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Osteoporosis is characterized by a decrease in bone mass and a deterioration in skeletal microarchitecture, which lead to increased fragility and susceptibility to fractures.^[1] In treating established osteoporosis, the objective is to prevent further skeletal deterioration, and to increase bone mass and/or improve bone microarchitecture to reduce the risk of vertebral and/or peripheral fractures.^[2] One of the major determinants of skeletal weakness is bone loss that occurs after menopause. The bone loss is a consequence of an increased osteoclastic resorption that is only partially compensated by a moderate rise in the rate of bone formation by osteoblasts.^[3]

Estrogens^[4,5] calcitonin,^[6,7] and early-generation bisphosphonates^[8] were considered effective and well-tolerated agents for maintaining bone mineral density (BMD) of trabecular and cortical bone at premenopausal levels by counteracting the exacerbated activity of osteoclasts induced by the sharp postmenopausal decrease in circulating endogenous estrogens. However, primary prevention of osteoporosis initiated in the immediate postmenopause is not yet considered a public health priority by many, including specialists dealing with bone metabolic disorders, primary care physicians, and the general population.^[9] Subsequently, caregivers often face complicated situations with women seeking treatment for the first time at later stages of the disease, namely, after the diagnosis of osteoporosis has already been made on the basis of random radiographs, densitometry, measurements, or, even worse, a clinical fracture.

None of the available medications has unequivocally demonstrated its ability to fully prevent the occurrence of new vertebral or peripheral osteoporotic fractures once the disease is established. Furthermore, some of these agents are jeopardized by either potential severe toxicity^[10-12] or prohibitive cost,^[13] discouraging their widespread or prolonged use. Therefore, new medications are developed with the goal of meeting a better risk-to-benefit (efficacy vs tolerance) ratio in comparison with available medications.

This clinical update will focus on the new challenging drugs contributing to a better preventive and therapeutic approach to postmenopausal osteoporosis (selective estrogen receptor modulators [SERMs] and second- or third-generation bisphosphonates) and highlight some of the promising new agents in the treatment of osteoporosis (parathyroid peptides and strontium [Sr] ranelate [S12911]).

Over the past decade, this new family of compounds has emerged. SERMs are defined as compounds that produce estrogen agonism in 1 or more desired target tissues (eg, bone, liver) together with estrogen antagonism and/or minimal agonism (ie, clinically insignificant) in reproductive tissues, such as the breast or uterus.^[14] Raloxifene and its hydrochloride salt form are benzothiophene derivatives that were initially investigated as a treatment for advanced breast cancer.^[15,16] Raloxifene was also shown to inhibit the hypertrophy of the uterus in response to estrogens,^[17,18] to reduce serum cholesterol levels, and to increase BMD.^[19] In light of this unique pharmacologic profile, extensive investigations of raloxifene were promptly undertaken to evaluate its skeletal properties.

Characterization of Raloxifene: Preclinical Studies

On a molecular basis, raloxifene activates the gene encoding transforming growth factor beta (TGF beta3), which, together with other growth factors and cytokines, induces production of osteoblasts and inhibits the activity of osteoclasts and shortens their life span.^[20,21] In vitro, raloxifene and estrogen inhibit -- with similar potency and magnitude -- interleukin (IL)-6-induced differentiation and resorptive activity of mammalian osteoclasts.^[22] In the human-female-derived SaOS-2 osteoblast-like cell line, raloxifene dose dependently stimulated creatine kinase activity, a marker of cell division.^[20]

Beneficial estrogen agonist-like effects of raloxifene have been characterized extensively in ovariectomized (OVX) rats. As an in vivo correlate of in vitro experiments, raloxifene and estrogens produce parallel reductions of serum IL-6 levels in OVX rats to levels observed in sham controls.^[23] In the same model, oral administration of raloxifene (0.1-10.0 mg/kg per day) or oral ethinylestradiol (0.1 mg/kg per day) for 5 weeks induced similar effects -- namely, preservation of BMD in the distal femur and proximal tibia.^[17] Noteworthy in this experiment was the lack of significant estrogenic effect on uterine tissue in raloxifene-treated animals. The effects of ovariectomy on 6-month-old rats' spinal BMD, femoral moment of inertia, femoral dry weight and volume, and, to a lesser extent, femoral BMD were similarly inhibited in an indistinguishable fashion by 17-beta estradiol (100 mcg/kg per day, subcutaneously) and raloxifene hydrochloride (1 mg/kg per day, orally) with a half-maximally effective dose of raloxifene on L1-L4 BMD between 0.1 and 1.0 mg/kg per day.^[24]

When these animals were examined by peripheral computed tomography, the proximal tibia showed a 17% reduction in BMD 31 days after ovariectomy with a progressive increase in the cross-sectional area of the proximal tibiae, loss of cancellous bone, widening of marrow spaces, and thinning of the cortical bone wall opposite the fibula. Regression analysis of the dose-dependent protective effects of raloxifene showed half-maximal efficacy on the tibial BMD at 0.4 mg/kg per day. By comparison, 17alpha-ethinylestradiol showed dose-dependent effects with ED₅₀ = 0.013 mg/kg per day.^[25] After 6 months of oral administration, raloxifene and ethinylestradiol produced equivalent beneficial effects on the biomechanical properties of the vertebra (load to fracture) and the femoral neck (shear to failure) compared with OVX controls, with a significant correlation between vertebral strength and vertebral BMD.^[26]

Characterization of Raloxifene: Studies in Postmenopausal Women

In early postmenopausal women who were randomly assigned to raloxifene (60 mg/day), estrogen (0.625 mg/day conjugated equine estrogens plus 5 mg medroxyprogesterone/day for the first 2 weeks of each month), or no treatment, both raloxifene and estrogen produced a significant positive calcium balance shift, assessed by using calcium tracer kinetic methods, for up to 31 weeks of therapy. At this time point, resorption was reduced by both agents, although to a greater extent with estrogens; formation was reduced by estrogens but not by raloxifene, so that the general pattern of bone remodeling was similarly affected by the 2 agents.^[27] In healthy postmenopausal women, an 8-week regimen of raloxifene hydrochloride (200-600 mg/day) and conjugated equine estrogens (0.625 mg/day) decreased to a similar extent biochemical markers of bone remodeling, ie, serum alkaline phosphatase (range, 10% to 11%), serum osteocalcin (range, 21% to 26%), urinary pyridinoline cross-links (range, 20% to 26%), and urinary calcium excretion (range, 45% to 72%).^[28]

This estrogen agonist-like effect of raloxifene on bone turnover translated into significant increases in BMD of the lumbar spine, hip, and total body when a group of postmenopausal women aged 45-60 years and within 2-8 years of menopause, with T-scores for BMD of the lumbar spine between -2.5 and +2.0, were randomized for 24 months to receive placebo or 30, 60, or 150 mg/day of raloxifene for 24 months. At 24 months, the mean (with standard deviation) difference in the change in BMD between the women receiving 60 mg raloxifene and those receiving placebo was 2.4% (0.4%) for the lumbar spine, 2.4% (0.4%) for the total hip, and 2.0% (0.4%) for the total body. A subgroup analysis demonstrated that during therapy, the increases in BMD in lumbar spine and hip were similar regardless of the initial BMD, level of bone turnover (as assessed by baseline biochemical determinations), age, body mass index, and history of estrogen or thiazide therapy.^[29]

Raloxifene (60 or 120 mg/day) was also administered to postmenopausal women with at least 1 prevalent vertebral fracture and compared in a 2-year, double-blind, placebo-controlled, prospective, randomized study to a control group receiving 750 mg of calcium and 400 IU vitamin D daily. With raloxifene (60 mg/day), biochemical markers of bone remodeling were significantly decreased -- serum bone-specific alkaline phosphatase [-24% (6%)], osteocalcin [-36% (6%)], and urinary C-telopeptide fragment of type I collagen/creatinine [-36% (8%)], and there was a nonsignificant trend of an increase over controls in BMD for lumbar spine, total body, and total hip.^[30] Similar results for biochemical markers of bone resorption and BMD were obtained in studies involving European^[31] and Asian^[32] populations.

The Multiple Outcomes of Raloxifene Evaluation (MORE) Trial

The MORE trial was a randomized, placebo-controlled study of raloxifene 60 or 120 mg/day vs placebo (all women received calcium 500 mg and vitamin D 400 IU/day) involving 7705 women who were at least 2 years postmenopause.^[33] This study was conducted at multiple centers throughout 25 countries. The primary end point of MORE was the determination of the percentage of women taking raloxifene who had at least 1 new vertebral fracture, as compared with the control group. Secondary end points were the relative risk (RR) of nonvertebral fractures, breast cancer, and cardiovascular events.

All women enrolled met the World Health Organization (WHO) criteria for osteoporosis (T-score </= -2.5). Approximately one third had prevalent vertebral fractures. The average age was 65 years in patients without prevalent fractures and 69 years in those with prevalent fractures, with body mass indices of 25 and 26, respectively.

Evaluable radiographs were available for 6828 women. A central laboratory assessed vertebral fractures in the spinal radiographs. This procedure was carried out by radiologists blinded to treatment group assignment but not to the temporal sequence of the radiograph. Women were grouped according to the presence or absence of an adjudicated vertebral fracture at baseline. An adjudicated fracture was confirmed by at least 2 of 3 determinations, consisting of 2 independent semiquantitative (SQ) assessments and 1 quantitative morphometric (QM) measurement. Normal vertebrae (grade 0) had minimal deformity, with < 20% reduction in the anterior, middle, and posterior vertebral height. Mild vertebral deformities (grade 1) corresponded to a 20% to 25% reduction in vertebral height. Moderate (grade 2) and severe (grade 3) vertebral fractures had decreases in vertebral height of 25% to 40% and > 40%, respectively. Vertebral fractures were also identified using QM criteria, consisting of a decrease in anterior, middle, and posterior vertebral height of >/= 20% and >/= 4 mm.

In clinical trials of osteoporosis therapies, the standard method used to define incident vertebral fractures from radiographs consists of a combination of SQ and QM assessment criteria.^[34] Incident vertebral fractures were described as new fractures in vertebrae that were not fractured at baseline.

At 36 months, of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/day of raloxifene, and 5.4% of those receiving 120 mg/day of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60 mg/day group: RR = 0.7; 95% confidence interval [CI] = 0.5-0.8; for 120 mg/day group: RR = 0.5; 95% CI = 0.4-0.7). Frequency of vertebral fracture was reduced in women who did not have prevalent fracture. In women with prevalent vertebral fractures who received 60 mg/day of raloxifene, the relative risk of new vertebral fracture was 0.7 (95% CI = 0.6-0.9); it was 0.5 (95% CI = 0.4-0.8) in those with low BMD but no prevalent vertebral fractures at inclusion. Compared with placebo, the 60-mg/day and 120-mg/day dosages of raloxifene increased BMD in the femoral neck by 2.1% and 2.4%, respectively, and in the spine by 2.6% and 2.7%, respectively (P < .001 for all comparisons).

At 1 year, raloxifene 60 mg/day decreased the risk for new clinical vertebral fractures by 68% (95% CI = 20% to 87%) compared with placebo in the overall study population and by 66% (95% CI = 23% to 89%) in women with prevalent vertebral fractures, who are at greater risk for subsequent fracture. The risk for clinical vertebral fractures in the raloxifene 60-mg/day group was decreased by 46% (95% CI = 14% to 66%) at 2 years and by 41% (95% CI = 17% to 59%) at 3 years. The cumulative incidence of new clinical vertebral fractures was lower in the group receiving raloxifene 60 mg/day compared with placebo (P < .001).^[34]

In the overall cohort, the risk of nonvertebral fractures for raloxifene (60 mg/day and 120 mg/day) vs placebo did not differ significantly (RR = 0.9, 95% CI = 0.8-1.1).^[35] However, when assessing separately women whose fracture severity grades, at baseline, corresponded to an estimated decrease in vertebral height of > 40% (grade 3), raloxifene 60 mg/day significantly decreased the risk of new vertebral fracture (RR = 0.73, 95% CI = 0.54-0.99) and nonvertebral fracture (RR = 0.53, 95% CI = 0.29-0.99) at 3 years.

Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (RR = 0.24, 95% CI = 0.13-0.44; P < .001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (RR = 0.10, 95% CI = 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR = 0.88, 95% CI = 0.26-3.0).^[36]

An additional annual mammogram, at 4 years, reflected 3004 additional patient-years of follow-up. At this follow-up, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (RR = 0.28, 95% CI = 0.17-0.46). These data indicate that 93 osteoporotic older postmenopausal women would need to be treated with raloxifene for 4 years to prevent 1 case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR = 0.16, 95% CI = 0.09-0.30).^[37]

Raloxifene also significantly reduced the risk of cardiovascular events in a subset of women with increased cardiovascular risk (determined by the presence of multiple cardiovascular risk factors or prior coronary events or revascularization procedure). In the overall cohort, there were no significant differences between treatment groups in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/day of raloxifene, and 94 (3.7%) with 120 mg/day of raloxifene. RRs were 0.86 (95% CI = 0.64-1.15) and 0.98 (95% CI = 0.74-1.30) for 60 mg/day and 120 mg/day of raloxifene, respectively. Similar results were obtained when coronary and cerebrovascular events were analyzed separately.

Among the subset of 1035 women with increased cardiovascular risk at baseline, however, those assigned to raloxifene had a significantly lower risk of cardiovascular events compared with placebo (RR = 0.60, 95% CI = 0.38-0.95). The number of cardiovascular events during the first year was not significantly different across groups in the overall cohort (P = .94) or among women at increased cardiovascular risk (P = .86) or with evidence of established coronary heart disease (P = .60).^[38] Hot flashes were the most common nonserious adverse event, prompting withdrawal in 0.1%, 0.7%, and 0.5% of the women in the placebo, raloxifene 60 mg, and raloxifene 120 mg groups, respectively. Leg cramps were also reported more frequently in the women given raloxifene (7.0% in the 60 mg and 6.9% in the 120 mg groups) than in the placebo group (3.7%).

After 3 years, raloxifene increased the risk of venous thromboembolic disease (RR = 3.1, 95% CI = 1.5-6.2) but did not increase the risk of endometrial cancer (RR = 0.8, 95% CI = 0.2-2.7).^[36]

From a cost-utility analysis of a Swedish database, it appears that raloxifene can be targeted cost-effectively to postmenopausal women with osteopenia with a risk for hip fracture (relative risk 2.6) and to women aged 65 or older or at high risk (relative risk 3.0) for hip fracture.^[39]

Etidronate

In the mid-1980s, etidronate could have been considered an interesting tool for the management of osteoporosis; it is now an obsolete compound because of its inferior antiresorption efficacy and low potential for inducing mineralization disorders compared with newer molecules under study.

Alendronate

Dose-dependent effects of alendronate in reducing bone turnover and increasing spinal bone mass were reported in postmenopausal women with low BMD. In this population, the 10-mg/day dose, suggested to correspond to the best risk/benefit ratio for treatment of osteoporosis, induced significant increases in BMD after 2 years^[40] and 3 years.^[41] In the 2-year study, mean increases in BMD with alendronate 10 mg/day were 7.21% at the spine, 5.27% for total hip, and 2.53% for total body, whereas biochemical markers of bone remodeling declined by about 50% after 3 months for bone resorption markers and by 6 months for bone formation markers.^[40]

The 3-year study showed similar results, with increases of 7.2%, 5.5%, and 2.4% for lumbar spine, femoral neck, and trochanter BMD, respectively.^[41] The results obtained from 2 studies, in which 3 doses of alendronate were given for 3 years (5 mg/day, 10 mg/day, and 20 mg/day for 2 years, followed by 5 mg/day for 1 year) to women with low BMD (including a 20% subset with prevalent fractures), were pooled.^[42] Compared with the placebo group, a significant reduction in the proportion of female patients with new vertebral fractures (3.2% vs 6.2%; P = .03) and a decrease in progression of vertebral deformities (33% vs 41%; P = .028) were observed.

However, the cornerstone of the development of alendronate for osteoporosis was the Fracture Intervention Trial (FIT), a 3-year randomized, controlled trial investigating the effects of alendronate on the risk of fractures in 2027 women with prevalent vertebral fractures^[43] and in 4432 women with low femoral BMD but no prevalent fractures.^[44] The dose of alendronate (initially 5 mg daily) was increased to 10 mg daily at 24 months. In the fracture arm of the study, 8% of women in the alendronate group had 1 or more new morphometric vertebral fractures compared with 15% in the placebo group (RR = 0.53, 95% CI = 0.41-0.68). For clinically apparent vertebral fractures, the relative hazard was 0.45 (95% CI = 0.27-0.72). In this arm of the study, a significant reduction in the risk of any clinical fracture (RR = 0.72, 95% CI = 0.58-0.90), hip fracture (RR = 0.49, 95% CI = 0.23-0.99), and wrist fracture (RR 0.49, 95% CI 0.23-0.99) was also reported for alendronate users.^[43]

In the patients without prevalent spinal fractures, who were treated for a mean duration of 4.2 years, alendronate increased BMD at all sites but did not reduce significantly the incidence of clinical fractures (RR = 0.86, 95% CI = 0.73-1.01) in the whole population. However, alendronate significantly decreased the risk of radiographic vertebral fractures by 44% overall (RR = 0.56, 95% CI = 0.39-0.80) and the risk of clinical fractures by 36% (RR = 0.64, 95% CI = 0.50-0.82) in women with baseline osteoporosis at the femoral neck.^[44] When analyzing the results of the FIT study of alendronate administration for 3-4 years in 3658 women with osteoporosis (with existing vertebral fractures or BMD in the osteoporotic range), the estimate of the effect of alendronate on RR of fracture was 0.47 (95% CI = 0.26-0.79) for the hip, 0.52 (95% CI = 0.42-0.66) for radiographic vertebral, 0.55 (95% CI = 0.36-0.82) for clinical vertebral, and 0.70 (95% CI = 0.59-0.82) for all clinical fractures.^[45]

Increases in spinal BMD with alendronate continued for up to 7 years (0.8% per year after the initial 18 months with the 10-mg/day dose), whereas other skeletal benefits (ie, increases in BMD at other skeletal sites and decreases in biochemical markers) remained stable during the same period.^[46] Reduction of fracture risk with alendronate was also shown to be consistent within fracture risk categories, with more fractures being prevented by treating women at highest risk due to advanced age or severe osteoporosis.^[47] Interestingly, individual response to alendronate can be monitored through BMD measurements. Women from the FIT study with increases of more than 3% in total hip BMD during the first year of treatment had the lowest incidence of new vertebral fractures after 3 years of treatment (odds ratio [OR] = 0.45, 95% CI = 0.27-0.72).^[48]

Esophageal erosion and ulcerative esophagitis were reported in association with the use of oral alendronate.^[49] However, particular recommendations for alendronate intake (swallowing alendronate with 180-240 mL water on arising in the morning, and remaining upright for at least 30 minutes after swallowing the tablet and until the first food of the day has been ingested) reduce the risk of esophagitis.

Dose-ranging studies suggest that the potential for esophageal irritation, observed with daily oral bisphosphonates, may also be substantially reduced with less frequent dosing. Furthermore, less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Therefore, a once-weekly (70-mg) formulation of alendronate was developed, which fully satisfied equivalence criteria (lumbar spine, hip or total body BMD, and rate of bone turnover assessed by biochemical markers) relative to daily therapy.^[50]

Risedronate

Risedronate is a pyridinyl bisphosphonate with high antiosteoclastic potency because of a nitrogen atom in its cyclic structure. In women with a mean lumbar spine T-score of </= -2, risedronate (5 mg/day) has been shown to increase BMD after 24 months, by 4% at the lumbar spine, 1.3% at the femoral neck, and 2.7% at the femoral trochanter. All these changes were significantly different from the evolution observed in the placebo group.^[51] The evidence for an antifracture efficacy of risedronate came from 3 randomized controlled clinical trials. In 2458 postmenopausal women who had at least 1 prevalent vertebral fracture, treatment with 5 mg/day of risedronate, compared with placebo, decreased the cumulative incidence of new vertebral fractures by 41% (RR = 0.59, 95% CI = 0.43-0.82) over 3 years.^[52]

In another study, 1226 postmenopausal women with 2 or more prevalent vertebral fractures were also exposed to the same protocol (risedronate 5 mg/day vs placebo) for 3 years. In this cohort, risedronate reduced the risk of new vertebral fractures by 49% (RR = 0.51, 95% CI = 0.36-0.73) after 3 years.^[53] In both studies, a reduction in the incidence of new vertebral fractures was seen after the first year of treatment, but further administration of risedronate during the second and third years did not provide significant additional benefit in terms of fracture reduction. The effects of risedronate on the risk of new nonvertebral fractures were significant, after 3 years, in the less severe osteoporotic population (RR = 0.6, 95% CI = 0.39-0.94)^[52] but not in the most severely affected women (RR = 0.67, 95% CI = 0.44-1.04).^[53]

In a cohort of 9331 women older than 70 years, the incidence of hip fracture among all women assigned to risedronate was significantly reduced compared with that of women assigned to placebo (RR = 0.7, 95% CI = 0.6-0.9). However, this effect was manifest only in women aged 70-79 years who had vertebral fractures at baseline (n = 1703) (RR = 0.4, 95% CI = 0.2-0.8); whereas no significant effect was observed in women aged 70-79 years with low BMD but no prevalent spinal fractures (RR = 0.6, 95% CI = 0.3-1.2) or in women over 80 years of age with at least 1 clinical risk factor for hip fracture (RR = 0.8, 95% CI = 0.6-1.2).^[54]

The risk for clinically important gastric irritation with risedronate was reported to be similar to that associated with alendronate and, in any case, very low even at the highest available doses.^[55] However, a statistical review by the author indicated that the prolonged use of risedronate in women with established osteoporosis has been linked with a statistically significant increase in the occurrence of pulmonary cancer (3.9/1000 patient-years of exposure and 1.9/1000 patient-years of exposure for 2.5 and 5 mg/day, respectively, compared with 1.2/1000 patient-years of exposure with placebo, based on the results of 10 phase 3 studies involving approximately 30000 patient-years of exposure).^[56] The European and American Regulatory authorities, following the opinion of an expert panel, concluded that a causal association between risedronate use and lung cancer was highly improbable. Other published studies have not to date found such a relationship; a retrospective cohort mortality study of 7981 patients comprising the intent-to-treat population in 3 North American risedronate osteoporosis trials conducted by the risedronate manufacturer found no differences in all-cause mortality and no differences in mortality due to all cancers, lung cancer, or gastrointestinal tract cancer in patients receiving risedronate treatment compared with patients receiving placebo.^[57] However, it is the author's opinion that these figures should be appropriately taken into account when evaluating the overall risk/benefit ratio of this bisphosphonate, particularly when other bisphosphonates do not show this statistically significant increase in lung cancer. (Editor's note: Please note that text in italics was added April 24, 2003 for clarification)

New Bisphosphonates: Ibandronate and Zoledronate

[1-hydroxy-3-(methylpentylamino) propylidene] bisphosphonate (ibandronate) and [1-hydroxy-2-(1H imidazole-1-yl) ethylidene] bisphosphonate (zoledronate) are interesting new compounds, currently in phase 3 development for the treatment of postmenopausal osteoporosis.

Ibandronate. Oral ibandronate was compared with placebo in 2946 women who had BMD T-score < -2.0 in at least 1 lumbar vertebra and 1 to 4 prevalent vertebral fractures. Two dosage regimens of ibandronate, either given daily (2.5 mg) or on alternate days for 12 doses every 3 months (20 mg), for 3 years, were investigated. Daily and intermittent oral ibandronate significantly reduced the risk of radiologically confirmed vertebral fractures by 62% and 50%, respectively, compared with placebo and showed a sustained effect over the trial period.

This study demonstrates for the first time significant fracture efficacy for intermittent bisphosphonate treatment with a dose-free interval of more than 2 months. Significant reductions in clinical vertebral fractures were also shown in the 2 treatment groups.^[58] In a subgroup of women from this trial whose BMD T-score of the femoral neck was < 3 standard deviations at baseline, daily and intermittent oral ibandronate administration reduced the incidence of clinical fracture by 66% and 50%, respectively, and nonvertebral fractures by 69% and 37%, respectively.^[59] These results confirm previous preclinical findings indicating that the efficacy of ibandronate is a function of the relationship between loaded dose and the dosing frequency.^[60] This obviously supports development of new flexible dosing regimens targeted to minimize the frequency of dosing, which are expected to improve convenience and lead to enhanced long-term patient compliance.

Oral once-weekly ibandronate (20 mg) and daily administration of ibandronate (2.5 mg) induced almost identical increases in lumbar spine BMD after 48 weeks, and the once-weekly regimen was proven to be statisticially noninferior to daily administered oral ibandronate. Three-monthly (2 mg) intravenous ibandronate bolus injections were related to even larger increases of lumbar spine BMD after 1 year (5%). Significant benefits were also reported at the femoral neck or at the trochanter.^[61]

Zoledronate. In a similar prospective study^[62] assessing the effects of the dose and dosing interval on changes in therapeutic effects of bisphosphonates, zoledronate was evaluated in a 1-year randomized controlled trial of 351 postmenopausal women with low BMD. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at 3-month intervals. In addition, 1 group received a total annual dose of 4 mg as a single dose, and another received 2 doses of 2 mg each, 6 months apart.

Similar increases in BMD were recorded in all the zoledronic acid groups to values for the spine that were 4.3% to 5.1% higher than those in the placebo group and values for the femoral neck that were 3.1% to 3.5% higher than those in the placebo group,^[62] suggesting that an annual infusion of zoledronate might be an effective treatment for postmenopausal osteoporosis.

Strontium (Sr) is a trace element that is distributed throughout the geosphere and biosphere. Terrestrial animals and humans consume varying amounts of Sr, depending on their source of food and water, leading to the presence of small physiologic amounts of Sr in soft tissues, blood, and bones. The first elaborate investigation of the effects of stable (nonradioactive) Sr on bone was conducted by Lehnerdt in 1910 showing that stable Sr greatly stimulates the formation of osteoid tissue and tends to repress the resorptive process in bones. Further studies were performed in animals kept on a low-calcium diet: they received either very high doses of Sr (leading to so-called Sr rickets) or radioactive Sr. However, some of the conclusions drawn from these studies were not directly applicable to the administration of stable Sr under normal feeding conditions. It was only in the 1980s that studies using low doses of stable Sr in animals kept on a standard-calcium diet were performed, demonstrating the potential interest of Sr in the treatment of osteoporosis.^[63]

In Vitro Studies

Strontium ranelate is composed of an organic moiety (ranelic acid) and 2 atoms of stable nonradioactive Sr. In vitro, Sr ranelate (10^-3 M) increased DNA synthesis by 3- to 4-fold in rat cell populations enriched with fibroblast and pre-osteoblastic cells. Sr ranelate (10^-3 M) also increased collagen and noncollagenic protein synthesis by 34% in mature osteoblast enriched cells. The effects of Sr ranelate (10^-3 M) on bone formation were evaluated in calvariae cultures using autoradiography and histomorphometry, which confirmed that the compound enhances pre-osteoblastic cell replication. A subsequent increase in the bone formation rate was observed up to 48 hours after the cessation of treatment. These effects seemed to be specific to Sr ranelate, because neither calcium ranelate nor sodium ranelate, at the same concentration, was able to induce similar effects.

In the mouse calvaria culture system, Sr ranelate induced a dose-dependent inhibition of ⁴⁵Ca release. This inhibition reached 28% at the highest concentration tested.^[63] The same experiment was repeated with calvariae previously heated in order to kill the cells. Sr ranelate had no effect on ⁴⁵Ca release from heated calvariae, indicating that the inhibitory effects of Sr ranelate on bone resorption were cell mediated.^[63] Calcium ranelate and sodium ranelate did not have any inhibitory effects in vitro on bone resorption in mouse long bone cultures treated with or without vitamin D₃. By contrast, Sr ranelate markedly inhibited the ⁴⁵Ca release from prelabeled bone both in the control culture and in the culture with vitamin D_3. The inhibitory effects of Sr ranelate were close to those of salmon calcitonin in this model.

In the isolated rat osteoclast assay, preincubation of bone slices with Sr ranelate at concentrations >/= 10^-4 M induced a dose-dependent inhibition of the bone-resorbing activity of untreated rat osteoclasts.^[64] The effect of Sr ranelate on osteoclast differentiation was assessed on the 1.25(OH)₂ vitamin D₃-induced expression of osteoclast markers in chicken bone marrow cultures.^[64] In this model, in which 1.25(OH)₂ vitamin D³ induces a 6- to 7-fold increase in the expression of the osteoclast markers carbonic anhydrase II (CAII) and vitronectin receptor (VNR), Sr ranelate dose-dependently inhibited the responses to 1,25(OH)₂ vitamin D₃. The expression of both CAII and the alpha_v subunit of the VNR were reduced by 40% to 45%, at 10^-3 M with the first significant effects being detected at 10^-4 M (30%).

Thus, on the basis of in vitro results, Sr ranelate appears to have a particular profile characterized by an inhibition of bone resorption and a stimulation of bone formation. Targeting this mechanism of action -- uncoupling the bone remodeling process -- presents a novel means to treat osteoporosis. Sr ranelate is the first agent with this potential to be investigated.

Animal Studies

In normal-growing 21-day-old rats, Sr ranelate was given at dose levels of 0, 154, and 411 mg.kg^-1.d^-1 for 8 weeks.^[65] Sr ranelate dose-dependently increased femoral bone mineral content (BMC) of the treated animals (11% at the 411 mg.kg^-1.d^-1 dose level). The increase in BMC was associated with a dose-dependent increase in trabecular bone volume of the tibial metaphysis. This was linked to an increase in trabecular number and an unchanged trabecular thickness. Subsequently, the trabecular separation decreased in treated animals. Bone resorption was slightly decreased in the metaphysis of treated animals, as eroded surface of metaphysis, osteoclast surface, and osteoclast number were reduced by 17%, 19%, and 18%, respectively, in the high-dose group. Sr ranelate did not modify the eroded surface of the tibial epiphysis.

A dramatic increase in bone-formation parameters was found both in the metaphysis and epiphysis of the treated animals. This increase reached +370% and +300% for osteoid volume in the metaphysis and epiphysis, respectively, and for the osteoid surface bone formation increased +400% and +160%, respectively. Osteoid thickness was only slightly modified at both sites of evaluation, and the mineral apposition rate was not affected by Sr ranelate administration, suggesting that Sr ranelate did not induce any mineralization defect.^[65]

In order to assess the effects of long-term exposure to Sr ranelate on bone biomechanics, long-term oral administration of 625 mg.kg^-1.d^-1 was performed over 104 weeks in male and female rats.^[66,67] At the midshaft humerus in treated females, Sr ranelate induced a borderline significant improvement in the ultimate strength (+13.5 %) without any modification in stiffness. A significant increase in energy was observed in the same animals. This improvement in bone biomechanics was associated with a significant increase in the midshaft outer diameter, suggesting that the improved bone strength could be due to an increase in periosteal apposition. Ultimate strength and energy were significantly correlated to bone diameter. No significant changes were found at the midshaft humerus level in treated males.

At the vertebral level in both sexes, Sr ranelate induced an increase in the maximal load (F: +14%, M: +18%) associated with a commensurate increase in energy (F: +30%, M: +39%). The stiffness of the lumbar vertebrae was not modified by Sr ranelate treatment. This improvement in vertebrae resistance was linked to an increase in vertebral volume. The bone mechanical properties of the vertebrae and humerus of treated animals were correlated with the values of BMC and BMD, suggesting that the increase in bone mass is related to an increase in bone strength. Femoral neck biomechanical properties were not affected by the treatment.^[66,67]

The effects of stable Sr were investigated in OVX rats by calcium balance and calcium kinetic studies, histomorphometric analysis, and measurements of calcium levels in bone.^[68] OVX rats were classified into 2 subgroups: those that were treated with Sr for 2 weeks and those that were not. Both groups were pair-fed with the sham control group. In the OVX group, urinary calcium and percent bone formation in the diaphyseal femora cortex decreased, whereas bone resorption, bone formation, and femoral length increased at the end of the experiment, as compared with those in the sham group. No such changes were observed in rats in the OVX + Sr group. The calcium balance, calcium levels in bone, and trabecular bone volume in the metaphysis did not change in any of the 3 groups. These results suggest that Sr is able to prevent the changes in bone turnover induced by estrogen deficiency.^[68]

In another study, female rats were sham operated or OVX and then treated orally with Sr ranelate or injected subcutaneously with 17 beta-estradiol for 60 days.^[69] In untreated animals, ovariectomy induced a significant bone loss associated with high bone turnover (increased bone resorption + increased bone formation). In OVX rats, Sr ranelate administration induced a significant increase in the femoral BMC associated with an increase in bone ash weight. No clear dose-dependent effects could be seen, presumably because of the narrow range of dose levels used in this study. Sr ranelate partially prevented trabecular bone loss and totally prevented the OVX-induced decrease in BMC. Bone volume was 30% to 36% higher in Sr ranelate-treated OVX rats than in untreated OVX rats. Estradiol treatment failed to totally prevent the ovariectomy-induced decrease in BMC while almost completely correcting trabecular bone volume.

Estradiol treatment also induced a normalization of the histomorphometric indices of bone resorption and bone formation. In Sr ranelate-treated rats, the histologic indices of bone resorption were reduced by 13% to 24% compared with untreated OVX rats and were not different from those of sham-operated animals or estradiol-treated animals. Both osteoclast surface and osteoclast number were reduced in Sr ranelate-treated animals, suggesting an effect on osteoclast recruitment.

As expected, estradiol treatment abolished the increased bone formation induced by ovariectomy. By contrast, Sr ranelate had no dampening effect on bone formation. The osteoid surface and osteoblast surface, the mineral apposition rate, and the bone formation rate in Sr ranelate-treated rats were as high as in untreated OVX rats.

Clinical Trials

Sr ranelate was administered to 160 postmenopausal women in a 24-month double-blind, placebo-controlled, prospective, randomized study.^[70] Daily oral doses of 125 mg, 500 mg, or 1 g of Sr ranelate were compared with placebo. All patients received 500 mg of elemental calcium daily. The main characteristics of the study population were as follows: age 54 years; duration of menopause 3 years, mean lumbar BMD (as measured by DXA) 0.931 g/cm².

At the conclusion of the study, the percent variation of lumbar-adjusted BMD from baseline was significantly different in the group receiving 1 g/day of Sr as compared with placebo: +1.41% vs -0.98%, respectively [95% CI = 0.010-4.776]. Increase in total hip and neck measured BMD averaged 3.2% and 2.5%, respectively.

The overall percentage of study withdrawals because of adverse reactions was 15% in the placebo group and 11% in Sr ranelate-treated patients. At the level of specific body systems, the percentages of adverse reactions for placebo and Sr ranelate groups are shown in the Table.^[70] In conclusion, while significantly increasing BMD of the spine and femur in early postmenopausal women, over 24 months, compared with placebo, 1 g/day of oral Sr ranelate did not induce any significant adverse reactions, as determined by comparison of events in the treatment and placebo groups.^[70]

Table. Adverse Reactions to Sr ranelate vs Placebo

Adverse Effect	Sr ranelate	Placebo
Gastrointestinal	13.3%	10%
Central nervous system	1.6%	0%
Metabolic	0.8%	2.5%
Vascular extracardiac	0.8%	2.5%
Cardiovascular	0.8%	0%
Pulmonary	0%	2.5%
Liver and biliary	0%	2.5%
Psychiatric	0.5%	0%

The effects of Sr ranelate in postmenopausal women with vertebral osteoporotic fractures were assessed during a double-blind, placebo-controlled trial.^[71] Either Sr ranelate (500 mg, 1 g, or 2 g/day) or placebo was given to 353 Caucasian women (age: 66 years; lumbar BMD by DXA, 0.699 g/cm²). All patients were also given a daily supplement of calcium (500 mg) and vitamin D2 (800 IU). At the conclusion of this 2-year study, the lumbar BMD values were: +1.2% for the placebo and +3.1%, +3.2%, and +5.5% for the groups receiving 500 mg, 1 g, and 2 g Sr ranelate, respectively. The annual increase in lumbar-adjusted BMD of the group receiving 2 g of Sr ranelate was +2.97%. This result was significantly different from that seen with placebo.

A significant decrease in N-terminal telopeptide of cross-linked type 1 collagen (NTX) and an increase in bone-specific alkaline phosphatase were evident after 3 and 6 months of treatment, respectively, in the group receiving 2 g of Sr ranelate. During the second year of treatment, the dose of 2 g was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralization defects. The same percentage of withdrawals following an adverse effect (10%) was observed for patients receiving placebo and for those receiving 2 g of Sr ranelate.^[71]

Further analysis of this trial investigated Sr interactions with bone mineral. Transiliac bone biopsies were quantified by x-ray microanalysis for Sr ranelate uptake and distribution in bone mineral. Changes in the mean and distribution of the degrees of mineralization of bone (MDMB) were measured by quantitative microradiography. Only traces of Sr were found in bone from women having received a placebo. In Sr ranelate-treated women, Sr ranelate was dose-dependently deposited into compact and cancellous bone, with significantly higher contents in new bone than in old bone. The uptake of Sr ranelate in new bone was also dose dependent. Although new bone was always rich in Sr ranelate, old bone did not contain Sr ranelate at doses of 0.5 and 1 g/day, and only small amounts of Sr ranelate were detected after treatment with 2 g/day. MDMB was not significantly different in Sr ranelate and placebo groups at either compact or cancellous bone levels. However, MDMB tended to increase at 0.5 g/day and to progressively decrease to placebo value at 1 and 2 g/day.^[72]

Sr ranelate is being investigated in a large phase 3 program initiated in 1996 that includes 2 extensive clinical trials for the treatment of severe osteoporosis. The Spinal Osteoporosis Therapeutic Intervention (SOTI) trial will assess the effect of Sr ranelate on the risk of vertebral fractures. The Treatment Of Peripheral Osteoporosis study (TROPOS) will evaluate the effect of Sr ranelate on peripheral (nonspinal) fractures.

All patients included in these 2 studies had previously participated in a normalization of calcium and vitamin D study called Fracture International Run-in Sr Trials (FIRST). The patients received a calcium/vitamin D supplement throughout the studies, which were individually adapted according to their deficiencies (500 or 1000 mg of calcium, and 400 or 800 IU of vitamin D₃). Both studies are multinational, randomized, double-blind, and placebo-controlled with 2 parallel groups (2 g/day Sr ranelate vs placebo) involving 75 clinical centers in 12 countries in Europe and Australia. The study duration is 5 years, with main statistical analysis planned after 3 years of follow-up.

From more than 9000 osteoporotic postmenopausal women having taken part in FIRST, 1649 patients were included in SOTI with a mean age of 70 years, and 5091 patients were included in TROPOS with a mean age of 77.^[73]

The primary analysis of the SOTI study evaluated the effect of 2 g of Sr ranelate on vertebral fracture rates. Throughout the 3-year study, treatment with Sr ranelate reduced the relative risk of experiencing a first new vertebral fracture (semiquantitative assessment) by 41% as compared with placebo: In the Sr ranelate group, 139 patients sustained a new vertebral fracture vs 222 in the placebo group (RR = 0.59, 95% CI = 0.48-0.73, P < .001) in the intent-to-treat population.

These results have also been confirmed when combining both diagnostic methods (semiquantitative + quantitative) for incident vertebral fracture. Bone-specific alkaline phosphatase increased, whereas serum cross-linked C terminal telopeptides of type 1 collagen (CTX) decreased. The lumbar BMD increased in the treated group when compared with the placebo group (+11.4% vs -1.3% respectively, P < .001). Sr ranelate was well tolerated without any specific adverse event, and no deleterious effects were observed on rates of nonvertebral fractures.^[74]

The primary analysis of the TROPOS Study, evaluating the effect of 2 g/day of Sr ranelate on nonvertebral fracture, showed significant (P = .05) reduction in relative risk of experiencing a first nonvertebral fracture in the group treated with Sr ranelate (RR = 0.84; 95% CI = 0.71-1.00) throughout the 3-year study compared with placebo, in the intent-to-treat population. A 41% (P = .0025) reduction in the relative risk of experiencing hip fracture was demonstrated in the population having had at least a minimal exposure to Sr ranelate for 18 months. The authors proposed that Sr ranelate is a new effective and safe treatment of vertebral and nonvertebral osteoporosis, with a unique mechanism of action.^[75]

Human PTH is the final product of a synthesis that includes 2 precursor molecules. A full-length precursor, called preproPTH, is synthesized by the ribosomes of the parathyroid chief cells, which is subsequently cleaved by a peptidase located on the inner surface of the endoplasmic reticulum. From the product of this cleavage, called proPTH, the amino-terminal "pro" sequence is removed in the Golgi apparatus, producing the mature PTH. This polypeptide hormone is comprised of 84 residues and is released in response to a decrease in the level of extracellular calcium.^[76] The role of PTH in the human is mainly to modulate the physiologic function of bone and kidney in order to restore mineral ion homeostasis.^[77,78] In vivo, the skeletal action of PTH is mainly to stimulate release of calcium from the bones by stimulating osteoclastic bone resorption.^[79] The activity of PTH on mature osteoclasts is mediated by the osteoblasts through direct cellular contact and/or local humoral mechanisms,^[80] and the hormone appears to increase the number of osteoclasts, by promoting the differentiation and/or fusion of the precursors.^[76,78] PTH also exerts a direct inhibitory effect on osteoblasts.^[81]

In primary hyperparathyroidism, an endocrine disease characterized by a sustained increase in PTH secretion, a decrease in BMD was consistently reported in areas of predominantly cortical bone whereas the cancellous bone was relatively well preserved in mild to moderate stages of the disease.^[82] However, it is important to note that in primary hyperparathyroidism, the physiologic pulsatile patterns of PTH secretion with its diurnal variations are lost. Furthermore, measurements of formation and resorption surfaces by microradiographs led to the conclusion that in hyperparathyroidism, both forming and resorbing surfaces increased.^[83] Paradoxically, reports were made several decades ago that PTH could also be viewed as an anabolic substance able to increase BMD.^[84,85]

In fact, the effects of PTH on bone formation seem to be more difficult to fully elucidate than the well-known stimulating action on bone resorption, because PTH exhibits both stimulating and inhibiting effects on the formation phase of the remodeling cycle. Perhaps the most important step in the understanding of this process was the demonstration that continuous exposure to raised PTH levels results in an inhibition of bone formation, whereas intermittent administration of the hormone stimulates bone formation.^[84,86,87] Continuous exposure of calvarial bone cells to PTH in vitro results in a dose-dependent (1 pM to 10 nM) inhibition of collagen synthesis through a direct action of PTH on osteoblasts, whereas noncollagenous proteins are not affected.^[87,88] By contrast, intermittent PTH (0.1-10 nM) directly stimulates production of type I collagen and noncollagen proteins by osteoblasts in the same cell culture system.^[88]

These effects of PTH on osteoblasts are likely to be mediated by local production of insulin-like growth factor 1 (IGF-1).^[87] PTH concentrations of 0.1-10 nM increase both IGF-1 mRNA and polypeptide levels through, at least in part, an increase in cAMP production.^[89] Prostaglandin E₂ (PGE₂) produced by osteogenic cells in response to PTH is known also to increase the skeletal IGF-1 system and was thus suggested as possible mechanism of action for PTH-stimulated IGF-1 production.^[90] However, indomethacin, a classical inhibitor of PGE₂ synthesis, does not, in cell culture, interfere with the ability of PTH to increase IGF-1 production.^[87] In addition, PTH increases transcripts of IGF-binding proteins (IGFBP) and, more specifically, IGFBP4 in human bone cells. The system is cAMP dependent.^[91]

PTH action on bone may also involve TGF beta. Although PTH does not increase TGF beta mRNA in osteoblastic cells, it may activate previously synthesized TGF beta and regulate the binding and activities of TGF beta in osteoblast cultures by increasing the number of apparent TGF beta receptors.^[89,92] PTH was also reported to increase the activity of ornithine decarboxylase, an enzyme that may stimulate cell differentiation.^[93] A possible influence on the proliferation of pre-osteoblasts and on the programmed removal of osteoblasts from bone formation by osteoporosis was also evoked.^[86,94] It was suggested that PTH exerts opposite effects on the phenotypic expression of osteoblasts, depending on their stage of differentiation. PTH might thus preferentially stimulate osteoblast differentiation in immature osteoblasts but inhibit it in more mature cells.^[95]

The initial observation that PTH may have both anabolic and catabolic actions on the rat skeleton^[84] has been exhaustively confirmed in different animal models. Once admitted, the anabolic bone properties of PTH were ascribed to the N-terminal portion of the hormone.^[96] Later, no difference in the bone response was observed between full-length PTH and the 1-34 human fragment.^[97]

In Vitro and Animal Studies

With regard to in vitro studies, intermittent administration of PTH leads to increasing bone mass, whereas continuous exposure is catabolic for the skeleton.^[98] Increasing the number of PTH injections from once to twice per day did not improve its anabolic effect on total body calcium in female rats,^[99] whereas PTH given by continuous infusion at doses that were anabolic when given intermittently was lethal in dogs and rats.^[98] In trabecular cells of young rats, in vivo, PTH was reported to upregulate cell differentiation by transient stimulation of the early response genes (c-fos, c-jun, c-mic) and IL-6 while downregulating cell proliferation.^[100] PTH given as a daily injection was proven anabolic for the skeleton of young^[101] or normal and osteoporotic adult rats.^[102,103] This effect was also obtained independently of sex and sexual maturity, as shown in both OVX and orchidectomized rats.^[104,105]

Besides the demonstration of the skeletal anabolic effects of PTH in rat bones by measurements of bone mass or by histomorphometry, the biochemical resistance of the skeleton after PTH treatment was also investigated. In the mature and elderly OVX rat models, increases in vertebral bone strength^[106,107] were reported after PTH treatment; similar findings were described for the femoral neck^[108] and diaphysis.^[109] The increase in femoral neck biochemical competence seen after treatment of OVX rats with PTH was more pronounced than that occurring after administration of estrogens or risedronate. Concurrent treatment with PTH plus estrogens or PTH plus risedronate also significantly increased the femoral neck bone strength, but neither showed any advantage compared with treatment with PTH alone.^[108]

In osteoporotic OVX rats, intermittent PTH treatment increased trabecular bone values to the level of control animals or higher by thickening existing trabeculae. However, the treatment did not re-establish trabecular connectivity when therapy was started after 50% of the trabecular connectivity had been lost.^[110] These results were not in accordance with previous findings, suggesting that combination of PTH and estrogens in the OVX rat was more effective than PTH alone^[111] and that treatment effect was maintained if estrogens were continued after PTH was stopped.^[112] In estrogen-deficient osteoporotic rats, prolonged high-dose PTH treatment was associated with the blunting of some skeletal responses and a slowing in the rate of increase in bone mass.^[113]

Only limited data are available from studies in large mammals, which, in contrast to rats, do exhibit a skeletal remodeling process. In beagles, PTH seems to be anabolic for bones, with a much slower pattern of response than in rats, taking at least 6 months for osteoid to be formed and mineralized.^[114] In these animals, low-dose PTH alters intracortical remodeling^[115] and increases bone turnover on all endosteal surfaces.^[116] PTH-stimulated bone turnover on all envelopes was unchanged by concomitant administration of 1-25(OH)₂ vitamin D₃ but normalized by low intermittent doses of risedronate. Co-administration of 1-25(OH)₂ vitamin D₃ and risedronate did not blunt the increase in wall thickness effected by intermittent PTH.^[116] The authors of this study concluded that intermittent PTH in combination with risedronate might be superior to PTH alone or in combination with 1-25(OH)₂ vitamin D₃ because of the protective effect of the co-administration of risedronate on the cortical and endocortical envelope.^[116]

In greyhounds, analyses of iliac crest bone biopsies after daily subcutaneous injection of PTH for 4 months revealed significant increases in trabecular bone volume and osteoid surfaces, whereas no changes in trabecular bone volume were observed when PTH was administered by continuous injections.^[117] These results were in accordance with the suggestion that continuous administration of PTH does not increase iliac crest trabecular bone mass.

Early Clinical Studies

Human subjects have been exposed to PTH in clinical investigations for more than 25 years.^[86,118,119] Short-term administration of 100 mcg/day (450 u/day) of PTH(1-34) improved calcium balance in osteoporotic patients, whereas 750 u/day worsened it.^[120] In a multicenter trial, 450 u/day of PTH(1-34) was administered to osteoporotic subjects of both sexes by subcutaneous injection for 6-24 months. Biochemical markers of bone turnover rose, but no significant changes in calcium balance were observed, although major increases were seen in bone formation rate and in trabecular osteoid surfaces. When assessed by bone biopsy, trabecular bone volume of the iliac crest increased dramatically, whereas no significant changes were observed in BMD of cortical area of the skeleton.^[118] No significant cortical loss from the femoral shaft appeared when patients with involutional osteoporosis (ie, excessive age-related bone loss) received PTH(1-34).^[121]

Because of this absence of parallel positive effects on the trabecular and cortical skeleton, there was concern that anabolic effects consistently observed at the trabecular level might result from "stealing" bone from the cortical areas. Thus, several early studies administered PTH in association with an antiresorptive drug. In a small study, 12 patients with vertebral fracture osteoporosis were given 500 u PTH(1-34) by daily subcutaneous injections for 1 year. Beginning at the fifth month, PTH treatment was combined with either conjugated equine estrogens or nandrolone decanoate. This regimen induced an increase in iliac cancellous bone mass and improved calcium balance. However, iliac indices of bone formation and resorption, assessed by histomorphometry, returned toward pretreatment values after 1 year of treatment.^[122]

Another small study of 30 postmenopausal osteoporotic women randomized for 1-2 years to either calcium supplementation or PTH(1-34) (400-500 u/day) plus 0.25 mcg/day calcitriol showed that spinal trabecular BMD (as determined by quantitative computed tomography) increased 2.5 times more than total spinal BMD ( dual photon absorptiometry) in the treated group, with no change observed in the calcium-treated patients. However, the decrease in cortical BMD was 3 times higher in the treated group and mainly occurred during the first year of the study; thereafter, cortical BMD did not decline further.^[123] Interestingly, cortical BMD did not decline when the same therapeutic regimen was applied to osteoporotic men.^[124] A small uncontrolled trial, in which a combination of subcutaneous PTH(1-38) (720 u/day) and nasal salmon calcitonin (200 lU/day) was given in alternate cycles to 6 men and 2 women selected on the basis of clinical and histologic signs of osteoporosis, resulted in significant increases in trabecular BMD without any significant changes in the forearm BMD.^[125]

The effect of PTH to prevent osteoporosis was also evaluated in women with estrogen deficiency caused by treatment of endometriosis with gonadotropin-releasing hormone analogues. PTH(1-34) (40 mcg or 500 u/day) was given subcutaneously for 6 months to a group of women (n = 20) receiving nafarelin acetate.^[126] The effect on BMD was compared with that in a randomly assigned control group for which the only intervention was to maintain an approximate calcium intake of 1200 mg/day. Lumbar BMD was preserved in PTH-treated women when measured in the anteroposterior projection and significantly increased in the lateral projection, whereas these parameters both decreased significantly in the control group, whatever the type of projection used. BMD of the femoral neck decreased slightly and similarly in the 2 groups, and radial BMD did not change in the 2 groups.^[126,127]

Recent Clinical Studies: Randomized Controlled Trials -- Fracture Prevention

In order to assess the effects of 1-34 amino-terminal fragment of PTH on fractures, 1637 postmenopausal women with prior vertebral fractures were randomly assigned to receive 20 or 40 mcg of PTH(1-34) or placebo, administered subcutaneously daily by the women. Vertebral radiographs were obtained at baseline and at the end of the study (median duration of observation, 21 months), and serial measurements of bone mass were performed by dual-energy x-ray absorptiometry.

New vertebral fractures occurred in 14% of the women in the placebo group and in 5% and 4%, respectively, of the women in the 20-mcg and 40-mcg PTH groups; the respective relative risks of fracture in the 20-mcg and 40-mcg groups, as compared with the placebo group, were 0.35 and 0.31 (95% CI = 0.22-0.55 and 0.19-0.50). New nonvertebral fragility fractures occurred in 6% of the women in the placebo group and 3% of those in each PTH (RR = 0.47 and 0.46, 95% CI = 0.25-0.88 and 0.25-0.86). As compared with placebo, the 20-mcg and 40-mcg doses of PTH increased BMD by 9% and 13%, respectively, in the lumbar spine and by 3% and 6%, respectively, in the femoral neck; the 40-mcg dose decreased BMD at the shaft of the radius by 2%. Both doses increased total body BMD by 2% to 4% more than did placebo. PTH had only minor side effects (occasional nausea and headache). The authors concluded that treatment of postmenopausal osteoporosis with PTH(1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body BMD; and is well tolerated. The 40-mcg dose increased BMD to a greater extent compared with the 20-mcg dose but had similar effects on the risk of fracture and was more likely to have side effects.^[128] Human recombinant PTH(1-34) (teriparatide) was approved for treatment of osteoporosis by the US Food and Drug Administration at the end of November 2002. Because of studies showing an increased risk of osteosarcoma in rats with prolonged treatment, 2 years is the maximum recommended treatment duration. This safety issue is highlighted in a "black box" warning in the drug's label for health professionals and explained in a brochure, called a Medication Guide, for patients. (Editor's note: Please note that text in italics was added April 24, 2003 for clarification.)

PTH and Antiresorptive Therapy

During the past few months, the potential combined or sequential use of PTH and antiresorptive therapy has again been of considerable interest. Animal studies suggest that antiresorptive therapy maintains effects produced by PTH, but few studies have been done in human subjects to confirm the work in animals. If confirmed, the issue of whether antiresorptive therapy should be administered before, during, or after PTH treatment will need to be addressed. In animal studies, the data suggest that antiresorptive therapy given after PTH maintains its effects, concurrent administration seems to offer no benefit over and above that achieved by PTH alone, and prior treatment with antiresorptive therapy may actually limit the effect of PTH.

Finkelstein and colleagues^[129] suggest that use of alendronate may inhibit the anabolic action of PTH at the spine on the basis of results of a study of 36 osteoporotic men completing at least 18 months of treatment. Patients were randomized to alendronate alone, PTH 40 mcg alone, or both. PTH was started 6 months after alendronate in the combined (alendronate plus PTH) group. Spine BMD increased by 10.7% in the combined group, whereas PTH alone increased spine BMD by 13.7% and alendronate alone increased spine BMD by 6.1%. Total body BMD increased by 4% with combined therapy, decreased by 0.4% with PTH alone, and increased by 2.9% in the alendronate-alone group. PTH increased alkaline phosphatase by 74%, but this bone formation marker remained unchanged with combined treatment and decreased by 18% with alendronate. However, the combined treatment produced a greater increase in BMD at the hip (+4%) than PTH alone (+2.6%) or alendronate alone (+2.2%). Because of the small number of patients, most of these differences between groups were not significant.

The same group of investigators, this time led by Neer and colleagues,^[130] assigned 93 women to alendronate, PTH, or both for 30 months. In the combined group, PTH (40 mcg subcutaneously daily) treatment commenced 6 months after alendronate. Among the 53 women completing at least 12 months, combined treatment increased spine BMD by 7.3%, and PTH increased spine BMD by 7.5%, whereas alendronate alone increased it by 4.7% -- a difference that failed to reach statistical significance. Alendronate increased radius BMD by 2.2%, whereas PTH decreased it by 2.2%; the combined treatment just prevented bone loss at the radius. Alendronate reduced alkaline phosphatase levels by 18%, PTH increased levels of this marker by 96%, whereas the combined treatment resulted in no change.

The authors suggest that the alendronate suppressed the alkaline phosphatase response to PTH. However, in both studies, it is not clear whether the changes in BMD were calculated from baseline of the study or at the 6-month time point; changes in BMD in the combined group may be over- or underestimated depending on the effect of the alendronate in the 6 months before PTH was administered. If the formation marker is suppressed by alendronate, the same increment in BMD from baseline will produce a seemingly lesser effect for combined treatment as compared with PTH alone. If BMD increased in the first 6 months with alendronate treatment and the change in BMD was calculated from baseline for all treatment groups, the effect of combined treatment on BMD may be overestimated. Analysis of the effect of combined treatment relative to the 6-month time point will be of interest.

Even more importantly, these 2 studies reflect the ambiguity of changes of BMD. Alendronate increases BMD by decreasing bone turnover without increasing bone mass. PTH increases bone mass and size but decreases BMD, at least initially, because of the increased bone turnover. Thus, changes of BMD in patients receiving PTH and alendronate are difficult to interpret and are unlikely to reflect true changes in bone mass.

Ettinger and colleagues^[131] report that commencing PTH immediately after long-term (28 months) antiresorptive therapy is associated with differences in response in bone turnover markers. Patients previously receiving raloxifene had a 2-3 times greater increase in bone formation markers after 1 month of PTH(1-34) than those previously taking alendronate. Data at 3 and 6 months of PTH treatment, however, showed a progressive increase in bone formation markers in the previous alendronate group, suggesting that alendronate delays rather than blunts the anabolic effect of PTH.

Ma and colleagues^[132] reported that the effect of PTH(1-34) on the skeleton is unaffected by pretreatment with alendronate, estrogen, or raloxifene in OVX rats. After ovariectomy, pretreatment with these drugs for 10 months was followed by PTH for 2 months. All agents prevented bone loss. Only alendronate preserved trabecular spongiosa. Trabecular area was greater in the OVX animals treated with any of the 3 drugs than in OVX controls, but trabecular number increased with alendronate, whereas OVX animals treated with estrogen or raloxifene had trabecular number between OVX control (no treatment) and control (not OVX, not treated) animals. Trabecular area increased by 105% (PTH), 113% (alendronate then PTH), 36% (estrogen then PTH), and 48% (raloxifene then PTH). The authors concluded that the anabolic response to PTH is not blocked by pretreatment with these antiresorptive agents -- at least in rats.

Rhee and colleagues^[133] reported that zoledronate maintains BMD in rats after cessation of intermittent PTH administration. And finally, Kharode and colleagues^[134] reported that bazedoxifene (an investigational drug), raloxifene, and estrogen prevent bone loss after cessation of PTH treatment in rats.

These studies suggest that, first, rat studies may not be extrapolated to humans for combined/sequential treatments of PTH and antiresorptive agents. Second, pretreatment for several years with alendronate -- but not raloxifene -- seems to delay the anabolic action of PTH, but probably only for a few months, which may not affect the efficacy of PTH. Third, combined alendronate-PTH treatment cannot be recommended with available data, but that does not preclude the sequential use of alendronate after PTH. The benefit of these associations on fracture risk is unknown.

New therapeutic approaches have emerged during the past 5 years that significantly improve the daily management of osteoporosis. Alendronate has unequivocally shown its ability to reduce fractures of the axial appendicular skeleton. Its new weekly formulation reduces the discomfort generated by the requirements for its oral ingestion without compromising the activity of the drug, hence improving the potential for patient compliance. Risedronate is effective but is of marginal interest as a new agent, compared with previous bisphosphonates. On the basis of the preliminary results shared in scientific meetings, however, intermittent regimens with the new agents ibandronate and zoledronate may substantially modify the perspective of bisphosphonate treatments by offering efficient, more user-friendly, and safer therapeutic regimens. Raloxifene has a rapid and sustained antifracture efficacy both in women with prevalent vertebral fractures and those with low BMD. Although its effect on spinal fractures was undisputed, the recent demonstration of a reduced risk of nonvertebral fractures in the population of women who are actually at high risk to experience such events confirms its position as a first-line approach to osteoporosis management. In the choice between bisphosphonates and raloxifene, the collateral benefits reported with the SERM, ie, the significant reduction in estrogen receptor-positive breast cancer incidence in older osteoporotic women and the decrease in the rate of cardiovascular events, in a high-risk population, may be important considerations. A potent anabolic action on bone is mediated by the parathyroid hormone fragment PTH(1-34), and Sr ranelate induces an uncoupling between an decreased bone resorption and an increased bone formation. Both compounds have demonstrated ability to reduce the risk of vertebral and nonvertebral fractures, and they undoubtedly correspond to a new paradigm in the treatment of osteoporosis. Combination use or sequential administration of some of these drugs will, most likely, constitute the next challenge to provide our patients with the most effective and safest therapeutic option in the management of osteoporosis.

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