Parathyroid Hormone for Treatment of Osteoporosis FREE

OSTEOPOROSIS IS a common condition. An estimated 17 to 23 million women and 8 to 15 million men older than 50 years in the United States have osteoporosis or low bone density, with consequential elevated fracture risk.¹ Osteoporosis is associated with multiple deleterious consequences, including deformity, pain, loss of ambulation, and death.^2- 6

To date, all approved osteoporosis treatments are of the antiresorptive class. Antiresorptive agents block resorption of bone, but they do not induce bone formation. They induce a significant decrease in fracture risk, but they do not decrease the risk completely.^7- 9 The increased bone density induced by antiresorptive agents is related to more complete secondary bone mineralization, rather than increased synthesis of new bone.¹⁰ Therefore, interest has intensified surrounding the potential role of bone formation inducers alone or in combination with antiresorptive agents.

Several of the bone formation inducers (also called anabolic agents) have been investigated in animal models of osteoporosis, but trial results in humans were initially disappointing. In humans, fluoride treatment unexpectedly increased the risk of fracture, presumably due to abnormal bone quality, despite impressive increases in bone density.^11- 13 Fluoride has not been approved for management of osteoporosis in the United States. More recent efforts have focused on different fluoride dosages and preparations, such as slow-release fluoride preparations, as well as other bone formation inducers, such as parathyroid hormone (PTH).

Preliminary studies^14- 15 of PTH have been overshadowed by concerns about adverse effects at nonspine areas, similar to concerns raised surrounding fluoride administration. Recent studies have attempted to address these questions and have sometimes involved combination therapy with antiresorptive agents to protect nonspine areas.

Parathyroid hormone is under review by the US Food and Drug Administration for use in injection form. It would be the first bone formation inducer integrated into clinical use. This article will discuss evidence for the efficacy and safety of PTH for treatment of osteoporosis.

A MEDLINE database (1966 to the present) keyword search was performed for randomized controlled trials in humans using the keywords osteoporosis and parathyroid hormone or parathyroid hormone and fracture. The Cochrane database was also searched using the search terms osteoporosis and parathyroid hormone. Reference lists of retrieved articles were reviewed for additional pertinent articles.

Results are shown in Table 1, Table 2, Table 3, Table 4, and Table 5. The MEDLINE and Cochrane literature searches retrieved 191 references, 20 of which described randomized controlled trials involving PTH and osteoporosis (Table 1). Outcomes of the same trial were sometimes reported in separate articles, and some articles were continuations of results of earlier trials.^16- 26 The number of subjects per trial ranged from 9³⁵ to 1637.²⁸

Treatment duration ranged from 6 weeks²⁷ to 3 years.²⁹ Most studies administered PTH subcutaneously (SC). Two studies^18- 19 investigated intranasal PTH. Parathyroid hormone has been combined with alendronate sodium, hormone replacement therapy (HRT), calcitonin, or calcitriol (Table 1). Parathyroid hormone has also been compared with placebo and has been studied for differing dose effects. The efficacy of PTH has been tested for prevention of gonadotropin-releasing hormone (GnRH)–associated bone loss in both sexes. Mechanisms of the other medications are briefly summarized in Table 3.

Results are discussed in this section according to dosage and duration of therapy, study size, age, sex, baseline disease, anatomical site, histomorphometric effects, bone marker changes, fracture outcome, adverse effects, and compliance. (Single-dose studies are not discussed.)

Dosages of PTH ranged markedly across trials. They were variously reported in micrograms or units per day in the different articles. Furthermore, because of different combinations across trials and different comparison groups, conclusions regarding dose effects are difficult. Three trials^28,30- 31 directly compared different dosages of PTH with each other. The first³⁰ of the 3 compared 50, 100, and 200 U/wk SC for 48 weeks. Corresponding amounts of the peptide were 15, 30, and 50 µg, respectively. Increases in lumbar bone mineral density (BMD) were dose-related (range, 0.6%-8.1%), but there were no changes at the femoral neck with any PTH dosage. The second trial³¹ compared 50, 75, or 100 µg/d SC for 1 year, followed by alendronate alone for 1 year. Although all dosages increased spine and femoral neck BMD compared with placebo, specific dose-effect analysis was not presented. Increases in bone density ranged from 4.3% to 9.2% at the lumbar spine. Although there was no change at the femoral neck with PTH compared with placebo, the group treated with PTH followed by alendronate had better femoral neck bone density than the group treated with placebo followed by alendronate. The third trial²⁸ compared 20 or 40 µg/d SC with placebo for 16 to 17 months. Both dosages increased spine and hip (total hip, femoral neck, and trochanter) BMD compared with placebo, but dose-effect analysis per se was not provided. Bone density increases with 20-µg dosaging were 9.7%, 2.6%, 2.8%, and 3.5% at the lumbar spine, total hip, femoral neck, and femoral trochanter, respectively. Corresponding values for the 40-µg/d dosage were 13.7%, 3.6%, 5.1%, and 4.4%. Both dosages were associated with decreases in radius BMD (−2.1% and −3.2% for 20- and 40-µg/d dosages, respectively) compared with placebo (Table 2).

Therefore, on the basis of the little existing data, it is possible that dose-related effects exist throughout the dosage range of 50 to 100 µg/d SC. More dose-effect information is needed.

Because almost all trials used human PTH–(1-34) (hPTH–[1-34]), conclusions about any relative advantage of hPTH–(1-38) or hPTH–(1-84) are not possible. The 2 trials (described in 3 articles) that did not involve hPTH–(1-34) were small and involved postmenopausal osteoporosis^16- 17,31 or idiopathic osteoporosis.^16- 17

All trials except 2 involved administration by the SC route. The first exception was 1 trial (2 articles^18- 19) testing intranasal PTH. The trial was designed with the goal of preventing bone loss induced by GnRH agonist therapy. Therefore, the intranasal route of PTH has not been tested in the context of glucocorticoid-induced osteoporosis or postmenopausal osteoporosis, nor has it been tested in men. The trial found that intranasal PTH for 12 months increased lumbar BMD 2.1% and protected against femoral neck and trochanter bone loss. Neither nafarelin acetate nor PTH plus nafarelin affected radius BMD.

Therefore, although a few studies support the intranasal administration of PTH to prevent bone loss in women receiving specific endometriosis therapies, most data available refer to the SC route.

Study duration varied substantially across trials, ranging from 6 weeks²⁷ to 3 years²⁹; the longest trial involving SC administration was 3 years (Table 1). The more recent trials had access to more advanced bone density measurement technology, such as dual-energy x-ray absorptiometry, and measured a greater number of sites than did the older studies (Table 2). Correspondingly, results are sometimes expressed in the context of different bone density measurement techniques.

First, the longer (1-year and 3-year) trials will be described. A 1-year trial²⁴ reported a greater increase in spine (11.9% higher) and total hip (3.4% higher) BMD 12 months after treatment with PTH plus estrogen compared with estrogen alone. However, changes were not significant with PTH plus estrogen or estrogen alone at the femoral neck, trochanter, or radius. The estrogen preparation and dosage were not specified. One 18-month trial³² revealed increases in lumbar (13.5% higher; P<.001) and femoral neck (2.9% higher; P<.05) BMD in subjects receiving PTH vs untreated control subjects (Table 2). However, total hip BMD did not change with PTH treatment, and radius BMD decreased insignificantly with PTH, compared with an increase in the untreated controls (P<.05 between groups). (The possible decrease in radius BMD emphasizes the importance of inclusion of control groups in trials of osteoporosis therapies.) In the other 18-month trial,³¹ lumbar BMD increased (range, 4.3%-9.2%, depending on the dosage) with 1 year of PTH administration compared with placebo, but did not change in the following year of alendronate administration. Increases were less marked at the femoral neck (Table 2). Subjects received PTH or placebo for 1 year, followed by a second year of open-label alendronate, 10 mg/d.

The single 3-year study,²⁹ which compared PTH plus HRT with PTH alone, showed that combination therapy with PTH plus HRT induced higher increases in spine and total hip BMD (13% and 2.7%, respectively) compared with HRT alone. Differences between groups were less marked at the trochanter and radius. One year after cessation of PTH, with continuation of HRT alone, gains in BMD were maintained.²⁵ The specific hormone regimen used in this trial was conjugated equine estrogen, 0.625 mg/d orally, or estradiol, 50 µg/d transdermally, combined with sequential or continuous medroxyprogesterone acetate. In contrast, the 1-year trial²⁴ already described did not specify exact hormone dosage and preparation.

A briefer duration of therapy also results in increased BMD³⁰ (Table 2). Therefore, overall effects of 48 weeks to 3 years of therapy with PTH appear to be more marked at the spine than at other sites, may be detrimental at the radius, may be enhanced by combination with estrogen, and may be advantageous when combined sequentially with alendronate vs alendronate alone. The longest duration of therapy involved 3 years of PTH combined with HRT and showed benefit at the spine and total hip. It may take 12 months after treatment cessation for the maximal anabolic effect of PTH to manifest at the hip.²⁴ (Combinations of PTH and other medications are the focus of the "PTH in Combination With Other Agents" subsection of the "Results" section.)

The largest studies involved 220³⁰ and 1637 patients.²⁸ Both trials made use of several different dosages of PTH. The first³⁰ found that each of the dosages tested (15, 30, and 60 µg/d SC) increased spine BMD during 48 weeks and that the increases were dose-related. The other study²⁸ described BMD increases at the spine, femoral neck, total hip, and trochanter, but decreases at the radius, with dosages of 20 and 40 µg/d SC vs placebo. Therefore, results of larger trials were conflicting as to whether effects were limited to the spine and suggested detrimental effects on radius BMD. In contrast, although smaller studies reported positive hip and lumbar effects, they generally suggested only minor bone loss at the radius (Table 2).

Only one study³⁰ was designed to formally compare bone density changes according to age and sex. Parathyroid hormone benefits on bone density were similar with subjects 65 years and older vs younger than 65, at a weight of at least 50 kg vs less than 50 kg, whether baseline vertebral fracture was present or not, and regardless of time since menopause.

Most studies pertained to older men and women with established osteoporosis, with 2 exceptions.^19,33 In the first study,¹⁹ PTH was added in an effort to prevent bone loss induced by GnRH agonists in young women with endometriosis (Table 1). Although lumbar BMD was increased compared with baseline in subjects receiving PTH along with the usual GnRH agonist treatment, femoral neck and trochanter BMD decreased with PTH and radius BMD did not change (with or without inclusion of PTH) compared with baseline. The second study³³ investigated bone marker changes in older men with advanced prostate cancer. Augmentation of bone resorption associated with GnRH agonist–induced hypogonadism was blunted by PTH administration. All other studies included older men and women already affected by osteoporosis (Table 1).

Specifically, osteoporosis was postmenopausal osteoporosis,^{16- 17,20- 21,27- 31,34- 35} idiopathic male osteoporosis,^16- 17,32 or glucocorticoid-induced osteoporosis.^22- 24 These 3 clinical scenarios are individually reviewed herein.

Postmenopausal osteoporosis is the setting of most studies. In this setting, PTH consistently increased lumbar BMD. This was observed when PTH was given alone or with sequential calcitonin, HRT, calcitriol, or alendronate. Effects were less consistently seen at the total hip, femoral neck, trochanter, and radius (Table 2). Second, glucocorticoid-induced osteoporosis was studied in 1 trial.²² Combined PTH and HRT had no advantage over estrogen alone at the hip or radius. Furthermore, the benefit of PTH at the lumbar spine was only apparent after 1 year, and the benefit at the total hip was only apparent 1 year after cessation of PTH. The benefit at the femoral neck or trochanter was not statistically significant. Effects of combination therapy on the radius showed an insignificant decrease compared with estrogen alone.^22,24 Last, idiopathic osteoporosis in men was investigated in 1 trial.¹⁷ Interestingly, increased lumbar spine BMD associated with PTH was counteracted by the addition of calcitonin, although calcitonin may have protected against PTH-induced bone loss at the radius. Bone turnover effects of PTH in idiopathic male osteoporosis are discussed in the "Effects on Bone Formation Markers" subsection of the "Results" section.

In summary, increases in lumbar BMD are induced by PTH (alone and possibly combined with other medications, as shown in the "PTH in Combination With Other Agents" subsection of the "Results" section) in postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and idiopathic osteoporosis. Effects at other sites are insignificant or conflicting. Parathyroid hormone may protect against GnRH agonist–related bone loss. Although BMD end points were beneficially affected by PTH in all studies, with some variability between sites, little data specifically analyzed the effects of PTH in older vs younger subjects or directly compared effects according to sex.

Parathyroid hormone increased lumbar spine BMD in all studies, at several dosages, for any duration, in different clinical situations, and in combination with multiple agents (Table 2). However, results at the different hip subsites were conflicting. Femoral neck bone loss induced by nafarelin was only partly prevented by PTH.¹⁹ Parathyroid hormone was protective against bone loss at the radius. In other settings, no changes in femoral neck BMD were attributable to PTH therapy.^{20,22,24,30- 31,35} In other studies,^28,32 femoral neck BMD increased with PTH therapy.

Femoral trochanter BMD loss caused by nafarelin was not prevented by PTH, and significant BMD changes at this site were not found in several trials.^22,24,35 Femoral trochanter BMD increased in other PTH trials.^28- 29 Therefore, PTH effects at the hip vary across studies and clinical diseases (see the "Effect by Age, Sex, and Baseline Disease" subsection of the "Results"section).

A single study²⁸ documented increases at all of the multiple sites (ie, spine and all hip sites). It was also the only trial comparing the effect of different dosages of PTH vs placebo at multiple sites for treatment of postmenopausal osteoporosis. This study was the largest, most recent, well-designed trial and was the only trial comparing different dosages of PTH with placebo, as opposed to use in sequential or combination regimens. This trial confirmed the detrimental effect of PTH on radius BMD suggested in other studies^17,32 of postmenopausal osteoporosis. However, 1 trial²⁹ reported a small BMD increase with PTH plus estrogen compared with estrogen alone at the radius. Because of the paucity of data, there is as yet no proof that the decrement in radius BMD translates into increased radius fractures.

In summary, when used for postmenopausal osteoporosis treatment, PTH compared with placebo increases BMD at the spine and at multiple sites of the hip. Effects are less clear at nonspine sites when PTH is used as part of combination or sequential therapy or for treatment of glucocorticoid-induced osteoporosis.

Bone quality must be assessed by histomorphometry to prevent unintentional augmentation in fracture risk, even if BMD increases occur. As an example, fluoride increased fracture risk, despite inducing impressive increases in BMD.^11- 13 Histomorphometric findings have been used as an indicator of bone quality.

Histomorphometric consequences of PTH use were investigated in 1 trial²¹ (Table 5). In women with postmenopausal osteoporosis, cyclical PTH increased trabecular bone turnover and induced positive remodeling balance, without detrimentally affecting cortical bone.²¹ The improvement of cortical and cancellous microarchitecture with daily PTH administrations has been reported in humans.²⁶

In a sex-comparative analysis after 3 years of combined PTH and HRT, cancellous bone area was maintained in women and increased in men²⁶ (Table 5). Wall width of trabecular packets was maintained in women and significantly increased in men. Cortical width increases slightly in women and significantly in men. Most patients had increased trabecular connectivity by three-dimensional scan.

Bone turnover markers are sometimes used as surrogates to assess therapeutic effects of osteoporosis medications, although whether such application is clinically relevant is a matter of active controversy. Bone markers can give useful insights into medication mechanisms. Markers of bone formation include serum alkaline phosphatase, serum osteocalcin, and C-terminal propeptide of type I procollagen. Parathyroid hormone would be expected to increase alkaline phosphatase on the basis of its mechanism as an inducer of bone formation. Correspondingly, in some trials,^{18- 20,22,25,30- 31} PTH increased serum alkaline phosphatase, although 1 brief trial²⁷ reported no increase during 6 weeks. Some investigators found an increase with PTH administered alone, but not when followed by antiresorptive treatment with calcitonin.^16- 17 Similarly, some trials^{18- 20,22,27,29,31- 32,35} reported an increase in serum osteocalcin resulting from PTH administration. One trial¹⁶ found an increase in serum osteocalcin with PTH alone and PTH followed by calcitonin treatment. Two studies^27,32 reported an increase in serum C-terminal propeptide of type I procollagen with PTH plus alendronate vs alendronate alone, or with PTH vs placebo.

Markers of bone resorption that increase during PTH therapy include urinary pyridinoline,^18,30,32 deoxypyridinoline,^19,22,30 and N-telopeptide^{20,29,31- 32} excretion.

Induction of hypogonadism in older men may cause changes in skeletal sensitivity to PTH.³³ The increase in urinary N-telopeptide excretion (but not deoxypyridinoline) during PTH infusion was greater after 6 months of leuprolide acetate therapy than before induction of hypogonadism caused by leuprolide.

Data regarding urinary hydroxyproline are conflicting. A decrease was reported in 1 trial.³⁰ Other trials^18- 20 reported increases in urinary hydroxyproline in women with endometriosis. One trial¹⁶ found no change from baseline with PTH therapy alone, although levels at the study end were lower after sequential PTH plus calcitonin vs PTH alone.

Some data suggest that the increase in bone formation and resorption is disproportionate, suggesting that PTH could be uncoupling bone formation and resorption.²² This idea may be supported by the observation that PTH plus HRT (compared with HRT alone) did not increase resorption as much as formation.²⁹

Results of combination therapy trials confirm what would be predicted according to medication mechanism. Neither alendronate nor HRT increased formation markers when administered alone.^25,27 Rather, only combination PTH with alendronate or HRT increased formation markers. Parathyroid hormone–induced increased bone resorption and formation peaked at 6 months.²⁵ They returned to baseline by 30 months. Subsequently, when patients were maintained on HRT alone for another year, no significant changes in turnover markers occurred.²⁵

It may be possible to make use of serial bone marker measurements to identify skeletal responders to anabolic therapy in estrogen-replete women with glucocorticoid-induced osteoporosis.²³ One study²³ suggests that the response of bone markers predicted a gain in BMD resulting from PTH therapy with high diagnostic accuracy, although it did not predict the magnitude of the gain.

In summary, PTH increases bone formation markers. The increase in bone formation is probably larger in magnitude and may have a different time of onset compared with the increase in resorption.

Antifracture efficacy is the single most critical efficacy outcome for osteoporosis treatment. As it is difficult to include adequate numbers of subjects to yield substantial numbers of fracture events, fracture outcome data for PTH are sparse. Although not a satisfactory state of affairs, this has historically been the case with other osteoporosis therapies as well. Often, fractures are only monitored as part of adverse outcome assessment, as opposed to constituting a primary outcome. Table 4 summarizes fracture outcome data for PTH. Rates of radiographically detected fractures were generally low. Fracture rates were sometimes so low as to prevent statistical analysis.^20,22,32,35

Rates of radiographically detected spinal fractures were not different among different doses of PTH over a 50- to 200-U dose range.³⁰ The incidence of radiographically detected vertebral fractures was no different with sequential PTH plus calcitonin compared with PTH alone, although differences between groups were not significant and the number of events was small.²⁰ When HRT was compared with HRT plus PTH, differences between groups in vertebral fracture incidence were not significant.³⁵ The vertebral fracture incidence was lower with PTH plus estrogen vs estrogen alone, although differences between groups were not significant.²⁹ Rates of nonvertebral fracture were lower, making analysis of reduced fracture rates difficult or impossible^20,22 (Table 4).

The largest trial²⁸ reported an impressive reduction in the rate of new vertebral fractures with PTH dosages of 20 and 40 µg/d SC for 17 months. The risk of 2 or more vertebral fractures was reduced, as was the risk of at least 1 moderate or severe vertebral fracture, regardless of which PTH dosage was used. Nonvertebral fractures were also decreased by PTH. Parathyroid hormone recipients were 35% to 40% less likely to have at least 1 new nonvertebral fracture compared with placebo and 53% to 54% less likely to have at least 1 new nonvertebral fragility fracture.²⁸ The numbers of nonvertebral fractures were too low to be broken down by individual site. It could not be concluded from the study if the notable decrease in radius BMD in this trial may have led to increased fracture rates.

These findings are replicated in the longest and most recent trial.²⁵ Radiographically detected vertebral fractures were significantly decreased with PTH plus HRT during 3 years compared with HRT alone. The percentage of women with incident vertebral fractures decreased from 37.5% to 8.3% by PTH plus HRT compared with HRT alone. Again, the rate of nonvertebral fractures was low.

In summary, when data were robust enough to allow adequate statistical power, PTH decreased the incidence of radiographically detected spinal fractures, decreased the incidence of nonvertebral fractures, and may have added to the fracture reduction ability of estrogen replacement therapy.

Adverse effects of PTH are summarized in Table 5. No serious medication-related adverse effects were attributed to PTH. In some trials,^19,22 PTH increased calcium levels, but they remained in the normal range. One trial³⁰ reported minor decreases in calcium levels with PTH therapy. Other trials^{20,29,32- 33} reported no change in calcium levels. The largest trial²⁸ reported mild hypercalcemia (>10.6 mg/dL [>2.65 mmol/L]) in 2%, 11%, and 28% of the placebo, 20-µg, and 40-µg PTH groups, respectively. Of the high serum calcium values, 95% were less than 11.2 mg/dL (2.80 mmol/L).

Monitoring of serum calcium levels varied across trials. In some trials, subjects were monitored every 3 months^22,25 or every 6 months,²⁹ whereas other subjects^{20- 21,24,28,30,32} were monitored more frequently at the beginning and less frequently later on. Women who did not manifest hypercalcemia during the first 6 months of treatment rarely developed hypercalcemia later on.²⁸ The trial allowed adjustment of calcium intake in patients experiencing hypercalcemia. Examples of protocol adjustments triggered by hypercalcemia include a decrease in PTH dosage for calcium levels greater than 10.5 mg/dL (2.63 mmol/L), with subsequent documentation of normalization of calcium levels,^18- 19 or a decrease in medication dosage only for persistence of hypercalcemia, despite a decrease in dietary intake.²⁸ In the latter trial, the numbers of subjects withdrawn for hypercalcemia were 1 in the placebo group, 1 in the 20-µg PTH group, and 9 in the 40-µg group.

Besides hypercalcemia, other adverse effects associated with PTH therapy include local injection site reactions, transient mild headaches, nausea, and arthralgia (Table 5). There was some suggestion that adverse effects increased with increasing dosage of PTH.³⁰ However, the largest trial,²⁸ which compared placebo, 20-µg PTH, and 40-µg PTH, reported no significant difference between groups in the incidence of serious adverse effects. Interestingly, the incidence of nausea and headache was higher with the 40-µg/d dosage compared with placebo, but were similar in the 20-µg/d and placebo groups. The longest (3-year) trial²⁵ reported that nausea did not occur.

Hypercalciuria occurred infrequently in some trials,^16,18,22 but by the study end returned to baseline in 1 study.²⁰ Generally, hypercalciuria resolved with a decrease in calcium intake.²² Other studies^29,32,35 reported no change from baseline in urinary calcium levels. One study³⁰ reported that urinary calcium fell below the basal level.

There was sometimes difficulty with PTH injection technique²⁰ or compliance³⁰ (Table 5). The largest trial²⁸ found more subject withdrawal from the study with PTH than with placebo treatment.

Rats that were given nearly lifetime daily injections of PTH manifested increased osteosarcoma incidence in a dose-dependent fashion as a result of PTH administration.²⁸ However, this effect is absent in primates (eg, monkey models). Furthermore, chronic hyperparathyroidism is not associated with osteosarcoma in humans.²⁸ None of the trials reviewed herein reported an increased cancer incidence associated with PTH, and the cancer incidence was higher with placebo vs PTH therapy.²⁸ In summary, PTH administration is associated with hypercalcemia in a small percentage of patients, possibly in a dose-dependent fashion, and early in treatment. Other minor adverse effects are also associated with PTH. No published trial results have indicated that cancer risk is increased by PTH use in humans.

A 28-day "pulse" of daily hPTH–(1-34) injections at a dosage sufficient to elevate serum calcium levels to the upper normal reference range was proposed as a way of activating bone turnover and osteoblastic synthesis of new bone matrix.²¹ The underlying hypothesis is that, once bone turnover had been activated, the anabolic phase of bone remodeling would be left to complete itself during the remainder of the 90-day treatment cycle before initiation of the next cycle. Calcitonin given sequentially after the PTH pulse would be designed to limit the degree of PTH-induced bone resorption, thereby enhancing the net anabolic effect of PTH.

The idea of pairing PTH with calcitonin in such a manner did not yield the anticipated beneficial effects, in that the 2 groups (PTH alone vs PTH with calcitonin) had the same incremental gain in vertebral BMD at the end of a 2-year trial.²⁰ The corresponding histomorphometric analyses for all the 29 treated patients vs a separate group of biopsies from control patients with untreated osteoporosis revealed an increase in trabecular bone turnover with a positive remodeling balance, without deleterious effect on cortical bone.²¹

Six other trials studied PTH given in combination with an antiresorptive (Table 1 and Table 2). These combined alendronate with PTH,^27,31 estrogen replacement with PTH,^{22- 24,29,35} or PTH with calcitriol.³⁴ These trials reported a bone density benefit over individual therapy at the lumbar spine^22- 24 and had conflicting results regarding different areas of the hip^{22- 24,29,31,35} (Table 2). During a 1-year observation on maintenance HRT, following 3 years of combined HRT plus PTH, the increases in BMD persisted.²⁵

These studies of combination therapy can be considered according to whether the components are given concomitantly or sequentially. Concomitant therapy will be considered first. In the only study²⁵ of combination therapy that reported fracture outcome, PTH was given simultaneously with HRT to treat postmenopausal osteoporosis. The concomitant use resulted in a decrease in radiographically detected vertebral fractures and in the percentage of women with incident vertebral fractures. Unfortunately, most studies of concomitant therapy had too few fractures to assess^22,29,35 or were not designed to determine^23- 24,27 fracture outcome. These latter studies^23- 24,27 with bone density outcomes suggested that concurrent PTH and estrogen use had an advantage over estrogen alone at the spine in women with postmenopausal osteoporosis. The advantage may^24,29 or may not³⁵ exist at the hip.

In considering sequential therapy, studies again had too few fractures to allow fracture outcome assessment^16,20,32 or were not designed for assessment of fracture outcome.^17,31 It seemed that the use of calcitonin following PTH therapy had no benefit in postmenopausal or idiopathic male osteoporosis,^17,20 but that the use of alendronate following PTH protected the bone density gains incurred during PTH therapy of postmenopausal osteoporosis.^25,31

Therefore, in comparing concurrent vs sequential PTH regimens, the data overall would support concurrent therapy with PTH plus estrogen to increase bone density and decrease the incidence of vertebral fractures, and sequential therapy with alendronate following PTH therapy to protect bone density gains. Data specifically do not support sequential therapy with PTH followed by calcitonin. These comments refer only to postmenopausal osteoporosis; data in other patient subgroups are lacking.

In summary, regarding the use of PTH in combination regimens for postmenopausal osteoporosis, the addition of PTH to combination HRT or alendronate had advantages over HRT alone at the lumbar spine, but effects at the radius, trochanter, and hip are conflicting. For glucocorticoid-induced osteoporosis, combined PTH and estrogen replacement may be of added benefit compared with estrogen replacement alone at the spine, but not necessarily at the total hip or radius. Because only one trial tested each regimen, conclusions cannot be made regarding any particular combination involving PTH or about relative advantages of sequential vs concomitant therapy. Effects of combining one HRT regimen vs another HRT regimen with PTH are not known.

The increase in BMD induced by PTH seems to be dose-dependent. Based on the results of 1 trial,³⁰ BMD increases are similar for subjects 65 years and older vs younger than 65, weighing at least 50 kg vs less than 50 kg, with or without baseline vertebral fractures, and regardless of time since menopause.

Parathyroid hormone protects against vertebral fracture.²⁸ It not only decreases the incidence of radiographically detected vertebral fractures but also decreases the clinical corollary—pain. Preliminary findings indicate that there was improvement in backache associated with PTH treatment in one trial³⁰ and that new or worsening back pain was reported less often with PTH than placebo in another trial.²⁸ The protective effects of PTH against new nonvertebral fractures and nonvertebral fragility fractures were rapid; effects were evident after 9 to 12 months of therapy.²⁸ Although direct comparisons have not been performed, approximately the same degree of fracture reduction results from PTH treatment as from risedronate sodium, alendronate, or raloxifene hydrochloride treatment in other trials.

When combined with standard oral or transdermal estrogen alone in postmenopausal osteoporosis, PTH induced increased BMD at the lumbar spine and femoral neck, but not at the femoral trochanter, compared with estrogen alone.²⁹ However long-term studies are lacking, and different routes of administration and dosages may have different effects. Moreover, estrogen and progesterone components were not investigated separately.^29,35 Each hormone component probably has different effects on bone metabolism. It is also conceivable that adding PTH to ongoing HRT may have effects different from those of initiating PTH and HRT concurrently.²⁹ Based on the data reviewed, because of differing regimens and subject characteristics across trials, it is difficult to say if calcium and vitamin D administration affected BMD or fracture outcome effects of PTH.

Cortical and trabecular bone are the 2 main types of bone. Cortical bone constitutes the shell around cancellous bone. The peripheral skeleton is predominantly cortical bone, but the axial skeleton (eg, spine) is a combination of cortical and trabecular bone.³⁶ Metabolism and rates of bone loss differ in the 2 types of bone, and diseases often differentially affect the 2 types of bone.³⁶ The theoretical possibility of unintentionally causing a fracture (or decreased bone density as a possible surrogate for fracture) at one type of bone while simultaneously benefiting another type of bone is the reason for strict attention to differentiating cortical and trabecular effects. In 1 trial,³⁴ cortical bone mass decreased 1.7% with PTH plus calcitriol vs 5.7% with calcium alone, but trabecular bone mass increased 32% with PTH plus calcitriol. The varying effects according to bone composition (ie, trabecular vs cortical) may relate to the varying results seen according to measurement technique. For example, spine BMD differences between estrogen and estrogen plus PTH groups were 9.8% by dual-energy x-ray absorptiometry and 33.5% by calcitonin treatment.²² There may be subtle differences between men and women in the degree of histomorphometric response to PTH.²⁶ The suggestion in several studies^17,24,32,34 of a decrease in radius BMD in association with PTH use parallels the recognized differing effects of hyperparathyroidism on trabecular vs cortical bone. Even if BMD effects at different sites become well established, BMD changes during therapy are only a surrogate for fractures.³⁷ We need to directly determine fracture rates site by site in prospective studies with adequate statistical power.

Strictly speaking, treatment with PTH should be limited to less than 2 years, given the lack of long-term safety and efficacy data. Parathyroid hormone treatment should be followed by antiresorptive therapy, with the goal of maintaining BMD gains. Evidence supports continuation of HRT after combination PTH plus HRT to preserve increases in BMD.²⁵ However, the latter medications must be continued long-term to preserve beneficial bone density effects. Long-term PTH effects are not clear; hence, optimal duration of therapy is not clear. Effects of intermittent vs continuous therapy are different and require additional elucidation.^38- 40 In the future, differences in response to PTH must be analyzed by sex. In addition, determination of a clinical algorithm regarding appropriate response to PTH-associated hypercalcemia will be necessary.

In placing future research into proper context, especially given that PTH will be studied in combination with other therapies, several potential pitfalls warrant mentioning. Identical bone density changes between 2 active treatment groups might signify that both regimens work to increase BMD or that neither regimen works to increase BMD. In addition, instead of being dismissed as proof of lack of efficacy, a lack of BMD change compared with baseline may signify that BMD is being preserved (ie, that bone loss is being prevented). Such considerations must determine appropriate comparison groups in the design and proper interpretation of results of randomized controlled trials.

Antifracture efficacy is the single most critical efficacy outcome for osteoporosis treatment, and fracture reduction data are not robust for PTH, especially at nonvertebral sites. Additional fracture data are anticipated and will be the ultimate proof of efficacy. Bone density effects of 48 weeks to 3 years of therapy with PTH appear more marked at the spine than at other sites, may be detrimental at the radius, may be enhanced by combination with estrogen, and may enhance effects of alendronate. Maximal anabolic effect of PTH may require 12 months after treatment cessation before manifesting at the hip. Dose-related bone density effects may exist in the dosage range of 50 to 100 µg/d SC. Although a few studies support the intranasal route of PTH administration to prevent bone loss in women receiving specific endometriosis therapies, most data available refer to the SC route. However, the SC route was associated with decreased compliance. Subjects in the trials reviewed had the support of clinical trial nurses. Older patients encountered in community practice may have difficulty with injections.

Results of larger trials were conflicting as to whether effects were limited to the spine and suggested detrimental effects on radius BMD. Little data analyzed the effects of PTH in older vs younger subjects or directly compared effects according to sex. Increases in lumbar BMD are induced by PTH in postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and idiopathic osteoporosis. Effects at other sites are insignificant or conflicting. When data were robust enough to achieve adequate statistical power, PTH decreased the risk of new spinal fractures in women with postmenopausal osteoporosis by 65% to 70% and may have decreased the overall incidence of nonvertebral fractures. However, there were several drawbacks to the lack of data: numbers of nonvertebral fractures were too low to be broken down by individual site, it is unknown whether the decrement in radius BMD associated with PTH results in an increased risk of future radius fracture, and the only population definitely demonstrated to have vertebral fracture reduction associated with PTH is women with established postmenopausal osteoporosis.

Parathyroid hormone administration induces hypercalcemia in a small percentage of patients, possibly in a dose-dependent fashion, and early in treatment. Other minor adverse effects are also associated with PTH. Although concerns were raised from animal research, published trial results indicate that cancer risk is not increased by PTH use in humans. Because only one trial tested each individual regimen, conclusions cannot be made regarding any particular combination regimen involving PTH.

Accepted for publication May 8, 2002.

Corresponding author and reprints: Carolyn Crandall, MD, Department of Medicine, David Geffen School of Medicine at University of California, Iris Cantor–UCLA Women's Health Center, UCLA School of Medicine, 100 UCLA Medical Plaza, Suite 250, Los Angeles, CA 90095-7023 (e-mail: ccrandall@mednet.ucla.edu).