This study investigated the effects of a single administration of teriparatide on bone turnover markers in postmenopausal women. Teriparatide caused a transient increase in bone resorption and inhibition of bone formation followed by a subsequent increase in bone formation and a decrease in resorption that lasted at least 1 week.
This study aims to investigate the effects of a single subcutaneous administration of teriparatide on bone turnover markers to elucidate why once weekly intermittent administration of teriparatide is effective on osteoporosis.
Pharmacokinetics and calcium metabolism and bone turnover parameters were measured in 30 postmenopausal women after two doses of teriparatide (28.2 or 56.5 μg injection) or placebo in a randomized, double-blind, placebo-controlled study.
Teriparatide plasma concentration increased in a dose-dependent manner, and the maximum concentration was achieved 1 h after injection. Serum levels of calcium and phosphorus were transiently increased and decreased after teriparatide injection, respectively. Calcium metabolism returned to baseline levels 24 h later. Two days after injection, the serum level of 1,25-dihydroxy vitamin D was increased by ~80 % from baseline for both doses of teriparatide. Serum levels of osteocalcin and procollagen type I N-terminal propeptide decreased during the first 24 h followed by a ~10 % increase for 14 days. The serum level of cross-linked N-telopeptide (NTX) of type I collagen increased during the first 24 h followed by a 10 to 12 % dose-dependent suppression from baseline for 14 days. Urinary cross-linked C-telopeptide of type I collagen changes occurred in the same direction as serum NTX, but not dose dependently.
A single administration of teriparatide caused an immediate, transient increase in bone resorption and inhibited bone formation followed by an increase in bone formation and decrease in resorption for ≥1 week. These findings may provide proof for the effect of a once-weekly regimen of teriparatide on bone turnover.
Bone formation; Bone resorption; Bone turnover marker; Human; Single administration; Teriparatide
Changes in bone turnover markers with weekly 56.5 μg teriparatide injections for 24 weeks were investigated in women with osteoporosis. Changes in bone turnover markers 24 h after each injection of teriparatide were constant. During the 24 week period, bone formation markers increased and baseline bone resorption marker levels were maintained.
This study aimed to clarify the changes in bone turnover markers during 24 weeks of once-weekly teriparatide injections in postmenopausal women with osteoporosis.
The 24 h changes in pharmacokinetics (PK), calcium metabolism, and bone turnover markers (serum osteocalcin, procollagen type I N-terminal propeptide (P1NP), urinary cross-linked N-telopeptide of type I collagen (NTX), deoxypiridinoline (DPD)) after each injection of 56.5 μg teriparatide at the data collection weeks (0, 4, 12, and 24 weeks) were investigated. The changes were evaluated by comparison with the data at 0 h in each data collection week.
Similar 24 h changes in each parameter after injection of teriparatide were observed in each data collection week. Serum calcium increased transiently, and intact PTH decreased 4–8 h after injection; serum calcium subsequently returned to baseline levels. Calcium and intact PTH levels decreased for 24 weeks. Although serum osteocalcin decreased at 24 h, it was significantly increased at 4 weeks. P1NP decreased transiently and then increased significantly at 24 h. P1NP was significantly increased at 4 weeks. Urinary NTX and DPD were significantly increased transiently and then decreased at 24 h. The urinary DPD level decreased significantly at 4 weeks.
Twenty-four hour changes in PK, calcium metabolism, and bone turnover markers showed the same direction and level after once-weekly teriparatide injections for 24 weeks, with no attenuation of the effect over time. After 24 weeks, the bone formation marker, serum osteocalcin, increased significantly, but the serum P1NP, did not. Bone resorption markers decreased or remained the same.
Bone formation; Bone resorption; Calcium metabolism; Human; Teriparatide
Teriparatide [rhPTH (1-34)] is an effective treatment for osteoporosis administered by daily subcutaneous injection. The objective of this study was to determine how much benefit women expect teriparatide to confer before agreeing to perform daily injections.
We recruited postmenopausal women who had recently undergone bone densitometry and were found to have either a T score less than −2.5 at the hip or spine and/or had a Fracture Index (FI) of ≥ 6. Participants completed an Adaptive Conjoint Analysis questionnaire to determine their treatment preferences.
The study sample included 185 women, mean age 71 (range 46 to 90). An increasing number of subjects preferred rhPTH (1-34) as the efficacy of teriparatide increased, but most women demanded efficacy advantages greater than those demonstrated in clinical studies. We found no association between absolute fracture risk and preference for rhPTH (1-34); however, subjects with an excessively high perceived risk of future fracture were more likely to accept daily subcutaneous injections compared to subjects with a lower perceived risk of future fracture (40% versus 15%, p=0.001).
Our results suggest that most women demand benefits far greater than those conferred by rhPTH (1-34) in order to administer daily subcutaneous injections to decrease their future risk of fractures.
Given the poor adherence for treatment of osteoporosis, and the choices older adults must make when paying for medications, development of novel treatment approaches should be based on older adults' treatment preferences.
Osteoporosis; Bisphosphonates; Recombinant Human Parathyroid Hormone; Decision-Making
Once-daily injections of teriparatide initially increase biochemical markers of bone formation and resorption, but markers peak after 6–12 months and then decline despite continued treatment. We sought to determine whether increasing teriparatide doses in a stepwise fashion could prolong skeletal responsiveness. We randomized 52 postmenopausal women with low spine and/or hip bone mineral density (BMD) to either a constant or an escalating subcutaneous teriparatide dose (30 mcg daily for 18 months or 20 mcg daily for 6 months, then 30 mcg daily for 6 months, then 40 mcg daily for 6 months). Serum procollagen I N-terminal propeptide, osteocalcin, and C-terminal telopeptide of type I collagen were assessed frequently. BMD of the spine, hip, radius, and total body was measured every 6 months. Acute changes in urinary cyclic AMP in response to teriparatide were examined in a subset of women in the constant dose group. All bone markers differed significantly between the two treatment groups. During the final six months, bone markers declined in the constant dose group but remained stable or increased in the escalating dose group (all markers, p<0.017). Nonetheless, mean area under the curve did not differ between treatments for any bone marker, and BMD increases were equivalent in both treatment groups. Acute renal response to teriparatide, as assessed by urinary cyclic AMP, did not change over 18 months of teriparatide administration. In conclusion, stepwise increases in teriparatide prevented the decline in bone turnover markers that is observed with chronic administration without altering BMD increases. The time-dependent waning of the response to teriparatide appears to be bone-specific.
teriparatide; parathyroid hormone; osteoporosis; bone turnover markers; bone densitometry
Osteoporosis that is by far the most common metabolic bone disease, has been defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Anabolic therapy with teriparatide, recombinant human parathyroid hormone (PTH 1-34), stimulates bone formation and resorption and improves trabecular and cortical microarchitecture. Teriparatide is indicated for the treatment of men and postmenopausal women with osteoporosis who are at high risk for fracture, including those who have failed or are intolerant of previous osteoporosis therapy. In conclusion, although teriparatide seems quite effective in the treatment of osteoporosis, it may cause life-threatening hypercalcemia. Therefore, patients should be closely monitored if symptoms of hypercalcemia are present during teriparatide treatment. Sustained hypercalcemia due to teriparatide treatment can not be seen in literature so we wanted to emphasize that severe hypercalcemia may develop due to teriperatide.
Hypercalcemia; osteoporosis; teriparatide
Current osteoporosis medications increase bone mineral density (BMD) modestly and reduce, but do not eliminate, fracture risk. Attempts to improve efficacy by administering anabolic agents and bisphosphonates concomitantly have been unsuccessful. Conversely, 12 months of concomitant denosumab and teriparatide therapy increases BMD more than either drug alone.
The purpose of this study was to determine whether 24 months of combined denosumab and teriparatide will increase hip and spine BMD more than either individual agent.
Preplanned continuation of the Denosumab and Teriparatide Administration (DATA) randomized controlled trial in which postmenopausal osteoporotic women received teriparatide (20 μg daily), denosumab (60 mg every 6 months), or both medications for 24 months.
Participants were 94 postmenopausal women with osteoporosis.
Lumbar spine, femoral neck, total hip, and distal radius BMD and serum markers of bone turnover were measured.
At 24 months, lumbar spine BMD increased more in the combination group (12.9 ± 5.0%) than in either the teriparatide (9.5 ± 5.9%, P = .01) or denosumab (8.3 ± 3.4%, P = .008) groups. Femoral neck BMD also increased more in the combination group (6.8 ± 3.6%) than in either the teriparatide (2.8 ± 3.9%, P = .003) or denosumab (4.1 ± 3.8%, P = .008) groups. Similarly, total hip BMD increased more in the combination group (6.3 ± 2.6%) than in the teriparatide (2.0 ± 3.0%) or denosumab (3.2 ± 2.5%) groups (P < .001 for both). Although spine and hip BMD continued to increase in the second year in all groups, these year 2 increases did not differ among groups. Serum C-telopeptide and N-terminal propeptide of type 1 procollagen were equally suppressed in the denosumab and combination groups, whereas osteocalcin decreased more in the denosumab group than in the combination group, a difference that persisted, but lessened, in the second year of therapy.
Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.
Visual changes on radionuclide bone scans have been reported with teriparatide treatment. To assess this, serial studies were evaluated and quantified in ten postmenopausal women with osteoporosis treated with teriparatide (20 μg/day subcutaneous) who had 99mTc-methylene diphosphonate (MDP) bone scans (baseline, 3 and 18 months, then after 6 months off therapy).
Women were injected with 600 MBq 99mTc-MDP, and diagnostic bone scan images were assessed at 3.5 h. Additional whole-body scans (10 min, 1, 2, 3 and 4 h) were analysed for 99mTc-MDP skeletal plasma clearance (Kbone). Regional Kbone differences were obtained for the whole skeleton and six regions (calvarium, mandible, spine, pelvis, upper and lower extremities). Bone turnover markers (BTM) were also measured.
Most subjects showed visual changes on 3- and 18-month bone scan images that disappeared after 6 months off therapy. Enhanced uptake was seen predominantly in the calvarium and lower extremities. Whole skeleton Kbone displayed a median increase of 22% (3 months, p = 0.004) and 34% (18 months, p = 0.002) decreasing to 0.7% (6 months off therapy). Calvarium Kbone changes were three times larger than other sites. After 6 months off therapy, all Kbone and BTM values returned towards baseline.
The increased 99mTc-MDP skeletal uptake with teriparatide indicated increased bone formation which was supported by BTM increases. After 6 months off therapy, metabolic activity diminished towards baseline. The modulation of 99mTc-MDP skeletal uptake during treatment was the result of teriparatide’s metabolic activity. These findings may aid the radiological evaluation of similar teriparatide patients having radionuclide bone scans.
Teriparatide; 99mTc-MDP bone scan; Bone turnover markers; Bone remodelling; Osteoporosis
We studied the use of teriparatide in postmenopausal women with severe osteoporosis.
Two groups (A and B) of patients affected by severe osteoporosis (T-score ⩽−2.5 at bone mineral density were analyzed and 2 vertebral fractures on radiograph).
Group A was treated for 18 months with 20 μg/day of teriparatide. Group B was treated with bisphosphonates 70 mg/week. Every woman assumed 1 g of calcium and 800 IU of vitamin D3 daily. We evaluated the effects of therapy after 18 months (T18) from the beginning with bone turnover markers (alkaline phosphatase, procollagen type 1 N-terminal propeptide, and N-telopeptide cross-links) and dual-energy X-ray absorptiometry.
Group A, at T18 procollagen type 1 N-terminal propeptide levels, increased 127%; bone alkaline phosphatase levels increased to 65%; N-telopeptide cross-links levels increased to 110%.
Group B, at T18 procollagen type 1 N-terminal propeptide levels, decreased to 74%; bone alkaline phosphatase levels decreased to 41%; N-telopeptide cross-links levels decreased to 72%.
After 18 months, lumbar bone mineral density increased to 12.4% and femoral bone mineral density increased to 5.2% in group A. Group B lumbar bone mineral density increased to 3.85% and femoral bone mineral density increased to 1.99%. Only a new vertebral fracture occurred in group A (2.4%), whereas 6 fractures occurred in group B (15.7%).
The quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO) revealed a significant improvement in daily living, performed domestic jobs, and locomotor function in groups A and B.
The use of rhPTH in patients with severe osteoporosis offers more protection against fractures and improves the QoL more than bisphosphonates.
teriparatide; quality of life; severe osteoporosis
Once-weekly administration of 56.5 μg teriparatide improved cortical bone parameters and biomechanical parameters at the proximal femur by CT geometry analysis.
The aim of this study was to evaluate the effects of weekly administration of teriparatide [human PTH (1–34)] on bone geometry, volumetric bone mineral density (vBMD), and parameters of bone strength at the proximal femur which were longitudinally investigated using computed tomography (CT).
The subjects were a subgroup of a recent, randomly assigned, double-blind study (578 subjects) comparing the anti-fracture efficacy of a once-weekly subcutaneous injection of 56.5 μg teriparatide with placebo (TOWER trial).
Sixty-six ambulatory postmenopausal women with osteoporosis were enrolled at 15 study sites having multi-detector row CT, and included women injected with teriparatide (n = 29, 74.2 ± 5.1 years) or with placebo (n = 37, 74.8 ± 5.3 years). CT data were obtained at baseline and follow-up scans were performed at 48 and 72 weeks. The data were analyzed to obtain cross-sectional densitometric, geometric, and biomechanical parameters including the section modulus (SM) and buckling ratio (BR) of the femoral neck, inter-trochanter, and femoral shaft. We found that once-weekly teriparatide increased cortical thickness/cross-sectional area (CSA) and total area, and improved biomechanical properties (i.e., decreasing BR) at the femoral neck and shaft. Teriparatide did not change the cortical perimeter.
Our longitudinal analysis of proximal femur geometry by CT revealed that once-weekly administration of 56.5 μg teriparatide improved cortical bone parameters at the femoral neck and shaft and also improved biomechanical parameters.
Once-weekly injection; Osteoporosis; Proximal femur geometry; Quantitative computed tomography; Teriparatide
Postmenopausal women with severe osteoporosis may require treatment with the bone anabolic drug teriparatide. While changes in bone mineral density (BMD) are one measure of response, BMD changes often require a minimum of one year to observe measureable changes. Biochemical markers of bone turnover change within 1 to 3 months of initiating osteoporosis therapy. Monitoring with a marker such as procollagen type I N propeptide (PINP), an osteoblast-derived protein, during teriparatide treatment may provide clinically useful information for managing patients with osteoporosis. Clinical trials have shown consistent increases in PINP within 3 months of initiating teriparatide, increases that are significantly greater than placebo and significantly different from baseline. Increases in PINP concentrations during teriparatide treatment correlate well with increases in skeletal activity assessed by radioisotope bone scans and quantitative bone histomorphometry parameters. Individuals treated with teriparatide in clinical trials usually experienced an increase in PINP > 10 mcg/L from baseline, while those given placebo usually did not. In the clinical setting, patients experiencing a significant increase in PINP > 10 mcg/L after initiating teriparatide therapy may receive an earlier confirmation of anabolic effect, while those who do not may be assessed for adherence, proper injection technique, or undetected secondary conditions that might mitigate an anabolic response. PINP monitoring may provide information supplemental to BMD monitoring and be a useful aid in managing patients receiving anabolic osteoporosis treatment in the same way that biochemical markers of bone resorption are useful in monitoring antiresorptive therapy. This review examines PINP as a biological response marker during teriparatide treatment for osteoporosis.
Anabolics; Biochemical markers of bone turnover; Osteoporosis; PINP; Teriparatide
Osteoanabolic therapy is an attractive therapeutic option for men with osteoporosis because it directly stimulates bone formation, an action not shared by any antiresorptive drug. Teriparatide (recombinant human PTH(1-34)) and PTH(1-84) are available in many countries but PTH(1-84) is not available in the United States. Only teriparatide is approved for the treatment of osteoporosis in men. It is also indicated in glucocorticoid-induced osteoporosis. Teriparatide is associated with major gains in bone density at the lumbar spine and, to a lesser extent, in the hip regions. Vertebral and nonvertebral fractures are reduced in postmenopausal women treated with teriparatide. Fracture reduction data in men are less secure because the number of study subjects is small and the studies have not been powered to document this endpoint. Nevertheless, observational data in men suggest a reduction in vertebral fractures with teriparatide. Attempts to show further beneficial effects of teriparatide in combination with antiresorptive agents have not been demonstrated yet to be superior to monotherapy with teriparatide alone. The duration of therapy with teriparatide is limited to 2 years. Thereafter, it is necessary to treat with an antiresorptive drug to maintain, and perhaps increase, densitometric gains. Teriparatide is well tolerated with a good safety profile.
Parathyroid hormone (PTH) changes morphology of osteoclasts within minutes after its systemic administration. The aim of our study was to test in healthy men whether both exogenous and endogenous PTH could change acutely (minutes to hours) the serum cross-linked C-telopeptide of type I collagen (beta CTX), which is released during osteoclastic resorption of bone. Twelve healthy men (age range 24–34 yr) were each studied during 180 min on a control period, after a single subcutaneous injection of teriparatide, and after 30 min EDTA infusion to stimulate endogenous PTH secretion. The tests were started after overnight fast, 3 h after a standard calcium load. The EDTA infusion induced a significant decrease in serum ionized calcium (by 8.5% at 33 min) and a significant increase in plasma PTH (by 305% at 33 min). Both the EDTA and teriparatide resulted in a significant increase in beta CTX (p < 0.001) with maximum increases of 64% and 80%, respectively. A mild, but significant decrease in beta CTX was observed during the control test period. In conclusion, single-dose teriparatide injection as well as a stimulation of endogenous PTH in healthy men results in an acute increase of the bone resorption marker.
bone resorption; calcium; C-telopeptide; parathyroid hormone; teriparatide
We report the changes in biochemical markers of bone formation during the first 6 months of teriparatide therapy in postmenopausal women with osteoporosis according to previous antiresorptive treatment. Prior therapy does not adversely affect the response to teriparatide treatment. Similar bone markers levels are reached after 6 months of treatment.
The response of biochemical markers of bone turnover with teriparatide therapy in subjects who have previously received osteoporosis drugs is not fully elucidated. We examined biochemical markers of bone formation in women with osteoporosis treated with teriparatide and determined: (1) whether the response is associated with prior osteoporosis therapy, (2) which marker shows the best performance for detecting a response to therapy, and (3) the correlations between early changes in bone markers and subsequent bone mineral density (BMD) changes after 24 months of teriparatide.
We conducted a prospective, open-label, 24-month study at 95 centers in 10 countries in 758 postmenopausal women with established osteoporosis (n = 181 treatment-naïve) who had at least one post-baseline bone marker determination. Teriparatide (20 μg/day) was administered for up to 24 months. We measured procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (b-ALP), and total alkaline phosphatase (t-ALP) at baseline, 1 and 6 months, and change in BMD at the lumbar spine, total hip and femoral neck from baseline to 24 months.
Significant increases in formation markers occurred after 1 month of teriparatide regardless of prior osteoporosis therapy. The absolute increase at 1 month was lower in previously treated versus treatment-naïve patients, but after 6 months all groups reached similar levels. PINP showed the best signal-to-noise ratio. Baseline PINP correlated positively and significantly with BMD response at 24 months.
This study suggests that the long-term responsiveness of bone formation markers to teriparatide is not affected in subjects previously treated with antiresorptive drugs.
BMD; Bone markers; Bone turnover; Osteoporosis; Postmenopausal women; Teriparatide
The Osteosarcoma Surveillance Study, an ongoing 15-year surveillance study initiated in 2003, is a postmarketing commitment to the United States (US) Food and Drug Administration to evaluate a potential association between teriparatide, rhPTH(1–34), a recombinant human parathyroid hormone analog (self-injectable medication to treat osteoporosis), and development of osteosarcoma in response to a finding from preclinical (animal) studies. Incident cases of primary osteosarcoma diagnosed in adults (aged ≥40 years) on or after January 1, 2003, are identified through population-based state, regional, and comprehensive cancer center registries in the US. Information on possible prior treatment with teriparatide, on demographics, and on risk factors is ascertained by patient or proxy telephone interview after patient consent. Between June 2004 and September 30, 2011, 1448 cases (diagnosed 2003 to 2009) were identified by participating cancer registries (estimated to be 62% of all adult cases in the US for that time period); 549 patients or proxies were interviewed. Interviewed patients were similar to noninterviewed patients with regard to mean age, sex, race, and geographical distribution and tumor type and site of tumor. Mean age of those interviewed was 61 years, 46% were female, 86% were white, and 77% were alive when the case was reported to the study investigators. Data collected in the study provide descriptive information on a large number of adults with osteosarcoma, an uncommon malignant bone tumor. After 7 years of the study, there were no osteosarcoma patients who had a prior history of teriparatide treatment. Thus, approximately halfway through this 15-year study, the study has not detected a pattern indicative of a causal association between teriparatide treatment and osteosarcoma in humans. © 2012 American Society for Bone and Mineral Research.
OSTEOSARCOMA; EPIDEMIOLOGY; TERIPARATIDE; SURVEILLANCE; PARATHYROID HORMONE (PTH)
In this observational study in postmenopausal women with severe osteoporosis, the incidence of fractures was decreased during 18 months of teriparatide treatment with no evidence of further change in the subsequent 18-month post-teriparatide period when most patients took other osteoporosis medications. Fracture reduction was accompanied by reductions in back pain.
To describe fracture outcomes and back pain in postmenopausal women with severe osteoporosis during 18 months of teriparatide treatment and 18 months post-teriparatide in normal clinical practice.
The European Forsteo Observational Study (EFOS) was a prospective, multinational, observational study. Data on incident clinical fractures and back pain (100 mm Visual Analogue Scale [VAS] and questionnaire) were collected. Fracture data were summarised in 6-month intervals and analysed using logistic regression with repeated measures. Changes from baseline in back pain VAS were analysed using a repeated measures model.
A total of 208 (13.2%) of 1,576 patients sustained 258 fractures during 36 months of follow-up: 34% were clinical vertebral fractures and 66% non-vertebral fractures. The adjusted odds of fracture were reduced during teriparatide treatment and there was no evidence of further change in the 18-month post-teriparatide period, during which 63.3% patients took bisphosphonates. A 74% decrease in the adjusted odds of fracture in the 30- to <36-month period compared with the first 6-month period was observed (p < 0.001). Back pain decreased during teriparatide treatment and this decrease was sustained after teriparatide discontinuation. Adjusted mean back pain VAS decreased by 26.3 mm after 36 months (p < 0.001) from baseline mean of 57.8 mm.
In a real-life clinical setting, the risk of fracture decreased during teriparatide treatment, with no evidence of further change after teriparatide was discontinued. The changes in back pain seen during treatment were maintained for at least 18 months after teriparatide discontinuation. These results should be interpreted in the context of the design of an observational study.
Electronic supplementary material
The online version of this article (doi:10.1007/s00198-010-1498-5) contains supplementary material, which is available to authorized users.
Back pain; Fracture; Osteoporosis; Teriparatide
To describe fracture rates, back pain, and health-related quality of life (HRQoL) in postmenopausal women with osteoporosis and prior bisphosphonate therapy, treated with teriparatide for up to 18 months and followed up for a further 18 months.
Prospective, multinational, and observational study.
Data on prior bisphosphonate use, clinical fractures, back pain visual analog scale (VAS), and HRQoL (EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month intervals and analyzed using logistic regression with repeated measures. Changes from baseline in back pain VAS and EQ-VAS were analyzed using a repeated measures model.
Of the 1581 enrolled patients with follow-up data, 1161 (73.4%) had a history of prior bisphosphonate use (median duration: 36 months). Of them, 169 (14.6%) sustained ≥1 fracture during 36-month follow-up. Adjusted odds of fracture were significantly decreased at each 6-month interval compared with the first 6 months of teriparatide treatment: 37% decrease in the 12 to <18 months period during teriparatide treatment (P=0.03) and a 76% decrease in the 12- to 18-month period after teriparatide was discontinued (P<0.001). Significant reductions in back pain and improvement in HRQoL were observed.
Postmenopausal women with severe osteoporosis previously treated with bisphosphonates had a significant reduction in the incidence of fractures compared with the first 6 months of therapy, a reduction in back pain and an improvement in HRQoL during up to 18 months of teriparatide treatment. These outcomes were still evident for at least 18 months after teriparatide was discontinued. The results should be interpreted in the context of an uncontrolled, observational study in a routine clinical setting.
We describe the case of a woman with hypophosphatasia previously exposed to bisphosphonate and subsequently treated with teriparatide (recombinant human PTH 1-34).
A Caucasian woman sustained bilateral femur stress fractures when she was fifty years old, which widened despite use of calcium, vitamin D and risedronate for 2.5 years and required intramedullary rods for stabilization. Hypophosphatasia was diagnosed in the interim due to low serum alkaline phosphatase (ALP) (ALP 20 IU/L; normal (N), 40-150 IU/L) and high pyridoxal 5' phosphate (3400 nmol/L; N 18-175 nmol/L). She was referred for further management. On presentation, she had significant fracture site pain and generalized bone pain (weight bearing and non-weight bearing) - making her walker dependent at home and wheel chair dependent outside home.
She could not sleep at night due to discomfort when she moved. Daily teriparatide injections, 20 mcg subcutaneously were prescribed.
At 8-weeks follow-up, fracture site pain, weight-bearing and non weight-bearing pain improved significantly allowing ambulation for prolonged periods without assistance. She slept at night without discomfort. Improvement persisted during her entire treatment period. Radiographs taken at 4 and 16 months of treatment demonstrated healing of femur fractures.
Biochemically, mean urine cross-link-N-telopeptide increased 11% as compared to her base-line, while bone specific alkaline phosphatase did not increase as expected.
In conclusion, we observed an uncoupling of bone formation and resorption markers during her treatment period in the face of notable clinical and radiological improvement. Off-label use of teriparatide may help patients with hypophosphatasia.
osteomalacia, alkaline phosphatase; pyridoxal phosphate.
A breakthrough in understanding of mechanisms of bone structure regulation has brought about the introduction of the new synthetic recombinant human parathyroid hormone 1–34 (PTH1-34; Teriparatide) in the treatment of osteoporosis. These mechanisms, involving the RANKL, RANK, and osteoprotegerin system, are also known to be involved in malignant myeloma (MM) and tumor and bone metastasis development.
We report a case in which MM was found after treatment of osteoporosis with teriparatide. We were unable to demonstrate any direct association between the MM and teriparatide treatment. However, it seemed intriguing that similar mechanisms are activated in the development of MM as those being working during teriparatide treatment.
In the view of our case, we propose that MM by examination of serum protein fraction should be searched for prior to treatment with teriparatide as it is an exclusion criterion in teriparatide treatment of secondary osteoporosis. A search for other metastatic diseases prior to teriparatide treatment should eventually also be considered. The theoretical basis for our proposal is discussed.
multiple myeloma; osteoporosis; parathyroid hormone; teriparatide; renal failure
Fracture leads to local and systemic catabolic physiologic changes. As teriparatide is an agent used to treat osteoporosis in patients with fragility fractures, it is unclear whether teriparatide treatment alters bone mineral density (BMD) and bone markers when given to patients with fractures.
We asked whether BMD and bone marker responses would be blunted in patients with fractures placed on teriparatide after fracture compared with patients without fractures on teriparatide.
Patients and Methods
We retrospectively collected data from 141 patients treated with teriparatide for osteoporosis. Seventy-seven patients received teriparatide after fractures (fracture group), whereas 64 were treated for other indications (nonfracture group). We determined BMD at the lumbar spine and at the proximal femur before and 12 and 24 months posttreatment. Bone markers (urine N-telopeptide [urine NTX], bone-specific alkaline phosphatase [BALP]) were measured at baseline and 3, 12, and 24 months posttreatment.
Mean lumbar spine and hip BMDs at last followup increased from baseline with no differences between groups to approximately 9% and 4% at 24 months, respectively. Both bone markers increased from baseline in the nonfracture group, peaking at 12 months. For the fracture group, only urine NTX increased at 3 and 12 months posttreatment. Although the peak levels of both bone markers in the nonfracture group were greater, there was no difference between the two groups.
Fracture does not have a negative effect on the BMD and bone marker responses to teriparatide treatment. Clinicians should anticipate comparable BMD responses when treating patients with teriparatide for osteoporotic fractures and for other indications.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Teriparatide, a recombinant PTH, is an anabolic treatment for osteoporosis that increases bone density. Transient hypercalcemia is a reported side effect of teriparatide that is seen few hours following administration of teriparatide and resolves usually within 16 hours of drug administration. Persistent hypercalcemia, although not observed in clinical trials, is rarely reported. The current case describes a rare complication of teriparatide induced delayed persistent hypercalcemia.
Cushing’s syndrome is characterised by a series of clinical manifestations due to hypersecretion of cortisol. These include: arterial hypertension, diabetes mellitus (DM), asthenia, amenorrhea, osteoporosis and pathological fractures. We describe the case of a 70-year-old woman with Cushing’s syndrome with right adrenal adenoma, vertebral compression fractures (VCFs) and severe secondary osteoporosis. This patient had been diagnosed with Cushing’s syndrome in May 2008, three years after the onset of arterial hypertension and type II DM, treated with insulin; in July 2008, she underwent right adrenalectomy and replacement therapy with cortisone acetate, 37.5 mg/day, in association with a multiple drug regimen for hypertension and DM; she also had an at least 10-year history of dorso-lumbar pain with multiple disc protrusions. As part of a series of investigations for Cushing’s syndrome the patient underwent femoral bone mineral densitometry, recording a T-score <−3, radiographic examination of the dorso-lumbar spine, which revealed collapse of the superior endplate of D7 and a wedge fracture of D8. At the endocrinology centre of reference for Cushing’s syndrome, she began treatment with alendronate 70 mg/day without undergoing blood chemistry tests of bone metabolism and without calcium and vitamin D supplementation. At the end of August 2009, she experienced worsening spinal pain due to a new severe fracture of D9, which was confirmed on MRI as a recent fracture. At the end of December 2009 she received kyphoplasty of D9, antiresorptive therapy and a CAMP-C35 brace.
In January 2010 she was admitted to the specialist rehabilitation unit for functional recovery, in view of her comorbidities, and bone disease investigation, with collection of history relating to osteoporosis risk factors. First- and second-level blood chemistry analyses revealed the presence of iron-deficiency anaemia, mild chronic renal insufficiency, and secondary hyerparathyroidism (PTH 101ng/ml); spinal radiography revealed severe VCFs of D7, D8 and D9, treated with kyphoplasty; the patient was also assessed using the VAS for pain, the FIM to evaluate independence in activities of daily living, and the SF-36 to investigate quality of life. The alendronate treatment was suspended and the patient was given cholecalciferol 300,000 IU, administered as an oral bolus, followed by a maintenance dose of 800 IU/day. When PTH values had returned to normal, she began treatment with teriparatide 20 mcg/day s.c. (therapeutic plan in compliance with Note 79 issued by the AIFA - Italian Drug Agency).
In conclusion, this case underlines the importance of a correct diagnostic and therapeutic approach in patients with severe osteoporosis. Over time, we will evaluate the efficacy of the treatment in preventing new fractures and the whether the use of a bone anabolic agent might be the correct choice also in order to control pain and improve quality of life. There are no reports in the literature of patients with Cushing’s syndrome treated with teriparatide.
Based on remarkable success of PTH as an anabolic drug for osteoporosis, case reports of off-label use of teriparatide (1-34 PTH) in patients with complicated fractures and non-unions are emerging. We investigated the mechanisms underlying PTH accelerated fracture repair. Bone marrow cells from 7 days 40cg/kg of teriparatide treated or saline control mice were cultured and Osx and osteoblast phenotypic gene expression assessed by real time RT-PCR in these cells. Fractured animals injected daily with either saline or 40cg/kg of teriparatide for up to 21 days were X-rayed and histological assessment performed, as well as immunohistochemical analyses of the Osx expression in the fracture callus. Osx, Runx2 and osteoblast or chondrocyte phenotypic gene expression was also assessed in fracture calluses. Our data shows that Osx and Runx2 are up-regulated in marrow-derived MSCs isolated from mice systemically treated with teriparatide. Furthermore, these MSCs undergo accelerated osteoblast maturation compared to saline injected controls. Systemic teriparatide treatments also accelerated fracture healing in these mice concomitantly with increased Osx expression in the PTH treated fracture calluses compared to controls. Collectively, these data suggest a mechanism for teriparatide mediated fracture healing possibly via Osx induction in MSCs.
Teriparatide; PTH; Osterix/Sp7; Runx2; fractures
The effect of PTH therapy on serum and urinary calcium levels and the risk of hypercalcemia or hypercalciuria has not been formally evaluated.
The objective was to examine changes in serum and urinary calcium associated with PTH(1–84) therapy in the PaTH trial and the extent to which a defined algorithm resolved the elevated values.
Design, Setting, Participants, and Intervention
A total of 178 postmenopausal women were randomized to PTH(1–84) either alone or in combination with alendronate during the first year of the PaTH study.
Main Outcome Measure(s)
The main outcome measures were fasting serum calcium at baseline and 1, 3, and 12 months and 24-h urinary calcium at baseline and 3 months.
In 14% of participants, serum calcium more than 10.5 mg/dl (>2.6 mmol/liter) developed. Following the defined algorithm, 58% of elevated measurements were normal on repeat testing; 38% required discontinuation of calcium and vitamin D supplementation, and one necessitated a decrease in PTH injection frequency to normalize serum calcium. One participant developed transient hypercalcemia between study visits and required hospitalization; the episode resolved with iv hydration and PTH discontinuation. Baseline characteristics associated with the development of hypercalcemia were serum calcium [relative hazards = 1.9 per 0.5 mg/dl (0.12 mmol/liter); 95% confidence interval = 1.1–3.2] and serum 1,25-dihydroxyvitamin D [relative hazard = 1.9 per 10 pg/ml (26 pmol/liter); 95% confidence interval = 1.2–3.1]. Fifteen women (8%) developed hypercalciuria [urinary calcium > 400 mg (100 mmol)/24 h or calcium/creatinine ratio > 0.4]; 80% of cases resolved after discontinuing calcium and vitamin D, 13% without intervention, and one after PTH injection frequency was decreased. Higher baseline urinary calcium excretion was associated with development of hypercalciuria [relative hazard = 1.5 per 50 mg/d (12.5 mmol/d); 95% confidence interval = 1.2–4.0]. Proportions of patients with elevated serum and urinary calcium were similar on single and combination therapy.
The frequency of episodic hypercalcemia or hypercalciuria in the PaTH trial was 21%. Episodes were generally mild, and nearly all cases resolved spontaneously or with discontinuation of calcium and vitamin D. The algorithms used to address hypercalcemia and hypercalciuria in the PaTH trial proved effective in safely resolving clinical episodes of increased urinary or serum calcium and might therefore be helpful to clinicians caring for patients on PTH.
The objective of this study was to describe the risk of fragility-related fractures in the 2 years following teriparatide initiation. In an administrative claims analysis of over 11,407 patients, approximately one in eight patients had a new or recurrent fragility-related fracture in the 2 years following teriparatide initiation.
The objective of this study was to describe the risk of fragility-related fractures in the 2 years following the initiation of teriparatide in a real-world setting.
This retrospective study used data from the 2002 to 2011 MarketScan® Commercial and Medicare Supplemental Databases to identify patients 50 years and older with a diagnosis of osteoporosis (ICD-9-CM code 733.0x) who were initiating teriparatide. Patients were required to have continuous medical and pharmacy benefit coverage for the 12 months prior to and 24 months following teriparatide initiation (index event). Teriparatide treatment patterns (persistence and adherence) were described, as was the use of antiresorptive therapy. The primary study outcome was the presence of a new or recurring fragility fracture following the initiation of teriparatide.
A total of 11,407 patients met the study criteria (mean age = 69.5, standard deviation = 10.6 years; 92.0 % female). One in four (25.6 %) patients had fragility fracture claims in the year prior to teriparatide initiation, of which 64.0 % were on existing antiresorptive therapy. Overall, 13.4 % (n = 1527) of patients had a new or recurrent fracture during the 2-year follow-up period. Forty-eight percent of patients on teriparatide treatment were considered persistent; fragility fractures were more common among patients nonpersistent with teriparatide (15.2 %) than among those persistent with teriparatide (11.4 %). A higher fracture rate (35.7 %) was observed in the cohort with previous fragility fracture then those without pre-index fractures (24 %).
More than 13.4 % of patients had new or recurrent fragility-related fractures during the 2 years following the initiation of teriparatide; these fractures were more in common in patients with pre-existing fractures and the patients who were nonpersistent with teriparatide.
Antiresorptive; Claims; Fracture; Osteoporosis; Teriparatide; Treatment persistence
Background. Adults with osteogenesis imperfecta (OI) have a high risk of fracture. Currently, few treatment options are available, and bone anabolic therapies have not been tested in clinical trials for OI treatment.
Methods. 79 adults with OI were randomized to receive 20 μg recombinant human parathyroid hormone (teriparatide) or placebo for 18 months in a double-blind, placebo-controlled trial. The primary endpoint was the percent change in areal bone mineral density (aBMD) of the lumbar spine (LS), as determined by dual-energy X-ray absorptiometry. Secondary endpoints included percent change in bone remodeling markers and vertebral volumetric BMD (vBMD) by quantitative computed tomography, estimated vertebral strength by finite element analysis, and self-reported fractures.
Results. Compared with the placebo group, the teriparatide group showed increased LS aBMD (6.1% ± 1.0% vs. 2.8% ± 1.0% change from baseline; P < 0.05) and total hip aBMD (2.6% ± 1.0% vs. –2.4% ± 1.0% change; P < 0.001). Vertebral vBMD and strength improved with teriparatide therapy (18% ± 6% and 15% ± 3% change, respectively), but declined with placebo (–5.0% ± 6% and –2.0% ± 3% change; P < 0.05 for both comparisons). Serum procollagen type 1 N-terminal propeptide (P1NP) and urine collagen N-telopeptide (NTx) levels increased with teriparatide therapy (135% ± 14% and 64% ± 10% change, respectively). Teriparatide-induced elevation of P1NP levels was less pronounced in severe forms of OI (type III/IV) compared with the milder form (type I). Type I OI patients exhibited robust BMD increases with teriparatide; however, there was no observed benefit for those with type III/IV OI. There was no difference in self-reported fractures between the 2 groups.
Conclusions. Adults with OI, particularly those with less severe disease (type I), displayed a teriparatide-induced anabolic response, as well as increased hip and spine aBMD, vertebral vBMD, and estimated vertebral strength.
Trial registration. Clinicaltrials.gov NCT00131469.
Funding. The Osteoporosis Imperfecta Foundation, Eli Lilly and Co., the National Center for Advancing Translational Science (NCATS) at the NIH (grant no. UL1RR024140), and the Baylor College of Medicine General Clinical Research Center (grant no. RR00188).