Teriparatide (recombinant human parathyroid hormone 1-34) therapy in myeloma patients with severe osteoporosis and fractures despite effective anti-myeloma therapy and bisphosphonates: A pilot study

To the Editor:

Patients with myeloma bone disease (MBD) may suffer devastating osteoporotic vertebral compression fractures (OVCF), despite standard anti-myeloma and antiresorptive bone therapies. In this high-risk cohort there may be a potential role for bone anabolic therapies. We performed a 12-month open-labeled study in a myeloma cohort who received subcutaneous teriparatide 20 mcg daily in combination with anti-myeloma therapy and previous intravenous bisphosphonates. They had severe osteoporosis, recurrent OVCF and no evidence of chronic kidney disease. After 12 months, there were no significant negative changes in hemoglobin, paraprotein, serum calcium, eGFR, 25 hydroxyvitamin D or parathyroid hormone (PTH). The serum propeptide of type 1 collagen (P1NP) increased by 4.8-fold (0.5-13) and lumbar spine quantitative tomography (QCT) bone mineral density (BMD) by 43.8% (12.2%-100%). No new fractures or lytic lesions were recorded. These data suggest that 12-months of teriparatide may have positive anabolic bone effects in myeloma patients who continue to fracture without negatively impacting on their myeloma activity or causing hypercalcemia.

MBD is characterized by severe osteoporosis, pathological fractures and lytic bone lesions. The uncoupling in bone remodeling causes increased bone resorption, and suppression in bone formation.¹ Intravenous bisphosphonates are considered as standard of care for MBD due to their potent inhibitory effects on osteoclastic activity and have been shown to significantly reduce skeletal-related events (SRE). Novel anti-myeloma agents such as the proteasome inhibitors and immunomodulatory drugs reduce not only the myeloma plasma cell burden but also significantly inhibit the osteoclast pathways.¹ Bortezomib has the added advantage of promoting osteoblast bone formation. Despite these advances, many myeloma patients continue to experience devastating bone destruction. Bone anabolic therapies have in recent years been shown to be superior to antiresorptive agents for the treatment of severe osteoporosis,² but to our knowledge have not been studied in myeloma patients. For this reason, we designed a study to determine the safety and efficacy of 12 months of teriparatide for treating myeloma patients with severe osteoporosis who fracture despite previous intravenous bisphosphonates.

We recruited 12 myeloma patients with (a) bone marrow evidence of active myeloma (plasma cell count >10%), (b) elevated serum paraprotein levels or presence of urine Bence Jones paraprotein, (c) low vertebral body QCT BMD T-score < −3.0, (d) prior history of OVCF, (e) exclusion of hypercalcemia (serum calcium >2.65 mmol/L) or chronic kidney disease (eGFR <30 mL/min), (f) current anti-myeloma therapy and (g) previous treatment with either pamidronic acid /zoledronic acid within 3 months of commencing the study. Patients were taught to self-administer subcutaneous teriparatide 20 mcg daily (recombinant human parathyroid hormone 1-34, Eli Lilly Pharma, USA) for 12 months and informed about the “black box” warning around the risk of osteosarcoma.² Anti-myeloma therapies were prescribed and hematological parameters monitored by the attending hematologists. No changes in anti-myeloma therapy occurred and no bisphosphonates were administered during the 12-months. Investigations were performed in the fasting state prior to the teriparatide injection and specimens were collected at baseline, 6 weeks and every 3 months to monitor hematological and serological parameters (see Table 1). Serum P1NP, marker of bone formation and urinary deoxypyridinoline excretion (u-DPyD), marker of bone resorption, were measured at baseline and after 12 months using standard chemiluminescence immunoassays (see supplementary data). Lateral thoracolumbar spine CT, vertebral body and total hip BMD was measured by QCT analysis using Siemens Somatom Definition Flash CT Scanner at baseline and after 12 months (see supplementary data). Quantitative tomography is preferable to dual X-ray absorptiometry (DXA) for assessing BMD in MBD, where lytic lesions or fractures may adversely affect DXA precision, and can be adequately identified and excluded from the analysis.³ All data are presented as mean ± 1 SEM and range. Paired Student t test was used for comparison of the initial and final data. Changes in BMD and bone formation were calculated as the percentage change of the final minus initial value and divided by initial value. Informed consent was given prior to commencing the study. Teriparatide is registered with the Therapeutic Goods and Administration in Australia for use in individuals with severe osteoporosis and recurrent fractures. The study had the approval of the National Health and Medical Research Council and local hospital ethics committee.

The nine men and three women who participated were aged 70.6 years (range 43-88 years) and had myeloma for 48.8 months (12-120 months). They all had IgG myeloma subtype apart from one patient with light chain disease. Their anti-myeloma treatments are outlined in Table 1. All patients had documented OVCF ranging from 2-9 per patient and severe osteoporosis with mean lumbar spine BMD T-Score of −4.9. One patient had mildly reduced serum 25 hydroxyvitamin D (<50 nmol/L) and was treated with oral cholecalciferol 1000 IU daily. All patients completed the 12 months of teriparatide without any major drug-related adverse events. There were no documented episodes of hypercalcemia or deterioration in eGFR. There were no significant changes in hemoglobin concentrations (125 vs 127 g/L) and paraprotein levels (23.6 vs 17.6 g/L). No new vertebral fractures or lytic lesions were observed. Teriparatide resulted in a significant increase in mean P1NP concentrations from 33 to 151 mcg/L (P value <.001), more than 4-fold increase above baseline. The u-DPyD excretion also increased to a lesser degree, from 5.4 to 9.6 nmol/mmol of creatinine (P value <.01). The net increase in bone turnover was evident by the positive change in lumbar spine BMD significantly increasing by 43.8% (12.2-100) above baseline from 45 to 61 mg/cm³ (P value < .001). Lumbar spine BMD was not possible in two patients due to pre-existing fractures/lytic lesions that interfered with their sequential BMD analysis. No significant changes were noted in the total hip BMD. Table 1 outlines the clinical data of the 12 individual patients.

Antiresorptive agents (predominantly bisphosphonates) are considered standard adjuvant treatments in MBD and have been shown to reduce SRE and afford survival benefits.¹ Osteoporosis and OVCF commonly occur in 60%-80% of myeloma patients but are not considered in the diagnostic criteria or as SRE. Osteoporosis is the result of changes in intercellular signaling cascades. Upregulation of receptor activator of nuclear factor kappa-B ligand ratio (RANK/RANKL) and tumor necrosis factor (TNF) stimulate osteoclast recruitment/activation, while downregulation of osteoprotegerin (OPG) and wingless-related integration site (WNT)/catenin inhibit osteoblastogenesis/bone formation.¹ Despite this, there are very few studies relating to bone anabolic therapies in MBD. This may partly be explained by a perception of their mitogenic effects on cancer growth.

The PTH, PTH analogues, WNT agonists and transforming growth factor beta (TGF-beta) ligands are bone anabolic agents shown to stimulate osteoblast recruitment and increase bone formation.¹ Teriparatide, abaloparatide and romosozumab (monoclonal antibody that binds to sclerostin) have demonstrated anti-fracture efficacy in phase III osteoporosis trials and are considered superior to antiresorptive agents.² None of these agents have been studied in MBD. Two recent in-vitro studies using an anti-sclerostin antibody in a myeloma cell line⁴ and anti-TGF beta antibody in a murine myeloma model⁵ have demonstrated positive bone anabolic effects when used in combinations with zoledronic acid. In our cohort, teriparatide when combined with standard anti-myeloma treatment (including prior bisphosphonates), resulted in 43.8% increase in lumbar spine BMD.

Bone turnover markers have been extensively studied in MBD and provide information on bone dynamics to reflect disease activity.⁶ The suppression in bone formation seen in the mouse model of MBD occurs in part due to Dickkopf (Dkk-1) inhibiting the WNT pathway. Note, P1NP has been shown to be a reliable marker of osteoblast activity and correlates with histomorphometric indices of bone formation. In our study, teriparatide resulted in a significant 4-fold increase in P1NP and to a lesser degree in u-DPyD excretion. By increasing bone resorption, PTH may cause release of growth factors from bone that are locally embedded, and could in theory impact on myeloma cell growth/disease progression. Although this did not appear to have occurred, it is nonetheless important to be vigilant when using bone anabolic agents.

Eleven percent of individuals in the phase III teriparatide trials developed mild hypercalcemia (serum calcium < 2.80 mmol/L) but this was largely found in patients receiving 40 mcg daily.² Hypercalcemia occurs in MBD and monitoring of the serum calcium is mandatory when prescribing teriparatide. There are no studies demonstrating the expression of PTH receptors on myeloma cells. So, PTH administered to severe combined immunodeficient (SCID) mice with myeloma⁷ resulted in a significant increase in bone formation as well as attenuation in bone resorption and myeloma growth. None of our patients developed hypercalcemia or deterioration in their eGFR and there was no demonstrable negative impact on their myeloma activity, possibly due to the effects of anti-myeloma therapies and previous bisphosphonates.

While antiresorptive therapies remain standard therapy for MBD, there is a need for assessing the benefits of the newer potent bone anabolic agents in patients with devastating osteoporosis and recurrent vertebral fractures. Our study highlights the positive changes in bone formation and BMD that can occur when bone anabolic therapies are administered to this high-risk cohort. Whether sequential (antiresorptive followed by bone anabolic) or combined (antiresorptive and bone anabolic) therapies will be superior and safer in this cohort will need to be determined. Careful evaluation of the myeloma burden, bone marrow plasma cell activity and plasma cell kinetics will be mandatory when studying these bone anabolic agents in MBD.

DISCLOSURES

None.