Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis

INTRODUCTION — The majority of osteoporosis medications (eg, bisphosphonates, denosumab, raloxifene, and estrogen) are antiresorptive agents that slow bone turnover, decrease bone resorption, and enhance bone mineral density (BMD), as more mineral is gradually deposited in older remodeling units. In contrast, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) analogs belong to a different class of osteoporosis drugs called "anabolic" agents because they increase bone formation. There are fundamental differences in the mode of action of and skeletal response to PTH/PTHrP analogs compared with antiresorptive drugs [1].

This topic will review the use of PTH and PTHrP analog therapy for osteoporosis. PTH physiology and other treatments for osteoporosis are reviewed in detail elsewhere. (See "Parathyroid hormone secretion and action" and "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)

AVAILABLE THERAPIES — In contrast to the mechanism of antiresorptive agents (eg, bisphosphonates, denosumab, raloxifene, and estrogen), parathyroid hormone (PTH [teriparatide]) and PTH-related protein (PTHrP; abaloparatide) analogs stimulate bone formation more than bone resorption and thereby reduce fracture risk.

●Teriparatide (PTH [1-34]) is a form of parathyroid hormone, consisting of amino acids 1-34. It retains all of the biologic activity of the intact peptide (1-84) (figure 1) (see "Parathyroid hormone secretion and action", section on 'Biological actions of PTH'). It has been available in several countries worldwide since 2002 for the treatment of postmenopausal women with osteoporosis at high risk for fracture and, subsequently, for the treatment of osteoporosis in men similarly at high risk for fracture.

A PTH (1-84) preparation has been studied for the treatment of osteoporosis [2-6] and was available in the United States for the treatment of patients with chronic hypoparathyroidism unable to maintain stable serum and urinary calcium levels with calcium and active vitamin D supplementation. It is no longer commercially available. (See "Hypoparathyroidism", section on 'PTH-based therapies'.)

●Abaloparatide (PTHrP [1-34]) is a synthetic analog of PTHrP with 76 percent homology that binds more selectively than teriparatide to the RG conformation of the PTH type 1 receptor (PTH1R) [7]. Selective binding to the RG conformation confers a more transient response, favoring bone formation while minimizing the effects of more prolonged activation (eg, bone resorption, hypercalcemia). Abaloparatide has been available in the United States since 2017.

PTHrP is produced in a wide variety of tissues and has diverse functions. It shares some of the actions of PTH, including stimulation of renal tubular calcium reabsorption and bone resorption, but it has minimal effect on intestinal calcium absorption, the latter due to weak stimulation of 1,25 dihydroxyvitamin D production. PTHrP also regulates cellular proliferation and is an important component of fetal calcium regulation, placental calcium transfer, and lactation [8,9]. PTHrP is produced by some cancers and is the primary cause of humeral hypercalcemia of malignancy. (See "Hypercalcemia of malignancy: Mechanisms", section on 'PTH-related protein'.)

RATIONALE FOR USE — The classical parathyroid hormone receptor, parathyroid hormone (PTH) type 1 receptor (PTH1R), recognizes both PTH and PTH-related protein (PTHrP) due to the substantial degree of homology in the N-terminal regions of these two peptides. (The first two amino acids in the N-terminal region of the molecule are obligatory for activation of PTH1R.) This accounts for the ability of PTHrP to simulate some of the actions of PTH, including increases in bone resorption and distal tubular calcium reabsorption and inhibition of proximal tubular phosphate transport. The two ligands, however, bind to the receptor slightly differently, and this is probably the reason the two agents differ slightly in their effects. (See "Parathyroid hormone secretion and action", section on 'Biological actions of PTH'.)

Chronic exposure to elevated PTH or PTHrP (as seen with primary or secondary hyperparathyroidism or hypercalcemia of malignancy, respectively) results predominantly in bone resorption. Given this observation, exogenous PTH/PTHrP analogs would seem unlikely candidates for the treatment of osteoporosis. However, intermittent administration of recombinant human PTH (either full-length 1-84 or fragment 1-34) or PTHrP (1-34) in individuals with normal endogenous levels of these hormones has been shown to stimulate bone formation more than resorption. (See "Parathyroid hormone secretion and action", section on 'Skeletal actions of PTH'.)

The actions of PTH/PTHrP on skeletal compartments are site specific. Areal bone mass measurements by dual-energy x-ray absorptiometry (DXA) capture only a small proportion of these qualitative effects that are important for skeletal integrity. With the introduction of high-resolution imaging, it has been established that intermittent PTH/PTHrP treatment enhances trabecular more than cortical bone mass. In this compartment, trabecular thickness, number, and connectivity are all increased by PTH [10,11]. Qualitative changes in trabecular microarchitecture from patients treated with PTH/PTHrP analog are responsible for much of the improvement in the mechanical strength of the skeleton and its resistance to fracture (figure 2) [12].

With respect to the cortical compartment, periosteal circumference may increase with PTH/PTHrP analog treatment, but there is a decrease in secondary mineralization in the cortical skeleton [13-15]. Hence, bone mineral density (BMD) in highly trabecular sites like the vertebrae are markedly increased by PTH, while bone in largely cortical regions, such as the radius, shows either no change or a decrease in areal BMD within the first year of treatment. Nonetheless, PTH analog therapy does not increase fracture risk and may improve bone strength at these predominantly cortical bone sites [13,16].

OVERVIEW OF APPROACH

Patient selection — Given their cost, subcutaneous route of administration, limited long-term safety data, and the availability of other agents, parathyroid hormone (PTH [teriparatide]) and PTH-related protein (PTHrP [abaloparatide]) analogs are generally not used as a first-line drug for treatment or prevention of osteoporosis. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy' and "Treatment of osteoporosis in men", section on 'Choice of therapy'.)

Potential candidates for PTH/PTHrP analog therapy include males or postmenopausal females who [17-20]:

●Have very high risk for fracture (eg, T-score of ≤-3.0 even in the absence of fractures, T-score of -2.5 or below plus a fragility fracture, history of multiple fractures, advanced age). (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Very high fracture risk'.)

●Have osteoporosis and are unable to tolerate bisphosphonates or who have relative contraindications to oral bisphosphonates (achalasia, scleroderma esophagus, esophageal strictures). (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Gastrointestinal malabsorption or difficulty with dosing requirements' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Contraindications or intolerance to any bisphosphonates'.)

●Do not derive benefit from other osteoporosis therapies (fracture and/or loss of bone mineral density [BMD] in spite of adherence to therapy). (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'BMD decreased or fracture during therapy'.)

PTH analog therapy can also be used for selected males and females with glucocorticoid-induced osteoporosis. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Parathyroid hormone'.)

Contraindications/precautions — PTH/PTHrP analog therapy should not be used in patients who have:

●Primary or secondary hyperparathyroidism, even if they have low BMD

●Other hypercalcemic disorders (eg, chronic granulomatous disorders, hypercalcemia of malignancy) because of the possibility of exacerbating hypercalcemia

●Increased baseline risk for osteosarcoma, such as those with Paget disease of bone or unexplained elevation of alkaline phosphatase, bone metastases or skeletal malignancies, history of prior radiation therapy involving the skeleton, or pediatric/young adult patients with open epiphyses. (See 'Long-term risks' below.)

In patients with preexisting nonskeletal malignancies, renal stones, or renal insufficiency, PTH/PTHrP analogs should not be considered unless other drugs have not prevented fractures and the benefits outweigh potential risks.

Choice of therapy — When a decision has been made to treat with a PTH/PTHrP analog, either teriparatide or abaloparatide can be prescribed. In a comparison trial, both teriparatide and abaloparatide reduced the risk of vertebral and nonvertebral fractures [21]. Teriparatide has a long track record of safety (when administered as the usual two-year course), whereas there is less experience with abaloparatide. For both medications, long-term safety data beyond a two-year treatment course are limited.

●Teriparatide – PTH increases spine and hip BMD in a dose-dependent manner [22-25] and markedly reduces the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis [22,26]. As an example, in the Fracture Prevention Trial (FPT), 1637 postmenopausal women with previous vertebral fractures were randomly assigned to receive teriparatide (20 or 40 mcg/day subcutaneously) or placebo [22]. After 18 months of treatment, the increase in areal BMD (dual-energy x-ray absorptiometry [DXA]) with 20 and 40 mcg of PTH was greater than with placebo (by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck). The beneficial effects of PTH were largely independent of age, baseline BMD, and prevalent vertebral fractures.

New vertebral fractures (5 and 4 versus 14 percent) and nonvertebral fractures (3 versus 6 percent) occurred less frequently with teriparatide than placebo [22]. Fracture risk reduction did not differ by dose, even though BMD changes were significantly greater with 40 mcg/day. The relative risks (RRs) for vertebral fractures for the 20 and 40 mcg doses compared with placebo were 0.35 (95% CI 0.22-0.55) and 0.31 (95% CI 0.19-0.50), respectively, and for nonvertebral fractures, the RRs were 0.47 and 0.46, respectively (95% CI 0.25-0.88 and 0.25-0.861). The risk reduction became apparent after six months of treatment. Unlike alendronate and risedronate trials, there were too few hip fractures over 21 months to conclude whether efficacy was also apparent for this type of fracture [27,28]. Radial BMD declined slightly in the first two years of PTH treatment, although the risk of radial fractures was not increased [24,26,29].

Recombinant PTH is also effective in men with osteoporosis and glucocorticoid-treated individuals. (See "Treatment of osteoporosis in men", section on 'Patient selection' and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Choice of therapy'.)

●Abaloparatide – Abaloparatide (PTHrP [1-34]) increases spine and hip BMD and reduces the risk of vertebral and nonvertebral fractures [30,31]. As an example, in an 18-month, phase III trial, 2463 postmenopausal women with osteoporosis were randomly assigned to abaloparatide (80 mcg daily by subcutaneous injection), placebo, or open-label teriparatide (20 mcg daily by subcutaneous injection) [21]. New radiographic vertebral fractures (0.58 versus 4.22 percent) and nonvertebral fractures (2.7 versus 4.7 percent) occurred less frequently in the abaloparatide group compared with placebo. Improvement in BMD and reduction in fracture rates were similar in the abaloparatide and teriparatide groups. However, the incidence of hypercalcemia was lower with abaloparatide (3.4 versus 6.4 percent with teriparatide). Post hoc analyses suggest that the reduction in fracture rate is independent of baseline fracture risk, as assessed by a variety of indicators [32,33].

Dosing

●Teriparatide – The dose of teriparatide (PTH [1-34]) is 20 mcg/day. It is administered via subcutaneous injection into the thigh or abdominal wall. A multidose, prefilled pen (containing 28 doses) is available. The initial dose should be administered in a setting where the patient can sit or lie flat, in case symptoms of orthostatic hypotension occur. PTH analog therapy is typically given for a maximum of two years. (See 'Duration of therapy' below.)

PTH treatment requires daily injection and is expensive. Although alternative approaches in which PTH is administered less frequently than once daily have been studied, these regimens have not received regulatory approval in most countries:

•Intermittent – Cyclic administration of teriparatide alternating with or concomitantly with an antiresorptive agent has not been shown to improve BMD more than standard therapy [34-36]. As an example, in a randomized trial in women who continued long-term treatment with alendronate, intermittent administration of teriparatide for 15 months (ie, once-daily injection for three months followed by three months off and then a return to three months daily) in postmenopausal women was as effective for increasing BMD as daily teriparatide [34].

•Once weekly – Several trials have investigated once-weekly dosing of PTH [37-39], a dosing regimen that has received regulatory approval in Japan based on the following trials:

-In a trial in postmenopausal women with osteoporosis, once-weekly teriparatide (60 mcg/dose/week) improved spine BMD (6 to 8 percent over baseline after 48 months) [37].

-In a trial of 578 postmenopausal women with vertebral fracture who were randomly assigned to once-weekly teriparatide (56.5 mcg) or placebo for 72 weeks, once-weekly injections reduced the risk of new vertebral fracture (cumulative incidence 3.1 versus 14.5 percent in the placebo group) [39].

-In a subsequent trial in women (age ≥75 years) with primary osteoporosis and high fracture risk, sequential therapy with once-weekly teriparatide (72 weeks) followed by alendronate (48 weeks) led to a lower incidence of morphometric vertebral fracture than continuous alendronate treatment over 120 weeks; however, sequential therapy did not reduce the risk of clinical vertebral fracture or nonvertebral fracture relative to alendronate alone [40].

●Abaloparatide – The recommended dose of abaloparatide (PTHrP [1-34]) is 80 mcg subcutaneously once daily. A multidose, prefilled pen (containing 30 doses) is available. It is administered via subcutaneous injection into the periumbilical region. The initial dose should be administered in a setting where the patient can sit or lie flat, in case symptoms of orthostatic hypotension occur. PTHrP analog treatment is usually given for a maximum of two years. (See 'Duration of therapy' below.)

Other formulations of PTH and PTHrP that do not require daily injections are under investigation. In a 12-month trial in 511 postmenopausal women with osteoporosis, transdermal abaloparatide increased BMD at the lumbar spine but not as robustly as subcutaneous abaloparatide (mean increase of 7.14 versus 10.86 percent, respectively) [41]. Transdermal abaloparatide similarly led to a smaller increase in BMD at the total hip compared with subcutaneous abaloparatide (mean increase of 1.97 versus 3.7 percent, respectively). The study was not designed to assess fracture risk.

Practical management issues — There are several general principles for the use of PTH/PTHrP analog therapy, as outlined below.

Pretreatment evaluation — Before starting PTH/PTHrP analog therapy, patients should have the following evaluation:

●DXA (if not performed in the past two years)

●Serum calcium, phosphorus, creatinine, alkaline phosphatase, albumin, 25-hydroxyvitamin D (25[OH]D) levels

●24-hour urine calcium and creatinine (or fasting specimen for calcium/creatine ratio) to evaluate for baseline hypercalciuria

Patients who have vitamin D deficiency should be replaced with vitamin D until the serum 25(OH)D concentration is normal prior to starting PTH/PTHrP analog therapy. (See 'Calcium and vitamin D' below and "Calcium and vitamin D supplementation in osteoporosis" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

If the patient has hypercalcemia or hypercalciuria (urinary calcium excretion >300 mg/24 hours in females or >400 mg/24 hours in males), further evaluation for primary hyperparathyroidism or other hypercalcemic disorder is necessary prior to initiation of PTH/PTHrP analog treatment. (See "Diagnostic approach to hypercalcemia".)

Treatment with PTH/PTHrP analogs is contraindicated in patients with hypercalcemic disorders unless the disorder is fully resolved. For patients with isolated hypercalciuria, PTH/PTHrP analog treatment should not be started unless hypercalciuria is resolved.

Calcium and vitamin D — Vitamin D insufficiency and inadequate calcium intake are common in patients with osteoporosis. In the majority of osteoporosis treatment trials, calcium and vitamin D supplements were also administered. Therefore, patients receiving PTH/PTHrP analogs should take supplemental calcium and vitamin D.

●The total calcium intake (diet plus supplements) should be approximately 1000 to 1200 mg/day and should not exceed 1500 mg/day. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Optimal intake'.)

●Vitamin D supplementation with approximately 800 international units/day is usually sufficient. Patients with vitamin D deficiency require higher doses initially. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)

Because of concern about hypercalcemia, caution about calcium supplementation is warranted (see 'Short-term risks' below). Clinical trials have used at least 500 mg elemental calcium and at least 400 international units of vitamin D per day. If hypercalcemia develops, the first step should be a reduction in calcium supplementation (no more than 500 mg calcium daily) and/or temporary cessation of vitamin D with repeat measurement of the serum calcium 24 hours after the last dose of PTH/PTHrP analog. If hypercalcemia persists, PTH/PTHrP analog dosing is adjusted to alternate-day therapy. If clinically significant hypercalcemia does not resolve, PTH/PTHrP analog should be discontinued.

Combination therapy not recommended — We suggest not using PTH/PTHrP analog therapy in combination with other osteoporosis agents. There are no data to suggest a benefit in fracture reduction, and there is an increase in cost and potential side effects. For patients who have received bisphosphonates but require additional therapy for osteoporosis, we suggest switching to, rather than adding, a PTH/PTHrP analog. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'BMD decreased or fracture during therapy'.)

Because PTH stimulates bone formation and other available osteoporosis agents reduce bone resorption, it has been hypothesized that combining the two therapies would increase bone density more than either therapy alone. Several trials have shown that the increase in BMD with combination therapy is either not additive (bisphosphonates) or is small (selective estrogen receptor modulators [SERMs], estrogen, denosumab). Although data are not yet available regarding the use of PTHrP analog therapy plus bisphosphonates or plus denosumab, we suggest not using PTHrP analog therapy with these agents in accord with the information described below for PTH.

The use of antiresorptive therapy after completion of a course of PTH analog therapy is reviewed below. (See 'Management after teriparatide' below and 'Management after abaloparatide' below.)

The use of PTH analog therapy after antiresorptive therapy is reviewed separately. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'BMD decreased or fracture during therapy'.)

●PTH analog plus bisphosphonates – Several trials have reported that PTH analog therapy plus alendronate (either started concurrently or six months prior to PTH analog) resulted in no additional benefit for spine or hip BMD compared with PTH analog alone (figure 3) [4,29,42]. In some small studies, the combination of PTH analog and a bisphosphonate improved BMD to a greater extent than either therapy alone; however fracture data are unavailable for these combinations [43,44].

●PTH analog plus denosumab – Combination therapy with a PTH analog and denosumab appears to increase BMD to a greater extent than either therapy alone, although fracture data are unavailable and optimal consolidation strategies following treatment have not been determined. As examples:

•In a trial comparing teriparatide (20 mcg subcutaneously daily), denosumab (60 mg subcutaneously every six months), or both in postmenopausal women with a high risk for fracture (BMD T-score <-2.5 or T-score <-2.0 with other fracture risk factor) [45]. After one year, lumbar spine, femoral neck, and total hip BMD increased significantly more in the combination than in the monotherapy groups (eg, mean change lumbar spine 9.1 versus 6.2 and 5.5 percent for teriparatide and denosumab, respectively). The trial was not powered to assess fracture outcomes. In a preplanned extension of this trial, lumbar spine and hip BMD continued to increase (eg, mean change lumbar spine 12.9, 9.5, and 8.3 percent, respectively); however, the changes between 12 and 24 months did not differ among groups [46].

•In a separate trial comparing teriparatide 40 mcg or 20 mcg daily for nine months in 76 postmenopausal women taking denosumab (starting at month 3 and continuing for one year), lumbar spine (17.5 versus 9.5 percent), femoral neck (6.8 versus 4.3 percent), and total hip BMD (6.1 versus 3.9 percent) increased significantly more in the 40 mcg group [47]. However, in the extension phase of this study that included 53 participants, a single dose of zoledronic acid administered 24 to 35 weeks after discontinuation of denosumab failed to prevent progressive declines in volumetric bone density, stiffness, failure load, and microarchitecture at cortical sites over 42 months of follow-up [48]. (See "Denosumab for osteoporosis", section on 'Discontinuation or delay of denosumab'.)

●Other combinations – In several trials, prior or concurrent treatment with raloxifene did not appear to compromise the effect of teriparatide on BMD and markers of bone turnover [44,49-51]. In patients not adequately treated with raloxifene who are switching to teriparatide, there is no need to delay teriparatide therapy once raloxifene is discontinued. In some trials, combined estrogen plus PTH analog therapy was more effective than hormone therapy alone in improving BMD [52-54]. However, there was no teriparatide monotherapy arm for comparison. Estrogen-progestin therapy is no longer a first-line approach for the treatment of osteoporosis in postmenopausal women, because of increased risk of breast cancer, stroke, venous thromboembolism (VTE), and perhaps coronary disease (although the risk-benefit profile in the unopposed estrogen trial was different). (See "Menopausal hormone therapy: Benefits and risks".)

Monitoring

●In patients with vascular insufficiency or orthostatic hypotension, pulse and blood pressure should be monitored carefully following the first PTH/PTHrP analog injection.

●There are no guidelines for when to measure calcium, although in the clinical trials, it is usually assessed at several time points, including at baseline, 1, 6, and 12 months [4,55]. However, there is wide variation in clinical practice for timing of follow-up serum calcium levels, from none to once every three months.

We typically measure serum calcium at least once, approximately one to three months after therapy is initiated. Patients who develop hypercalcemia will require more frequent monitoring to establish that there is not an underlying cause for the hypercalcemia or that calcium/vitamin D intake is not excessive.

●Frequency of BMD measurements is subjective, but most authorities do not consider a follow-up BMD for at least one to two years.

Duration of therapy — The trials of fracture efficacy lasted only 18 to 21 months (Treatment of Osteoporosis with Parathyroid Hormone [TOP] [2], FPT [22], Abaloparatide Comparator Trial In Vertebral Endpoints [ACTIVE] [21]).

Due to the lack of proven efficacy beyond two years and cost, a single course of PTH/PTHrP analog treatment in most patients should be limited to two years duration. In selected patients at high risk for fracture (eg, chronic glucocorticoid therapy, multiple vertebral compression fractures but none while on teriparatide), some clinicians may continue teriparatide beyond two years [56]. The theoretical increased risk of osteosarcoma, which has been observed in rats receiving high doses of PTH/PTHrP analogs, has not been observed in humans, and there is no direct evidence linking the development of osteosarcoma to dose or duration of teriparatide. (See 'Long-term risks' below.)

For most patients completing a two-year course of PTH/PTHrP analog treatment, an antiresorptive agent is typically started to preserve gains in BMD acquired with teriparatide or abaloparatide. (See 'Management after teriparatide' below and 'Management after abaloparatide' below.)

Management after teriparatide — We typically prescribe an antiresorptive, preferably a bisphosphonate, after teriparatide is discontinued. The goal is to preserve or increase gains in BMD acquired with teriparatide. Denosumab (females or males) or raloxifene (females) are alternatives for individuals who are unable to tolerate oral or intravenous bisphosphonates. Some experts may advise a second course of teriparatide treatment after bisphosphonates, although there are no fracture efficacy or safety data to support or discourage such use.

After discontinuation of PTH analog therapy, BMD decreases, as illustrated by the findings from the Parathyroid Hormone and Alendronate for Osteoporosis (PaTH) trial, which was a randomized, two-year study with one year of PTH (1-84) with or without alendronate, followed by alendronate or placebo. Women randomized to placebo after 12 months of PTH (1-84) lost nearly 2 percent of their spine BMD over the subsequent 12 months [4,57]. Loss of trabecular volumetric BMD (as measured by quantitative computed tomography [QCT]) was more striking (17 percent) (figure 4).

There are few data on fracture risk after PTH analog therapy is discontinued. In an open-label extension of the FPT, reduction in fracture incidence appeared to be maintained for at least 18 months after discontinuation of PTH analog therapy, despite a decrease in BMD [58]. Women who were initially randomized to teriparatide still had a 40 percent relative risk reduction in vertebral fractures during the follow-up 18-month period compared with those who had received placebo during the FPT, even though more women in the former placebo group used antiresorptive therapy in the open-label extension when compared with the former teriparatide group.

●Antiresorptive therapy – Although preservation of fracture risk reduction with the use of antiresorptive therapy after teriparatide is discontinued has not yet been firmly established, treatment with an antiresorptive agent after teriparatide preserves the gains in BMD achieved with teriparatide. This was illustrated by findings from the PaTH trial described above. Women randomized to receive alendronate following PTH analog discontinuation had a further increase in areal BMD of nearly 6 percent, coupled with a 6 percent increase during the first year [57]. Treatment with alendronate during that year following PTH (1-84) preserved the increase of 30 percent in trabecular BMD gained in the first year by PTH (1-84) alone (figure 4) [57]. (See "Bisphosphonate therapy for the treatment of osteoporosis".)

Similar findings were reported in studies using denosumab, raloxifene, or estrogen after PTH analog therapy [59-62]. However, the use of denosumab in this setting raises concern due to the risk of bone loss and vertebral fracture after denosumab discontinuation. (See "Denosumab for osteoporosis", section on 'Discontinuation or delay of denosumab' and "Selective estrogen receptor modulators for prevention and treatment of osteoporosis" and "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)

As examples:

•Postmenopausal women (n = 27) who received teriparatide for 24 months followed by denosumab for 24 months had increases in BMD at the lumbar spine, femoral neck, and total hip of 8.6, 5.6, and 4.7 percent, respectively, during the 24 months of denosumab therapy [62]. In contrast, the 27 women who received denosumab first, followed by teriparatide, had smaller increases in lumbar spine (4.8 percent) and femoral neck (1.2 percent) BMD and a decrease in total hip BMD (-0.7 percent).

•In the European Study of Forsteo (EUROFORS), postmenopausal women who had received one year of teriparatide were randomly assigned for a second year to continue teriparatide or to switch to either raloxifene or placebo [61]. BMD in the women who received teriparatide for a second year continued to increase, whereas BMD was maintained in the women who received raloxifene and decreased in women who received placebo. The overall changes in lumbar spine BMD in the three groups from baseline to 24 months were 10.7, 7.8, and 3.8 percent, respectively.

•Postmenopausal women who had a nearly 30 percent increase in areal BMD with PTH analog therapy lost <4 percent of that rise when PTH was discontinued and estrogen therapy was continued [59].

●Retreatment with PTH – Some clinicians may repeat the dosing schedule as a second course of treatment after intercurrent use of bisphosphonates in patients with very high fracture risk who remain at or who return to having a high risk of fracture [63]. Retreatment with teriparatide does appear to increase spine BMD, but the increase is less than that of initial treatment [29,64,65]. There are no data on fracture efficacy or safety with retreatment.

Management after abaloparatide — For patients at high risk for subsequent fracture after discontinuing abaloparatide, we suggest starting a bisphosphonate. In an extension of the ACTIVE trial described above (see 'Choice of therapy' above), 1139 patients who completed 18 months of abaloparatide or placebo received open-label alendronate for up to 24 months [66]. Over the course of the entire trial (active and extension), there was a significantly lower rate of new morphometric vertebral fractures (0.9 versus 5.6 percent) and nonvertebral fractures (5.5 versus 8.4 percent) in the abaloparatide/alendronate compared with the placebo/alendronate group [67], suggesting that sequential treatment is effective in maintaining fracture risk reduction.

ADVERSE EVENTS

Short-term risks — In general, both teriparatide (parathyroid hormone [PTH] [1-34]) and abaloparatide (PTH-related protein [PTHrP] [1-34]) are well tolerated [4,5,22,29]. Hypercalcemia and hypercalciuria are the two most common side effects of both types of treatment.

●Hypercalcemia – A single teriparatide injection raises PTH (1-34) levels 10-fold above baseline, but these return to baseline within four hours [17].

In one trial, 11 percent of women receiving teriparatide (20 mcg) had an elevated serum calcium concentration from samples obtained at one time point; with retesting, only 3 percent had persistent hypercalcemia requiring dose reduction [22]. Hypercalcemia appears to be more common with PTH (1-84) (ie, closer to 10 percent of subjects after retesting), although the mechanism responsible for this difference between PTH analogs is unknown [5]. Hypercalcemia appears to be less common with abaloparatide than teriparatide (3.4 versus 6.4 percent in the Abaloparatide Comparator Trial In Vertebral Endpoints [ACTIVE] trial) [21].

Significant hypercalcemia (ie, serum calcium greater than 11.0 mg/dL) rarely occurs. Generally, a reduction in calcium supplementation (no more than 500 mg calcium daily) and/or temporary cessation of vitamin D treatment leads to resolution of hypercalcemia. If hypercalcemia persists, PTH/PTHrP analog dosing can be adjusted to alternate-day therapy, with ongoing monitoring of serum calcium. If hypercalcemia does not resolve, the PTH/PTHrP analog should be discontinued. Persistent hypercalcemia after discontinuation of a PTH/PTHrP analog should lead to an evaluation for other secondary causes. (See "Diagnostic approach to hypercalcemia".)

●Calciphylaxis – Case reports of worsening cutaneous calcification and nonuremic calciphylaxis have been reported during treatment with teriparatide [68-70]. Possible predisposing factors include underlying autoimmune disease, glucocorticoid therapy, and warfarin use. In the setting of calciphylaxis or worsening of cutaneous calcification, teriparatide treatment should be discontinued [63].

●Hypercalciuria – Although hypercalciuria can be detected with teriparatide and abaloparatide, the urinary calcium/creatinine ratio rarely exceeds 0.4, and there are no reported cases of nephrocalcinosis [22,29] or increased incidence of nephrolithiasis [71] associated with teriparatide therapy. Nevertheless, PTH/PTHrP analogs should probably not be used in individuals with a history of kidney stones or persistent hypercalciuria. (See 'Contraindications/precautions' above.)

●Other – Occasional hypotension or tachycardia can occur with the first few doses of PTH/PTHrP analogs. Nausea and headache are reported among individuals treated with teriparatide or abaloparatide, but these do not appear to be significantly different from placebo [21,22]. There was a higher frequency of nausea and vomiting in women receiving PTH (1-84) versus placebo in the Treatment of Osteoporosis with Parathyroid Hormone (TOP) trial, but this could be related to a greater frequency of hypercalcemia in that study [2,5]. Debilitating muscle cramps have also been reported following PTH treatment [72].

Serum uric acid increases with teriparatide, abaloparatide, and PTH (1-84) and, in some patients, may precipitate an attack of gout [4].

Long-term risks — Although there are no long-term safety data with abaloparatide, very few long-term side effects have been reported with teriparatide. Anecdotally, investigators have reported improvement in back pain with teriparatide therapy, but it is unclear whether this is a function of fewer fractures or a true analgesic response [22]. (See 'Back pain' below.)

●Osteosarcoma – The most theoretically worrisome adverse event is the development of osteosarcoma, which was noted in preclinical animal studies where teriparatide was administered from infancy through senescence (most of the rats' lives) [73]. Outside groups have studied the potential risk for osteosarcoma in humans and concluded there is minimal risk [55,63,74-76]. However, there are limited data with use of teriparatide beyond two years, the duration of the usual treatment course.

•In the Osteosarcoma Surveillance Study, the number of incident cases of osteosarcoma in teriparatide users was not different from the number expected based on the background incidence rate of osteosarcoma [75]. There were 3808 cases of osteosarcoma diagnosed in the United States between 2003 and 2016. Among the 1173 osteosarcoma patients who were interviewed, three reported a history of teriparatide use (0.2 percent, standardized incidence ratio 0.72 [90% CI 0.2-1.86]) [75].

•In a United States population-based cohort study using a Medicare Part D prescription database and 26 state cancer registries to evaluate the incidence of osteosarcoma among teriparatide users versus nonusers, the number of cases of osteosarcoma identified by linkage to the participating cancer registries was low (0 and <11 in the teriparatide and comparator groups, respectively) [76]. The incidence rate in the comparator group was consistent with expected background incidence, with no difference between the two groups (incidence rate difference -4.5 per million person-years [95% CI -8.2 to -0.8]; incidence rate ratio 0.0 [95% CI 0.0-3.2]).

OTHER POSSIBLE USES

Primary hypoparathyroidism — Parathyroid hormone (PTH) for the treatment of hypoparathyroidism is reviewed separately. (See "Hypoparathyroidism", section on 'PTH-based therapies'.)

Back pain — A meta-analysis of five trials revealed that patients receiving teriparatide therapy have a lower risk of new or worsening back pain compared with patients receiving placebo, estrogen, or alendronate [77]. In some of the individual trials included in the analysis, the reduced risk of back pain appeared to correlate with a reduction in the risk of new painful vertebral fractures. A few studies have examined the use of teriparatide in the setting of spinal fusion surgery to improve healing [78,79], but data remain scarce and largely anecdotal.

Fracture healing — Although not approved by the US Food and Drug Administration (FDA) to enhance fracture healing, some investigators have used PTH analog therapy in clinical practice for this indication, particularly for nonunion fractures. In animal studies, teriparatide enhanced callus formation and mechanical strength of fractures [80], and in observational studies in humans with intertrochanteric fractures who underwent surgical intervention, it appeared to reduce time to union [81]. However, in randomized trials in humans, the results are conflicting [82-84].

As examples:

●In a randomized trial of teriparatide (20 or 40 mcg daily) or placebo in 112 postmenopausal women with distal radius fractures, teriparatide did not significantly accelerate fracture repair compared with placebo [82]. A similar absence of improved fracture healing was reported in 40 women with proximal humerus fractures randomly assigned to teriparatide (20 mcg daily) or placebo [84].

●In contrast, a randomized trial of PTH (1-84) (100 mcg once daily) in 65 women with pelvic fractures showed acceleration of fracture healing in those who received PTH (1-84) compared with those who did not (mean time to fracture healing 7.8 versus 12.6 weeks) [83].

The difference in results may be related to differences in study design, including site of fracture. More evidence from randomized trials is needed to know if teriparatide accelerates or induces fracture repair. Unfortunately, a trial designed to determine whether teriparatide for six months compared with placebo improves femoral neck fracture healing after internal fixation was terminated early due to poor enrollment (only 159 enrolled patients of 2400 planned) [85]. Analysis of available data did not show any difference in radiographic signs of fracture healing at 12 months. Given the small sample size and early termination of the trial, however, the results do not permit conclusions to be drawn about teriparatide and fracture healing.

The use of PTH analog therapy for the treatment of atypical femur fractures in the setting of chronic antiresorptive therapy is discussed separately. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Atypical femur fracture'.)

Periodontal disease — The effect of teriparatide on alveolar bone loss associated with periodontal disease has been studied. Severe periodontal disease, a major cause of tooth loss worldwide, is characterized by gingival inflammation and loss of supportive connective tissues, including alveolar bone. In one trial, 40 adults with chronic periodontitis who had periodontal surgery were randomly assigned to receive teriparatide (20 mcg) or placebo daily for six weeks [86]. After one year, radiographic resolution of periodontal bone defects in the teriparatide group was significantly greater than that in the placebo group (mean linear gain in bone 1.86 versus 0.16 mm). There was also significant improvement in some clinical parameters, including probing depth and clinical attachment level. Until larger and longer trials with additional clinical (eg, reduction in tooth loss) and safety endpoints are available, we do not recommend teriparatide for the treatment of chronic periodontitis. (See "Overview of gingivitis and periodontitis in adults".)

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

SUMMARY AND RECOMMENDATIONS

●Patient selection – Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) analogs are effective osteoporosis drugs that increase bone mineral density (BMD) and reduce fracture risk. Potential candidates for PTH/PTHrP analog therapy include males or postmenopausal females who have very high risk of fracture (eg, T-score of ≤-3.0 even in the absence of fractures, T-score of -2.5 or below plus a fragility fracture, history of multiple fractures, advanced age), have osteoporosis and are unable to tolerate or have contraindications to bisphosphonates, or have fracture and/or loss of BMD in spite of adherence to other osteoporosis therapies. (See 'Patient selection' above.)

●Contraindications/precautions – PTH/PTHrP analogs are contraindicated in patients with primary or secondary hyperparathyroidism; in patients with hypercalcemia due to other disorders (eg, chronic granulomatous disorders, hypercalcemia of malignancy); and in patients at increased baseline risk for osteosarcoma, such as those with Paget disease of bone or unexplained elevation of alkaline phosphatase, bone metastases or skeletal malignancies, history of prior radiation therapy involving the skeleton, or pediatric/young adult patients with open epiphyses. In patients with preexisting malignancies, history of kidney stones, persistent hypercalciuria, or impaired kidney function, PTH/PTHrP analogs should not be considered unless treatment with alternative drugs has failed and the benefits of PTH/PTHrP analogs outweigh potential risks. (See 'Contraindications/precautions' above.)

●Choice of therapy – When a decision has been made to treat with a PTH/PTHrP analog, either teriparatide or abaloparatide can be prescribed. Both teriparatide and abaloparatide have been shown to reduce the risk of vertebral and nonvertebral fractures. Teriparatide has a long track record of safety (when administered as the usual two-year course), whereas there is less experience with abaloparatide. For both medications, long-term safety data beyond a two-year treatment course are limited. (See 'Choice of therapy' above.)

●Pretreatment evaluation – Before starting PTH/PTHrP analog therapy, patients should undergo dual-energy x-ray absorptiometry (DXA; if not performed in the past two years). Patients should also have baseline measurement of serum calcium, phosphorus, creatinine, alkaline phosphatase, albumin, and 25-hydroxyvitamin D levels, as well as 24-hour urine calcium and creatinine. (See 'Pretreatment evaluation' above.)

●Calcium and vitamin D supplementation – Patients receiving PTH/PTHrP analogs should take supplemental calcium and vitamin D. The total calcium intake (diet plus supplements) should be approximately 1000 to 1200 mg/day and should not exceed 1500 mg/day. Vitamin D supplementation with approximately 800 international units/day is usually sufficient. Patients with vitamin D deficiency require higher doses initially and should be replaced with vitamin D prior to starting PTH/PTHrP analog therapy. (See 'Calcium and vitamin D' above.)

●Avoid combination therapy – We suggest not using PTH/PTHrP analog therapy in combination with other osteoporosis agents (Grade 2B). There are no data to suggest a benefit in fracture reduction, and there is an increase in cost and potential side effects. (See 'Combination therapy not recommended' above.)

●Monitoring – Monitoring patients taking PTH/PTHrP analog treatment should include measurement of serum calcium and kidney function at least once during their course. Monitoring of BMD is reviewed separately. (See 'Monitoring' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Monitoring response to initial pharmacotherapy'.)

●Duration of therapy – For most patients, we suggest an initial treatment duration of up to two years (Grade 2C). This limit is due to the lack of proven fracture benefit beyond two years and cost of therapy. The theoretical risk of osteosarcoma, which has been observed in rats receiving high doses of PTH/PTHrP analogs, has not been substantiated in humans, and there is no direct evidence linking the development of osteosarcoma to dose or duration of teriparatide. (See 'Duration of therapy' above and 'Long-term risks' above.)

●Management after an initial course of PTH/PTHrP analog therapy – For patients at high risk for subsequent fracture after discontinuing PTH/PTHrP analog therapy, we suggest starting a bisphosphonate after discontinuing a PTH/PTHrP analog (Grade 2B). Denosumab (females or males) or raloxifene (females) are alternatives for individuals who are intolerant of oral or intravenous bisphosphonates. (See 'Management after teriparatide' above and 'Management after abaloparatide' above.)