, cardiovascular events) have made HT undesirable for treating osteoporosis, given the availability of other options. Present recommendations are that HT be used for as short a time as possible after menopause, in the lowest possible doses, and mainly for the control of vasomotor symptoms.
Over the last 10–15 years, a large body of molecular, cellular and preclinical studies has established the central importance of the RANK-L (receptor activator of nuclear factor kappa B ligand/RANK/OPG (osteoprotegerin) pathway in regulating the differentiation of cells in the osteoclast lineage and in the ability of mature osteoclasts to resorb bone. Preclinical studies strongly supported the approach of targeting RANK-L, a cytokine in the tumor necrosis factor superfamily, using denosumab, a monoclonal antibody that neutralizes this molecule essential to the formation and function of osteoclasts. Denosumab has been tested in several large clinical trials that have included postmenopausal women with osteoporosis, men with prostate cancer undergoing androgen deprivation therapy, and patients with various malignancies.
The phase 3 trial testing the safety and efficacy of RANK-L inhibition as a treatment for postmenopausal osteoporosis randomized 7868 women to subcutaneous placebo or denosumab injections (60 mg every 6 months) for 3 years. All patients were treated with either 400 or 800 international units vitamin D3 daily, based on their initial 25 hydroxyvitamin D level, and at least 1000 mg calcium daily. This multicenter international trial enrolled women between age 60 and 90 years with T scores of <–2.5 at the lumbar spine or total hip but >–4.0. Women were excluded if they had any severe clinical fracture or more than two moderate vertebral fractures. At randomization, women were on average 72-years-old with average BMD T-scores as follows: –2.8 (lumbar spine), –1.9 (total hip), and –2.2 (femoral neck). Prevalent vertebral fractures were noted in the initial baseline spine radiographs in 23–24% of patients enrolled. Thus, this was a moderately osteoporotic elderly population.
After 3 years of therapy with denosumab, BMD increased significantly in the lumbar spine by 9.2% (95% CI, 8.2–10.1) and in the total hip by 6.0% (95% CI, 5.2–6.7) compared to placebo. Markers of bone turnover were suppressed promptly post-injection with the denosumab. Treatment with denosumab was associated with statistically significant reductions in radiographic vertebral fractures by 68% (2.3% of denosumab- vs 7.2% of placebo-treated patients; P <.001); nonvertebral fractures by 20% (6.5% of denosumab- vs 8.0% of placebo-treated patients; P =.01), and hip fractures by 40% (0.7% of denosumab- vs 1.2% of placebo-treated patients; P =.04). New clinical vertebral fractures and multiple vertebral fractures were reduced by 69% and 61%, respectively, by denosumab vs placebo therapy (P <.001 for both). Adverse events were similar in the placebo- vs denosumab-treated groups for cardiovascular events, deaths, cancer, renal toxicity, or serious infections. There were no cases of osteonecrosis of the jaw. Eczema occurred at a greater frequency in denosumab- (3%) vs placebo-treated (1.7%) patients (P <.001). Although there were no differences in the overall rate of cellulitis reported as adverse events, there were more cases of cellulitis as a serious adverse event in denosumab-treated (N = 12) vs placebo-treated women (N = 1) (P =.002). The overall number of cases was small; however, this has led to increased surveillance for infection in general in patients who may be considered for therapy with this agent.
The 3-year clinical trial testing denosumab in men recruited 1468 men receiving androgen deprivation therapy (bilateral orchiectomy or gonadotropin-releasing hormone agonist therapy) for nonmetastatic prostate cancer. Enrolled men were expected to be androgen-deprived for at least 12 months. Men were recruited if they were over 70 years of age or younger than 70 years of age with either a low BMD (T score <–1.0 at either the spine or hip sites) or a history of a fracture. In the full trial, men were on average 75 years of age on enrollment and had BMD scores indicating normal mineralization (lumbar spine and total hip) and mild osteopenia (femoral neck). Participants were treated with denosumab (60 mg every 6 months) or placebo for 36 months. BMD rose significantly at 24 and 36 months in denosumab compared to placebo-treated men achieving 6.7%, 4.8%, 3.9%, and 5.5% differences at the lumbar spine, total hip, femoral neck, and distal one third radius, respectively (P <.001 for all). These changes in BMD were associated with statistically significant reductions in new radiographic vertebral fractures assessed after 12, 24, and 36 months of treatment with denosumab with a cumulative reduction of 62% (relative risk, 0.38; 95% CI, 0.19–0.78; P =.0006) compared to placebo treatment. No statistically significant differences were seen in nonvertebral fractures between the denosumab- vs placebo-treated men over the 36 months of the trial. There were no differences in deaths, serious infections, renal toxicity, cancers or cardiovascular events in patients receiving denosumab vs placebo injections.
Based on the findings from these and other studies, denosumab (dosing of 60 mg every 6 months by subcutaneous injection) was approved by the US Food and Drug Administration for the treatment of osteoporosis. The indications in the prescribing information include the following: postmenopausal women at high risk for fracture, men receiving androgen deprivation therapy for nonmetastatic cancer of the prostate, and women with breast cancer at high risk for fracture receiving adjuvant aromatase inhibitor therapy. In clinical practice, denosumab offers an advantage over bisphosphonates in that it is not contraindicated when renal function is impaired and is conveniently administered twice yearly by injection assuring full absorption of the active medication. Denosumab has been used in patients with rheumatic disorders receiving glucocorticoids but does not have the specific indication for glucocorticoid-induced osteoporosis. Because of the potency of denosumab in suppressing bone turnover and the substantial amount of drug administered per dose, it is imperative that patients scheduled to receive the medication be treated with daily calcium (at least 1000 mg per day) and vitamin D supplements; 25 hydroxyvitamin D levels be checked prior to dosing and be sufficient. In addition, patients with renal dysfunction who have received the potent antiresorptive agent in small studies of short duration have demonstrated a greater tendency to hypocalcemia. Thus, calcium and vitamin D supplements remain a key component of therapy with denosumab.
Combination & Sequential Regimens
A small number of trials have combined approved agents for the treatment of osteoporosis, either together or in sequence. In general, these studies are smaller than the pivotal trials that established the efficacy of individual therapies in the treatment of osteoporosis and prevention of fractures. The combination of two antiresorptive therapies typically achieves a small additional increase in BMD beyond that attained with either agent alone. None of the combination or sequential studies has had fracture reduction as an end point, and therefore a clear role for these approaches to prevent fractures is not yet established. Furthermore, costs and adverse events are potentially additive. There has been the additional concern that excessive blockade of resorption (with two antiresorptive agents) might produce such marked suppression of turnover as to impair the ability of bone to repair microdamage and microfractures and to respond to the normal forces acting on the remodeling process.
There is theoretical appeal for sequential regimens that first use anabolic agents like teriparatide to promote bone formation and then use antiresorptive drugs to maintain the bone mass gained. In this regard, the Parathyroid Hormone and Alendronate Study in postmenopausal women, compared alendronate (10 mg/d) and full-length PTH (PTH [1-84], 100 mcg/d) individually or in combination. There was no evidence of synergy when the agents were used concurrently; indeed at 1 year, the concurrent use of alendronate appeared to diminish bone formation. The second year of the study, however, showed that the gains in BMD achieved with PTH (1-84) alone for 12 months were not maintained unless PTH (1-84) was followed by alendronate. Similar conclusions were reached in a study of men using PTH (1-34) and alendronate. It appears that potent antiresorptive agents such as alendronate tend to blunt the “anabolic” effects of PTH when used concurrently but can maintain PTH-induced increases in BMD when used in a sequential or cyclic regimen. Not all antiresorptives behave in the same way. Raloxifene or HT in combination with PTH (1-34) did not blunt the anabolic actions of PTH (1-34). Currently, there are insufficient data to establish the superiority of one combination or sequence over another for the prevention of fractures.